rifampin and Tuberculosis

rifampin has been researched along with Tuberculosis* in 2267 studies

Reviews

211 review(s) available for rifampin and Tuberculosis

ArticleYear
A review of formulations and preclinical studies of inhaled rifampicin for its clinical translation.
    Drug delivery and translational research, 2023, Volume: 13, Issue:5

    Inhaled drug delivery is a promising approach to achieving high lung drug concentrations to facilitate efficient treatment of tuberculosis (TB) and to reduce the overall duration of treatment. Rifampicin is a good candidate for delivery via the pulmonary route. There have been no clinical studies yet at relevant inhaled doses despite the numerous studies investigating its formulation and preclinical properties for pulmonary delivery. This review discusses the clinical implications of pulmonary drug delivery in TB treatment, the drug delivery systems reported for pulmonary delivery of rifampicin, animal models, and the animal studies on inhaled rifampicin formulations, and the research gaps hindering the transition from preclinical development to clinical investigation. A review of reports in the literature suggested there have been minimal attempts to test inhaled formulations of rifampicin in laboratory animals at relevant high doses and there is a lack of appropriate studies in animal models. Published studies have reported testing only low doses (≤ 20 mg/kg) of rifampicin, and none of the studies has investigated the safety of inhaled rifampicin after repeated administration. Preclinical evaluations of inhaled anti-TB drugs, such as rifampicin, should include high-dose formulations in preclinical models, determined based on allometric conversions, for relevant high-dose anti-TB therapy in humans.

    Topics: Animals; Antitubercular Agents; Drug Delivery Systems; Humans; Lung; Rifampin; Tuberculosis

2023
Management and outcomes of surgical site tuberculosis infection due to infected bone graft in spine surgery: a single-institution experience and 1-year postoperative follow-up.
    Journal of neurosurgery. Spine, 2023, 02-01, Volume: 38, Issue:2

    In 2021, several patients across the United States received bone allograft contaminated with Mycobacterium tuberculosis (TB). TB is typically a pulmonary infection with many possible extrapulmonary manifestations, including skeletal tuberculosis. However, TB is a rare causative organism of postoperative surgical site infection. Iatrogenic skeletal TB infections are not widely reported in the medical literature; therefore, treatment and associated outcomes are relatively unknown. In this series, the authors report 6 cases of patients who received a mesenchymal stem cell-enhanced bone graft infected with TB at their institution, including the clinical courses, imaging findings, management plans, and outcomes at 1 year postoperatively.. A retrospective review was performed of 6 consecutive patients who underwent spinal fusion surgery at the authors' institution and received bone graft from a lot contaminated with TB. Collected data included patient demographic characteristics, indications for surgery, surgical procedures performed, timing of contamination discovery, medical treatment, and follow-up information including reoperation, healing progress, and imaging findings.. Five of 6 patients (83.3%) eventually tested positive for TB via interferon-gamma release assay or wound culture. They experienced significant complications, including surgical site infections with neck swelling, pain, dysphagia, and wound dehiscence. Extensive soft-tissue infection was common; however, significant bony involvement was not observed. Surgical wound debridement was required in 4 patients, and all patients received medical management with standard RIPE (rifampin, isoniazid pyrazinamide, pyridoxine, and ethambutol) therapy for 8 weeks with extension of rifampin and isoniazid for scheduled 12 months. All patients (excluding 1 patient who died of COVID-19) showed signs of improvement with adequately healing wounds at the most recent follow-up at a median (range) of 12 (6-13) months postoperatively. To date, no patients have developed pulmonary TB.. Direct inoculation with TB via contaminated bone grafts resulted in a high rate of severe soft-tissue infection, although extensive skeletal and pulmonary involvement has not been observed at 1 year postoperatively; this review includes the longest reported follow-up period for this TB outbreak. Medical management remains the mainstay of therapy for these patients, with most patients showing recovery with oral antibiotic therapy. The severity of these infections arising from mesenchymal stem cell-containing bone allografts that undergo an alternative sterilization process than standard allografts raises concerns regarding the added risks of infection, which should be weighed against the expected benefits of these grafts.

    Topics: COVID-19; Follow-Up Studies; Humans; Isoniazid; Retrospective Studies; Rifampin; Surgical Wound Infection; Treatment Outcome; Tuberculosis

2023
Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023, 05-03, Volume: 76, Issue:9

    Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic (PK) exposures.. Titles, abstracts, and full-text articles were screened. We searched PubMed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children aged <18 years being treated for drug-susceptible tuberculosis with rifampicin (RIF), pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO (no. CRD42021274222).. Of 304 studies identified, 46 were eligible for full-text review, and 12 and 18 articles were included for the efficacy and PK analyses, respectively. Of 1830 children included in the efficacy analysis, 82% had favorable outcomes (range, 25%-95%). At World Health Organization-recommended doses, exposures to RIF, pyrazinamide, and ethambutol were lower in children than in adults. Children ≤6 years old have 35% lower areas under the concentration-time curve (AUCs) than older children (mean of 14.4 [95% CI 9.9-18.8] vs 22.0 [13.8-30.1] μg·h/mL) and children with human immunodeficiency virus (HIV) had 35% lower RIF AUCs than HIV-negative children (17.3 [11.4-23.2] vs 26.5 [21.3-31.7] μg·h/mL). Heterogeneity and small sample sizes were major limitations.. There is large variability in outcomes, with an average of 82% favorable outcomes. Drug exposures are lower in children than in adults. Younger children and/or those with HIV are underexposed to RIF. Standardization of PK pediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing.

    Topics: Adolescent; Adult; Antitubercular Agents; Child; Ethambutol; HIV; HIV Infections; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2023
The Impact of N-nitrosamine Impurities on Clinical Drug Development.
    Journal of pharmaceutical sciences, 2023, Volume: 112, Issue:5

    Over the past few years, an increasing number of commercially available drugs have been reported to contain N-nitrosamine impurities above acceptable intake limits. Consequent interruption or discontinuation of the manufacturing and distribution of several marketed drugs has culminated into shortages of marketed drugs, including the antidiabetic drug metformin and the potentially life-saving drug rifampin for the treatment of tuberculosis. Alarmingly, the clinical development of new investigational products has been complicated as well by the presence of N-nitrosamine impurities in batches of marketed drug. In particular, rifampin is a key clinical index drug employed in drug-drug interaction (DDI) studies, and as a result of nitrosamine impurities regulatory bodies no longer accept the administration of rifampin in DDI studies involving healthy subjects. Drug developers are now forced to look at alternative approaches for commonly employed perpetrators, which will be discussed in this review.

    Topics: Drug Development; Drug Interactions; Humans; Pharmaceutical Preparations; Rifampin; Tuberculosis

2023
[Annual progress on molecular biological diagnosis of tuberculosis 2022].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2023, Feb-12, Volume: 46, Issue:2

    Tuberculosis (TB) continues to be a global public health issue that threatens human health, and rapid and accurate pathogen detection is the key to early diagnosis and effective treatment. In recent years, the pathogenic diagnosis of tuberculosis is expanding from traditional bacteriological diagnosis to molecular diagnosis. In the past year, Xper MTB/RIF Ultra technology with good diagnostic performance has been applied more often to the detection of non-respiratory samples, and Xpert XDR and second-generation linear probe technology provided more basis for early and accurate diagnosis of multidrug resistance; genome sequencing technology has also been developed and applied more often to the detection of non-culture sample detection, and the cost and time required for detection have been relatively reduced. Truenat technology, which is more suitable for primary care centers, is more widely used; new TB detection technologies, such as cell-free DNA testing and mass spectrometry, are also being developed and are expected to become important tools for early and rapid diagnosis of TB and drug-resistant TB. In this review, we synthesized the major research results of molecular biology diagnosis of tuberculosis around the world from 1. 结核病仍然是威胁人类健康的全球公共卫生问题,快速准确的病原体检测是实现早期诊断和有效治疗的关键。近年来,结核病的病原学诊断由传统的细菌学诊断向分子诊断扩展。近1年,具有良好诊断性能的Xper MTB/RIF Ultra技术更多被应用于非呼吸道样本的检测,Xpert XDR和二代线性探针技术为MDR-TB的早期快速准确诊断提供了更多依据;基因组测序技术也被更多开发应用于非培养物样本的检测,其检测成本和所需时间已相对降低和减少;更适合初级医疗保健中心开展的Truenat技术被更广泛应用;游离DNA检测及质谱检测等新型结核病检测技术同样不断发展,有望成为结核病及耐药结核病早期快速诊断的重要手段。本文综合2021年10月1日至2022年9月30日国内外结核病病原体分子生物学诊断的重要进展成果,评估分子生物学检测技术的优缺点及应用现状,为临床选择和应用提供重要依据。.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2023
Abdominal Lymphadenopathies: Lymphoma, Brucellosis or Tuberculosis? Multidisciplinary Approach-Case Report and Review of the Literature.
    Medicina (Kaunas, Lithuania), 2023, Feb-04, Volume: 59, Issue:2

    Abdominal pain represents a frequent symptom for referral to emergency departments and/or internal medicine outpatient setting. Similarly, fever, fatigue and weight loss are non-specific manifestations of disease. The present case describes the diagnostic process in a patient with abdominal pain and a palpable abdominal mass. Abdominal ultrasonography confirmed the presence of a mass in the mesogastrium. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) scans oriented toward calcific lymphadenopathies with increased metabolism in the positron emission tomography-computed tomography (PET-CT) scan. Laboratory examinations were inconclusive, although serology for Brucella and the Quantiferon test were positive. After multidisciplinary discussion, the patient underwent surgical excision of the abdominal mass. Histological examination excluded malignancies and oriented toward brucellosis in a patient with latent tuberculosis. The patient was treated with rifampin 600 mg qd and doxycycline 100 mg bid for 6 weeks with resolution of the symptoms. In addition, rifampin was continued for a total of 6 months in order to treat latent tuberculosis. This case underlines the need for a multidisciplinary approach in the diagnostic approach to abdominal lymphadenopathies.

    Topics: Abdominal Pain; Brucellosis; Humans; Latent Tuberculosis; Lymphadenopathy; Lymphoma; Positron Emission Tomography Computed Tomography; Rifampin; Tuberculosis

2023
Completion, safety, and efficacy of tuberculosis preventive treatment regimens containing rifampicin or rifapentine: an individual patient data network meta-analysis.
    The Lancet. Respiratory medicine, 2023, Volume: 11, Issue:9

    3 months of weekly rifapentine plus isoniazid (3HP) and 4 months of daily rifampicin (4R) are recommended for tuberculosis preventive treatment. As these regimens have not been compared directly, we used individual patient data and network meta-analysis methods to compare completion, safety, and efficacy between 3HP and 4R.. We conducted a network meta-analysis of individual patient data by searching PubMed for randomised controlled trials (RCTs) published between Jan 1, 2000, and Mar 1, 2019. Eligible studies compared 3HP or 4R to 6 months or 9 months of isoniazid and reported treatment completion, adverse events, or incidence of tuberculosis disease. Deidentified individual patient data from eligible studies were provided by study investigators and outcomes were harmonised. Methods for network meta-analysis were used to generate indirect adjusted risk ratios (aRRs) and risk differences (aRDs) with their 95% CIs.. We included 17 572 participants from 14 countries in six trials. In the network meta-analysis, treatment completion was higher for people on 3HP than for those on 4R (aRR 1·06 [95% CI 1·02-1·10]; aRD 0·05 [95% CI 0·02-0·07]). For treatment-related adverse events leading to drug discontinuation, risks were higher for 3HP than for 4R for adverse events of any severity (aRR 2·86 [2·12-4·21]; aRD 0·03 [0·02-0·05]) and for grade 3-4 adverse events (aRR 3·46 [2·09-6·17]; aRD 0·02 [0·01-0·03]). Similar increased risks with 3HP were observed with other definitions of adverse events and were consistent across age groups. No difference in the incidence of tuberculosis disease between 3HP and 4R was found.. In the absence of RCTs, our individual patient data network meta-analysis indicates that 3HP provided an increase in treatment completion over 4R, but was associated with a higher risk of adverse events. Although findings should be confirmed, the trade-off between completion and safety must be considered when selecting a regimen for tuberculosis preventive treatment.. None.. For the French and Spanish translations of the abstract see Supplementary Materials section.

    Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Network Meta-Analysis; Rifampin; Tuberculosis

2023
A pro-oxidant property of vitamin C to overcome the burden of latent
    Frontiers in cellular and infection microbiology, 2023, Volume: 13

    Tuberculosis (TB), caused by the bacillus

    Topics: Antitubercular Agents; Ascorbic Acid; Humans; Latent Tuberculosis; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Reactive Oxygen Species; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Vitamins

2023
    Zeitschrift fur Gesundheitswissenschaften = Journal of public health, 2023, Jun-08

    To develop the 'Stronger Towns Index': a deprivation index that took into account characteristics of areas encompassing towns that may be eligible for redevelopment funding and explore how this index was associated with self-rated health and migration within England between 2001 and 2011.. There were areas in the lowest deciles of Town Strength who did not receive funding. After multiple adjustment, LS members living in areas with higher deciles were significantly more likely (7% to 38%) to report good health than those in the lowest decile in 2001. Remaining in the same decile between 2001 and 2011 was associated with 7% lower odds of good self-rated health in 2011.. It is important to consider health in towns when allocating funding. Areas in the Midlands may have missed out on funding which might help mitigate poor health.. Ferritin levels <30µg/L were associated with unexplained infertility and might be screened in the future. Further studies with a focus on iron deficiency and iron treatment on women with unexplained infertility are warranted.. This EGM provides a valuable resource for researchers, policy-makers and the public to access the available evidence on the determinants of various COVID-19 health-related behaviours. The map can also be used to help guide research commissioning, by evidence synthesis teams and evidence intermediaries to inform policy during the ongoing pandemic and potential future outbreaks of COVID-19 or other respiratory infections. Evidence included in the map will be explored further through a series of systematic reviews examining the strength of the associations between malleable determinants and the uptake and maintenance of individual protective behaviours.. Patients with polymicrobial bloodstream infections are typically critically ill and harbor multidrug-resistant bacteria. Thus, to minimize mortality rate in critically ill patients, changes in infectious flora should be monitored, antibiotics selected reasonably, and invasive procedures reduced.. Altogether, these findings clearly revealed the great potential of the in vitro biological activity of linseed extract as a safe source for combatting multidrug-resistant. In this work, the capture of carbon dioxide using a dense hollow fiber membrane was studied experimentally and theoretically. The factors affecting the flux and recovery of carbon dioxide were studied using a lab-scale system. Experiments were conducted using a mixture of methane and carbon dioxide to simulate natural gas. The effect of changing the CO. Persistent gender and racial disparities in high-impact medical and critical care journals underscore the need to revise policies and strategies to encourage greater diversity in critical care research.. Thirty evaluable patients were enrolled. Median age was 60.5 years. Median follow-up for all patients was 17 months. Ten patients (33%) experienced grade ≥ 3 treatment-related adverse events, the most common being neutropenia and diarrhea; 50% required ≥ 1 dose reduction. The disease control rate was 90% (progressive disease: 10%, partial response: 23%, stable disease: 67%). There was zero treatment-related mortality. Twenty-two patients (73%, 90% CI 57-86; p = 0.008) completed all chemotherapy and surgery. Two patients (9%) who successfully underwent resection had minor postoperative complications. Median length of hospital stay was 4 days. Median RFS was 7.1 months. Median OS for the entire cohort was 24 months and was not reached in patients who underwent surgical resection.. Neoadjuvant treatment with gemcitabine, cisplatin, and nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes.

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2023
Rifampicin drug resistance and host immunity in tuberculosis: more than meets the eye.
    Trends in immunology, 2023, Volume: 44, Issue:9

    Tuberculosis (TB) is the leading cause of death due to an infectious agent, with more than 1.5 million deaths attributed to TB annually worldwide. The global dissemination of drug resistance across Mycobacterium tuberculosis (Mtb) strains, causative of TB, resulted in an estimated 450 000 cases of drug-resistant (DR) TB in 2021. Dysregulated immune responses have been observed in patients with multidrug resistant (MDR) TB, but the effects of drug resistance acquisition and impact on host immunity remain obscure. In this review, we compile studies that span aspects of altered host-pathogen interactions and highlight research that explores how drug resistance and immunity might intersect. Understanding the immune processes differentially induced during DR TB would aid the development of rational therapeutics and vaccines for patients with MDR TB.

    Topics: Antitubercular Agents; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Emerging impact of triazoles as anti-tubercular agent.
    European journal of medicinal chemistry, 2022, Aug-05, Volume: 238

    Tuberculosis, a disease of poverty is a communicable infection with a reasonably high mortality rate worldwide. 10 Million new cases of TB were reported with approx 1.4 million deaths in the year 2019. Due to the growing number of drug-sensitive and drug-resistant tuberculosis cases, there is a vital need to develop new and effective candidates useful to combat this deadly disease. Despite tremendous efforts to identify a mechanism-based novel antitubercular agent, only a few have entered into clinical trials in the last six decades. In recent years, triazoles have been well explored as the most valuable scaffolds in drug discovery and development. Triazole framework possesses favorable properties like hydrogen bonding, moderate dipole moment, enhanced water solubility, and also the ability to bind effectively with biomolecular targets of M. tuberculosis and therefore this scaffold displayed excellent potency against TB. This review is an endeavor to summarize an up-to-date innovation of triazole-appended hybrids during the last 10 years having potential in vitro and in vivo antitubercular activity with structure activity relationship analysis. This review may help medicinal chemists to explore the triazole scaffolds for the rational design of potent drug candidates having better efficacy, improved selectivity and minimal toxicity so that these hybrid NCEs can effectively be explored as potential lead to fight against M. tuberculosis.

    Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Structure-Activity Relationship; Triazoles; Tuberculosis

2022
Tuberculosis screening among ambulatory people living with HIV: a systematic review and individual participant data meta-analysis.
    The Lancet. Infectious diseases, 2022, Volume: 22, Issue:4

    The WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population.. In this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895.. C-reactive protein reduces the need for further rapid diagnostic tests without compromising sensitivity and has been included in the updated WHO tuberculosis screening guidelines. However, C-reactive protein data were scarce for outpatients on ART, necessitating future research regarding the utility of C-reactive protein in this group. Chest x-ray can be useful in outpatients on ART when combined with W4SS. The WHO-recommended algorithm has suboptimal sensitivity; Xpert for all offers slight sensitivity gains and would have major resource implications.. World Health Organization.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Child; Cross-Sectional Studies; HIV Infections; Humans; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Pulmonary

2022
Diagnostic accuracy of Xpert ultra for childhood tuberculosis: A preliminary systematic review and meta-analysis.
    Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, 2022, Volume: 33 Suppl 27

    Diagnosis of childhood tuberculosis (TB) is challenging. Xpert MTB/RIF and the new version Xpert MTB/RIF Ultra (Ultra) are molecular tests currently used to rapidly identify the infection. We reviewed the literature for the accuracy of Ultra assay in the diagnosis of tuberculosis and rifampicin resistance in children. We conducted a full search in PubMed, Web of Science (WOS), Embase, and Scopus, up to April 2021. A bivariate random-effects model was used to determine the pooled sensitivity and specificity of Ultra, with a 95% confidence interval (CI), compared with culturing and the composite reference standard (CRS). In the ten included studies (2,427 participants), the pooled Ultra sensitivity and specificity, in diagnosing pulmonary tuberculosis (PTB), were 78% (95% CI, 73-82) and 92% (95% CI, 91-94), respectively, against culture. Since a high heterogeneity was found between studies, we created subgroups based on different samples and ages. Ultra-pooled sensitivity was consistently lower against CRS (95% CI, 35%, 32-38). Compared to Xpert MTB/RIF, Ultra sensitivity tended toward higher values (Ultra: 73%, 67%-78% vs. Xpert MTB/RIF: 66%, 60%-72%), but specificity was lower (Ultra: 95%, 94%-96% vs. Xpert MTB/RIF: 99%, 98%-99%). Ultra has improved the definitive diagnosis of PTB, particularly in subjects with paucibacillary TB, including children. The lower specificity could be due to the fact that culture is an imperfect reference standard. Further studies are needed to evaluate the accuracy of Ultra in the diagnosis of childhood TB.

    Topics: Antibiotics, Antitubercular; Child; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2022
The impact of diabetes mellitus on the pharmacokinetics of rifampicin among tuberculosis patients: A systematic review and meta-analysis study.
    Diabetes & metabolic syndrome, 2022, Volume: 16, Issue:2

    Diabetes mellitus has a negative impact on the treatment outcome of tuberculosis, increasing the incidence of treatment failure and relapse. There is a scarcity of knowledge concerning the impact of diabetes mellitus on the pharmacokinetics of rifampicin. This study was conducted to evaluate the impact of diabetes mellitus on the pharmacokinetics of rifampicin among patients with tuberculosis.. We explored the Web of Science, Cochrane Library, PubMed, and Scopus databases for articles that reported the pharmacokinetic parameters of rifampicin in diabetic and nondiabetic patients with tuberculosis published until September 2020. Based on the presence or absence of heterogeneity, pooled estimates were calculated using a random or fixed effect model.. Seven studies were relevant and included in this study. The Tmax of rifampicin increased in diabetic patients with tuberculosis compared with nondiabetic patients with tuberculosis (MD 0.84, 95% CI (0.32, 1.35), p = 0.002). No significant differences were detected in rifampicin Cmax (MD 0.18, 95% CI (-0.52, 0.88), p = 0.61), AUC0-24 (SMD -0.02, 95% CI (-0.34, 0.30), p = 0.90), Vd (MD -3.89, 95% CI (-11.17, 3.38), p = 0.29), CL (MD -0.13, 95%CI (-0.88, 0.61), p = 0.72), and MRT (MD 1.89, 95% CI (-0.03, 3.81), p = 0.05) between diabetic and nondiabetic patients with tuberculosis.. Diabetes mellitus increased the Tmax of rifampicin without further impact on other rifampicin pharmacokinetic parameters such as Cmax, AUC0-24, Vd, CL and MRT. Early therapeutic drug monitoring of rifampicin is necessary for diabetic tuberculosis patients.

    Topics: Antibiotics, Antitubercular; Diabetes Mellitus; Humans; Rifampin; Tuberculosis

2022
Can the GeneXpert MTB/XDR deliver on the promise of expanded, near-patient tuberculosis drug-susceptibility testing?
    The Lancet. Infectious diseases, 2022, Volume: 22, Issue:4

    Early diagnosis, including universal drug-susceptibility testing for all patients with tuberculosis, remains a key priority for tuberculosis elimination by 2035. The drug-resistant tuberculosis care cascade remains persistently challenged by substantial gaps in timely diagnosis and treatment of drug-resistant tuberculosis. Current diagnostics for drug-resistant tuberculosis are limited with respect to accuracy, time to results, affordability, suitability for resource-poor endemic settings, and accessibility for use at the point of care. WHO endorsement of the novel Xpert MTB/XDR assay holds notable promise for expanding access to testing and rapid diagnosis of tuberculosis drug resistance. The Xpert MTB/XDR assay detects resistance to isoniazid, ethionamide, fluoroquinolones, and second-line injectables, and is indicated for testing in patients with confirmed pulmonary tuberculosis. However, this iteration of the Xpert MTB/XDR cartridge might have less of an effect than expected, as WHO has since downgraded the role of second-line injectable agents in treating drug-resistant tuberculosis, and has revised case definitions of drug-resistant tuberculosis to incorporate resistance to new drugs. This Personal View explores the strengths and limitations of the Xpert MTB/XDR assay in the detection of drug resistance, the assay's ability to inform appropriate drug-resistant tuberculosis drug selection, and the optimal placement of the Xpert XDR assay in the laboratory diagnostic workflow.

    Topics: Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
25 years of surveillance of drug-resistant tuberculosis: achievements, challenges, and way forward.
    The Lancet. Infectious diseases, 2022, Volume: 22, Issue:7

    Tuberculosis is second only to COVID-19 as a cause of death from a single infectious agent. In 2020, almost 10 million people were estimated to have developed tuberculosis and it caused 1·5 million deaths. Around a quarter of deaths caused by antimicrobial resistance are due to rifampicin-resistant tuberculosis. Antimicrobial resistance surveillance systems for many bacterial pathogens are still in the early stages of implementation in many countries, and do not yet allow for the estimation of disease burden at the national level. In this Personal View, we present the achievements, challenges, and way forward for the oldest and largest global antimicrobial resistance surveillance system. Hosted by WHO since 1994, the Global Project on Anti-Tuberculosis Drug Resistance Surveillance has served as a platform for the evaluation of the trends in anti-tuberculosis drug resistance for over 25 years at country, regional, and global levels. With an estimated 465 000 incident cases of multidrug-resistant and rifampicin-resistant tuberculosis in 2019, drug-resistant tuberculosis remains a public health crisis. The COVID-19 pandemic has reversed years of progress in providing essential tuberculosis services and reducing disease burden. The number of people diagnosed with drug-resistant tuberculosis has dropped by 22% since before the pandemic, and the number of patients provided with treatment for drug-resistant tuberculosis has dropped by 15%. Now more than ever, closing gaps in the detection of drug-resistant tuberculosis requires investment in research and development of new diagnostic tools and their rollout, expansion of sample transport systems, and the implementation of data connectivity solutions.

    Topics: Antitubercular Agents; COVID-19; Humans; Mycobacterium tuberculosis; Pandemics; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Rapid molecular tests for tuberculosis and tuberculosis drug resistance: a qualitative evidence synthesis of recipient and provider views.
    The Cochrane database of systematic reviews, 2022, 04-26, Volume: 4

    Programmes that introduce rapid molecular tests for tuberculosis and tuberculosis drug resistance aim to bring tests closer to the community, and thereby cut delay in diagnosis, ensure early treatment, and improve health outcomes, as well as overcome problems with poor laboratory infrastructure and inadequately trained personnel. Yet, diagnostic technologies only have an impact if they are put to use in a correct and timely manner. Views of the intended beneficiaries are important in uptake of diagnostics, and their effective use also depends on those implementing testing programmes, including providers, laboratory professionals, and staff in health ministries. Otherwise, there is a risk these technologies will not fit their intended use and setting, cannot be made to work and scale up, and are not used by, or not accessible to, those in need.. To synthesize end-user and professional user perspectives and experiences with low-complexity nucleic acid amplification tests (NAATs) for detection of tuberculosis and tuberculosis drug resistance; and to identify implications for effective implementation and health equity.. We searched MEDLINE, Embase, CINAHL, PsycInfo and Science Citation Index Expanded databases for eligible studies from 1 January 2007 up to 20 October 2021. We limited all searches to 2007 onward because the development of Xpert MTB/RIF, the first rapid molecular test in this review, was completed in 2009.. We included studies that used qualitative methods for data collection and analysis, and were focused on perspectives and experiences of users and potential users of low-complexity NAATs to diagnose tuberculosis and drug-resistant tuberculosis. NAATs included Xpert MTB/RIF, Xpert MTB/RIF Ultra, Xpert MTB/XDR, and the Truenat assays. Users were people with presumptive or confirmed tuberculosis and drug-resistant tuberculosis (including multidrug-resistant (MDR-TB)) and their caregivers, healthcare providers, laboratory technicians and managers, and programme officers and staff; and were from any type of health facility and setting globally. MDR-TB is tuberculosis caused by resistance to at least rifampicin and isoniazid, the two most effective first-line drugs used to treat tuberculosis.. We used a thematic analysis approach for data extraction and synthesis, and assessed confidence in the findings using GRADE CERQual approach. We developed a conceptual framework to illustrate how the findings relate.. We found 32 studies. All studies were conducted in low- and middle-income countries. Twenty-seven studies were conducted in high-tuberculosis burden countries and 21 studies in high-MDR-TB burden countries. Only one study was from an Eastern European country. While the studies covered a diverse use of low-complexity NAATs, in only a minority of studies was it used as the initial diagnostic test for all people with presumptive tuberculosis. We identified 18 review findings and grouped them into three overarching categories. Critical aspects users value People with tuberculosis valued reaching diagnostic closure with an accurate diagnosis, avoiding diagnostic delays, and keeping diagnostic-associated cost low. Similarly, healthcare providers valued aspects of accuracy and the resulting confidence in low-complexity NAAT results, rapid turnaround times, and keeping cost to people seeking a diagnosis low. In addition, providers valued diversity of sample types (for example, gastric aspirate specimens and stool in children) and drug resistance information. Laboratory professionals appreciated the improved ease of use, ergonomics, and biosafety of low-complexity NAATs compared to sputum microscopy, and increased staff satisfaction. Challenges reported to realizing those values People with tuberculosis and healthcare workers were reluctant to test for tuberculosis (including MDR-TB) due to fears, stigma, or cost concerns. Thus, low-complexity NAAT testing is not implemented with sufficient support or discretion to overcome barriers that are common to other approaches to testing for tuberculosis. Delays were reported at many steps of the diagnostic pathway owing to poor sample quality; difficulties with transporting specimens; lack of sufficient resources; maintenance of low-complexity NAATs; increased workload; inefficient work and patient flows; over-reliance on low-complexity NAAT results in lieu of clinical judgement; and lack of data-driven and inclusive implementation processes. These challenges were reported to lead to underutilization.  Concerns for access and equity The reported concerns included sustainable funding and maintenance and equitable use of resources to access low-complexity NAATs, as well as conflicts of interest between donors and people implementing the tests. Also, lengthy diagnostic delays, underutilization of low-complexity NAATs, lack of tuberculosis diagnostic facilities in the community, and too many eligibility restrictions hampered. Low-complexity diagnostics have been presented as a solution to overcome deficiencies in laboratory infrastructure and lack of skilled professionals. This review indicates this is misleading. The lack of infrastructure and human resources undermine the added value new diagnostics of low complexity have for recipients and providers. We had high confidence in the evidence contributing to these review findings. Implementation of new diagnostic technologies, like those considered in this review, will need to tackle the challenges identified in this review including weak infrastructure and systems, and insufficient data on ground level realities prior and during implementation, as well as problems of conflicts of interest in order to ensure equitable use of resources.

    Topics: Child; Drug Resistance; Humans; Nucleic Acid Amplification Techniques; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Evaluating the efficacy of stool sample on Xpert MTB/RIF Ultra and its comparison with other sample types by meta-analysis for TB diagnostics.
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2022, Volume: 41, Issue:6

    Precise and timely detection of tuberculosis (TB) is crucial to reduce transmission. This study aims to assess the accuracy of Xpert MTB/RIF Ultra on stool samples and systematically review the performance of Xpert MTB/RIF Ultra with different sample types by meta-analysis. Stool samples of smear-negative pulmonary TB (PTB), cervical lymph node TB, and abdominal TB patients were tested on the Xpert MTB/RIF Ultra system. Meta-analysis was performed on a set of 44 studies. Data were grouped by sample type, and the pooled sensitivity and specificity of Xpert MTB/RIF Ultra were calculated. The sensitivity of Xpert MTB/RIF Ultra with stool samples was 100% for smear-negative PTB, 27.27% for cervical lymph node TB, and 50% for abdominal TB patients, with 100% specificity for all included TB groups. The summary estimate for all PTB samples showed 84.2% sensitivity and 94.5% specificity, and EPTB samples showed 88.6% sensitivity and 96.4% specificity. Among all sample types included in our meta-analysis, urine showed the best performance for EPTB diagnosis. This pilot study supports the use of stool as an alternative non-invasive sample on Xpert MTB/RIF Ultra for rapid testing, suitable for both PTB and EPTB diagnosis.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Pilot Projects; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2022
Xpert MTB/RIF Ultra versus Xpert MTB/RIF for diagnosis of tuberculous pleural effusion: A systematic review and comparative meta-analysis.
    PloS one, 2022, Volume: 17, Issue:7

    We compared diagnostic accuracy of pleural fluid Xpert MTB/RIF (Xpert) and Xpert MTB/RIF Ultra (Ultra) assays for diagnosing tuberculous pleural effusion (TPE), through systematic review and comparative meta-analysis.. We searched PubMed and Embase databases for publications reporting diagnostic accuracy of Xpert or Ultra for TPE. We used bivariate random-effects modeling to summarize diagnostic accuracy information from individual studies using either mycobacterial culture or composite criteria as reference standard. We performed meta-regression through hierarchical summary receiver operating characteristic (HSROC) modeling to evaluate comparative performance of the two tests from studies reporting diagnostic accuracy of both in the same study population.. We retrieved 1097 publications, and included 74 for review. Summary estimates for sensitivity and specificity for Xpert were 0.52 (95% CI 0.43-0.60, I2 82.1%) and 0.99 (95% CI 0.97-0.99, I2 85.1%), respectively, using culture-based reference standard; and 0.21 (95% CI 0.17-0.26, I2 81.5%) and 1.00 (95% CI 0.99-1.00, I2 37.6%), respectively, using composite reference standard. Summary estimates for sensitivity and specificity for Ultra were 0.68 (95% CI 0.55-0.79, I2 80.0%) and 0.97 (95% CI 0.97-0.99, I2 92.1%), respectively, using culture-based reference standard; and 0.47 (95% CI 0.40-0.55, I2 64.1%) and 0.98 (95% CI 0.95-0.99, I2 54.8%), respectively, using composite reference standard. HSROC meta-regression yielded relative diagnostic odds ratio of 1.28 (95% CI 0.65-2.50) and 1.80 (95% CI 0.41-7.84) respectively in favor of Ultra, using culture and composite criteria as reference standard.. Ultra provides superior diagnostic accuracy over Xpert for diagnosing TPE, mainly because of its higher sensitivity.

    Topics: Antibiotics, Antitubercular; Humans; Mycobacterium tuberculosis; Pleural Effusion; Rifampin; Sensitivity and Specificity; Tuberculosis

2022
Molecular genetic tests GeneXpert MTB/RIF and Xpert MTB/RIF (Ultra) in the diagnosis of tuberculosis (review of literature).
    Klinicheskaia laboratornaia diagnostika, 2022, Sep-12, Volume: 67, Issue:9

    In recent tuberculosis years is the main cause of morbidity and death among patients with HIV infection. Modern diagnostics of tuberculosis includes mass screening of the population: digital fluorography from the age of 15 and immunodiagnostics in children and adolescents. Detection of mycobacterium tuberculosis by microscopy occurs in forms of tuberculosis with the decay of lung tissue. Such patients represent a high epidemic risk. To improve the verification of diagnosis in the practice of a phthisiologist, molecular genetic methods for the search for mycobacteria are increasingly used, based on the identification of specific fragments of the DNA chain in the diagnostic material. The most widely used method is the polymerase chain reaction (PCR), which is based on directed DNA amplification. The latest innovation is fully automated systems using cartridge technology GeneXpert. The advantages of GeneXpert are high sensitivity, speed (result in 2 hours), real-time PCR detection, exclusion of sample contamination. The technique of cartridge technology is constantly being improved, various cartridges are used on its platform, which not only detect M. tuberculosis, but also determine the sensitivity to anti-tuberculosis drugs - rifampicin (MTB / RIF cartridge) or several anti-TB drugs (MTB / XDR). Cartridges have been developed that are able to detect Mycobacterium tuberculosis (MBT) at an even lower concentration in the test material - MTB / RIF (Ultra). GeneXpert technology can be used to diagnose extrapulmonary tuberculosis by examining various biological materials, which are more effective in detecting tuberculosis in children and adolescents, in HIV-positive individuals.

    Topics: Adolescent; Child; HIV Infections; Humans; Molecular Biology; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis

2022
Impact of molecular diagnostic tests on diagnostic and treatment delays in tuberculosis: a systematic review and meta-analysis.
    BMC infectious diseases, 2022, Dec-14, Volume: 22, Issue:1

    Countries with high TB burden have expanded access to molecular diagnostic tests. However, their impact on reducing delays in TB diagnosis and treatment has not been assessed. Our primary aim was to summarize the quantitative evidence on the impact of nucleic acid amplification tests (NAAT) on diagnostic and treatment delays compared to that of the standard of care for drug-sensitive and drug-resistant tuberculosis (DS-TB and DR-TB).. We searched MEDLINE, EMBASE, Web of Science, and the Global Health databases (from their inception to October 12, 2020) and extracted time delay data for each test. We then analysed the diagnostic and treatment initiation delay separately for DS-TB and DR-TB by comparing smear vs Xpert for DS-TB and culture drug sensitivity testing (DST) vs line probe assay (LPA) for DR-TB. We conducted random effects meta-analyses of differences of the medians to quantify the difference in diagnostic and treatment initiation delay, and we investigated heterogeneity in effect estimates based on the period the test was used in, empiric treatment rate, HIV prevalence, healthcare level, and study design. We also evaluated methodological differences in assessing time delays.. A total of 45 studies were included in this review (DS = 26; DR = 20). We found considerable heterogeneity in the definition and reporting of time delays across the studies. For DS-TB, the use of Xpert reduced diagnostic delay by 1.79 days (95% CI - 0.27 to 3.85) and treatment initiation delay by 2.55 days (95% CI 0.54-4.56) in comparison to sputum microscopy. For DR-TB, use of LPAs reduced diagnostic delay by 40.09 days (95% CI 26.82-53.37) and treatment initiation delay by 45.32 days (95% CI 30.27-60.37) in comparison to any culture DST methods.. Our findings indicate that the use of World Health Organization recommended diagnostics for TB reduced delays in diagnosing and initiating TB treatment. Future studies evaluating performance and impact of diagnostics should consider reporting time delay estimates based on the standardized reporting framework.

    Topics: Delayed Diagnosis; Humans; Mycobacterium tuberculosis; Pathology, Molecular; Rifampin; Sensitivity and Specificity; Time-to-Treatment; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2022
Pediatric neurobrucellosis: a systematic review with case report.
    Journal of tropical pediatrics, 2022, 12-05, Volume: 69, Issue:1

    Pediatric neurobrucellosis represents a common anthropozoonosis in endemic areas but only anecdotal reports are available till date. Using appropriate search terms in the database platforms of MEDLINE, SCOPUS and Web of Sciences, we performed a systematic review of all the cases of pediatric neurobrucellosis published in the medical literature till date, in the light of a case report. The protocol was registered under PROSPERO (CRD42022333907). Our search strategy yielded 187 citations of which 51 citations were included. A total of 119 cases were reviewed. Of these cases, eight of them had insufficient data. The most common presentation was meningitis with or without encephalitis (n = 79, 71.2%). A high prevalence of cranial neuropathies (n = 22, 20.7%) was observed in the pediatric population in which abducens palsy was the most common (n = 9, 8.1%). Diagnosis was based on multimodal investigations including standard agglutination test (n = 44, 39.6%), Rose Bengal test (n = 37, 33.3%), blood culture (n = 23, 20.7%), serology (n = 20, 18.0%) and cerebrospinal fluid (CSF) culture (n = 11, 9.9%). Rifampicin-based triple drug regimen was the most commonly employed (83/102, 81.4%). Pediatric neurobrucellosis was associated with greater frequency of sequalae (5.4%), deafness (2.7%) and mortality (2.7%), when compared to that of general population. Neurobrucellosis mimics neuro-tuberculosis in various aspects. The review highlights several unique aspects of this entity in children. A high index of suspicion can ensure prompt diagnosis, timely initiation of management and favorable outcomes.. Pediatric neurobrucellosis represents a common zoonosis in endemic areas but only anecdotal reports are available till date. Using appropriate search terms in the database platforms of MEDLINE, SCOPUS and Web of Sciences, we performed a systematic review of all the cases of pediatric neurobrucellosis published in the medical literature till date, in the light of a case report. Our search strategy yielded 187 citations of which 51 citations were included. A total of 119 cases were reviewed. When compared to the largest series in neurobrucellosis, a higher frequency of meningitis was observed in the pediatric age group (71.2% vs. 37%). A high prevalence of cranial neuropathies (n = 22, 20.7%) was observed in the pediatric population in which abducens palsy was the most common (n = 9, 8.1%). Diagnosis was based on multimodal investigations including standard agglutination test (n = 44, 39.6%), Rose Bengal test (n = 37, 33.3%), blood culture (n = 23, 20.7%), serology (n = 20, 18.0%) and CSF culture (n = 11, 9.9%). Rifampicin-based triple drug regimen was the most commonly employed (83/102, 81.4%). Our systematic review highlighted the wide and heterogeneous spectrum of manifestations of neurobrucellosis in the pediatric population. A high index of suspicion can ensure prompt diagnosis, timely initiation of management and favorable outcomes.

    Topics: Brucellosis; Child; Humans; Meningitis; Rifampin; Tuberculosis

2022
Pretomanid for tuberculosis: a systematic review.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2022, Volume: 28, Issue:1

    Outcomes of treatment of tuberculosis patients with regimens including pretomanid have not yet been systematically reviewed.. To appraise existing evidence on efficacy and safety of pretomanid in tuberculosis.. Pubmed, clinicaltrials.gov. and Cochrane library.. Quantitative studies presenting original data on clinical efficacy or safety of pretomanid.. Patients with tuberculosis.. Treatment with pretomanid or pretomanid-containing regimens in minimum one study group.. Two authors independently extracted data and assessed risk of bias. Data on efficacy (early bactericidal activity, bactericidal activity, end-of-treatment outcomes and acquired resistance) and safety were summarized in tables. Mean differences in efficacy outcomes between regimens across studies were calculated.. Eight studies were included; four randomized controlled trials on 2-week early bactericidal activity in rifampicin-susceptible tuberculosis, three trials with randomized rifampicin-susceptible tuberculosis arms and a single rifampicin-resistant tuberculosis arm (two on 8-week bactericidal activity, one on end-of-treatment outcomes), one single-arm trial with end-of-treatment outcomes in highly resistant tuberculosis. Activity of pretomanid-moxifloxacin-pyrazinamide was superior to standard treatment on daily change in colony-forming units at days 0-2, 0-56 and 7-56 and time to culture conversion in rifampicin-susceptible tuberculosis (hazard ratio: 1.7; 95% CI 1.1-2.7), but not at end of treatment in one study. This study was stopped due to serious hepatotoxic adverse events, including three deaths, in 4% (95% CI 2-8) patients on pretomanid-moxifloxacin-pyrazinamide and none in controls. In patients with uncomplicated rifampicin-resistant tuberculosis on pretomanid-moxifloxacin-pyrazinamide treatment, 91% (95% CI 59-100) had favourable end-of-treatment outcomes. In patients with highly resistant tuberculosis, 90% (95% CI 83-95) on pretomanid-bedaquiline-linezolid had favourable outcomes six months after treatment, but linezolid-related toxicity was frequent. No acquired resistance to pretomanid was reported.. Evidence suggests an important role for pretomanid in rifampicin-resistant and highly resistant tuberculosis. Trials comparing pretomanid to existing core and companion drugs are needed to further define that role.

    Topics: Antitubercular Agents; Humans; Linezolid; Moxifloxacin; Nitroimidazoles; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Anti-tuberculosis activity and its structure-activity relationship (SAR) studies of oxadiazole derivatives: A key review.
    European journal of medicinal chemistry, 2021, Jan-01, Volume: 209

    With the increasing number of cases of inactive and drug-resistance tuberculosis, there is an urgent need to develop new potent molecules set for fighting this brutal disease. Medicinal chemistry concerns the discovery, the development, the identification, and the interpretation of the mode of action of biologically active compounds at the molecular level. Molecules bearing oxadiazoles are one such class that could be considered to satisfy this need. Oxadiazole regioisomers have been investigated in drug discovery programs for their capacity to go about as powerful linkers and as pharmacophoric highlights. Oxadiazoles can go about as bioisosteric substitutions for the hydrazide moiety which can be found in first-line anti-TB drugs, and some have been likewise answered to cooperate with more current anti-TB targets. This present review summarizes the current innovations of oxadiazole-based derivatives with potential antituberculosis activity and bacteria discussing various aspects of structure-activity relationship (SAR).

    Topics: Animals; Antitubercular Agents; Drug Discovery; Humans; Models, Molecular; Mycobacterium tuberculosis; Oxadiazoles; Structure-Activity Relationship; Tuberculosis

2021
Lipolytic enzymes inhibitors: A new way for antibacterial drugs discovery.
    European journal of medicinal chemistry, 2021, Jan-01, Volume: 209

    Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains the deadliest infectious disease worldwide with 1.5 million deaths in 2018, of which about 15% are attributed to resistant strains. Another significant example is Mycobacterium abscessus (M. abscessus), a nontuberculous mycobacteria (NTM) responsible for cutaneous and pulmonary infections, representing up to 95% of NTM infections in cystic fibrosis (CF) patients. M. abscessus is a new clinically relevant pathogen and is considered one of the most drug-resistant mycobacteria for which standardized chemotherapeutic regimens are still lacking. Together the emergence of M. tb and M. abscessus multi-drug resistant strains with ineffective and expensive therapeutics, have paved the way to the development of new classes of anti-mycobacterial agents offering additional therapeutic options. In this context, specific inhibitors of mycobacterial lipolytic enzymes represent novel and promising antibacterial molecules to address this challenging issue. The results highlighted here include a complete overview of the antibacterial activities, either in broth medium or inside infected macrophages, of two families of promising and potent anti-mycobacterial multi-target agents, i.e. oxadiazolone-core compounds (OX) and Cyclophostin & Cyclipostins analogs (CyC); the identification and biochemical validation of their effective targets (e.g., the antigen 85 complex and TesA playing key roles in mycolic acid metabolism) together with their respective crystal structures. To our knowledge, these are the first families of compounds able to target and impair replicating as well as intracellular bacteria. We are still impelled in deciphering their mode of action and finding new potential therapeutic targets against mycobacterial-related diseases.

    Topics: Antitubercular Agents; Carboxylic Ester Hydrolases; Drug Design; Enzyme Inhibitors; Humans; Lactones; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycolic Acids; Organophosphorus Compounds; Orlistat; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
An appraisal of anti-mycobacterial activity with structure-activity relationship of piperazine and its analogues: A review.
    European journal of medicinal chemistry, 2021, Jan-15, Volume: 210

    Piperazine, is privileged six membered nitrogen containing heterocyclic ring also known as 1,4-Diazacyclohexane. Consequently, piperazine is a versatile medicinally important scaffold and is an essential core in numerous marketed drugs with diverse pharmacological activities. In recent years several potent molecules containing piperazine as an essential subunit of the structural frame have been reported, especially against Mycobacterium tuberculosis (MTB). Remarkably, a good number of these reported molecules also displayed potential activity against multidrug-resistant (MDR), and extremely drug-resistant (XDR) strains of MTB. In this review, we have made a concerted effort to retrace anti-mycobacterial compounds for the past five decades (1971-2019) specifically where piperazine has been used as a vital building block. This review will benefit medicinal chemists as it elaborates on the design, rationale and structure-activity relationship (SAR) of the reported potent piperazine based anti-TB molecules, which in turn will assist them in addressing the gaps, exploiting the reported strategies and developing safer, selective, and cost-effective anti-mycobacterial agents.

    Topics: Animals; Antitubercular Agents; Drug Design; Drug Discovery; Humans; Mycobacterium tuberculosis; Piperazine; Structure-Activity Relationship; Tuberculosis

2021
Antibiotic heteroresistance in Mycobacterium tuberculosis isolates: a systematic review and meta-analysis.
    Annals of clinical microbiology and antimicrobials, 2021, Oct-13, Volume: 20, Issue:1

    Mycobacterium tuberculosis (MTB) is responsible for tuberculosis; that continues to be a public health threat across the globe. Furthermore, increasing heteroresistance (HR)-the presence of resistant and susceptible isolates among MTB strains- has been reported from around the world. This phenomenon can lead to full resistance development and treatment failure.. We systematically searched the relevant studies in PubMed, Scopus, and Embase (Until October 21, 2020). The study outcomes revealed the weighted pooled prevalence of antibiotic HR in MTB isolates with subgroup analysis by year, quality of study, and heteroresistance detection method.. A total of 38 studies which had investigated MTB isolates were included in the meta-analysis. Geographically, the highest number of studies were reported from Asia (n  =  24), followed by Africa (n  =  5). Nineteen studies reported HR to isoniazid, with a weighted pooled prevalence of 5% (95% CI 0-12) among 11,761 MTB isolates. Also, there is no important trend for the subgroup analysis by the study period (2001-2014 vs 2015-2017 vs 2018-2020). HR to rifampin was reported in 17 studies, with a weighted pooled prevalence of 7% (95% CI 2-14) among 3782 MTB isolates. HR to fluoroquinolone and ethambutol were reported in 12 and 4 studies, respectively, with weighted pooled prevalence of 10% and 1% among 2153 and 1509 MTB isolates, correspondingly.. Based on our analysis, HR in MTB isolates with different frequency rate is present worldwide. Thus, the selection of appropriate and reliable methods for HR detection is crucial for TB eradication.

    Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2021
Use of Xpert MTB/RIF and Xpert Ultra in extrapulmonary tuberculosis.
    Expert review of anti-infective therapy, 2021, Volume: 19, Issue:1

    Tuberculosis (TB) remains a major global health burden. There still remains a large gap between the notified and estimated incident cases. Extrapulmonary (EP) TB represents 15% of all TB cases and the diagnosis is more challenging due to the paucity of the organism. Smear microscopy is often insensitive and culture methods are prolonged. With the introduction of Xpert MTB/RIF and more recently Xpert Ultra, this has changed TB diagnostics by providing a rapid accessible platform to diagnose TB and identify rifampicin resistance within 2 h.. The diagnostic accuracy and the clinical role of Xpert MTB/RIF and Xpert Ultra in the different forms of EPTB.. Whilst significant advances have been made in TB diagnostics, there is still a need to optimize the diagnostic yield of Xpert MTB/RIF and Xpert Ultra in EPTB samples. Research is needed to facilitate standardization and optimal preparation of samples as well as understanding the role of Xpert MTB/RIF and Xpert Ultra in different burden settings. Alongside the current GeneXpert platform, the launch of rapid second-line drug resistance polymerase chain reactions and whole genome sequencing may help tackle the global health burden with a more comprehensive diagnostic approach and appropriate treatment.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Humans; Polymerase Chain Reaction; Rifampin; Time Factors; Tuberculosis

2021
Diagnostic accuracy of centralised assays for TB detection and detection of resistance to rifampicin and isoniazid: a systematic review and meta-analysis.
    The European respiratory journal, 2021, Volume: 57, Issue:2

    Topics: Antibiotics, Antitubercular; Cross-Sectional Studies; Drug Resistance, Bacterial; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2021
Xpert MTB/RIF Ultra and Xpert MTB/RIF assays for extrapulmonary tuberculosis and rifampicin resistance in adults.
    The Cochrane database of systematic reviews, 2021, 01-15, Volume: 1

    Xpert MTB/RIF Ultra (Xpert Ultra) and Xpert MTB/RIF are World Health Organization (WHO)-recommended rapid nucleic acid amplification tests (NAATs) widely used for simultaneous detection of Mycobacterium tuberculosis complex and rifampicin resistance in sputum. To extend our previous review on extrapulmonary tuberculosis (Kohli 2018), we performed this update to inform updated WHO policy (WHO Consolidated Guidelines (Module 3) 2020).. To estimate diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for extrapulmonary tuberculosis and rifampicin resistance in adults with presumptive extrapulmonary tuberculosis.. Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, 2 August 2019 and 28 January 2020 (Xpert Ultra studies), without language restriction.. Cross-sectional and cohort studies using non-respiratory specimens. Forms of extrapulmonary tuberculosis: tuberculous meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, disseminated tuberculosis. Reference standards were culture and a study-defined composite reference standard (tuberculosis detection); phenotypic drug susceptibility testing and line probe assays (rifampicin resistance detection).. Two review authors independently extracted data and assessed risk of bias and applicability using QUADAS-2. For tuberculosis detection, we performed separate analyses by specimen type and reference standard using the bivariate model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs). We applied a latent class meta-analysis model to three forms of extrapulmonary tuberculosis. We assessed certainty of evidence using GRADE.. 69 studies: 67 evaluated Xpert MTB/RIF and 11 evaluated Xpert Ultra, of which nine evaluated both tests. Most studies were conducted in China, India, South Africa, and Uganda. Overall, risk of bias was low for patient selection, index test, and flow and timing domains, and low (49%) or unclear (43%) for the reference standard domain. Applicability for the patient selection domain was unclear for most studies because we were unsure of the clinical settings. Cerebrospinal fluid Xpert Ultra (6 studies) Xpert Ultra pooled sensitivity and specificity (95% CrI) against culture were 89.4% (79.1 to 95.6) (89 participants; low-certainty evidence) and 91.2% (83.2 to 95.7) (386 participants; moderate-certainty evidence). Of 1000 people where 100 have tuberculous meningitis, 168 would be Xpert Ultra-positive: of these, 79 (47%) would not have tuberculosis (false-positives) and 832 would be Xpert Ultra-negative: of these, 11 (1%) would have tuberculosis (false-negatives). Xpert MTB/RIF (30 studies) Xpert MTB/RIF pooled sensitivity and specificity against culture were 71.1% (62.8 to 79.1) (571 participants; moderate-certainty evidence) and 96.9% (95.4 to 98.0) (2824 participants; high-certainty evidence). Of 1000 people where 100 have tuberculous meningitis, 99 would be Xpert MTB/RIF-positive: of these, 28 (28%) would not have tuberculosis; and 901 would be Xpert MTB/RIF-negative: of these, 29 (3%) would have tuberculosis. Pleural fluid Xpert Ultra (4 studies) Xpert Ultra pooled sensitivity and specificity against culture were 75.0% (58.0 to 86.4) (158 participants; very low-certainty evidence) and 87.0% (63.1 to 97.9) (240 participants; very low-certainty evidence). Of 1000 people where 100 have pleural tuberculosis, 192 would be Xpert Ultra-positive: of these, 117 (61%) would not have tuberculosis; and 808 would be Xpert Ultra-negative: of these, 25 (3%) would have tuberculosis. Xpert MTB/RIF (25 studies) Xpert MTB/RIF pooled sensitivity and specificity against culture were 49.5% (39.8 to 59.9) (644 participants; low-certainty evidence) and 98.9% (97.6 to 99.7) (2421 participants; high-certainty evidence). Of 1000 people where 100 have pleural tuberculosis, 60 would be Xpert MTB/RIF-positive: of these, 10 (17%) would not have tuberculosis; and 940 would be Xpert MTB/RIF-negative: of these, 50 (5%) would have tuberculosis. Lymph node aspirate Xpert Ultra (1 study) Xpert Ultra sensitivity and specificity (95% confidence interval) against composite reference standard we. Xpert Ultra and Xpert MTB/RIF may be helpful in diagnosing extrapulmonary tuberculosis. Sensitivity varies across different extrapulmonary specimens: while for most specimens specificity is high, the tests rarely yield a positive result for people without tuberculosis. For tuberculous meningitis, Xpert Ultra had higher sensitivity and lower specificity than Xpert MTB/RIF against culture. Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity for rifampicin resistance. Future research should acknowledge the concern associated with culture as a reference standard in paucibacillary specimens and consider ways to address this limitation.

    Topics: Adult; Antibiotics, Antitubercular; Bias; Drug Resistance, Bacterial; False Negative Reactions; False Positive Reactions; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pleural

2021
A rare case of primary sinonasal tuberculosis presented with phlyctenular keratoconjunctivitis in a pediatric patient: A case report and literature review.
    Medicine, 2021, Feb-19, Volume: 100, Issue:7

    Tuberculosis is a common cause of phlyctenular keratoconjunctivitis, especially for patients who live in a high endemic area of tuberculosis. We report a rare case of pediatric phlyctenular keratoconjunctivitis associated with primary sinonasal tuberculosis.. A 7-year-old boy presented with a 5-month history of redness of the left eye accompanied by mild visual impairment. Physical examination revealed elevated pinkish-white nodules with a circumcorneal hypervascularized lesion on the left conjunctiva.. Computed tomography revealed an enhancing soft tissue mass in the left maxillary sinus with bone destruction. Histopathology of maxillary tissue showed chronic inflammation without granuloma. Special stain, culture and polymerase chain reaction for mycobacterium were initially negative. Left maxillary sinus tuberculosis was diagnosed by positive Mycobacterium tuberculosis polymerase chain reaction from formalin-fixed paraffin-embedded maxillary tissue.. Two month of oral isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by 10 months of oral isoniazid and rifampicin without topical eye drops agent were prescribed.. Two months after initiation of treatment, the phlyctenular lesion had significantly improved. A follow-up computed tomography showed a significant reduction in the size of the maxillary sinus lesion and the extent of adjacent bone destruction.. Primary sinonasal tuberculosis is an uncommon cause of phlyctenular keratoconjunctivitis in children. When microbiological and histopathological evidences are absent, polymerase chain reaction analysis has a crucial role in the diagnosis of tuberculosis, especially in patient with uncommon presentation.

    Topics: Antibiotics, Antitubercular; Child; Child, Preschool; Female; Humans; Isoniazid; Keratoconjunctivitis; Male; Mycobacterium tuberculosis; Orbit; Paranasal Sinus Diseases; Rifampin; Tomography, X-Ray Computed; Tuberculosis

2021
Decentralized Care for Rifampin-Resistant Tuberculosis, Western Cape, South Africa.
    Emerging infectious diseases, 2021, Volume: 27, Issue:3

    In 2011, South Africa implemented a policy to decentralize treatment for rifampin-resistant tuberculosis (TB) to reduce durations of hospitalization and enable local treatment. We assessed policy implementation in Western Cape Province, where services expanded from 6 specialized TB hospitals to 406 facilities, by analyzing National Health Laboratory Service data on TB during 2012-2015. We calculated the percentage of patients who visited a TB hospital <1 year after rifampin-resistant TB diagnosis, the median duration of their hospitalizations, and the total distance between facilities visited. We assessed temporal changes with linear regression and stratified results by location. Of 2,878 patients, 65% were from Cape Town. In Cape Town, 29% visited a TB hospital; elsewhere, 68% visited a TB hospital. We found that hospitalizations and travel distances were shorter in Cape Town than in the surrounding areas.

    Topics: Humans; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
The Treatment of Tuberculosis.
    Clinical pharmacology and therapeutics, 2021, Volume: 110, Issue:6

    Tuberculosis (TB) remains a leading cause of infectious death worldwide, and poverty is a major driver. Clinically, TB presents as "latent" TB and active TB disease, and the treatment for each is different. TB drugs can display "early bactericidal activity (EBA)" and / or "sterilizing activity" (clearing persisters). Isoniazid is excellent at the former, and rifampin is excellent at the latter. Pyrazinamide and ethambutol complete the first-line regimen for drug-susceptible TB, each playing a specific role. Drug-resistant TB is an increasing concern, being met, in part, with repurposed drugs (including moxifloxacin, levofloxacin, linezolid, clofazimine, and beta-lactams) and new drugs (including bedaquiline, pretomanid, and delamanid). One challenge is to select drugs without overlapping adverse drug reaction profiles. QTc interval prolongation is one such concern, but to date, it has been manageable. Drug penetration into organism sanctuaries, such as the central nervous system, bone, and pulmonary TB cavities remain important challenges. The pharmacodynamics of most TB drugs can be described by the area under the curve (AUC) divided by the minimal inhibitory concentration (MIC). The hollow fiber infection model (HFIM) and various animal models (especially mouse and macaque) allow for sophisticated pharmacokinetic/pharmacodynamic experiments. These experiments may hasten the selection of the most potent, shortest possible regimens to treat even extremely drug resistant TB. These findings can be translated to humans by optimizing drug exposure in each patient, using therapeutic drug monitoring and dose individualization.

    Topics: Animals; Antitubercular Agents; Drug Monitoring; Drug Therapy, Combination; Humans; Isoniazid; Levofloxacin; Rifampin; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
Mechanisms and detection methods of Mycobacterium tuberculosis rifampicin resistance: The phenomenon of drug resistance is complex.
    Tuberculosis (Edinburgh, Scotland), 2021, Volume: 128

    Tuberculosis (TB) is an infectious disease that poses a serious threat to human health. Rifampin (RIF) is an important first-line anti-TB drug, and rifampin resistance (RIF-R) is a key factor in formulating treatment regimen and evaluating the prognosis of TB. Compared with other drugs resistance, the RIF-R mechanism of Mycobacterium tuberculosis (M. tuberculosis) is one of the clearest, which is mainly caused by RIF resistance-related mutations in the rpoB gene. This provides a convenient condition for developing rapid detection methods, and also an ideal object for studying the general drug resistance mechanisms of M. tuberculosis. This review focuses on the mechanisms that influence the RIF resistance of M. tuberculosis and related detection methods. Besides the mutations in rpoB, M. tuberculosis can decrease the amount of drugs entering the cells, enhance the drugs efflux, and be heterogeneous RIF susceptibility to resist drug pressure. Based on the results of current researches, many genes participate in influencing the susceptibility to RIF, which indicates the phenomenon of M. tuberculosis drug resistance is very complex.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2021
Impact of diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people living with HIV.
    The Cochrane database of systematic reviews, 2021, 08-20, Volume: 8

    Tuberculosis is the primary cause of hospital admission in people living with HIV, and the likelihood of death in the hospital is unacceptably high. The Alere Determine TB LAM Ag test (AlereLAM) is a point-of-care test and the only lateral flow lipoarabinomannan assay (LF-LAM) assay currently commercially available and recommended by the World Health Organization (WHO). A 2019 Cochrane Review summarised the diagnostic accuracy of LF-LAM for tuberculosis in people living with HIV. This systematic review assesses the impact of the use of LF-LAM (AlereLAM) on mortality and other patient-important outcomes.. To assess the impact of the use of LF-LAM (AlereLAM) on mortality in adults living with HIV in inpatient and outpatient settings. To assess the impact of the use of LF-LAM (AlereLAM) on other patient-important outcomes in adults living with HIV, including time to diagnosis of tuberculosis, and time to initiation of tuberculosis treatment.. We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); Science Citation Index Expanded (Web of Science), BIOSIS Previews, Scopus, LILACS; ProQuest Dissertations and Theses; ClinicalTrials.gov; and the WHO ICTRP up to 12 March 2021.. Randomized controlled trials that compared a diagnostic intervention including LF-LAM with diagnostic strategies that used smear microscopy, mycobacterial culture, a nucleic acid amplification test such as Xpert MTB/RIF, or a combination of these tests. We included adults (≥ 15 years) living with HIV.. Two review authors independently assessed trials for eligibility, extracted data, and analysed risk of bias using the Cochrane tool for assessing risk of bias in randomized studies. We contacted study authors for clarification as needed. We used risk ratio (RR) with 95% confidence intervals (CI). We used a fixed-effect model except in the presence of clinical or statistical heterogeneity, in which case we used a random-effects model. We assessed the certainty of the evidence using GRADE.. We included three trials, two in inpatient settings and one in outpatient settings. All trials were conducted in sub-Saharan Africa and assessed the impact of diagnostic strategies that included LF-LAM on mortality when the test was used in conjunction with other tuberculosis diagnostic tests or clinical assessment for clinical decision-making in adults living with HIV. Inpatient settings  In inpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy likely reduces mortality in people living with HIV at eight weeks compared to routine tuberculosis diagnostic testing without LF-LAM (pooled RR 0.85, 95% CI 0.76 to 0.94; 5102 participants, 2 trials; moderate-certainty evidence). That is, people living with HIV who received LF-LAM had 15% lower risk of mortality. The absolute effect was 34 fewer deaths per 1000 (from 14 fewer to 55 fewer). In inpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy probably results in a slight increase in the proportion of people living with HIV who were started on tuberculosis treatment compared to routine tuberculosis diagnostic testing without LF-LAM (pooled RR 1.26, 95% CI 0.94 to 1.69; 5102 participants, 2 trials; moderate-certainty evidence).  Outpatient settings In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may reduce mortality in people living with HIV at six months compared to routine tuberculosis diagnostic testing without LF-LAM (RR 0.89, 95% CI 0.71 to 1.11; 2972 participants, 1 trial; low-certainty evidence). Although this trial did not detect a difference in mortality, the direction of effect was towards a mortality reduction, and the effect size was similar to that in inpatient settings.  In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may result in a large increase in the proportion of people living with HIV who were started on tuberculosis treatment compared to routine tuberculosis diagnostic testing without LF-LAM (RR 5.44, 95% CI 4.70 to 6.29, 3022 participants, 1 trial; low-certainty evidence). Other patient-important outcomes Assessment of other patient-important and implementation outcomes in the trials varied. The included trials demonstrated that a higher proportion of people living with HIV were able to produce urine compared to sputum for tuberculosis diagnostic testing; a higher proportion of people living with HIV were diagnosed with t. In inpatient settings, the use of LF-LAM as part of a tuberculosis diagnostic testing strategy likely reduces mortality and probably results in a slight increase in tuberculosis treatment initiation in people living with HIV. The reduction in mortality may be due to earlier diagnosis, which facilitates prompt treatment initiation. In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may reduce mortality and may result in a large increase in tuberculosis treatment initiation in people living with HIV. Our results support the implementation of LF-LAM to be used in conjunction with other WHO-recommended tuberculosis diagnostic tests to assist in the rapid diagnosis of tuberculosis in people living with HIV.

    Topics: Adult; Antibiotics, Antitubercular; HIV Infections; Humans; Lipopolysaccharides; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Pulmonary

2021
Does Xpert® MTB/RIF assay give rifampicin resistance results without identified mutation? Review of cases from Addis Ababa, Ethiopia.
    BMC infectious diseases, 2020, Jan-30, Volume: 20, Issue:1

    Xpert® MTB/RIF assay is currently used in Ethiopia for the rapid diagnosis of Mycobacterium tuberculosis (MTB) and mutations that confer Rifampicin resistance. Rifampicin resistance is determined based on any mutation in the 81 bp of rpoB gene using five overlapping probes represented as Probe A (codons 507-511), Probe B (codons 512-518), Probe C (codons 518-523), Probe D (codons 523-529) and Probe E (codons 529-533). In this review, we assessed the frequency of missed probe types for Rifampicin Resistance results.. Data were reviewed from specimens received and tested using Xpert® MTB/RIF assay at Ethiopian National Tuberculosis Reference Laboratory, in Addis Ababa from 15 July 2016 to 31 December 2018 retrospectively. All archived data were reviewed carefully to describe missed probe types and the quantity of DNA in the sample.. A total of 100 specimens were reported as MTB Detected Rifampicin Resistance Detected by Xpert® MTB/RIF assay. More than half (55%) of these results were reported from male patients. The median age was 28.0 years (5 months to 88 years). Majorities (62%) of the cases were detected from sputum. Among the total of 38 extrapulmonary samples, lymph node aspirates were accounted for 50% (19/38). The most common mutations (81.0%) were found in the Probe E region followed by Probe D (10.0%), and Probe B (3.0%). Mutations in Probe A and Probe C regions were not observed. However, six (6.0%) Rifampicin resistance cases were found without any missed probe type. The delta Ct max is ≥4.3. No specimen yielded Rifampicin resistance associated with more than one probe failure or mutation combinations.. Mutations associated with Probe E (codons 529-533) region were identified as the commonest rpoB gene mutations. The Rifampicin resistance results found without any identified missing probe needs further study. The lower DNA amount was observed in extrapulmonary specimens compared with sputum.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Codon; DNA; Drug Resistance, Bacterial; Ethiopia; Female; Genetic Testing; Humans; Infant; Male; Middle Aged; Mutation; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Young Adult

2020
Inhalable dry powders of rifampicin highlighting potential and drawbacks in formulation development for experimental tuberculosis aerosol therapy.
    Expert opinion on drug delivery, 2020, Volume: 17, Issue:3

    Topics: Administration, Inhalation; Aerosols; Biological Availability; Dry Powder Inhalers; Excipients; Humans; Lung; Powders; Rifampin; Tuberculosis

2020
Tuberculosis treatment in children: The changing landscape.
    Paediatric respiratory reviews, 2020, Volume: 36

    Traditionally children have been treated for tuberculosis (TB) based on data extrapolated from adults. However, we know that children present unique challenges that deserve special focus. New data on optimal drug selection and dosing are emerging with the inclusion of children in clinical trials and ongoing research on age-related pharmacokinetics and pharmacodynamics. We discuss the changing treatment landscape for drug-susceptible and drug-resistant paediatric tuberculosis in both the most common (intrathoracic) and most severe (central nervous system) forms of disease, and address the current knowledge gaps for improving patient outcomes.

    Topics: Antitubercular Agents; Child; Drug Therapy, Combination; Duration of Therapy; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Central Nervous System; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2020
The impact of diabetes mellitus on drug resistance in patients with newly diagnosed tuberculosis: a systematic review and meta-analysis.
    Annals of palliative medicine, 2020, Volume: 9, Issue:2

    Tuberculosis and diabetes mellitus are both important global health problems now. Previous studies have drawn different conclusions about the impact of diabetes on drug resistance in patients with newly diagnosed tuberculosis.. We conducted a systematic search in four databases: PubMed, EMBSE, Cochrane Library, and Web of Science. The relative risk (RR) was applied to assess the association of diabetes with drug resistance and the STATA version 12.0 was used for data synthesis.. A total of 13 studies involving 33,747 patients were included in our study. The pooled results revealed that presence of diabetes was significantly associated with isoniazid resistance (RR =1.22, 95% CI: 1.04-1.43) in patients with newly diagnosed tuberculosis. However, no significant impact of diabetes on rifampicin resistance (RR =0.67, 95% CI: 0.41-1.11) or multi-drug resistance (MDR) (RR =1.28, 95% CI: 0.93-1.75) was observed. The results of subgroup analysis were similar to the pooled results. No significant publication bias for the results of MDR was found.. In patients with newly diagnosed tuberculosis, diabetes is associated with isoniazid resistance. However, there is no significant impact of diabetes on the rifampicin resistance or MDR. However, these findings still need to be verified in the future.

    Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Antitubercular Agents; Comorbidity; Diabetes Complications; Drug Resistance; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
[Molecular diagnosis of tuberculosis].
    Revue des maladies respiratoires, 2020, Volume: 37, Issue:5

    Tuberculosis is caused by the M. tuberculosis complex. Its slow growth delays the bacteriological diagnosis based on phenotypic tests. Molecular biology has significantly reduced this delay, notably thanks to the deployment of the Xpert® MTB/RIF test (Cepheid), which detects the M. tuberculosis complex and rifampicin resistance in 2hours. Other tests detecting isoniazid and second-line antituberculous drugs resistance have been developed. However, the performances of molecular tests are significantly reduced if the acid-fast bacilli microscopy screening is negative. It is therefore crucial to limit their indication to strong clinical suspicions. Resistance detection tests only explore certain characterized positions; however, not all drug-resistance mutations are known. Moreover, the performances vary for different antituberculous drugs. The advent of genomic sequencing is promising. Its integration into routine workflow still needs to be evaluated and the data analysis remains to be standardized. The rise of molecular biology techniques has revolutionized the diagnosis of tuberculosis and drug resistance. However, they remain screening tests; results still have to be confirmed by phenotypic reference methods.

    Topics: Antitubercular Agents; Diagnostic Tests, Routine; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
Immunometabolism during Mycobacterium tuberculosis Infection.
    Trends in microbiology, 2020, Volume: 28, Issue:10

    Over a quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Approximately 3.4% of new and 18% of recurrent cases of TB are multidrug-resistant (MDR) or rifampicin-resistant. Recent evidence has shown that certain drug-resistant strains of Mtb modulate host metabolic reprogramming, and therefore immune responses, during infection. However, it remains unclear how widespread these mechanisms are among circulating MDR Mtb strains and what impact drug-resistance-conferring mutations have on immunometabolism during TB. While few studies have directly addressed metabolic reprogramming in the context of drug-resistant Mtb infection, previous literature examining how drug-resistance mutations alter Mtb physiology and differences in the immune response to drug-resistant Mtb provides significant insights into how drug-resistant strains of Mtb differentially impact immunometabolism.

    Topics: Animals; Antitubercular Agents; Bacterial Proteins; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2020
A novel risk factor for predicting anti-tuberculosis drug resistance in patients with tuberculosis complicated with type 2 diabetes mellitus.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2020, Volume: 97

    This study aimed to explore the relationship between glycosylated hemoglobin (HbA1c) and the risk of anti-tuberculosis (TB) drug resistance for TB-type 2 diabetes mellitus (T2DM) patients.. From March 2014 to June 2019, medical records from multiple centers were searched. Logistic regression analyses were performed. A predictive model for multidrug-resistance (MDR) was developed and validated. Calibration and discrimination of the model were assessed.. Inconsistent results were found in the systemic review. A multicenter chart review with 657 records was thus conducted. The HbA1c <7% group and HbA1c ≥7% group had 390 and 267 patients, respectively. The HbA1c<7% group had a lower risk of developing rifampicin resistance, isoniazid resistance and MDR, with odd ratios (ORs) of 1.904 (p=0.001), 2.896 (p<0.001) and 3.228 (p<0.001), respectively. The between-group differences in the risk of anti-TB drug resistance were analyzed based on data from three provinces in China. After adding HbA1c grading, the predictive model for MDR (https://mengyuan.shinyapps.io/Shinyapp/) showed excellent capacity with an AUC of 75.4% in the training set (Sichuan and Gansu) and 73.9% in the internal validation set (Henan). The performances in calibration, prediction probabilities and net clinical benefit were significantly improved by HbA1c grading.. HbA1c grading was an independent risk factor for isoniazid resistance and MDR in TB-T2DM patients.

    Topics: Adult; Aged; Antitubercular Agents; Diabetes Mellitus, Type 2; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Female; Glycated Hemoglobin; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Odds Ratio; Rifampin; Risk Factors; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
Tuberculosis in 2019.
    The Indian journal of tuberculosis, 2020, Volume: 67, Issue:2

    Tuberculosis (TB) updates and guidelines have been published rapidly in last few years. The WHO and RNTCP have recommended suggestions that have changed the diagnostics and therapeutics paradigm in 2019. The rapid nature of these changes need to be appraised at the pulmonologist end. We conducted a google survey to study these gaps and subsequently review TB in 2019 focusing on the gaps in the survey. We narrate a short review covering the important diagnostic and therapeutic aspects in brief. We discuss the results of our google survey to address the knowledge gaps. Diagnosis, principles and rationale of therapy and treatment of drug sensitive and drug resistant tuberculosis including the shorter regimen and regrouping of drugs are important considerations of our review.

    Topics: Antitubercular Agents; Ethambutol; Health Policy; Humans; India; Isoniazid; Molecular Diagnostic Techniques; Nucleic Acid Amplification Techniques; Polymerase Chain Reaction; Practice Guidelines as Topic; Pulmonologists; Pyrazinamide; Rifampin; Surveys and Questionnaires; Tuberculosis; Tuberculosis, Multidrug-Resistant; World Health Organization

2020
Factors influencing diagnosis and treatment initiation for multidrug-resistant/rifampicin-resistant tuberculosis in six sub-Saharan African countries: a mixed-methods systematic review.
    BMJ global health, 2020, Volume: 5, Issue:7

    Drug-resistant tuberculosis burdens fragile health systems in sub-Saharan Africa (SSA), complicated by high prevalence of HIV. Several African countries reported large gaps between estimated incidence and diagnosed or treated cases. Our review aimed to identify barriers and facilitators influencing diagnosis and treatment for drug-resistant tuberculosis (DR-TB) in SSA, which is necessary to develop effective strategies to find the missing incident cases and improve quality of care.. Using an integrative design, we reviewed and narratively synthesised qualitative, quantitative and mixed-methods studies from nine electronic databases: Medline, Global Health, CINAHL, EMBASE, Scopus, Web of Science, International Journal of Tuberculosis and Lung Disease, PubMed and Google Scholar (January 2006 to June 2019).. Of 3181 original studies identified, 55 full texts were screened, and 29 retained. The studies included were from 6 countries, mostly South Africa. Barriers and facilitators to DR-TB care were identified at the health system and patient levels. Predominant health system barriers were laboratory operational issues, provider knowledge and attitudes and information management. Facilitators included GeneXpert MTB/RIF (Xpert) diagnosis and decentralisation of services. At the patient level, predominant barriers were patients being lost to follow-up or dying due to lengthy diagnostic and treatment delays, negative public sector care perceptions, family, work or school commitments and using private sector care. Some patient-level facilitators were HIV positivity and having more symptoms.. Case detection and treatment for DR -TB in SSA currently relies on individual patients presenting voluntarily to the hospital for care. Specific interventions targeting identified barriers may improve rates and timeliness of detection and treatment.

    Topics: Humans; Mycobacterium tuberculosis; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
Marine natural products as potential anti-tubercular agents.
    European journal of medicinal chemistry, 2019, Mar-01, Volume: 165

    Tuberculosis has been one of the greatest global health challenges of all time. Although the current first-line anti-tuberculosis (anti-TB) medicines used in the clinic have reduced mortality, multidrug-resistance and extensively drug-resistance forms of the disease have now spread worldwide and become a global problem. Even so, few new clinically approved drugs have emerged during the past 30 years. Highly biodiverse marine organisms have received considerable attention for drug discovery in the past couple of decades, and emerging TB drug resistance has motivated interest in assessing marine natural products (MNPs) in the treatment of this disease. So far, more than 170 compounds have been isolated from marine organisms with anti-TB properties, ten of which exhibit potent activity and have the potential for further development. This review systematically surveys MNPs with anti-TB activity and illustrates the impact of these compounds on drug discovery research against tuberculosis.

    Topics: Animals; Antitubercular Agents; Aquatic Organisms; Biological Products; Humans; Tuberculosis

2019
Pharmacokinetics of First-Line Anti-Tubercular Drugs.
    Indian journal of pediatrics, 2019, Volume: 86, Issue:5

    Determining the optimal dosages of isoniazid, rifampicin, pyrazinamide and ethambutol in children is necessary to obtain therapeutic serum concentrations of these drugs. Revised dosages have improved the exposure of 1st line anti-tubercular drugs to some extent; there is still scope for modification of the dosages to achieve exposures which can lead to favourable outcome of the disease. High dose of rifampicin is being investigated in clinical trials in adults with some benefit; studies are required in children. Inter-individual pharmacokinetic variability and the effect of age, nutritional status, Human immunodeficiency virus (HIV) infection, acetylator genotype may need to be accounted for in striving for the dosages best suited for an individual.

    Topics: Age Factors; Antitubercular Agents; Child; Drug Overdose; Ethambutol; Food; Genotype; HIV Infections; Humans; Isoniazid; Malnutrition; Nutritional Status; Polymorphism, Genetic; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2019
The rapid molecular test Xpert MTB/RIF ultra: towards improved tuberculosis diagnosis and rifampicin resistance detection.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2019, Volume: 25, Issue:11

    Tuberculosis diagnosis has dramatically improved since the introduction of the rapid molecular test Xpert MTB/RIF (Xpert) detecting M. tuberculosis and rifampicin resistance directly from clinical specimens, therefore shortening the turnaround time, reducing patient's isolation period and decreasing the time to start anti-TB drugs. The new version, Xpert MTB/RIF Ultra (Ultra), displays a higher sensitivity and an improved rifampicin resistance detection. Both tests have been endorsed by the World Health Organisation.. Xpert and Ultra rapidly became widespread and paved the way for new approaches and new paradigms as well as for the development of molecular point-of-care tests (POCTs). In this narrative review, we aimed to address their performance in the diagnosis of tuberculosis and to discuss the expectations of these tests as well as their limits and the unmet needs.. Peer-reviewed publications addressing the diagnostic performance of Ultra and Xpert.. We focused on publications that evaluated the performance of Ultra and Xpert on the same group of patients or the same set of specimens in different tuberculosis-burden settings.. The studies published so far reported an increased sensitivity of Ultra when compared to Xpert, which represents a benefit for tuberculosis diagnosis. The fact that such a sensitive assay cannot distinguish between alive and dead bacilli emphasizes that caution should be exercised regarding indications and interpretation of results. Additional studies are needed to determine the true performance for the diagnosis of extrapulmonary tuberculosis because of the great diversity of the specimens.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2019
Diagnostic Accuracy of the Xpert MTB/RIF Assay for Lymph Node Tuberculosis: A Systematic Review and Meta-Analysis.
    BioMed research international, 2019, Volume: 2019

    To evaluate the performance of Xpert MTB/RIF for lymph node tuberculosis (LNTB).. We searched databases for published reports. We reviewed the studies and identified the performance of Xpert MTB/RIF with respect to a composite reference standard (CRS) and culture. We used a bivariate random-effects model to perform meta-analyses and used metaregression to analyze sources of heterogeneity.. 15 independent studies compared Xpert MTB/RIF with CRS while 21 comparing it with culture were included. The pooled sensitivity and specificity of Xpert MTB/RIF were 79% and 98% compared to that of CRS, respectively, and 84% and 91% compared to that of culture, respectively. The pooled sensitivity and specificity using fine needle aspiration (FNA) samples versus CRS were 80% and 96%, whereas those against culture were 90% and 89%, respectively. The percentages while working with tissue samples versus CRS were 76% and 100%, respectively, whereas those against culture were 76% and 92%, respectively. There was no significant difference in diagnostic efficiency among the types of specimen.. Xpert MTB/RIF demonstrates good diagnostic efficiency for LNTB and is not related to the type of specimen, obtained via different routes.

    Topics: Biological Assay; Humans; Lymph Nodes; Mycobacterium tuberculosis; Reference Standards; Rifampin; Tuberculosis

2019
Fluoroquinolone derivatives and their anti-tubercular activities.
    European journal of medicinal chemistry, 2018, Feb-25, Volume: 146

    Tuberculosis (TB) remains one of the most widespread and leading deadliest diseases, around one-third of the world's population harbor a latent infection by Mycobacterium tuberculosis (MTB), and 5-10% eventually develop an active TB. The emergency of MTB new virulent forms as well as the co-infection between MTB and HIV alarming the serious problem in TB control and demanding the need for new drugs more potent than earlier with safe ADME profile. Fluoroquinolones are emerged as a large family of synthetic broad spectrum antibiotics, and some of them were recommended as the second-line agents for the treatment of TB mainly in cases involving resistance or intolerance to first-line anti-TB therapy by WHO. Numerous of FQs derivatives have been synthesized for seeking for new anti-TB agents, and some of them exhibited promising potency. This review aims to summarize the recent advances made towards the discovery of FQs derivatives as anti-TB agents and the structure-activity relationship of these derivatives.

    Topics: Animals; Antitubercular Agents; Dose-Response Relationship, Drug; Fluoroquinolones; Humans; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis

2018
Recent advances of imidazole-containing derivatives as anti-tubercular agents.
    European journal of medicinal chemistry, 2018, Apr-25, Volume: 150

    Tuberculosis still remains one of the most common, communicable, and leading deadliest diseases known to mankind throughout the world. Drug-resistance in Mycobacterium tuberculosis which threatens to worsen the global tuberculosis epidemic has caused great concern in recent years. To overcome the resistance, the development of new drugs with novel mechanisms of actions is of great importance. Imidazole-containing derivatives endow with various biological properties, and some of them demonstrated excellent anti-tubercular activity. As the most emblematic example, 4-nitroimidazole delamanid has already received approval for treatment of multidrug-resistant tuberculosis infected patients. Thus, imidazole-containing derivatives have caused great interests in discovery of new anti-tubercular agents. Numerous of imidazole-containing derivatives were synthesized and screened for their in vitro and in vivo anti-mycobacterial activities against both drug-sensitive and drug-resistant Mycobacterium tuberculosis pathogens. This review aims to outline the recent advances of imidazole-containing derivatives as anti-tubercular agents, and summarize the structure-activity relationship of these derivatives. The enriched structure-activity relationship may pave the way for the further rational development of imidazole-containing derivatives as anti-tubercular agents.

    Topics: Animals; Antitubercular Agents; Dose-Response Relationship, Drug; Humans; Imidazoles; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis

2018
Pharmacokinetics and pharmacogenetics of anti-tubercular drugs: a tool for treatment optimization?
    Expert opinion on drug metabolism & toxicology, 2018, Volume: 14, Issue:1

    WHO global strategy is to end tuberculosis epidemic by 2035. Pharmacokinetic and pharmacogenetic studies are increasingly performed and might confirm their potential role in optimizing treatment outcome in specific settings and populations. Insufficient drug exposure seems to be a relevant factor in tuberculosis outcome and for the risk of phenotypic resistance. Areas covered: This review discusses available pharmacokinetic and pharmacogenetic data of first and second-line antitubercular agents in relation to efficacy and toxicity. Pharmacodynamic implications of optimized drugs and new options regimens are reviewed. Moreover a specific session describes innovative investigations on drug penetration. Expert opinion: The optimal use of available antitubercular drugs is paramount for tuberculosis control and eradication. Whilst trials are still on-going, higher rifampicin doses should be reserved to treatment for tubercular meningitis. Therapeutic Drug Monitoring with limiting sampling strategies is advised in patients at risk of failure or with slow treatment response. Further studies are needed in order to provide definitive recommendations of pharmacogenetic-based individualization: however lower isoniazid doses in NAT2 slow acetylators and higher rifampicin doses in individuals with SLCO1B1 loss of function genes are promising strategies. Finally in order to inform tailored strategies we need more data on tissue drug penetration and pharmacological modelling.

    Topics: Animals; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Monitoring; Drug Resistance, Bacterial; Humans; Isoniazid; Models, Biological; Pharmacogenetics; Rifampin; Tuberculosis

2018
Pharmacokinetics of efavirenz in patients on antituberculosis treatment in high human immunodeficiency virus and tuberculosis burden countries: A systematic review.
    British journal of clinical pharmacology, 2018, Volume: 84, Issue:8

    Efavirenz (EFV) and rifampicin-isoniazid (RH) are cornerstone drugs in human immunodeficiency virus (HIV)-tuberculosis (TB) coinfection treatment but with complex drug interactions, efficacy and safety challenges. We reviewed recent data on EFV and RH interaction in TB/HIV high-burden countries.. We conducted a systematic review of studies conducted in the high TB/HIV-burden countries between 1990 and 2016 on EFV pharmacokinetics during RH coadministration in coinfected patients. Two reviewers conducted article screening and data collection.. Anti-TB drug coadministration minimally affect the EFV exposure, efficacy and safety among TB-HIV coinfected African and Asian patients. This supports the current 600 mg EFV dosing when coadministered with anti-TB drugs.

    Topics: Africa; Anti-HIV Agents; Antitubercular Agents; Asia; Body Weight; Central Nervous System Diseases; Chemical and Drug Induced Liver Injury; Coinfection; Cost of Illness; Cytochrome P-450 CYP2B6; Drug Interactions; Female; HIV Infections; Humans; Isoniazid; Latin America; Male; Polymorphism, Single Nucleotide; Rifampin; Sex Factors; Treatment Outcome; Tuberculosis

2018
Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis.
    The Journal of antimicrobial chemotherapy, 2018, 09-01, Volume: 73, Issue:9

    The objectives of this study were to explore inter-study heterogeneity in the pharmacokinetics (PK) of orally administered rifampicin, to derive summary estimates of rifampicin PK parameters at standard dosages and to compare these with summary estimates for higher dosages.. A systematic search was performed for studies of rifampicin PK published in the English language up to May 2017. Data describing the Cmax and AUC were extracted. Meta-analysis provided summary estimates for PK parameter estimates at standard rifampicin dosages. Heterogeneity was assessed by estimation of the I2 statistic and visual inspection of forest plots. Summary AUC estimates at standard and higher dosages were compared graphically and contextualized using preclinical pharmacodynamic (PD) data.. Substantial heterogeneity in PK parameters was evident and upheld in meta-regression. Treatment duration had a significant impact on the summary estimates for rifampicin PK parameters, with Cmax 8.98 mg/L (SEM 2.19) after a single dose and 5.79 mg/L (SEM 2.14) at steady-state dosing, and AUC 72.56 mg·h/L (SEM 2.60) and 38.73 mg·h/L (SEM 4.33) after single and steady-state dosing, respectively. Rifampicin dosages of at least 25 mg/kg are required to achieve plasma PK/PD targets defined in preclinical studies.. Vast inter-study heterogeneity exists in rifampicin PK parameter estimates. This is not explained by the available modifying variables. The recommended dosage of rifampicin should be increased to improve efficacy. This study provides an important point of reference for understanding rifampicin PK at standard dosages as efforts to explore higher dosing strategies continue in this field.

    Topics: Administration, Oral; Adult; Antibiotics, Antitubercular; Female; Healthy Volunteers; Humans; Male; Rifampin; Tuberculosis

2018
A comprehensive review on Primary gallbladder tuberculosis.
    Polski przeglad chirurgiczny, 2018, Apr-30, Volume: 90, Issue:2

    Tuberculosis (TB) is an infectious disease that can affect any organ system of the body. Abdominal TB can be gastrointestinal, lymph nodal, visceral or peritoneal. The gallbladder (GB) is rarely involved in abdominal TB as a primary organ. Extensive research literature on gallbladder TB is limited to case reports. There has been no review on this rare abdominal pathology. GB tuberculosis is a difficult diagnosis preoperatively. It is a rare differential among the more common gallbladder pathologies such as cholelithiasis, or a gallbladder malignancy. Typical histopathology of the resected specimen helps to establish this rare diagnosis. Subjecting every specimen to histopathological examination followed by medical treatment offers the chance of cure. Through this review, the authors attempt to provide an insight into this disease entity.

    Topics: Adolescent; Adult; Antitubercular Agents; Child; Female; Gallbladder Diseases; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis; Young Adult

2018
Xpert
    The Cochrane database of systematic reviews, 2018, 08-27, Volume: 8

    To determine the diagnostic accuracy of Xpert a) for extrapulmonary TB by site of disease in people presumed to have extrapulmonary TB; and b) for rifampicin resistance in people presumed to have extrapulmonary TB.. We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature (LILACS), Scopus, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number (ISRCTN) Registry, and ProQuest up to 7 August 2017 without language restriction.. We included diagnostic accuracy studies of Xpert in people presumed to have extrapulmonary TB. We included TB meningitis and pleural, lymph node, bone or joint, genitourinary, peritoneal, pericardial, and disseminated TB. We used culture as the reference standard. For pleural TB, we also included a composite reference standard, which defined a positive result as the presence of granulomatous inflammation or a positive culture result. For rifampicin resistance, we used culture-based drug susceptibility testing or MTBDRplus as the reference standard.. Two review authors independently extracted data, assessed risk of bias and applicability using the QUADAS-2 tool. We determined pooled predicted sensitivity and specificity for TB, grouped by type of extrapulmonary specimen, and for rifampicin resistance. For TB detection, we used a bivariate random-effects model. Recognizing that use of culture may lead to misclassification of cases of extrapulmonary TB as 'not TB' owing to the paucibacillary nature of the disease, we adjusted accuracy estimates by applying a latent class meta-analysis model. For rifampicin resistance detection, we performed univariate meta-analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected. We used theoretical populations with an assumed prevalence to provide illustrative numbers of patients with false positive and false negative results.. We included 66 unique studies that evaluated 16,213 specimens for detection of extrapulmonary TB and rifampicin resistance. We identified only one study that evaluated the newest test version, Xpert MTB/RIF Ultra (Ultra), for TB meningitis. Fifty studies (76%) took place in low- or middle-income countries. Risk of bias was low for patient selection, index test, and flow and timing domains and was high or unclear for the reference standard domain (most of these studies decontaminated sterile specimens before culture inoculation). Regarding applicability, in the patient selection domain, we scored high or unclear concern for most studies because either patients were evaluated exclusively as inpatients at tertiary care centres, or we were not sure about the clinical settings.Pooled Xpert sensitivity (defined by culture) varied across different types of specimens (31% in pleural tissue to 97% in bone or joint fluid); Xpert sensitivity was > 80% in urine and bone or joint fluid and tissue. Pooled Xpert specificity (defined by culture) varied less than sensitivity (82% in bone or joint tissue to 99% in pleural fluid and urine). Xpert specificity was ≥ 98% in cerebrospinal fluid, pleural fluid, urine, and peritoneal fluid.Xpert testing in cerebrospinal fluidXpert pooled sensitivity and specificity (95% credible interval (CrI)) against culture were 71.1% (60.9% to 80.4%) and 98.0% (97.0% to 98.8%), respectively (29 studies, 3774 specimens; moderate-certainty evidence).For a population of 1000 people where 100 have TB meningitis on culture, 89 would be Xpert-positive: of these, 18 (20%) would not have TB (false-positives); and 911 would be Xpert-negative: of these, 29 (3%) would have TB (false-negatives).For TB meningitis, ultra sensitivity and specificity against culture (95% confidence interval (CI)) were 90% (55% to 100%) and 90% (83% to 95%), respectively (one study, 129 participants).Xpert testing in pleural fluidXpert pooled sensitivity and specificity (95% CrI) against culture were 50.9% (39.7% to 62.8%) and 99.2% (98.2% to 99.7%), respectively (27 studies, 4006 specimens; low-certainty evidence).For a population of 1000 people where 150 have pleural TB on culture, 83 would be Xpert-positive: of these, seven (8%) would not have TB (false-positives); and 917 would be Xpert-negative: of these, 74 (8%) would have TB (false-negatives).Xpert testing in urineXpert pooled sensitivity and specificity (95% CrI) against culture were 82.7% (69.6% to 91.1%) and 98.7% (. In people presumed to have extrapulmonary TB, Xpert may be helpful in confirming the diagnosis. Xpert sensitivity varies across different extrapulmonary specimens, while for most specimens, specificity is high, the test rarely yielding a positive result for people without TB (defined by culture). Xpert is accurate for detection of rifampicin resistance. For people with presumed TB meningitis, treatment should be based on clinical judgement, and not withheld solely on an Xpert result, as is common practice when culture results are negative.

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; False Negative Reactions; False Positive Reactions; Humans; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Reference Standards; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Meningeal

2018
Clinical management of combined tuberculosis and diabetes.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2018, 12-01, Volume: 22, Issue:12

    Optimal management of combined tuberculosis (TB) and diabetes (DM) is important but challenging in terms of achieving good disease outcomes and avoiding toxicity, drug interactions and other challenges. DM management during anti-tuberculosis treatment, aimed at improving TB treatment outcomes and reducing DM-related morbidity and mortality, consists of glycaemic control and measures to reduce the risk of cardiovascular disease. Metformin, the glucose-lowering drug of choice for TB patients, has no meaningful interaction with rifampicin (RMP), and may reduce TB mortality. Insulin is effective for severe hyperglycaemia, but has several disadvantages that limit its use in TB patients. Cardiovascular risk assessment should be considered in TB-DM patients to guide management in terms of counselling and prescription of antihypertensive, lipid-lowering and anti-platelet treatment. With regard to anti-tuberculosis treatment, DM is associated with an increased risk of drug resistance, lower exposure to anti-tuberculosis drugs, treatment failure and recurrent TB. Patients therefore need careful assessment before, during and possibly after anti-tuberculosis treatment. Although no studies have been performed, anti-tuberculosis treatment may also have to be prolonged or intensified in terms of regimen or drug dosage if DM is present. With regard to service delivery, combined treatment should probably be administered, supervised and monitored as much as possible in a TB clinic. Local circumstances and severity of DM will guide the need for referral of patients to specialised DM care, and continuation of DM care after completion of anti-tuberculosis treatment. More data are also needed for the management of TB-DM patients with human immunodeficiency virus co-infection.

    Topics: Antitubercular Agents; Diabetes Mellitus, Type 2; Drug Interactions; Humans; Hypoglycemic Agents; Metformin; Recurrence; Rifampin; Risk Assessment; Treatment Outcome; Tuberculosis

2018
Isoniazid derivatives and their anti-tubercular activity.
    European journal of medicinal chemistry, 2017, Jun-16, Volume: 133

    Tuberculosis (TB), which has been a scourge of humanity for thousands of years, is a worldwide pandemic disease caused mainly by Mycobacterium tuberculosis (MTB). The emergence of drug-resistant TB (DR-TB), multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB) and totally drug-resistant TB (TDR-TB) increase the challenges to eliminate TB worldwide. Isoniazid (INH), a critical frontline anti-TB drug, is one of the most effective drugs used to treatment of TB infection for more than 60 years. Unfortunately, bacterial strains resistant to INH are becoming common which mainly due to the long-term widely use even abuse. Therefore, there is an urgent need to develop novel anti-TB agents. Numerous efforts have been undertaken to develop new anti-TB agents, but no new drug has been introduced for more than 5 decades. It has been suggested that the incorporation of lipophilic moieties into the framework of INH can increase permeation of the drug into bacterial cells, thereby enhancing the anti-TB. Therefore, INH derivatives with greater lipophilicity are emerging as one of the most potential anti-TB agents. Indeed, the INH derivative LL-3858 is in initial stages of phase II clinical trial for the treatment of TB and may be approved to treat TB in the near future. This review aims to summarize the recent advances made towards the discovery anti-TB agents holding INH as a nucleus including INH hybrids and INH hydrazide-hydrazone derivatives.

    Topics: Animals; Antitubercular Agents; Drug Discovery; Humans; Isoniazid; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis, Multidrug-Resistant

2017
Triazole derivatives and their anti-tubercular activity.
    European journal of medicinal chemistry, 2017, Sep-29, Volume: 138

    Tuberculosis (TB) remains one of the most widespread and leading deadliest diseases, threats one-third of the world's population. Although numerous efforts have been undertaken to develop new anti-TB agents, only a handful of compounds have entered human trials in the past 5 decades. Triazoles including 1,2,3-triazole and 1,2,4-triazole are one of the most important classes of nitrogen containing heterocycles that exhibited various biological activities. Triazole derivatives are regarded as a new class of effective anti-TB candidates owing to their potential anti-TB potency. Thus, molecules containing triazole moiety may show promising in vitro and in vivo anti-TB activities and might be able to prevent the drug resistant to certain extent. This review outlines the advances in the application of triazole-containing hybrids as anti-TB agents, and discusses the structure-activity relationship of these derivatives.

    Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Triazoles; Tuberculosis

2017
Recent advances of pyrazole-containing derivatives as anti-tubercular agents.
    European journal of medicinal chemistry, 2017, Oct-20, Volume: 139

    One-third of the world's population infected tuberculosis (TB), and more than 1 million deaths annually. The co-infection between the mainly pathogen Mycobacterium tuberculosis (MTB) and HIV, and the incidence of drug-resistant TB, multi-drug resistant TB, extensively drug-resistant TB as well as totally drug-resistant TB have further aggravated the mortality and spread of this disease. Thus, there is an urgent need to develop novel anti-TB agents against both drug-susceptible and drug-resistant TB. The wide spectrum of biological activities and successful utilization of pyrazole-containing drugs in clinic have inspired more and more attention towards this kind of heterocycles. Numerous of pyrazole-containing derivatives have been synthesized for searching new anti-TB agents, and some of them showed promising potency and may have novel mechanism of action. This review aims to outline the recent achievements in pyrazole-containing derivatives as anti-TB agents and their structure-activity relationship.

    Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Humans; Molecular Structure; Mycobacterium tuberculosis; Pyrazoles; Structure-Activity Relationship; Tuberculosis

2017
Musculoskeletal Tuberculosis.
    Microbiology spectrum, 2017, Volume: 5, Issue:2

    Musculoskeletal tuberculosis (TB) accounts for approximately 10% of all extrapulmonary TB cases in the United States and is the third most common site of extrapulmonary TB after pleural and lymphatic disease. Vertebral involvement (tuberculous spondylitis, or Pott's disease) is the most common type of skeletal TB, accounting for about half of all cases of musculoskeletal TB. The presentation of musculoskeletal TB may be insidious over a long period and the diagnosis may be elusive and delayed, as TB may not be the initial consideration in the differential diagnosis. Concomitant pulmonary involvement may not be present, thus confusing the diagnosis even further. Early diagnosis of bone and joint disease is important to minimize the risk of deformity and enhance outcome. The introduction of newer imaging modalities, including MRI (imaging procedure of choice) and CT, has enhanced the diagnostic evaluation of patients with musculoskeletal TB and for directed biopsies of affected areas of the musculoskeletal system. Obtaining appropriate specimens for culture and other diagnostic tests is essential to establish a definitive diagnosis and recover M. tuberculosis for susceptibility testing. A total of 6 to 9 months of a rifampin-based regimen, like treatment of pulmonary TB, is recommended for the treatment of drug susceptible musculoskeletal disease. Randomized trials of tuberculous spondylitis have demonstrated that such regimens are efficacious. These data and those from the treatment of pulmonary TB have been extrapolated to form the basis of treatment regimen recommendations for other forms of musculoskeletal TB.

    Topics: Antitubercular Agents; Bacteriological Techniques; Diagnostic Tests, Routine; Humans; Musculoskeletal Diseases; Mycobacterium tuberculosis; Optical Imaging; Rifampin; Tuberculosis; United States

2017
Xpert® MTB/RIF: Usefulness for the diagnosis of tuberculosis and resistance to rifampicin.
    Medicina clinica, 2017, Nov-09, Volume: 149, Issue:9

    The advent of the Xpert® MTB/RIF technique was a revolution in the diagnosis of tuberculosis, especially in areas with high incidence and low resources. It allows the detection of Mycobacterium tuberculosis complex and simultaneously the most common resistance mutations to rifampicin in less than 2h. For respiratory samples the sensitivity is very high, but it decreases for extrapulmonary samples and children. Although it is faster and simpler than conventional methods, it presents some limitations and new and better techniques are needed to reduce the number of cases and deaths caused by tuberculosis. This review aims to assess the scientific evidence around the diagnostic performance of Xpert® MTB/RIF in different types of samples and populations, as well as analyse its strengths and limitations for TB diagnosis.

    Topics: Bacterial Proteins; Comorbidity; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Incidence; Male; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2017
A Review of Moxifloxacin for the Treatment of Drug-Susceptible Tuberculosis.
    Journal of clinical pharmacology, 2017, Volume: 57, Issue:11

    Moxifloxacin, an 8-methoxy quinolone, is an important drug in the treatment of multidrug-resistant tuberculosis and is being investigated in novel drug regimens with pretomanid, bedaquiline, and pyrazinamide, or rifapentine, for the treatment of drug-susceptible tuberculosis. Early results of these studies are promising. Although current evidence does not support the use of moxifloxacin in treatment-shortening regimens for drug-susceptible tuberculosis, it may be recommended in patients unable to tolerate standard first-line drug regimens or for isoniazid monoresistance. Evidence suggests that the standard 400-mg dose of moxifloxacin used in the treatment of tuberculosis may be suboptimal in some patients, leading to worse tuberculosis treatment outcomes and emergence of drug resistance. Furthermore, a drug interaction with the rifamycins results in up to 31% reduced plasma concentrations of moxifloxacin when these are combined for treatment of drug-susceptible tuberculosis, although the clinical relevance of this interaction is unclear. Moxifloxacin exhibits extensive interindividual pharmacokinetic variability. Higher doses of moxifloxacin may be needed to achieve drug exposures required for improved clinical outcomes. Further study is, however, needed to determine the safety of proposed higher doses and clinically validated targets for drug exposure to moxifloxacin associated with improved tuberculosis treatment outcomes. We discuss in this review the evidence for the use of moxifloxacin in drug-susceptible tuberculosis and explore the role of moxifloxacin pharmacokinetics, pharmacodynamics, and drug interactions with rifamycins, on tuberculosis treatment outcomes when used in first-line tuberculosis drug regimens.

    Topics: Animals; Antitubercular Agents; Drug Interactions; Fluoroquinolones; Humans; Moxifloxacin; Rifampin; Tuberculosis

2017
Rifampin vs. rifapentine: what is the preferred rifamycin for tuberculosis?
    Expert review of clinical pharmacology, 2017, Volume: 10, Issue:10

    One-third of the world's population is infected with Mycobacterium tuberculosis (M.tb.). Latent tuberculosis infection (LTBI) can progress to tuberculosis disease, the leading cause of death by infection. Rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against M.tb. What are the advantages of each for LTBI or tuberculosis treatment? Areas covered: We review studies assessing the pharmacokinetics (PK), pharmacodynamics (PD), drug interaction risk, safety, and efficacy of rifampin and rifapentine and provide basis for comparing them. Expert commentary: Rifampin has shorter half-life, higher MIC against M.tb, lower protein binding, and better distribution into cavitary contents than rifapentine. Drug interactions for the two drugs maybe similar in magnitude. For LTBI, rifapentine is effective as convenient, once-weekly, 12-week course of treatment. Rifampin is also effective for LTBI, but must be given daily for four months, therefore, drug interactions are more problematic. For drug-sensitive tuberculosis disease, rifampin remains the standard of care. Safety profile of rifampin is better-described; adverse events differ somewhat for the two drugs. The registered once-weekly rifapentine regimen is inadequate, but higher doses of either drugs may shorten the treatment duration required for effective management of TB. Results of clinical trials evaluating high-dose rifamycin regimens are eagerly awaited.

    Topics: Animals; Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Half-Life; Humans; Latent Tuberculosis; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2017
Clinical and pharmacological hallmarks of rifapentine's use in diabetes patients with active and latent tuberculosis: do we know enough?
    Drug design, development and therapy, 2017, Volume: 11

    Rifapentine is a rifamycin derivate approved by the US Food and Drug Administration in 1998 for the treatment of active, drug-susceptible tuberculosis (TB). In 2014, rifapentine was approved for the treatment of latent TB infection in patients at high risk of progression to active disease and is currently under evaluation by the European Medicines Agency. Expanding indications of rifapentine largely affect diabetes patients, since about one-third of them harbor latent TB. Clinical consequences of rifapentine use in this population and potentially harmful interactions with hypoglycemic agents are widely underexplored and generally considered similar to the ones of rifampicin. Indeed, rifapentine too may decrease blood levels of many oral antidiabetics and compete with them for protein-binding sites and/or transporters. However, the two drugs differ in protein-binding degree, the magnitude of cytochrome P450 induction and auto-induction, the degree of renal elimination, and so on. Rifapentine seems to be more suitable for use in diabetes patients with renal impairment, owing to the fact that it does not cause renal toxicity, and it is eliminated via kidneys in smaller proportions than rifampicin. On the other hand, there are no data related to rifapentine use in patients >65 years, and hypoalbuminemia associated with diabetic kidney disease may affect a free fraction of rifapentine to a greater extent than that of rifampicin. Until more pharmacokinetic information and information on the safety of rifapentine use in diabetic patients and drug-drug interactions are available, diabetes in TB patients treated with rifapentine should be managed with insulin analogs, and glucose and rifapentine plasma levels should be closely monitored.

    Topics: Antibiotics, Antitubercular; Diabetes Mellitus; Drug Interactions; Humans; Hypoglycemic Agents; Latent Tuberculosis; Rifampin; Tuberculosis

2017
Liver transplantation is associated with good clinical outcome in patients with active tuberculosis and acute liver failure due to anti-tubercular treatment.
    Transplant infectious disease : an official journal of the Transplantation Society, 2017, Volume: 19, Issue:2

    Active tuberculosis (TB) is commonly considered a contraindication for liver transplantation (LT). However, in patients with TB who develop acute liver failure (ALF) due to toxicity induced by anti-tubercular treatment (ATT), LT could be the only opportunity for treatment. The aim of this study was to evaluate the feasibility of LT in this scenario.. We described 2 cases and comprehensively reviewed the literature finding 26 cases of LT performed in patients having a concomitant active TB and liver failure secondary to ATT toxicity.. TB was classified as pulmonary in 18/26 (69%), nodal in 3/26 (11%) TB cases, while the remaining 5/26 cases included disseminated, pleural, renal, ovarian, and vertebral TB localization (1 case each). ATT following LT consisted mainly of isoniazid or rifampin (RIF)-sparing regimens and included primarily fluoroquinolones and ethambutol. Rejection episodes and liver toxicity were reported in 19% and 8% of patients respectively. Graft rejection was more frequent among patients treated with RIF-containing regimens (P<.001). Mortality rate was 15% after a median follow up of 12 months. In only one case was death attributed to uncontrolled TB infection.. Our findings suggest that LT is an effective therapeutic option for patients with active TB developing ALF following ATT and should be considered for patients failing medical treatment.

    Topics: Adolescent; Antitubercular Agents; Bronchoalveolar Lavage Fluid; Ethambutol; Feasibility Studies; Female; Fluoroquinolones; Graft Rejection; Humans; Isoniazid; Liver Failure, Acute; Liver Transplantation; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Prognosis; Rifampin; Treatment Outcome; Tuberculosis

2017
Molecular Players in Tuberculosis Drug Development: Another Break in the Cell Wall.
    Current medicinal chemistry, 2017, Nov-24, Volume: 24, Issue:36

    Tuberculosis is a leading killer, especially for people living with HIV. It is a real medical need to tackle this disease, which is made difficult to treat due to the increasing spread of multi-drug-resistant and extensively drug-resistant bacterial strains. Cases of tuberculosis that are resistant to virtually all drugs currently available are increasing at an alarming rate around the world. Here, we review the current knowledge in the field of drug development against tuberculosis with a focus on the mechanisms of action of drugs and the targeted bacterial cell processes involved. Particular emphasis is dedicated to the process of cell wall synthesis, which has proven to provide strong potentialities for drug development. It is hoped that a deeper understanding of key molecular machineries to tackle will provide us with a better outline of possible antibacterial mechanisms of action and offer hints for the design of more efficient strategies to treat resistant tuberculosis in the future.

    Topics: Antitubercular Agents; Benzothiazoles; Cell Wall; Drug Discovery; Humans; Molecular Docking Simulation; Mycobacterium tuberculosis; Nitroimidazoles; Rifampin; Tuberculosis

2017
Isolated tuberculous liver abscess in an immunocompetent adult patient: A case report and literature review.
    Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi, 2016, Volume: 49, Issue:3

    Tuberculous liver abscess is a rare disease entity even in endemic areas of Mycobacterium tuberculosis. It is usually accompanied by pulmonary tuberculosis or enteric tuberculosis. Further, an isolated tuberculous liver abscess is extremely rare. The disease is diagnosed by laparotomy or postmortem autopsy in most cases, and some authors adopted a 9-month antituberculosis regimen. We herein report a case of an isolated tuberculous liver abscess that initially manifested as persistent fever and general malaise, which was diagnosed by liver biopsy and treated successfully with a 6-month antituberculosis regimen and percutaneous abscess drainage.

    Topics: Aged; Antitubercular Agents; Biopsy; Blood Chemical Analysis; Drug Combinations; Ethambutol; Humans; Isoniazid; Laparotomy; Liver; Liver Abscess; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

2016
Critical Review: What Dose of Rifabutin Is Recommended With Antiretroviral Therapy?
    Journal of acquired immune deficiency syndromes (1999), 2016, Jun-01, Volume: 72, Issue:2

    Since the advent of combination antiretroviral therapy to successfully treat HIV infection, drug-drug interactions (DDIs) have become a significant problem as many antiretrovirals (ARVs) are metabolized in the liver. Antituberculous therapy traditionally includes rifamycins, particularly rifampicin. Rifabutin (RBT) has shown similar efficacy as rifampicin but induces CYP3A4 to a lesser degree and is less likely to have DDIs with ARVs. We identified 14 DDI pharmacokinetic studies on HIV monoinfected and HIV-tuberculosis coinfected individuals, and the remaining studies were healthy volunteer studies. Although RBT may be coadministered with most nonnucleoside reverse transcriptase inhibitors, identifying the optimal dose with ritonavir-boosted or cobicistat-boosted protease inhibitors is challenging because of concern about adverse effects with increased RBT exposure. Limited healthy volunteer studies on other ARV drug classes and RBT suggest that dose modification may be unnecessary. The paucity of data assessing clinical tuberculosis endpoints concurrently with RBT and ARV pharmacokinetics limits evidence-based recommendations on the optimal dose of RBT within available ARV drug classes.

    Topics: Anti-HIV Agents; Antitubercular Agents; Coinfection; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Practice Guidelines as Topic; Rifabutin; Rifampin; Ritonavir; Tuberculosis

2016
Therapeutic drug monitoring in anti-tuberculosis treatment: a systematic review and meta-analysis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:6

    Therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes, but there is little evidence to guide TDM in clinical practice.. We performed a systematic review and meta-analysis to summarise existing literature on TDM in first-line drugs.. We identified 41 studies that reported 2 h post-dose drug concentrations (C2h) for first-line drugs and 12 studies that reported clinical outcomes. We pooled data by study quality, design, region, dosing modality and patient characteristics. The pooled proportion of subjects with low isoniazid C2h was 0.43 (95%CI 0.32-0.55), 0.67 (95%CI 0.60-0.74) had low rifampicin C2h, 0.27 (95%CI 0.17-0.38) had low ethambutol C2h, and 0.12 (95%CI 0.07-0.19) had low pyrazinamide C2h. Patients with diabetes had a non-significant increase in the proportion of subjects with low C2h levels across all four drugs. Only three of 12 studies that examined clinical outcomes demonstrated an association between low C2h and unsuccessful treatment outcomes.. Across a wide variety of studies, a high proportion of patients undergoing first-line anti-tuberculosis treatment had 2 h drug concentrations below the accepted normal threshold. These findings point to a discrepancy between accepted 2 h TDM thresholds and TB drug dosing recommendations.

    Topics: Antitubercular Agents; Databases, Factual; Dose-Response Relationship, Drug; Drug Monitoring; Ethambutol; Humans; Isoniazid; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Treatment Outcome; Tuberculosis

2016
Rifamycins, Alone and in Combination.
    Cold Spring Harbor perspectives in medicine, 2016, 07-01, Volume: 6, Issue:7

    Rifamycins inhibit RNA polymerase of most bacterial genera. Rifampicin remains part of combination therapy for treating tuberculosis (TB), and for treating Gram-positive prosthetic joint and valve infections, in which biofilms are prominent. Rifabutin has use for AIDS patients in treating mycobacterial infections TB and Mycobacterium avium complex (MAC), having fewer drug-drug interactions that interfere with AIDS medications. Rifabutin is occasionally used in combination to eradicate Helicobacter pylori (peptic ulcer disease). Rifapentine has yet to fulfill its potential in reducing time of treatment for TB. Rifaximin is a monotherapeutic agent to treat gastrointestinal (GI) disorders, such as hepatic encephalopathy, irritable bowel syndrome, and travelers' diarrhea. Rifaximin is confined to the GI tract because it is not systemically absorbed on oral dosing, achieving high local concentrations, and showing anti-inflammatory properties in addition to its antibacterial activity. Resistance issues are unavoidable with all the rifamycins when the bioburden is high, because of mutations that modify RNA polymerase.

    Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Drug Therapy, Combination; Gastrointestinal Diseases; Humans; Rifabutin; Rifampin; Rifamycins; Rifaximin; Tuberculosis

2016
Treatment regimens for rifampicin-resistant tuberculosis: highlighting a research gap.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:7

    Treatment guidance for non-multidrug-resistant (MDR) rifampicin-resistant (RMP-R) tuberculosis (TB) is variable. We aimed to undertake a systematic review and meta-analysis of the randomised controlled trial (RCT) data behind such guidelines to identify the most efficacious treatment regimens. Ovid MEDLINE, the Web of Science and EMBASE were mined using search terms for TB, drug therapy and RCTs. Despite 12 604 records being retrieved, only three studies reported treatment outcomes by regimen for patients with non-MDR RMP-R disease, preventing meta-analysis. Our systematic review highlights a substantial gap in the literature regarding evidence-based treatment regimens for RMP-R TB.

    Topics: Antibiotics, Antitubercular; Biomedical Research; Drug Resistance, Bacterial; Evidence-Based Medicine; Humans; Microbial Sensitivity Tests; Predictive Value of Tests; Professional Practice Gaps; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis

2016
Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring.
    European journal of clinical pharmacology, 2016, Volume: 72, Issue:8

    Tuberculosis (TB) remains one of the world's deadliest communicable diseases. Although cure rates of the standard four-drug (rifampicin, isoniazid, pyrazinamide, ethambutol) treatment schedule can be as high as 95-98 % under clinical trial conditions, success rates may be much lower in less well resourced countries. Unsuccessful treatment with these first-line anti-TB drugs may lead to the development of multidrug resistant and extensively drug resistant TB. The intrinsic interindividual variability in the pharmacokinetics (PK) of the first-line anti-TB drugs is further exacerbated by co-morbidities such as HIV infection and diabetes.. Therapeutic drug monitoring has been proposed in an attempt to optimize treatment outcome and reduce the development of drug resistance. Several studies have shown that maximum plasma concentrations (C max), especially of rifampicin and isoniazid, are well below the proposed target C max concentrations in a substantial fraction of patients being treated with the standard four-drug treatment schedule, even though treatment's success rate in these studies was typically at least 85 %.. The proposed target C max concentrations are based on the concentrations of these agents achieved in healthy volunteers and patients receiving the standard doses. Estimation of C max based on one or two sampling times may not have the necessary accuracy since absorption rate, especially for rifampicin, may be highly variable. In addition, minimum inhibitory concentration (MIC) variability should be taken into account to set clinically meaningful susceptibility breakpoints. Clearly, there is a need to better define the key target PK and pharmacodynamic (PD) parameters for therapeutic drug monitoring (TDM) of the first-line anti-TB drugs to be efficacious, C max (or area under the curve (AUC)) and C max/MIC (or AUC/MIC).. Although TDM of first-line anti-TB drugs has been successfully used in a limited number of specialized centers to improve treatment outcome in slow responders, a better characterization of the target PK and/or PK/PD parameters is in our opinion necessary to make it cost-effective.

    Topics: Antitubercular Agents; Drug Monitoring; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2016
Pharmacological interactions between rifampicin and antiretroviral drugs: challenges and research priorities for resource-limited settings.
    Therapeutic drug monitoring, 2015, Volume: 37, Issue:1

    Coadministration of antituberculosis and antiretroviral therapy is often inevitable in high-burden countries where tuberculosis (TB) is the most common opportunistic infection associated with HIV/AIDS. Concurrent use of rifampicin and many antiretroviral drugs is complicated by pharmacokinetic drug-drug interactions. Rifampicin is a very potent enzyme inducer, which can result in subtherapeutic antiretroviral drug concentrations. In addition, TB drugs and antiretroviral drugs have additive (pharmacodynamic) interactions as reflected in overlapping adverse effect profiles. This review provides an overview of the pharmacological interactions between rifampicin-based TB treatment and antiretroviral drugs in adults living in resource-limited settings. Major progress has been made to evaluate the interactions between TB drugs and antiretroviral therapy; however, burning questions remain concerning nevirapine and efavirenz effectiveness during rifampicin-based TB treatment, treatment options for TB-HIV-coinfected patients with nonnucleoside reverse transcriptase inhibitor resistance or intolerance, and exact treatment or dosing schedules for vulnerable patients including children and pregnant women. The current research priorities can be addressed by maximizing the use of already existing data, creating new data by conducting clinical trials and prospective observational studies and to engage a lobby to make currently unavailable drugs available to those most in need.

    Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Drug Interactions; HIV Infections; Humans; Rifampin; Tuberculosis

2015
Tuberculosis: current treatment, diagnostics, and newer antitubercular agents in clinical trials.
    Infectious disorders drug targets, 2015, Volume: 15, Issue:1

    Tuberculosis (TB), a dreadful disease is one of the most important health problems worldwide, and is responsible for approximately 1.3 million death tolls in 2012. DOTS is the currently used drug therapy in TB and the long term drug regimens and patients' poor compliance lead to emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB, which invigorates the research efforts to address the urgent need for the quick diagnosis and for newer antitubercular agents and vaccines to completely eradicate TB. Today we have at least 20 new diagnostic test platforms, 14 TB vaccine candidates in clinical trials and over 35 candidates in preclinical development, and among the antitubercular agents under clinical investigation, 4 anti-TB agents are in Phase III (efficacy) trials and 7 anti-TB agents are in Phase II, early bactericidal activity and sputum culture conversion trials (rifapentine is in a Phase II and a Phase III trial), 5 anti-TB agents in preclinical development and 3 anti-TB agents in Good Laboratory Practice toxicity evaluation. Recently US FDA has approved TMC207 as a part of combination therapy to treat adults with MDR pulmonary TB in the absence of other alternatives. We provide here the concise review on the chemical entities currently in the clinical trials, the new vaccines in the developmental pipeline, and the new diagnostic test.

    Topics: Adult; Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Directly Observed Therapy; Drug Discovery; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis Vaccines

2015
Impact of the Xpert MTB/RIF diagnostic test for tuberculosis in countries with a high burden of disease.
    Current opinion in pulmonary medicine, 2015, Volume: 21, Issue:3

    Control of tuberculosis necessitates prompt diagnosis and access to effective treatment. We discuss the impact of a new nucleic acid amplification test to assist diagnosis and detect rifampicin resistance. Following encouraging clinical performance studies, an automated PCR-based test, the Xpert MTB/RIF (Cepheid, Sunnyvale, CA), has been implemented on a global scale. Clinical trials to assess the impact of the new technology in primary healthcare clinics have been undertaken in tuberculosis (TB) endemic countries.. Clinical trials at the point of care in TB endemic countries demonstrated that increased numbers of TB patients are identified using the Xpert MTB/RIF assay as the frontline diagnostic test in place of sputum smear microscopy. Decreased times from sample collection to initiation of treatment were also reported when using the molecular test. However, overall case notification rates did not improve, and no significant impact on patient outcome (morbidity or mortality) was reported.. Sensitive molecular tests to assist diagnosis of tuberculosis may provide a faster diagnostic result when used in clinics and laboratories, but the limited impact on patient outcomes suggests additional interventions are needed to enhance TB control.

    Topics: Antibiotics, Antitubercular; Clinical Trials as Topic; Cost of Illness; Endemic Diseases; Humans; Nucleic Acid Amplification Techniques; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2015
New tuberculosis diagnostics and rollout.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2015, Volume: 32

    Early detection and effective treatment are crucial for tuberculosis control, but global case detection rates remain low. The diagnosis of paediatric and extrapulmonary disease is problematic and there are, as yet, no rapid screening tests to assist active case finding in the community. Progress has been made in clinic-based detection tools with the introduction of Xpert MTB/RIF, a nucleic acid amplification test that combines sample processing and analysis in a single instrument to provide a diagnostic result and detection of resistance to rifampicin in under 2h. Enthusiasm for Xpert MTB/RIF has been high and global rollout has been facilitated by donor agencies. However, concerns remain about access and sustainability due to the high cost and infrastructure requirements. Although more sensitive than smear microscopy, early studies suggest the impact of the new test on case detection rates and patient survival has been limited. Alternative technologies are being developed, including non-sputum-based tests to assist the detection of extrapulmonary disease. Evaluation studies are needed to provide evidence of the impact of the new technologies on patient outcomes. This will enable appropriate placement of new diagnostic products in the healthcare system to support the control and eventual eradication of tuberculosis disease.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mass Screening; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Tuberculosis

2015
Tuberculosis Drug Development: History and Evolution of the Mechanism-Based Paradigm.
    Cold Spring Harbor perspectives in medicine, 2015, Apr-15, Volume: 5, Issue:8

    Modern tuberculosis (TB) chemotherapy is widely viewed as a crowning triumph of anti-infectives research. However, only one new TB drug has entered clinical practice in the past 40 years while drug resistance threatens to further destabilize the pandemic. Here, we review a brief history of TB drug development, focusing on the evolution of mechanism(s)-of-action studies and key conceptual barriers to rational, mechanism-based drugs.

    Topics: Antitubercular Agents; Diarylquinolines; Drug Design; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Evolution, Chemical; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2015
[Tuberculosis in 2015: From diagnosis to the detection of multiresistant cases].
    Revue des maladies respiratoires, 2015, Volume: 32, Issue:8

    Incidence of pulmonary tuberculosis, a contagious infectious disease, decreases in France with 4934 reported cases in 2013. Tuberculosis remains a global health problem as smear is positive in only 50% cases and culture methods require time. In such a context, genotypic diagnostic tools such as Xpert® MTB/RIF gained interest. This rapid and simple-to-use nucleic acid amplification test allows a diagnosis in two hours and prevents further invasive investigations in pulmonary and mediastinal tuberculosis. Because of its low sensitivity, it cannot be used in pleural fluid. Indirect immunologic tests are of no use to diagnose active tuberculosis disease. Another current area of interest is the emergence of resistant tuberculosis. In France, approximately 100 cases of multidrug resistant tuberculosis and a few extensively drug resistant tuberculosis have been reported in 2014. Even though these forms of tuberculosis are imported, it is crucial to identify hazardous situations and to optimize care of these patients. Xpert® MTB/RIF is again of marked interest here as it detects rifampin resistance with a 95% sensitivity and a 98% specificity. Interpretation of genotypic tests such as Genotype® MTBDR or Xpert® MTB/RIF depends on known detected mutations, although they do not always have a clinical or phenotypic expression. In multidrug resistant tuberculosis, the new drug bedaquiline obtained approval for temporarily use in combination with other molecules when there is no other treatment option. Results of bedaquiline are encouraging but adverse events like QT prolongation or the development of new specific drug resistance should convince clinicians to use it with caution.

    Topics: Antitubercular Agents; Bacterial Proteins; Bacterial Proton-Translocating ATPases; Diarylquinolines; DNA, Bacterial; France; Genotyping Techniques; Humans; Incidence; Interferon-gamma Release Tests; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Phenotype; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Sputum; Tuberculin Test; Tuberculosis; Tuberculosis, Multidrug-Resistant

2015
Optimising plasma levels of clozapine during metabolic interactions: a review and case report with adjunct rifampicin treatment.
    BMC psychiatry, 2015, Aug-12, Volume: 15

    Clozapine is the only licensed medication for treatment-resistant schizophrenia. The metabolism of clozapine is affected by multiple pharmacokinetic interactions, so the co-administration of adjunct medications can have a significant clinical effect. The anti- tuberculosis medication rifampicin is a potent inducer of the cytochrome P450 system and therefore can cause a reduction in the plasma concentration of clozapine. There is limited clinical evidence regarding co-administration of these medications; in particular there is a lack of data regarding the effect on plasma clozapine levels, which is the key factor determining clinical efficacy. This is clinically relevant given evidence of an increased risk of tuberculosis in patients with schizophrenia.. We present a case of a 28 year old British man with a diagnosis of schizoaffective disorder who presented with persistent psychotic symptoms. He developed a systemic inflammatory condition, diagnosed as tuberculosis, and was commenced on a six month course of treatment that included rifampicin. This case presents comprehensive data to illustrate the effect on clozapine plasma levels of a complete course of tuberculosis therapy.. This case report provides guidance to clinicians in managing drug interactions between clozapine and rifampicin to enable safe and effective treatment. The co-administration of these medications is likely to increase as the existing underuse of clozapine is recognised whilst the incidence of tuberculosis increases.

    Topics: Adult; Antibiotics, Antitubercular; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Humans; Male; Psychotic Disorders; Rifampin; Treatment Outcome; Tuberculosis

2015
Pharmacologically active metabolites, combination screening and target identification-driven drug repositioning in antituberculosis drug discovery.
    Bioorganic & medicinal chemistry, 2014, Aug-15, Volume: 22, Issue:16

    There has been renewed interest in alternative strategies to address bottlenecks in antibiotic development. These include the repurposing of approved drugs for use as novel anti-infective agents, or their exploitation as leads in drug repositioning. Such approaches are especially attractive for tuberculosis (TB), a disease which remains a leading cause of morbidity and mortality globally and, increasingly, is associated with the emergence of drug-resistance. In this review article, we introduce a refinement of traditional drug repositioning and repurposing strategies involving the development of drugs that are based on the active metabolite(s) of parental compounds with demonstrated efficacy. In addition, we describe an approach to repositioning the natural product antibiotic, fusidic acid, for use against Mycobacterium tuberculosis. Finally, we consider the potential to exploit the chemical matter arising from these activities in combination screens and permeation assays which are designed to confirm mechanism of action (MoA), elucidate potential synergies in polypharmacy, and to develop rules for drug permeability in an organism that poses a special challenge to new drug development.

    Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Drug Discovery; Fusidic Acid; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis

2014
SAR analysis of new anti-TB drugs currently in pre-clinical and clinical development.
    European journal of medicinal chemistry, 2014, Oct-30, Volume: 86

    Despite enormous efforts have been made in the hunt for new drugs, tuberculosis (TB) still remains the first bacterial cause of mortality worldwide, causing an estimated 8.6 million new cases and 1.3 million deaths in 2012. Multi-drug resistant-TB strains no longer respond to first-line drugs and are inexorably spreading with an estimated 650,000 cases as well as extensively-drug resistant-TB strains, which are resistant to any fluoroquinolone and at least one of the second-line drugs, with 60,000 cases. Thus the discovery and development of new medicines is a major keystone for tuberculosis treatment and control. After decades of dormancy in the field of TB drug development, recent efforts from various groups have generated a promising TB drug pipeline. Several new therapeutic agents are concurrently studied in clinical trials together with much activity in the hittolead and lead optimization stages. In this article we will review the recent advances in TB drug discovery with a special focus on structure activity relationship studies of the most advanced compound classes.

    Topics: Animals; Antitubercular Agents; Humans; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis; Tuberculosis, Multidrug-Resistant

2014
The association between CYP2E1 polymorphisms and hepatotoxicity due to anti-tuberculosis drugs: a meta-analysis.
    Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2014, Volume: 24

    Although there have been previous studies on the potential association between cytochrome P450 2E1 (CYP2E1) polymorphisms and the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH), the results have generally been controversial.. We searched Medline/PubMed, EMBASE, Web of Science, and the Cochrane Library using the following key words: cytochrome P450 2E1, CYP2E1, polymorphism, tuberculosis and TB. The strength of the association between the CYP2E1 PstI/RsaI and DraI polymorphism and ATDH risk as measured by odds ratios (OR) with 95% confidence intervals (CIs) was studied.. Compared with the wild genotype (c1/c1), the OR of ATDH was 1.41 (95% CI: 1.1-1.82, P=0.007) for the PstI/RsaI polymorphism, and 0.78 (95% CI: 0.51-1.18, P=0.23) for the DraI polymorphism. Compared with individuals with N-acetyltransferase 2 (NAT2) fast or intermediate acetylator genotype and c1/c1 genotype patients who were NAT2 slow acetylators and carried the high activity CYP2E1 c1/c1 genotype had higher risk for ATDH (OR=3.10, P<0.0001).. The present meta-analysis indicates that the CYP2E1 c1/c1 genotype may be a risk factor for ATDH, and the concomitant presence of the slow acetylator NAT2 genotype may further increase this risk.

    Topics: Antitubercular Agents; Arylamine N-Acetyltransferase; Cytochrome P-450 CYP2E1; Gene Frequency; Genetic Predisposition to Disease; Genotype; Hepatocytes; Humans; Isoniazid; Liver Failure, Acute; Odds Ratio; Polymorphism, Genetic; Pyrazinamide; Rifampin; Tuberculosis

2014
Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a systematic review and meta-analysis.
    The European respiratory journal, 2014, Volume: 44, Issue:2

    Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is endorsed for the detection of pulmonary tuberculosis (TB). We performed a systematic review and meta-analysis to assess the accuracy of Xpert for the detection of extrapulmonary TB. We searched multiple databases to October 15, 2013. We determined the accuracy of Xpert compared with culture and a composite reference standard (CRS). We grouped data by sample type and performed meta-analyses using a bivariate random-effects model. We assessed sources of heterogeneity using meta-regression for predefined covariates. We identified 18 studies involving 4461 samples. Sample processing varied greatly among the studies. Xpert sensitivity differed substantially between sample types. In lymph node tissues or aspirates, Xpert pooled sensitivity was 83.1% (95% CI 71.4-90.7%) versus culture and 81.2% (95% CI 72.4-87.7%) versus CRS. In cerebrospinal fluid, Xpert pooled sensitivity was 80.5% (95% CI 59.0-92.2%) against culture and 62.8% (95% CI 47.7-75.8%) against CRS. In pleural fluid, pooled sensitivity was 46.4% (95% CI 26.3-67.8%) against culture and 21.4% (95% CI 8.8-33.9%) against CRS. Xpert pooled specificity was consistently >98.7% against CRS across different sample types. Based on this systematic review, the World Health Organization now recommends Xpert over conventional tests for diagnosis of TB in lymph nodes and other tissues, and as the preferred initial test for diagnosis of TB meningitis.

    Topics: Antibiotics, Antitubercular; Databases, Factual; Drug Resistance, Bacterial; HIV Infections; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Prevalence; Reference Standards; Regression Analysis; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Tuberculosis; World Health Organization

2014
Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: a systematic review and meta-analysis.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2014, Volume: 25

    Antiretroviral therapy (ART) reduces the morbidity and mortality of patients infected with HIV. Standard ART includes either nevirapine or efavirenz, however the efficacy of these drugs is limited in patients receiving rifampin treatment for tuberculosis (TB). We compared the efficacy and safety of nevirapine- and efavirenz-based ART regimens in patients co-infected with both HIV and TB through a systematic review and meta-analysis.. A comprehensive search of the literature was carried out to identify clinical trials comparing the efficacy and safety of nevirapine- and efavirenz-based ART regimens in HIV-associated TB. Eligible clinical studies included at least one primary or secondary event; the primary event was virological response and secondary events were TB treatment outcomes, mortality, and safety profile.. This meta-analysis compared five randomized clinical trials and four retrospective clinical trials. Both included patients co-infected with HIV and TB; 833 received nevirapine, while 1424 received efavirenz. The proportion of patients achieving a virological response by the end of the follow-up was higher in the efavirenz group: plasma viral load <400 copies/ml, risk ratio (RR) 1.10, 95% confidence interval (CI) 1.03-1.17 (p = 0.004); plasma viral load<50 copies/ml, RR 1.07, 95% CI 0.98-1.16 (p = 0.146). No significant differences were found in either mortality (RR 0.70, 95% CI 0.44-1.13, p = 0.142) or TB treatment outcomes (RR 1.01, 95% CI 0.96-1.06, p = 0.766). Due to adverse advents, nevirapine-based regimens significantly increased the risk of discontinuation of assigned ART (RR 0.43, 95% CI 0.23-0.81, p = 0.009).. Although efavirenz-based ART was associated with more satisfactory virological outcomes, nevirapine-based ART could be considered an acceptable alternative for patients for whom efavirenz cannot be administered.

    Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Benzoxazines; CD4 Lymphocyte Count; Clinical Trials as Topic; Coinfection; Cyclopropanes; HIV Infections; Humans; Nevirapine; Rifampin; Treatment Outcome; Tuberculosis; Viral Load

2014
From milk to rifampicin and back again: history of failures and successes in the treatment for tuberculosis.
    The Journal of antibiotics, 2014, Volume: 67, Issue:9

    The millennial flight against tuberculosis has been characterized by several defeats. Roman physicians suggested to consumptives better nutrition, sea voyages and change of air, while, during the Middle Ages, 'royal touch' were considered as an effective remedy for scrofula. In the following centuries, phthisis was cured using old herbal preparations and new chemical compounds, mainly aimed at soothing symptoms; in addition, harmful approaches (for example, bleeding and purging) were commonly accepted, according to medical theories of that time. In the second part of the nineteenth century, the discovery of the contagious nature of consumption (Villemin, Koch) addressed physicians and scientists toward often-unsuccessful remedies, such as antiparasitic treatment, immunomodulants, vaccination and serum therapy. In that period only sanatorium regimen--based on aerotherapy, bed rest, better nutrition, sunbathing and moderate physical exercise--appeared to provide first partial successes. In these structures, more invasive approaches were also employed, such as lung collapse surgical interventions (for example, phrenicotomy, thoracoplasty) and artificial pneumothorax. Since the second part of the twentieth century, the industrialization of pharmacotherapy, the development of antimicrobial chemotherapy and the introduction of new antibiotics (streptomycin, isoniazid, para-aminosalicylic acid, ethambutol and pyrazinamide) deeply revolutionized treatment for tuberculosis, allowing to achieve important successes. In this same period, the figure of Piero Sensi (1920-2013) deserves to be recalled for his contribution in the development of rifampicin that played a decisive role in the chemical fight against the white plague. Nowadays, antibiotic resistance is an emerging problem, representing a new challenge for physicians and scientists who sometimes re-proposed old 'historical' approaches.

    Topics: Animals; Antitubercular Agents; Drug Discovery; Drug Resistance, Bacterial; History, 19th Century; History, 20th Century; History, 21st Century; History, Medieval; Humans; Milk; Rifampin; Tuberculosis

2014
Trends in discovery of new drugs for tuberculosis therapy.
    The Journal of antibiotics, 2014, Volume: 67, Issue:9

    After the introduction of isoniazid and rifampicin, the second one discovered in the Lepetit Research Laboratories (Milan, Italy), under the supervision of Professor Piero Sensi, tuberculosis (TB) was considered an illness of the past. Unfortunately, this infectious disease is still a global health fear, due to the multidrug-resistant Mycobacterium tuberculosis and extensively circulating drug-resistant strains, as well as the unrecognized TB transmission, especially in regions with high HIV incidence. In the last few years, new antitubercular molecules appeared on the horizon both in preclinical and clinical stage of evaluation. In this review, we focus on a few of them and on their mechanism of action. Two new promising drug targets, DprE1 and MmpL3, are also discussed.

    Topics: Alcohol Oxidoreductases; Animals; Antitubercular Agents; Bacterial Proteins; Drug Discovery; Extensively Drug-Resistant Tuberculosis; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2014
Treating tuberculosis in solid organ transplant recipients.
    Current opinion in infectious diseases, 2014, Volume: 27, Issue:6

    To summarize recent findings in the management of active tuberculosis (TB) in solid organ transplant (SOT) recipients.. Mycobacterium tuberculosis causes substantial morbidity and mortality in SOT recipients. According to the literature, transplantation might not be an absolute contraindication for patients with active TB. Although the use of rifampin, resulting in the decreased levels of calcineurin inhibitors, might lead to rejection, studies showed that rifampin-based regimens did not appear to be associated with post-TB rejection or mortality. Nevertheless, judicious adjustment and close monitoring of immunosuppressant levels during concurrent rifampin use for patients with active TB are needed. TB-associated immune reconstitution syndrome occurred in 14% of SOT recipients; liver transplantation, cytomegalovirus infection, and rifampin use are identified risk factors for the development of immune reconstitution syndrome.. Patients with active TB might be able to undergo transplantation if indicated. Rifampin-based regimen can be considered in the treatment of TB in SOT recipients. In addition to HIV-positive patients, immune reconstitution syndrome also occurs in SOT recipients, and deserves the recognition by primary care physicians to avoid unnecessary management.

    Topics: Antitubercular Agents; Chemoprevention; Contraindications; Cytomegalovirus Infections; Graft Rejection; Humans; Immune Reconstitution Inflammatory Syndrome; Immunosuppressive Agents; Mycobacterium tuberculosis; Organ Transplantation; Rifampin; Risk Factors; Transplant Recipients; Treatment Outcome; Tuberculosis

2014
[What Hansen's disease research learned from tuberculosis research: from molecular biological aspect].
    Nihon Hansenbyo Gakkai zasshi = Japanese journal of leprosy : official organ of the Japanese Leprosy Association, 2014, Volume: 83, Issue:3

    As for the Mycobacterium leprae which is a causative agent of Hansen's disease, many studies had been done since it was identified in 1873. However, those studies, at the same time, experienced many struggles because of the difficulty of culture of M. leprae on the artificial growth media. Hence, the study of Hansen's disease progressed by taking the knowledge from the study of tuberculosis caused by the bacteria belonging to the same genus, genus Mycobacterium. For instance, the knowledge of mutations in specific genes responsible for rifampicin- and quinolone-resistance in M. tuberculosis led the elucidation of drug-resistant acquisition mechanism of M. leprae. Similarly, it is necessary for the researcher of Hansen's disease to get important information from the latest topic of the tuberculosis study and utilize them to the study of the disease.

    Topics: Antibiotics, Antitubercular; DNA Gyrase; Drug Resistance, Microbial; Humans; Leprosy; Molecular Biology; Mutation; Mycobacterium leprae; Mycobacterium tuberculosis; Quinolones; Research; Rifampin; Tuberculosis

2014
A medicinal chemists' guide to the unique difficulties of lead optimization for tuberculosis.
    Bioorganic & medicinal chemistry letters, 2013, Sep-01, Volume: 23, Issue:17

    Tuberculosis is a bacterial disease that predominantly affects the lungs and results in extensive tissue pathology. This pathology contributes to the complexity of drug development as it presents discrete microenvironments within which the bacterium resides, often under conditions where replication is limited and intrinsic drug susceptibility is low. This consolidated pathology also results in impaired vascularization that limits access of potential lead molecules to the site of infection. Translating these considerations into a target-product profile to guide lead optimization programs involves implementing unique in vitro and in vivo assays to maximize the likelihood of developing clinically meaningful candidates.

    Topics: Animals; Antitubercular Agents; Drug Discovery; Humans; Lung; Mycobacterium tuberculosis; Tuberculosis

2013
[Tuberculosis: new treatment options and updated recommendations].
    Deutsche medizinische Wochenschrift (1946), 2013, Volume: 138, Issue:14

    Topics: Antitubercular Agents; Aza Compounds; Cross-Sectional Studies; Diagnosis, Differential; Diarylquinolines; Fluoroquinolones; Germany; Humans; Moxifloxacin; Nitroimidazoles; Oxazoles; Prognosis; Quinolines; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2013
[Pseudotumor form of primary nasopharyngeal tuberculosis: apropos of 2 new cases and review of the literature].
    The Pan African medical journal, 2013, Volume: 14

    Topics: Antitubercular Agents; Biopsy; Diagnosis, Differential; Drug Therapy, Combination; Humans; Isoniazid; Male; Middle Aged; Nasal Obstruction; Nasopharyngeal Diseases; Nasopharyngeal Neoplasms; Pyrazinamide; Rifampin; Smoking; Tuberculosis; Tuberculosis, Lymph Node; Young Adult

2013
Rapid diagnosis of Mycobacterium tuberculosis infection and drug susceptibility testing.
    Archives of pathology & laboratory medicine, 2013, Volume: 137, Issue:6

    The global control of tuberculosis remains a challenge from the standpoint of diagnosis, detection of drug resistance, and treatment. This is an area of special concern to the health of women and children, particularly in regions of the world with high infant mortality rates and where women have limited access to health care.. Because treatment can only be initiated when infection is detected, and is guided by the results of antimicrobial susceptibility testing, there recently has been a marked increase in the development and testing of novel assays designed to detect Mycobacterium tuberculosis complex, with or without simultaneous detection of resistance to isoniazid and/or rifampin. Both nonmolecular and molecular assays have been developed. This review will summarize the current knowledge about the use of rapid tests to detect M tuberculosis and drug resistance.. Review of the most recent World Health Organization Global Tuberculosis Report, as well as selected publications in the primary research literature, meta-analyses, and review articles.. To a large extent, nonmolecular methods are refinements or modifications of conventional methods, with the primary goal of providing more rapid test results. In contrast, molecular methods use novel technologies to detect the presence of M tuberculosis complex and genes conferring drug resistance. Evaluations of molecular assays have generally shown that these assays are of variable sensitivity for detecting the presence of M tuberculosis complex, and in particular are insensitive when used with smear-negative specimens. As a group, molecular assays have been shown to be of high sensitivity for detecting resistance to rifampin, but of variable sensitivity for detecting resistance to isoniazid.

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Child; Child, Preschool; Coinfection; Comorbidity; DNA, Bacterial; Drug Resistance, Bacterial; Female; Global Health; HIV; Humans; Infant; Isoniazid; Meta-Analysis as Topic; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis; Women's Health

2013
Treatment of latent tuberculosis infection.
    Therapeutic advances in respiratory disease, 2013, Volume: 7, Issue:6

    Treatment of latent tuberculosis (TB) infection is an important component of TB control programs in both high- and low-prevalence countries. Clinical trials of treatment of latent TB conducted over several decades have demonstrated that preventive treatment can reduce the risk of developing active TB up to 90%. Although 9 months of daily, self-administered isoniazid has been the most widely used and recommended regimen for the treatment of latent infection, other regimens such as 3 months of daily isoniazid and rifampin, or 4 months of daily rifampin alone have also been recommended and used. Most recently, a 12-dose regimen of once-weekly isoniazid and rifapentine has been shown to be noninferior to 9 months of daily isoniazid in a large and well conducted clinical trial. Adoption of such a regimen on a large scale could have significant implications for TB elimination efforts.

    Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Time Factors; Tuberculosis

2013
Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis.
    The Lancet. Infectious diseases, 2013, Volume: 13, Issue:3

    The effects of corticosteroids are systemic, but their benefits in tuberculosis are thought to be organ specific, with clinicians using them routinely to treat some forms of tuberculosis (such as meningitis), but not others. We aimed to assess the effects of steroids on mortality attributable to all forms of tuberculosis across organ systems.. We did a systematic review and meta-analysis to estimate the efficacy of steroids for the prevention of mortality in all forms of tuberculosis, and to quantify heterogeneity in this outcome between affected organ systems. We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Central Register of Controlled Trials, Medline, Embase, and Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) for studies published up to Sept 6, 2012, and checked reference lists of included studies and relevant reviews. We included all trials in people with tuberculosis in any organ system, with tuberculosis defined clinically or microbiologically. There were no restrictions by age, comorbidity, publication language, or type, dose, or duration of steroid treatment. We used the Mantel-Haenszel method to summarise mortality across trials.. We identified 41 eligible trials, 18 of which assessed pulmonary tuberculosis. 20 of the 41 trials (including 13 of those for pulmonary tuberculosis) were done before the introduction of modern rifampicin-containing antituberculosis chemotherapy. Meta-analysis stratified by affected organ systems identified no heterogeneity; steroids reduced mortality by 17% (risk ratio [RR] 0·83, 95% CI 0·74-0·92; I(2) 0%), consistent across all organ groups. In a sensitivity analysis that only included trials that used rifampicin-containing regimens, the results were similar (RR 0·85, 95% CI 0·74-0·98; I(2) 21%). A sensitivity analysis in pulmonary tuberculosis that excluded trials with high potential risks of bias suggested a slight benefit, but the point estimate was closer to no effect and the difference was not significant (RR 0·93, 95% CI 0·60-1·44).. Steroids could be effective in reducing mortality for all forms of tuberculosis, including pulmonary tuberculosis. However, further evidence is needed since few recent trials have assessed the effectiveness of corticosteroids in patients with pulmonary tuberculosis.. UK Department for International Development.

    Topics: Adrenal Cortex Hormones; Antitubercular Agents; Humans; Rifampin; Tuberculosis

2013
Tuberculosis: the drug development pipeline at a glance.
    European journal of medicinal chemistry, 2012, Volume: 51

    Tuberculosis is a major disease causing every year 1.8 million deaths worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60's of first-line drug regimen resulted in the control of the disease and TB was perceived as defeating. However, since the progression of HIV leading to co-infection with AIDS and the emergence of drug resistant strains, the need of new anti-tuberculosis drugs was not overstated. However in the past 40 years any new molecule did succeed in reaching the market. Today, the pipeline of potential new treatments has been fulfilled with several compounds in clinical trials or preclinical development with promising activities against sensitive and resistant Mycobacterium tuberculosis strains. Compounds as gatifloxacin, moxifloxacin, metronidazole or linezolid already used against other bacterial infections are currently evaluated in clinical phases 2 or 3 for treating tuberculosis. In addition, analogues of known TB drugs (PA-824, OPC-67683, PNU-100480, AZD5847, SQ609, SQ109, DC-159a) and new chemical entities (TMC207, BTZ043, DNB1, BDM31343) are under development. In this review, we report the chemical synthesis, mode of action when known, in vitro and in vivo activities and clinical data of all current small molecules targeting tuberculosis.

    Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Drug Discovery; Humans; Tuberculosis

2012
A model of tuberculosis screening for pregnant women in resource-limited settings using Xpert MTB/RIF.
    Journal of pregnancy, 2012, Volume: 2012

    Timely diagnosis and treatment of maternal tuberculosis (TB) is important to reduce morbidity and mortality for both the mother and child, particularly in women who are coinfected with HIV. The World Health Organization (WHO) recommends the integration of TB/HIV screening into antenatal services but available diagnostic tools are slow and insensitive, resulting in delays in treatment initiation. Recently the WHO endorsed Xpert MTB/RIF, a highly sensitive, real-time PCR assay for Mycobacterium tuberculosis that simultaneously detects rifampicin resistance directly from sputum and provides results within 100 minutes. We propose a model for same-day TB screening and diagnosis of all pregnant women at antenatal care using Xpert MTB/RIF. Pilot studies are urgently required to evaluate strategies for the integration of TB screening into antenatal clinics using new diagnostic technologies.

    Topics: Antibiotics, Antitubercular; Decision Support Techniques; Developing Countries; DNA, Bacterial; Drug Resistance, Bacterial; Female; Humans; Mass Screening; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pregnancy; Pregnancy Complications, Infectious; Prenatal Care; Reagent Kits, Diagnostic; Real-Time Polymerase Chain Reaction; Rifampin; Tuberculosis

2012
[Not just a success story. On the history of tuberculosis treatment].
    Pharmazie in unserer Zeit, 2012, Volume: 41, Issue:1

    Topics: Antitubercular Agents; Ethambutol; History, 17th Century; History, 18th Century; History, 19th Century; History, 20th Century; History, Medieval; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Streptomycin; Tuberculin; Tuberculosis

2012
An updated systematic review and meta-analysis on the treatment of active tuberculosis in patients with HIV infection.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2012, Volume: 55, Issue:8

    Human immunodeficiency virus (HIV) infection increases the risk of poor outcomes in active tuberculosis. We updated a systematic review and meta-analysis assessing the effects of duration of rifamycins, schedule of dosing, and antiretroviral therapy (ART) on failure, relapse, death during treatment, and acquired drug resistance (ADR) in patients with HIV and active tuberculosis.. We searched for randomized control trials (RCTs) and observational studies published between January 2008 and November 2011. We pooled risk differences (RD) from RCTs comparing rifampin for ≥9 months and 6 months. Within strata of the 3 treatment covariates, we calculated pooled risks and adjusted odds ratios (aORs) using outcomes from RCTs and observational studies.. After screening 2293 citations, 7 studies were added in the update. Risk of relapse was lowered with rifampin treatment for ≥9 months compared with 6 months (pooled RD = -9.1%; 95% CI, -16.5, -1.8). Odds of relapse were higher with shorter durations of rifamycins (aOR 2 vs ≥8 months = 5.0 [1.9, 13.2]; 6 vs ≥8 months = 2.4 [1.2, 5.0]) and in the absence of ART (aOR = 14.3, [2.1, 97.8]). Post hoc meta-regression restricted to arms with ART demonstrated no associations between rifamycin duration, dosing schedule, and outcomes.. In patients with HIV and active tuberculosis, ART reduces the risk of TB relapse. Use of rifamycins for ≥8 months and daily dosing in the intensive phase also improve TB treatment outcomes; however, a paucity of evidence makes their importance less clear for patients on ART. There is an urgent need to increase the number of coinfected patients receiving ART.

    Topics: Anti-Retroviral Agents; Antibiotics, Antitubercular; Coinfection; HIV Infections; Humans; Rifampin; Tuberculosis

2012
[Diagnostic value of Xpert MTB/RIF assay for tuberculosis].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2012, Volume: 35, Issue:5

    Topics: Humans; Polymerase Chain Reaction; Rifampin; Tuberculosis

2012
Contacts of infectious tuberculosis patients: monitor those at highest risk of developing tuberculosis.
    Prescrire international, 2012, Volume: 21, Issue:132

    It is essential to identify and treat contacts of tuberculosis patients with active disease. Persons exposed through close, prolonged or frequent contact may develop tuberculosis, usually within two years following exposure. What is the harm-benefit balance of tuberculosis prophylaxis in contacts at risk? To answer this question, we conducted a review of the literature, using the standard Prescrire methodology. Standard prophylaxis for pulmonary tuberculosis consists of isoniazid monotherapy for 6 to 12 months.This regimen has been tested in randomised placebo-controlled trials involving tens of thousands of persons with a positive tuberculin skin test (TST). Pulmonary tuberculosis occurred in 0.6% of patients in the isoniazid groups versus 1.7% in the placebo groups, after a follow-up of at least 2 years. However, isoniazid can cause severe hepatic disorders and numerous drug interactions. Rifampicin monotherapy was shown to be effective in only one placebo-controlled trial in patients with silicosis, who have a very high risk of developing tuberculosis. Rifampicin also carries a high risk of drug interactions but is less hepatotoxic than isoniazid. A 3-month course of the isoniazid+ rifampicin combination had a similar harm-benefit balance as a 6- or 9-month course of isoniazid monotherapy. The rifampicin + pyrazinamide combination is no more effective than isoniazid monotherapy but has more hepatic adverse effects. British guidelines issued in 2011 recommend treatment for contacts who have signs of latent tuberculosis infection, based mainly on a positive TST or gamma interferon release assay, and are at high risk of developing active tuberculosis. patients aged at least 2 years who are strongly suspected of having latent tuberculosis infection: either tuberculosis treatment, or chest radiography 3 and 12 months after initial diagnosis. In practice, contacts of infectious patients have a low risk of developing clinical tuberculosis.Treatment reduces the risk of tuberculosis but exposes a large number of persons to numerous, sometimes serious, adverse effects. Watchful waiting for 2 years, without treatment, is often the best option.

    Topics: Drug Interactions; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Risk Factors; Tuberculosis

2012
Treatment of tuberculosis and optimal dosing schedules.
    Thorax, 2011, Volume: 66, Issue:11

    Intermittent tuberculosis treatment regimens have been developed to facilitate treatment supervision. Their efficacy has been substantiated by clinical trials and tuberculosis control programmes, notwithstanding the lack of head-to-head comparison between daily and intermittent regimens. Recently, there has been opposing evidence from observational studies, pharmacokinetic-pharmacodynamic studies and animal models that intermittent treatment increases the risk of relapse, treatment failure or acquired rifamycin resistance, especially among HIV-infected patients. Systematic reviews have been conflicting. PubMed, Ovid MEDLINE and EMBASE were systematically searched for publications in English to evaluate the evidence about dosing schedules and treatment efficacy. Levels of evidence and grades of recommendation were assigned largely according to clinical evidence with reference to the Scottish Intercollegiate Guidelines Network guideline development handbook. A total of 32 articles were included after excluding 331 ineligible articles, 42 non-analytical studies, 22 narrative reviews or expert opinions and 44 articles embedded in systematic reviews. These included 9 systematic reviews, 8 controlled studies, 9 pharmacokinetic-pharmacodynamic studies, 5 mouse studies and 1 article about guinea pig experiments. Findings suggest high levels of evidence for using daily dosing schedules, especially during the initial phase in the presence of cavitation, isoniazid resistance and advanced HIV co-infection, to reduce the risk of treatment failure, recurrence and acquired drug resistance including acquired rifamycin resistance. This review justifies the use of daily schedules in standard tuberculosis treatment regimens (particularly in the initial phase), corroborates prevailing understanding of pharmacokinetics-pharmacodynamics and mycobacterial persisters, and supports exploration of rifapentine-containing regimens in higher dosages and frequency.

    Topics: AIDS-Related Opportunistic Infections; Animals; Antitubercular Agents; Child; Disease Models, Animal; Drug Administration Schedule; Humans; Isoniazid; Rifampin; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2011
New drugs for tuberculosis treatment.
    Enfermedades infecciosas y microbiologia clinica, 2011, Volume: 29 Suppl 1

    Available data on anti-tuberculosis drug research reveal different properties of the agents and provoke speculation about future directions. Higher doses of the rifamycins are promising and are currently being evaluated in regimens of shorter duration that the isoniazid plus rifampin-based, six-to-nine month-course therapy. Moxifloxacin and gatifloxacin might shorten tuberculosis treatment as well, possibly in combination with rifapentine, while SQ109 could enhance the activity of rifampin-containing regimens. On the other hand, co-administration of moxifloxacin and PA-824 could be active against latent tuberculosis, whereas linezolid, PA-824 and TMC207 are candidates for a rifampin-free regimen in multidrug-resistant and extensively-resistant tuberculosis. Unfortunately, shorter than existent treatment regimens based on the new agents discussed here are likely to take at least another decade to be fully developed and implemented in clinical practice.

    Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Therapy, Combination; Forecasting; Guinea Pigs; Humans; Mice; Primates; Rabbits; Rifampin; Tuberculosis

2011
Why Do We Use 600 mg of Rifampicin in Tuberculosis Treatment?
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2011, Volume: 52, Issue:9

    The 600-mg once daily dose of rifampicin plays a key role in tuberculosis treatment. The evidence underpinning this dose is scant. A review of the historical literature identified 3 strands of reasoning. The first is the pharmacokinetic argument: The 600-mg dose yields serum drug concentrations well above the minimum inhibitory concentration of rifampicin against Mycobacterium tuberculosis. The second is the argument that adverse events may be dose related. The third is the economic argument: Rifampicin was prohibitively expensive at the time of its introduction. Recent in vitro, animal, and early bactericidal activity studies suggest that the 600-mg once daily dose is at the lower end of the dose-response curve, refuting the pharmacokinetic argument. The reduced cost and the lack of evidence of toxicity at higher daily doses remove the other arguments. To optimize tuberculosis treatment, the clinical value of higher doses of rifampicin should be tested in clinical trials.

    Topics: Antitubercular Agents; Drug Administration Schedule; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2011
Clinical practice. Latent tuberculosis infection in the United States.
    The New England journal of medicine, 2011, Apr-14, Volume: 364, Issue:15

    Topics: Adult; Antigens, Bacterial; Antitubercular Agents; Drug Therapy, Combination; Female; Global Health; Humans; Interferon-gamma; Isoniazid; Mycobacterium tuberculosis; Practice Guidelines as Topic; Rifampin; Tuberculosis; Virus Latency

2011
Recent advances in the laboratory detection of Mycobacterium tuberculosis complex and drug resistance.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2011, Volume: 52, Issue:11

    The global control of tuberculosis remains a challenge from the standpoint of diagnosis, detection of drug resistance, and treatment. Because treatment can only be initiated when infection is detected and is based on the results of antimicrobial susceptibility testing, there recently has been a marked increase in the development and testing of novel assays designed to detect Mycobacterium tuberculosis complex, with or without simultaneous detection of resistance to isoniazid and/or rifampin. Both nonmolecular and molecular assays have been developed. To a large extent, the nonmolecular methods are refinements or modifications of conventional methods, with the primary goal of providing more-rapid test results. Evaluations of molecular assays have generally shown that these assays have variable sensitivity for detecting the presence of M. tuberculosis complex and, in particular, are insensitive when used with smear-negative specimens; high sensitivity for detecting resistance to rifampin; and variable sensitivity for detecting resistance to isoniazid.

    Topics: Antitubercular Agents; Bacteriological Techniques; Drug Resistance, Bacterial; Humans; Isoniazid; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2011
Xpert® MTB/RIF assay: development, evaluation and implementation of a new rapid molecular diagnostic for tuberculosis and rifampicin resistance.
    Future microbiology, 2011, Volume: 6, Issue:9

    Global TB control efforts have been severely hampered by the lack of diagnostic tests that are accurate, simple to use and can be applied at the point of clinical care. This has been further compounded by the widespread inability to test for drug resistance. The Xpert(®) MTB/RIF assay is a rapid molecular assay that can be used close to the point of care by operators with minimal technical expertise, enabling diagnosis of TB and simultaneous assessment of rifampicin resistance to be completed within 2 h. Moreover, this can be accomplished using unprocessed sputum samples as well as clinical specimens from extrapulmonary sites. We review in detail the development of this assay, its evaluation within the laboratory, its utility among adult and pediatric TB suspects, its use as a screening tool for HIV-associated TB and studies of its implementation at the district and sub-district levels in resource-limited settings. Following endorsement by the WHO in 2010, we consider the next steps in the implementation of the assay and its potential impact in high burden settings.

    Topics: Clinical Trials as Topic; Diagnostic Test Approval; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Rifampin; Sensitivity and Specificity; Tuberculosis

2011
Intermittent or daily short course chemotherapy for tuberculosis in children: meta-analysis of randomized controlled trials.
    Indian pediatrics, 2010, Volume: 47, Issue:1

    To compare the effectiveness of intermittent with daily chemotherapy (both containing rifampicin) in childhood tuberculosis (age 16yrs) in achieving cure significant improvement.. Systematic Review and Meta-analysis.. MEDLINE and the Cochrane Library were searched for randomized trials of antitubercular regimens containing rifampicin, in children 16 yrs or less with tuberculosis. Two reviewers independently assessed trial eligibility and quality. Data from full articles of selected studies were independently extracted by two authors and analyzed. The odds ratio was obtained for the pooled data in two groups (intermittent and daily therapy).. Cure/significant improvement, relapse rate and adverse events.. Four randomized controlled trials comparing twice weekly and daily therapy including 466 children (pulmonary 439; extrapulmonary 27) met the inclusion criteria. Baseline data were comparable. On quality assessment, 3 studies scored 2 and one study scored 3 out of 5 points. Per protocol analysis showed that children receiving intermittent regimen were less likely to be cured than those receiving daily therapy (OR 0.27; 95% CI: 0.14, 0.51). The results of intention to treat analysis suggest similar trend towards lower cure rates with twice weekly regimen (OR 0.66; 95% CI: 0.23-1.84).. Twice weekly intermittent short course therapy is less likely to cure tuberculosis in children as compared to daily therapy. There is a need for better quality randomized controlled trials for assessing efficacy of alternate schedule for intermittent therapy for childhood tuberculosis.

    Topics: Antibiotics, Antitubercular; Child; Drug Administration Schedule; Humans; Randomized Controlled Trials as Topic; Rifampin; Treatment Outcome; Tuberculosis

2010
Dose adjustment of the non-nucleoside reverse transcriptase inhibitors during concurrent rifampicin-containing tuberculosis therapy: one size does not fit all.
    Expert opinion on drug metabolism & toxicology, 2010, Volume: 6, Issue:1

    HIV/tuberculosis (TB) co-infection is common and associated with high mortality. Simultaneous highly active antiretroviral therapy during TB treatment is associated with substantial survival benefit but drug-drug interactions complicate NNRTI dosing.. We reviewed the impact of rifampicin-containing TB therapy on the NNRTIs pharmacokinetics and clinical outcome. PubMed database was searched from 1966 to July 2009 using the terms efavirenz, rifampicin, nevirapine, pharmacokinetics, pharmacogenetics, HIV, TB, CYP2B6, CYP3A4 and metabolism. References from identified articles and abstracts from meetings were also reviewed.. A comprehensive review of the literature on this subject including pharmacokinetic and clinical studies. Most studies were small, observational or underpowered to detect the true effect of rifampicin on NNRTI-based therapy. None of the studies were controlled for genetic factors and there were limited data on children.. There were insufficient data to make definitive recommendations about dose adjustment of the NNRTIs during rifampin-containing therapy. Current data suggest that the standard dose of efavirenz or nevirapine is adequate in most HIV/TB co-infected adults. However, more research is needed in pediatric populations as well as to define role of drug-gene interactions.

    Topics: Adult; Alkynes; Antitubercular Agents; Benzoxazines; Child; Cyclopropanes; Drug Interactions; HIV Infections; Humans; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

2010
Update in tuberculosis 2009.
    American journal of respiratory and critical care medicine, 2010, Mar-15, Volume: 181, Issue:6

    Topics: Acetamides; Animals; Antitubercular Agents; Aza Compounds; Diarylquinolines; Fluoroquinolones; Humans; Linezolid; Mice; Moxifloxacin; Oxazolidinones; Quinolines; Rifampin; Tuberculosis; Tuberculosis Vaccines; Vitamin D; Vitamins

2010
Treatment of active tuberculosis in HIV-coinfected patients: a systematic review and meta-analysis.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2010, May-01, Volume: 50, Issue:9

    Patients with human immunodeficiency virus (HIV) infection and tuberculosis have an increased risk of death, treatment failure, and relapse.. A systematic review and meta-analysis of randomized, controlled trials and cohort studies was conducted to evaluate the impact of duration and dosing schedule of rifamycin and use of antiretroviral therapy in the treatment of active tuberculosis in HIV-positive patients. In included studies, the initial tuberculosis diagnosis, failure, and/or relapse were microbiologically confirmed, and patients received standardized rifampin- or rifabutin-containing regimens. Pooled cumulative incidence of treatment failure, death during treatment, and relapse were calculated using random-effects models. Multivariable meta-regression was performed using negative binomial regression.. After screening 5158 citations, 6 randomized trials and 21 cohort studies were included. Relapse was more common with regimens using 2 months rifamycin (adjusted risk ratio, 3.6; 95% confidence interval, 1.1-11.7) than with regimens using rifamycin for at least 8 months. Compared with daily therapy in the initial phase (n=3352 patients from 35 study arms), thrice-weekly therapy (n=211 patients from 5 study arms) was associated with higher rates of failure (adjusted risk ratio, 4.0; 95% confidence interval, 1.5-10.4) and relapse [adjusted risk ratio, 4.8; 95% confidence interval, 1.8-12.8). There were trends toward higher relapse rates if rifamycins were used for only 6 months, compared with > or =8 months, or if antiretroviral therapy was not used.. This review raises serious concerns regarding current recommendations for treatment of HIV-tuberculosis coinfection. The data suggest that at least 8 months duration of rifamycin therapy, initial daily dosing, and concurrent antiretroviral therapy might be associated with better outcomes, but adequately powered randomized trials are urgently needed to confirm this.

    Topics: Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Cohort Studies; HIV Infections; Humans; Incidence; Randomized Controlled Trials as Topic; Recurrence; Rifampin; Treatment Failure; Tuberculosis

2010
Pediatric intracranial subdural empyema caused by Mycobacterium tuberculosis--a case report and review of literature.
    Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 2010, Volume: 26, Issue:8

    Intracranial subdural tubercular empyema is an extremely rare entity. To our knowledge, only one such case has been previously reported in the pediatric population (Cayli et al. J Neurosurg 94(6):988-991, 2001). We report a case of intracranial tubercular subdural empyema in a child, with both convexity and interhemispheric fissure involvement.. A 12-year-old boy with history of exposure to an active case of pulmonary tuberculosis (his father) presented to our institution with features of raised intracranial pressure and fever for 1 month and altered sensorium for 2 days. Computerized tomography (contrast enhanced) revealed a left fronto-parietal and interhemispheric subdural space abscess. A left fronto-parietal craniotomy was performed and the subdural empyema was evacuated, and adjacent calvarium was normal. Ziehl-Neelsen staining revealed acid-fast bacilli and the subsequent polymerase chain reaction test was positive. Histopathological examination showed granulation tissue including scattered multinucleated giant cells and caseation. Mycobacterium tuberculosis bacilli were the sole organisms cultured after 6 weeks. Anti-tuberculous treatment was given in appropriate doses for 18 months at the end of which the patient was doing well with no deficits.. Intracranial tubercular subdural empyema in the pediatric age group is an extremely rare but curable entity.

    Topics: Adolescent; Antibiotics, Antitubercular; Craniotomy; Dura Mater; Empyema, Subdural; Humans; Isoniazid; Male; Pyrazinamide; Pyridoxine; Rifampin; Tuberculosis

2010
PCR-single-strand conformational polymorphism method for rapid detection of rifampin-resistant Mycobacterium tuberculosis: systematic review and meta-analysis.
    Journal of clinical microbiology, 2010, Volume: 48, Issue:10

    The reference standard methods for drug susceptibility testing of Mycobacterium tuberculosis, such as culture on Lowenstein-Jensen or Middlebrook 7H10/11 medium, are very slow to give results; and due to the emergence of multidrug-resistant M. tuberculosis and extensively drug-resistant M. tuberculosis, there is an urgent demand for new, rapid, and accurate drug susceptibility testing methods. PCR-single-strand conformational polymorphism (PCR-SSCP) analysis has been proposed as a rapid method for the detection of resistance to rifampin, but its accuracy has not been systematically evaluated. We performed a systematic review and meta-analysis to evaluate the accuracy of PCR-SSCP analysis for the detection of rifampin-resistant tuberculosis. We searched the Medline, Embase, Web of Science, BIOSIS, and LILACS databases and contacted authors if additional information was required. Ten studies met our inclusion criteria for rifampin resistance detection. We applied the summary receiver operating characteristic (SROC) curve to perform the meta-analysis and to summarize diagnostic accuracy. The sensitivity of PCR-SSCP analysis for the rapid detection of rifampin-resistant tuberculosis was 0.79 (95% confidence interval [CI], 0.75 to 0.82), the specificity was 0.96 (95% CI, 0.94 to 0.98), the positive likelihood ratio was 16.10 (95% CI, 5.87 to 44.13), the negative likelihood ratio was 0.20 (95% CI, 0.10 to 0.40), and the diagnostic odds ratio was 100.93 (95% CI, 31.95 to 318.83). PCR-SSCP analysis is a sensitive and specific test for the rapid detection of rifampin-resistant M. tuberculosis. Additional studies in countries with a high prevalence of multidrug-resistant M. tuberculosis and also cost-effectiveness analysis are required in order to obtain a complete picture on the utility of this method for rapid drug resistance detection in M. tuberculosis.

    Topics: Antitubercular Agents; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Rifampin; Sensitivity and Specificity; Time Factors; Tuberculosis

2010
New drugs against tuberculosis: problems, progress, and evaluation of agents in clinical development.
    Antimicrobial agents and chemotherapy, 2009, Volume: 53, Issue:3

    Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Mycobacterium tuberculosis; Rifamycins; Tuberculosis

2009
Pacemaker wire infection with Mycobacterium tuberculosis: a case report and literature review.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2009, Volume: 13, Issue:2

    Post-operative reactivation of Mycobacterium tuberculosis (TB) is a recognized complication of surgery. We report a case of reactivation TB involving pacemaker wires and review the literature on surgical site TB infections following cardiac surgery to examine the clinical features and outcomes of this rare but important presentation of TB.

    Topics: Aged, 80 and over; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Mycobacterium tuberculosis; Pacemaker, Artificial; Recurrence; Rifampin; Surgical Wound Infection; Tomography, X-Ray Computed; Tuberculosis

2009
Tuberculosis (HIV-negative people).
    BMJ clinical evidence, 2009, Apr-14, Volume: 2009

    About a third of the world's population has latent tuberculosis. In 2004, over 14 million people had active tuberculosis. Approximately 1.7 million people died from the infection. Over 80% of new cases diagnosed in 2004 were in people in Africa, South-East Asia, and Western Pacific regions.. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing tuberculosis? What are the effects of interventions to prevent tuberculosis in people without HIV infection at high risk of developing multidrug-resistant tuberculosis? What are the effects of different drug regimens in people with newly diagnosed pulmonary tuberculosis without HIV infection? What are the effects of different drug regimens in people with multidrug-resistant tuberculosis without HIV infection? What are the effects of low-level laser therapy in people with tuberculosis without HIV infection? Which interventions improve adherence to treatment in people with tuberculosis without HIV infection? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).. We found 31 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.. In this systematic review we present information relating to the effectiveness and safety of the following interventions: adding pyrazinamide in chemotherapy regimens lasting up to 6 months; adding rifampicin to isoniazid regimens; benefits of different regimens; chemotherapy for less than 6 months; daily chemotherapy; direct observation treatment; intermittent chemotherapy for 6 months or longer; isoniazid; low-level laser therapy for pulmonary tuberculosis; regimens containing quinolones; rifampicin plus isoniazid; substituting rifampicin with ethambutol in the continuous phase; and support mechanisms for directly observed treatment.

    Topics: Antitubercular Agents; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Low-Level Light Therapy; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2009
4 months of rifampin compared with 9 months of isoniazid for the management of latent tuberculosis infection: a meta-analysis and cost-effectiveness study that focuses on compliance and liver toxicity.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2009, Dec-15, Volume: 49, Issue:12

    One-third of the world's population is infected with tuberculosis, and 9 months of isoniazid monotherapy is the treatment of choice for latent tuberculosis infection. However, this approach has been associated with hepatotoxicity and poor compliance. A shorter (4-month) rifampin regimen has been evaluated in recent clinical trials.. We performed a meta-analysis of the published studies to compare compliance, toxicity, and cost-effectiveness between the 2 strategies. Pooled effects were calculated as risk ratios (RRs) by means of random-effects and fixed-effects models.. Pooled data from 3586 patients suggested that 4-month rifampin therapy was associated with a significant reduction in the risk of noncompletion (RR for random-effects model, 0.53; 95% confidence interval [CI], 0.44-0.63). Noncompletion rates were lower among patients who received 4-month rifampin therapy (range, 8.6%-28.4%), compared with noncompletion rates among patients who received 9-month isoniazid therapy (range, 24.1%-47.4%). Also, rates of hepatotoxicity (defined as grade 3 or 4 liver failure leading to drug discontinuation) were lower for patients who received 4-month rifampin therapy (range, 0%-0.7%), compared with the corresponding rates for patients who received 9-month isoniazid therapy (range, 1.4%-5.2%), and rifampin was associated with significant reduction in the risk of hepatotoxicity (RR for fixed-effects model, 0.12; 95% CI, 0.05-0.30). Notably, with the data from our meta-analysis, we calculated that the 4-month rifampin strategy is also cost-effective and results in $213 savings per patient treated ($90/patient when doctor fees are not included).. The improved compliance, safety, and cost associated with the 4-month rifampin therapy suggest that the efficacy of this approach needs to be evaluated in detail. An extended posttreatment follow-up in future studies will clarify the unresolved issue of tuberculosis reactivation rates.

    Topics: Antitubercular Agents; Cost-Benefit Analysis; Health Care Costs; Humans; Isoniazid; Liver; Medication Adherence; Rifampin; Tuberculosis

2009
Effectiveness and safety of antiretrovirals with rifampicin: crucial issues for high-burden countries.
    Antiviral therapy, 2009, Volume: 14, Issue:8

    Coadministration of antitubercular and antiretroviral therapy is common in high-burden countries where tuberculosis is the commonest opportunistic infection. Concomitant use of rifampicin and many antiretroviral drugs is complicated by drug-drug interactions caused by the potent induction by rifampicin of genes involved in drug metabolism and transport, which could result in subtherapeutic antiretroviral drug concentrations. This review focuses on drug-drug interactions involving antiretrovirals used in resource-limited settings: the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz or nevirapine, and ritonavir-boosted protease inhibitors. The reduction of nevirapine concentrations with concomitant rifampicin is greater than with efavirenz, particularly during the lead-in dose period when subtherapeutic concentrations occur in the majority of patients. There is reassuring data on the effectiveness of standard doses of efavirenz with concomitant rifampicin, but the largest cohort study found a higher risk of virological failure with nevirapine. The drug-drug interaction between rifampicin and ritonavir-boosted protease inhibitors is more marked than with the NNRTIs, and therapeutic concentrations have only been achieved with adjusted doses of lopinavir/ritonavir or with saquinavir/ritonavir (400/400 mg every 12 h). The major barrier to using adjusted dose protease inhibitors with rifampicin is the high rates of hepatotoxicity seen in healthy volunteers. The alternative strategy followed in resource-rich settings is to replace rifampicin with rifabutin, but even if the price of rifabutin were to be dramatically reduced it would be difficult to implement in high-burden countries where standardized antitubercular regimens with fixed-dose combinations are used.

    Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Rifampin; Treatment Outcome; Tuberculosis

2009
New approaches to the treatment of latent tuberculosis.
    Seminars in respiratory and critical care medicine, 2008, Volume: 29, Issue:5

    It is estimated that one third of the global population is infected with MYCOBACTERIUM TUBERCULOSIS. Treatment of M. TUBERCULOSIS infection is an important strategy for tuberculosis elimination, but the effectiveness of this strategy is limited by poor adherence to therapy, which is due at least in part to the long duration of treatment. A 9-month course of isoniazid is the currently preferred treatment regimen for M. TUBERCULOSIS infection, due to the extensive data regarding the effectiveness and tolerability of isoniazid, and limited data on the effectiveness and tolerability of alternative shorter-course regimens. This review covers all currently available regimens, including less established alternative treatment regimens (e.g., rifampin for 4 months and isoniazid + rifampin for 3 months), as well as regimens that are currently under investigation (e.g., isoniazid + rifapentine for 3 months). Potential future regimens and experimental approaches are also discussed.

    Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Mycobacterium tuberculosis; Patient Compliance; Rifampin; Treatment Outcome; Tuberculosis

2008
Antituberculosis drug-induced hepatotoxicity: concise up-to-date review.
    Journal of gastroenterology and hepatology, 2008, Volume: 23, Issue:2

    The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug-induced hepatotoxicity, discuss the metabolism and mechanisms of toxicity of isoniazid, rifampicin and pyrazinamide, and describe risk factors and management of antituberculosis drug-induced hepatotoxicity. The reported incidence of antituberculosis drug-induced hepatotoxicity, the most serious and potentially fatal adverse reaction, varies between 2% and 28%. Risk factors are advanced age, female sex, slow acetylator status, malnutrition, HIV and pre-existent liver disease. Still, it is difficult to predict what patient will develop hepatotoxicity during tuberculosis treatment. The exact mechanism of antituberculosis drug-induced hepatotoxicity is unknown, but toxic metabolites are suggested to play a crucial role in the development, at least in the case of isoniazid. Priorities for future studies include basic studies to elucidate the mechanism of antituberculosis drug-induced hepatotoxicity, genetic risk factor studies and the development of shorter and safer tuberculosis drug regimens.

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Incidence; Isoniazid; Liver Diseases; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis

2008
The nitrate reductase assay for the rapid detection of isoniazid and rifampicin resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis.
    The Journal of antimicrobial chemotherapy, 2008, Volume: 62, Issue:1

    The reference standard methods for drug susceptibility testing (DST) of M. tuberculosis are very slow to give results, and due to the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis, there is an urgent demand for new, rapid and accurate DST methods, particularly in low-income countries. The nitrate reductase assay (NRA) has been proposed as a rapid method for the detection of resistance to rifampicin and isoniazid, but its accuracy has not been systematically evaluated.. We performed a systematic review and meta-analysis to evaluate the accuracy of the NRA for the detection of rifampicin- and isoniazid-resistant tuberculosis. We searched Medline PubMed (NCBI), Global Health-CAB, EJS-E (EbscoHost), ISI Web, Web of Science and IFCC and contacted authors if additional information was required. Fifteen studies met our inclusion criteria for rifampicin resistance detection and 13 for isoniazid. Of these, the majority of the studies used culture isolates on solid medium, four used culture isolates on liquid medium and three used sputum samples. We applied the summary receiver operating characteristic (SROC) curve to perform meta-analysis and to summarize diagnostic accuracy.. For rifampicin, the majority of the studies that applied NRA to isolates had a sensitivity and specificity >94% and for isoniazid, >92%. The three studies that applied NRA directly on sputum samples had a sensitivity and specificity that ranged between 88% and 100%. The SROC curve had an area of >0.99 for both drugs.. There is evidence that NRA is highly sensitive and specific for the rapid detection of rifampicin and isoniazid resistance in culture isolates. More evidence is required for the NRA applied directly on sputum samples, but preliminary results appear promising and show a good sensitivity and specificity. Additional studies are required in countries with a high prevalence of MDR-TB and also cost-effectiveness analysis in order to obtain a complete picture on the utility of this method for rapid drug resistance detection in tuberculosis.

    Topics: Anti-Bacterial Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitrate Reductase; Rifampin; Sensitivity and Specificity; Tuberculosis

2008
Rifampin.
    Tuberculosis (Edinburgh, Scotland), 2008, Volume: 88, Issue:2

    Topics: Animals; Antibiotics, Antitubercular; Humans; Rifampin; Treatment Outcome; Tuberculosis

2008
Rifapentine.
    Tuberculosis (Edinburgh, Scotland), 2008, Volume: 88, Issue:2

    Topics: Animals; Antibiotics, Antitubercular; Humans; Rifampin; Treatment Outcome; Tuberculosis

2008
[Diagnostic methods for mycobacterial diseases].
    Nihon rinsho. Japanese journal of clinical medicine, 2007, Feb-28, Volume: 65 Suppl 2 Pt. 1

    Topics: Bacterial Proteins; Bacterial Typing Techniques; Bacteriological Techniques; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Mutation; Mycobacterium; Nucleic Acid Amplification Techniques; Rifampin; Sensitivity and Specificity; Tuberculosis

2007
Complications of antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and immune reconstitution inflammatory syndrome.
    The Journal of infectious diseases, 2007, Aug-15, Volume: 196 Suppl 1

    Access to antiretroviral therapy is rapidly expanding in resource-limited settings, where tuberculosis is the most common opportunistic infection. Coadministration of antitubercular and antiretroviral agents is, therefore, occurring commonly, and it is associated with 3 major complications. First, induction of cytochrome P-450 enzymes and P-glycoprotein by rifampin results in reduced concentrations of nonnucleoside reverse-transcriptase inhibitors and, particularly, protease inhibitors. This potentially results in the loss of antiviral efficacy and the development of viral resistance. Replacing rifampin with rifabutin, which does not significantly affect the concentrations of antiretroviral agents, is advocated but is currently unaffordable in resource-limited settings. Second, overlapping toxicities of antitubercular and antiretroviral agents occur frequently, necessitating discontinuation of therapy and increasing the risk of nonadherence. Third, immunopathological reactions, termed "the immune reconstitution inflammatory syndrome," occur frequently when antiretroviral therapy is initiated in patients with tuberculosis. These complexities of coadministration of antitubercular and antiretroviral agents are reviewed, and research priorities are highlighted.

    Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 Enzyme System; Developing Countries; Drug Interactions; Drug Resistance, Viral; Enzyme Induction; HIV; Humans; Immune System Diseases; Inflammation; Protease Inhibitors; Reverse Transcriptase Inhibitors; Rifampin; Rifamycins; Tuberculosis

2007
[Systematic review of anti-tuberculosis drug induced adverse reactions in China].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2007, Volume: 30, Issue:6

    To study the incidences of adverse reactions induced by anti-tuberculosis drugs in China.. Articles about adverse drug reactions (ADR) induced by anti-tuberculosis drugs published in 1996 - 2005 in China were searched. The incidences, possible risk factors, and prognoses of these ADR were analyzed.. According to our searching strategy and including criteria, 117 studies were included. The overall incidence of anti-tuberculosis drug induced ADR of these studies was 12.62%, and the overall incidence of hepatic injury was 11.9%, which was the highest among all kinds of ADR induced by anti-tuberculosis therapy. For different types of study, different diagnostic standards of hepatic injury, and different study institutions, the reported incidences of hepatic injury varied. Retrospective cohort studies showed that HBV(+) tuberculosis patients had a significantly higher risk of hepatic injury than HBV(-) patients. The prognosis of hepatic injury was good; 85.84% patients were cured of hepatic injury according to the articles which reported outcomes. The whole study was finished by 2006.. The incidence of adverse reactions induced by anti-tuberculosis drugs is high in China. Prevention and treatment of ADR are very important for improving the adherence of patients.

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; China; Drug-Related Side Effects and Adverse Reactions; Humans; Incidence; Isoniazid; Liver Diseases; Rifampin; Tuberculosis

2007
Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor.
    Annals of clinical microbiology and antimicrobials, 2006, Feb-15, Volume: 5

    Rifampicin, an important drug in the treatment of tuberculosis, is used extensively despite its broad effects on drug-drug interactions, creating serious problems. The clinical importance of such interactions includes autoinduction leading to suboptimal or failed treatment. The concomitantly administered effects of rifampicin on other drugs can result in their altered metabolism or transportation that are metabolised by cytochromes P450 or transported by p-glycoprotein in the gastrointestinal tract and liver. This review paper summarises recent findings with emphases on the molecular mechanisms used to explain these broad drug-drug interactions. In general, rifampicin can act on a pattern: rifampicin activates the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This pattern of action may explain many of the rifampicin inducing drug-drug interactions. However, effects through other mechanisms have also been reported and these make any explanation of such drug-drug interactions more complex.

    Topics: Antibiotics, Antitubercular; Cell Nucleus; Drug Interactions; Glucuronosyltransferase; Humans; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Rifampin; Tuberculosis

2006
Rifampicin plus pyrazinamide versus isoniazid for treating latent tuberculosis infection: a meta-analysis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2006, Volume: 10, Issue:10

    Six trials from Haiti, Mexico, the U.S.A., Brazil, Spain, Zambia and Hong Kong.. To evaluate the efficacy and safety of rifampicin plus pyrazinamide (RZ) vs. isoniazid (INH) for the prevention of tuberculosis (TB) among persons with or without human immunodeficiency virus (HIV) infection.. Meta-analysis of randomised controlled trials (RCTs) and quasi-RCTs that compared RZ for 2-3 months with INH for 6-12 months. Endpoints were development of active TB, severe adverse effects and death. Treatment effects were summarised as risk difference (RD) with 95% confidence intervals (CI).. Three trials conducted in HIV-infected patients and three trials conducted in non-HIV-infected persons were identified. The rates of TB in the RZ group were similar to those in the INH group, whether the subjects were HIV-infected or not (HIV-infected patients: pooled RD = 0%, 95% CI -1-2, P = 0.89; non-HIV-infected persons: pooled RD = 0%, 95% CI -2-1, P = 0.55). There was no difference in mortality between the two treatment groups (HIV-infected patients: pooled RD = -1%, 95% CI -4-2, P = 0.53; non-HIV-infected persons: pooled RD = 0%, 95% CI -1-1, P = 1.00). However, both subgroup analyses showed that a higher incidence of all severe adverse events was associated with 2RZ than INH among non-HIV-infected persons (RD = 29%, 95% CI 13-46, P = 0.0005 vs. RD = 7%, 95% CI 4-10, P < 0.0001).. RZ is equivalent to INH in terms of efficacy and mortality in the treatment of latent tuberculosis infection. However, this regimen increases the risk of severe adverse effects compared with INH in non-HIV-infected persons.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Comorbidity; Drug Therapy, Combination; HIV Infections; Humans; Isoniazid; Liver; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Risk Assessment; Tuberculosis

2006
Antituberculosis drugs and hepatotoxicity.
    Respirology (Carlton, Vic.), 2006, Volume: 11, Issue:6

    Isoniazid, pyrazinamide and rifampicin have hepatotoxic potential, and can lead to such reactions during antituberculosis chemotherapy. Most of the hepatotoxic reactions are dose-related; some are, however, caused by drug hypersensitivity. The immunogenetics of antituberculosis drug-induced hepatotoxicity, especially inclusive of acetylaor phenotype polymorphism, have been increasingly unravelled. Other principal clinical risk factors for hepatotoxicity are old age, malnutrition, alcoholism, HIV infection, as well as chronic hepatitis B and C infections. Drug-induced hepatic dysfunction usually occurs within the initial few weeks of the intensive phase of antituberculosis chemotherapy. Vigilant clinical (including patient education on symptoms of hepatitis) and biochemical monitoring are mandatory to improve the outcomes of patients with drug-induced hepatotoxicity during antituberculosis chemotherapy. Some fluoroquinolones like ofloxacin/levofloxacin may have a role in constituting non-hepatotoxic drug regimens for management of tuberculosis (TB) in the presence of hepatic dysfunction. Isoniazid administration is currently the standard therapy for latent TB infection. Rifamycins like rifampicin or rifapentine, alone or in combination with isoniazid, may also be considered as alternatives, pending accumulation of further clinical data. During treatment of latent TB infection, regular follow up is essential to ensure adherence to therapy and facilitate clinical monitoring for hepatic dysfunction. Monitoring of liver chemistry is also required for those patients at risk of drug-induced hepatotoxicity.

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Immunogenetics; Isoniazid; Liver; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis

2006
[Modern diagnosis of tuberculosis].
    Presse medicale (Paris, France : 1983), 2006, Volume: 35, Issue:11 Pt 2

    Microscopic examination of sputum smears (search for acid-fast bacilli or AFB) is the most rapid procedure for diagnosis of contagious tuberculosis. Gene amplification is not yet reliable for direct detection of M. tuberculosis in clinical specimens that are AFB smear-negative. Culture (3 to 8 weeks on Lowenstein-Jensen medium or 1 to 4 weeks in liquid media) remains essential to identify AFB and conduct antibiotic susceptibility testing. AFB from culture can be identified in a few hours by molecular approaches with specific DNA probes. Results of susceptibility testing, even in liquid media, are not available until 2 to 4 weeks after the recovery of specimens, although mutations of the rpoB and katG 315 genes, which confer resistance to rifampin and isoniazid, can be detected within hours by molecular hybridization with specific probes fixed on strips. Immunologic tests that measure the interferon gamma produced by sensitized lymphocytes are promising tools for the diagnosis of latent tuberculosis.

    Topics: Adenosine Deaminase; Antibiotics, Antitubercular; Antitubercular Agents; Bacteriological Techniques; Culture Media; DNA Probes; DNA, Bacterial; Drug Resistance, Bacterial; Gene Amplification; Genes, Bacterial; Genotype; Humans; Immunologic Tests; Interferon-gamma; Isoniazid; Lymphocytes; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Sputum; Time Factors; Tuberculosis

2006
[Trends in tuberculosis treatment duration].
    Presse medicale (Paris, France : 1983), 2006, Volume: 35, Issue:11 Pt 2

    The two principal characteristics of tuberculosis treatment are its length (several months) and the need to use several antibiotics simultaneously (multiple drug therapy). Multiple drug therapy is intended to prevent the selection of resistant mutants at the beginning of treatment, when the bacilli population is largest. The length of treatment is due to dormant bacilli, which are much more difficult for antibiotics to kill than actively multiplying bacilli are. Rifampin and pyrazinamide are the most potent drugs against these dormant bacilli. The so-called sterilizing activity of rifampin has reduced the duration of treatment from 18 to 9 months, and the contribution of pyrazinamide reduced this time still further, to 6 months. When one of these drugs cannot be used because of resistance or toxicity, duration of treatment increases to the earlier levels. In the extreme case of multidrug-resistant tuberculosis where neither isoniazid nor rifampin can be used, and sometimes even not pyrazinamide, treatment is recommended for 18 to 24 months. New antituberculosis drugs under development allow us to envision further reduction in the duration of treatment of both drug-resistant and drug-sensitive tuberculosis.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Disease Models, Animal; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Isoniazid; Mice; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Time Factors; Tuberculosis; Tuberculosis, Multidrug-Resistant

2006
Chemotherapy and diagnosis of tuberculosis.
    Respiratory medicine, 2006, Volume: 100, Issue:12

    Since after the first streptomycin 1944 trials, anti-tuberculous chemotherapy research has been focused upon establishing drug combination regimens capable of overcoming drug resistance and amenable to ambulatory treatment in resource strapped countries. The first milestone being the 1959 Madras trial comparing home and sanatorium treatment in South India. Subsequently, the MRC trials led Fox and Mitchison to indicate rifampicin, isoniazid and pyrazinamide as the first line drugs for short course, 6 month, regimens and the 1982 Hong Kong Chest Service trials established intermittent therapy as the ambulatory treatment standard for directly observed therapy (DOT). The rising of the HIV epidemic at the beginning of the 1980s has refuelled tuberculosis spread in Africa and Asia and contributed to the expansion of drug-resistant tuberculosis worldwide making the development of new drugs and drug regimens for ambulatory treatment a top priority. Led by biotechnological advances, molecular biology has been brought into TB laboratory diagnosis for the highly sensitive and specific rapid identification of Mycobacterium tuberculosis in biological samples. The field of immunological diagnosis of TB infection, dominated since the early 1900s by the intradermal tuberculin reaction has been put back in motion by the discovery of M. tuberculosis-specific proteins and peptides, now employed in blood tests of high sensitivity and specificity for the diagnosis of latent TB which may help with the identification of contacts at higher risk of active disease and the eradication of epidemic cases.

    Topics: Ambulatory Care; Antibiotics, Antitubercular; Antibodies, Bacterial; Antitubercular Agents; Disease Outbreaks; Drug Resistance, Multiple, Bacterial; History, 20th Century; HIV Infections; Humans; Hypersensitivity, Delayed; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Tuberculosis

2006
Short-course therapy with rifampin plus isoniazid, compared with standard therapy with isoniazid, for latent tuberculosis infection: a meta-analysis.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2005, Mar-01, Volume: 40, Issue:5

    A major difficulty associated with the use of standard therapy with isoniazid for latent tuberculosis infection is poor patient adherence to therapy because of the prolonged course required. Shorter courses of therapy involving > or =2 drugs have been proposed as an alternative to standard therapy, but they have not undergone enough testing.. We performed a meta-analysis to determine the equivalence of daily short-course therapy with rifampin plus isoniazid for 3 months and standard therapy with isoniazid for 6-12 months. The end points that were evaluated were development of active tuberculosis, severe adverse drug reactions, and death. We searched published information in the Cochrane Library, MEDLINE, and Embase databases, as well as unpublished information in the Cambridge Scientific Abstracts Internet database, Conference Papers Index, AIDS and Cancer Research Abstracts, and ClinicalTrials.gov. We also scanned the reference lists of articles. We only included trials in which individuals were randomly allocated to receive treatment. Two reviewers independently applied the criteria for trial selection, assessed trial quality, and extracted data.. Five trials comprising 1926 adults from Hong Kong, Spain, and Uganda were identified. The mean duration of follow-up varied from 13 to 37 months. Overall, development of active tuberculosis was equivalent in association with both regimens (pooled risk difference, 0%; 95% confidence interval [CI], -1% to 2%; percentage of total variation across the studies that is the result of heterogeneity rather than chance [I2], 0%; P=.86). Severe adverse effects were reported with a similar frequency for both regimens (pooled risk difference, -1%; 95% CI, -7% to 5%) but with statistically significant heterogeneity detected (I2, 78%; P=.001). However, a subanalysis of high-quality trials (including 74% of the sample size) suggested that both regimens were equally safe. In 3 trials (comprising 1390 patients) that provided data on mortality, the regimens showed equivalence (pooled risk difference, -1%; 95% CI, -4% to 2%; I2, 2.7%; P=.38).. Short-course therapy with rifampin plus isoniazid was equivalent to standard therapy with isoniazid in terms of efficacy, the proportion of severe side effects that occurred, and mortality.

    Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Tuberculosis

2005
Mycobacteriophage and their application to disease control.
    Journal of applied microbiology, 2005, Volume: 99, Issue:2

    Topics: Antibiotics, Antitubercular; Drug Resistance, Microbial; Genome, Bacterial; Humans; Luciferases, Bacterial; Mycobacteriophages; Rifampin; Sensitivity and Specificity; Tuberculosis

2005
Management of adults living with HIV/AIDS in low-income, high-burden settings, with special reference to persons with tuberculosis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2005, Volume: 9, Issue:9

    Because of the increasing availability of antiretroviral (ARV) agents for HIV in low-income countries, many clinicians now need training on their use. This is especially true for clinicians caring for individuals with tuberculosis (TB), given its close relationship with HIV/AIDS. This article summarizes the key decisions facing clinicians who manage HIV-infected persons, with particular reference to issues regarding those dually infected with TB. Health care provider-initiated diagnostic testing using rapid HIV tests should be offered to all individuals with symptoms and signs suggesting HIV infection, including all persons with TB. Issues to be included in pre- and post-test counseling sessions are discussed. HIV-infected patients should be evaluated to determine clinical staging of HIV; certain laboratory examinations should ideally be performed to assess the degree of immunosuppression and to aid decisions about when best to start ARV therapy and preventive therapies. The recommended ARV regimens and guidance on proposed patient follow-up are presented. Good adherence to ARVs is required and factors that induce and reinforce compliance are suggested. The treatment of TB is a high priority, and follows the same principles whether the patient is HIV-infected or not. Suggestions are made about ARV use in patients with TB. A standardized and complementary information system should be developed to monitor management of HIV-TB patients and performance of joint TB and HIV care efforts. By diagnosing and managing additional HIV cases detected through the portal of the TB control programme, clinicians will contribute to diminishing the burden of HIV, and thus, TB.

    Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Anti-Retroviral Agents; Antibiotics, Antitubercular; Comorbidity; HIV Infections; Humans; Patient Compliance; Poverty Areas; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

2005
[Anti-retroviral treatment in patients with AIDS and mycobacterial diseases].
    Medicina, 2005, Volume: 65, Issue:4

    Tuberculosis and other mycobacterial diseases are frequent coinfections in AIDS patients with an increased related mortality. In this review we have updated the treatment of the main mycobacterial diseases (tuberculosis and Mycobacterium avium disease), under the scope of pharmacological interactions between antimycobacterial drugs, specially rifampicin and clarithromycin, and anti-retroviral drugs. Antimycobacterial treatment schemes, their duration, primary and secondary chemoprophylaxis and the optimal time to start the anti-retroviral therapy are analized. Finally, the immnune reconstitution inflammatory syndrome and its treatment are discussed.

    Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Anti-Retroviral Agents; Clarithromycin; Drug Interactions; Humans; Mycobacterium Infections; Rifampin; Tuberculosis

2005
Review editorial: prevention of tuberculosis in resource-poor countries with increasing access to highly active antiretroviral treatment.
    Tropical medicine & international health : TM & IH, 2005, Volume: 10, Issue:12

    The administration of isoniazid (INH) has been proposed, evaluated and implemented to prevent tuberculosis (TB) disease among patients who are infected with the human immunodeficiency virus (HIV). This strategy has been developed in communities where TB is highly endemic and at a time when antiretroviral (ARV) treatment was not, or was rarely available. Although INH prevention programmes were somewhat pushed to the background due to the worldwide advocacy for ARV drugs, prevention of TB remains of paramount importance. The dual HIV-TB infection poses problems, not only for the individual and his/her clinician but also for the programme manager. We review various aspects of TB preventive treatment in countries with a high prevalence of HIV-TB co-infection and limited resources but with increasing access to ARV treatment.

    Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Antitubercular Agents; CD4 Lymphocyte Count; Developing Countries; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Tuberculosis

2005
Biopharmaceutic and pharmacokinetic aspects of variable bioavailability of rifampicin.
    International journal of pharmaceutics, 2004, Mar-01, Volume: 271, Issue:1-2

    Even today the treatment outcome of tuberculosis is questionable due to variable bioavailability of rifampicin, which was discovered four decades back. In this manuscript, results of bioequivalence trials reported are presented in the form of a figure that provides a comprehensive look at the rifampicin bioavailability literature, provides understanding of the problem and clears 'myths and assumptions' regarding rifampicin bioavailability from fixed-dose combination (FDC) formulations. It was found that FDCs of good as well as bad quality rifampicin containing formulations with reduced or increased relative bioavailability are available. In addition, 'rifampicin alone' formulations also show variability in bioavailability. In the context of anomalous bioavailability of rifampicin, reasons postulated in literature are summarized. Approaches needed to solve the issue of rifampicin bioavailability are discussed on the basis of LADMER and BCS.

    Topics: Antibiotics, Antitubercular; Biological Availability; Clinical Trials as Topic; Dosage Forms; Drug Combinations; Humans; Rifampin; Solubility; Technology, Pharmaceutical; Tuberculosis

2004
Rifampin.
    Pediatrics in review, 2004, Volume: 25, Issue:6

    Topics: Antibiotics, Antitubercular; Bacterial Infections; Child; Drug Therapy, Combination; Female; Humans; Pregnancy; Pregnancy Complications, Infectious; Rifampin; Tuberculosis

2004
Rifampin in dermatology.
    Disease-a-month : DM, 2004, Volume: 50, Issue:7

    Topics: Adult; Antibiotics, Antitubercular; Child; Drug Interactions; Female; Half-Life; Humans; Intestinal Absorption; Leprosy; Male; Microbial Sensitivity Tests; Middle Aged; Psoriasis; Rifampin; Tuberculosis

2004
Considering the role of four months of rifampin in the treatment of latent tuberculosis infection.
    American journal of respiratory and critical care medicine, 2004, Oct-15, Volume: 170, Issue:8

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Costs and Cost Analysis; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Emigration and Immigration; Humans; Isoniazid; Mice; Mycobacterium tuberculosis; Patient Compliance; Rifampin; Time Factors; Tuberculosis; United States

2004
Rifampin and pyrazinamide for latent tuberculosis infection: clinical trials and general practice.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2004, Aug-15, Volume: 39, Issue:4

    Topics: Clinical Trials as Topic; Family Practice; Humans; Pyrazinamide; Rifampin; Tuberculosis

2004
[Phage amplified biologically assay and its application in rapid detection of Mycobacterium tuberculosis].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2004, Volume: 27, Issue:12

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Mycobacteriophages; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis

2004
New guidelines: what to do about an unexpected positive tuberculin skin test.
    Cleveland Clinic journal of medicine, 2003, Volume: 70, Issue:1

    The 2000 recommendations for tuberculosis testing from the American Thoracic Society and the Centers for Disease Control and Prevention advocate a shift in focus from screening the general population to testing only patients at increased risk of developing tuberculosis.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Guideline Adherence; Humans; Isoniazid; Practice Guidelines as Topic; Rifampin; Risk Factors; Time Factors; Tuberculin Test; Tuberculosis

2003
Rifampin and pyrazinamide for treatment of latent tuberculosis infection: is it safe?
    American journal of respiratory and critical care medicine, 2003, Mar-15, Volume: 167, Issue:6

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Costs; Drug Therapy, Combination; HIV Infections; Humans; Liver Function Tests; Patient Compliance; Patient Selection; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Risk Factors; Safety; Tuberculin Test; Tuberculosis

2003
Latent tuberculosis in pregnancy: screening and treatment.
    Current women's health reports, 2003, Volume: 3, Issue:4

    Currently, most cases of active tuberculosis in the United States are a result of activation of latent tuberculosis infection. In this article, the history of the epidemiology of tuberculosis and latent tuberculosis infection is reviewed. Previous and current recommendations for screening and treatment for latent tuberculosis during pregnancy and the postpartum period are discussed. A review of the literature regarding postpartum and antepartum treatment is included. Finally, the question of whether antepartum or postpartum treatment is the most beneficial is discussed.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury, Chronic; Female; Hispanic or Latino; Humans; Isoniazid; Mass Screening; Patient Compliance; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Prenatal Diagnosis; Rifampin; Tuberculosis; United States; Withholding Treatment

2003
[Tuberculosis-current therapeutic principles].
    Der Internist, 2003, Volume: 44, Issue:11

    Chemotherapy for tuberculosis is indicated in case of disease as well as in latent tuberculosis infection. Standard medication for drug-susceptible tuberculosis consists of isoniazid and rifampicin for six months with additional pyrazinamide and ethambutol for the first two months. Prolonged treatment is necessary in cases of cavernous pulmonary tuberculosis with lack of negative cultures by two months of therapy, in tuberculosis of the central nervous system and in some cases of superficial lymph node disease. Especially in multiple-drug resistant tuberculosis prolonged treatment with three or more drugs, that have been proven to be effective by susceptability testing, is mandatory. Attention must be payed to reliable delivery of chemotherapy as well as to side effects of antituberculosis medications. The classical treatment for latent tuberculosis infection is isoniazid. Multidrug short-course therapy, which has been shown to be equally effective, enhances patients' compliance, but toxicity is increased.

    Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Humans; Isoniazid; Practice Patterns, Physicians'; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2003
Tuberculosis in blood and marrow transplant recipients.
    Hematological oncology, 2002, Volume: 20, Issue:2

    Although one third of the world's population is infected with tuberculosis (TB), TB in blood and marrow transplant (BMT) recipients is relatively less well studied, as the incidence of TB is relatively low in developed countries with BMT units. Since the report of the first two cases in 1983, 52 cases of TB complicating BMT have been reported in the English literature from BMT centers in ten different countries. Not unexpectedly, the two largest series were reported from areas with a high incidence of TB in the general population, with about 45 cases per 10(5) inhabitants per year in Spain and about 100 cases per 10(5) inhabitants per year in Hong Kong respectively. The overall frequency of occurrence of TB in BMT recipients was 0.4% (52 cases among 13 881 BMT recipients), with a male:female ratio of 11:9 and median age of 33 (range 7-57). The incidence of TB in the general population is a major predictor of a higher frequency of occurrence in BMT recipients. Moreover, allogeneic transplantation, graft-versus-host disease, and total body irradiation were found to be risk factors associated with TB. Among the 48 cases in whom the time of manifestation were reported, only one case manifested during the neutropenic period (day 11). On the other hand, 11 cases (23%) manifest after engraftment but before day 100, and 36 (75%) manifest after day 100. The most important aspect towards making the diagnosis is a high index of suspicion, as TB occurred in relatively low frequencies especially in developed countries, and the clinical patterns usually mimic other more common infectious and non-infectious complications after BMT. As the incidence of drug resistant TB is increasing, we prefer to treat our patients for at least one year (as compared with six months in immunocompetent hosts) with four drugs in the first six months and two or three drugs for another six months. In those patients who could not tolerate oral medication, we used an intravenous regimen of rifampicin, ciprofloxacin, and amikacin until oral therapy could be instituted. The absence of relapse after termination of treatment in our patients suggested that secondary prophylaxis would not be necessary as long as immune function has been restored. With the rising incidence of TB in countries that previously enjoyed a very low prevalence of TB, attributed to the growing population of HIV-infected subjects with TB, and the changing patterns of population migration, it is important to bear a high index

    Topics: Adult; Amikacin; Anti-Bacterial Agents; Bone Marrow Transplantation; Ciprofloxacin; Female; Graft vs Host Disease; Humans; Incidence; Male; Mycobacterium tuberculosis; Rifampin; Risk Factors; Transfusion Reaction; Tuberculosis; Whole-Body Irradiation

2002
Clinical practice. Latent tuberculosis infection.
    The New England journal of medicine, 2002, Dec-05, Volume: 347, Issue:23

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Male; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Risk Factors; Sensitivity and Specificity; Tuberculin Test; Tuberculosis

2002
[Tuberculosis].
    La Revue du praticien, 2002, Oct-15, Volume: 52, Issue:16

    Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antitubercular Agents; BCG Vaccine; Drug Therapy, Combination; Ethambutol; France; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculin Test; Tuberculosis; Tuberculosis, Pulmonary

2002
[Diagnosed tuberculosis using specific DNA probe hybridization methods].
    Rinsho byori. The Japanese journal of clinical pathology, 2002, Volume: Suppl 123

    In Japan, reported cases of tuberculosis had declined nearly every year until 1995. However, in 1997 newly recorded cases began increasing for the first time in more than 38 years. Recent studies using DNA fingerprinting show that person- to person transmission may account for as many as one-third of new cases of tuberculosis in citizen populations. Nucleic acid hybridization methods using specific DNA probes can specifically identify M. tuberculosis and other mycobacterial species. Rapid nucleic acid amplification techniques such as polymerase chain reaction methods allow direct identification of M. tuberculosis in clinical specimens. Is 6110 has been exploited extensively as a clonal marker in molecular epidemiology studies of tuberculosis. The emergence of resistance to antituberculosis drugs is a relevant matter worldwide. A recent genotypic method allows earlier detection of RFP-resistant and INH-resistant stains using probes for mutation in rpoB and in katG.

    Topics: Bacterial Proteins; DNA Probes; DNA-Directed RNA Polymerases; Drug Resistance; Humans; Isoniazid; Molecular Diagnostic Techniques; Mutation; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Peroxidases; Polymerase Chain Reaction; Rifampin; Tuberculosis

2002
Clinically significant interactions with drugs used in the treatment of tuberculosis.
    Drug safety, 2002, Volume: 25, Issue:2

    Clinically significant interactions occurring during antituberculous chemotherapy principally involve rifampicin (rifampin), isoniazid and the fluoroquinolones. Such interactions between the antituberculous drugs and coadministered agents are definitely much more important than among antituberculous drugs themselves. These can be associated with consequences even amounting to therapeutic failure or toxicity. Most of the interactions are pharmacokinetic rather than pharmacodynamic in nature. The cytochrome P450 isoform enzymes are responsible for many interactions (especially those involving rifampicin and isoniazid) during drug biotransformation (metabolism) in the liver and/or intestine. Generally, rifampicin is an enzyme inducer and isoniazid acts as an inhibitor. The agents interacting significantly with rifampicin include anticoagulants, anticonvulsants, anti-infectives, cardiovascular therapeutics, contraceptives, glucocorticoids, immunosuppressants, psychotropics, sulphonylureas and theophyllines. Isoniazid interacts principally with anticonvulsants, theophylline, benzodiapines, paracetamol (acetaminophen) and some food. Fluoroquinolones can have absorption disturbance due to a variety of agents, especially the metal cations. Other important interactions of fluoroquinolones result from their enzyme inhibiting potential or pharmacodynamic mechanisms. Geriatric and immunocompromised patients are particularly at risk of drug interactions during treatment of their tuberculosis. Among the latter, patients who are HIV infected constitute the most important group. This is largely because of the advent of new antiretroviral agents such as the HIV protease inhibitors and the non-nucleoside reverse transcriptase inhibitors in the armamenterium of therapy. Compounding the complexity of drug interactions, underlying medical diseases per se may also contribute to or aggravate the scenario. It is imperative for clinicians to be on the alert when treating tuberculosis in patients with difficult co-morbidity requiring polypharmacy. With advancement of knowledge and expertise, it is hoped that therapeutic drug monitoring as a new paradigm of care can enable better management of these drug interactions.

    Topics: AIDS-Related Opportunistic Infections; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Drug Interactions; Fluoroquinolones; Humans; Rifampin; Tuberculosis

2002
A review of efficacy studies of 6-month short-course therapy for tuberculosis among patients infected with human immunodeficiency virus: differences in study outcomes.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2001, Feb-15, Volume: 32, Issue:4

    Six-month regimens that include rifampin for the treatment of tuberculosis in patients without human immunodeficiency virus (HIV) infection are recommended because of low percentage of relapses. Whether a similar duration of therapy should be used to treat tuberculosis in HIV-infected patients is unclear. Six studies of patients with HIV-infection and 3 of patients without HIV infection were reviewed and compared. The studies differed in terms of design, eligibility criteria, site of disease, frequency of dosing, dose administration methods, and outcome definitions. Among HIV-infected patients, the following percentages were found: cure, 59.4%--97.1%; treatment success, 34.0%--100%; effective treatment, 29.4%--88.2%; and relapse, 0%--10%. In those without HIV infection, percentages were as follows: cure, 62.3%--88.0%; treatment success, 91.2%--98.8%; effective treatment, 70.6%--83.8%; and relapse, 0%--3.4%. Although the rate of relapse appeared to be higher in some studies of HIV-infected patients with tuberculosis, this review demonstrates the limitation in the use of relapse as the exclusive outcome of interest when comparing studies.

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Clinical Trials as Topic; Humans; Patient Selection; Prospective Studies; Randomized Controlled Trials as Topic; Recurrence; Research Design; Rifampin; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary

2001
Treatment of latent tuberculosis infection: renewed opportunity for tuberculosis control.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2000, Volume: 31, Issue:1

    New recommendations for targeted tuberculin testing and treatment of latent tuberculosis (TB) infection have recently been published. Changes in nomenclature from screening to targeted tuberculin testing and from preventive therapy to treatment of latent TB infection (LTBI) are intended to promote more widespread implementation by programs and health care providers. Targeted tuberculin testing is designed to identify persons at high risk for TB and is discouraged for persons at low risk. New recommendations for treatment of LTBI in both human immunodeficiency virus (HIV)-infected and HIV-uninfected patients include isoniazid for 9 months as the preferred regimen: isoniazid for 6 months based on local program conditions, rifampin and pyrazinamide for 2 months, and rifampin for 4 months. Treatment monitoring now places greater emphasis on clinical, rather than routine, laboratory monitoring. More widespread implementation of targeted tuberculin testing and treatment of LTBI is an important control strategy that will enhance efforts to eliminate TB in the United States.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Humans; Isoniazid; Rifampin; Tuberculin Test; Tuberculosis

2000
A current approach to the management of tuberculosis infection.
    Current clinical topics in infectious diseases, 2000, Volume: 20

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; BCG Vaccine; Ethambutol; Forecasting; Humans; Immunocompetence; Isoniazid; Mass Screening; Patient Compliance; Rifampin; Risk Factors; Tuberculin Test; Tuberculosis

2000
Role of individual drugs in the chemotherapy of tuberculosis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2000, Volume: 4, Issue:9

    During the course of chemotherapy, certain drugs are predominant in their bactericidal activities. Isoniazid is responsible for an initial kill of about 95% of organisms during the first 2 days of treatment. Its bactericidal role is then replaced by rifampicin and pyrazinamide during the intensive phase. In the continuation phase with an isoniazid/rifampicin regimen, rifampicin is the only effective drug against persisters, as shown by the similarity of response by patients with initially isoniazid-resistant or sensitive strains. If the continuation phase regimen does not contain rifampicin but does contain isoniazid, the dominant bactericidal drug is isoniazid. In this case, the response of patients with initial isoniazid resistance is appreciably less good than in those with sensitive organisms. The review suggests exploration in randomised control trials of a continuation phase of rifampicin (or rifapentine) alone. It also suggests the importance of the dose size of rifampicin and the need for exploring a higher dose. Finally, it emphasises the importance of finding drugs that act on persisting organisms that are phenotypically but not genetically resistant to rifampicin.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Humans; Isoniazid; Microbial Sensitivity Tests; Primary Prevention; Pyrazinamide; Rifampin; Sputum; Time Factors; Treatment Outcome; Tuberculosis

2000
Tuberculosis in patients with human immunodeficiency virus infection.
    The New England journal of medicine, 1999, Feb-04, Volume: 340, Issue:5

    Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; Disease Susceptibility; HIV Infections; Humans; Polymorphism, Restriction Fragment Length; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

1999
The tuberculosis pandemic--which way now?
    The Journal of infection, 1999, Volume: 38, Issue:2

    Topics: Adult; Animals; Antibiotics, Antitubercular; Antitubercular Agents; Cattle; Child; Disease Outbreaks; Disease Reservoirs; Drug Resistance, Microbial; HIV Infections; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis; World Health Organization

1999
Uses of rifampin for infections other than tuberculosis.
    The Pediatric infectious disease journal, 1999, Volume: 18, Issue:7

    Rifampin has limited use in monotherapy because of the rapid development of resistance. In combination therapy with a variety of antimicrobials, it has many applications for treatment of serious infections.

    Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Bacterial Infections; Drug Therapy, Combination; Humans; Mycoses; Rifampin; Tuberculosis

1999
Rifapentine: its role in the treatment of tuberculosis.
    The Annals of pharmacotherapy, 1999, Volume: 33, Issue:11

    To review the pharmacokinetics, efficacy, adverse effects, and cost of the newest antitubercular drug, rifapentine.. A MEDLINE search using key terms such as rifapentine, rifampin, isoniazid, Mycobacterium tuberculosis, and pyrazinamide was conducted for the time period 1966-November 1998.. Animal data were used for basic information and human studies were selected for inclusion if they were randomized, controlled studies assessing efficacy, or if they were single- or multiple-dose studies assessing the pharmacokinetics of rifapentine. Background articles on the pathophysiology of tuberculosis and cost of care and noncontrolled studies assessing drug interactions were also included.. Compared with an oral solution, the relative bioavailability of rifapentine is 70% following oral admninistration of tablets. Food increased bioavailability by 55%. Rifapentine accumulated significantly in human macrophages and its elimination half-life was longer than that of rifampin. Comparative studies of rifapentine and rifampin in humans during intensive- and continuation-phase treatment of tuberculosis suggest that at currently accepted doses, rifapentine was slightly less effective than rifampin. The most significant drug interaction with rifapentine involves indinavir: the maximum concentration and AUC of indinavir are reduced by 55% and 70%, respectively, when rifapentine is coadministered with indinavir. Adverse events of rifapentine may occur less frequently at the currently recommended 600-mg dose as compared with rifampin; however, the difference was not statistically significant. If only drug costs were evaluated during the six-month treatment of tuberculosis, rifapentine is more expensive than rifampin.. Rifapentine can be administered twice weekly during the intensive phase of tuberculosis treatment and then once weekly during the continuation phase of treatment. This may improve patient adherence over some other treatments and possibly reduce costs of treatment by preventing development of resistant tubercular strains due to nonadherence. Rifapentine is well tolerated, with most patients experiencing adverse effects at a similar rate as rifampin. Rifapentine induces cytochrome P450 somewhat less than rifampin, although few drug interaction studies have been done with rifapentine. Its efficacy at the currently approved dosage of 600 mg may be slightly lower than that of rifampin. Studies are needed to determine if equal or greater efficacy can be achieved with higher doses of rifapentine. Rifampin is less expensive than rifapentine. Further pharmacoeconomic studies are needed to evaluate costs of relapse and failure in patients receiving these agents.

    Topics: Abnormalities, Drug-Induced; Animals; Antibiotics, Antitubercular; Drug Interactions; Female; Humans; Lactation; Mycobacterium tuberculosis; Pregnancy; Pregnancy Complications; Rifampin; Tuberculosis

1999
Rifampicin bioavailability: a review of its pharmacology and the chemotherapeutic necessity for ensuring optimal absorption.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1999, Volume: 3, Issue:11 Suppl 3

    The World Health Organization encourages the use of fixed dose combinations (FDCs) of rifampicin (RMP) and isoniazid together with pyrazinamide or pyrazinamide plus ethambutol for the treatment of tuberculosis. The main advantages of such FDCs are the simplification of procurement and prescribing practices and the protection they afford against the potential selection of RMP-resistant strains of Mycobacterium tuberculosis. There is convincing evidence, however, that the rifampicin absorption from FDCs manufactured under suboptimal conditions may be significantly impaired, and this appears to be especially problematic with combined formulations of rifampicin, isoniazid and pyrazinamide. In view of the marked dose-dependence of rifampicin's bacterial sterilizing action, it is therefore essential that tuberculosis control programmes only use rifampicin-containing FDCs with proven rifampicin bioavailability. The comprehensive literature on the pharmacology of rifampicin is reviewed, together with the methods employed for determining it and its most important metabolite, desacetyl-rifampicin, in either serum or urine. By contrast, published information concerning the absorption of rifampicin from currently marketed combined formulations and on laboratory methods for precisely assessing their bioavailability is very sparse. There is therefore a crucial need to establish the quality of currently marketed rifampicin-containing FDCs in studies using adequate numbers of volunteers, precise analytical techniques and sophisticated statistical techniques.

    Topics: Absorption; Antibiotics, Antitubercular; Antitubercular Agents; Biological Availability; Drug Combinations; Humans; Rifampin; Tuberculosis

1999
[Pharyngeal tuberculosis: an analytical study and report of 10 cases].
    Revue de laryngologie - otologie - rhinologie, 1998, Volume: 119, Issue:3

    Pharyngeal tuberculosis is an uncommon condition. We report here an analysis of 10 cases collected from 1990 to 1996. The patients were aged between 16 and 75 years, with an equal sex distribution. Topographically there were 7 nasopharyngeal cases and 3 tonsillar cases, the presenting features being those of a chronic pharyngeal disorder, sometimes with cervical adenopathy. Macroscopically, the main features were those of misleading pseudo-tumours. The diagnosis rests on the histology. Anti-tuberculous medical treatment is usually effective.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Female; Humans; Isoniazid; Male; Middle Aged; Pharyngeal Diseases; Pyrazinamide; Rifampin; Tuberculosis

1998
Rifapentine.
    Drugs, 1998, Volume: 56, Issue:4

    Rifapentine is a rifamycin antibiotic with antimycobacterial activity. Rifapentine is generally more active against Mycobacterium tuberculosis than rifampicin (rifampin), although strains resistant to rifampicin are usually cross-resistant to rifapentine. Sputum culture conversion rates were slightly higher after 6 months of rifapentine- versus rifampicin-based therapy in patients with pulmonary tuberculosis in a Western study; however, relapse rates were higher in rifapentine recipients during follow-up. The excess relapses in the rifapentine group appeared to be related to poor compliance with nonrifamycin antituberculosis drugs during the intensive phase (first 2 months) of therapy. Rifapentine- and rifampicin-containing regimens produced similar sputum culture conversion rates with low rates of relapse in 2 randomised clinical trials in patients with smear-positive tuberculosis in China. In one trial, there was no difference in sputum culture conversion rates in patients treated with rifapentine once weekly or rifampicin twice weekly in combination with isoniazid and ethambutol during the continuation phase of treatment. Hyperuricaemia, which was reported only during the intensive phase, elevated ALT and AST levels and neutropenia were the most common treatment-related adverse events reported in patients receiving rifapentine- or rifampicin-containing regimens for tuberculosis in 1 Western study.

    Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Humans; Rifampin; Tuberculosis

1998
Clinical relevance of reduced bioavailability of rifampicin.
    The Journal of the Association of Physicians of India, 1998, Volume: 46, Issue:8

    Bioavailability (BA) of rifampicin (RMP) is a critical factor in successful treatment of tuberculosis. The BA of RMP can be reduced by pharmaceutical factors, patient factors and drug interactions. Failure of treatment and development of drug resistance are potential consequences of reduction in BA and it is necessary to understand and control the factors influencing BA of RMP.

    Topics: Antitubercular Agents; Biological Availability; Drug Interactions; Humans; Rifampin; Tuberculosis

1998
[Antitubercular drug-induced liver injuries].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 1998, Volume: 21, Issue:5

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Rifampin; Tuberculosis

1998
New horizons in the treatment of tuberculosis.
    Biochemical pharmacology, 1997, Dec-01, Volume: 54, Issue:11

    The development of new chemotherapy for the treatment of tuberculosis has three major objectives: first, the development of faster-acting drugs to shorten the duration of treatment; second, the development of novel antimicrobials to counter the emergence of bacteria resistant to current therapies; and, third, the development of chemotherapeutics that specifically target dormant bacilli to treat the one-third of the world's population latently infected with tubercle bacilli. Strategies based upon optimizing the inhibition of known targets require an extensive knowledge of the detailed mechanism of action of current antimycobacterial agents. For many agents such as isoniazid, ethambutol, rifampin, and pyrazinamide such knowledge is now available. Strategies based upon the identification of novel targets will necessitate the identification of biochemical pathways specific to mycobacteria and related organisms. Many unique metabolic processes occur during the biosynthesis of mycobacterial cell wall components, and some attractive new targets have emerged. The development of targets specific to latency will require a detailed picture of the metabolism and biochemical pathways occurring in dormant bacilli. Recent evidence suggests that anaerobic metabolic pathways may operate in dormant bacilli, and the enzymes involved in such pathways may also provide significant new targets for intervention. The combination of the mycobacterial genome sequence that is anticipated to become available this year with an improved understanding of the unique metabolic processes that define mycobacteria as a genus offers the greatest hope for the elimination of one of mankind's oldest enemies.

    Topics: Animals; Drug Design; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Mycolic Acids; Pyrazinamide; Rifampin; Tuberculosis

1997
[Antitubercular chemotherapy].
    Revue des maladies respiratoires, 1997, Volume: 14 Suppl 5

    Treatment of tuberculosis has three major goals: healing the patient, preventing selection of resistant strains and control transmission of tuberculosis. A 6 month regimen consisting of isoniazid, rifampin with addition of pyrazinamide for 2 months is the preferred treatment for pulmonary and extra-pulmonary tuberculosis. If resistance to isoniazid is suspected, ethambutol should be added until drug susceptibility studies become available. This treatment is effective in both HIV infected and uniinfected persons. Treatment failure is mostly related to lack of patient adherence to the drug regimen and to multidrug-resistant tuberculosis. The treatment of multidrug-resistant tuberculosis requires second line drugs which are less effective and poorly tolerated. Prevention of resistant tuberculosis needs adequate treatment of each case of tuberculosis and improving of the patient compliance.

    Topics: Aged; AIDS-Related Opportunistic Infections; Antitubercular Agents; Child; Clinical Protocols; Drug Combinations; Ethambutol; Follow-Up Studies; HIV Seronegativity; Humans; Isoniazid; Patient Compliance; Patient Education as Topic; Pyrazinamide; Rifampin; Treatment Failure; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

1997
[Role of immune responses in tuberculosis].
    Kekkaku : [Tuberculosis], 1997, Volume: 72, Issue:12

    Topics: Antibiotics, Antitubercular; Female; Humans; Macrophage Activation; Macrophages; Male; Middle Aged; Mycobacterium tuberculosis; Platelet Count; Rifampin; Tuberculosis

1997
Feline tuberculosis: a literature review and discussion of 19 cases caused by an unusual mycobacterial variant.
    The Veterinary record, 1996, Jan-20, Volume: 138, Issue:3

    The literature relating to feline mycobacterial disease is reviewed and 19 cats with tuberculosis caused by a previously unknown strain of mycobacterium are discussed. The bacteria were found to have characteristics between those of Mycobacterium tuberculosis and M bovis. The paper considers the clinical signs, epidemiology and diagnosis of the cases, and discusses the possible origins of the organism, treatment regimens and zoonotic potential.

    Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Cat Diseases; Cats; Diagnosis, Differential; Dihydrostreptomycin Sulfate; Drug Therapy, Combination; Female; Incidence; Isoniazid; Male; Mycobacterium; Mycobacterium bovis; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Skin; Tuberculosis; Tuberculosis, Cutaneous; United Kingdom; Weight Loss

1996
Primary esophageal tuberculosis: a case report and 1996 update.
    The American journal of gastroenterology, 1996, Volume: 91, Issue:6

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Esophageal Diseases; Female; Humans; Isoniazid; Rifampin; Tuberculosis

1996
[Current developments in Mycobacteria diagnosis].
    Schweizerische medizinische Wochenschrift, 1995, Sep-16, Volume: 125, Issue:37

    The reemergence of tuberculosis in the industrialized countries has hastened the development of new laboratory techniques. Hence, well-known shortcomings of traditional techniques such as the lack of a rapid and specific detection system, the delayed availability of species identification and drug susceptibility results, and the lack of a reliable method for determining strain identity for epidemiological purposes, have become immediate targets for implementing molecular biology techniques. In particular, nucleic acid amplification techniques, restriction fragment-length polymorphism and single-strand conformation polymorphism analyses have dramatically improved diagnostic timeliness and accuracy of mycobacteriology laboratory results. Our paper reviews recent developments and comments on the diagnostic applications of the new tools as compared to traditional techniques.

    Topics: Amino Acid Sequence; Drug Resistance; Humans; Molecular Sequence Data; Mycobacterium; Mycobacterium Infections; Mycobacterium tuberculosis; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Random Amplified Polymorphic DNA Technique; Rifampin; Switzerland; Tuberculosis

1995
Preventive therapy for tuberculosis in HIV-infected persons: international recommendations, research, and practice.
    Lancet (London, England), 1995, Apr-01, Volume: 345, Issue:8953

    The World Health Organization estimates that more than four million people worldwide are infected with both Mycobacterium tuberculosis and HIV. HIV infection is the strongest known risk factor for the development of tuberculosis (TB). Mechanisms for the development of active TB include the reactivation of latent infection, rapid progression in primary infection, and/or reinfection with Mycobacterium tuberculosis. Indeed, HIV-infected people with a positive tuberculin skin test have a 5-8% annual risk and a 30% or greater lifetime risk of developing TB. Case-finding and treatment, preventive therapy, the use of BCG, and environmental measures can, however, control TB. Emphasis in developing countries has been upon case-finding and treatment, and providing infants with BCG. Preventive therapy has not been recommended except for breastfeeding infants of mothers with pulmonary TB or other children under five years old living with infectious persons. The high incidence of TB in HIV-infected people in developing countries has, however, led to reconsideration of the role of preventive therapy as a public health strategy. The authors briefly discuss preventive therapy for TB in HIV-infected persons, research issues, and the international role of preventive therapy.

    Topics: AIDS Serodiagnosis; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Administration Schedule; Humans; Isoniazid; Research; Rifampin; Tuberculin Test; Tuberculosis

1995
Clinically significant drug interactions with antituberculosis agents.
    Drug safety, 1994, Volume: 11, Issue:4

    Standard short-course regimens for tuberculosis are used worldwide with very few problems. Unfortunately, the emergence of multiple drug-resistant tuberculosis in many parts of the world is leading to a diversification of drug regimens and to the use of drugs that are more toxic per se and more likely to interact with others. In addition, the treatment of HIV/AIDS patients with tuberculosis or disease due to Mycobacterium avium-intracellulare complex (MAC) infection with new drugs and multidrug regimens has added to the problem of drug interactions, especially as such patients may often be receiving concomitant treatment for a range of bacterial, fungal and viral infections. In general, there are very few clinically significant interactions between the first-line antituberculosis drugs themselves, although problems of bioavailability, notably of rifampicin (rifampin), have been encountered in the manufacture of combination tablets. Of the first-line drugs used to treat tuberculosis, i.e. rifampicin, isoniazid and pyrazinamide, rifampicin is particularly likely to cause clinically significant drug interactions as it is a potent inducer of the cytochrome P450 enzyme group, which is involved in the metabolism of many drugs, in particular oral contraceptives, corticosteroids, oral anticoagulants and cyclosproin. The use of quinolones to treat multiple drug-resistant tuberculosis and AIDS-related MAC disease raises further problems of drug interactions as, in contrast to rifampicin, these drugs inhibit some cytochrome isoenzymes, leading to reduced metabolism of certain drugs.

    Topics: Absorption; Antitubercular Agents; Biotransformation; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; Humans; Isoenzymes; Isoniazid; Quinolones; Rifabutin; Rifampin; Tissue Distribution; Tuberculosis

1994
Multidrug-resistant tuberculosis and its control.
    Research in microbiology, 1993, Volume: 144, Issue:2

    Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Drug Resistance, Microbial; Drug Therapy, Combination; HIV Infections; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary

1993
Failure of therapy for tuberculosis in human immunodeficiency virus infection.
    The American journal of the medical sciences, 1992, Volume: 304, Issue:3

    Optimum treatment of tuberculosis in persons with human immunodeficiency virus (HIV) infection is still being defined. Tuberculosis treatment failure in an HIV-infected patient is described and 10 similar cases from the medical literature are reviewed to search for common patterns associated with an adverse outcome of therapy in this setting. Six patients were poorly compliant. In nine patients, the subsequent episode of tuberculosis was disseminated or extrapulmonary; in four the central nervous system was involved. In five patients, a problem with rifampin usage was encountered: Three had rifampin-resistant Mycobacterium tuberculosis, one experienced an adverse reaction to rifampin, leading to withdrawal from the regimen after 1 week, and one was receiving a drug that may interfere with rifampin's antimycobacterial effect. This case report and literature review suggest that particular attention should be directed toward ensuring that patients with HIV infection comply with treatment of tuberculosis. For the majority of patients, the already stretched resources available for the treatment of tuberculosis and HIV infection should be devoted to compliance enhancement rather than to more prolonged or intensive drug regimens. However, it should be emphasized that patients with disseminated tuberculosis or central nervous system disease and those who are not able to receive rifampin because of drug resistance or an adverse reaction should be managed individually.

    Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Drug Therapy, Combination; Ethambutol; Female; HIV Seropositivity; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Pyridoxine; Rifampin; Tuberculosis

1992
Pharmacokinetic drug interactions with rifampicin.
    Clinical pharmacokinetics, 1992, Volume: 22, Issue:1

    Rifampicin, an antituberculosis drug, is usually administered for 4 to 12 months with other antituberculosis drugs or medications from other classes. A potential for drug interactions often exists because rifampicin is a potent inducer of hepatic drug metabolism, as evidenced by a proliferation of smooth endoplasmic reticulum and an increase in the cytochrome P450 content in the liver. The induction is a highly selective process and not every drug metabolised via oxidation is affected. Case reports and studies have demonstrated enhanced metabolism of several drugs; most of these interactions are clinically important. At the start of rifampicin treatment, and again at the end, clinicians must check the dosages of any accompanying medications with which rifampicin may potentially interact. Monitoring of clinical response and blood drug concentrations is essential to adjust the drug dosage during rifampicin therapy. Rifampicin also interacts with cholephils such as bilirubin and bromosulphthalein. Its pharmacokinetics are reported to be altered by ethambutol, p-aminosalicylic acid (through its excipient component), ketoconazole, cyclosporin, clofazimine, probenecid and phenobarbital through one or other of the following mechanisms--impaired absorption of rifampicin, competition between the drug and rifampicin for hepatic uptake and altered hepatic metabolism of rifampicin. Most interactions affecting rifampicin have been relatively minor or are not expected to alter its therapeutic efficacy.

    Topics: Drug Incompatibility; Drug Interactions; Humans; Liver; Rifampin; Tuberculosis

1992
[Chemoprophylaxis of tuberculosis (lecture)].
    Problemy tuberkuleza, 1992, Issue:1-2

    Topics: Adolescent; Adult; Age Factors; Antitubercular Agents; BCG Vaccine; Child; Ethambutol; Humans; Infant, Newborn; Isoniazid; Pyrazinamide; Rifampin; Time Factors; Tuberculosis

1992
[Tuberculosis and corticosteroids. Physiopathological and therapeutical implications].
    Anales de medicina interna (Madrid, Spain : 1984), 1992, Volume: 9, Issue:7

    Topics: Adrenal Cortex Hormones; Humans; Rifampin; Tuberculosis

1992
Toxic hepatitis with isoniazid and rifampin. A meta-analysis.
    Chest, 1991, Volume: 99, Issue:2

    Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Isoniazid; Meta-Analysis as Topic; Rifampin; Tuberculosis

1991
[Chemotherapy of extrapulmonary tuberculosis].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 1991, Volume: 14, Issue:3

    Topics: Antitubercular Agents; Drug Therapy, Combination; Isoniazid; Rifampin; Tuberculosis

1991
[Therapy of tuberculosis].
    Deutsche medizinische Wochenschrift (1946), 1990, Nov-23, Volume: 115, Issue:47

    Topics: Antitubercular Agents; Contraindications; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Prothionamide; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1990
Adverse reactions to rifampicin given in daily regimens: a review.
    Journal of the Indian Medical Association, 1990, Volume: 88, Issue:9

    Topics: Humans; Rifampin; Tuberculosis

1990
Treatment of extrapulmonary tuberculosis.
    Seminars in respiratory infections, 1989, Volume: 4, Issue:3

    The duration of therapy for pulmonary tuberculosis (TB) is now shortened to 6 or 9 months with the use of bactericidal drugs. There are few reports on the results of short course chemotherapy (SCC) in extrapulmonary tuberculosis (EP). It is unlikely that many controlled studies shall be forthcoming in the future because of involvement of many sites with the disease, each of which has special problems. However, available controlled studies and clinical experiences in EP indicate early success. The site of the disease appears to be less important since the bacterial population is much smaller in EP than in TB and is easily amenable to the bactericidal drugs. Present bactericidal drugs (isoniazid [INH], rifampin [RIF], pyrazinamide [PZA]) penetrate well into tissues and attain bactericidal levels to kill the organisms. Our experience with 9-month SCC consisting of INH 300 mg and RIF 600 mg daily for one month, followed by INH 900 mg and RIF 600 mg twice weekly for another 8 months in 478 cases of EP showed overall success in over 95% of those patients who completed therapy over a median follow-up of 42 months. The drugs may be given daily throughout with the same success. Thus, 9-month therapy with INH and RIF is highly effective in EP due to drug sensitive organisms. In TB, the duration may be shortened to 6-months with initial intensive four-drug therapy consisting of INH, RIF, PZA and streptomycin (SM) or ethambutol (EMB) daily for 2 months, followed by INH and RIF daily or twice weekly for another 4 months.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Isoniazid; Middle Aged; Rifampin; Tuberculosis

1989
[Which treatment for primary tuberculosis?].
    Pediatrie, 1989, Volume: 44, Issue:9

    Primary tuberculosis should be treated in all cases. In adults, the total treatment course for pulmonary tuberculosis can be shortened to 6 months. If the disease is not symptomatic, the rifampicin-isoniazid combination (10 mg/kg/day each) appears to be preferable to single drug therapy. In patients with symptomatic disease, pyrazinamide (30 mg/kg/day) should be added during the first 6-8 weeks and in some cases, corticosteroid therapy is also required. The drugs are usually well tolerated, but hepatic function should be monitored.

    Topics: Acquired Immunodeficiency Syndrome; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1989
Respiratory pharmacology. Antituberculosis drugs.
    Clinics in chest medicine, 1986, Volume: 7, Issue:3

    Tuberculosis remains a significant health problem. Its control and treatment depend on a thorough understanding of the basic principles and application of antituberculosis chemotherapy. The pharmacology of the major antituberculosis drugs is presented, including the management of adverse and allergic reactions.

    Topics: Aminosalicylic Acids; Antitubercular Agents; Cyclosporins; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

1986
Rifampin. No longer just for tuberculosis.
    Postgraduate medicine, 1985, Feb-15, Volume: 77, Issue:3

    Topics: Adult; Bacterial Infections; Child; Drug Combinations; Humans; Isoniazid; Rifampin; Tuberculosis

1985
[New findings concerning the biochemical mechanisms of the tuberculous process and the correction of biochemical abnormalities using etiopathogenetic preparations].
    Problemy tuberkuleza, 1984, Issue:11

    Topics: Antitubercular Agents; Drug Therapy, Combination; Ethionamide; Fatty Acids; Humans; Isoniazid; Liver; Malates; Metabolic Diseases; Mitochondria; Oxidative Phosphorylation; Rifampin; Succinates; Succinic Acid; Tuberculosis

1984
Short-course therapy for tuberculosis.
    Drugs, 1982, Volume: 24, Issue:2

    The discovery of rifampicin was the turning point away from the standard long term treatment for tuberculosis of 18 to 24 months and towards a 6-month curative programme. Rifampicin has proven to be highly effective and vital to short-course tuberculosis therapy, but its disadvantage is its cost. This makes it relatively unavailable where it is most needed, i.e. in countries where tuberculosis is still rampant, but which are economically underdeveloped. In such areas other needs take precedence over a chronic and non-spectacular medical condition like tuberculosis. During the past 10 years pyrazinamide has been 'rediscovered' and restudied, and when used in combination with rifampicin has been shown to play an important role in short-course chemotherapy. Its contribution to efficacy does not appear to extend beyond the first 2 months of therapy, and it should be discontinued after 2 months. This relatively short administration period helps to minimise adverse reactions to the drug. The main measure of success in short-course chemotherapy is the relapse rate, and this has been higher, sometimes unacceptably so, in regimens where bacteriostatic drugs were substituted for bactericidal ones. In conclusion, isoniazid, rifampicin and pyrazinamide in combination may be deemed essential to an effective short-course regimen of 6 months' duration. Curtailing the duration of treatment to less than 6 months in smear-positive tuberculosis results in high relapse rates and thus is not acceptable. Several studies have been undertaken varying the drug combinations, the dosages and the drug administration routines (i.e. whether daily followed by intermittent or intermittent throughout), in an effort to arrive at the simplest, most effective, least toxic and most economical all-round treatment programme. Such studies are still in progress. When recommended dosage regiments are followed, the incidence of adverse reactions is low with short-course therapy, and in only 5% or less of patients is it necessary to withdraw one or more drugs.

    Topics: Drug Therapy, Combination; Humans; Pyrazinamide; Rifampin; Streptomycin; Substance-Related Disorders; Time Factors; Tuberculosis

1982
[Toxicity of pyrazinamide in antituberculous treatments (author's transl)].
    Revue francaise des maladies respiratoires, 1980, Volume: 8, Issue:4

    Pyrazinamide, an antituberculous drug discovered in 1952, was first considered as a toxic drug. As it appeared as a bactericidal drug for the organisms inside macrophages, its usefulness has been re-appraised. In combination with other bactericidal drugs, it contributes to speed up the sterilization of tuberculous lesions. A review of the more recent clinical trials allows to assess the real toxicity of Pyrazinamide. Prescribed at a daily dosage of 30 to 35 mg/kg (1,5 to 2 g daily), it gives no major side effects.

    Topics: Chemical and Drug Induced Liver Injury; Diarrhea; Drug Eruptions; Gout; Humans; Isoniazid; Nausea; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1980
Interaction of rifampicin with other drugs.
    Tubercle, 1980, Volume: 61, Issue:3

    Topics: Antitubercular Agents; Bilirubin; Digitalis Glycosides; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; Female; Humans; Rifampin; Tuberculosis

1980
Diagnosis and management of tuberculosis.
    Primary care, 1979, Volume: 6, Issue:1

    Topics: Adrenal Cortex Hormones; Ambulatory Care; Aminosalicylic Acid; Antitubercular Agents; BCG Vaccine; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Mycobacterium Infections; Mycobacterium tuberculosis; Rifampin; Sputum; Streptomycin; Tuberculin Test; Tuberculosis; Tuberculosis, Pulmonary

1979
Advances in the treatment of tuberculosis.
    Journal of the Royal Naval Medical Service, 1976,Summer, Volume: 62, Issue:2

    Topics: Aminosalicylic Acids; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Osteoarticular; Tuberculosis, Pulmonary; Tuberculosis, Urogenital

1976
Chemotherapy of tuberculosis.
    American journal of hospital pharmacy, 1976, Volume: 33, Issue:3

    Drug treatment of tuberculosis is reviewed. Factors influencing the choice of antituberculosis agents and antituberculosis regimens are discussed. The advantages of two regimens are emphasized--isoniazid and ethambutol, and isoniazid and rifampin. Short-term and intermittent therapy, and retreatment of previous infections, are discussed. The toxicity of isoniazid, ethambutol, rifampin and streptomycin is summarized. Other topics are the use of second-line drugs (aminosalicylic acid, pyrazinamide, cycloserine and ethionamide), hospitalization of tuberculosis patients, chemoprophylaxis, follow-up of patients with isoniazid prophylaxis, and the use of corticosteroids.

    Topics: Adrenal Cortex Hormones; Antitubercular Agents; Ethambutol; Follow-Up Studies; Humans; Isoniazid; Rifampin; Time Factors; Tuberculosis

1976
Diagnosis, prevention and early therapy of tuberculosis.
    Disease-a-month : DM, 1976, Volume: 22, Issue:8

    Topics: Aminosalicylic Acids; Ethambutol; Female; Humans; Hypersensitivity, Delayed; Isoniazid; Male; Mycobacterium tuberculosis; Recurrence; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Cardiovascular; Tuberculosis, Female Genital; Tuberculosis, Lymph Node; Tuberculosis, Male Genital; Tuberculosis, Meningeal; Tuberculosis, Osteoarticular; Tuberculosis, Pulmonary; Tuberculosis, Renal; United States

1976
Treatment of tuberculosis.
    Advances in internal medicine, 1975, Volume: 20

    Topics: Adult; Aminosalicylic Acids; Capreomycin; Child; Cycloserine; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Streptomycin; Time Factors; Tuberculosis; Viomycin

1975
New trends in the chemotherapy of tuberculosis--current aspects.
    Pneumonologie. Pneumonology, 1974, Jun-14, Volume: 150, Issue:1

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Ethionamide; Follow-Up Studies; Humans; Isoniazid; Pyrazinamide; Rifampin; Sputum; Streptomycin; Thioacetazone; Time Factors; Tuberculosis

1974
[Pregnancy and tuberculosis].
    Medizinische Klinik, 1974, Oct-04, Volume: 69, Issue:40

    Topics: Abortion, Therapeutic; Adult; Antitubercular Agents; Birth Rate; Female; Fetal Diseases; Germany, West; Humans; Isoniazid; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Infectious; Radiation Dosage; Recurrence; Rifampin; Streptomycin; Tuberculosis

1974
Tuberculosis.
    British medical journal, 1973, May-05, Volume: 2, Issue:5861

    Topics: Aminosalicylic Acids; Bronchitis; Cough; Diagnosis, Differential; Ethambutol; Humans; Isoniazid; Mass Screening; Rifampin; Streptomycin; Thioacetazone; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary

1973
[Proceedings: Tuberculosis therapy. Review on today's knowledge, developmental trends and still open problems].
    Zeitschrift fur Erkrankungen der Atmungsorgane mit Folia bronchologica, 1973, Volume: 138, Issue:1

    Topics: Aminosalicylic Acids; Antitubercular Agents; Capreomycin; Dose-Response Relationship, Drug; Drug Combinations; Drug Resistance, Microbial; Ethambutol; Ethionamide; Germany, West; Humans; Isoniazid; Length of Stay; Rifampin; Streptomycin; Tuberculosis

1973
Acute forms of tuberculosis.
    The Medical clinics of North America, 1973, Volume: 57, Issue:6

    Topics: Acute Disease; Antitubercular Agents; Child; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Isoniazid; Lung; Middle Aged; Mycobacterium tuberculosis; Peritonitis, Tuberculous; Pneumonia; Radiography; Rifampin; Sputum; Tuberculosis; Tuberculosis, Cardiovascular; Tuberculosis, Meningeal; Tuberculosis, Miliary

1973
Therapeutics. XVII. "Reserve" drugs in the treatment of tuberculosis.
    The British journal of dermatology, 1972, Volume: 86, Issue:2

    Topics: Chemical and Drug Induced Liver Injury; Costs and Cost Analysis; Drug Eruptions; Drug Resistance, Microbial; Ethambutol; Humans; Liver; Optic Neuritis; Rifampin; Thioacetazone; Tuberculosis

1972
Rifampin: a semisynthetic derivative of rifamycin--a prototype for the future.
    Annual review of microbiology, 1972, Volume: 26

    Topics: Animals; Antibiotics, Antineoplastic; Antitubercular Agents; Antiviral Agents; Bacteria; Bacterial Infections; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemistry; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Humans; Leprosy; Microbial Sensitivity Tests; Rifampin; Tuberculosis

1972
[Antitubercular agents].
    Internationale Zeitschrift fur klinische Pharmakologie, Therapie, und Toxikologie. International journal of clinical pharmacology, therapy, and toxicology, 1971, Volume: 4, Issue:4

    Topics: Anti-Bacterial Agents; Antitubercular Agents; Cycloserine; Kanamycin; Neomycin; Oxytetracycline; Peptides; Rifampin; Streptomycin; Tuberculosis; Viomycin

1971
[Rifampicin and its clinical use].
    Wiadomosci lekarskie (Warsaw, Poland : 1960), 1971, Jul-01, Volume: 24, Issue:3

    Topics: Administration, Oral; Animals; Bacteria; Drug Tolerance; Humans; Intestinal Absorption; Liver; Rifampin; Time Factors; Tuberculosis; Urinary Tract Infections

1971
[New anti-tubercular agents--rifampicin and ethambutol].
    Klinicheskaia meditsina, 1971, Volume: 49, Issue:5

    Topics: Adolescent; Adult; Aged; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

1971
Rifampicin: a review.
    Drugs, 1971, Volume: 1, Issue:5

    Topics: Abnormalities, Drug-Induced; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Infections; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Resistance, Microbial; Endocarditis, Bacterial; Gonorrhea; Humans; Intestinal Absorption; Leprosy; Meningococcal Infections; Mycobacterium; Respiratory Tract Infections; Rifampin; Thrombocytosis; Tuberculosis; Tuberculosis, Pulmonary; Urologic Diseases; Viruses

1971
[New antitubercular drugs and their clinical use].
    Polski tygodnik lekarski (Warsaw, Poland : 1960), 1971, Feb-15, Volume: 26, Issue:7

    Topics: Administration, Oral; Age Factors; Anti-Bacterial Agents; Antitubercular Agents; Chronic Disease; Drug Resistance, Microbial; Drug Synergism; Drug Tolerance; Ethambutol; Fasting; Humans; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

1971
Chemical and biological properties of rifampicin.
    Antibiotica et chemotherapia. Fortschritte. Advances. Progres, 1970, Volume: 16

    Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Chemical Phenomena; Chemistry; Dogs; Drug Resistance, Microbial; Female; Guinea Pigs; Humans; Male; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rabbits; Rats; Rifampin; Staphylococcal Infections; Tuberculosis

1970
Advances in the treatment of respiratory disorders.
    The Practitioner, 1969, Volume: 203, Issue:216

    Topics: Acute Disease; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Aerosols; Asthma; Bronchitis; Chromones; Chronic Disease; Ethambutol; Humans; Mycoplasma Infections; Respiratory Insufficiency; Respiratory Tract Diseases; Respiratory Tract Infections; Rifampin; Tuberculosis; Tuberculosis, Pulmonary; Virus Diseases

1969
[Experimental chemotherapy of tuberculosis].
    Zeitschrift fur Erkrankungen der Atmungsorgane mit Folia bronchologica, 1969, Volume: 130, Issue:5

    Topics: Aminosalicylic Acids; Antitubercular Agents; Cycloserine; Drug Synergism; Ethambutol; Ethionamide; Humans; Isoniazid; Phenylthiourea; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1969
Advances in antibiotics.
    The Practitioner, 1969, Volume: 203, Issue:216

    Topics: Adult; Anti-Bacterial Agents; Cephaloridine; Enterobacteriaceae Infections; Fusidic Acid; Gentamicins; Humans; Infant; Infections; Lincomycin; Nalidixic Acid; Penicillin Resistance; Penicillins; Pseudomonas Infections; Respiratory Tract Infections; Rifampin; Sulfamethoxazole; Tuberculosis; Urinary Tract Infections

1969
[New drugs in antitubercular therapy].
    Helvetica medica acta. Supplementum, 1969, Volume: 49

    Topics: Aminosalicylic Acids; Anti-Bacterial Agents; Antitubercular Agents; Ethambutol; Humans; Isoniazid; Rifampin; RNA Nucleotidyltransferases; Tuberculosis; Tuberculosis, Pulmonary

1969

Trials

174 trial(s) available for rifampin and Tuberculosis

ArticleYear
Decreased Dolutegravir and Efavirenz Concentrations With Preserved Virological Suppression in Patients With Tuberculosis and Human Immunodeficiency Virus Receiving High-Dose Rifampicin.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023, 02-08, Volume: 76, Issue:3

    Higher doses of rifampicin may improve treatment outcomes and reduce the duration of tuberculosis (TB) therapy. However, drug-drug interactions with antiretroviral therapy (ART) and safety in people with human immunodeficiency virus (HIV) have not been evaluated.. This was a randomized, open-label trial where newly diagnosed TB patients were randomized to higher (35 mg/kg) or standard (10 mg/kg) daily-dose rifampicin. ART treatment-naive patients were randomized to dolutegravir- or efavirenz-based ART. At week 6, trough dolutegravir or mid-dose efavirenz plasma concentrations were assayed. HIV viral load was measured at week 24.. Among 128 patients randomized, the median CD4 count was 191 cells/mm3. The geometric mean ratio (GMR) for trough dolutegravir concentrations on higher- vs standard-dose rifampicin was 0.57 (95% confidence interval [CI], .34-.97; P = .039) and the GMR for mid-dose efavirenz was 0.63 (95% CI, .38-1.07; P = .083). There was no significant difference in attainment of targets for dolutegravir trough or efavirenz mid-dose concentrations between rifampicin doses. The incidence of HIV treatment failure at week 24 was similar between rifampicin doses (14.9% vs 14.0%, P = .901), as was the incidence of drug-related grade 3-4 adverse events (9.8% vs 6%). At week 8, fewer patients remained sputum culture positive on higher-dose rifampicin (18.6% vs 37.0%, P = .063).. Compared with standard-dose rifampicin, high-dose rifampicin reduced dolutegravir and efavirenz exposures, but HIV suppression was similar across treatment arms. Higher-dose rifampicin was well tolerated among people with HIV and associated with a trend toward faster sputum culture conversion.. NCT03982277.

    Topics: Anti-HIV Agents; Benzoxazines; HIV; HIV Infections; Humans; Rifampin; Tuberculosis

2023
Rifapentine With and Without Moxifloxacin for Pulmonary Tuberculosis in People With Human Immunodeficiency Virus (S31/A5349).
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023, 02-08, Volume: 76, Issue:3

    Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH).. PWH and CD4+ counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz.. A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/μL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%).. In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/μL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe.. NCT02410772.

    Topics: Antitubercular Agents; Drug Therapy, Combination; HIV; HIV Infections; Humans; Isoniazid; Moxifloxacin; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2023
Pharmacokinetics of dose-adjusted levonorgestrel emergency contraception combined with efavirenz-based antiretroviral therapy or rifampicin-containing tuberculosis regimens.
    Contraception, 2023, Volume: 121

    To determine if double-dose levonorgestrel emergency contraception (EC) in combination with efavirenz or rifampicin, 2 drugs known to decrease levonorgestrel exposure, resulted in similar pharmacokinetics compared to standard-dose levonorgestrel EC without drug-drug interactions.. We conducted a phase 2, open-label, multicenter, partially randomized, 4 parallel group trial in pre-menopausal females ≥16 years old without an indication for EC and not on hormonal contraception. Participants on dolutegravir-based antiretroviral therapy (ART) received levonorgestrel 1.5 mg (control group); those on rifampicin-containing tuberculosis therapy received levonorgestrel 3 mg; those on efavirenz-based ART were randomized 1:2 to levonorgestrel 1.5 mg or 3 mg. Plasma was collected through 48 hours post-dose to assess levonorgestrel pharmacokinetics. Area under the concentration-time curve (AUC) over 8 hours was the primary outcome. Levonorgestrel pharmacokinetic parameters were compared between groups using geometric mean ratios (GMR) with 90% confidence intervals.. The median (Q1, Q3) age for all participants (n = 118) was 34 (27, 41) years and BMI was 23.2 (20, 26.3) kg/m. Doubling the dose of levonorgestrel EC successfully increased levonorgestrel exposure over the first 8 hours in participants receiving either efavirenz-based ART or rifampicin-containing tuberculosis therapy.. Adjusting levonorgestrel emergency contraception from 1.5 mg to 3 mg improves levonorgestrel pharmacokinetic exposure in participants receiving either efavirenz-based antiretroviral regimens or rifampicin-containing tuberculosis therapy. These data support guideline recommendations to double the dose of levonorgestrel emergency contraception in persons on medications that decrease levonorgestrel exposure by inducing levonorgestrel metabolism.

    Topics: Adolescent; Benzoxazines; Contraception, Postcoital; Female; HIV Infections; Humans; Levonorgestrel; Rifampin; Tuberculosis

2023
Factors Associated With Discontinuation of Tuberculosis Preventive Treatment: Post Hoc Analysis of 2 Randomized, Controlled Trials.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023, 07-05, Volume: 77, Issue:1

    Adherence to tuberculosis preventive treatment (TPT) is an important determinant of clinical benefit. We assessed the association of participant behaviors early in TPT with subsequent discontinuation.. We used data from a phase 3 randomized trial and the preceding phase 2 trial to compare 4 months of rifampin to 9 months of isoniazid for TPT. We excluded participants whose providers discontinued TPT due to adverse events or tuberculosis disease. We analyzed 4 outcomes: discontinuing TPT within the first month of treatment, discontinuing TPT between the first and second month, discontinuing TPT after the second month, and completing treatment but not per protocol. We analyzed the association of outcomes with regimen and participant characteristics and 4 behavioral predictors of discontinuation recorded at the month 1 and month 2 follow-up visits: reporting symptoms of intolerance, missing >20% of doses, rescheduling appointments, and not bringing their medication bottle.. Overall, 6656 participants were included (phase 3, 5848; phase 2, 808), of whom 4318 (64.9%) completed treatment per protocol. Participant characteristics were inconsistently associated with discontinuation. Phase 3 trial participants with 1, 2, or 3-4 behavioral predictors at the month 1 follow-up had 5.0 (95% confidence interval, 3.6-6.7), 18.6 (13.3-26.1), and 79.4 (38.2-165.0), respectively, higher odds of discontinuing before the second month. The corresponding number of predictors at the month 2 follow-up had 1.8 (1.4-2.2), 4.7 (3.6-6.2), and 7.4 (4.6-11.9) higher odds of discontinuing before completing treatment; phase 2 findings were similar.. Four behavioral predictors recorded early in therapy were more strongly associated with subsequent discontinuation than participant characteristics, particularly when more than 1 behavioral predictor was recorded. Clinical Trials Registration. NCT00170209; NCT00931736.

    Topics: Antitubercular Agents; Clinical Protocols; Drug Administration Schedule; Humans; Isoniazid; Rifampin; Tuberculosis

2023
Rosuvastatin adjunctive therapy for rifampicin-susceptible pulmonary tuberculosis: a phase 2b, randomised, open-label, multicentre trial.
    The Lancet. Infectious diseases, 2023, Volume: 23, Issue:7

    Shorter treatments are needed for drug-susceptible tuberculosis. Adjunctive statins increase bactericidal activity in preclinical tuberculosis models. We investigated the safety and efficacy of adjunctive rosuvastatin in people with tuberculosis. We tested the hypothesis that adjunctive rosuvastatin accelerates sputum culture conversion within the first 8 weeks of treatment of rifampicin-susceptible tuberculosis.. This phase 2b, randomised, open-label, multicentre trial conducted in five hospitals or clinics in three countries with high tuberculosis burden (ie, the Philippines, Viet Nam, and Uganda) enrolled adult participants aged 18-75 years with sputum smear or Xpert MTB/RIF positive, rifampicin-susceptible tuberculosis who had received less than 7 days of previous tuberculosis treatment. Participants were randomly assigned via a web-based system to receive either 10 mg rosuvastatin once per day for 8 weeks plus standard tuberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol; rosuvastatin group) or standard tuberculosis therapy alone (control group). Randomisation was stratified by trial site, history of diabetes, and HIV co-infection. Laboratory staff and central investigators involved in data cleaning and analysis were masked to treatment allocation, but study participants and site investigators were not. Both groups continued standard treatment to week 24. Sputum samples were collected once per week for the first 8 weeks after randomisation, and then at weeks 10, 12, and 24. The primary efficacy outcome was time to culture conversion (TTCC; days) in liquid culture by week 8, assessed in randomised participants who had microbiological confirmation of tuberculosis, took at least one dose of rosuvastatin, and who did not show resistance to rifampicin (modified intention-to-treat population), for which groups were compared with the Cox proportional hazards model. The main safety outcome was grade 3-5 adverse events by week 24, assessed in the intention-to-treat population, for which groups were compared with Fisher's exact test. All participants completed 24 weeks of follow-up. This trial is registered with ClinicalTrials.gov (NCT04504851).. Between Sept 2, 2020, and Jan 14, 2021, 174 participants were screened and 137 were randomly assigned to the rosuvastatin group (70 participants) or control group (67 participants). In the modified intention-to-treat population of 135 participants, 102 (76%) were men and 33 (24%) were women. Median TTCC in liquid media was 42 days (95% CI 35-49) in the rosuvastatin group (68 participants) and 42 days (36-53) in the control group (67 participants; hazard ratio 1·30 [0·88-1·91], p=0·19). Grade 3-5 adverse events occurred in six (9%) of 70 in the rosuvastatin group (none were considered related to rosuvastatin) and four (6%) of 67 in the control group (p=0·75). There were no serious adverse events that were considered to be related to rosuvastatin.. Adjunctive rosuvastatin at 10 mg once per day was safe but did not produce substantive benefits on culture conversion in the overall study population. Future trials could explore the safety and efficacy of higher doses of adjunctive rosuvastatin.. National Medical Research Council, Singapore.

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Male; Rifampin; Rosuvastatin Calcium; Tuberculosis; Tuberculosis, Pulmonary

2023
Model-based analysis of bactericidal activity and a new dosing strategy for optimised-dose rifampicin.
    International journal of antimicrobial agents, 2023, Volume: 61, Issue:6

    Higher doses of rifampicin for tuberculosis have been shown to improve early bactericidal activity (EBA) and at the same time increase the intolerability due to high exposure at the beginning of treatment. To support dose optimisation of rifampicin, this study investigated new and innovative staggered dosing of rifampicin using clinical trial simulations to minimise tolerability problems and still achieve good efficacy.. Rifampicin population pharmacokinetics and time-to-positivity models were applied to data from patients receiving 14 days of daily 10-50 mg/kg rifampicin to characterise the exposure-response relationship. Furthermore, clinical trial simulations of rifampicin exposure were performed following four different staggered dosing scenarios. The simulated exposure after 35 mg/kg was used as a relative comparison for efficacy. Tolerability was derived from a previous model-based analysis relating exposure at day 7 and the probability of having adverse events.. The linear relationship between rifampicin exposure and bacterial killing rate in sputum indicated that the maximum rifampicin EBA was not reached at doses up to 50 mg/kg. Clinical trial simulations of a staggered dosing strategy starting the treatment at a lower dose (20 mg/kg) for 7 days followed by a higher dose (40 mg/kg) predicted a lower initial exposure with lower probability of tolerability problems and better EBA compared with a regimen of 35 mg/kg daily.. Staggered dosing of 20 mg/kg for 7 days followed by 40 mg/kg is predicted to reduce tolerability while maintaining exposure levels associated with better efficacy.

    Topics: Antitubercular Agents; Humans; Rifampin; Sputum; Tuberculosis

2023
Optimizing (O) rifapentine-based (RI) regimen and shortening (EN) the treatment of drug-susceptible tuberculosis (T) (ORIENT) using an adaptive seamless design: study protocol of a multicenter randomized controlled trial.
    BMC infectious diseases, 2023, May-08, Volume: 23, Issue:1

    Standard treatment for drug-susceptible tuberculosis (DS-TB) includes a multidrug regimen requiring at least 6 months of treatment, and this lengthy treatment easily leads to poor adherence. There is an urgent need to simplify and shorten treatment regimens to reduce interruption and adverse event rates, improve compliance, and reduce costs.. ORIENT is a multicenter, randomized controlled, open-label, phase II/III, non-inferiority trial involving DS-TB patients to evaluate the safety and efficacy of short-term regimens compared with the standardized six-month treatment regimen. In stage 1, corresponding to a phase II trial, a total of 400 patients are randomly divided into four arms, stratified by site and the presence of lung cavitation. Investigational arms include 3 short-term regimens with rifapentine 10 mg/kg, 15 mg/kg, and 20 mg/kg, while the control arm uses the standardized six-month treatment regimen. A combination of rifapentine, isoniazid, pyrazinamide, and moxifloxacin is administered for 17 or 26 weeks in rifapentine arms, while a 26-week regimen containing rifampicin, isoniazid, pyrazinamide, and ethambutol is applied in the control arm. After the safety and preliminary effectiveness analysis of patients in stage 1, the control arm and the investigational arm meeting the conditions will enter into stage 2, which is equivalent to a phase III trial and will be expanded to recruit DS-TB patients. If all investigational arms do not meet the safety conditions, stage 2 will be canceled. In stage 1, the primary safety endpoint is permanent regimen discontinuation at 8 weeks after the first dose. The primary efficacy endpoint is the proportion of favorable outcomes at 78 weeks after the first dose for both two stages.. This trial will contribute to the optimal dose of rifapentine in the Chinese population and suggest the feasibility of the short-course treatment regimen containing high-dose rifapentine and moxifloxacin for DS-TB.. The trial has been registered on ClinicalTrials.gov on 28 May 2022 with the identifier NCT05401071.

    Topics: Clinical Trials, Phase II as Topic; Humans; Isoniazid; Moxifloxacin; Multicenter Studies as Topic; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis

2023
Standard-dose versus double-dose dolutegravir in HIV-associated tuberculosis in South Africa (RADIANT-TB): a phase 2, non-comparative, randomised controlled trial.
    The lancet. HIV, 2023, Volume: 10, Issue:7

    The drug-drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy.. RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 24 analysed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03851588.. Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis.. Wellcome Trust.

    Topics: Adult; Anti-Retroviral Agents; Antitubercular Agents; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Infant; Isoniazid; Lamivudine; Rifampin; RNA; South Africa; Tenofovir; Tuberculosis; Viral Load

2023
    Zeitschrift fur Gesundheitswissenschaften = Journal of public health, 2023, Jun-08

    To develop the 'Stronger Towns Index': a deprivation index that took into account characteristics of areas encompassing towns that may be eligible for redevelopment funding and explore how this index was associated with self-rated health and migration within England between 2001 and 2011.. There were areas in the lowest deciles of Town Strength who did not receive funding. After multiple adjustment, LS members living in areas with higher deciles were significantly more likely (7% to 38%) to report good health than those in the lowest decile in 2001. Remaining in the same decile between 2001 and 2011 was associated with 7% lower odds of good self-rated health in 2011.. It is important to consider health in towns when allocating funding. Areas in the Midlands may have missed out on funding which might help mitigate poor health.. Ferritin levels <30µg/L were associated with unexplained infertility and might be screened in the future. Further studies with a focus on iron deficiency and iron treatment on women with unexplained infertility are warranted.. This EGM provides a valuable resource for researchers, policy-makers and the public to access the available evidence on the determinants of various COVID-19 health-related behaviours. The map can also be used to help guide research commissioning, by evidence synthesis teams and evidence intermediaries to inform policy during the ongoing pandemic and potential future outbreaks of COVID-19 or other respiratory infections. Evidence included in the map will be explored further through a series of systematic reviews examining the strength of the associations between malleable determinants and the uptake and maintenance of individual protective behaviours.. Patients with polymicrobial bloodstream infections are typically critically ill and harbor multidrug-resistant bacteria. Thus, to minimize mortality rate in critically ill patients, changes in infectious flora should be monitored, antibiotics selected reasonably, and invasive procedures reduced.. Altogether, these findings clearly revealed the great potential of the in vitro biological activity of linseed extract as a safe source for combatting multidrug-resistant. In this work, the capture of carbon dioxide using a dense hollow fiber membrane was studied experimentally and theoretically. The factors affecting the flux and recovery of carbon dioxide were studied using a lab-scale system. Experiments were conducted using a mixture of methane and carbon dioxide to simulate natural gas. The effect of changing the CO. Persistent gender and racial disparities in high-impact medical and critical care journals underscore the need to revise policies and strategies to encourage greater diversity in critical care research.. Thirty evaluable patients were enrolled. Median age was 60.5 years. Median follow-up for all patients was 17 months. Ten patients (33%) experienced grade ≥ 3 treatment-related adverse events, the most common being neutropenia and diarrhea; 50% required ≥ 1 dose reduction. The disease control rate was 90% (progressive disease: 10%, partial response: 23%, stable disease: 67%). There was zero treatment-related mortality. Twenty-two patients (73%, 90% CI 57-86; p = 0.008) completed all chemotherapy and surgery. Two patients (9%) who successfully underwent resection had minor postoperative complications. Median length of hospital stay was 4 days. Median RFS was 7.1 months. Median OS for the entire cohort was 24 months and was not reached in patients who underwent surgical resection.. Neoadjuvant treatment with gemcitabine, cisplatin, and nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes.

    Topics: Acetogenins; Acute Disease; Acute Kidney Injury; Administration, Intravenous; Aged; Albumins; Alcoholism; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; alpha-Glucosidases; Anemia; Animals; Anthozoa; Anti-Bacterial Agents; Anti-Infective Agents; Antibodies, Bacterial; Antigens, Bacterial; Antihypertensive Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Apoptosis; Ascites; Asthma; Bacteria; beta-Lactamases; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Binding Sites; Biological Availability; Biomass; Borderline Personality Disorder; Brain; Brucella abortus; Brucella melitensis; Brucellosis; Calcium; Carbapenems; Case-Control Studies; Caseins; Cattle; CD8-Positive T-Lymphocytes; Ceftaroline; Cell Line; Cell Line, Tumor; Cell Physiological Phenomena; Cell Proliferation; Cephalosporins; Chemotherapy, Adjuvant; China; Chitin; Chlorella; Chlorophyll; Chlorophyll A; Chlorophyta; Cholangiocarcinoma; Cisplatin; Conotoxins; Contrast Media; Conus Snail; Cross-Sectional Studies; Cytokines; Decapodiformes; Deoxycytidine; Diagnostic and Statistical Manual of Mental Disorders; Dietary Fiber; Diterpenes; DNA Methylation; Dogs; Double-Blind Method; Drug Design; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Screening Assays, Antitumor; Eicosapentaenoic Acid; Enzyme-Linked Immunosorbent Assay; Epidermis; Escherichia coli; Escherichia coli Infections; Extraintestinal Pathogenic Escherichia coli; Fatty Acids; Fatty Acids, Unsaturated; Fatty Acids, Volatile; Feasibility Studies; Feces; Female; Ferritins; Fluorodeoxyglucose F18; Gastrectomy; Gastrointestinal Microbiome; Gemcitabine; Glomerular Filtration Rate; Glucose; Glycerol; Granulocyte-Macrophage Colony-Stimulating Factor; HeLa Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Immunoassay; Immunoglobulin G; India; Infant, Newborn; Infertility; Inflammation; Intensive Care Units; Iron; Iron Deficiencies; Kidney; Lacticaseibacillus rhamnosus; Laurencia; Leukocytes; Lipids; Liver Cirrhosis; Long Interspersed Nucleotide Elements; Longitudinal Studies; Male; Mesenchymal Stem Cells; Methicillin-Resistant Staphylococcus aureus; Mice; Microalgae; Microbial Sensitivity Tests; Microscopy; Middle Aged; Minerals; Molecular Conformation; Molecular Docking Simulation; Molecular Structure; Mycobacterium tuberculosis; Myeloid Cells; Myeloid-Derived Suppressor Cells; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Nephropidae; Nicotinic Antagonists; Nitrogen; Obesity; Oxaliplatin; Paclitaxel; Panax; Pancreatic Neoplasms; Pancreatitis; Personality; Personality Disorders; Personality Inventory; Photobioreactors; Plant Extracts; Plasmalogens; Plasmids; Polymorphism, Genetic; Polynesia; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Prebiotics; Predictive Value of Tests; Prognosis; Prolyl-Hydroxylase Inhibitors; Rabbits; Radiopharmaceuticals; Rats; Rats, Wistar; Receptors, Nicotinic; Recombinant Proteins; Retrospective Studies; Rifampin; Risk Factors; RNA, Ribosomal, 16S; Salinity; Seaweed; Sensitivity and Specificity; Sepsis; Sesquiterpenes; Severity of Illness Index; Shock, Septic; Silicones; Single Photon Emission Computed Tomography Computed Tomography; Skin; Snails; Solubility; Solvents; Sputum; Staphylococcal Infections; Stomach Neoplasms; Stramenopiles; Structure-Activity Relationship; Technetium Tc 99m Exametazime; Technology; Terpenes; Tuberculosis; Tuberculosis, Multidrug-Resistant; Urinary Catheters; Urinary Tract Infections; Vascular Endothelial Growth Factor A; Virulence Factors; Water; Wound Healing

2023
Efavirenz Pharmacokinetics and Human Immunodeficiency Virus Type 1 (HIV-1) Viral Suppression Among Patients Receiving Tuberculosis Treatment Containing Daily High-Dose Rifapentine.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022, 09-10, Volume: 75, Issue:4

    A 4-month regimen containing rifapentine and moxifloxacin has noninferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB).. In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing antiretroviral therapy (ART) (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200 mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB cotreatment (Weeks 4, 8, 12, and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if > 80% of participants had mid-interval efavirenz concentrations meeting this target.. EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs without TB drugs was 0.79 (90% confidence interval [CI] .72-.85) in EFV1 and 0.84 [90% CI .69-.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations > 1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%.. TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment.. NCT02410772.

    Topics: Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; HIV Infections; HIV-1; Humans; Moxifloxacin; Rifampin; Tuberculosis

2022
Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children.
    The New England journal of medicine, 2022, 03-10, Volume: 386, Issue:10

    Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen.. We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment.. From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups).. Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).

    Topics: Adolescent; Africa; Antitubercular Agents; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; India; Infant; Intention to Treat Analysis; Isoniazid; Male; Patient Acuity; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2022
Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin: a study protocol of a phase II clinical trial (HighShort-RP).
    BMJ open, 2022, 03-10, Volume: 12, Issue:3

    Increased dosing of rifampicin and pyrazinamide seems a viable strategy to shorten treatment and prevent relapse of drug-susceptible tuberculosis (TB), but safety and efficacy remains to be confirmed. This clinical trial aims to explore safety and pharmacokinetics-pharmacodynamics of a high-dose pyrazinamide-rifampicin regimen.. Adult patients with pulmonary TB admitted to six hospitals in Sweden and subjected to receive first-line treatment are included. Patients are randomised (1:3) to either 6-month standardised TB treatment or a 4-month regimen based on high-dose pyrazinamide (40 mg/kg) and rifampicin (35 mg/kg) along with standard doses of isoniazid and ethambutol. Plasma samples for measurement of drug exposure determined by liquid chromatography tandem-mass spectrometry are obtained at 0, 1, 2, 4, 6, 8, 12 and 24 hours, at day 1 and 14. Maximal drug concentration (C. The study is approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. Informed written consent is collected before study enrolment. The study results will be submitted to a peer-reviewed journal.. NCT04694586.

    Topics: Adult; Antitubercular Agents; Clinical Trials, Phase II as Topic; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Randomized Controlled Trials as Topic; Recurrence; Rifampin; Tuberculosis

2022
Pregnancy in Women With HIV in a Tuberculosis Preventive Therapy Trial.
    Journal of acquired immune deficiency syndromes (1999), 2022, 12-01, Volume: 91, Issue:4

    Tuberculosis preventive therapy (TPT) is recommended for people with HIV infection, including during pregnancy. The effect of TPT exposure at conception and during pregnancy is poorly documented.. We report pregnancy outcomes among South African women with HIV enrolled in a randomized trial of 4 TPT regimens (two 3-month regimens, rifapentine/isoniazid [3HP] or rifampin/isoniazid [3HR], isoniazid for 6 months, or isoniazid continuously). Descriptive statistics and risk ratios were assessed to examine relationships between study regimens and outcomes.. 216/896 women (24%) conceived during the study. Women who conceived were younger (27.9 vs 31.3 years) and had higher mean CD4 counts (589.1 vs 536.7). The odds of pregnancy were higher in women in the rifamycin-isoniazid arms than those in the isoniazid arms (3HP: relative risk [RR] 1.73, P = 0.001; 3HR:RR 1.55, P = 0.017) despite increased contraceptive use compared with the standard 6H therapy. Thirty-four women became pregnant while taking preventive treatment (8 rifamycin and 26 isoniazid monotherapy). Pregnancy outcomes in these women were as follows: 17 (50%) mother/baby healthy, 3 (9%) spontaneous abortions, 6 (18%) elective abortions, 1 (3%) premature delivery, 2 (6%) neonatal deaths [1 rifamycin-isoniazid and 1 isoniazid], and 5 (15%) unknown.. Pregnancy was common in women who had received TPT and more frequent in women who had received rifamycin-isoniazid-based regimens.

    Topics: Antitubercular Agents; Contraceptive Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant, Newborn; Isoniazid; Latent Tuberculosis; Pregnancy; Rifampin; Rifamycins; Tuberculosis

2022
Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis.
    The New England journal of medicine, 2022, 09-01, Volume: 387, Issue:9

    The bedaquiline-pretomanid-linezolid regimen has been reported to have 90% efficacy against highly drug-resistant tuberculosis, but the incidence of adverse events with 1200 mg of linezolid daily has been high. The appropriate dose of linezolid and duration of treatment with this agent to minimize toxic effects while maintaining efficacy against highly drug-resistant tuberculosis are unclear.. We enrolled participants with extensively drug-resistant (XDR) tuberculosis (i.e., resistant to rifampin, a fluoroquinolone, and an aminoglycoside), pre-XDR tuberculosis (i.e., resistant to rifampin and to either a fluoroquinolone or an aminoglycoside), or rifampin-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. We randomly assigned the participants to receive bedaquiline for 26 weeks (200 mg daily for 8 weeks, then 100 mg daily for 18 weeks), pretomanid (200 mg daily for 26 weeks), and daily linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks. The primary end point in the modified intention-to-treat population was the incidence of an unfavorable outcome, defined as treatment failure or disease relapse (clinical or bacteriologic) at 26 weeks after completion of treatment. Safety was also evaluated.. A total of 181 participants were enrolled, 88% of whom had XDR or pre-XDR tuberculosis. Among participants who received bedaquiline-pretomanid-linezolid with linezolid at a dose of 1200 mg for 26 weeks or 9 weeks or 600 mg for 26 weeks or 9 weeks, 93%, 89%, 91%, and 84%, respectively, had a favorable outcome; peripheral neuropathy occurred in 38%, 24%, 24%, and 13%, respectively; myelosuppression occurred in 22%, 15%, 2%, and 7%, respectively; and the linezolid dose was modified (i.e., interrupted, reduced, or discontinued) in 51%, 30%, 13%, and 13%, respectively. Optic neuropathy developed in 4 participants (9%) who had received linezolid at a dose of 1200 mg for 26 weeks; all the cases resolved. Six of the seven unfavorable microbiologic outcomes through 78 weeks of follow-up occurred in participants assigned to the 9-week linezolid groups.. A total of 84 to 93% of the participants across all four bedaquiline-pretomanid-linezolid treatment groups had a favorable outcome. The overall risk-benefit ratio favored the group that received the three-drug regimen with linezolid at a dose of 600 mg for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications. (Funded by the TB Alliance and others; ZeNix ClinicalTrials.gov number, NCT03086486.).

    Topics: Aminoglycosides; Antitubercular Agents; Diarylquinolines; Fluoroquinolones; Humans; Linezolid; Nitroimidazoles; Rifampin; Risk Assessment; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
INSTIs for the management of HIV-associated TB (INSIGHT study): a phase 2b study to evaluate the efficacy, safety and pharmacokinetics of a combination of bictegravir, emtricitabine and tenofovir alafenamide fumarate for the treatment of HIV-1 infection i
    BMJ open, 2022, 11-10, Volume: 12, Issue:11

    Cotreatment of HIV and tuberculosis (TB) reduces morbidity and mortality in coinfected patients. Availability of antiretroviral treatment (ART) drug options, including within drug classes, is important, particularly in high HIV/TB burden low and middle-income countries.. This is a phase 2b, open-label, non-comparative randomised controlled trial to assess the antiretroviral activity of a fixed-drug, single tablet, combination of bictegravir (BIC) 50 mg/emtricitabine (FTC) 200 mg/tenofovir alafenamide (TAF) 25 mg (Biktarvy). The primary objective is to determine the efficacy, safety and pharmacokinetics of two times per day, coformulated BIC 50 mg/FTC 200 mg/TAF 25 mg in HIV-positive ART-naïve patients with TB who are receiving a rifampicin-based treatment regimen and to characterise viral suppression rates at week 24 through to week 48 in the BIC/FTC/TAF arm. We will enrol 120 patients randomised in a 2:1 ratio to the intervention or control arm of the study. A non-comparative contemporaneous control arm in which participants receive a dolutegravir-based regimen (standard of care) will also be enrolled.. The University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and the South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval (trial reference numbers: BREC/00001300/2020 and SAHPRA 20200810). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry.. Clinicaltrials.gov; Trial registration number: NCT04734652; South African National Clinical Trials Register (SANCTR DOH-27-012021-6789).

    Topics: Adenine; Anti-HIV Agents; Anti-Retroviral Agents; Emtricitabine; Fumarates; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Pyridones; Rifampin; Tuberculosis

2022
Pharmacokinetics and Safety of 3 Months of Weekly Rifapentine and Isoniazid for Tuberculosis Prevention in Pregnant Women.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022, 05-03, Volume: 74, Issue:9

    Pregnancy increases the risk of tuberculosis and its complications. A 3-month regimen of weekly isoniazid and rifapentine (3HP) is safe and effective for tuberculosis prevention in adults and children, including those with HIV, but 3HP has not been evaluated in pregnancy.. IMPAACT 2001 was a phase I/II trial evaluating the pharmacokinetics and safety of 3HP among pregnant women with indications for tuberculosis preventative therapy in Haiti, Kenya, Malawi, Thailand, and Zimbabwe (NCT02651259). Isoniazid and rifapentine were provided at standard doses (900 mg/week). Pharmacokinetic sampling was performed with the first (second/third trimester) and twelfth (third trimester/postpartum) doses. Nonlinear mixed-effects models were used to estimate drug population pharmacokinetics.. Of 50 participants, 20 had HIV and were taking efavirenz-based antiretroviral therapy. Among women without HIV, clearance of rifapentine was 28% lower during pregnancy than postpartum (1.20 vs 1.53 L/hour, P < .001), with area under the concentration-time curve (AUCSS) of 786 and 673 mg × hour/L, respectively. In pregnant women with HIV, clearance was 30% higher than women without HIV (P < .001), resulting in lower AUCss (522 mg × hour/L); clearance did not change significantly between pregnancy and postpartum. Pregnancy did not impact isoniazid pharmacokinetics. There were no drug-related serious adverse events, treatment discontinuations, or tuberculosis cases in women or infants.. 3HP does not require dose adjustment in pregnancy. Rifapentine clearance is higher among women with HIV, but all women achieved exposures of rifapentine and isoniazid associated with successful tuberculosis prevention. The data support proceeding with larger safety-focused studies of 3HP in pregnancy.. ClinicalTrials.gov, NCT02651259.

    Topics: Adult; Antitubercular Agents; Child; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Pregnancy; Pregnant Women; Rifampin; Tuberculosis

2022
Pharmacogenetics of interaction between depot medroxyprogesterone acetate and efavirenz, rifampicin, and isoniazid during treatment of HIV and tuberculosis.
    Pharmacogenetics and genomics, 2022, 01-01, Volume: 32, Issue:1

    In AIDS Clinical Trials Group study A5338, concomitant rifampicin, isoniazid, and efavirenz was associated with more rapid plasma medroxyprogesterone acetate (MPA) clearance compared to historical controls without tuberculosis or HIV therapy. We characterized the pharmacogenetics of this interaction.. In A5338, women receiving efavirenz-based HIV therapy and rifampicin plus isoniazid for tuberculosis underwent pharmacokinetic evaluations over 12 weeks following a 150-mg intramuscular injection of depot MPA. Data were interpreted with nonlinear mixed-effects modelling. Associations between individual pharmacokinetic parameters and polymorphisms relevant to rifampicin, isoniazid, efavirenz, and MPA were assessed.. Of 62 A5338 participants in four African countries, 44 were evaluable for pharmacokinetic associations, with 17 CYP2B6 normal, 21 intermediate, and 6 poor metabolizers, and 5 NAT2 rapid, 20 intermediate, and 19 slow acetylators. There were no associations between either CYP2B6 or NAT2 genotype and MPA Cmin at week 12, apparent clearance, Cmax, area under the concentration-time curve (AUC) or half-life, or unexplained interindividual variability in clearance, and uptake rate constant or mean transit time of the slow-release fraction (P > 0.05 for each). In exploratory analyses, none of 28 polymorphisms in 14 genes were consistently associated with MPA pharmacokinetic parameters, and none withstood correction for multiple testing.. Study A5338 suggested that more frequent depot MPA dosing may be appropriate for women receiving rifampicin, isoniazid, and efavirenz. The present results suggest that knowledge of CYP2B6 metabolizer or NAT2 acetylator status does not inform individualized DMPA dosing in this setting.

    Topics: Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Drug Interactions; Female; HIV Infections; Humans; Isoniazid; Medroxyprogesterone Acetate; Pharmacogenetics; Rifampin; Tuberculosis

2022
Completion of isoniazid-rifapentine (3HP) for tuberculosis prevention among people living with HIV: Interim analysis of a hybrid type 3 effectiveness-implementation randomized trial.
    PLoS medicine, 2021, Volume: 18, Issue:12

    Scaling up shorter regimens for tuberculosis (TB) prevention such as once weekly isoniazid-rifapentine (3HP) taken for 3 months is a key priority for achieving targets set forth in the World Health Organization's (WHO) END TB Strategy. However, there are few data on 3HP patient acceptance and completion in the context of routine HIV care in sub-Saharan Africa.. The 3HP Options Trial is a pragmatic, parallel type 3 effectiveness-implementation randomized trial comparing 3 optimized strategies for delivering 3HP-facilitated directly observed therapy (DOT), facilitated self-administered therapy (SAT), or informed choice between DOT and SAT using a shared decision-making aid-to people receiving care at a large urban HIV clinic in Kampala, Uganda. Participants and healthcare providers were not blinded to arm assignment due to the nature of the 3HP delivery strategies. We conducted an interim analysis of participants who were enrolled and exited the 3HP treatment period between July 13, 2020 and April 30, 2021. The primary outcome, which was aggregated across trial arms for this interim analysis, was the proportion who accepted and completed 3HP (≥11 of 12 doses within 16 weeks of randomization). We used Bayesian inference analysis to estimate the posterior probability that this proportion would exceed 80% under at least 1 of the 3HP delivery strategies, a coprimary hypothesis of the trial. Through April 2021, 684 participants have been enrolled, and 479 (70%) have exited the treatment period. Of these 479 participants, 309 (65%) were women, mean age was 41.9 years (standard deviation (SD): 9.2), and mean time on antiretroviral therapy (ART) was 7.8 years (SD: 4.3). In total, 445 of them (92.9%, 95% confidence interval (CI): [90.2 to 94.9]) accepted and completed 3HP treatment. There were no differences in treatment acceptance and completion by sex, age, or time on ART. Treatment was discontinued due to a documented adverse event (AE) in 8 (1.7%) patients. The probability that treatment acceptance and completion exceeds 80% under at least 1 of the three 3HP delivery strategies was greater than 99%. The main limitations are that the trial was conducted at a single site, and the interim analysis focused on aggregate outcome data to maintain blinding of investigators to arm-specific outcomes.. 3HP was widely accepted by people living with HIV (PLHIV) in Uganda, and very high levels of treatment completion were achieved in a programmatic setting. These findings show that 3HP can enable effective scale-up of tuberculosis preventive therapy (TPT) in high-burden countries, particularly when delivery strategies are tailored to target known barriers to treatment completion.. ClinicalTrials.gov NCT03934931.

    Topics: Adult; Antitubercular Agents; Directly Observed Therapy; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis; Uganda

2021
Pharmacokinetics and Safety of a Raltegravir-Containing Regimen in Children Aged 4 Weeks to 2 Years Living With Human Immunodeficiency Virus and Receiving Rifampin for Tuberculosis.
    Journal of the Pediatric Infectious Diseases Society, 2021, Mar-26, Volume: 10, Issue:2

    Pharmacological interactions limit treatment options for children living with human immunodeficiency virus (HIV) and tuberculosis (TB). We found that 12 mg/kg twice daily raltegravir chewable tablets (administered after crushing) safely achieved pharmacokinetic targets in children living with HIV aged 4 weeks to <2 years receiving concurrent rifampin to treat TB.. NCT01751568.

    Topics: Anti-HIV Agents; Child; HIV; HIV Infections; Humans; Raltegravir Potassium; Rifampin; Tuberculosis

2021
Early or deferred initiation of efavirenz during rifampicin-based TB therapy has no significant effect on CYP3A induction in TB-HIV infected patients.
    British journal of pharmacology, 2021, Volume: 178, Issue:16

    In TB-HIV co-infection, prompt initiation of TB therapy is recommended but anti-retroviral treatment (ART) is often delayed due to potential drug-drug interactions between rifampicin and efavirenz. In a longitudinal cohort study, we evaluated the effects of efavirenz/rifampicin co-treatment and time of ART initiation on CYP3A induction.. Treatment-naïve TB-HIV co-infected patients (n = 102) were randomized to efavirenz-based-ART after 4 (n = 69) or 8 weeks (n = 33) of commencing rifampicin-based anti-TB therapy. HIV patients without TB (n = 94) receiving efavirenz-based-ART only were enrolled as control. Plasma 4β-hydroxycholesterol/cholesterol (4β-OHC/Chol) ratio, an endogenous biomarker for CYP3A activity, was determined at baseline, at 4 and 16 weeks of ART.. In patients treated with efavirenz only, median 4β-OHC/Chol ratios increased from baseline by 269% and 275% after 4 and 16 weeks of ART, respectively. In TB-HIV patients, rifampicin only therapy for 4 and 8 weeks increased median 4β-OHC/Chol ratios from baseline by 378% and 576% respectively. After efavirenz/rifampicin co-treatment, 4β-OHC/Chol ratios increased by 560% of baseline (4 weeks) and 456% of baseline (16 weeks). Neither time of ART initiation, sex, genotype nor efavirenz plasma concentration were significant predictors of 4β-OHC/Chol ratios after 4 weeks of efavirenz/rifampicin co-treatment.. Rifampicin induced CYP3A more potently than efavirenz, with maximum induction occurring within the first 4 weeks of rifampicin therapy. We provide pharmacological evidence that early (4 weeks) or deferred (8 weeks) ART initiation during anti-TB therapy has no significant effect on CYP3A induction.. This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.

    Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP3A; HIV Infections; Humans; Longitudinal Studies; Rifampin; Tuberculosis

2021
Biomarker-guided tuberculosis preventive therapy (CORTIS): a randomised controlled trial.
    The Lancet. Infectious diseases, 2021, Volume: 21, Issue:3

    Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design.. Adult volunteers aged 18-59 years were recruited at five geographically distinct communities in South Africa. Whole blood was sampled for RISK11 by quantitative RT-PCR assay from eligible volunteers without HIV, recent previous tuberculosis (ie, <3 years before screening), or comorbidities at screening. RISK11-positive participants were block randomised (1:2; block size 15) to once-weekly, directly-observed, open-label isoniazid and rifapentine for 12 weeks (ie, RISK11 positive and 3HP positive), or no treatment (ie, RISK11 positive and 3HP negative). A subset of eligible RISK11-negative volunteers were randomly assigned to no treatment (ie, RISK11 negative and 3HP negative). Diagnostic discrimination of prevalent tuberculosis was tested in all participants at baseline. Thereafter, prognostic discrimination of incident tuberculosis was tested in the untreated RISK11-positive versus RISK11-negative groups, and treatment efficacy in the 3HP-treated versus untreated RISK11-positive groups, during active surveillance through 15 months. The primary endpoint was microbiologically confirmed pulmonary tuberculosis. The primary outcome measures were risk ratio [RR] for tuberculosis of RISK11-positive to RISK11-negative participants, and treatment efficacy. This trial is registered with ClinicalTrials.gov, NCT02735590.. 20 207 volunteers were screened, and 2923 participants were enrolled, including RISK11-positive participants randomly assigned to 3HP (n=375) or no 3HP (n=764), and 1784 RISK11-negative participants. Cumulative probability of prevalent or incident tuberculosis disease was 0·066 (95% CI 0·049 to 0·084) in RISK11-positive (3HP negative) participants and 0·018 (0·011 to 0·025) in RISK11-negative participants (RR 3·69, 95% CI 2·25-6·05) over 15 months. Tuberculosis prevalence was 47 (4·1%) of 1139 versus 14 (0·78%) of 1984 in RISK11-positive compared with RISK11-negative participants, respectively (diagnostic RR 5·13, 95% CI 2·93 to 9·43). Tuberculosis incidence over 15 months was 2·09 (95% CI 0·97 to 3·19) vs 0·80 (0·30 to 1·30) per 100 person years in RISK11-positive (3HP-negative) participants compared with RISK11-negative participants (cumulative incidence ratio 2·6, 95% CI 1·2 to 5·9). Serious adverse events related to 3HP included one hospitalisation for seizures (unintentional isoniazid overdose) and one death of unknown cause (possibly temporally related). Tuberculosis incidence over 15 months was 1·94 (95% CI 0·35 to 3·50) versus 2·09 (95% CI 0·97 to 3·19) per 100 person-years in 3HP-treated RISK11-positive participants compared with untreated RISK11-positive participants (efficacy 7·0%, 95% CI -145 to 65).. The RISK11 signature discriminated between individuals with prevalent tuberculosis, or progression to incident tuberculosis, and individuals who remained healthy, but provision of 3HP to signature-positive individuals after exclusion of baseline disease did not reduce progression to tuberculosis over 15 months.. Bill and Melinda Gates Foundation, South African Medical Research Council.

    Topics: Adult; Antitubercular Agents; Biomarkers; Drug Administration Schedule; Female; HIV Seronegativity; Humans; Incidence; Isoniazid; Male; Mycobacterium tuberculosis; Reverse Transcriptase Polymerase Chain Reaction; Rifampin; RNA, Bacterial; South Africa; Treatment Outcome; Tuberculosis; Young Adult

2021
Optimising pyrazinamide for the treatment of tuberculosis.
    The European respiratory journal, 2021, Volume: 58, Issue:1

    Pyrazinamide is a potent sterilising agent that shortens the treatment duration needed to cure tuberculosis. It is synergistic with novel and existing drugs for tuberculosis. The dose of pyrazinamide that optimises efficacy while remaining safe is uncertain, as is its potential role in shortening treatment duration further.Pharmacokinetic data, sputum culture, and safety laboratory results were compiled from Tuberculosis Trials Consortium (TBTC) studies 27 and 28 and Pan-African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) multi-arm multi-stage tuberculosis (MAMS-TB), multi-centre phase 2 trials in which participants received rifampicin (range 10-35 mg·kg

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2021
Treatment Outcomes of Isoniazid-Resistant (Rifampicin Susceptible) Tuberculosis Patients in Uzbekistan, 2017-2018.
    International journal of environmental research and public health, 2021, 03-14, Volume: 18, Issue:6

    Tuberculosis patients "resistant to isoniazid and susceptible to rifampicin (Hr-TB)" remain neglected, despite a high burden and poor outcomes. The World Health Organization (WHO) recommends a 6 month regimen consisting of levofloxacin, rifampicin, ethambutol, and pyrazinamide (LRZE) to treat Hr-TB. In contrast, Uzbekistan uses a 9 month regimen (LRZE plus a second-line injectable in the first 3 months). We aimed to assess the treatment outcomes of this novel regimen among Hr-TB patients treated in two regions of Uzbekistan (Fergana and Bukhara) in 2017-2018. We conducted a cohort study involving secondary analysis of routine surveillance data. Of 132 Hr-TB patients, 105 (80%) were successfully treated. Death was the predominant unsuccessful outcome (13, 10%) followed by "treatment failure" (10, 8%) and "lost to follow-up" (4, 2%). High treatment success is an indicator of the potential effectiveness of the novel regimen and adds to the limited global evidence on this issue. However, the sample size was small and there was no comparison group. Since the study was conducted in two regions of Uzbekistan only, the findings have limited generalizability. We recommend future research using an adequate sample size and an appropriate study design (randomized controlled trial or prospective cohort with a control group receiving the WHO-recommended regimen).

    Topics: Antitubercular Agents; Cohort Studies; Humans; Isoniazid; Prospective Studies; Rifampin; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Uzbekistan

2021
Safety and Pharmacokinetics of Double-Dose Lopinavir/Ritonavir + Rifampin Versus Lopinavir/Ritonavir + Daily Rifabutin for Treatment of Human Immunodeficiency Virus-Tuberculosis Coinfection.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021, 08-16, Volume: 73, Issue:4

    Protease inhibitor-based antiretroviral therapy may be used in resource-limited settings in persons with human immunodeficiency virus and tuberculosis (HIV-TB). Data on safety, pharmacokinetics/pharmacodynamics (PK/PD), and HIV-TB outcomes for lopinavir/ritonavir (LPV/r) used with rifampin (RIF) or rifabutin (RBT) are limited.. We randomized adults with HIV-TB from July 2013 to February 2016 to arm A, LPV/r 400 mg/100 mg twice daily + RBT 150 mg/day; arm B, LPV/r 800 mg/200 mg twice daily + RIF 600 mg/day; or arm C, LPV/r 400 mg/100 mg twice daily + raltegravir (RAL) 400 mg twice daily + RBT 150 mg/day. All received two nucleoside reverse transcriptase inhibitors and other TB drugs. PK visits occurred on day 12 ± 2. Within-arm HIV-TB outcomes were summarized using proportions and 95% CIs; PK were compared using Wilcoxon tests.. Among 71 participants, 52% were women; 72% Black; 46% Hispanic; median age, 37 years; median CD4+ count, 130 cells/mm3; median HIV-1 RNA, 4.6 log10 copies/mL; 46% had confirmed TB. LPV concentrations were similar across arms. Pooled LPV AUC12 (157 203 hours × ng/mL) and Ctrough (9876 ng/mL) were similar to historical controls; RBT AUC24 (7374 hours × ng/mL) and Ctrough (208 ng/mL) were higher, although 3 participants in arm C had RBT Cmax <250 ng/mL. Proportions with week 48 HIV-1 RNA <400 copies/mL were 58%, 67%, and 61%, respectively, in arms A, B, and C.. Double-dose LPV/r+RIF and LPV/r+RBT 150mg/day had acceptable safety, PK and TB outcomes; HIV suppression was suboptimal but unrelated to PK. Faster RBT clearance and low Cmax in 3 participants on RBT+RAL requires further study.

    Topics: Adult; Anti-HIV Agents; Coinfection; Drug Therapy, Combination; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Rifabutin; Rifampin; Ritonavir; Tuberculosis

2021
Preventive tuberculosis treatment effect on QuantiFERON TB-Gold in-tube testing in a high tuberculosis-endemic country: A clinical trial.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2020, Volume: 91

    Whether T-cell interferon-γ responses to Mycobacterium tuberculosis-specific antigens can be influenced by tuberculosis preventive treatment in a high-endemic country is uncertain.. In this prospective, open-label, controlled study, 513 individuals with silicosis were randomly selected for TB preventive treatment with rifapentine and isoniazid or for observation. QuantiFERON-TB Gold in-tube (QFT-GIT) assay was used to measure IFN-γ response to M. tuberculosis antigens at baseline (T0) and at 6 (T1) and 33 (T2) months after completion of therapy.. A total of 220 subjects were included in the final analysis: 105 and 115 in the prevention and observation arms, respectively. The proportions of QFT-GIT reversion from baseline to T1 were similar in the prevention and observation arms (18.4% vs 12.8%, P=0.566). However, reversion from baseline to T2 was more frequent in the prevention arm than in the observation arm, but the difference was not significant (24.2% vs 6.3%, P=0.881). No significant difference was observed in the quantitative responses of QFT-GIT between the two arms during follow-up at T1 (P=0.648) and T2 (P=0.918).. Preventive tuberculosis treatment has no effect on interferon-γ responses measured by serial QFT-GIT assays in a high tuberculosis-endemic country.. http://www.clinicaltrials.gov NCT02430259.

    Topics: Antigens, Bacterial; Antitubercular Agents; China; Diagnostic Tests, Routine; Endemic Diseases; Female; Follow-Up Studies; Humans; Interferon-gamma; Interferon-gamma Release Tests; Isoniazid; Male; Middle Aged; Prospective Studies; Rifampin; Tuberculin Test; Tuberculosis

2020
Pharmacokinetics, SAfety/tolerability, and EFficacy of high-dose RIFampicin in tuberculosis-HIV co-infected patients on efavirenz- or dolutegravir-based antiretroviral therapy: study protocol for an open-label, phase II clinical trial (SAEFRIF).
    Trials, 2020, Feb-13, Volume: 21, Issue:1

    Tuberculosis (TB) is a significant public health problem that causes substantial morbidity and mortality. Current first-line anti-TB chemotherapy, although very effective, has limitations including long-treatment duration with a possibility of non-adherence, drug interactions, and toxicities. Dose escalation of rifampicin, an important drug within the regimen, has been proposed as a potential route to higher treatment efficacy with shorter duration and some studies have suggested that dose escalation is safe; however, these have almost entirely been conducted among human immunodeficiency (HIV)-negative TB patients. TB-HIV co-infected patients on antiretroviral therapy (ART) are at increased risk of drug-drug interactions and drug-related toxicities. This study aims to determine the safety of higher doses of rifampicin and its effect on the pharmacokinetics of efavirenz (EFV) and dolutegravir (DTG) in TB-HIV co-infected patients.. This study is a randomized, open-label, phase IIb clinical trial among TB-HIV infected adult outpatients attending an HIV clinic in Kampala, Uganda. Patients newly diagnosed with TB will be randomized to either standard-dose or high-dose rifampicin (35 mg/kg) alongside standard TB treatment. ART-naïve patients will be randomly assigned to first-line ART regimens (DTG or EFV). Those who are already on ART (DTG or EFV) at enrollment will be continued on the same ART regimen but with dose adjustment of DTG to twice daily dosing. Participants will be followed every 2 weeks with assessment for toxicities at each visit and measurement of drug concentrations at week 6. At the end of intensive-phase therapy (8 weeks), all participants will be initiated on continuation-phase treatment using standard-dose rifampicin and isoniazid.. This study should avail us with evidence about the effect of higher doses of rifampicin on the pharmacokinetics of EFV and DTG among TB-HIV co-infected patients. The trial should also help us to understand safety concerns of high-dose rifampicin among this vulnerable cohort.. ClinicalTrials.gov, ID: NCT03982277. Registered retrospectively on 11 June 2019.

    Topics: Adult; Alkynes; Antibiotics, Antitubercular; Antitubercular Agents; Benzoxazines; Clinical Trials, Phase II as Topic; Coinfection; Cyclopropanes; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2B6 Inducers; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Randomized Controlled Trials as Topic; Rifampin; Treatment Outcome; Tuberculosis; Uganda

2020
Once-weekly rifapentine and isoniazid for tuberculosis prevention in patients with HIV taking dolutegravir-based antiretroviral therapy: a phase 1/2 trial.
    The lancet. HIV, 2020, Volume: 7, Issue:6

    Short-course preventive therapy with 12 doses of once-weekly rifapentine (900 mg) plus isoniazid (900 mg) could greatly improve tuberculosis control, especially in areas with high co-endemicity with HIV. However, a small previous trial of such therapy with dolutegravir in healthy, HIV-negative adults was halted early after two of the four patients developed serious adverse events. Because of the potential use of this therapy, and variable safety outcomes of tuberculosis drugs seen in patients with and without HIV, we aimed to characterise safety, pharmacokinetics, and virological suppression in adults who are HIV positive.. DOLPHIN was a phase 1/2, single-arm trial done at The Aurum Institute (Tembisa Clinical Research Site, Tembisa, South Africa), with pharmacokinetic visits done at VxPharma (Pretoria, South Africa). Adults (≥18 years) with HIV infection and undetectable viral load (<40 copies per mL) after at least 8 weeks of efavirenz-based or dolutegravir-based regimens were recruited in three consecutive groups, subject to approval by the independent safety monitoring committee. Participants received 50 mg of daily dolutegravir in place of efavirenz for 8 weeks, then began once-weekly rifapentine (900 mg)-isoniazid (900 mg) for 12 weeks. Groups 1A (n=12) and 1B (n=18) had intensive dolutegravir pharmacokinetic sampling at week 8 (before rifapentine-isoniazid), at week 11 (after the third dose of rifapentine)-isoniazid and at week 16 after the eighth dose. Group 2 (n=30) were treated with the same schedule and had sparse dolutegravir pharmacokinetic sampling at weeks 8, 11, and 16. Participants were followed 4 weeks after completion of prophylactic tuberculosis treatment. HIV viral loads were measured at baseline and at weeks 11 and 24. Primary endpoints were adverse events (grade 3 or higher) and dolutegravir population pharmacokinetics, assessed in participants who began rifapentine-isoniazid. This trial was registered at ClinicalTrials.gov, NCT03435146.. Between Jan 24, 2018, and Nov 25, 2018, 61 participants were enrolled into three groups; one participant withdrew (from group 1A). 43 (70%) of 60 participants were women and all participants were black African. Median age was 40 years (IQR 35-48), CD4 cell count was 683 cells per μL (447-935), and body-mass index was 28·9 kg/m. Our results suggest 12 doses of once-weekly rifapentine-isoniazid can be given for tuberculosis prophylaxis to patients with HIV taking dolutegravir-based antiretroviral therapy, without dose adjustments. Further exploration of the pharmacokinetics, safety, and efficacy in children and pharmacodynamics in individuals naive to antiretroviral therapy is needed.. UNITAID.

    Topics: Adult; Drug Administration Schedule; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Isoniazid; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Rifampin; South Africa; Treatment Outcome; Tuberculosis; Viral Load

2020
Twice-Daily Doravirine Overcomes the Interaction Effect from Once-Weekly Rifapentine and Isoniazid in Healthy Volunteers.
    Clinical and translational science, 2020, Volume: 13, Issue:6

    Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of HIV-1. Its use in combination with rifapentine (RPT), an antituberculosis (TB) antibiotic, may reduce the exposure of DOR compromising viral suppression in those living with HIV-1 co-infected with TB. We conducted a prospective, phase I, open label, two-period, fixed sequence, drug interaction study to evaluate the effect of once-weekly RPT and isoniazid (INH) on the pharmacokinetics (PKs) of DOR in healthy volunteers. DOR 100 mg was administered alone twice-daily for 4 days in period 1. In period 2, once-weekly RPT + INH were co-administered with multiple doses of DOR 100 mg twice-daily for study days 7, 14, and 21. Plasma was obtained for DOR PKs when given alone and co-administered with RPT + INH. Eleven healthy volunteers enrolled and completed the study. The geometric mean ratios and 90% confidence intervals for DOR area under the concentration-time curve from zero to 12 hours (AUC

    Topics: Adolescent; Adult; Antitubercular Agents; Area Under Curve; Drug Administration Schedule; Drug Interactions; Female; Healthy Volunteers; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Pyridones; Reverse Transcriptase Inhibitors; Rifampin; Triazoles; Tuberculosis; Young Adult

2020
Assessing whether isoniazid is essential during the first 14 days of tuberculosis therapy: a phase 2a, open-label, randomised controlled trial.
    The Lancet. Microbe, 2020, Volume: 1, Issue:2

    Clinical studies suggest that isoniazid contributes rapid bacterial killing during the initial two days of tuberculosis treatment but that isoniazid's activity declines significantly after day three. We conducted a 14-day phase IIa open label, randomized trial to assess the essentiality of isoniazid in standard tuberculosis therapy.. A total of 69 adults with newly diagnosed sputum-positive tuberculosis from the South African Western Cape region were enrolled and randomized to a four-arm parallel assignment model. Participants were followed for 14 days as inpatients at either the University of Cape Town Lung Institute or at the TASK Applied Science clinical research organization. All arms received standard daily rifampicin, ethambutol, and pyrazinamide but differed as follows: isoniazid only on days one and two (n=17), isoniazid on days one and two then moxifloxacin on days three through 14 (n=16), no isoniazid (n=18), and a control group that received isoniazid for all 14 days (standard therapy, n=18). The primary endpoint was the rate of colony forming unit (CFU) decline during the first 14 days of treatment.. For 62 participants analyzed, the initial 14-day mean daily fall in log. The 14 day EBA for the combination rifampicin, ethambutol, and pyrazinamide was not significantly changed by the addition of isoniazid for the first two days or for the first 14 days of treatment. In a post hoc analysis, significantly higher day-two EBAs were observed for all groups among participants with higher baseline sputum CFUs. Our finding that INH does not contribute to EBA suggests that INH could be replaced with another drug during standard treatment to improve efficacy and decrease rates of resistance to first-line drugs. (Funded by the NIH AIDS Clinical Trial Groups and NIH; A5307 ClinicalTrials.gov number, NCT01589497).

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Moxifloxacin; Pyrazinamide; Rifampin; Tuberculosis

2020
Wirelessly observed therapy compared to directly observed therapy to confirm and support tuberculosis treatment adherence: A randomized controlled trial.
    PLoS medicine, 2019, Volume: 16, Issue:10

    Excellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment.. We evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2-3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18-80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [-1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid remote identification of those who needed more support to maintain adherence. This stu. In terms of accuracy, WOT was equivalent to DOT. WOT was superior to DOT in supporting confirmed daily adherence to TB medications during the continuation phase of TB treatment and was overwhelmingly preferred by participants. WOT should be tested in high-burden TB settings, where it may substantially support low- and middle-income country (LMIC) TB programs.. ClinicalTrials.gov NCT01960257.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; California; Directly Observed Therapy; Drug Administration Schedule; Drug Monitoring; Female; Humans; Isoniazid; Male; Medication Adherence; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Self Administration; Treatment Outcome; Tuberculosis; Wireless Technology; Young Adult

2019
Pharmacokinetics and safety of a raltegravir-containing regimen in HIV-infected children aged 2-12 years on rifampicin for tuberculosis.
    AIDS (London, England), 2019, 11-15, Volume: 33, Issue:14

    Drug-drug interactions limit current antiretroviral treatment options for HIV-infected children with tuberculosis (TB). Rifampicin (RIF) induces UDP-glucuronosyltransferase activity, accelerating the clearance of raltegravir (RAL). We sought to establish an optimal and well tolerated dose of RAL when administered with RIF to HIV and TB co-infected children.. P1101 is a phase I/II open-label dose-finding study of RAL with RIF for children 2 to less than 12 years of age beginning treatment for HIV and active TB.. Four sites in South Africa.. Chewable RAL was given at 12 mg/kg per dose twice daily (twice the usual pediatric dose) with two nucleoside reverse transcriptase inhibitors. Intensive RAL pharmacokinetic sampling was conducted 5 to 8 days after antiretroviral therapy was initiated; a fourth antiretroviral agent was then added.. Children were recruited into two age-defined groups: cohort 1 (2 to <6 years old) and cohort 2 (6 to <12 years old). Pharmacological targets [geometric mean (GM) AUC12 h of 14-45 μmol/l h and GM C12 h ≥75 nmol/l) were reached in both cohort 1 (28.8 μmol/l h and 229 nmol/l) and cohort 2 (38.8 μmol/l h and 228 nmol/l). The RAL-based ART was well tolerated by most participants: one participant discontinued treatment because of grade 4 hepatitis that was possibly treatment-related. At week 8, 22 of 24 participants (92%) had HIV RNA concentrations below 400 copies/ml; 19 of 24 (79%) were below 50 copies/ml.. Giving 12 mg/kg twice daily of the chewable RAL formulation achieved pharmacokinetic targets safely in HIV-infected children receiving RIF for TB.

    Topics: Anti-HIV Agents; Antibiotics, Antitubercular; CD4 Lymphocyte Count; Child; Child, Preschool; Coinfection; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Raltegravir Potassium; Rifampin; South Africa; Tuberculosis; Viral Load

2019
Effect of efavirenz-based antiretroviral therapy and high-dose rifampicin on the pharmacokinetics of isoniazid and acetyl-isoniazid.
    The Journal of antimicrobial chemotherapy, 2019, 01-01, Volume: 74, Issue:1

    To describe the pharmacokinetics of isoniazid and acetyl-isoniazid in TB/HIV-coinfected patients, and assess the effects of efavirenz co-administration and a 50% increase in the dose of rifampicin on the pharmacokinetic parameters of isoniazid and acetyl-isoniazid.. TB/HIV-coinfected patients participating in the three-treatment-arm RAFA randomized controlled trial conducted in West Africa were recruited into the pharmacokinetics sub-study. Five serial blood samples were collected on a single visit between 4 and 8 weeks after initiation of antituberculosis treatment. Concentration-time data for isoniazid and acetyl-isoniazid were analysed using non-linear mixed-effects models.. Isoniazid concentrations from 150 patients were available for analysis, and 79 of these (53%) also had concentrations of acetyl-isoniazid. Isoniazid pharmacokinetics was best described with a two-compartment disposition model with lagged first-order absorption and elimination using a semi-mechanistic model describing hepatic extraction. The model identified two elimination pathways, separating formation of acetyl-isoniazid from other routes of metabolism. The predicted AUC0-24 is reduced by 29% in patients who are fast acetylators of isoniazid and receiving efavirenz-based ART (6.73 versus 4.68 mg·h/L). In slow acetylators, efavirenz-based ART had no effect on isoniazid exposure (AUC0-24 = 17.5 mg·h/L).. Efavirenz-based ART affects the acetylation metabolic pathway amongst rapid acetylators, resulting in reduced exposure to isoniazid. Pharmacokinetics of isoniazid and acetyl-isoniazid were not influenced by the 50% increase in rifampicin dose.

    Topics: Adolescent; Adult; Africa, Western; Aged; Aged, 80 and over; Alkynes; Anti-Retroviral Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Benzoxazines; Blood Chemical Analysis; Cyclopropanes; Drug Interactions; Female; HIV Infections; Humans; Inactivation, Metabolic; Isoniazid; Male; Middle Aged; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis; Young Adult

2019
Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India.
    British journal of clinical pharmacology, 2019, Volume: 85, Issue:3

    Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens.. Data were collected from 41 children, aged 2-16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed-effects model.. Isoniazid pharmacokinetics were described by a one-compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one-compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed-dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed-dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg. The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose-effect relationship of higher doses of rifampicin.

    Topics: Adolescent; Age Factors; Antitubercular Agents; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Female; Humans; India; Infant; Isoniazid; Male; Metabolic Clearance Rate; Models, Biological; Rifampin; Tuberculosis

2019
Household contact investigation for the detection of tuberculosis in Vietnam: economic evaluation of a cluster-randomised trial.
    The Lancet. Global health, 2019, Volume: 7, Issue:3

    Active case finding is recommended as an important strategy to control tuberculosis, particularly in low-income and middle-income countries with a high prevalence of the disease. However, the costs and cost-effectiveness of active case finding are unclear due to the absence of evidence from randomised trials. We assessed the costs and cost-effectiveness of an active case finding strategy in Vietnam, where there is a high prevalence of tuberculosis.. We conducted an economic evaluation alongside the Active Case Finding in Tuberculosis (ACT2) trial-a pragmatic cluster-randomised controlled trial in 70 districts across eight provinces of Vietnam. Patients aged 15 years and older with smear-positive pulmonary tuberculosis were recruited to the trial if they lived with one or more other household members. Household contacts were verbally invited to the clinic by the index patient with tuberculosis. ACT2 compared a combination of active and passive case finding with usual care (passive case finding) of household contacts of patients with tuberculosis from a health system perspective. Clustering occurred at the district and household level. Districts were the unit of randomisation, and we used minimisation to ensure balance of intervention and control districts within each province. In the intervention group, participants were invited to attend screening at baseline, 6 months, 12 months, and 24 months. We determined health-care costs with a standardised national costing survey and reported results in 2017 $US. The primary outcome of our study was disability-adjusted life years (DALYs) averted over a 24-month period. ACT2 was registered prospectively with the Australian and New Zealand Clinical Trials Registry, number ACTRN126.100.00600044.. Between Aug 11, 2010, and Aug 11, 2015, 10 964 index patients and 25 707 household contacts completed the ACT2 study. There were 10 069 household contacts in the intervention group and 15 638 household contacts in the control group. The incremental cost-effectiveness ratio per DALY averted was $544 (330-1375).. Active case finding was shown to be highly cost-effective in a setting with a high prevalence of tuberculosis. Investment in the wide-scale implementation of this programme in Vietnam should be strongly supported.. Australian National Health and Medical Research Council.

    Topics: Adult; Antibiotics, Antitubercular; Contact Tracing; Cost-Benefit Analysis; Ethambutol; Family Characteristics; Female; Global Burden of Disease; Humans; Isoniazid; Male; Middle Aged; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary; Vietnam

2019
One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis.
    The New England journal of medicine, 2019, 03-14, Volume: 380, Issue:11

    Tuberculosis is the leading killer of patients with human immunodeficiency virus (HIV) infection. Preventive therapy is effective, but current regimens are limited by poor implementation and low completion rates.. We conducted a randomized, open-label, phase 3 noninferiority trial comparing the efficacy and safety of a 1-month regimen of daily rifapentine plus isoniazid (1-month group) with 9 months of isoniazid alone (9-month group) in HIV-infected patients who were living in areas of high tuberculosis prevalence or who had evidence of latent tuberculosis infection. The primary end point was the first diagnosis of tuberculosis or death from tuberculosis or an unknown cause. Noninferiority would be shown if the upper limit of the 95% confidence interval for the between-group difference in the number of events per 100 person-years was less than 1.25.. A total of 3000 patients were enrolled and followed for a median of 3.3 years. Of these patients, 54% were women; the median CD4+ count was 470 cells per cubic millimeter, and half the patients were receiving antiretroviral therapy. The primary end point was reported in 32 of 1488 patients (2%) in the 1-month group and in 33 of 1498 (2%) in the 9-month group, for an incidence rate of 0.65 per 100 person-years and 0.67 per 100 person-years, respectively (rate difference in the 1-month group, -0.02 per 100 person-years; upper limit of the 95% confidence interval, 0.30). Serious adverse events occurred in 6% of the patients in the 1-month group and in 7% of those in the 9-month group (P = 0.07). The percentage of treatment completion was significantly higher in the 1-month group than in the 9-month group (97% vs. 90%, P<0.001).. A 1-month regimen of rifapentine plus isoniazid was noninferior to 9 months of isoniazid alone for preventing tuberculosis in HIV-infected patients. The percentage of patients who completed treatment was significantly higher in the 1-month group. (Funded by the National Institute of Allergy and Infectious Diseases; BRIEF TB/A5279 ClinicalTrials.gov number, NCT01404312.).

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Rifampin; Tuberculosis

2019
Rifampin Pharmacokinetics and Safety in Preterm and Term Infants.
    Antimicrobial agents and chemotherapy, 2019, Volume: 63, Issue:6

    Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We performed a multicenter, prospective pharmacokinetic (PK) and safety study of intravenous rifampin in infants of <121 days postnatal age (PNA). We enrolled 27 infants; the median (range) gestational age was 26 weeks (23 to 41 weeks), and the median PNA was 10 days (0 to 84 days). We collected 102 plasma PK samples from 22 of the infants and analyzed safety data from all 27 infants. We analyzed the data using a population PK approach. Rifampin PK was best characterized by a one-compartment model; drug clearance increased with increasing size (body weight) and maturation (PNA). There were no adverse events related to rifampin. Simulated weight and PNA-based intravenous dosing regimens administered once daily (<14 days PNA, 8 mg/kg; ≥14 days PNA, 15 mg/kg) in infants resulted in comparable exposures to adults receiving therapeutic doses of rifampin against staphylococcal infections and TB. (This study has been registered at ClinicalTrials.gov under identifier NCT01728363.).

    Topics: Female; Gestational Age; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Prospective Studies; Rifampin; Staphylococcal Infections; Tuberculosis

2019
Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2018, 05-01, Volume: 22, Issue:5

    Rifampicin (RMP) drives treatment response in drug-susceptible tuberculosis. Low RMP concentrations increase the risk of poor outcomes, and drug quality needs to be excluded as a contributor to low RMP exposure.. We performed an open-label, three-way cross-over study of three licensed RMP-containing formulations widely used in South Africa to evaluate the bioavailability of RMP in a two-drug fixed-dose combination tablet (2FDC) and a four-drug FDC (4FDC) against a single-drug reference. RMP dosed at 600 mg was administered 2 weeks apart in random sequence. Plasma RMP concentrations were measured pre-dose and 1, 2, 3, 4, 6, 8 and 12 h post-dose. The area under the concentration-time curve (AUC0-12) of the FDCs was compared to the single drug reference. Simulations were used to predict the impact of our findings.. Twenty healthy volunteers (median age 22.8 years, body mass index 24.2 kg/m2) completed the study. The AUC0-12 of the 4FDC/reference (geometric mean ratio [GMR] 78%, 90%CI 69-89) indicated an average 20% reduction in RMP bioavailability in the 4FDC. The 2FDC/reference (GMR 104%, 90%CI 97-111) was bioequivalent. Simulations suggested dose adjustments to compensate for the poor bioavailability of RMP with the 4FDC, and revised weight-band doses to prevent systematic underdosing of low-weight patients.. Post-marketing surveillance of in vivo bioavailability of RMP and improved weight band-based dosing are recommended.

    Topics: Adult; Antitubercular Agents; Biological Availability; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Combinations; Female; Healthy Volunteers; Humans; Male; Rifampin; South Africa; Tablets; Therapeutic Equivalency; Tuberculosis; Young Adult

2018
Rapid urine-based screening for tuberculosis in HIV-positive patients admitted to hospital in Africa (STAMP): a pragmatic, multicentre, parallel-group, double-blind, randomised controlled trial.
    Lancet (London, England), 2018, 07-28, Volume: 392, Issue:10144

    Current diagnostics for HIV-associated tuberculosis are suboptimal, with missed diagnoses contributing to high hospital mortality and approximately 374 000 annual HIV-positive deaths globally. Urine-based assays have a good diagnostic yield; therefore, we aimed to assess whether urine-based screening in HIV-positive inpatients for tuberculosis improved outcomes.. We did a pragmatic, multicentre, double-blind, randomised controlled trial in two hospitals in Malawi and South Africa. We included HIV-positive medical inpatients aged 18 years or more who were not taking tuberculosis treatment. We randomly assigned patients (1:1), using a computer-generated list of random block size stratified by site, to either the standard-of-care or the intervention screening group, irrespective of symptoms or clinical presentation. Attending clinicians made decisions about care; and patients, clinicians, and the study team were masked to the group allocation. In both groups, sputum was tested using the Xpert MTB/RIF assay (Xpert; Cepheid, Sunnyvale, CA, USA). In the standard-of-care group, urine samples were not tested for tuberculosis. In the intervention group, urine was tested with the Alere Determine TB-LAM Ag (TB-LAM; Alere, Waltham, MA, USA), and Xpert assays. The primary outcome was all-cause 56-day mortality. Subgroup analyses for the primary outcome were prespecified based on baseline CD4 count, haemoglobin, clinical suspicion for tuberculosis; and by study site and calendar time. We used an intention-to-treat principle for our analyses. This trial is registered with the ISRCTN registry, number ISRCTN71603869.. Between Oct 26, 2015, and Sept 19, 2017, we screened 4788 HIV-positive adults, of which 2600 (54%) were randomly assigned to the study groups (n=1300 for each group). 13 patients were excluded after randomisation from analysis in each group, leaving 2574 in the final intention-to-treat analysis (n=1287 in each group). At admission, 1861 patients were taking antiretroviral therapy and median CD4 count was 227 cells per μL (IQR 79-436). Mortality at 56 days was reported for 272 (21%) of 1287 patients in the standard-of-care group and 235 (18%) of 1287 in the intervention group (adjusted risk reduction [aRD] -2·8%, 95% CI -5·8 to 0·3; p=0·074). In three of the 12 prespecified, but underpowered subgroups, mortality was lower in the intervention group than in the standard-of-care group for CD4 counts less than 100 cells per μL (aRD -7·1%, 95% CI -13·7 to -0·4; p=0.036), severe anaemia (-9·0%, -16·6 to -1·3; p=0·021), and patients with clinically suspected tuberculosis (-5·7%, -10·9 to -0·5; p=0·033); with no difference by site or calendar period. Adverse events were similar in both groups.. Urine-based tuberculosis screening did not reduce overall mortality in all HIV-positive inpatients, but might benefit some high-risk subgroups. Implementation could contribute towards global targets to reduce tuberculosis mortality.. Joint Global Health Trials Scheme of the Medical Research Council, the UK Department for International Development, and the Wellcome Trust.

    Topics: Adult; AIDS-Related Opportunistic Infections; Developing Countries; Double-Blind Method; Drug Resistance, Bacterial; Female; HIV Seropositivity; Humans; Malawi; Male; Mass Screening; Middle Aged; Rifampin; South Africa; Sputum; Tuberculosis; Urinalysis

2018
Bacterial Factors That Predict Relapse after Tuberculosis Therapy.
    The New England journal of medicine, 2018, Aug-30, Volume: 379, Issue:9

    Approximately 5% of patients with drug-susceptible tuberculosis have a relapse after 6 months of first-line therapy, as do approximately 20% of patients after 4 months of short-course therapy. We postulated that by analyzing pretreatment isolates of Mycobacterium tuberculosis obtained from patients who subsequently had a relapse or were cured, we could determine any correlations between the minimum inhibitory concentration (MIC) of a drug below the standard resistance breakpoint and the relapse risk after treatment.. Using data from the Tuberculosis Trials Consortium Study 22 (development cohort), we assessed relapse and cure isolates to determine the MIC values of isoniazid and rifampin that were below the standard resistance breakpoint (0.1 μg per milliliter for isoniazid and 1.0 μg per milliliter for rifampin). We combined this analysis with clinical, radiologic, and laboratory data to generate predictive relapse models, which we validated by analyzing data from the DMID 01-009 study (validation cohort).. In the development cohort, the mean (±SD) MIC of isoniazid below the breakpoint was 0.0334±0.0085 μg per milliliter in the relapse group and 0.0286±0.0092 μg per milliliter in the cure group, which represented a higher value in the relapse group by a factor of 1.17 (P=0.02). The corresponding MIC values of rifampin were 0.0695±0.0276 and 0.0453±0.0223 μg per milliliter, respectively, which represented a higher value in the relapse group by a factor of 1.53 (P<0.001). Higher MIC values remained associated with relapse in a multivariable analysis that included other significant between-group differences. In an analysis of receiver-operating-characteristic curves of relapse based on these MIC values, the area under the curve (AUC) was 0.779. In the development cohort, the AUC in a multivariable model that included MIC values was 0.875. In the validation cohort, the MIC values either alone or combined with other patient characteristics were also predictive of relapse, with AUC values of 0.964 and 0.929, respectively. The use of a model score for the MIC values of isoniazid and rifampin to achieve 75.0% sensitivity in cross-validation analysis predicted relapse with a specificity of 76.5% in the development cohort and a sensitivity of 70.0% and a specificity of 100% in the validation cohort.. In pretreatment isolates of M. tuberculosis with decrements of MIC values of isoniazid or rifampin below standard resistance breakpoints, higher MIC values were associated with a greater risk of relapse than lower MIC values. (Funded by the National Institute of Allergy and Infectious Diseases.).

    Topics: Adult; Antitubercular Agents; Area Under Curve; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Recurrence; Rifampin; ROC Curve; Treatment Failure; Tuberculosis

2018
Adjunctive use of celecoxib with anti-tuberculosis drugs: evaluation in a whole-blood bactericidal activity model.
    Scientific reports, 2018, 09-10, Volume: 8, Issue:1

    COX-2 inhibition may be of benefit in the treatment of tuberculosis (TB) through a number of pathways including efflux pump inhibition (increasing intracellular TB drug levels) and diverse effects on inflammation and the immune response. We investigated celecoxib (a COX-2 inhibitor) alone and with standard anti-tuberculosis drugs in the whole-blood bactericidal activity (WBA) model. Healthy volunteers took a single dose of celecoxib (400 mg), followed (after 1 week) by a single dose of either rifampicin (10 mg/kg) or pyrazinamide (25 mg/kg), followed (after 2 or 7 days respectively) by the same anti-tuberculosis drug with celecoxib. WBA was measured at intervals until 8 hours post-dose (by inoculating blood samples with Mycobacterium tuberculosis and estimating the change in bacterial colony forming units after 72 hours incubation). Celecoxib had no activity alone in the WBA assay (cumulative WBA over 8 hours post-dose: 0.03 ± 0.01ΔlogCFU, p = 1.00 versus zero). Celecoxib did not increase cumulative WBA of standard TB drugs (mean cumulative WBA -0.10 ± 0.13ΔlogCFU versus -0.10 ± 0.12ΔlogCFU for TB drugs alone versus TB drugs and celecoxib; mean difference -0.01, 95% CI -0.02 to 0.00; p = 0.16). The lack of benefit of celecoxib suggests that efflux pump inhibition or eicosanoid pathway-related responses are of limited importance in mycobacterial killing in the WBA assay.

    Topics: Adult; Antitubercular Agents; Biological Assay; Blood Bactericidal Activity; Celecoxib; Cyclooxygenase 2 Inhibitors; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Synergism; Female; Healthy Volunteers; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2018
Clinical effect of lamivudine in treating liver function lesion caused by hepatitis B combined with Anti-TB drugs.
    Pakistan journal of pharmaceutical sciences, 2018, Volume: 31, Issue:4(Special)

    The present study is designed to conduct, the analysis on the curative effect of Lamivudine in treating liver function lesion caused by hepatitis B combined anti-TB drugs. The 4200 patients who have been treated for hepatitis B combined with pulmonary TB in 8 different hospitals from Feb 2014 to Feb 2016 were selected as research objects. They were randomly divided into control group and observation group, each containing 2100 patients. In control group, patients were applied with conventional Anti-TB therapy and liver-protecting therapy; while in observation group, patients were applied with lamivudine in addition to conventional therapies. The variations of liver functions of both groups before and after therapies were observed. After treatment, the liver function lesions of patients in observation group were significantly lower than that in control group; moreover, the drug withdrawal rates of patients in control group were significantly higher. There was statistical difference between both group, P<0.05. In the process of treating patients with liver function lesions caused by hepatitis B combined with anti-TB, applying Lamivudine on the basis of conventional liver protection therapy and anti-TB therapy can effectively inhibit HBV replication, and prevent liver disease from getting worse, so as to reduce the liver function lesions in treating patients with hepatitis B combined with anti-TB and accelerate rehabilitation.

    Topics: Adult; Aged; Antitubercular Agents; Antiviral Agents; Drug Therapy, Combination; Female; Hepatitis B; Humans; Isoniazid; Lamivudine; Liver; Liver Function Tests; Male; Middle Aged; Rifampin; Treatment Outcome; Tuberculosis; Withholding Treatment; Young Adult

2018
Daily 800 mg versus 600 mg Efavirenz for HIV Patients Treating Tuberculosis with a Rifampicin-Based Regimen: An Open Label Randomized Controlled Trial.
    BioMed research international, 2018, Volume: 2018

    Pharmacokinetics studies recommend increasing efavirenz dosage in tuberculosis/HIV patients using rifampicin. We aimed to evaluate efficacy and safety of 600 versus 800 mg of efavirenz in tuberculosis/HIV patients using rifampicin.. We conducted an open label, multicentre, randomized trial from 2006 to 2012. The primary outcome was the proportion of undetectable viral load (HIV-VL) within six months. Secondary outcomes were time to achieve primary endpoint, trajectories of HIV-VL, proportion of any adverse events (AE), proportion of severe and serious AE (SSAE), and time to treatment interruption due to SSAE.. Efavirenz-naïve patients were randomized 30 days after rifampicin-containing regimens initiation to receive 600 (comparison arm) or 800 mg (intervention arm) efavirenz-based regimens and followed-up for 180 days.. Sixty-five and 67 participants were respectively included in the comparison and intervention arms with 64.6% (52.5%-65.1%) and 62.7% (50.7%-73.3%) attaining undetectable HIV-VL in six months. Median time to attain undetectable HIV-VL was 70 days in both arms, with HIV-VL overlapping trajectories during follow-up. Cough, acne, and dizziness were more frequent in the intervention arm. SSAE were observed in 19.1% (13.8%-25.8%) and 25.0% (18.9%-33.2%), respectively. Survival curves up to the first SSAE-attributed treatment interruption were similar. None of the differences were statistically significant.. Efficacy of efavirenz was similar regardless of dosage. Differences regarding safety occurred as mild and transient events, which did not interfere with treatment. Similar efficacy and safety (SSAE) and lower tolerance (minor AE) in the intervention group favour the use of 600 mg efavirenz in patients using rifampicin.

    Topics: Adult; Alkynes; Benzoxazines; Cyclopropanes; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Male; Middle Aged; Rifampin; Tuberculosis

2018
Predictors of delayed culture conversion among Ugandan patients.
    BMC infectious diseases, 2017, 04-24, Volume: 17, Issue:1

    Estimates of month-2 culture conversion, a proxy indicator of tuberculosis (TB) treatment efficacy in phase-2 trials can vary by culture-type and geographically with lower rates reported among African sites. The sub-study aimed at comparing TB detection rates of different culture media, within and across rifampicin-based regimens (R10, 15 and 20 mg/Kg) over a 6-month treatment follow-up period, and to establish predictors of month-2 culture non-conversion among HIV-negative TB patients enrolled at RIFATOX trial site in Uganda.. Unlike in other Rifatox Trial sites, it is only in Uganda were Lowenstein-Jensen (LJ) and Mycobacteria growth indicator tube (MGIT) were used throughout 6-months for treatment monitoring. Conversion rates were compared at month-2, 4 and 6 across cultures and treatment-type. Binomial regression analysis performed for predictors of month-2 non-conversion.. Of the 100 enrolled patients, 45% had converted based on combined LJ and MGIT by month-2, with no significant differences across treatment arms, p = 0.721. LJ exhibited higher conversion rates than MGIT at month-2 (58.4% vs 56.0%, p = 0.0707) and month-4 (98.9% vs 88.4%, p = 0.0391) respectively, more so within the high-dose rifampicin arms. All patients had converted by month-6. Time-to-TB detection (TTD) on MGIT and social service jobs independently predict month-2 non-conversion.. The month-2 culture conversion used in phase 2 clinical trials as surrogate marker of treatment efficacy is influenced by the culture method used for monitoring mycobacterial response to TB treatment. Therefore, multi-centric TB therapeutic trials using early efficacy endpoint should use the same culture method across sites. The Time-to-detection of MTB on MGIT prior to treatment and working in Social service jobs bear an increased risk of culture non-conversion at month-2.. ISRCTN ISRCTN55670677 . Registered 09th November 2010. Retrospectively registered.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Culture Media; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sputum; Treatment Outcome; Tuberculosis; Uganda; Young Adult

2017
DOT or SAT for Rifampicin-resistant tuberculosis? A non-randomized comparison in a high HIV-prevalence setting.
    PloS one, 2017, Volume: 12, Issue:5

    Daily directly-observed therapy (DOT) is recommended for rifampicin-resistant tuberculosis (RR-TB) patients throughout treatment. We assessed the impact of self-administered treatment (SAT) in a South African township with high rates of RR-TB and HIV.. Community-supported SAT for patients who completed the intensive phase was piloted in five primary care clinics in Khayelitsha. We compared final treatment outcomes among RR-TB patients initiating treatment before (standard-of-care (SOC)-cohort, January 2010-July 2013) and after the implementation of the pilot (SAT-cohort, January 2012-December 2014). All patients with outcomes before January 1, 2017 were considered in the analysis of outcomes.. One-hundred-eighteen patients in the SOC-cohort and 174 patients in the SAT-cohort had final RR-TB treatment outcomes; 70% and 73% were HIV-co-infected, respectively. The proportion of patients with a final outcome of loss to follow-up (LTFU) did not differ whether treated in the SOC (25/118, 21.2%) or SAT-cohort (31/174, 17.8%) (P = 0.47). There were no significant differences in the time to 24-month LTFU among HIV-infected and uninfected patients (HR 0.90, 95% CI: 0.51-1.6, P = 0.71), or among patients enrolled in the SOC-cohort versus the SAT-cohort (HR 0.83, 95% CI: 0.49-1.4, P = 0.50) who received at least 6-months of RR-TB treatment.. The introduction of SAT during the continuation phase of RR-TB treatment does not adversely affect final RR-TB treatment outcomes in a high TB and HIV-burden setting. This differentiated, patient-centred model of care could be considered in RR-TB programmes to decrease the burden of DOT on patients and health facilities.

    Topics: Adult; Anti-Retroviral Agents; Antitubercular Agents; Directly Observed Therapy; Drug Resistance; Female; HIV Infections; Humans; Male; Prevalence; Rifampin; Treatment Outcome; Tuberculosis

2017
Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis.
    Antimicrobial agents and chemotherapy, 2017, Volume: 61, Issue:8

    Topics: Administration, Oral; Adolescent; Adult; Antitubercular Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Mycobacterium tuberculosis; Peru; Rifampin; Tuberculosis; Young Adult

2017
Anti-tuberculosis drug concentrations in tuberculosis patients with and without diabetes mellitus.
    European journal of clinical pharmacology, 2017, Volume: 73, Issue:1

    The aim of the study was to compare plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between tuberculosis (TB) patients with and without diabetes mellitus (DM).. Two-hour post-dosing concentrations of RMP, INH and PZA were determined in adult TB patients that were studied with (n = 452) and without DM (n = 1460), treated with a thrice-weekly regimen in India. Drug concentrations were estimated by HPLC.. The median (IQR) INH [6.6 (3.9-10.0) and 7.8 (4.6-11.3)] and PZA [31.0 (22.3-38.0) and 34.1 (24.6-42.7)] microgram per milliliter concentrations were significantly lower in diabetic than non-diabetic TB patients (p < 0.001 for both drugs). Blood glucose was negatively correlated with plasma INH (r = -0.09, p < 0.001) and PZA (r = -0.092, p < 0.001). Multiple linear regression analysis showed RMP, INH and PZA concentrations were influenced by age and drug doses, INH and PZA by DM, RMP by alcohol use and PZA by gender and category of ATT. DM reduced INH and PZA concentrations by 0.8 and 3.0 μg/ml, respectively.. TB patients with DM had lower INH and PZA concentrations. Negative correlation between blood glucose and drug concentrations suggests delayed absorption/faster elimination of INH and PZA in the presence of elevated glucose.

    Topics: Adult; Antitubercular Agents; Diabetes Mellitus; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis

2017
Long-Term Effect of Rifampicin-Based Anti-TB Regimen Coadministration on the Pharmacokinetic Parameters of Efavirenz and 8-Hydroxy-Efavirenz in Ethiopian Patients.
    Journal of clinical pharmacology, 2016, Volume: 56, Issue:12

    We compared the pharmacokinetic (PK) exposure parameters of efavirenz (EFV) and its major inactive metabolite, 8-hydroxy-efavirenz (8-OH-EFV), in an open-label, single-sequence, and parallel design of HIV-infected and tuberculosis (TB)-HIV-coinfected Ethiopian patients in the HIV-TB Pharmagene study with 20 and 33 patients, respectively. Both treatment groups underwent PK sampling following oral 600 mg EFV in week 16 of initiating EFV-based combination antiretroviral therapy. The TB-HIV-coinfected group repeated the PK sampling 8 weeks after stopping rifampin (RIF)-based anti-TB treatment. Between-treatment group analysis indicated no significant effect of RIF-based anti-TB cotreatment on PK exposure parameters of EFV, nor was there a significant effect after controlling for sex or CYP2B6 genotype. However, RIF-based therapy in TB-HIV-coinfected patients had significantly increased 8-OH-EFV PK exposure measures and metabolic ratio relative to HIV-only patients, AUC

    Topics: Adult; Alkynes; Antitubercular Agents; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2B6 Inducers; Drug Therapy, Combination; Ethiopia; Female; HIV Infections; Humans; Male; Middle Aged; Rifampin; Time Factors; Treatment Outcome; Tuberculosis; Young Adult

2016
Tackling the unknowns of short-course rifapentine-based treatment for active tuberculosis: a decision analysis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:6

    Shorter treatment regimens for tuberculosis (TB) are deemed vital for advancing TB control. Murine studies have suggested potential new regimens; however, Phase II human studies of these drug combinations have not shown clear improvement in 2-month culture conversion over current therapy. Nevertheless, drugs such as rifapentine (RPT) may have additional sterilizing effects after 2 months that are difficult to measure in current Phase II studies.. To model potential bactericidal effects of RPT in a Phase III trial of a 4-month anti-tuberculosis regimen.. We developed a Markov model of anti-tuberculosis treatment to compare two regimens for treating TB: a 6-month standard (rifampin-based) treatment and a 4-month regimen using high-dose RPT. The primary outcome was the number of relapses.. In the base-case scenario, standard therapy resulted in fewer relapses; improvement in 2-month culture conversion rates in the RPT arm did not change this result. However, while RPT has better sterilizing ability during months 3 and 4 (as observed in the mouse model), the 4-month regimen results in fewer relapses.. Higher 2-month culture conversion rates are neither sufficient nor necessary for making a theoretical 4-month anti-tuberculosis treatment regimen advantageous.

    Topics: Antitubercular Agents; Decision Support Techniques; Ethambutol; Humans; Isoniazid; Markov Chains; Pyrazinamide; Recurrence; Rifampin; Treatment Outcome; Tuberculosis

2016
Three months of weekly rifapentine and isoniazid for treatment of Mycobacterium tuberculosis infection in HIV-coinfected persons.
    AIDS (London, England), 2016, 06-19, Volume: 30, Issue:10

    Compare the effectiveness, tolerability, and safety of 3 months of weekly rifapentine and isoniazid under direct observation (3HP) versus 9 months of daily isoniazid (9H) in HIV-infected persons.. Prospective, randomized, and open-label noninferiority trial.. The United States , Brazil, Spain, Peru, Canada, and Hong Kong.. HIV-infected persons who were tuberculin skin test positive or close contacts of tuberculosis cases.. 3HP versus 9H.. The effectiveness endpoint was tuberculosis; the noninferiority margin was 0.75%. The tolerability endpoint was treatment completion; the safety endpoint was drug discontinuation because of adverse drug reaction.. Median baseline CD4 cell counts were 495 (IQR 389-675) and 538 (IQR 418-729) cells/μl in the 3HP and 9H arms, respectively (P = 0.09). In the modified intention-to-treat analysis, there were two tuberculosis cases among 206 persons [517 person-years (p-y) of follow-up] in the 3HP arm (0.39 per 100 p-y) and six tuberculosis cases among 193 persons (481 p-y of follow-up) in the 9H arm (1.25 per 100 p-y). Cumulative tuberculosis rates were 1.01 versus 3.50% in the 3HP and 9H arms, respectively (rate difference: -2.49%; upper bound of the 95% confidence interval of the difference: 0.60%). Treatment completion was higher with 3HP (89%) than 9H (64%) (P < 0.001), and drug discontinuation because of an adverse drug reaction was similar (3 vs. 4%; P = 0.79) in 3HP and 9H, respectively.. Among HIV-infected persons with median CD4 cell count of approximately 500 cells/μl, 3HP was as effective and safe for treatment of latent Mycobacterium tuberculosis infection as 9H, and better tolerated.

    Topics: Adolescent; Adult; Americas; Antitubercular Agents; Asia; Child; Drug-Related Side Effects and Adverse Reactions; Female; HIV Infections; Humans; Isoniazid; Male; Prospective Studies; Rifampin; Treatment Outcome; Tuberculosis; Young Adult

2016
Urine colorimetry to detect Low rifampin exposure during tuberculosis therapy: a proof-of-concept study.
    BMC infectious diseases, 2016, 06-01, Volume: 16

    The cost and complexity of current approaches to therapeutic drug monitoring during tuberculosis (TB) therapy limits widespread use in areas of greatest need. We sought to determine whether urine colorimetry could have a novel application as a form of therapeutic drug monitoring during anti-TB therapy.. Among healthy volunteers, we evaluated 3 dose sizes of rifampin (150 mg, 300 mg, and 600 mg), performed intensive pharmacokinetic sampling, and collected a timed urine void at 4 h post-dosing. The absorbance peak at 475 nm was measured after rifamycin extraction. The optimal cutoff was evaluated in a study of 39 HIV/TB patients undergoing TB treatment in Botswana.. In the derivation study, a urine colorimetric assay value of 4.0 × 10(-2) Abs, using a timed void 4 h after dosing, demonstrated a sensitivity of 92 % and specificity of 60 % to detect a peak rifampin concentration (Cmax) under 8 mg/L, with an area under the ROC curve of 0.92. In the validation study, this cutoff was specific (100 %) but insensitive (28 %). We observed similar test characteristics for a target Cmax target of 6.6 mg/L, and a target area under the drug concentration-versus-time curve (AUC0-8) target of 24.1 mg•hour/L.. The urine colorimetric assay was specific but insensitive to detect low rifampin serum concentrations among HIV/TB patients. In future work we will attempt to optimize sampling times and assay performance, with the goal of delivering a method that can translate into a point-of-care assessment of rifampin exposure during anti-TB therapy.

    Topics: Adult; Antitubercular Agents; Botswana; Colorimetry; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Monitoring; Female; Healthy Volunteers; Humans; Male; Rifampin; ROC Curve; Sensitivity and Specificity; Specimen Handling; Tuberculosis; Urinalysis

2016
Bioavailability of two licensed paediatric rifampicin suspensions: implications for quality control programmes.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:7

    To assess the revised World Health Organization-recommended dose of 10-20 mg/kg rifampicin (RMP), we studied the steady state pharmacokinetics of RMP in South African children who received standard treatment for drug-susceptible tuberculosis (TB).. To determine the formulation effect on the pharmacokinetics of RMP.. RMP plasma concentrations were characterised in 146 children (median age 1.4 years, range 0.2-10.2). The morning dose on the day of the pharmacokinetic evaluation was administered as one of two RMP single-drug oral suspensions.. While one formulation achieved 2 h concentrations in the range of those observed in adults (median 6.54 mg/l, interquartile range [IQR] 4.47-8.84), the other attained a median bioavailability of only 25% of this, with a median 2 h concentration of 1.59 mg/l (IQR 0.89-2.38).. RMP is a key drug for the treatment of TB. It is critical that the quality of RMP suspensions used to treat childhood TB is ensured.

    Topics: Administration, Oral; Antibiotics, Antitubercular; Biological Availability; Child; Child, Preschool; Drug Approval; Drug Compounding; Drug Monitoring; Female; Humans; Infant; Licensure; Male; Pharmaceutical Solutions; Quality Assurance, Health Care; Quality Control; Rifampin; South Africa; Tuberculosis

2016
Effect of intermittent rifampicin on the pharmacokinetics and safety of raltegravir.
    The Journal of antimicrobial chemotherapy, 2015, Volume: 70, Issue:2

    Previous studies of raltegravir and rifampicin have not studied the interaction when rifampicin is dosed intermittently. This study aimed to assess the pharmacokinetics of twice daily raltegravir and intermittently dosed rifampicin.. This was a prospective, open, single-arm, three-part, controlled study in healthy volunteers. Over a period of 38 days subjects received 5 days of standard-dose raltegravir (400 mg twice daily) followed by 28 days of standard-dose raltegravir plus rifampicin three times a week followed by 5 days of high-dose (800 mg twice daily) raltegravir plus rifampicin three times a week. Pharmacokinetic sampling was performed on days 5, 33 and 38. Raltegravir pharmacokinetic parameters were determined by non-compartmental analysis and reported as geometric means and 90% CIs. ClinicalTrials.gov: NCT01424826.. Sixteen subjects (12 females) completed the study. Raltegravir trough plasma concentration (C12) was significantly lower in the presence of rifampicin when dosed at 400 mg twice daily (40%), which was not observed with 800 mg twice daily dosing. Raltegravir Cmax and AUC0-12 were both significantly higher in the presence of rifampicin when dosed at 800 mg twice daily (76% and 84%, respectively), but this dose was well tolerated.. This study suggests that rifampicin induction of raltegravir is comparable between daily and intermittent rifampicin. In the absence of definitive clinical efficacy data to suggest otherwise, doses of 800 mg of raltegravir twice daily with rifampicin thrice weekly are well tolerated and yield higher AUCs and comparable C12 when compared with raltegravir alone.

    Topics: Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Coinfection; Drug Administration Schedule; Drug Interactions; Female; Healthy Volunteers; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Rifampin; Tuberculosis; Young Adult

2015
Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis.
    Antimicrobial agents and chemotherapy, 2015, Volume: 59, Issue:1

    The relationships between antituberculosis drug exposure and treatment effects on humans receiving multidrug therapy are complex and nonlinear. In patients on treatment, an analysis of the rate of decline in the sputum bacillary burden reveals two slopes. The first is the α-slope, which is thought to reflect bactericidal effect, followed by a β-slope, which is thought to reflect sterilizing activity. We sought to characterize the effects of standard first-line treatment on sterilizing activity. Fifty-four patients receiving combination therapy for pulmonary tuberculosis in a clinical trial had drug concentrations measured and Mycobacterium tuberculosis isolates available for MIC identification. Sputum sample cultures were performed at baseline and weekly for 8 weeks. A time-to-event model based on the days to positivity in the liquid cultures was used to estimate the β-slope. The pharmacokinetic parameters of rifampin, isoniazid, ethambutol, and pyrazinamide were determined for each patient. Multivariate adaptive regression splines analyses, which simultaneously perform linear and nonlinear analyses, were used to identify the relationships between the predictors and the β-slope. The potential predictors examined included HIV status, lung cavitation, 24-h area under the concentration-time curve (AUC), peak drug concentration (Cmax), AUC/MIC ratio, Cmax/MIC ratio, and the time that that concentration persisted above MIC. A rifampin Cmax of >8.2 mg/liter and a pyrazinamide AUC/MIC of >11.3 were key predictors of the β-slope and interacted positively to increase the β-slope. In patients with a rifampin AUC of <35.4 mg · h/liter, an increase in the pyrazinamide AUC/MIC and/or ethambutol Cmax/MIC increased the β-slope, while increasing isoniazid Cmax decreased it, suggesting isoniazid antagonism. Antibiotic concentrations and MICs interact in a nonlinear fashion as the main drivers of a sterilizing effect. The results suggest that faster speeds of sterilizing effect might be achieved by omitting isoniazid and by increasing rifampin, pyrazinamide, and ethambutol exposures. However, isoniazid and ethambutol exposures may only be of importance when rifampin exposure is low. These findings need confirmation in larger studies. (This study has been registered at controlled-trials.com under registration no. ISRCTN80852505.).

    Topics: Adolescent; Adult; Antitubercular Agents; Area Under Curve; Disinfection; Drug Antagonism; Drug Synergism; Drug Therapy, Combination; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Sputum; Sterilization; Treatment Outcome; Tuberculosis; Young Adult

2015
Pharmacokinetics of first-line antituberculosis drugs in HIV-infected children with tuberculosis treated with intermittent regimens in India.
    Antimicrobial agents and chemotherapy, 2015, Volume: 59, Issue:2

    The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (Cmax) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median Cmax and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC0-8]) of INH (Cmax, 2.5 versus 5.1 μg/ml, respectively [P=0.016]; AUC0-8, 11.1 versus 22.0 μg/ml·h, respectively [P=0.047[) and PZA (Cmax, 34.1 versus 42.3 μg/ml, respectively [P=0.055]; AUC0-8, 177.9 versus 221.7 μg/ml·h, respectively [P=0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median Cmax of RMP (1.0 versus 2.8 μg/ml, respectively; P=0.002) and PZA (31.9 versus 44.4 μg/ml, respectively; P=0.045) were significantly lower. Among all factors studied, the PZA Cmax influenced TB treatment outcome (P=0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP Cmax. The PZA Cmax significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized.

    Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Female; HIV Infections; Humans; India; Infant; Isoniazid; Male; Pyrazinamide; Regression Analysis; Rifampin; Treatment Outcome; Tuberculosis

2015
Relative bioavailability of rifampicin in four Chinese fixed-dose combinations compared with rifampicin in free combinations.
    Chinese medical journal, 2015, Feb-20, Volume: 128, Issue:4

    Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure. Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.. Eighteen and twenty healthy Chinese male volunteers participated in two open-label, randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study, respectively. The washout period between treatments was 7 days. Bioequivalence was assessed based on 90% confidence intervals, according to two one-sided t-tests. All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China, Shanghai, China).. Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (C max ), 91.43 ± 30.82 μg·h-1·ml-1 , 55.49 ± 37.58 μg·h-1·ml-1 , 96.50 ± 47.24 μg·h-1·ml-1 , 101.47 ± 33.07 μg·h-1·ml-1 , respectively, for area under the concentration-time curve (AUC 0-24 h ).. Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product. The three two-drug FDCs (formulations B, C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451).

    Topics: Adult; Asian People; Biological Availability; Drug Combinations; Humans; Male; Rifampin; Tuberculosis; Young Adult

2015
A randomized trial comparing standard outcomes in two treatment models for substance users with tuberculosis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:3

    Chicago Department of Public Health (CDPH), TB Control Program.. To compare anti-tuberculosis treatment outcomes using two different types of directly observed therapy (DOT) outreach workers.. Substance users diagnosed with TB from October 1996 to July 2000 were randomized to DOT administered by either 1) CDPH personnel (standard arm) or 2) previous substance-using human immunodeficiency virus/acquired immune-deficiency syndrome outreach workers (enhanced arm). Treatment completion was physician-determined, and adherence was estimated based on risk of missed DOT appointments.. Of 94 patients, 46 were randomized to the standard and 48 to the enhanced arm. The standard arm had a significantly higher risk of non-completion of treatment (39% vs. 15%, RR 2.7, 95%CI 1.2-5.8), and a significantly higher risk of missing DOT appointments (RR 2.6, 95%CI 1.4-4.8). For both outcomes, housing instability was a significant predictor in multivariate analyses.. TB treatment completion and adherence among substance users was improved by the enhanced intervention; the familiarity of enhanced-arm DOT workers with the patients' social norms due to their own previous substance use may have made them more effective. Successful DOT in hard-to-reach populations may require strategies that directly address the population's circumstances and utilize DOT workers who are intimately familiar with patients' life situations.

    Topics: Adult; Antitubercular Agents; Directly Observed Therapy; Drug Users; Ethambutol; Ethnicity; Female; Humans; Isoniazid; Male; Patient Compliance; Pyrazinamide; Rifampin; Socioeconomic Factors; Substance-Related Disorders; Treatment Outcome; Tuberculosis

2015
Bioequivalence of fixed-dose combination RIN®-150 to each reference drug in loose combination.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:3

    RIN(®)-150 is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg) and isoniazid (INH, 75 mg) developed for the treatment of tuberculosis.. This study was conducted at a single center: the Pfizer Clinical Research Unit in Singapore.. To demonstrate bioequivalence of each drug component between RIN-150 and individual products in a loose combination.. This was a randomized, open-label, single-dose, two-way crossover study. Subjects received single doses of RIN-150 or two individual reference products under fasting conditions in a crossover fashion, with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (Cmax) and the area under plasma concentration-time curve (AUC).. Of 28 subjects enrolled, 26 completed the study. The adjusted geometric mean ratios of Cmax and AUClast between the FDC and single-drug references and 90% confidence intervals were respectively 91.63% (90%CI 83.13-101.01) and 95.45% (90%CI 92.07-98.94) for RMP, and 107.58% (90%CI 96.07-120.47) and 103.45% (90%CI 99.33-107.75) for INH. Both formulations were generally well tolerated in this study.. The RIN-150 FDC tablet formulation is bioequivalent to the two single-drug references for RMP and INH at equivalent doses.

    Topics: Adult; Antitubercular Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Combinations; Female; Healthy Volunteers; Humans; Isoniazid; Male; Middle Aged; Rifampin; Singapore; Tablets; Therapeutic Equivalency; Tuberculosis; Young Adult

2015
Exposure to total and protein-unbound rifampin is not affected by malnutrition in Indonesian tuberculosis patients.
    Antimicrobial agents and chemotherapy, 2015, Volume: 59, Issue:6

    Nutritional status may have a profound impact on the pharmacokinetics of drugs, yet only few data are available for tuberculosis (TB) drugs. As malnutrition occurs frequently among TB patients, we assessed the effect of malnutrition on the steady-state pharmacokinetics of total and protein-unbound rifampin during the intensive phase of TB treatment. In a descriptive pharmacokinetic study in Bandung, Indonesia, patients received a fixed standard rifampin dose of 450 mg once daily during the intensive phase of TB treatment. A full pharmacokinetic curve for rifampin was recorded, and total and unbound concentrations of rifampin were analyzed in all samples. Rifampin pharmacokinetic parameters were compared between severely malnourished (BMI of <16.0 kg/m(2)), malnourished (BMI of <18.5 kg/m(2)), and well-nourished (BMI of ≥18.5 kg/m(2)) individuals. No difference in total and protein-unbound pharmacokinetic parameters between severely malnourished (n = 7), malnourished (n = 11), and well-nourished (n = 25) patients could be demonstrated. In addition, no significant correlation between BMI and exposure (area under the concentration-time curve from 0 to 24 h [AUC0-24] and maximum concentration of drug in serum [Cmax]) was found. Females had significantly higher total AUC0-24 (geometric mean, 59.2 versus 48.2 h · mg/liter; P = 0.02) and higher unbound AUC0-24 (geometric mean, 6.2 versus 4.8 h · mg/liter; P = 0.02) than males. Overall, a marked 2-fold interindividual variation in the free fraction was observed (7.6 to 15.0%; n = 36). Nutritional status and BMI do not appear to have a major effect on total and protein-unbound pharmacokinetic parameters of rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships.

    Topics: Adolescent; Adult; Antitubercular Agents; Body Mass Index; Drug Administration Schedule; Female; Humans; Indonesia; Male; Malnutrition; Middle Aged; Rifampin; Tuberculosis; Young Adult

2015
Is there a need to increase the dose of efavirenz during concomitant rifampicin-based antituberculosis therapy in sub-Saharan Africa? The HIV-TB pharmagene study.
    Pharmacogenomics, 2015, Volume: 16, Issue:10

    The current HIV treatment guidelines are inconsistent about the need for weight-based efavirenz dose adjustment during rifampicin containing antituberculosis (anti-TB) cotreatment. We investigated effect of rifampicin-based anti-TB cotreatment on plasma efavirenz exposure and treatment outcome, considering effect of CYP2B6 genotype and bodyweight.. HIV-only (arm 1, n = 285) or TB-HIV (arm 2, n = 208) coinfected patients were enrolled and received efavirenz-based ART alone or with rifampicin-based anti-TB therapy, respectively. Plasma efavirenz concentrations at 4th and 16th weeks, viral load and CD4 cell count at 24th and 48th weeks were determined.. The mean plasma efavirenz concentration at weeks 4 (p = 0.03) and 16 (p = 0.08) was inconsistently higher in arm 2 than arm 1, mainly in CYP2B6*6 carriers. Effect of bodyweight on efavirenz pharmacokinetics was significant only in arm 1, but not in arm 2. Proportion of patients with nondetectable viral load (≤50 copies/ml) at week 24 was higher in arm 1 than arm 2 patients (91.0 vs 76.3%; p = 0.002), but no significant difference was observed at week 48 (89.5 vs 87.8%; p = 0.22).. Rifampicin-based anti-TB cotreatment has no significant influence on long-term efavirenz plasma exposure and efficacy. Hence, there is no need to increase the dose of efavirenz during concomitant rifampicin-based anti-TB cotreatment in the sub-Saharan African population.

    Topics: Adult; Africa South of the Sahara; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Coinfection; Cyclopropanes; Cytochrome P-450 CYP2B6; Female; Genotype; HIV Infections; Humans; Male; Pharmacogenetics; Prospective Studies; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

2015
Impact on Patients' Treatment Outcomes of XpertMTB/RIF Implementation for the Diagnosis of Tuberculosis: Follow-Up of a Stepped-Wedge Randomized Clinical Trial.
    PloS one, 2015, Volume: 10, Issue:4

    The impact on treatment outcomes of XpertMTB/RIF, a molecular-based test that provides rapid diagnosis of tuberculosis (TB) and rifampicin resistance with high accuracy, has not been reported despite its adoption in a few countries. We here report treatment outcomes in a step-wedged cluster randomized trial for patients diagnosed with XpertMTB/RIF compared to patients diagnosed with sputum smear examination in public health facilities in Brazil.. Treatment outcome data were added to the trial database of patients diagnosed from 4 February to 4 October 2012, and crosschecked with data from the national mortality and the drug-resistant TB registers. Treatment outcomes in the intervention (n=2232) and baseline (n=1856) arms were compared using a multilevel regression model.. Unfavourable outcomes were frequent in both arms, mainly due to loss to follow-up (16%). Overall unfavourable outcomes were not reduced in the intervention arm (29.6% versus 31.7%, OR=0.93; 95%CI=0.79-1.08). However, the overall TB-attributed death rate was lower in the intervention arm (2.3% vs. 3.8%). Adjusted for HIV status, age group and city, the intervention resulted in a 35% decrease in TB-attributed deaths (OR=0.65, 95%CI=0.44-0.97).. The proportion of patients successfully treated did not increase with Xpert MTB/RIF implementation, with high loss to follow-up rates in both arms. We did observe a 35% reduction in TB-related mortality, which we hypothesize may be explained by less advanced disease among the smear-negative patients diagnosed by Xpert. In conclusion, XpertMTB/RIF introduction did not improve TB treatment outcomes in Brazil.. clinicaltrials.gov NCT01363765.

    Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Drug Resistance, Microbial; Female; Follow-Up Studies; Humans; Infant; Male; Middle Aged; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Rifampin; Sputum; Treatment Outcome; Tuberculosis

2015
Efavirenz Pharmacokinetics and Pharmacodynamics in HIV-Infected Persons Receiving Rifapentine and Isoniazid for Tuberculosis Prevention.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015, Oct-15, Volume: 61, Issue:8

    Concomitant use of rifamycins to treat or prevent tuberculosis can result in subtherapeutic concentrations of antiretroviral drugs. We studied the interaction of efavirenz with daily rifapentine and isoniazid in human immunodeficiency virus (HIV)-infected individuals receiving a 4-week regimen to prevent tuberculosis.. Participants receiving daily rifapentine and isoniazid with efavirenz had pharmacokinetic evaluations at baseline and weeks 2 and 4 of concomitant therapy. Efavirenz apparent oral clearance was estimated and the geometric mean ratio (GMR) of values before and during rifapentine and isoniazid was calculated. HIV type 1 (HIV-1) RNA was measured at baseline and week 8.. Eighty-seven participants were evaluable: 54% were female, and the median age was 35 years (interquartile range [IQR], 29-44 years). Numbers of participants with efavirenz concentrations ≥1 mg/L were 85 (98%) at week 0; 81 (93%) at week 2; 78 (90%) at week 4; and 75 (86%) at weeks 2 and 4. Median efavirenz apparent oral clearance was 9.3 L/hour (IQR, 6.42-13.22 L/hour) at baseline and 9.8 L/hour (IQR, 7.04-15.59 L/hour) during rifapentine/isoniazid treatment (GMR, 1.04 [90% confidence interval, .97-1.13]). Seventy-nine of 85 (93%) participants had undetectable HIV-1 RNA (<40 copies/mL) at entry; 71 of 75 (95%) participants had undetectable HIV-1 RNA at week 8. Two participants with undetectable HIV-1 RNA at study entry were detectable (43 and 47 copies/mL) at week 8.. The proportion of participants with midinterval efavirenz concentrations ≥1 mg/L did not cross below the prespecified threshold of >80%, and virologic suppression was maintained. Four weeks of daily rifapentine plus isoniazid can be coadministered with efavirenz without clinically meaningful reductions in efavirenz mid-dosing concentrations or virologic suppression.. NCT 01404312.

    Topics: Administration, Oral; Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Isoniazid; Male; Reverse Transcriptase Inhibitors; Rifampin; RNA, Viral; Tuberculosis

2015
Pharmacokinetics of Raltegravir in HIV-Infected Patients on Rifampicin-Based Antitubercular Therapy.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015, Oct-15, Volume: 61, Issue:8

    Rifampicin (RIF) induces UGT1A1, an enzyme involved in raltegravir (RAL) elimination, thereby potentially lowering RAL exposure. We examined the pharmacokinetics of RAL in human immunodeficiency virus (HIV)-infected patients on RIF-based antitubercular therapy in the French National Agency for HIV/AIDS and Viral Hepatitis Research 12 180 Reflate Tuberculosis trial.. Patients started RAL in combination with tenofovir disoproxil fumarate and lamivudine after initiation of RIF (10 mg/kg/day). In arm 1 (n = 21), they received 400 mg RAL twice daily; in arm 2 (n = 16), they received RAL 800 mg twice daily initially then 400 mg twice daily 4 weeks after RIF discontinuation. Pharmacokinetic sampling was performed over 12-hour periods, 4 weeks after initiation of RAL together with RIF (period 1), 4 weeks after RIF discontinuation (period 2), and after the RAL dose reduction in arm 2 (period 3).. In arm 1, the geometric mean ratio (GMR) between period 1 and period 2 was 0.94 (90% confidence interval [CI], .64-1.37) for the 12-hour area under the time-concentration curve (AUC0-12), and 0.69 (90% CI, .42-1.13) for the concentration at 12 hours (C12). In arm 2, the corresponding GMRs were 0.75 (90% CI, .48-1.17) and 1.10 (90% CI, .61-2.00) for period 1 vs period 2, and 1.10 (90% CI, .78-1.55) and 1.68 (90% CI, .88-3.23) for period 1 vs period 3.. The double dose of RAL overcompensated for RIF induction, but the standard dose was associated with only small decreases in AUC0-12 and C12 during RIF coadministration, warranting further evaluation in patients with HIV/tuberculosis coinfection.. NCT0082231.

    Topics: Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Coinfection; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Raltegravir Potassium; Rifampin; Tenofovir; Tuberculosis

2015
Dependence of efavirenz- and rifampicin-isoniazid-based antituberculosis treatment drug-drug interaction on CYP2B6 and NAT2 genetic polymorphisms: ANRS 12154 study in Cambodia.
    The Journal of infectious diseases, 2014, Feb-01, Volume: 209, Issue:3

    We investigated the population pharmacokinetics and pharmacogenetics of efavirenz in 307 patients coinfected with human immunodeficiency virus and tuberculosis and included in the Cambodian Early vs Late Initiation of Antiretrovirals trial (CAMELIA) in Cambodia. Efavirenz (600 mg/d) and stavudine plus lamivudine were administered in addition to standard antituberculosis treatment, including rifampicin and isoniazid. Blood samples were obtained a mean of 14 hours after efavirenz intake at weeks 2 and 6 after initiation of efavirenz and weeks 22 (efavirenz plus antituberculosis drugs) and 50 (efavirenz alone) after initiation of antituberculosis treatment. Ten patients participated in an extensive pharmacokinetic study after week 50. CYP2B6 G516T and C485-18T polymorphisms were the most significant covariates, with weight showing a significant minor effect. Change in efavirenz apparent clearance in patients taking both efavirenz and antituberculosis treatment was highly dependent on NAT2 polymorphism, as a possible surrogate of isoniazid exposure. Patients carrying the CYP2B6 516 TT genotype and slow-acetylation NAT2 phenotype had the lowest efavirenz apparent clearance. These data suggest that the inducing effect of rifampicin is counterbalanced by a concentration-dependant inhibitory effect of isoniazid on efavirenz clearance.

    Topics: Alkynes; Anti-HIV Agents; Antitubercular Agents; Aryl Hydrocarbon Hydroxylases; Arylamine N-Acetyltransferase; Benzoxazines; Cambodia; Chromatography, Liquid; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Interactions; HIV Infections; Humans; Isoniazid; Lamivudine; Plasma; Polymorphism, Single Nucleotide; Rifampin; Spectrophotometry, Ultraviolet; Stavudine; Tuberculosis

2014
Population pharmacokinetics of rifapentine and desacetyl rifapentine in healthy volunteers: nonlinearities in clearance and bioavailability.
    Antimicrobial agents and chemotherapy, 2014, Volume: 58, Issue:6

    Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h(-1), respectively, after a single dose to 2.2 and 5.0 liters · h(-1), respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.).

    Topics: Adult; Antibiotics, Antitubercular; Biological Availability; Cohort Studies; Dose-Response Relationship, Drug; Female; Healthy Volunteers; Humans; Male; Middle Aged; Nonlinear Dynamics; Rifampin; Time Factors; Tuberculosis; Young Adult

2014
Pharmacokinetics of rifampin and isoniazid in tuberculosis-HIV-coinfected patients receiving nevirapine- or efavirenz-based antiretroviral treatment.
    Antimicrobial agents and chemotherapy, 2014, Volume: 58, Issue:6

    This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4(+) T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of rifampin and isoniazid when coadministered with nevirapine or efavirenz were not altered to a clinically significant extent in these severely immunosuppressed HIV-infected patients. Patients experienced favorable clinical outcomes. (This study has been registered at ClinicalTrials.gov under registration no. NCT00495326.).

    Topics: Adult; Alkynes; Antitubercular Agents; Benzoxazines; Coinfection; Cyclopropanes; Female; Half-Life; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Treatment Outcome; Tuberculosis; Young Adult

2014
Nutritional supplementation increases rifampin exposure among tuberculosis patients coinfected with HIV.
    Antimicrobial agents and chemotherapy, 2014, Volume: 58, Issue:6

    Nutritional supplementation to tuberculosis (TB) patients has been associated with increased weight and reduced mortality, but its effect on the pharmacokinetics of first-line anti-TB drugs is unknown. A cohort of 100 TB patients (58 men; median age, 35 [interquartile range {IQR}, 29 to 40] years, and median body mass index [BMI], 18.8 [17.3 to 19.9] kg/m(2)) were randomized to receive nutritional supplementation during the intensive phase of TB treatment. Rifampin plasma concentrations were determined after 1 week and 2 months of treatment. The effects of nutritional supplementation, HIV, time on treatment, body weight, and SLCO1B1 rs4149032 genotype were examined using a population pharmacokinetic model. The model adjusted for body size via allometric scaling, accounted for clearance autoinduction, and detected an increase in bioavailability (+14%) for the patients in the continuation phase. HIV coinfection in patients not receiving the supplementation was found to decrease bioavailability by 21.8%, with a median maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC0-24) of 5.6 μg/ml and 28.6 μg · h/ml, respectively. HIV-coinfected patients on nutritional supplementation achieved higher Cmax and AUC0-24 values of 6.4 μg/ml and 31.6 μg · h/ml, respectively, and only 13.3% bioavailability reduction. No effect of the SLCO1B1 rs4149032 genotype was observed. In conclusion, nutritional supplementation during the first 2 months of TB treatment reduces the decrease in rifampin exposure observed in HIV-coinfected patients but does not affect exposure in HIV-uninfected patients. If confirmed in other studies, the use of defined nutritional supplementation in HIV-coinfected TB patients should be considered in TB control programs. (This study has the controlled trial registration number ISRCTN 16552219.).

    Topics: Adult; Biological Availability; Body Mass Index; Body Weight; Cohort Studies; Coinfection; Dietary Supplements; Female; Genotype; HIV Infections; Humans; Male; Middle Aged; Rifampin; Tuberculosis; Weight Gain

2014
Pharmacokinetics of rifampicin in Mexican patients with tuberculosis and healthy volunteers.
    The Journal of pharmacy and pharmacology, 2014, Volume: 66, Issue:10

    The aim of this study was to compare the pharmacokinetics (PK) of rifampicin (RIF) between healthy volunteers and patients with tuberculosis (TB).. RIF was administered as a single 600-mg dose to 24 healthy volunteers and 24 TB patients, followed by serial blood sampling. Plasma concentrations were analysed using a chromatographic method, and the PK parameters were estimated using WinNonlin software.. Peak plasma concentration ranged from 6.4 to 19.9 mg/l, which was subtherapeutic for 15% of the study participants in both groups, mostly in men (71.4%). The mean area under the concentration-time curve (AUC0-24h ) did not show differences between these groups (P > 0.05). The absorption rate was slower in TB patients and the volume of distribution normalized by total body weight (Vd/kg) was greater than healthy volunteers (P < 0.05). A greater Vd and clearance were found in male subjects. The lag time (tlag) and the time before reach Cmax (Tmax) were longer for female TB patients (P < 0.05).. The main differences in PK parameters of RIF between Mexican TB patients and healthy volunteers were demonstrated in absorption and distribution processes. In addition, differences in PK parameters observed by sex should be considered for further dosing recommendations.

    Topics: Adult; Antibiotics, Antitubercular; Area Under Curve; Dose-Response Relationship, Drug; Female; Healthy Volunteers; Humans; Intestinal Absorption; Male; Mexico; Middle Aged; Reference Values; Rifampin; Sex Factors; Tuberculosis; Young Adult

2014
Intermittent tuberculosis treatment for patients with isoniazid intolerance or drug resistance.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2014, Volume: 18, Issue:5

    Twenty tuberculosis (TB) clinics in the United States and Canada.. To evaluate the efficacy and safety of a 6-month intermittent regimen of rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB) in human immunodeficiency virus (HIV) negative patients with culture-confirmed pulmonary or extra-pulmonary tuberculosis and either isoniazid (INH) resistance or INH intolerance.. Patients were enrolled in a single-arm clinical trial to receive intermittent dosing after at least 14 initial daily doses of RMP+PZA+EMB. Treatment was continued twice (BIW) or thrice weekly (TIW) per physician/patient preference for a total of 6 months, with 2 years of follow-up for relapse after treatment.. From 1999 to 2004, 98 patients were enrolled, 78 with reported INH resistance and 20 with INH intolerance. BIW dosing was used in 77 and TIW in 21. Study treatment was completed in 73 (74%). Reasons for discontinuation were hepatic adverse events (n= 12), other adverse effects (n= 3) and other reasons (n= 10). Failure (n= 1) and relapse (n= 2) occurred in 3 (3.5%, 95%CI 1.2-9.8) of 86 patients eligible for efficacy analysis, all occurring in patients with cavitary, acid-fast bacilli smear-positive pulmonary TB.. Intermittent RMP+PZA+EMB appears to be effective in HIV-negative patients, but the regimen is poorly tolerated, possibly due to the prolonged use of PZA. Alternative regimens of lower toxicity are needed.

    Topics: Adult; Ambulatory Care Facilities; Antitubercular Agents; Canada; Directly Observed Therapy; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis; United States

2014
Acquired rifampicin resistance in thrice-weekly antituberculosis therapy: impact of HIV and antiretroviral therapy.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2014, Dec-15, Volume: 59, Issue:12

    Risk factors for acquired rifampicin resistance (ARR) in human immunodeficiency virus (HIV)/tuberculosis coinfection, in the highly active antiretroviral therapy (HAART) era, needs evaluation. We studied the impact of HIV and HAART on ARR among patients taking thrice-weekly antituberculosis therapy.. This cross-protocol analysis included patients with newly diagnosed, rifampicin-susceptible pulmonary tuberculosis, with and without HIV, enrolled in clinical trials (who took >80% of medication) at the National Institute for Research in Tuberculosis between 1999 and 2013. All patients received rifampicin and isoniazid for 6 months reinforced with pyrazinamide and ethambutol in the first 2 months, given thrice-weekly throughout the study along with HAART in one of the groups. Outcomes were categorized and multivariate logistic regression analysis performed to identify risk factors for ARR.. The per-protocol results included patients with tuberculosis: 246 HIV-uninfected patients (HIV(-)TB(+)), 212 HIV patients not on HAART (non-HAART), and 116 HIV-infected patients on HAART. Median CD4 counts of the latter 2 groups were 150 and 93 cells/µL, respectively, and the median viral loads were 147 000 and 266 000 copies/mL, respectively. Compared with HIV(-)TB(+), the relative risks (RRs) for an unfavorable response in the coinfected, non-HAART and HAART groups were 2.1 (95% confidence interval [CI], 1.7-14.8; P<.0001) and 2.1 (95% CI, .9-5.2; P=.3), whereas for ARR, the RRs were 21.1 (95% CI, 2.6-184; P<.001) and 8.2 (95% CI, .6-104; P=.07), respectively.. HIV-infected patients with tuberculosis treated with a thrice-weekly antituberculosis regimen are at a higher risk of ARR, compared with HIV-uninfected patients, in the presence of baseline isoniazid resistance. HAART reduces but does not eliminate the risk of ARR.

    Topics: Adolescent; Adult; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Male; Rifampin; Risk Factors; Tuberculosis; Young Adult

2014
Effect of micronutrient supplementation on treatment outcomes in children with intrathoracic tuberculosis: a randomized controlled trial.
    The American journal of clinical nutrition, 2014, Volume: 100, Issue:5

    Micronutrients play an important role in immune function. To our knowledge, there have been no comprehensive studies on the role of micronutrient supplementation in children with tuberculosis.. We assessed the effect of micronutrient supplementation in children treated with antituberculosis therapy (ATT).. A randomized, double-blind, placebo-controlled trial that used a 2 × 2 factorial design was undertaken at 2 teaching hospitals in Delhi. Children with newly diagnosed intrathoracic tuberculosis were enrolled, and they received ATT together with daily supplementation for 6 mo with either zinc alone, micronutrients without zinc, micronutrients in combination with zinc, or a placebo. Main outcomes were weight gain and an improvement in a chest X-ray (CXR) lesion assessed at 6 mo of treatment.. A total of 403 children were enrolled and randomly assigned. A microbiological diagnosis of tuberculosis was confirmed in 179 children (44.4%). The median (95% CI) increase in weight-for-age z score at 6 mo was not significantly different between subjects who received micronutrients [0.75 (0.66, 0.84)] and those who did not receive micronutrients [0.76 (0.67, 0.85)] and between subjects who received zinc [0.76 (0.68, 0.85)] and those who did not receive zinc [0.75 (0.66, 0.83)]. An improvement in CXR was observed in 285 children, but there was no difference between those receiving zinc and no zinc or between those receiving micronutrients and no micronutrients after 6 mo of ATT. However, children who received micronutrients had a faster gain in height over 6 mo than did those who did not receive micronutrients (height-for-age z score Δ = 0.08; P = 0.014).. Micronutrient supplementation did not modify the weight gain or clearance of lesions on CXR in children with intrathoracic tuberculosis. However, micronutrient supplementation during treatment may improve height gain in children with intrathoracic tuberculosis. This trial was registered at clinicaltrials.gov as NCT00801606.

    Topics: Adolescent; Antitubercular Agents; Body Height; Body Mass Index; Body Weight; Child; Child, Preschool; Dietary Supplements; Double-Blind Method; Ethambutol; Female; Humans; India; Infant; Isoniazid; Male; Micronutrients; Patient Compliance; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis; Zinc

2014
Impact of Xpert MTB/RIF for TB diagnosis in a primary care clinic with high TB and HIV prevalence in South Africa: a pragmatic randomised trial.
    PLoS medicine, 2014, Volume: 11, Issue:11

    Xpert MTB/RIF is approved for use in tuberculosis (TB) and rifampicin-resistance diagnosis. However, data are limited on the impact of Xpert under routine conditions in settings with high TB burden.. A pragmatic prospective cluster-randomised trial of Xpert for all individuals with presumptive (symptomatic) TB compared to the routine diagnostic algorithm of sputum microscopy and limited use of culture was conducted in a large TB/HIV primary care clinic. The primary outcome was the proportion of bacteriologically confirmed TB cases not initiating TB treatment by 3 mo after presentation. Secondary outcomes included time to TB treatment and mortality. Unblinded randomisation occurred on a weekly basis. Xpert and smear microscopy were performed on site. Analysis was both by intention to treat (ITT) and per protocol. Between 7 September 2010 and 28 October 2011, 1,985 participants were assigned to the Xpert (n = 982) and routine (n = 1,003) diagnostic algorithms (ITT analysis); 882 received Xpert and 1,063 routine (per protocol analysis). 13% (32/257) of individuals with bacteriologically confirmed TB (smear, culture, or Xpert) did not initiate treatment by 3 mo after presentation in the Xpert arm, compared to 25% (41/167) in the routine arm (ITT analysis, risk ratio 0.51, 95% CI 0.33-0.77, p = 0.0052). The yield of bacteriologically confirmed TB cases among patients with presumptive TB was 17% (167/1,003) with routine diagnosis and 26% (257/982) with Xpert diagnosis (ITT analysis, risk ratio 1.57, 95% CI 1.32-1.87, p<0.001). This difference in diagnosis rates resulted in a higher rate of treatment initiation in the Xpert arm: 23% (229/1,003) and 28% (277/982) in the routine and Xpert arms, respectively (ITT analysis, risk ratio 1.24, 95% CI 1.06-1.44, p = 0.013). Time to treatment initiation was improved overall (ITT analysis, hazard ratio 0.76, 95% CI 0.63-0.92, p = 0.005) and among HIV-infected participants (ITT analysis, hazard ratio 0.67, 95% CI 0.53-0.85, p = 0.001). There was no difference in 6-mo mortality with Xpert versus routine diagnosis. Study limitations included incorrect intervention allocation for a high proportion of participants and that the study was conducted in a single clinic.. These data suggest that in this routine primary care setting, use of Xpert to diagnose TB increased the number of individuals with bacteriologically confirmed TB who were treated by 3 mo and reduced time to treatment initiation, particularly among HIV-infected participants.. Pan African Clinical Trials Registry PACTR201010000255244. Please see later in the article for the Editors' Summary.

    Topics: Adolescent; Adult; Aged; Ambulatory Care Facilities; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Prevalence; Primary Health Care; Prospective Studies; Real-Time Polymerase Chain Reaction; Rifampin; South Africa; Time-to-Treatment; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2014
Impact of replacing smear microscopy with Xpert MTB/RIF for diagnosing tuberculosis in Brazil: a stepped-wedge cluster-randomized trial.
    PLoS medicine, 2014, Volume: 11, Issue:12

    Abundant evidence on Xpert MTB/RIF accuracy for diagnosing tuberculosis (TB) and rifampicin resistance has been produced, yet there are few data on the population benefit of its programmatic use. We assessed whether the implementation of Xpert MTB/RIF in routine conditions would (1) increase the notification rate of laboratory-confirmed pulmonary TB to the national notification system and (2) reduce the time to TB treatment initiation (primary endpoints).. We conducted a stepped-wedge cluster-randomized trial from 4 February to 4 October 2012 in 14 primary care laboratories in two Brazilian cities. Diagnostic specimens were included for 11,705 baseline (smear microscopy) and 12,522 intervention (Xpert MTB/RIF) patients presumed to have TB. Single-sputum-sample Xpert MTB/RIF replaced two-sputum-sample smear microscopy for routine diagnosis of pulmonary TB. In total, 1,137 (9.7%) tests in the baseline arm and 1,777 (14.2%) in the intervention arm were positive (p<0.001), resulting in an increased bacteriologically confirmed notification rate of 59% (95% CI = 31%, 88%). However, the overall notification rate did not increase (15%, 95% CI =  -6%, 37%), and we observed no change in the notification rate for those without a test result (-3%, 95% CI = -37%, 30%). Median time to treatment decreased from 11.4 d (interquartile range [IQR] = 8.5-14.5) to 8.1 d (IQR = 5.4-9.3) (p = 0.04), although not among confirmed cases (median 7.5 [IQR = 4.9-10.0] versus 7.3 [IQR = 3.4-9.0], p = 0.51). Prevalence of rifampicin resistance detected by Xpert was 3.3% (95% CI = 2.4%, 4.3%) among new patients and 7.4% (95% CI = 4.3%, 11.7%) among retreatment patients, with a 98% (95% CI = 87%, 99%) positive predictive value compared to phenotypic drug susceptibility testing. Missing data in the information systems may have biased our primary endpoints. However, sensitivity analyses assessing the effects of missing data did not affect our results.. Replacing smear microscopy with Xpert MTB/RIF in Brazil increased confirmation of pulmonary TB. An additional benefit was the accurate detection of rifampicin resistance. However, no increase on overall notification rates was observed, possibly because of high rates of empirical TB treatment.. ClinicalTrials.gov NCT01363765. Please see later in the article for the Editors' Summary.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Brazil; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2014
Model-based evaluation of the pharmacokinetic differences between adults and children for lopinavir and ritonavir in combination with rifampicin.
    British journal of clinical pharmacology, 2013, Volume: 76, Issue:5

    Rifampicin profoundly reduces lopinavir concentrations. Doubled doses of lopinavir/ritonavir compensate for the effect of rifampicin in adults, but fail to provide adequate lopinavir concentrations in young children on rifampicin-based antituberculosis therapy. The objective of this study was to develop a population pharmacokinetic model describing the pharmacokinetic differences of lopinavir and ritonavir, with and without rifampicin, between children and adults.. An integrated population pharmacokinetic model developed in nonmem 7 was used to describe the pharmacokinetics of lopinavir and ritonavir in 21 HIV infected adults, 39 HIV infected children and 35 HIV infected children with tuberculosis, who were established on lopinavir/ritonavir-based antiretroviral therapy with and without rifampicin-containing antituberculosis therapy.. The bioavailability of lopinavir was reduced by 25% in adults whereas children on antituberculosis treatment experienced a 59% reduction, an effect that was moderated by the dose of ritonavir. Conversely, rifampicin increased oral clearance of both lopinavir and ritonavir to a lesser extent in children than in adults. Rifampicin therapy in administered doses increased CL of lopinavir by 58% in adults and 48% in children, and CL of ritonavir by 34% and 22% for adults and children, respectively. In children, the absorption half-life of lopinavir and the mean transit time of ritonavir were lengthened, compared with those in adults.. The model characterized important differences between adults and children in the effect of rifampicin on the pharmacokinetics of lopinavir and ritonavir. As adult studies cannot reliably predict their magnitude in children, drug-drug interactions should be evaluated in paediatric patient populations.

    Topics: Adult; Age Factors; Anti-HIV Agents; Antitubercular Agents; Biological Availability; Child, Preschool; Cohort Studies; Drug Interactions; Female; Half-Life; HIV Infections; Humans; Infant; Lopinavir; Male; Middle Aged; Models, Biological; Nonlinear Dynamics; Rifampin; Ritonavir; Tuberculosis

2013
Efficacy and safety of thrice weekly DOTS in tuberculosis patients with and without HIV co-infection: an observational study.
    BMC infectious diseases, 2013, Oct-07, Volume: 13

    Despite the latest World Health Organization guidelines advocating daily therapy in HIV-TB co-infected individuals, there are few recent studies comparing outcomes of thrice-weekly anti-tuberculosis treatment in HIV-positive and HIV-negative patients with TB. The present study sets out to compare TB treatment outcomes in these two groups in the Indian national programme, which currently involves thrice-weekly therapy for all, regardless of HIV status.. HIV-positive and HIV-negative were consecutively screened for enrolment into this prospective observational study, carried out at the All India Institute of Medical Sciences hospital, New Delhi, India, between 2006 and 2010. Patients were given short-course thrice-weekly rifampicin-based therapy, with all HIV-positive patients being started on highly active antiretroviral therapy at least 14 days after commencing TB treatment. Patients were regularly followed-up for 24 months after completion of treatment.. 150 HIV-positive, 155 HIV-negative patients were enrolled consecutively for the study. Significantly higher treatment success (93.5% vs. 76.7% at end of treatment, p < 0.001) and lower mortality (2.8% vs. 21.6% on follow up, p < 0.001) were observed in HIV-negative patients. No significant difference was found in treatment failure (p = 0.16), sputum smear (p = 0.58) and culture conversion (p = 0.55), and non-serious adverse event incidence (p = 0.851) between the two groups. Low baseline CD4 cell count (<100 cells/ mm3) was the only predictor of mortality in HIV-TB patients (odds ratio 8 · 43, p = 0 · 013).. Thrice-weekly anti-tuberculosis therapy is more effective in HIV-negative than in HIV-positive patients. However, outcomes in this HIV co-infected cohort were found to be similar to those reported previously with daily therapy, with no safety concerns. This should prompt further study into whether intermittent or daily therapy should be used universally in resource-poor settings, using large well executed randomised controlled trials.. NCT No. 00698334.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; CD4 Lymphocyte Count; Coinfection; Drug Administration Schedule; Female; HIV Infections; Humans; India; Male; Middle Aged; Prospective Studies; Rifampin; Treatment Outcome; Tuberculosis; Young Adult

2013
Early changes in hepatic function among HIV-tuberculosis patients treated with nevirapine or efavirenz along with rifampin-based anti-tuberculosis therapy.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2013, Volume: 17, Issue:12

    To describe the longitudinal changes in hepatic function among HIV-infected tuberculosis (TB) patients receiving once-daily nevirapine (NVP)- or efavirenz (EFV)-based antiretroviral treatment (ART) along with rifampin-containing anti-TB treatment.. This was a nested study within a randomized clinical trial, taking place between May 2006 and June 2008 at the National Institute for Research in Tuberculosis, Chennai, India. Antiretroviral-naïve HIV-infected TB patients were initiated on an intermittent short-course regimen and randomized to receive didanosine and lamivudine with either NVP (400 mg) or EFV (600 mg) once-daily. Blood was analyzed for alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum alkaline phosphatase (SAP), and bilirubin at baseline, at ART initiation, fortnightly after ART initiation until 2 months, then monthly until 6 months and 6-monthly thereafter.. Of the 168 patients included (79% men, median CD4 count 93 cells/mm3, median viral load 242,000 copies/ml), 104 were on EFV-based ART and 64 on NVP-based ART. There was a small but statistically significant elevation in ALT and SAP at 2 weeks and AST at 6 weeks after ART initiation. The proportion of patients with rate-limiting toxicity of liver enzymes was small. None had treatment terminated because of hepatotoxicity.. Hepatotoxicity is not a major concern when HIV-infected TB patients, with normal baseline liver function initiate treatment for both infections simultaneously.

    Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Benzoxazines; CD4 Lymphocyte Count; Coinfection; Cyclopropanes; Female; HIV Infections; Humans; Liver; Liver Function Tests; Male; Nevirapine; Rifampin; Time Factors; Treatment Outcome; Tuberculosis; Viral Load

2013
Nevirapine versus efavirenz-based antiretroviral therapy regimens in antiretroviral-naive patients with HIV and tuberculosis infections in India: a pilot study.
    BMC infectious diseases, 2013, Oct-17, Volume: 13

    Administration of rifampicin along with nevirapine reduces the plasma concentration of nevirapine in human immunodeficiency virus positive individuals with concomitant tuberculosis (HIV-TB patients). Nevirapine is a much cheaper drug than its alternative efavirenz, and might be beneficial in resource constrained settings.. A randomised open label trial was conducted at All India Institute of Medical Sciences, New Delhi, India. During the regimen of an antiretroviral therapy (ART), naive HIV-TB patients were randomly assigned to receive either nevirapine or efavirenz based ART with concomitant rifampicin based anti-tubercular therapy (ATT). Participants were followed for 24 months after starting ART. The end points were virological, immunological and clinical responses, and progression of HIV disease marked by failure of ART.. Of the 135 HIV-TB patients, who were receiving rifampicin based ATT, 68 were selected randomly to receive efavirenz based ART and 67 to receive nevirapine based ART. The virological failure rates in the overall population, and the nevirapine and efavirenz groups were 14.1% (19/135); 14.9% (10/67) and 13.2% (9/68), respectively (p =0.94). No significant difference was found between the groups in the rate of clinical, immunological or virological failures. The overall mortality was 17% with no significant difference between the two groups. Except for the lead in period on day 14, the mean nevirapine concentration remained above 3 mg/L. No association was found between plasma levels of nevirapine and incidence of unfavourable outcomes in this group.. Outcome of ART in HIV-TB patients on rifampicin based ATT showed no significant difference, irrespective of whether efavirenz or nevirapine was used. Therefore, nevirapine based ART could be an alternative in the resource limited settings in patients with HIV and tuberculosis co-infection.. NCT No. 01805258.

    Topics: Adult; Alkynes; Anti-Retroviral Agents; Antitubercular Agents; Benzoxazines; Coinfection; Cyclopropanes; Female; HIV Infections; Humans; India; Male; Middle Aged; Nevirapine; Pilot Projects; Rifampin; Tuberculosis

2013
Population pharmacokinetics of rifampicin in Mexican patients with tuberculosis.
    Journal of clinical pharmacy and therapeutics, 2013, Volume: 38, Issue:1

    Rifampicin (RIF) shows wide variability in its pharmacokinetics. The purpose of this study was to develop and validate a population pharmacokinetic model to characterize the inter- and intra-individual variability in pharmacokinetic parameters of RIF in Mexican patients.. Ninety-four patients receiving antituberculosis therapy participated in this prospective study. Plasma concentration-time data were described using a one-compartment model with lag time, absorption and first-order elimination. The potential influence of demographic and clinical characteristics of the patients, and the pharmaceutical formulation (A, B, C and D) on the pharmacokinetics parameters, was evaluated by non-linear mixed-effect modelling (nonmem). Seventy-seven additional patients participated in the validation of the model.. The final population pharmacokinetic model obtained was as follows: apparent clearance CL/F = 8·17 L/h (1·40 as high for males), apparent distribution volume V(d)/F = 50·1 L (1·29 as high for males), absorption rate constant K(aA) = 0·391/h, K(aB,C,D) = 2·70/h, relative bioavailability F(A) = 0·468, F(B,C,D) = 1, lag time in the absorption phase T(lag) = 0·264 h. The final model improved the precision on the parameter estimates (CL/F, V(d) /F and K(a) by 31·9%, 16·7% and 92·9%, respectively). The residual variability was 27·3%.. Gender was associated with changes in CL/F and V(d) /F whereas the pharmaceutical formulation was associated with changes in F and altered the K(a) . The validation data set showed that the model could be used in clinical practice for Bayesian dose adjustment of RIF in TB patients.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Biological Availability; Female; Humans; Male; Mexico; Middle Aged; Models, Biological; Nonlinear Dynamics; Prospective Studies; Rifampin; Sex Factors; Tissue Distribution; Tuberculosis; Young Adult

2013
The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis.
    European journal of clinical pharmacology, 2012, Volume: 68, Issue:5

    Drug interactions are of concern when treating patients co-infected with human immunodeficiency virus (HIV) and tuberculosis. Concomitant use of efavirenz (EFV) with the enzyme inducer rifampicin might be expected to increase EFV clearance. We investigated the influence of concomitant tuberculosis treatment on the plasma clearance of EFV.. Fifty-eight patients were randomized to receive their EFV-containing antiretroviral therapy either during or after tuberculosis treatment. Steady-state EFV plasma concentrations (n = 209 samples) were measured, 83 in the presence of rifampicin. Data were analyzed using a non-linear mixed effects model, and the model was evaluated using non-parametric bootstrap and visual predictive checks.. The patients had a median age of 32 (range 19-55) years and 43.1% were women. There was a bimodal distribution of apparent clearance, with slow EFV metabolizers accounting for 23.6% of the population and having a metabolic capacity 36.4% of that of the faster metabolizers. Apparent EFV clearance after oral administration in fast metabolizers was 12.9 L/h/70 kg whilst off tuberculosis treatment and 9.1 L/h/70 kg when on tuberculosis treatment. In slow metabolizers, the clearance estimates were 3.3 and 4.7 L/h/70 kg in the presence and absence of TB treatment, respectively. Overall there was a 29.5% reduction in EFV clearance during tuberculosis treatment.. Unexpectedly, concomitant rifampicin-containing tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure. While the reasons for this interaction require further investigation, cytochrome P450 2B6 polymorphisms in the population studied may provide some explanation.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Biotransformation; Cyclopropanes; Drug Administration Schedule; Drug Interactions; Female; Half-Life; HIV Infections; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Reverse Transcriptase Inhibitors; Rifampin; South Africa; Tuberculosis; Young Adult

2012
Pharmacokinetics of nevirapine in HIV-infected children under 3 years on rifampicin-based antituberculosis treatment.
    AIDS (London, England), 2012, Jul-31, Volume: 26, Issue:12

    There is an urgent need to optimize cotreatment for children with tuberculosis and HIV infection. We described nevirapine pharmacokinetics in Zambian children aged less than 3 years, cotreated with nevirapine, lamivudine and stavudine in fixed-dose combination (using WHO weight bands) and rifampicin-based antituberculosis treatment.. Twenty-two children received antituberculosis and antiretroviral therapy (ART) concurrently for 4 weeks before pharmacokinetic sampling. Plasma nevirapine concentrations were determined in samples taken immediately before, and 1, 2 and 6 h after an observed dose. Nevirapine pharmacokinetics were compared with those in 16 children aged less than 3 years without tuberculosis.. Twenty-two children were treated for HIV/TB coinfection, 10 of whom were girls. One boy was excluded from analysis for nonadherence. The median age was 1.6 years (range: 0.7-3.2). Median weight was 8.0 kg (range: 5.1-10.5). The baseline CD4% was 13.1 (range: 3.9-43.6). Median predose concentration of nevirapine was 2.93 mg/l (range: 1.06-11.4), and peak concentration was 6.33 mg/l (range: 2.61-14.5). The nevirapine AUC up to 12 h was estimated as 52.0 mg.h/l (range: 22.6-159.7) compared with 90.9 mg.h/l (range: 40.4-232.1) in children without tuberculosis (P < 0.001). Predose concentrations of nevirapine were less than 3.0 mg/l in 11 children on tuberculosis treatment versus none of the 16 children without tuberculosis treatment (P = 0.001). AUC was 41% (95% CI: 23-54%) lower in children with tuberculosis than without tuberculosis (P < 0.001) after adjusting for dose per square meter.. : We found substantial reductions in nevirapine concentrations in young children receiving rifampicin. Further studies are needed to define the pharmacokinetics, safety and efficacy of adjusted doses of nevirapine-based ART in young children with tuberculosis.

    Topics: Anti-HIV Agents; Antibiotics, Antitubercular; Case-Control Studies; Child, Preschool; Coinfection; Female; HIV Infections; Humans; Infant; Lamivudine; Male; Nevirapine; Rifampin; Stavudine; Treatment Outcome; Tuberculosis; Zambia

2012
The diagnostic accuracy of urine-based Xpert MTB/RIF in HIV-infected hospitalized patients who are smear-negative or sputum scarce.
    PloS one, 2012, Volume: 7, Issue:7

    Hospitals in sub-Saharan Africa are inundated with HIV-infected patients and tuberculosis (TB) is the commonest opportunistic infection in this sub-group. Up to one third of TB-HIV co-infected patients fail to produce a sputum sample (sputum scarce) and diagnosis is thus often delayed or missed. We investigated the sensitivity of urine-based methods (Xpert MTB/RIF, LAM strip test and LAM ELISA) in such patients.. 281 HIV-infected hospitalised patients with clinically suspected TB provided a spot urine sample. The reference standard was culture positivity for Mycobacterium tuberculosis on ≥1 sputum or extra-pulmonary sample. MTB/RIF was performed using 1 ml of both unprocessed and, when possible, concentrated urine. Each unconcentrated urine sample was also tested using the Clearview LAM ELISA and Alere LAM strip test. 42% (116/242) of patients had culture-proven TB. 18% (20/54) were sputum scarce. In sputum-scarce patients, the sensitivity of urine MTB/RIF and LAM ELISA was 40% (95%CI: 22-61) and 60% (95%CI: 39-78), respectively. Urine MTB/RIF specificity was 98% (95%CI: 95-100). Combined sensitivity of urine LAM ELISA and MTB/RIF was better than MTB/RIF alone [MTB/RIF and LAM: 70% (95%CI: 48-85) vs. MTB/RIF: 40% (95%CI: 22-61), p = 0.03]. Significant predictors of urine MTB/RIF positivity were CD4<50 cells/ml (p = 0.001), elevated protein-to-creatinine ratio (p<0.001) and LAM ELISA positivity (p<0.001). Urine centrifugation and pelleting significantly increased the sensitivity of MTB/RIF over unprocessed urine in paired samples [42% (95%CI: 26-58) vs. 8% (95%CI: 0-16), p<0.001]. Urine MTB/RIF-generated C(T) values correlated poorly with markers of bacillary burden (smear grade and time-to-positivity).. This preliminary study indicates that urine-based MTB/RIF, alone or in combination with LAM antigen detection, may potentially aid the diagnosis of TB in HIV-infected patients with advanced immunosuppression when sputum-based diagnosis is not possible. Concentration of urine prior to MTB/RIF-testing significantly improves sensitivity.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antigens, Bacterial; Centrifugation; Drug Resistance, Bacterial; Enzyme-Linked Immunosorbent Assay; Feasibility Studies; HIV Infections; Hospitalization; Humans; Male; Mycobacterium tuberculosis; Reagent Strips; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Urinalysis

2012
The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial.
    Annals of internal medicine, 2012, Sep-04, Volume: 157, Issue:5

    Concerns about the immune reconstitution inflammatory syndrome (IRIS) remain a barrier to antiretroviral therapy (ART) initiation during antituberculosis treatment in co-infected patients.. To assess IRIS incidence, severity, and outcomes relative to the timing of ART initiation in patients with HIV-related tuberculosis.. Randomized, open-label clinical trial. (ClinicalTrials.gov registration number: NCT00398996). An outpatient clinic in Durban, South Africa.. 642 patients co-infected with HIV and tuberculosis.. In a secondary analysis of the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial, IRIS was assessed in patients randomly assigned to initiate ART within 4 weeks of tuberculosis treatment initiation (early integrated treatment group), within 4 weeks of completion of the intensive phase of tuberculosis treatment (late integrated treatment group), or within 4 weeks after tuberculosis therapy completion (sequential treatment group). The syndrome was defined as new-onset or worsening symptoms, signs, or radiographic manifestations temporally related to treatment initiation, accompanied by a treatment response. Severity of IRIS, hospitalization, and time to resolution were monitored.. Incidence of IRIS was 19.5 (n = 43), 7.5 (n = 18), and 8.1 (n = 19) per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Among patients with a baseline CD4+ count less than 0.050 × 109 cells/L, IRIS incidence was 45.5, 9.7, and 19.7 per 100 person-years in the early integrated, late integrated, and sequential treatment groups, respectively. Incidence of IRIS was higher in the early integrated treatment group than in the late integrated (incidence rate ratio, 2.6 [95% CI, 1.5 to 4.8]; P < 0.001) or sequential (incidence rate ratio, 2.4 [CI, 1.4 to 4.4]; P < 0.001) treatment groups. More severe IRIS cases occurred in the early integrated treatment group than in the other 2 groups (35% vs. 19%; P = 0.179), and patients in the early integrated treatment group had significantly higher hospitalization rates (42% vs. 14%; P = 0.007) and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) than patients in the other 2 groups.. It was not possible to assess IRIS in more patients in the sequential treatment group (n = 74) than in the late integrated (n = 50) and early integrated (n = 32) treatment groups because of loss to follow-up, withdrawal, or death within 6 months of scheduled ART initiation. This study did not assess IRIS risk in nonambulatory patients or in those with extrapulmonary and smear-negative tuberculosis.. Initiation of ART in early stages of tuberculosis treatment resulted in significantly higher IRIS rates, longer time to resolution, and more severe cases of IRIS requiring hospitalization. These findings are particularly relevant to patients initiating ART with a CD4+ count less than 0.050 × 109 cells/L, given the increased survival benefit of early ART initiation in this group.. Comprehensive International Program of Research on AIDS.

    Topics: Adult; AIDS-Related Opportunistic Infections; Anti-Retroviral Agents; Antibiotics, Antitubercular; CD4 Lymphocyte Count; Female; HIV Infections; Humans; Immune Reconstitution Inflammatory Syndrome; Immunocompromised Host; Incidence; Kaplan-Meier Estimate; Male; Prospective Studies; Rifampin; Risk Factors; Severity of Illness Index; Tuberculosis

2012
Influence of ABCB-1 C3435T polymorphisms on plasma nevirapine and efavirenz levels and their effects on virologic and immunological outcomes in HIV/TB co-infected Thai adults under anti-retroviral therapy.
    The Southeast Asian journal of tropical medicine and public health, 2012, Volume: 43, Issue:1

    ATP-binding cassette, sub-family B (encoded by ABCB-1 or MDR-1) has an important role in cellular export of antiretroviral agents. A previous study showed that ABCB-1 C3435T polymorphism affects plasma efavirenz and nelfinavir concentrations and rate of CD4+ T cell recovery after starting antiretroviral treatment (ART). The present study examined the influence of ABCB-1 polymorphisms on plasma nevirapine and efavirenz levels when co-administered with rifampicin in 124 HIV/TB patients who received nevirapine- (400 mg/day) (n = 59) and efavirenz- (600 mg/day) (n = 65) based ART. ABCB-1 C3435T polymorphisms were genotyped using real-time PCR. CD4 T cell counts and HIV-1 viral RNA were evaluated in response to ART. The frequencies of CC, CT and TT genotypes of ABCB-1 C3435T polymorphism were 34% (n = 42), 55% (n = 68) and 12% (n = 14), respectively. Contrary to the previous report, no association was found among these genotypes and plasma drug concentrations at weeks 6 and 12 of ART and after rifampicin discontinuation. We also observed no differences in CD4+ T cell recovery rate among different ABCB-1 C3435T genotypes. In nevirapine group, however, all the patients with CT genotype achieved HIV-1 RNA levels of < 50 copies/ml, while 67% of those with TT and 95% with CC genotypes achieved < 50 copies/ml (p = 0.040). These data suggested that ABCB-1 C3435T polymorphisms do not affect plasma nevirapine and efavirenz concentrations in HIV/TB co-infected Thai patients or their immunological outcome, but had an effect on virologic outcome in the nevirapine-treated group.

    Topics: Adult; Alkynes; Analysis of Variance; Antiretroviral Therapy, Highly Active; Antitubercular Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Nevirapine; Polymorphism, Genetic; Real-Time Polymerase Chain Reaction; Rifampin; Thailand; Tuberculosis; Viral Load

2012
Tailored release drug delivery system for rifampicin and isoniazid for enhanced bioavailability of rifampicin.
    Pharmaceutical development and technology, 2011, Volume: 16, Issue:2

    The front line antitubercular drugs rifampicin (RMP) and isoniazid (INH), when co-administered, face the problem of reduced bioavailability of RMP. Stabilization of RMP in the presence of INH under acidic environment may improve the bioavailability of RMP. In vitro degradation studies showed around 15-25% degradation of RMP under the aforesaid conditions if the ratio of RMP: INH is above 1:0.5.This degradation is reduced to less than 10% when the ratio of RMP: INH is below 1:0.25. Based on these findings, an innovative drug delivery system was designed with the immediate release of RMP and tailored prolonged release of INH. The bilayer tablets prepared with this concept were subjected to relative bioavailability studies in healthy human volunteers in an open label, balanced, randomized, single-dose, cross-over study under fasted state. A validated LC-MS/MS bioanalytical method was employed for estimation of RMP and INH in plasma. Bioavailability studies revealed that C(max) and AUC for RMP increased by 18 and 20%, respectively, confirming the above innovative concept. Even in the case of INH, AUC increased significantly by around 30% and thus time above minimum inhibitory concentration (MIC) would also increase, which may result in further improved clinical outcome.

    Topics: Adult; Antitubercular Agents; Biological Availability; Cross-Over Studies; Delayed-Action Preparations; Humans; Isoniazid; Male; Rifampin; Tuberculosis

2011
Nevirapine pharmacokinetics when initiated at 200 mg or 400 mg daily in HIV-1 and tuberculosis co-infected Ugandan adults on rifampicin.
    The Journal of antimicrobial chemotherapy, 2011, Volume: 66, Issue:1

    rifampicin lowers nevirapine plasma concentrations by inducing cytochrome P450. However, few data are available on this interaction during the lead-in period of nevirapine treatment.. eighteen HIV-1/tuberculosis co-infected adults receiving rifampicin daily as part of anti-tuberculosis therapy were evenly randomized to nevirapine initiation by dose escalation (NVP200) or nevirapine initiation at 200 mg twice daily (NVP400). Subjects underwent 12 h intensive pharmacokinetic sampling on Days 7, 14 and 21 of nevirapine treatment. A minimum effective concentration (MEC) of 3000 ng/mL was used to interpret nevirapine concentrations 12 h after dosing (C(12)).. NCT00617643 (www.clinicaltrials.gov).. day 7 geometric mean nevirapine C(12) [90% confidence interval (CI)] was 1504 (1127-2115) ng/mL and 3148 (2451-4687) ng/mL in the NVP200 and NVP400 arms, respectively (P < 0.01). Nevirapine C(12) on Days 14 and 21 was similar. On Day 21, nevirapine concentration in 64% of patients was below the MEC. On Day 7, geometric mean area under the curve (AUC(0-12)) was lower in the NVP200 arm, 25 223 (90% CI, 21 978-29 695) ng·h/mL versus 43 195 (35 607-57 035) ng·h/mL in the NVP400 arm (P  <  0.01). Similarly, on Day 14, nevirapine AUC(0-12) was lower in the NVP200 arm 23 668 (18 253-32 218) ng·h/mL versus the NVP400 arm 44 918 (36 264-62 769) ng·h/mL (P = 0.03).. in co-treated patients, nevirapine concentrations were below the MEC during initiation with dose escalation. Nevirapine initiation at the maintenance dose of 200 mg twice daily is preferred. Sub-therapeutic nevirapine concentrations were common at Day 21 with either regimen. Evaluation of higher nevirapine maintenance doses may be considered.

    Topics: Adult; Anti-Bacterial Agents; Anti-HIV Agents; Drug Interactions; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine; Plasma; Rifampin; Time Factors; Tuberculosis; Uganda

2011
Efavirenz and rifampicin in the South African context: is there a need to dose-increase efavirenz with concurrent rifampicin therapy?
    Antiviral therapy, 2011, Volume: 16, Issue:4

    Increasing efavirenz (EFV) dose from 600 mg to 800 mg daily has been suggested with concomitant rifampicin (RFN), as induction of cytochrome P450 isoenzymes may reduce EFV plasma concentrations.. Individuals from the CIPRA-South Africa cohort taking EFV-based antiretroviral therapy with concomitant tuberculosis (TB) were dosed with either increased (800 mg) or standard (600 mg) dose EFV during TB treatment. After TB therapy, all individuals took 600 mg EFV. Two mid-dosing interval EFV concentrations were determined from each individual: after 4 weeks of concomitant EFV and RFN therapy, and ≥4 weeks after TB therapy completion. Mid-dosing interval EFV concentrations were compared within individuals using the Wilcoxon signed-rank test.. Paired samples were collected from 72 individuals. Overall, 45 (63%) were women and median weight was 59 kg (IQR 52-67). At antiretroviral therapy start, median CD4(+) T-cell count was 114 cells/mm(3) (IQR 37-165), median viral load was 5.5 log (IQR 5.1-5.9). A total of 38 (53%) individuals took 800 mg EFV during TB treatment and 34 (47%) took 600 mg. EFV concentrations in the 800 mg group were higher with RFN (2.9 mg/l [IQR 1.8-5.6]) than without (2.1 mg/l [IQR 1.4-3.0]; P=0.0003). There was no significant difference in EFV concentrations with RFN (2.4 mg/l [IQR 1.2-5.1]) or without (2.2 mg/l [IQR 1.4-3.7]) in the 600 mg group. There was no increase in EFV-linked adverse effects in either group. The proportion of virologically suppressed individuals at 48 weeks was similar in both groups.. EFV concentrations were significantly increased in the EFV 800 mg group on RFN. There was no significant decrease in EFV concentrations when on RFN in the 600 mg group. Dose escalation of EFV 600 mg to 800 mg is not required during concomitant TB therapy in South Africa.

    Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors; Rifampin; South Africa; Treatment Outcome; Tuberculosis

2011
Hepatotoxicity in patients co-infected with tuberculosis and HIV-1 while receiving non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy and rifampicin-containing anti-tuberculosis regimen.
    The Southeast Asian journal of tropical medicine and public health, 2011, Volume: 42, Issue:3

    To evaluate the rate of and risk factors for hepatotoxicity in tuberculosis (TB) and human immunodeficiency virus type 1 (HIV-1) co-infected patients while receiving non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) and a rifampicin (RMP)-containing anti-TB regimen. We analyzed data from the N2R study which was an open label, randomized, comparative trial comparing treatment outcomes between 71 TB/HIV-1 co-infected patients receiving efavirenz (EFV)-based and nevirapine (NVP)-based ART; all of whom were receiving RMP-containing anti-TB treatment. Demographic data, liver function test, CD4 cell count, plasma HIV-1 RNA, hepatitis B surface antigen and anti-hepatitis C virus antibody were collected before initiating ART (week 0). Liver enzymes and total bilirubin levels were monitored at 6 weeks, 12 weeks and 24 weeks after ART initiation. All patients were followed until TB therapy was completed. Of 142 patients, 8 patients were excluded. Among the remaining 134 patients, the mean+/-SD age was 36.8+/-8.6 years and 67.2% were male. Severe hepatotoxicity (grade 3 or 4) developed in 4 patients (2.9%); 3 patients (4.6%) in the NVP group and 1 patient (1.4%) in the EFV group. Severe hyperbilirubinemia (grade 3 or 4) occurred in 7 patients (5.2%); 5 patients (7.7%) in the NVP group and 2 patients (2.9%) in the EFV group. Grade 1 or 2 hepatotoxicity occurred in 34 patients (31.4%). Hepatitis C virus co-infection (adjusted OR 3.03; 95%CI 1.26-7.29) was an independent risk factor associated with grade 1-4 hepatotoxicity (p=0.013). Monitoring of hepatotoxicity should be considered in TB/HIV-1 co-infected patients who are infected with HCV and receiving NVP.

    Topics: Adult; Alkynes; Antibiotics, Antitubercular; Benzoxazines; Chemical and Drug Induced Liver Injury; Cyclopropanes; Female; HIV Infections; HIV-1; Humans; Hyperbilirubinemia; Liver Function Tests; Logistic Models; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Risk Factors; Thailand; Tuberculosis; Young Adult

2011
New regimens to prevent tuberculosis in adults with HIV infection.
    The New England journal of medicine, 2011, Jul-07, Volume: 365, Issue:1

    Treatment of latent tuberculosis in patients infected with the human immunodeficiency virus (HIV) is efficacious, but few patients around the world receive such treatment. We evaluated three new regimens for latent tuberculosis that may be more potent and durable than standard isoniazid treatment.. We randomly assigned South African adults with HIV infection and a positive tuberculin skin test who were not taking antiretroviral therapy to receive rifapentine (900 mg) plus isoniazid (900 mg) weekly for 12 weeks, rifampin (600 mg) plus isoniazid (900 mg) twice weekly for 12 weeks, isoniazid (300 mg) daily for up to 6 years (continuous isoniazid), or isoniazid (300 mg) daily for 6 months (control group). The primary end point was tuberculosis-free survival.. The 1148 patients had a median age of 30 years and a median CD4 cell count of 484 per cubic millimeter. Incidence rates of active tuberculosis or death were 3.1 per 100 person-years in the rifapentine-isoniazid group, 2.9 per 100 person-years in the rifampin-isoniazid group, and 2.7 per 100 person-years in the continuous-isoniazid group, as compared with 3.6 per 100 person-years in the control group (P>0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person-years) than in the other treatment groups (8.7 to 15.4 per 100 person-years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance.. On the basis of the expected rates of tuberculosis in this population of HIV-infected adults, all secondary prophylactic regimens were effective. Neither a 3-month course of intermittent rifapentine or rifampin with isoniazid nor continuous isoniazid was superior to 6 months of isoniazid. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00057122.).

    Topics: Adult; AIDS-Related Opportunistic Infections; Anti-Retroviral Agents; Antitubercular Agents; Cause of Death; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Isoniazid; Kaplan-Meier Estimate; Male; Mycobacterium tuberculosis; Patient Compliance; Proportional Hazards Models; Rifampin; Risk; Tuberculosis; Tuberculosis, Multidrug-Resistant

2011
Effect of rifampicin and CYP2B6 genotype on long-term efavirenz autoinduction and plasma exposure in HIV patients with or without tuberculosis.
    Clinical pharmacology and therapeutics, 2011, Volume: 90, Issue:3

    We performed a prospective comparative study to examine, from a pharmacogenetics perspective, the effect of rifampicin (RIF) on long-term efavirenz (EFV) autoinduction and kinetics. In a study population of patients with HIV receiving EFV with RIF (arm 2, n = 54) or without RIF (arm 1, n = 128 controls), intraindividual and interindividual plasma EFV and 8-hydroxyefavirenz levels were compared at weeks 4 and 16 of EFV therapy. In arm 2, RIF was initiated 4 weeks before starting EFV. In controls (arm 1), the plasma EFV was significantly lower whereas 8-hydroxyefavirenz was higher at week 16 as compared to week 4. By contrast, there were no significant differences in plasma EFV and 8-hydroxyefavirenz concentrations over time in arm 2. At week 4, the plasma EFV concentration was significantly lower in arm 2 as compared to arm 1, but no significant differences were observed by week 16. When stratified by CYP2B6 genotype, significant differences were observed only with respect to CYP2B6*1/*1 genotypes. Ours is the first report of the CYP2B6 genotype-dependent effect of RIF on long-term EFV autoinduction.

    Topics: Alkynes; Alleles; Anti-HIV Agents; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Aryl Hydrocarbon Hydroxylases; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Drug Interactions; Enzyme Induction; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Oxidoreductases, N-Demethylating; Polymorphism, Single Nucleotide; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

2011
Pharmacokinetics of isoniazid, rifampin, and pyrazinamide in children younger than two years of age with tuberculosis: evidence for implementation of revised World Health Organization recommendations.
    Antimicrobial agents and chemotherapy, 2011, Volume: 55, Issue:12

    The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dosage recommendations for children. No pharmacokinetic studies for these revised dosages are available for children <2 years. The aim of the study was to document the pharmacokinetics of the first-line anti-TB agents in children <2 years of age comparing previous and revised WHO dosages of isoniazid (INH; 5 versus 10 mg/kg/day), rifampin (RMP; 10 versus 15 mg/kg/day), and pyrazinamide (PZA; 25 versus 35 mg/kg/day) and to investigate the effects of clinical covariates, including HIV coinfection, nutritional status, age, gender, and type of tuberculosis (TB), and the effect of NAT2 acetylator status. Serum INH, PZA, and RMP levels were prospectively assessed in 20 children <2 years of age treated for TB following the previous and the revised WHO dosage recommendations. Samples were taken prior to dosing and at 0.5, 1.5, 3, and 5 h following dosing. The maximum drug concentration in serum (C(max)), the time to C(max) (t(max)), and the area under the concentration-time curve (AUC) were calculated. Eleven children had pulmonary and 9 had extrapulmonary TB. Five were HIV infected. The mean C(max) (μg/ml) following the administration of previous/revised dosages were as follows: INH, 3.19/8.11; RMP, 6.36/11.69; PZA, 29.94/47.11. The mean AUC (μg·h/ml) were as follows: INH, 8.09/20.36; RMP, 17.78/36.95; PZA, 118.0/175.2. The mean C(max) and AUC differed significantly between doses. There was no difference in the t(max) values achieved. Children less than 2 years of age achieve target concentrations of first-line anti-TB agents using revised WHO dosage recommendations. Our data provided supportive evidence for the implementation of the revised WHO guidelines for first-line anti-TB therapy in young children.

    Topics: Antitubercular Agents; Area Under Curve; Child, Preschool; Coinfection; Female; HIV Infections; Humans; Isoniazid; Male; Nutritional Status; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary; World Health Organization

2011
Three months of rifapentine and isoniazid for latent tuberculosis infection.
    The New England journal of medicine, 2011, Dec-08, Volume: 365, Issue:23

    Treatment of latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control and elimination. The current standard regimen of isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion.. We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain and followed for 33 months. The primary end point was confirmed tuberculosis, and the noninferiority margin was 0.75%.. In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P=0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001).. The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.).

    Topics: Adult; Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Humans; Intention to Treat Analysis; Isoniazid; Male; Middle Aged; Prospective Studies; Rifampin; Risk Factors; Self Administration; Tuberculosis; Virus Latency

2011
Efficacy of a 6-month versus 9-month intermittent treatment regimen in HIV-infected patients with tuberculosis: a randomized clinical trial.
    American journal of respiratory and critical care medicine, 2010, Apr-01, Volume: 181, Issue:7

    The outcome of fully intermittent thrice-weekly antituberculosis treatment of various durations in HIV-associated tuberculosis is unclear.. To compare the efficacy of an intermittent 6-month regimen (Reg6M: 2EHRZ(3)/4HR(3) [ethambutol, 1,200 mg; isoniazid, 600 mg; rifampicin, 450 or 600 mg depending on body weight <60 or > or =60 kg; and pyrazinamide, 1,500 mg for 2 mo; followed by 4 mo of isoniazid and rifampicin at the same doses]) versus a 9-month regimen (Reg9M: 2EHRZ(3)/7HR(3)) in HIV/tuberculosis (TB).. HIV-infected patients with newly diagnosed pulmonary or extrapulmonary TB were randomly assigned to Reg6M (n = 167) or Reg9M (n = 160) and monitored by determination of clinical, immunological, and bacteriological parameters for 36 months. Primary outcomes included favorable responses at the end of treatment and recurrences during follow-up, whereas the secondary outcome was death. Intent-to-treat and on-treatment analyses were performed. All patients were antiretroviral treatment-naive during treatment.. Of the patients, 70% had culture-positive pulmonary TB; the median viral load was 155,000 copies/ml and the CD4(+) cell count was 160 cells/mm(3). Favorable response to antituberculosis treatment was similar by intent to treat (Reg6M, 83% and Reg9M, 76%; P = not significant). Bacteriological recurrences occurred significantly more often in Reg6M than in Reg9M (15 vs. 7%; P < 0.05) although overall recurrences were not significantly different (Reg6M, 19% vs. Reg9M, 13%). By 36 months, 36% of patients undergoing Reg6M and 35% undergoing Reg9M had died, with no significant difference between regimens. All 19 patients who failed treatment developed acquired rifamycin resistance (ARR), the main risk factor being baseline isoniazid resistance.. Among antiretroviral treatment-naive HIV-infected patients with TB, a 9-month regimen resulted in a similar outcome at the end of treatment but a significantly lower bacteriological recurrence rate compared with a 6-month thrice-weekly regimen. ARR was high with these intermittent regimens and neither mortality nor ARR was altered by lengthening TB treatment. Clinical Trials Registry Information: ID# NCT00376012 registered at www.clinicaltrials.gov.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Kaplan-Meier Estimate; Logistic Models; Male; Medication Adherence; Pyrazinamide; Rifampin; Tuberculosis; Viral Load

2010
Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2010, Mar-15, Volume: 50, Issue:6

    Drug-induced hepatotoxicity (DIH) is the most common adverse drug reaction leading to interruption of antituberculosis treatment. Worldwide, different reintroduction regimens have been advocated, but no consensus guidelines are available. Reintroduction of antituberculosis drugs in patients with DIH has never been studied systematically. We aimed to compare the safety of 3 different reintroduction regimens of antituberculosis drugs in patients with antituberculosis DIH.. A total of 175 patients with a diagnosis of antituberculosis DIH were randomized to receive 1 of 3 different predefined reintroduction regimens of antituberculosis drugs and were evaluated prospectively. Patients in arm I were given isoniazid, rifampicin, and pyrazinamide simultaneously at full dosage from day 1. In arm II, drugs were administered in a manner similar to that recommended in the American Thoracic Society guidelines for reintroduction. In arm III, drugs were administered in accordance with British Thoracic Society guidelines.. Nineteen patients (10.9%) had recurrence of DIH during follow-up. Eight, 6, and 5 patients had recurrence of hepatitis in arms I, II, and III, respectively (P = .69). Of all the clinical and laboratory parameters, pretreatment serum albumin level was the only statistically significant predictor of future recurrence of DIH on reintroduction of antituberculosis drugs (P < .01).. The recurrence rate of hepatotoxicity was not significantly different between the 3 groups. According to the findings of the present study, all 3 of the potentially hepatotoxic drugs (isoniazid, rifampicin, and pyrazinamide) can be reintroduced simultaneously at full dosage safely from day 1, especially for patients with bilateral extensive pulmonary tuberculosis, to halt disease transmission or to treat patients with life-threatening tuberculosis.. ClinicalTrials.gov identifier number: NCT00405301.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis; Young Adult

2010
Tuberculosis treatment in HIV infected Ugandans with CD4 counts>350 cells/mm reduces immune activation with no effect on HIV load or CD4 count.
    PloS one, 2010, Feb-22, Volume: 5, Issue:2

    Both HIV and TB cause a state of heightened immune activation. Immune activation in HIV is associated with progression to AIDS. Prior studies, focusing on persons with advanced HIV, have shown no decline in markers of cellular activation in response to TB therapy alone.. This prospective cohort study, composed of participants within a larger phase 3 open-label randomized controlled clinical trial, measured the impact of TB treatment on immune activation in persons with non-advanced HIV infection (CD4>350 cells/mm3) and pulmonary TB. HIV load, CD4 count, and markers of immune activation (CD38 and HLA-DR on CD4 and CD8 T cells) were measured prior to starting, during, and for 6 months after completion of standard 6 month anti-tuberculosis (TB) therapy in 38 HIV infected Ugandans with smear and culture confirmed pulmonary TB.. Expression of CD38, and co-expression of CD38 and HLA-DR, on CD8 cells declined significantly within 3 months of starting standard TB therapy in the absence of anti-retroviral therapy, and remained suppressed for 6 months after completion of therapy. In contrast, HIV load and CD4 count remained unchanged throughout the study period.. TB therapy leads to measurable decreases in immune activation in persons with HIV/TB co-infection and CD4 counts>350 cells/mm3.

    Topics: Adult; Antitubercular Agents; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cohort Studies; Ethambutol; Female; Flow Cytometry; HIV Infections; HIV-1; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis; Uganda; Viral Load; Young Adult

2010
Effects of tuberculosis, race, and human gene SLCO1B1 polymorphisms on rifampin concentrations.
    Antimicrobial agents and chemotherapy, 2010, Volume: 54, Issue:10

    Rifampin has concentration-dependent activity against Mycobacterium tuberculosis. However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes SLCO1B1, SLCO1B3, and MDR1. Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC(0-24)] of 40.2 versus 40.9 μg.h/ml; P = 0.9). However, in multivariable analyses, the rifampin AUC(0-24) was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the SLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC(0-24) was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC(0-24) was also 36% lower among participants with SLCO1B1 genotype c.463CA than that among participants with SLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 μg.h/ml; P = 0.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC(0-24) values was observed, but the mean values of the AUC(0-24) did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.

    Topics: Adult; Africa; Antibiotics, Antitubercular; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Female; Genotype; Humans; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Multivariate Analysis; North America; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Polymorphism, Single Nucleotide; Rifampin; Solute Carrier Organic Anion Transporter Family Member 1B3; Spain; Tuberculosis; Young Adult

2010
Rapid molecular detection of tuberculosis and rifampin resistance.
    The New England journal of medicine, 2010, Sep-09, Volume: 363, Issue:11

    Global control of tuberculosis is hampered by slow, insensitive diagnostic methods, particularly for the detection of drug-resistant forms and in patients with human immunodeficiency virus infection. Early detection is essential to reduce the death rate and interrupt transmission, but the complexity and infrastructure needs of sensitive methods limit their accessibility and effect.. We assessed the performance of Xpert MTB/RIF, an automated molecular test for Mycobacterium tuberculosis (MTB) and resistance to rifampin (RIF), with fully integrated sample processing in 1730 patients with suspected drug-sensitive or multidrug-resistant pulmonary tuberculosis. Eligible patients in Peru, Azerbaijan, South Africa, and India provided three sputum specimens each. Two specimens were processed with N-acetyl-L-cysteine and sodium hydroxide before microscopy, solid and liquid culture, and the MTB/RIF test, and one specimen was used for direct testing with microscopy and the MTB/RIF test.. Among culture-positive patients, a single, direct MTB/RIF test identified 551 of 561 patients with smear-positive tuberculosis (98.2%) and 124 of 171 with smear-negative tuberculosis (72.5%). The test was specific in 604 of 609 patients without tuberculosis (99.2%). Among patients with smear-negative, culture-positive tuberculosis, the addition of a second MTB/RIF test increased sensitivity by 12.6 percentage points and a third by 5.1 percentage points, to a total of 90.2%. As compared with phenotypic drug-susceptibility testing, MTB/RIF testing correctly identified 200 of 205 patients (97.6%) with rifampin-resistant bacteria and 504 of 514 (98.1%) with rifampin-sensitive bacteria. Sequencing resolved all but two cases in favor of the MTB/RIF assay.. The MTB/RIF test provided sensitive detection of tuberculosis and rifampin resistance directly from untreated sputum in less than 2 hours with minimal hands-on time. (Funded by the Foundation for Innovative New Diagnostics.)

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Polymerase Chain Reaction; Prospective Studies; Reference Standards; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2010
Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients.
    European journal of clinical pharmacology, 2009, Volume: 65, Issue:1

    The aim was to develop a model to describe the population pharmacokinetics of nevirapine in South African human immunodeficiency virus (HIV)-infected patients who were taking nevirapine-based antiretroviral therapy concomitantly or in the absence of rifampicin-based tuberculosis therapy.. Patients were divided into two groups: (1) patients receiving nevirapine-containing antiretroviral regimen (200 mg twice daily) and continuation phase rifampicin-containing tuberculosis therapy (n = 27) in whom blood samples were obtained before and not less than 14 days after they completed tuberculosis therapy; (2) patients without tuberculosis who were receiving a nevirapine-containing antiretroviral regimen for at least 3 weeks (n = 26). The population pharmacokinetics of nevirapine was described using nonlinear mixed effects modelling with NONMEM software. Based on the developed model, plasma concentration profiles after 300, 400 and 500 mg of nevirapine twice daily were simulated.. Concomitant administration of rifampicin increased nevirapine oral clearance (CL/F) by 37.4% and reduced the absorption rate constant (k(a)) by almost sixfold. Rifampicin reduced the nevirapine average minimum concentration by 39%. Simulated doses of 300 mg twice daily elevated nevirapine concentrations above subtherapeutic levels in most patients, with minimum exposure above the recommended maximum concentration. The area under the concentration-time curve of 12-hydroxynevirapine was not different in the presence of rifampicin. 2-, 3- and 8-Hydroxynevirapine were not detectable (LLOQ = 0.025 mg/L).. The developed model adequately describes nevirapine population pharmacokinetics in a South African population when taken with/and in the absence of rifampicin treatment. The simulations suggest that an increased dose of 300 mg twice daily would achieve adequate nevirapine concentrations in most patients during rifampicin-containing treatment for tuberculosis.

    Topics: Administration, Oral; Adult; Antibiotics, Antitubercular; Computer Simulation; Cross-Sectional Studies; Drug Administration Schedule; Drug Interactions; Female; HIV Infections; Humans; Male; Middle Aged; Models, Biological; Nevirapine; Nonlinear Dynamics; Reverse Transcriptase Inhibitors; Rifampin; South Africa; Treatment Outcome; Tuberculosis; Young Adult

2009
Effect of rifampicin on efavirenz pharmacokinetics in HIV-infected children with tuberculosis.
    Journal of acquired immune deficiency syndromes (1999), 2009, Apr-15, Volume: 50, Issue:5

    Rifampicin may reduce plasma efavirenz concentrations by inducing the expression of the cytochrome P450 2B6, which metabolizes efavirenz. However, there is no data in pediatric patient populations.. We measured plasma efavirenz concentrations in 15 children during and after rifampicin-based antitubercular treatment. They were receiving standard doses of efavirenz as part of antiretroviral treatment. Trough concentration (Cmin) was estimated by extrapolation of the log-linear concentration-time line to 24 hours after the previous dose.. Wide interpatient variation and marked bimodality of efavirenz concentrations were observed. Efavirenz Cmin was not significantly different during vs. after antitubercular treatment (median 0.83 mg/L interquartile range 0.59-6.57 vs. median 0.86 mg/L interquartile range 0.61-3.56; P = 0.125). Nine (60%) and 8 (53%) children had subtherapeutic Cmin (<1 mg/L) during and after antitubercular treatment, respectively.. Concomitant rifampicin-based antitubercular treatment was not an important determinant of efavirenz concentrations. The substantial proportion of participants with estimated Cmin <1 mg/L could result in the rapid emergence of efavirenz-resistant mutations and treatment failure.

    Topics: Adolescent; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Drug Interactions; Female; HIV Infections; Humans; Linear Models; Male; Rifampin; Tuberculosis; Viral Load

2009
Rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis.
    BMC medicine, 2009, Apr-22, Volume: 7

    Rifampin is a key drug in antituberculosis chemotherapy because it rapidly kills the majority of bacilli in tuberculosis lesions, prevents relapse and thus enables 6-month short-course chemotherapy. Little is known about the pharmacokinetics of rifampin in children. The objective of this study was to evaluate the pharmacokinetics of rifampin in children with tuberculosis, both human immunodeficiency virus type-1-infected and human immunodeficiency virus-uninfected.. Fifty-four children, 21 human immunodeficiency virus-infected and 33 human immunodeficiency virus-uninfected, mean ages 3.73 and 4.05 years (P = 0.68), respectively, admitted to a tuberculosis hospital in Cape Town, South Africa with severe forms of tuberculosis were studied approximately 1 month and 4 months after commencing antituberculosis treatment. Blood specimens for analysis were drawn in the morning, 45 minutes, 1.5, 3.0, 4.0 and 6.0 hours after dosing. Rifampin concentrations were determined by liquid chromatography tandem mass spectrometry. For two sample comparisons of means, the Welch version of the t-test was used; associations between variables were examined by Pearson correlation and by multiple linear regression.. The children received a mean rifampin dosage of 9.61 mg/kg (6.47 to 15.58) body weight at 1 month and 9.63 mg/kg (4.63 to 17.8) at 4 months after commencing treatment administered as part of a fixed-dose formulation designed for paediatric use. The mean rifampin area under the curve 0 to 6 hours after dosing was 14.9 and 18.1 microg/hour/ml (P = 0.25) 1 month after starting treatment in human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children, respectively, and 16.52 and 17.94 microg/hour/ml (P = 0.59) after 4 months of treatment. The mean calculated 2-hour rifampin concentrations in these human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children were 3.9 and 4.8 microg/ml (P = 0.20) at 1 month after the start of treatment and 4.0 and 4.6 microg/ml (P = 0.33) after 4 months of treatment. These values are considerably less than the suggested lower limit for 2-hour rifampin concentrations in adults of 8.0 microg/ml and even 4 microg/ml. Both human immunodeficiency virus-infected and human immunodeficiency virus-uninfected children with tuberculosis have very low rifampin serum concentrations after receiving standard rifampin dosages similar to those used in adults. Pharmacokinetic studies of higher dosages of rifampin are urgently needed in children to assist in placing the dosage of rifampin used in childhood on a more scientific foundation.

    Topics: Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; C-Reactive Protein; Child; Child, Preschool; Cyclopropanes; Female; HIV Infections; Humans; Male; Metabolic Clearance Rate; Rifampin; Ritonavir; Tuberculosis

2009
A randomized trial comparing plasma drug concentrations and efficacies between 2 nonnucleoside reverse-transcriptase inhibitor-based regimens in HIV-infected patients receiving rifampicin: the N2R Study.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2009, Jun-15, Volume: 48, Issue:12

    To our knowledge, to date, no prospective, randomized, clinical trial has compared standard doses of efavirenz- and nevirapine-based antiretroviral therapy among patients with concurrent human immunodeficiency virus type 1 (HIV-1) infection and tuberculosis (TB) who are receiving rifampicin.. Rifampicin recipients with concurrent HIV-1 infection and TB were randomized to receive antiretroviral therapy that included either efavirenz (600 mg per day) or nevirapine (400 mg per day). Efavirenz and nevirapine concentrations at 12 h after dosing (C12) were monitored at weeks 6 and 12. CD4+ cell counts and HIV-1 RNA levels were assessed every 12 weeks.. One hundred forty-two patients were randomized into 2 groups equally. The mean body weight of patients was 53 kg, the mean CD4+ cell count was 65 cells/mm3, and the median HIV-1 RNA level was 5.8 log10 copies/mL. At weeks 6 and 12, the mean C12 of efavirenz (+/- standard deviation) were 4.27+/-4.49 and 3.54+/-3.78 mg/L, respectively, and those for nevirapine were 5.59+/-3.48 and 5.6+/-2.65 mg/L, respectively. Interpatient variability in the efavirenz group was 2.3-fold greater than that in the nevirapine group (coefficient of variation, 107% vs. 47%). At week 12, 3.1% of patients in the efavirenz group and 21.3% in the nevirapine group had C12 values that were less than the recommended minimum concentrations (odds ratio, 8.396; 95% confidence interval, 1.808-38.993; P= .002). Intention-to-treat analysis revealed that 73.2% and 71.8% of patients in the efavirenz and nevirapine groups, respectively, achieved HIV-1 RNA levels <50 copies/mL at week 48, with respective mean CD4+ cell counts of 274 and 252 cells/mm3 (P> .05). Multivariate analysis revealed that patients with low C12 values and those with a body weight <55 kg were 3.6 and 2.4 times more likely, respectively, to develop all-cause treatment failure (P< .05).. Antiretroviral therapy regimens containing efavirenz (600 mg per day) were less compromised by concomitant use of rifampicin than were those that contained nevirapine (400 mg per day) in patients with concurrent HIV-1 infection and TB. Low drug exposure and low body weight are important predictive factors for treatment failure.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Interactions; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nevirapine; Plasma; Prospective Studies; Reverse Transcriptase Inhibitors; Rifampin; RNA, Viral; Treatment Outcome; Tuberculosis; Viral Load

2009
Effect of rifampicin-based antitubercular therapy and the cytochrome P450 2B6 516G>T polymorphism on efavirenz concentrations in adults in South Africa.
    Antiviral therapy, 2009, Volume: 14, Issue:5

    Rifampicin induces expression of the cytochrome P450 isoenzyme 2B6 (CYP2B6), which metabolizes efavirenz. The CYP2B6 516G>T polymorphism impairs efavirenz metabolism and occurs more commonly in Africans than in Caucasians. We explored the effect of rifampicin-based antitubercular therapy and the 516G>T polymorphism on efavirenz concentrations in HIV-infected patients in South Africa.. Between-patient and within-patient comparisons were made of mid-dosing interval efavirenz plasma concentrations in adults on antiretroviral therapy including efavirenz 600 mg daily, with and without antitubercular therapy.. There were 142 participants (40 were on antitubercular therapy and 102 were controls), the mean weight was 66 kg. Median efavirenz concentration was 2.4 mg/l (interquartile range [IQR] 1.3-3.1) and 1.8 mg/l (IQR 1.4-4.4) in participants on antitubercular therapy and controls, respectively (P=0.734). Paired efavirenz concentrations during and after antitubercular therapy in 17 participants were also similar (P=0.113). Genotyping results were 60 (49%) G/G homozygotes, 46 (38%) G/T heterozygotes and 16 (13%) T/T homozygotes. In a multivariate logistic regression model adjusted for sex, weight and concomitant antitubercular therapy, the 516G>T polymorphism was strongly associated with high (>4 mg/l) efavirenz concentrations: odds ratio (OR) 4.4 (95% confidence interval [CI] 1.3-14.9) for G/T versus G/G and 31.1 (95% CI 6.6-146.6) for T/T versus G/G. High efavirenz concentrations were associated with severe sleep disturbance (P=0.048). Low (<1 mg/l) efavirenz concentrations were associated with virological failure (OR 12.5, 95% CI 2.7-57.3).. Efavirenz can be used together with rifampicin-based antitubercular therapy without dose adjustment in this population. The 516G>T polymorphism occurred commonly and was associated with high efavirenz concentrations.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Polymorphism, Genetic; Reverse Transcriptase Inhibitors; Rifampin; Risk Factors; South Africa; Tuberculosis

2009
Patient-centred tuberculosis treatment delivery under programmatic conditions in Tanzania: a cohort study.
    BMC medicine, 2009, Dec-21, Volume: 7

    Directly observed therapy (DOT) remains the cornerstone of the global tuberculosis (TB) control strategy. Tanzania, one of the 22 high-burden countries regarding TB, changed the first-line treatment regimen to contain rifampicin-containing fixed-dose combination for the full 6 months of treatment. As daily health facility-based DOT for this long period is not feasible for the patient, nor for the health system, Tanzania introduced patient centred treatment (PCT). PCT allows patients to choose for daily DOT at a health facility or at their home by a supporter of choice. The introduction of fixed dose combinations in the intensive and continuation phase made PCT feasible by eliminating the risk of selective drug taking by patients and reducing the number of tablets to be taken. The approach was tested in three districts with the objective to assess the effect of this strategy on TB treatment outcomes. Cohort analysis comparing patients treated under the PCT strategy (registered April-September 2006) with patients treated under health-facility-based DOT (registered April-September 2005). The primary outcome was the cure rate. Differences were assessed by calculating the risk ratios. Associations between characteristics of the supporters and treatment outcomes in the group of patients opting for home-based DOT were assessed through logistic regression.. In the PCT cohort there were 1208 patients and 1417 were included in the historic cohort. There was no significant difference in cure rates between the cohorts (risk ratio [RR]: 1.06; 95% confidence interval [CI]: 0.96-1.16). In the PCT cohort, significantly more patients had successful treatment (cure or treatment completed; RR: 1.10; 95%CI: 1.01-1.15). There were no characteristics of supporters that were associated with treatment outcome.. The PCT approach showed similar cure rates and better treatment success rates compared to daily health-facility DOT. The results indicate that there are no specific prerequisites for the supporter chosen by the patient. The programmatic setting of the study lends strong support for scaling-up of TB treatment observation outside the health facility.

    Topics: Adult; Antitubercular Agents; Cohort Studies; Directly Observed Therapy; Ethambutol; Humans; Isoniazid; Middle Aged; Pyrazinamide; Rifampin; Tanzania; Treatment Outcome; Tuberculosis; Young Adult

2009
Concomitant use of nonnucleoside analogue reverse transcriptase inhibitors and rifampicin in TB/HIV type 1-coinfected patients.
    AIDS research and human retroviruses, 2008, Volume: 24, Issue:7

    Pharmacokinetic interactions between rifampicin and nonnucleoside analogue reverse transcriptase inhibitors (NNRTIs) pose challenges in the treatment of TB/HIV coinfection. We describe NNRTI plasma concentrations (PC) and treatment outcomes in TB/HIV coinfected patients receiving rifampicin and NNRTIs concomitantly. Single center prospective data were collected on all TB/HIV-coinfected patients who received concomitant NNRTI and rifampicin between 2001 and 2005. Of 103 TB/HIV coinfected patients, 26 received concomitant rifampicin with efavirenz (EFV) and 17 with nevirapine (NVP). NNRTIs were commenced after rifampicin in 18/26 (69%) and 7/17 (41%) subjects treated with EFV and NVP, respectively. Of these 88% completed antituberculosis therapy. There were two (5%) deaths, both due to lymphoproliferative malignancy. Three (7%) patients transferred care or discontinued therapy. Of subjects 83% had normal liver function tests (LFTs) and 11% had Grade 1-2 and 6% Grade 3-4 LFT abnormalities during concomitant therapy. PCs were measured in 31 patients. The first PCs were within the therapeutic range in 5/7 on NVP 200 mg bd, 2/4 on NVP 300 mg bd, 3/7 EFV 600 mg od, and 7/13 on EFV 800 mg od. PCs were subtherapeutic in 4/11 (36%) and 3/20 (20%) subjects on NVP and EFV, respectively. No virological rebounds were observed. Of subjects receiving concomitant NVP or EFV with rifampicin, 64% and 80%, respectively, had therapeutic NNRTI PCs. Subtherapeutic PCs were not associated with virological failure. Good clinical outcomes and a low incidence of hepatotoxicity were observed.

    Topics: Adult; Alkynes; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Benzoxazines; Chemical and Drug Induced Liver Injury; Cyclopropanes; Drug Administration Schedule; Drug Monitoring; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine; Prospective Studies; Reverse Transcriptase Inhibitors; Rifampin; Treatment Outcome; Tuberculosis

2008
Pharmacokinetics and 48-week efficacy of nevirapine: 400 mg versus 600 mg per day in HIV-tuberculosis coinfection receiving rifampicin.
    Antiviral therapy, 2008, Volume: 13, Issue:4

    We aim here to determine the appropriate dose of nevirapine (NVP) in Thai HIV-tuberculosis (TB)-coinfected patients receiving rifampicin.. Thirty-two HIV-infected adults with CD4+ T-cell counts <200 cells/mm3 and active TB, receiving rifampicin for 2-6 weeks were randomized to receive either NVP 400 mg (NVP400) or 600 mg (NVP600) per day plus two nucleoside reverse transcriptase inhibitors; a 2-week NVP lead-in was performed at 200 mg once daily (OD) and 200 mg twice daily, respectively. Plasma NVP levels were determined at weeks 2, 4 and 12. Twelve-hour pharmacokinetics (PK) were obtained (n=20) at week 4.. Baseline body weight was comparable. There were more patients with NVP plasma concentration at 12 h (C12) <3.1 mg/l at week 2 in NVP400 than in NVP600 (79% versus 19%, respectively; P=0.002). However, the proportions were comparable at weeks 4 and 12. From week 4, 12 h PK studies showed that NVP400 had lower median NVP area under the plasma concentration-0-12 h (AUC0-12 h, maximum concentration in plasma (Cmax) and C12 than NVP600 (P<0.05). Four patients in NVP600 developed NVP hypersensitivity. At week 48, the median CD4+ T-cell count rise and proportion with viral load <50 copies/ml (intention-to-treat analysis 56% versus 50% and as-treated analysis 75% versus 89%) were comparable.. In rifampicin-treated patients, 200 mg NVP OD lead-in led to a significant short-term suboptimal NVP C12 level, while NVP 400 mg lead-in then 600 mg/day was associated with a high rate of NVP hypersensitivity. Forty-eight week efficacy was comparable. Thus, NVP 600 mg/day in rifampicin-treated patients is not recommended.

    Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Thailand; Treatment Outcome; Tuberculosis

2008
Prevention of hepatotoxicity due to anti tuberculosis treatment: a novel integrative approach.
    World journal of gastroenterology, 2008, Aug-14, Volume: 14, Issue:30

    To evaluate the ability of Curcuma longa (CL) and Tinospora cordifolia (TC) formulation to prevent anti-tuberculosis (TB) treatment (ATT) induced hepatotoxicity.. Patients with active TB diagnosis were randomized to a drug control group and a trial group on drugs plus an herbal formulation. Isoniazid, rifampicin, pyrazinamide and ethambutol for first 2 mo followed by continuation phase therapy excluding Pyrazinamide for 4 mo comprised the anti-tuberculous treatment. Curcumin enriched (25%) CL and a hydro-ethanolic extract enriched (50%) TC 1 g each divided in two doses comprised the herbal adjuvant. Hemogram, bilirubin and liver enzymes were tested initially and monthly till the end of study to evaluate the result.. Incidence and severity of hepatotoxicity was significantly lower in trial group (incidence: 27/192 vs 2/316, P<0.0001). Mean aspartate transaminase (AST) (195.93+/-108.74 vs 85+/-4.24, P<0.0001), alanine transaminase (ALT) (75.74+/-26.54 vs 41+/-1.41, P<0.0001) and serum bilirubin (5.4+/-3.38 vs 1.5+/-0.42, P<0.0001). A lesser sputum positivity ratio at the end of 4 wk (10/67 vs 4/137, P=0.0068) and decreased incidence of poorly resolved parenchymal lesion at the end of the treatment (9/152 vs 2/278, P=0.0037) was observed. Improved patient compliance was indicated by nil drop-out in trial vs 10/192 in control group (P<0.0001).. The herbal formulation prevented hepatotoxicity significantly and improved the disease outcome as well as patient compliance without any toxicity or side effects.

    Topics: Adult; Antitubercular Agents; Blood Sedimentation; Body Weight; Chemical and Drug Induced Liver Injury; Curcuma; Drug Therapy, Combination; Ethambutol; Female; Hemoglobins; Humans; Isoniazid; Liver Diseases; Male; Middle Aged; Patient Compliance; Plant Preparations; Pyrazinamide; Rifampin; Tinospora; Treatment Outcome; Tuberculosis

2008
Pharmacokinetics of efavirenz when co-administered with rifampin in TB/HIV co-infected patients: pharmacogenetic effect of CYP2B6 variation.
    Journal of clinical pharmacology, 2008, Volume: 48, Issue:9

    The goal of this study was to determine the effect of CYP2B6 genetic variation on the steady-state pharmacokinetics of efavirenz (600 mg/d) in TB/HIV co-infected patients receiving concomitant rifampin, a potent CYP inducer. In the 26 patients studied, CYP2B6 c.516GG, GT, and TT genotype frequencies were 0.27, 0.50, and 0.23, respectively. Mean plasma efavirenz area under the curve was significantly higher in patients with CYP2B6 c.516TT than in those with GT (107 vs 27.6 microg x h/mL, P< .0001) or GG genotype (107 vs 23.0 microg x h/mL, P< .0001). Apparent oral clearance (CL/F) was significantly lower in patients with CYP2B6 c.516TT than in those with GT genotype (2.1 vs 8.4 mL/min/kg, P<0.0001) and GG genotype (2.1 vs 9.9 mL/min/kg, P< .0001). No differences in efavirenz exposure or CL/F existed between patients with CYP2B6 c.516GT and GG genotypes. Our results indicate that CYP2B6 c.516TT genotype can be used to identify efavirenz poor metabolizers in patients co-treated with rifampin.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Enzyme Induction; Female; Gene Frequency; Genetic Variation; Haplotypes; HIV Infections; Humans; Male; Middle Aged; Oxidoreductases, N-Demethylating; Phenotype; Prospective Studies; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

2008
Adverse events with 4 months of rifampin therapy or 9 months of isoniazid therapy for latent tuberculosis infection: a randomized trial.
    Annals of internal medicine, 2008, Nov-18, Volume: 149, Issue:10

    Treatment of latent tuberculosis infection with isoniazid for 9 months is complicated by poor patient adherence and the need for close follow-up of side effects, especially hepatotoxicity. Shorter and safer regimens are needed.. To compare the frequency of adverse events and treatment completion in 2 treatment regimens for latent tuberculosis infection.. Multicenter, randomized, open-label trial.. Tuberculosis clinics located in university hospitals in Canada, Brazil, and Saudi Arabia.. 847 patients without a contraindication for rifampin and requiring treatment for latent tuberculosis infection.. Four months of daily rifampin therapy or 9 months of daily isoniazid therapy.. Grade 3 to 4 drug-related adverse events resulting in drug discontinuation (primary outcome), and on-time treatment completion, grade 1 to 2 drug-related adverse events, and changes in liver enzymes and hematologic variables (secondary outcomes).. Seventeen of 422 participants who started isoniazid therapy developed grade 3 to 4 adverse events compared with 7 of 418 who started rifampin therapy (risk difference [rifampin minus isoniazid], -2.3% [95% CI, -5% to -0.1%]; P = 0.040). Grade 3 or 4 hepatitis occurred in 16 of 422 isoniazid recipients compared with 3 of 418 rifampin recipients (risk difference, -3.1% [CI, -5% to -1%]; P = 0.003). Grade 1 or 2 adverse events attributed to study drugs occurred with similar frequency. Asymptomatic reduction in platelet and leukocyte counts were more frequent in rifampin recipients. More patients completed rifampin treatment (78%) than isoniazid treatment (60%) (difference, 18% [CI, 12% to 24%]; P < 0.001]).. The study did not measure efficacy, and the open-label design may increase the chance of bias in ascertainment of adverse events.. Treatment of latent tuberculosis with 4 months of rifampin leads to fewer serious adverse events and better adherence than 9 months of isoniazid. These findings justify a large-scale trial to compare the efficacy of rifampin with that of isoniazid.

    Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Female; Humans; Isoniazid; Liver; Male; Patient Compliance; Patient Dropouts; Prospective Studies; Rifampin; Transaminases; Tuberculosis; Young Adult

2008
[Short-course isoniazid and rifampin compared with isoniazid for latent tuberculosis infection: a randomized clinical trial].
    Enfermedades infecciosas y microbiologia clinica, 2007, Volume: 25, Issue:5

    The aim of this study was to compare the adherence to, and side effects of a 3-month short-course treatment for latent tuberculosis infection as compared to the standard 6-month course.. Prospective, comparative, randomized, open trial including patients with a positive tuberculin skin test and appropriate criteria for treatment in accordance with the CDC guidelines, and excluding patients with HIV infection. Group I (6H) was assigned to isoniazid 300 mg per day for 6 months and Group II (3HR) was assigned to isoniazid 300 mg per day plus rifampin 600 mg per day for 3 months. The patients were followed up for five years.. A total of 105 patients were included, among which 9 refused treatment; 45 patients were placed in Group I and 51 patients in Group II. Both groups were comparable at baseline. Hepatotoxicity was 44% in Group 6H and 29% in Group 3HR (P = 0.07). Hepatotoxicity was severe in 6.7% of Group 6H and 5.8% of Group 3HR, requiring treatment interruption in 4.4% and 1.9%, respectively (P = NS). Among the total, 75.6% of patients in group 6H, and 90.2% in group 3HR completed the study treatment (P = 0.05). Tuberculous disease was detected in only one patient in the 6H group, occurring in the second month of treatment.. In the treatment of latent tuberculosis infection, a 3-month course of isoniazid plus rifampin resulted in better adherence and a lower percentage of discontinued treatments than a 6-month isoniazid course. Tolerance was similar in the two regimens.

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Virus Latency

2007
[Randomized clinical trial investigating three chemoprophylaxis regimens for latent tuberculosis infection in HIV-infected patients].
    Enfermedades infecciosas y microbiologia clinica, 2007, Volume: 25, Issue:5

    To evaluate the adherence to, and safety of three chemoprophylaxis regimens for latent tuberculosis (TB) infection in HIV-infected patients with a positive tuberculin skin test.. A randomized, comparative, open clinical assay was carried out in 316 HIV-infected patients in 12 Spanish hospitals. Patients were randomly assigned to one of three regimens, 108 to isoniazid for six months (6H), 103 to rifampin and isoniazid for three months (3RH), and 105 to rifampin and pyrazinamide for two months (2RZ). After completion of treatment, patients were followed-up for two years.. The period of observation following completion of treatment was 115, 108 and 101 person-years for 6H, 3RH and 2RZ, respectively. Twenty-seven percent of patients voluntarily abandoned chemoprophylaxis and 9.7% were withdrawn due to adverse side-effects or interactions. Seven patients were withdrawn due to hepatotoxicity (5 in 6H, 2 in 3RH and 0 in 2RZ). No appreciable differences were found among the three regimens. There were 11 cases of tuberculosis during follow-up. The TB rates (cases per 100 person-years) in the three treatment groups were 3.48 in 6H, 4.63 in 3RH and 1.98 in 2RZ. With respect to 2RZ, the relative risk for TB in the 6H and 3RH regimens was 1.76 and 2.34, respectively.. The safety of the 2RZ regimen for prophylaxis of latent TB infection in HIV patients was similar to that of the 6H and 3RH regimens. The incidence of hepatotoxicity was not higher in patients who received 2RZ.

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Virus Latency

2007
Ethambutol in paediatric tuberculosis: aspects of ethambutol serum concentration, efficacy and toxicity in children.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2007, Volume: 11, Issue:9

    Ethambutol (EMB) is used as a fourth drug in paediatric anti-tuberculosis treatment. In current recommendations the dosage of EMB is calculated per kg body weight.. To present two studies investigating an appropriate EMB dosage in children, and observational data on its toxicity and efficacy.. EMB serum levels in children of different age groups were determined after single oral administration of EMB alone as well as after EMB combined with rifampicin, and optimal dosages were established. The efficacy and toxicity of these EMB dosages were examined retrospectively.. EMB serum levels were lower than those expected in adults receiving a similar oral dose, due to different pharmacokinetics and pharmacodynamics in childhood. Thereafter, children were treated with EMB doses calculated by body surface (867 mg/m2). Ocular toxicity occurred in 0.7% of cases and relapses in 0.8%.. Current recommended EMB dosages in childhood tuberculosis lead to subtherapeutic serum levels. It appears to be more valid to calculate the EMB dosage on the basis of body surface rather than body weight, leading to higher dosages especially in younger children. With these dosages, therapeutic serum levels are reached in all age groups, leading to a high efficacy of anti-tuberculosis treatment without increased ocular toxicity.

    Topics: Administration, Oral; Adolescent; Adult; Age Factors; Antitubercular Agents; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethambutol; Eye Diseases; Female; Humans; Male; Microbial Sensitivity Tests; Recurrence; Retrospective Studies; Rifampin; Tuberculosis

2007
Low serum concentrations of anti-tuberculosis drugs and determinants of their serum levels.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2007, Volume: 11, Issue:9

    Low serum concentrations of anti-tuberculosis drugs have occasionally been associated with treatment failure.. To determine the prevalence of low serum concentrations of anti-tuberculosis drugs and to identify the determinants of drug concentrations.. Venous blood was obtained 2 h after drug ingestion, and serum levels of isoniazid (INH), rifampicin (RMP), ethambutol (EMB), pyrazinamide (PZA), acetyl INH and 25-desacetyl RMP were analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Patients with human immunodeficiency virus co-infection and gastrointestinal disease or diarrhoea were excluded.. Among 69 enrolled TB patients, the prevalence of a low 2 h serum concentration of at least one anti-tuberculosis drug was 46.4%. Prevalences of a low concentration of INH, RMP, EMB or PZA were 15.2%, 23.5%, 22.4% and 4.5%, respectively. By multivariate linear regression analysis, the serum concentrations of INH, RMP and PZA were positively associated with dose per kg of body weight (P < 0.05). Moreover, INH concentration was associated with acetyl INH/INH ratio (beta = -8.588, P < 0.001) and EMB concentration was associated with calculated creatinine clearance (beta = -0.025, P < 0.001).. Low concentrations of anti-tuberculosis drugs are common, and although the clinical significance of low concentrations remains uncertain, it may be necessary to optimise drug doses by therapeutic drug monitoring, especially in patients with an inadequate clinical response to chemotherapy.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Chromatography, Liquid; Drug Monitoring; Ethambutol; Female; Humans; Isoniazid; Linear Models; Male; Mass Spectrometry; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis

2007
The effectiveness of a 9-month regimen of isoniazid alone versus 3- and 4-month regimens of isoniazid plus rifampin for treatment of latent tuberculosis infection in children: results of an 11-year randomized study.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2007, Sep-15, Volume: 45, Issue:6

    A 9-month course of isoniazid monotherapy is currently recommended for the treatment of latent tuberculosis infection (LTBI) and has been shown to be effective in both children and adults. Reduced compliance with this regimen has forced physicians to explore shorter regimens. The aim of this study was to compare 3- and 4-month combination regimens of isoniazid plus rifampin with a 9-month regimen of isoniazid monotherapy for the treatment of LTBI in children.. This prospective, randomized, controlled study was conducted over an 11-year period (1995-2005). In period 1 (1995-1998), 232 patients received isoniazid therapy for 9 months (group A), and 238 patients received isoniazid and rifampin for 4 months (group B). In period 2 (1999-2002), 236 patients were treated with isoniazid and rifampin for 4 months (group C), and 220 patients received the same regimen for 3 months (group D). All patients were observed for > or = 3 years.. Overall compliance with treatment was good, but patients who received isoniazid monotherapy were less compliant than were those who received short-course combination therapy (P=.011, for group A vs. group B; P=.510, for group C vs. group D). No patient in any group developed clinical disease during the follow-up period. New radiographic findings suggestive of possible active disease were more common in patients who received isoniazid monotherapy (24%) than in those treated with shorter regimens (11.8%, 13.6%, and 11% for groups B, C, and D, respectively; P=.001 for group A vs. group B; P=.418 for group C vs. group D). Serious drug-related adverse effects were not detected.. Short-course treatment with isoniazid and rifampin for 3-4 months is safe and seems to be superior to a 9-month course of isoniazid monotherapy.

    Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Prospective Studies; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

2007
[Effectiveness of prophylaxis against tuberculosis in patients infected with HIV].
    Biomedica : revista del Instituto Nacional de Salud, 2007, Volume: 27, Issue:4

    Prophylaxis against tuberculosis has been recognized as important for preventing clinical forms of tuberculosis, mainly in HIV positive patients. However, in countries with high tuberculosis prevalence, prophylaxis application and effectiveness remains controversial.. Effectiveness was established for two prophylaxis regimens -isoniazid treatment for nine months and pirazinamid/rifampin for 60 days.. Two cohort groups of patients diagnosed with HIV/AIDS were compared. One consisted of 131 volunteer patients, who received one of the two prophylactic regimens -pirazinamid/rifampin or isoniazid. The tuberculosis treatment drugs were self-administered and independent of tuberculin response tests. The second group consisted of 200 patients selected from the records of a HIV/AIDS control program. Follow up for both groups was conducted over a two-year period through clinical records.. The 2 groups were similar with respect to clinical and demographic variables. A higher proportion of patients in the control group had CD4 counts <200/ml and viral load >100,000 copies. In the prophylactic group, 8% of patients reported adverse effects due to the drug, and one person had tuberculosis in that group (0.8%). Ten persons in the control group contracted tuberculosis (5%) RR=0.15, 95%CI 0.02-1.18, p=0.07. The prophylaxis protective level was calculated to be 80%, after taking into account CD4, viral load, and effective antiretroviral therapy.. The prophylaxis against tuberculosis was effective in HIV positive patients, independently of the immune status, viral load, and highly effective antiretroviral therapy.

    Topics: Adult; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Cohort Studies; Comorbidity; Female; HIV Seropositivity; Humans; Isoniazid; Male; Middle Aged; Multivariate Analysis; Rifampin; Survival Rate; Treatment Outcome; Tuberculosis; Viral Load

2007
Efavirenz 600 mg/day versus efavirenz 800 mg/day in HIV-infected patients with tuberculosis receiving rifampicin: 48 weeks results.
    AIDS (London, England), 2006, Jan-02, Volume: 20, Issue:1

    The potential of drug-drug interaction between efavirenz and rifampicin is a major concern in the treatment of HIV and tuberculosis. The optimal efavirenz dosage is still unclear. Our randomized control trial study recently reported the similar efavirenz level between efavirenz 600 and 800 mg/day in HIV-infected patients receiving rifampicin. We report the similar virological and immunological outcomes at 48 weeks between the two groups. Efavirenz 600 mg/day should be sufficient for concurrent use with rifamipicin.

    Topics: Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Body Weight; Cyclopropanes; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; HIV Infections; Humans; Oxazines; Rifampin; Treatment Outcome; Tuberculosis

2006
Effect of treatment of latent tuberculosis infection on the T cell response to Mycobacterium tuberculosis antigens.
    The Journal of infectious diseases, 2006, Feb-01, Volume: 193, Issue:3

    Most cases of latent tuberculosis infection (LTBI) do not cause symptoms during the lifetime of the infected person. Longitudinal analysis of the immune response of healthy Mycobacterium tuberculosis-infected people might, therefore, give insight into the basis of protective immunity. In a longitudinal study, we documented the effect that treatment had on the T cell response to M. tuberculosis antigens in 33 healthy people with LTBI. Preventive treatment of LTBI resulted in a 1.8-fold average increase in the numbers of interferon (IFN)- gamma -producing T cells within 26 +/- 4 days (P = .006), followed by a decrease by the end of the treatment period (82 +/- 6 days; P = .004). There was no significant overall change in the T cell response to any antigen in a control group (n = 8) of patients who elected radiological follow-up. Using live M. tuberculosis strain H37Rv as a stimulant in an enzyme-linked immunospot assay in sensitized individuals, we showed that isoniazid, but not rifampin, led to an increase in the number of IFN- gamma -producing cells. These results suggest that the integrity of the bacterial cell wall is important for M. tuberculosis in avoiding immune recognition by T cells and favor a dynamic model of LTBI.

    Topics: Adult; Antigens, Bacterial; Antitubercular Agents; Cells, Cultured; Female; Humans; Interferon-gamma; Isoniazid; Longitudinal Studies; Lymphocyte Count; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; T-Lymphocytes; Treatment Outcome; Tuberculosis

2006
Evaluation of high- versus standard-dose rifampin in Indonesian patients with pulmonary tuberculosis.
    Antimicrobial agents and chemotherapy, 2006, Volume: 50, Issue:2

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Female; Humans; Male; Middle Aged; Rifampin; Tuberculosis

2006
Lack of weight gain and relapse risk in a large tuberculosis treatment trial.
    American journal of respiratory and critical care medicine, 2006, Aug-01, Volume: 174, Issue:3

    Readily identified markers of tuberculosis relapse risk are needed, particularly in resource-limited settings. The association between weight gain or loss during antituberculosis therapy and relapse has not been well studied.. Subjects in the Tuberculosis Trials Consortium Study 22 were studied. Underweight was defined as 10% or more below ideal body weight at diagnosis. Weight change was assessed between (1) diagnosis and completion of induction phase therapy, (2) diagnosis and end of continuation phase therapy, and (3) completion of induction to completion of continuation phase therapy.. A total of 857 subjects were monitored for 2 yr, and 61 of 857 (7.1%) relapsed. Relapse risk was high among persons who were underweight at diagnosis (19.1 vs. 4.8%; p < 0.001) or who had a body mass index of less than 18.5 kg/m(2) (19.5 vs. 5.8%; p < 0.001). Among persons who were underweight at diagnosis, weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy was moderately associated with an increased relapse risk (18.4 vs. 10.3%; relative risk, 1.79, 95% confidence interval, 0.96-3.32; p = 0.06). In a multivariate logistic regression model that was adjusted for other risk factors, a weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy among persons underweight at diagnosis was significantly associated with relapse risk (odds ratio, 2.4; p = 0.03).. Among persons underweight at diagnosis, weight gain of 5% or less during the first 2 mo of treatment is associated with an increased relapse risk. Such high-risk patients can be easily identified, even in resource-poor settings. Additional studies are warranted to identify interventions to decrease risk of relapse in such patients.

    Topics: Adult; Antitubercular Agents; Body Mass Index; Body Weight; Female; Humans; Isoniazid; Male; Middle Aged; Prognosis; Recurrence; Rifampin; Risk Factors; Thinness; Tuberculosis; Weight Gain

2006
Efavirenz trough levels are not associated with virological failure throughout therapy with 800 mg daily and a rifampicin-containing antituberculosis regimen.
    The Journal of antimicrobial chemotherapy, 2006, Volume: 58, Issue:5

    To assess the safety and efficacy of efavirenz 800 mg daily in HIV-infected patients with tuberculosis receiving a rifampicin-containing regimen and to analyse whether a relationship exists between efavirenz Cmin and its virological efficacy.. Prospective, open-labelled study including HIV-infected patients on rifampicin and efavirenz 800 mg daily. Treatment adherence, adverse events (AEs), HIV-RNA levels, CD4 cell counts and efavirenz Cmin during and after finishing rifampicin treatment were evaluated.. Eighty patients met the inclusion criteria. A permanent drug withdrawal due to AEs occurred in 10 patients, 5 attributable to efavirenz, and 10 patients were lost to follow-up before the third month. Efavirenz Cmin levels with 800 mg plus rifampicin were similar to those with 600 mg after withdrawing rifampicin. Sixty patients were included in the efficacy analysis, eight experiencing virological failure. No relation was observed between the rate of virological failure and efavirenz Cmin, previous antiretroviral treatment or not, baseline CD4 counts or RNA-HIV. The only variable related to virological failure was irregular adherence [odds ratio, 81 (95% CI: 5-1280); P=0.002].. Given the lack of a demonstrated relationship between efavirenz Cmin and its efficacy in our study, a firm recommendation cannot be made to always increase the dose to 800 mg/day when concomitantly given with rifampicin, but it seems a cautious approach to maintain the same efavirenz plasma levels as with 600 mg daily without rifampicin. Patients weighing<55 kg and also black, Asian and Hispanic subjects in whom genetic-based increased efavirenz plasma levels and rates of AEs have been observed may benefit from a dose of 600 mg.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Cyclopropanes; Drug Administration Schedule; Drug Interactions; Female; HIV; HIV Infections; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Oxazines; Prospective Studies; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

2006
Safety, efficacy and pharmacokinetics of ritonavir 400mg/saquinavir 400mg twice daily plus rifampicin combined therapy in HIV patients with tuberculosis.
    Clinical drug investigation, 2006, Volume: 26, Issue:8

    To assess the drug concentrations, efficacy and safety of concomitant use of rifampicin and regimens containing ritonavir/saquinavir (400mg/400mg twice daily) in tuberculosis-HIV treatment-naive patients.. This was an open-label, non-randomised, multiple-dose study. On study day (D)1, tuberculosis treatment (rifampicin 600mg/isoniazid 400mg per day fasting plus pyrazinamide 2 g/day) was introduced in 30 patients. On D31, highly active antiretroviral therapy (HAART) consisting of two nucleoside analogues plus ritonavir/saquinavir 400mg/400mg twice daily was initiated (n = 20). The pharmacokinetics were assayed with a validated reversed-phase HPLC method before the introduction of HAART on D30 (for rifampicin), after 30 days of HAART at D60 (for rifampicin plus ritonavir/saquinavir), and at the end of the study (without rifampicin) on D210 (for ritonavir/saquinavir). Clinical evaluations were performed on a monthly basis. CD4 counts and viral load were collected on D30, D60 and D180. Genotyping test for HIV was collected at baseline and at D180. Primary endpoints were drug concentration and viral load at D180 (<80 copies/mL). Secondary endpoints were presence of grade 3 and serious adverse events, clinical improvement, CD4 count and genotypic resistance to ritonavir/saquinavir.. Ten patients dropped out of the study during tuberculosis therapy alone. Mean (+/- SD) baseline CD4 count (on D30) was 151.89 (+/- 146.77) cells/mm(3) and viral load was 5.34 (+/- 0.4) log. During the antiretroviral therapy, 15 patients dropped out, 14 because of adverse events. One patient (of five) presented a viral load of <80 copies/mL at D180. All but one patient increased CD4 counts from baseline. No genotypic resistance was detected. Clinical improvement was evident in all five patients who tolerated the therapy. Serum concentrations of ritonavir/saquinavir and rifampicin remained within the therapeutic range.. Therapeutic concentrations of the studied drugs and reduction of viral load were achieved; adverse events are the main limitation of use of a ritonavir/saquinavir regimen in treatment-naive patients, but its clinical benefits were evident.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Area Under Curve; Bisexuality; CD4 Lymphocyte Count; Drug Administration Schedule; Female; Half-Life; HIV Infections; HIV Protease Inhibitors; Homosexuality; Humans; Karnofsky Performance Status; Male; Metabolic Clearance Rate; Rifampin; Ritonavir; Saquinavir; Time Factors; Treatment Outcome; Tuberculosis; Viral Load

2006
A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.
    Science (New York, N.Y.), 2005, Jan-14, Volume: 307, Issue:5707

    The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.

    Topics: Amino Acid Sequence; Animals; Antitubercular Agents; Bacterial Proton-Translocating ATPases; Diarylquinolines; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Male; Mice; Microbial Sensitivity Tests; Molecular Sequence Data; Mycobacterium smegmatis; Mycobacterium tuberculosis; Point Mutation; Protein Subunits; Quinolines; Tuberculosis; Tuberculosis, Multidrug-Resistant

2005
Establishment of a reference formulation for bioequivalence assessment of rifampicin-containing FDCs: an essential step towards improving tuberculosis treatment.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2005, Volume: 9, Issue:7

    Selection of a reference product for bioequivalence studies of rifampicin (RMP) in prequalifying fixed-dose combinations (FDC) for worldwide distribution through the WHO is critical.. To investigate the feasibility of establishing FDC formulations as reference products for bioequivalence studies of RMP in prequalification programmes.. A biostudy was conducted as an open, two-period randomised cross-over trial. Two three-drug FDCs containing RMP, isoniazid and ethambutol hydrochloride were administered to a group of 22 volunteers with a wash-out period of 1 week. Plasma samples were collected and analysed for the concentration of RMP and desacetyl-RMP, a major active metabolite of RMP, up to 24 h. Pharmacokinetic parameters of RMP were calculated: Cmax, AUC0-24, Tmax, kel and absorption efficiencies.. No significant difference was observed between the administered formulations with respect to the major pharmacokinetic parameters Cmax, Tmax and AUC0-24 when evaluated by parametric (two-way ANOVA) and non-parametric (Hauschke's analysis) statistical analysis. The concentration of RMP falls within the reported acceptable therapeutic range.. FDCs can be developed as a reference product for bioequivalence studies.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Area Under Curve; Cross-Over Studies; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Therapeutic Equivalency; Tuberculosis

2005
Efavirenz levels and 24-week efficacy in HIV-infected patients with tuberculosis receiving highly active antiretroviral therapy and rifampicin.
    AIDS (London, England), 2005, Sep-23, Volume: 19, Issue:14

    Concomitant use of efavirenz and rifampicin is common for treatment of HIV and tuberculosis. Plasma efavirenz levels can be reduced by rifampicin, but the appropriate daily dosage of efavirenz is unclear.. HIV-infected patients with active tuberculosis, receiving rifampicin > 1 month, were randomized to receive stavudine and lamivudine plus efavirenz 600 or 800 mg daily. Plasma efavirenz levels were measured (at 12 h after dosing and on day 14) by high-performance liquid chromatography. Plasma HIV RNA was assessed at 16 and 24 weeks after antiretroviral therapy.. Baseline characteristics were comparable in the 84 patients (two groups of 42). Median plasma efavirenz levels were 3.02 mg/l (range, 0.07-12.21) in the 600 mg group and 3.39 mg/l (range, 1.03-21.31) in the 800 mg group (P = 0.632). Plasma efavirenz levels were < 1 mg/l in 3 of 38 (7.9%) patients in the 600 mg group and in none of the 800 mg group (P = 0.274). Approximately 40 and 45% of patients had efavirenz levels > 4 mg/l, respectively. There was no significant difference in time to HIV RNA < 50 copies/ml (P = 0.848).. Median plasma efavirenz levels were comparable among both groups. Efavirenz 600 mg/day should be sufficient for most Thai HIV-infected patients receiving rifampicin with body weight approximately 50 kg. These results may not be applicable to other ethic populations who have higher body weights. However, the study of long-term virological and immunological outcomes is needed and under further investigation.

    Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Benzoxazines; Cyclopropanes; Dose-Response Relationship, Drug; Female; HIV-1; Humans; Male; Middle Aged; Oxazines; Rifampin; RNA, Viral; Treatment Outcome; Tuberculosis

2005
Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a cost-effectiveness analysis based on a multicenter clinical trial.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2004, Feb-01, Volume: 38, Issue:3

    Two months of treatment with rifampin-pyrazinamide (RZ) and 9 months of treatment with isoniazid are both recommended for treatment of latent tuberculosis infection in adults without human immunodeficiency virus infection, but the relative cost-effectiveness of these 2 treatments is unknown. We used a Markov model to conduct a cost-effectiveness analysis to assess the impact on life expectancy and costs based on the results of a recent clinical trial that compared the rates of adverse events and completion of the 2 treatment regimens. Compared with no treatment, both regimens increased life expectancy by 1.2 years, but RZ cost 273 dollars more per patient. Sensitivity analyses showed that, assuming equal efficacy between the 2 regimens, there was no threshold completion rate for RZ at which the 2 treatments would be of equal net cost. Under most circumstances, treatment of latent tuberculosis infection with isoniazid is cost-saving than treatment with RZ.

    Topics: Adolescent; Adult; Antitubercular Agents; Cost Savings; Cost-Benefit Analysis; Costs and Cost Analysis; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2004
[Treatment of latent tuberculosis among homeless population. Comparison between wo therapeutic approaches].
    Medicina clinica, 2004, Jan-24, Volume: 122, Issue:2

    We aimed to compare treatment adherence and toxicity of isoniazide (H) (6 months) compared with rifampicine (R) + pirazinamide (Z) (2 months) in homeless patients in latent tuberculous infection (LTBI).. Randomized and controlled prospective study.. We included 172 patients (116 males and 56 females) with an age average of 42.3 (12.8) years; 31 (18%) had recent conversion and 72 (41.8%) had some risk factor of hepatotoxicity. Both bivariate and multivariate analysis (p < 0.001; OR = 5.15 [2.34-11.35]) showed that the treatment was completed by 61.5% of patients administered the R+Z regimen, while it was completed only by 28.2% of those administered H for 6 months. Moreover, treatment was completed by 48.4% of Spanish or foreign patients with legal residence, while it was completed only by 28.6% of immigrant patients with no legal residence (p = 0.044 in bivariate analysis).. The R+Z regimen for 2 months as treatment of LTBI in homeless patients displays a higher adherence than H for 6 months. There were no differences in toxicity.

    Topics: Adult; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Ill-Housed Persons; Isoniazid; Male; Patient Compliance; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis

2004
Short-course treatment regimen to identify potential antituberculous agents in a murine model of tuberculosis.
    The Journal of antimicrobial chemotherapy, 2004, Volume: 53, Issue:4

    Designing a more rapid method to test antimycobacterial agents in a murine model would significantly improve the drug development process. We describe a short-course in vivo treatment model that could be used to screen potential antituberculous drugs.. In this model, C57BL/6 mice were infected intranasally with approximately 10(6) viable Mycobacterium tuberculosis organisms. Treatment began 1 day post-infection and was administered for 2 days. Mice were euthanized 3 days post-infection and their right lungs were removed and cell counts determined. Several antimycobacterial agents with superior in vivo activity in a 4 week treatment model were tested to evaluate the short-course treatment model.. Two days of isoniazid (25 mg/kg), rifampicin (20 mg/kg), PNU-100480 (100 mg/kg), gatifloxacin (100 mg/kg), levofloxacin (100 mg/kg) and sparfloxacin (100 mg/kg) were all able to significantly reduce the mycobacterial load in the lungs compared with the untreated control mice.. Use of this model to screen potential chemotherapeutic agents will save time and resources.

    Topics: Acetamides; Animals; Antitubercular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Fluoroquinolones; Gatifloxacin; Isoniazid; Linezolid; Mice; Mice, Inbred C57BL; Oxazolidinones; Rifampin; Time Factors; Tuberculosis

2004
Treatment completion and costs of a randomized trial of rifampin for 4 months versus isoniazid for 9 months.
    American journal of respiratory and critical care medicine, 2004, Aug-15, Volume: 170, Issue:4

    There is little published information regarding treatment completion, safety, and efficacy of rifampin administered daily for 4 months-a recommended alternative to 9 months of isoniazid for therapy of latent tuberculosis infection. In an open-label randomized trial at a university-affiliated respiratory hospital, consenting patients whose treating physician had recommended therapy for latent tuberculosis infection were randomized to daily self-administered rifampin for 4 months or daily self-administered isoniazid for 9 months. Of 58 patients randomized to rifampin, 53 (91%) took 80% of doses, and 50 (86%) took more than 90% of doses within 20 weeks compared with 44 (76%) and 36 (62%) who took 80 and 90%, respectively, of doses of isoniazid within 43 weeks (relative risks: 80% of doses, 1.2 [95% confidence interval: 1.02, 1.4]; 90% of doses, 1.4 [1.1, 1.7]). Adverse events resulted in permanent discontinuation of therapy for two (3%) patients taking rifampin, and for eight (14%) patients taking isoniazid. Three patients developed drug-induced hepatitis--all were taking isoniazid. Total costs of therapy were significantly higher for isoniazid. In conclusion, completion of therapy was significantly better with 4 months of rifampin and major side effects were somewhat lower. Further studies are needed to assess the safety and efficacy of the 4-month rifampin regimen.

    Topics: Adult; Antitubercular Agents; Costs and Cost Analysis; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Isoniazid; Male; Outcome and Process Assessment, Health Care; Patient Compliance; Rifampin; Tuberculosis

2004
Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS.
    Clinical pharmacokinetics, 2004, Volume: 43, Issue:11

    To study the effect of rifampicin on the pharmacokinetics of fluconazole and on clinical outcomes of fluconazole treatment in patients with AIDS-related cryptococcal meningitis.. Forty Thai patients with AIDS and cryptococcal meningitis, of whom 20 had been receiving oral rifampicin for at least 2 weeks to treat tuberculosis.. Patients were treated for cryptococcal meningitis with amphotericin 0.7 mg/kg/day for 14 days followed by fluconazole 400 mg/day, which was reduced to 200 mg/day once culture of cerebrospinal fluid (CSF) became negative. Patients with tuberculosis received oral rifampicin 600 mg/day at night. Blood samples were collected from the first 12 patients in each group and pharmacokinetic parameters for fluconazole were calculated. CSF samples were collected by lumbar puncture and monitored for eradication of Cryptococcus neoformans.. Concomitant administration of rifampicin with fluconazole resulted in significant changes in the pharmacokinetic parameters of fluconazole, including a 39% increase in elimination rate constant, 28% shorter elimination half-life, 22% decrease in area under the concentration-time curve, 17% decrease in maximum concentration and 30% increase in clearance (p < 0.05). Different fluconazole regimens did not affect the extent of change in the elimination rate constant. Although serum concentrations of fluconazole during the time that patients received rifampicin concomitantly with fluconazole 200 mg/day were generally lower than the minimum inhibitory concentration for C. neoformans, there were no significant differences in clinical outcomes between the two groups to date (p = 0.792).. Coadministration of rifampicin with fluconazole caused significant changes in the pharmacokinetic parameters of fluconazole. Long-term monitoring for recurrence rates of cryptococcal meningitis is required to assess the clinical significance of this interaction.

    Topics: Acquired Immunodeficiency Syndrome; Adult; Antibiotics, Antitubercular; Antifungal Agents; Area Under Curve; Chromatography, High Pressure Liquid; Cryptococcus neoformans; Drug Interactions; Female; Fluconazole; Half-Life; Humans; Male; Meningitis, Cryptococcal; Middle Aged; Rifampin; Spectrophotometry, Ultraviolet; Tuberculosis

2004
Safety and antiretroviral effectiveness of concomitant use of rifampicin and efavirenz for antiretroviral-naive patients in India who are coinfected with tuberculosis and HIV-1.
    Journal of acquired immune deficiency syndromes (1999), 2004, Sep-01, Volume: 37, Issue:1

    To study the safety and antiretroviral effectiveness of concomitant use of rifampicin and efavirenz for antiretroviral-naïve patients in India who are coinfected with tuberculosis (TB) and HIV-1.. The study was an observational longitudinal cohort investigation. HIV-1-infected patients with CD4 cell counts of < or = 200/microL who attended the Infectious Disease Clinic of Sterling Hospital (Ahmedabad, India) from June 2001 to December 2002 were recruited for the study. Patients were divided in 2 groups: group A, patients with active TB (n = 126); and group B, patients without TB (n = 129). Group A patients were given efavirenz with 2 nucleoside reverse transcriptase inhibitors along with rifampicin-containing anti-TB treatment. Group B patients were treated for presenting opportunistic infections and started therapy with efavirenz plus 2 nucleoside reverse transcriptase inhibitors. The nucleoside reverse transcriptase inhibitors were either zidovudine and lamivudine (n = 30) or stavudine and lamivudine (n = 225). Patients self-funded their investigations and medications (antiretroviral, anti-TB, and other opportunistic infection-related agents). Indian generic medications were used.. Efavirenz-based highly active antiretroviral therapy with rifampicin for HIV/TB-coinfected patients resulted in an immunologic response that was comparable with that of the group not receiving rifampicin. Median CD4 cell counts at baseline, 3 months, 6 months, and 9 months in group A were 84/microL (range, 5-200/microL), 225/microL (range, 26-528/microL), 251/microL (range, 65-775/microL), and 275/microL (range, 61-611/microL), respectively, and in group B, these values were 118/microL (range, 2-200/microL), 244/microL (range, 38-881/microL), 294/microL (range, 23-1322/microL), and 295/microL (range, 26-991/microL), respectively. The overall increase in CD4 cell count was greater in group A than in group B at 9 months (190 vs. 176/microL, respectively). Patients in both groups tolerated the therapy well; the adverse effects profile was comparable except that group A patients had a higher incidence of hepatitis than group B patients (13.49% vs. 0, respectively; P < 0.0001).. Clinical and immunologic benefits are comparable for patients receiving efavirenz-based antiretroviral therapy with or without rifampicin.

    Topics: Adult; Alkynes; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; India; Male; Middle Aged; Oxazines; Rifampin; Treatment Outcome; Tuberculosis

2004
Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease.
    Antimicrobial agents and chemotherapy, 2004, Volume: 48, Issue:11

    We evaluated the effects of human immunodeficiency virus (HIV) disease on pharmacokinetics of antituberculosis medications by measuring concentrations of isoniazid and rifampin in blood and of pyrazinamide and ethambutol in urine. Peak concentration and exposure were reduced for rifampin, and rapid acetylators of isoniazid had lower drug levels. HIV and HIV-tuberculosis patients who have diarrhea and cryptosporidial infection exhibit decreased bioavailability of antituberculosis drugs.

    Topics: Acetylation; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Biological Availability; Ethambutol; Feces; Female; HIV Infections; Humans; Intestinal Absorption; Isoniazid; Male; Middle Aged; Phenotype; Pyrazinamide; Rifampin; Tuberculosis

2004
Use of intermittent rifampin and pyrazinamide therapy for latent tuberculosis infection in a targeted tuberculin testing program.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2004, Dec-15, Volume: 39, Issue:12

    To determine the rates of hepatotoxicity and treatment completion associated with intermittent rifampin and pyrazinamide (RZ) therapy for latent tuberculosis infection, we evaluated a cohort of patients from a targeted tuberculin testing site in Tennessee.. From 4 February 2000 through 9 November 2001, a total of 423 patients with latent tuberculosis infection received directly observed preventive therapy (DOPT) with RZ given twice weekly for 2 months. Most of the patients were young, Hispanic males who had recently immigrated to the United States.. During treatment, hepatotoxicity developed in 29 patients (6.9%; hereafter referred to as "case patients"), and peak alanine aminotransferase (ALT) levels that were >10 times the upper limit of normal were noted in 18 case patients. Of the case patients, 14 had asymptomatic hepatotoxicity, and 2 required hospitalization; none of the case patients died. Hepatotoxicity developed after the receipt of 12 doses in more than half of the case patients, and 4 case patients received all 16 doses. The risk of RZ-associated hepatotoxicity was independently associated with older age (odds ratio [OR], 1.07 per year; P=.01). In total, 352 patients (83.2%) completed RZ therapy. The strongest predictors for noncompletion of RZ treatment were the development of a clinical symptom (OR, 9.73; P<.001) and older age (OR, 1.08 per year; P=.001).. Despite the use of DOPT, intermittent dosing, and vigilant monitoring throughout therapy, RZ was associated with an unacceptable risk of hepatotoxicity.

    Topics: Adolescent; Adult; Antitubercular Agents; Female; Humans; Male; Middle Aged; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculin Test; Tuberculosis

2004
Initial experience on rifampin and pyrazinamide vs isoniazid in the treatment of latent tuberculosis infection among patients with silicosis in Hong Kong.
    Chest, 2003, Volume: 124, Issue:6

    To compare the adverse effects and treatment adherence between 2 months of rifampin plus pyrazinamide (2RZ) and 6 months of isoniazid (6H).. Patients with silicosis in Hong Kong are at high risk of acquiring tuberculosis. A previous study showed that treatment with 6H reduced the risk of silico-tuberculosis by one half.. Patients with silicosis and a Mantoux skin test reaction > or =10 mm were randomized to receive either 2RZ or 6H daily. Liver function testing was done monthly during the initial 2 months. The adverse effects and treatment adherence were compared between the two regimens.. Forty patients (mean age, 61.6 +/- 9.1 years) and 36 patients (mean age, 57.6 +/- 9.7 years) were randomized to the 2RZ and 6H arms, respectively (p > 0.05) [+/- SD]. Baseline characteristics were comparable. Nineteen patients in the 2RZ arm had peak alanine transaminase (ALT) levels > 1.5 times the upper limit of normal (ULN) in comparison with only five study subjects of the 6H arm (47.5% vs 13.9%, p < 0.01). Fourteen patients (35%) in the 2RZ arm and 1 patient (2.8%) in the 6H arm had peak ALT levels more than five times the ULN (p < 0.001). Only seven patients had symptoms suggestive of hepatitis; none of the patients had jaundice. All recovered after withholding treatment. In the 2RZ study arm, none of the baseline characteristics predicted hepatotoxicity. Other adverse effects were generally mild and comparable between both study arms. Treatment was stopped prematurely in 45% and 36.1% of patients in the 2RZ and 6H arms, respectively (p = 0.43). The main reasons were hepatotoxicity for the 2RZ arm and voluntary withdrawal after experiencing other minor adverse effects for the 6H arm.. A higher incidence of hepatotoxicity was associated with rifampin plus pyrazinamide than isoniazid in the treatment of latent tuberculosis infection among patients with silicosis in Hong Kong.

    Topics: Aged; Antitubercular Agents; Drug Administration Schedule; Female; Hong Kong; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Pyrazinamide; Rifampin; Risk Factors; Silicosis; Tuberculosis

2003
Pharmacokinetic interactions between efavirenz and rifampicin in HIV-infected patients with tuberculosis.
    Clinical pharmacokinetics, 2002, Volume: 41, Issue:9

    To evaluate the pharmacokinetic interactions between efavirenz and rifampicin (rifampin) in patients with HIV infection and tuberculosis.. Nonblind, randomised, pharmacokinetic study.. 24 patients (21 male, 3 female; mean age 37 years) with HIV infection and tuberculosis.. Patients were randomised to one of the following treatments: group A (n = 16) received antituberculosis drugs without rifampicin, plus highly active antiretroviral therapy (HAART) including efavirenz 600 mg once daily, on days 1 to 7. Patients were then switched to rifampicin in bodyweight-adjusted fixed-dose combination plus HAART including efavirenz 600 mg once daily (group A-1; n = 8) or efavirenz 800 mg once daily (group A-2; n = 8). Group B (n = 8) received rifampicin in bodyweight-adjusted fixed-dose combination on days 1 to 7; on day 8, HAART including efavirenz 800 mg once daily was added. Blood samples were obtained on days 7 and 14.. Plasma concentrations of efavirenz and rifampicin were quantified by using validated high performance liquid chromatography assays, and pharmacokinetic parameter values were determined by noncompartmental methods. The differences between pharmacokinetic parameters on days 7 and 14 were used to assess interactions.. There was a correlation between the pharmacokinetic parameters of efavirenz and the dose/kg administered. For efavirenz, mean (median) peak concentration, trough concentration and area under the concentration-time curve over the administration interval decreased 24% (24%), 25% (18%) and 22% (10%), respectively, in the presence of rifampicin. Large interpatient variability was observed, suggesting that plasma concentration monitoring of efavirenz may be advisable. Overall, the pharmacokinetics of efavirenz 800 mg plus rifampicin were similar to those of efavirenz 600 mg without rifampicin. The pharmacokinetics of rifampicin did not change substantially in the presence of efavirenz. Differences in patients' bodyweight appeared to cause further differences in exposure to efavirenz. Plasma concentrations of efavirenz in patients weighing <50 kg were similar to those previously described in HIV-infected patients without concomitant tuberculosis. However, plasma concentrations in patients weighing >or=50 kg were almost halved compared with those in patients weighing <50 kg.. Although the minimal effective efavirenz plasma concentration that assures virological success is not currently known, it may be advisable to increase the dosage of efavirenz to 800 mg once daily when it is coadministered with rifampicin. Rifampicin can be used with efavirenz without dosage modification.

    Topics: Adult; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antitubercular Agents; Area Under Curve; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Drug Interactions; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Oxazines; Rifampin; Tuberculosis

2002
Bioequivalence assessment of rifampicin, isoniazid and pyrazinamide in a fixed dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol vs. separate formulations.
    International journal of clinical pharmacology and therapeutics, 2002, Volume: 40, Issue:10

    Depending on the patient category, tuberculosis requires treatment with 3 to 5 drugs which means that patient's compliance to therapy may not be optimal. To increase patient's adherence to treatment schedules, these drugs can be given as single drug preparations or fixed dose combinations (FDCs) of 2 or more drugs in a single formulation. However, an important issue associated with a rifampicin-containing FDC is its quality. Hence, to avoid spurious formulations entering the market, the World Health Organization and the International Union Against Tuberculosis and Lung Disease have recommended FDCs only of proven bioavailability. In this study, the relative bioavailability of rifampicin, isoniazid and pyrazinamide was assessed in a group of 14 healthy male subjects using the FDC tablet containing 4 drugs versus separate formulations at the same dose levels. The study was designed as an open, crossover trial. A total of 9 blood samples were collected over a period of 24 h. The concentration of rifampicin, its main metabolite desacetyl rifampicin, isoniazid and pyrazinamide in plasma were assessed using HPLC analysis. The pharmacokinetic parameters AUC(0-24) and Cmax were subjected to parametric and non-parametric statistical tests at 90% confidence interval. In addition, time to reach peak concentration (tmax), elimination rate constant (Kel) and terminal elimination half-life (t1/2) for each drug were also calculated. It was concluded that the FDC tablet containing 4 drugs is bioequivalent to separate rifampicin, isoniazid and pyrazinamide formulations at the same dose levels.

    Topics: Analysis of Variance; Antibiotics, Antitubercular; Cross-Over Studies; Drug Combinations; Ethambutol; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Therapeutic Equivalency; Time Factors; Tuberculosis

2002
A prospective, randomized, double-blind study of the tolerability of rifapentine 600, 900, and 1,200 mg plus isoniazid in the continuation phase of tuberculosis treatment.
    American journal of respiratory and critical care medicine, 2002, Jun-01, Volume: 165, Issue:11

    Once-weekly rifapentine 600 mg plus isoniazid (INH) during the continuation phase treatment of tuberculosis is associated with a relapse rate higher than that of twice-weekly rifampin plus INH. The safety and tolerability of higher rifapentine doses need to be determined. We conducted a prospective, randomized, double-blind trial of rifapentine at three doses (600, 900, and 1,200 mg) plus INH 15 mg/kg once weekly in the continuation phase treatment of culture-positive tuberculosis in 150 human immunodeficiency virus-seronegative adults. Outcome measures were discontinuation of therapy for any reason and adverse events on therapy. Treatment was discontinued in 3 of 52 (6%), 2 of 51 (4%), and 3 of 47 (6%) in the rifapentine 600-, 900-, and 1,200-mg treatment arms, respectively. Only one discontinuation, in the rifapentine 1,200-mg arm, was due to an adverse event possibly associated with study therapy. There was a trend toward more adverse events, possibly associated with study therapy, in the highest-dose arms (p = 0.051). Rifapentine 900-mg, once-weekly dosing appears to be safe and well tolerated and is being evaluated in Phase III efficacy trials of treatment of latent tuberculosis. Further evaluation of the safety and tolerability of rifapentine 1,200 mg is warranted.

    Topics: Adult; Aged; Antitubercular Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Reference Values; Rifampin; Treatment Outcome; Tuberculosis

2002
Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults.
    AIDS (London, England), 2001, Jan-26, Volume: 15, Issue:2

    To determine the long-term effect of preventive therapy (PT) for tuberculosis on the rates of tuberculosis, mortality and HIV progression.. In a randomized controlled trial, 1053 HIV-positive Zambian adults received isoniazid (H) for 6 months, rifampicin plus pyrazinamide (RZ) for 3 months, or a placebo. CD4 percentage, neopterin, absolute lymphocyte count and haemoglobin were measured from enrolment (absolute CD4 cell counts from 12 months after enrolment). Because PT reduced the incidence of tuberculosis, eligible placebo subjects were offered H. Here, tuberculosis and mortality rates are compared in the three original arms (intention to treat) using data beyond the end of the trial (average follow-up 3 years; maximum 7 years).. There were 102 cases of tuberculosis and 281 deaths (rates 3.6 and 9.0/100 person-years, respectively). There was no significant difference between the tuberculosis rates in the H and RZ groups at any time. The effect of H/RZ on tuberculosis diminished over time (P = 0.011) but the cumulative risk of tuberculosis in the first 2.5 years was significantly lower in the H/RZ group than the placebo group (rate ratio 0.55; 95% confidence interval 0.32-0.93; P = 0.028). There was no significant effect of PT on mortality or progression markers. Tuberculosis was associated with an increased mortality (adjusted rate ratio 1.96; 95% confidence interval 1.21-3.18; P = 0.006).. Both PT regimens protect against tuberculosis for at least 2.5 years but appear to have no effect on HIV progression or mortality. These results may be used in cost-effectiveness models of PT.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; CD4 Lymphocyte Count; Cohort Studies; Disease Progression; Female; Follow-Up Studies; HIV Infections; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis; Zambia

2001
Inhibition of isoniazid-induced expression of Mycobacterium tuberculosis antigen 85 in sputum: potential surrogate marker in tuberculosis chemotherapy trials.
    Antimicrobial agents and chemotherapy, 2001, Volume: 45, Issue:4

    Mycobacterium tuberculosis antigen 85 is induced in vitro by isoniazid (INH); its sustained induction in sputum during tuberculosis (TB) therapy predicts relapse. In this trial, rifampin or rifalazil inhibited the induction of sputum antigen 85 by INH in a dose-dependent fashion. This approach may facilitate the evaluation of new TB drugs.

    Topics: Acyltransferases; Antibiotics, Antitubercular; Antigens, Bacterial; Antitubercular Agents; Biomarkers; Colony Count, Microbial; Humans; Isoniazid; Kinetics; Recurrence; Rifampin; Rifamycins; Sputum; Tuberculosis

2001
Substandard tuberculosis drugs on the global market and their simple detection.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2001, Volume: 5, Issue:5

    The prevalence of substandard anti-tuberculosis drugs is unknown. To maximize the effectiveness of tuberculosis (TB) control efforts, simple, inexpensive drug quality screening methods are needed.. Isoniazid (INH) and rifampin (RMP) single- and fixed-dose combination (FDC) formulations were collected from selected TB programs and pharmacies in Colombia, Estonia, India, Latvia, Russia and Vietnam. Samples were screened using a recently developed thin-layer chromatography (TLC) kit. All abnormal samples and a 40% random sample of normal formulations were further analyzed using confirmatory techniques. Samples outside of 85% to 115% of stated content, and/or containing compounds other than the stated drug, were defined as being substandard.. Overall, 10% (4/40) of all samples, including 13% (4/30) RMP samples, contained <85% of stated content. More FDCs (5/24, 21%) than single-drug samples (2/16, 13%) were substandard. A comparison of TLC with the confirmatory analysis for RMP analysis showed a sensitivity of 100% (4/4), a specificity of 92% (24/26), a positive predictive value (PPV) of 67% (4/6), and a negative predictive value (NPV) of 100% (24/24). An analysis of INH showed a specificity of 90% (9/10). However, sensitivity, PPV, and NVP could not be determined.. A substantial number of anti-tuberculosis drugs from several countries, in particular FDCs, were found to be substandard. Such drugs may contribute to the creation of drug-resistant TB. TLC is an effective, convenient, and inexpensive method for the detection of substandard drugs.

    Topics: Antitubercular Agents; Asia; Chromatography, Thin Layer; Colombia; Drug Combinations; Europe, Eastern; Humans; Isoniazid; Predictive Value of Tests; Quality Control; Reference Standards; Rifampin; Sensitivity and Specificity; Tuberculosis

2001
The potential use of urinary excretion data for assessing the relative bioavailability of rifampicin in fixed dose combination anti-tuberculosis formulations.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2001, Volume: 5, Issue:8

    The perceived need for simple, non-invasive methods of assessing the relative bioavailability of rifampicin in fixed-dose combination (FDC) anti-tuberculosis formulations.. To compare the performance of methods based on urinary excretion data with those utilising plasma concentration-time profiles to assess the relative bioavailability of rifampicin in combined and single-drug formulations.. A two-period randomised crossover bioequivalence study in healthy male volunteers with a 1 week washout period between treatments. Plasma rifampicin concentrations were measured at 0, 1, 2, 4, 6 and 8 hours after each drug administration using a high performance liquid chromatography (HPLC) method. The rifampicin and desacetylrifampicin content of complete urinary collections made from 0-4 and 4-8 hours after dosage were determined using both the HPLC and a much simpler colorimetric procedure.. There was good agreement between the relative bioavailability of the formulations using plasma and urinary excretion data, although the precision of the urinary-based estimates was slightly less than those derived from the plasma findings. There was also good agreement between the HPLC and colorimetric estimates of the combined urinary excretion of rifampicin plus desacetylrifampicin.. Urinary excretion data may be used for ongoing quality control to confirm that commercial combined rifampicin-containing formulations that were initially shown to be satisfactory continue to be so.

    Topics: Antibiotics, Antitubercular; Area Under Curve; Biological Availability; Chromatography, High Pressure Liquid; Colorimetry; Cross-Over Studies; Drug Combinations; Ethambutol; Humans; Isoniazid; Male; Pyrazinamide; Quality Control; Reference Values; Rifampin; Therapeutic Equivalency; Tuberculosis; Urinalysis

2001
Reintroducing antituberculosis therapy after Stevens-Johnson syndrome in human immunodeficiency virus-infected patients with tuberculosis: role of desensitization.
    International journal of dermatology, 2001, Volume: 40, Issue:7

    Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Desensitization, Immunologic; Dose-Response Relationship, Drug; Ethambutol; Female; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Stevens-Johnson Syndrome; Treatment Outcome; Tuberculosis

2001
Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons: an international randomized trial. Terry Beirn Community Programs for Clinical Research on AIDS, the Adult AIDS Clinical Trials Group, the Pan American Health O
    JAMA, 2000, Mar-15, Volume: 283, Issue:11

    Because of problems with adherence, toxicity, and increasing resistance associated with 6- to 12-month isoniazid regimens, an alternative short-course tuberculosis preventive regimen is needed.. To compare a 2-month regimen of daily rifampin and pyrazinamide with a 12-month regimen of daily isoniazid in preventing tuberculosis in persons with human immunodeficiency virus (HIV) infection.. Randomized, open-label controlled trial conducted from September 1991 to May 1996, with follow-up through October 1997.. Outpatient clinics in the United States, Mexico, Haiti, and Brazil.. A total of 1583 HIV-positive persons aged 13 years or older with a positive tuberculin skin test result.. Patients were randomized to isoniazid, 300 mg/d, with pyridoxine hydrochloride for 12 months (n = 792) or rifampin, 600 mg/d, and pyrazinamide, 20 mg/kg per day, for 2 months (n = 791).. The primary end point was culture-confirmed tuberculosis; secondary end points were proven or probable tuberculosis, adverse events, and death, compared by treatment group.. Of patients assigned to rifampin and pyrazinamide, 80% completed the regimen compared with 69% assigned to isoniazid (P<.001). After a mean follow-up of 37 months, 19 patients (2.4%) assigned to rifampin and pyrazinamide and 26 (3.3%) assigned to isoniazid developed confirmed tuberculosis at rates of 0.8 and 1.1 per 100 person-years, respectively (risk ratio, 0.72 [95% confidence interval, 0.40-1.31]; P = .28). In multivariate analysis, there were no significant differences in rates for confirmed or probable tuberculosis (P = .83), HIV progression and/or death (P = .09), or overall adverse events (P = .27), although drug discontinuation was slightly higher in the rifampin and pyrazinamide group (P = .01). Neither regimen appeared to lead to the development of drug-resistant tuberculosis.. Our data suggest that for preventing tuberculosis in HIV-infected patients, a daily 2-month regimen of rifampin and pyrazinamide is similar in safety and efficacy to a daily 12-month regimen of isoniazid. This shorter regimen offers practical advantages to both patients and tuberculosis control programs.

    Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Proportional Hazards Models; Pyrazinamide; Rifampin; Statistics, Nonparametric; Tuberculin Test; Tuberculosis

2000
A randomised controlled trial of lay health workers as direct observers for treatment of tuberculosis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2000, Volume: 4, Issue:6

    Study conducted in a suburb of Cape Town, South Africa.. Comparison of successful tuberculosis treatment outcome rates between self supervision, supervision by lay health worker (LHW), and supervision by clinic nurse.. Open, randomised, controlled trial with intention-to-treat analysis.. All groups (n = 156) achieved similar outcomes (LHW vs. clinic nurse: risk difference 17.2%, 95% confidence interval [CI] -0.1-34.5; LHW vs. self supervision 15%, 95%CI -3.7-33.6). New patients benefit from LHW supervision (LHW vs clinic nurse: risk difference 24.2%, 95%CI 6-42.5, LHW vs. self supervision 39.1%, 95%CI 17.8-60.3) as do female patients (LHW vs. clinic nurse 48.3%, 95%CI 22.8-73.8, LHW vs. self supervision 32.6%, 95%CI 6.4-58.7).. LHW supervision approaches statistically significant superiority, but fails to reach it most likely due to the study's limitation, the small sample size. It is possible that subgroups (new and female patients) do well under LHW supervision. LHW supervision could be offered as one of several supervision options within TB control programmes.

    Topics: Adult; Antitubercular Agents; Community Health Workers; Drug Combinations; Female; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; South Africa; Tuberculosis

2000
[Evaluation of 2 tuberculosis chemoprophylaxis regimens in patients infected with human immunodeficiency virus. The GECMEI Group].
    Medicina clinica, 2000, Jul-01, Volume: 115, Issue:5

    To assess the compliance, tolerance and efficacy of a short chemoprophylaxis regimen (IR) for tuberculosis using isoniazid (INH) plus rifampin (RIF) during 3 months versus a standard regimen (I) of isoniazid during 12 months in HIV positive patients.. Prospective, comparative, randomized and open clinical trial in four general hospitals and one prison hospital of Castilla-La Mancha. Prophylaxis was administered to PPD-positive patients and to anergic patients according to the CDC recommendations (1991). Patients were randomized in two treatment groups: regimen IR, isoniazid 300 mg daily and rifampin 600 mg daily; regimen I, isoniazid 300 mg during 12 months.. 133 patients were included, 64 to regimen I and 69 to regimen IR. Regimen IR had a better tolerance with a 28% of adverse effects versus 55% in regimen I. Hepatotoxicity was more frequent in regimen I with a RR = 2.2 (CI 95% 1.23-4.01). Severe hepatotoxicity leading to treatment withdrawal was related to drug administration time and was more frequent in the 12 months regimen group. Short regimen showed a better compliance, without significant differences. Tuberculosis incidence rate was a 4.23 cases/100 persons--year for regimen I and 2.08 in regimen IR, with a relative risk for developing tuberculosis with regimen IR group of 0.51 (CI 95% 0.09-2.8) versus regimen I group, without statistical significance. Prison stay was associated to a significant risk for tuberculosis, regardless of both regimens (RR = 9.2 CI 95%, 1.06-80.2).. In HIV-infected patients with PPD(+) or anergic, regimen with IR is at least as effective as regimen I for preventing the development of tuberculous disease, and has less adverse effects.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antitubercular Agents; Female; Humans; Incidence; Isoniazid; Liver; Male; Prospective Studies; Rifampin; Time Factors; Tuberculin Test; Tuberculosis

2000
[Desensitization therapy for allergic reactions of antituberculous drugs--evaluation of desensitization therapy according to the guideline of the Japanese Society for Tuberculosis].
    Kekkaku : [Tuberculosis], 2000, Volume: 75, Issue:12

    We prospectively evaluated the effectiveness of desensitization therapy for cases showing side-effects to antituberculous drugs (Isoniazid and Rifampicin) according to the guideline proposed by the Treatment Committee of the Japanese Society for Tuberculosis. Nineteen patients (23-88 years old, male 9, female 10) who had experienced adverse effects after receiving antituberculous drugs and underwent desensitization therapy between August 1998 and March 2000 were studied. Underlying diseases were 14 cases of pulmonary tuberculosis, 2 cases of cervical tuberculous lymphadenitis, 1 case of pulmonary atypical mycobacteriosis, 1 case of pulmonary tuberculosis and tuberculous pleuritis, 1 case of pulmonary tuberculosis and tuberculous lymphadenitis. The regimens of treatment for tuberculosis were INH + RFP + EB in 8 cases, INH + RFP + EB + PZA in 7 cases, INH + RFP + SM in 2 cases, INH + RFP + SM + PZA in 1 case, and INH + RFP in 1 case. Adverse reactions were 8 cases of eruption, 7 cases of drug fever, 3 cases of drug fever and eruption, and 1 case of drug fever and cervical lymphadenopathy. The causative drugs suggested from DLST or the clinical course were RFP in 17 cases and INH in 8 cases. The clinical effect of desensitization therapy for these antituberculous drugs was good in 14 out of the 17 cases (82%) for RFP, and in 6 out of 8 cases (75%) for INH. The effectiveness rate of the present desensitization therapy according to the guideline of the Japanese Society for Tuberculosis was almost equal to that of previous desensitization therapy, and the clinical results were almost same in present and previous studies despite the different methods of administration of the antituberculous drugs.

    Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Desensitization, Immunologic; Drug Hypersensitivity; Female; Humans; Isoniazid; Japan; Male; Middle Aged; Practice Guidelines as Topic; Prospective Studies; Rifampin; Tuberculosis; Tuberculosis Societies

2000
Hepatic enzyme abnormalities in children on triple therapy for tuberculosis.
    Pediatric pulmonology, 1999, Volume: 27, Issue:1

    Standard chemotherapy for tuberculosis (TB) in children uses hepatotoxic drugs. Published data and guidelines on monitoring of liver function during TB treatment are often contradictory and not directly relevant to the pediatric population. We carefully monitored 43 children (age 6.6 years, 0.7-15.1 [median, range]; 49% male; 72% Caucasian) being treated for TB infection (n = 8) or disease (n = 35) with triple therapy, using pyrazinamide, rifampicin, and isoniazid in standard recommended doses. Children on other hepatotoxic drugs were excluded. Measurements of liver function tests (LFT) included aspartate transaminase (AST), alanine transaminase (ALT), and bilirubin, and they were checked before and a median of 5 times (1-23) during treatment. Only one child had mildly abnormal LFTs pretreatment. Thirteen children (n = 13, [30%]; age 7.6 years, 1.8-10.9; 54% male; 77% Caucasian) developed abnormal LFTs (> mean + 2 SD) and of these 10 had TB disease. Eight of the 13 had mildly elevated enzymes (< twice upper limit of normal) while in five, all with disease, the enzymes were more markedly raised. In the group with normal LFTs (n = 30, [70%]; age 6.6 years 0.7-15.1; 47% male; 70% Caucasian) 25 had disease (83%). Liver enzyme elevation occurred early (1.65 weeks, 0.6-16.6). Only two children had symptoms (one jaundice, one pruritus) with treatment being stopped temporarily only in the jaundiced child. Otherwise, LFTs normalized without interrupting treatment. We conclude that elevated liver enzymes are not uncommon in children receiving triple therapy for TB, generally occurring early in treatment. Symptoms are rare. Current British Thoracic Society and American Thoracic Society guidelines (that if LFTs are normal prior to treatment then further monitoring should only be performed if clinically indicated) seem adequate for children.

    Topics: Adolescent; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Isoniazid; Liver; Liver Function Tests; Male; Monitoring, Physiologic; Prognosis; Pyrazinamide; Rifampin; Tuberculosis

1999
Pharmacokinetics of rifapentine in subjects seropositive for the human immunodeficiency virus: a phase I study.
    Antimicrobial agents and chemotherapy, 1999, Volume: 43, Issue:5

    Rifapentine is undergoing development for the treatment of pulmonary tuberculosis. This study was conducted to characterize the single-dose pharmacokinetics of rifapentine and its 25-desacetyl metabolite and to assess the effect of food on the rate and extent of absorption in participants infected with human immunodeficiency virus (HIV). Twelve men and four women, mean age, 38.6 +/- 6.9 years, received a single 600-mg oral dose of rifapentine in an open-label, randomized two-way, complete crossover study. Each volunteer received rifapentine following a high-fat breakfast or during a fasting period. Serial blood samples were collected for 72 h and both rifapentine and its metabolite were assayed by a validated high-performance liquid chromatography method. Pharmacokinetics of rifapentine and 25-desacetylrifapentine were determined by noncompartmental methods. Mean (+/- the standard deviation) maximum concentrations of rifapentine in serum and areas under the curve from time zero to infinity following a high-fat breakfast were 14.09 +/- 2.81 and 373.63 +/- 78.19 micrograms/ml, respectively, and following a fasting period they were 9.42 +/- 2.67 and 256.10 +/- 86.39 micrograms. h/ml, respectively. Pharmacokinetic data from a previously published healthy volunteer study were used for comparison. Administration of rifapentine with a high-fat breakfast resulted in a 51% increase in rifapentine bioavailability, an effect also observed in healthy volunteers. Although food increased the exposure of these patients to rifapentine, the infrequent dosing schedule for the treatment of tuberculosis (e.g., once- or twice-weekly dosing) would be unlikely to lead to accumulation. Additionally, autoinduction has been previously studied and has not been demonstrated with this compound, unlike with rifabutin and rifampin. Rifapentine was well tolerated by HIV-infected study participants. The results of our study suggest that no dosage adjustments may be required for rifapentine in HIV-infected patients (Centers for Disease Control and Prevention classification A1, A2, B1, or B2) undergoing treatment for tuberculosis.

    Topics: Administration, Oral; Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Cross-Over Studies; Female; Food; HIV Seropositivity; HIV-1; Humans; Male; Middle Aged; Mycobacterium Infections; Rifampin; Tuberculosis

1999
Recent bioequivalence studies on fixed-dose combination anti-tuberculosis drug formulations available on the global market.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1999, Volume: 3, Issue:11 Suppl 3

    Concern has been expressed about the bioavailability of rifampicin in some fixed-dose combination (FDC) anti-tuberculosis formulations.. To evaluate the relative bioavailability of rifampicin in various FDC formulations currently in use in tuberculosis control programmes in the global market.. A two-period randomised crossover bioequivalence study in healthy male volunteers, with a 1 week washout period between treatments. Plasma rifampicin concentrations were measured at 0, 1, 2, 4, 6, 8 and 12 hours after each drug administration.. The AUC0-8, AUC0-12 and Cmax for rifampicin in seven of 10 FDC formulations was not found to be bioequivalent to the reference administered as loose (separate) formulations. This was confirmed using parametric and non-parametric statistical methods.. The poor relative bioavailability of rifampicin from some FDCs has been documented. The implications for tuberculosis programmes are extremely serious and warrant urgent attention.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Area Under Curve; Biological Availability; Cross-Over Studies; Drug Combinations; Humans; Male; Rifampin; Therapeutic Equivalency; Tuberculosis

1999
Bioavailability of rifampicin in a separate formulation and fixed dose combination with isoniazid NIH: a case for a fixed dose combination (FDC) for the treatment of tuberculosis.
    The Central African journal of medicine, 1999, Volume: 45, Issue:6

    To study and compare the bioavailability of rifampicin (RIF), in two locally manufactured formulations; an FDC and a separate formulation and an imported FDC formulation.. Open within subjects, single blind cross over study.. Each volunteer subject, acting as their own control, received the two fixed dose combinations and the separate formulation with the same amount of 450 mg RIF.. Cmax (peak drug concentration achieved), Tmax (time at which peak drug concentration is achieved), T1/2el (biological half-life of elimination) and area under the curve (AUC) for zero to 10 hours and zero to infinity. These are obtained from plotting plasma concentration against time.. There was a significant difference in the Cmax between free and RIF combined with INH (6.1 and 7.6 mg/l respectively) and no significant difference in the other parameters measured, of the local products. Comparison of the local products and imported product showed no significant difference in AUC but significant differences in T1/2el, C max and Tmax (p = 0.003, 0.041 and 0.025 respectively).. The Zimbabwe manufactured and the German products had "demonstrable bioavailability" as defined by the International Union Against Tuberculosis and Lung Diseases (IUATLD). The local manufacturer appeared to have the technological capability to produce a registrable combined RIF/INH table to be used in the treatment of tuberculosis and to prevent the irrational use of RIF.

    Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Biological Availability; Chemistry, Pharmaceutical; Cross-Over Studies; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Metabolic Clearance Rate; Rifampin; Single-Blind Method; Time Factors; Tuberculosis

1999
[Compliance, tolerance and effectiveness of a short chemoprophylaxis regimen for the treatment of tuberculosis].
    Medicina clinica, 1998, Oct-10, Volume: 111, Issue:11

    To evaluate compliance, side effects and the efficacy of a short course of chemoprophylaxis for tuberculosis with isoniazid plus rifampin during 3 months, compared with the classic course of isoniazid for 9 months.. Prospective, comparative, randomized and open study of patients with the suitable criteria for chemoprophylaxis, in accordance with the guidelines of the Centers for Disease Control of 1990. Patients were divided into 2 groups: the group of isoniazid plus rifampin, received isoniazid (300 mg per day) plus rifampin (600 mg per day) for 3 months, and the group of isoniazid, that received isoniazid at a dose of 300 mg per day for 9 months.. 238 patients were included, of which 42 refused chemoprophylaxis. Of the remaining 196 patients, 98 were included in each group. Both groups were comparable at base level. The side effects, neither light nor severe showed significant differences. The appearance of adverse effects obliged the suspension of treatment in 7 patients in group isoniazid and of 9 patients in group isoniazid plus rifampin. Three patients in group isoniazid plus rifampin and 11 in group isoniazid stopped treatment (OR 4.14, 95% CI 1.02-19.45; p = 0.04). Efficacy was comparable in the two groups; only one case of tuberculosis was detected in a patient who gave up chemoprophylaxis at day 30.. Tolerance in group isoniazid plus rifampin compared with group I was similar. Compliance was better in the short-term group with a lower percentage of abandonment. On comparing, both groups have shown similar efficacy in preventing the appearance of tuberculosis.

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Prospective Studies; Rifampin; Time Factors; Tuberculosis

1998
[Compliance, efficacy and tolerability of the therapeutic regimen recommended by National Consensus on Tuberculosis].
    Enfermedades infecciosas y microbiologia clinica, 1997, Volume: 15, Issue:3

    To study the degree of adhesion, efficacy, and tolerance of therapeutic guidelines advocated by the National Consensus on tuberculosis.. A prospective study of a cohort of 84 patients receiving a diagnosis of tuberculosis in a Basic General Health Area between 1-3-1993 and 28-2-1994 treated with the regimen recommended by the National Council. The patients were evaluated clinically and microbiologically during the treatment and during twelve months follow-up.. Fifty-two patients (61.9%) were male and 32 (38.1%) female, aged 29.9 +/- 19.7 years (r = 1-84 years). Seventy-four (88.1%) were index cases and 10 (11.4%) household contacts. Eight patients (9.5%) were also infected with HIV, 71 (84.5%) presented pulmonary tuberculosis and 13 (15.5%) extrapulmonary forms. Therapeutic compliance was correct in 80 cases (95.2%) and incorrect in 4 (4.8%). It was well-tolerated in 73 patients (91.2%), there was slight toxicity in five (6.3%) and severe in two (2.5%). Seventy-four patients (88.1%) were cured, there was one therapeutic failure (1.2%) and five relapses (6%). Overall mortality was 4.8% and attributable mortality 1.2%.. Our results seem to confirm a high degree of adhesion, good tolerance and acceptable therapeutic efficacy of the scheme proposed by the National Council.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; HIV Infections; Humans; Infant; Isoniazid; Male; Middle Aged; Patient Compliance; Prospective Studies; Pyrazinamide; Recurrence; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

1997
Pharmacokinetics of antimycobacterial drugs in patients with tuberculosis, AIDS, and diarrhea.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 1997, Volume: 25, Issue:1

    To test the hypothesis that antituberculous drug disposition is altered in patients with AIDS, we studied the steady-state pharmacokinetics of isoniazid (300 mg/d), rifampin (600 mg/d), and pyrazinamide (1,500 mg/d) in 29 adults (14 patients infected with human immunodeficiency virus [HIV] and 15 non-HIV-infected patients) with tuberculosis in Nairobi, Kenya. Intestinal integrity was assessed with xylose. Neither HIV infection nor diarrhea accounted for the interpatient variability in the area-under-the-plasma concentration vs. time curve (AUC), the maximum concentration, or the terminal half-life (t1/2) of isoniazid, rifampin, and pyrazinamide. No significant association between HIV infection or diarrhea and pharmacokinetics was seen for any of the compounds. In addition, neither the AUC nor the t1/2 of any of these drugs reflected interpatient differences in CD4 lymphocyte counts. Xylose absorption was uniformly low. We did not demonstrate that HIV infection, diarrhea, or CD4 lymphocyte counts contributed significantly to the variability in pharmacokinetics of isoniazid, rifampin, and pyrazinamide in TB patients in Nairobi.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Biological Availability; Diarrhea; Female; Humans; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis

1997
Susceptibility to levofloxacin of Myocobacterium tuberculosis isolates from patients with HIV-related tuberculosis and characterization of a strain with levofloxacin monoresistance. Community Programs for Clinical Research on AIDS 019 and the AIDS Clinica
    AIDS (London, England), 1997, Volume: 11, Issue:12

    To characterize the susceptibility to levofloxacin of clinical isolates of Mycobacterium tuberculosis (MTB) obtained from patients with HIV-related tuberculosis and to characterize the molecular genetics of levofloxacin resistance.. Isolates from culture-positive patients in a United States multicenter trial of HIV-related TB were tested for susceptibility to levofloxacin by minimum inhibitory concentration (MIC) determinations in Bactec 7H12 broth. Automated sequencing of the resistance determining region of gyrA was performed.. Of the 135 baseline MTB isolates tested, 134 (99%; 95% exact binomial confidence interval, 95.9-99.9%) were susceptible to levofloxacin with an MIC < or = 1.0 microg/ml. We identified a previously unrecognized mis-sense mutation occurring at codon 88 of gyrA in a levofloxacin mono-resistant MTB isolate obtained from a patient with AIDS who had received ofloxacin for 8 months prior to the diagnosis of tuberculosis.. Clinical MTB isolates from HIV-infected patients were generally susceptible to levofloxacin. However, the identification of a clinical isolate with mono-resistance to levofloxacin highlights the need for circumspection in the use of fluoroquinolones in the setting of potential HIV-related tuberculosis and for monitoring of rates of resistance of MTB isolates to fluoroquinolones.

    Topics: AIDS-Related Opportunistic Infections; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Humans; In Vitro Techniques; Isoniazid; Levofloxacin; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Ofloxacin; Pyrazinamide; Rifampin; Sputum; Tuberculosis

1997
Bioavailability of Chinese rifapentine during a clinical trial in Hong Kong.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1997, Volume: 1, Issue:5

    A clinical trial of rifapentine in Hong Kong.. Assessment of the bioavailability of the Chinese rifapentine used in the trial.. The content of rifapentine in serum samples taken from 287 patients during the administration of four batches of the drug was measured by microbiological assay.. An initial comparison of areas under curve obtained in a random allocation to 40 patients of rifapentine either of Western or Chinese origin indicated that the bioavailability of the Chinese drug was 74% of the Western drug. The bioavailability of the second batch was found to be about 66% of the Western drug. The dose of the last two batches of rifapentine was therefore increased from the planned 600 mg to 750 mg, or briefly to 900 mg; serum concentrations were then similar to those obtained with the Western drug. Bioavailability did not change during the use of each drug batch.. A comparison of the results obtained in the trial with the initial two batches and the final batches will estimate the effects of rifapentine dose size on its efficacy and toxicity.

    Topics: Adult; Antitubercular Agents; Area Under Curve; Biological Availability; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Design; Drug Stability; Female; Hong Kong; Humans; Male; Middle Aged; Regression Analysis; Rifampin; Treatment Outcome; Tuberculosis

1997
Adverse drug reactions and outcome of elderly patients on antituberculosis chemotherapy with and without rifampicin.
    Journal of medicine, 1995, Volume: 26, Issue:1-2

    Antituberculosis (anti-TB) chemotherapy with concomitant administration of rifampicin and isoniazid may cause a higher incidence of hepatotoxicity than isoniazid alone. We carried out a prospective study of the adverse reactions to anti-TB drugs and the clinical outcome in elderly patients on anti-TB chemotherapy, to find out whether the omission of rifampicin from standard anti-TB regime would result in a reduction of adverse reactions and/or mortality during anti-TB treatment. Eighty elderly patients (age > 65 years) with TB were recruited into the study. They were randomised to receive anti-TB chemotherapy consisting of isoniazid, pyrazinamide and ethambutol with or without rifampicin for six months. Adverse reactions and mortality occurring during treatment were noted. A significantly higher number of patients on rifampicin had elevated liver enzymes compared with those not receiving rifampicin. All of these reactions responded favorably to adjustment of anti-TB drugs. There was no significant difference between the two groups in the incidence of symptomatic adverse reactions or mortality during treatment. However, five patients not given rifampicin had unsatisfactory resolution radiographically and required additional therapy. We conclude that the inclusion of rifampicin in the anti-TB regime offers a better therapeutic response but without significantly affecting the incidence of adverse reactions or mortality during treatment in elderly patients with TB.

    Topics: Aged; Antitubercular Agents; Female; Humans; Male; Prospective Studies; Rifampin; Survival Analysis; Treatment Outcome; Tuberculosis

1995
Correlation between steady-state plasma concentration of antituberculous drugs and age, inclusion of rifampicin in the treatment regimen, adverse drug reactions and other clinical parameters.
    Journal of medicine, 1995, Volume: 26, Issue:5-6

    A regional hospital in Hong Kong examined the correlation between plasma concentrations of rifampicin, pyrazinamide, isoniazid and its metabolite hydrazine and age, inclusion of rifampicin in the treatment regimen, adverse drug reactions and other clinical parameters. One hundred eighty subjects with tuberculosis were admitted consecutively to the medical wards of the Prince of Wales Hospital over a one and a half year period. Elderly patients > 65 years were randomized into one of two treatments with and without rifampicin in addition to isoniazid, pyrazinamide and ethambutol; younger patients received all four drugs. Plasma antituberculous drug concentrations were determined using high performance liquid chromatography. Elderly patients taking rifampicin had a higher mean steady-state concentration of isoniazid, together with a higher incidence of adverse effects compared with those not taking rifampicin. No age related differences were observed for the other drugs. For the whole group, higher mean concentrations of hydrazine, rifampicin and pyrazinamide were associated with a higher incidence of adverse effects and the presence of coexisting diseases. It is concluded that in sick elderly patients with coexisting diseases, use of rifampicin in the antituberculous regimen should be accompanied by close monitoring for side effects, and that there may be an indication for use of lower dosages of antituberculous drugs in such patients.

    Topics: Adult; Aged; Aging; Antitubercular Agents; Female; Homeostasis; Humans; Isoniazid; Male; Middle Aged; Osmolar Concentration; Rifampin; Tuberculosis

1995
Evaluation of the 3-drug combination, Rifater, versus 4-drug therapy in the ambulatory treatment of tuberculosis in Cape Town.
    South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 1994, Volume: 84, Issue:6

    The subjective impression among clinicians that the use of Rifater was causing delayed sputum conversion and increased drug resistance was tested in a prospective study. Adults in the Cape Town municipal area with a first episode of pulmonary tuberculosis were treated either with Rifater or a regimen consisting of isoniazid, rifampicin, pyrazinamide and ethambutol. All patients who took the treatment as prescribed (67 Rifater, 39 the 4-drug regimen) converted to a negative sputum culture by the time 90 doses had been taken. The rates of inadequate compliance and of side-effects were similar in the two groups. Drug sensitivity testing of bacteria cultured from pre-treatment sputum specimens revealed an overall primary resistance rate of 4.84% in the population studied, sufficiently low to preclude any necessity for routine pre-treatment drug sensitivity testing.

    Topics: Antitubercular Agents; Drug Combinations; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Patient Compliance; Prospective Studies; Pyrazinamide; Rifampin; Sputum; Streptomycin; Tuberculosis

1994
Clinically significant drug interactions with antituberculosis agents.
    Drug safety, 1994, Volume: 11, Issue:4

    Standard short-course regimens for tuberculosis are used worldwide with very few problems. Unfortunately, the emergence of multiple drug-resistant tuberculosis in many parts of the world is leading to a diversification of drug regimens and to the use of drugs that are more toxic per se and more likely to interact with others. In addition, the treatment of HIV/AIDS patients with tuberculosis or disease due to Mycobacterium avium-intracellulare complex (MAC) infection with new drugs and multidrug regimens has added to the problem of drug interactions, especially as such patients may often be receiving concomitant treatment for a range of bacterial, fungal and viral infections. In general, there are very few clinically significant interactions between the first-line antituberculosis drugs themselves, although problems of bioavailability, notably of rifampicin (rifampin), have been encountered in the manufacture of combination tablets. Of the first-line drugs used to treat tuberculosis, i.e. rifampicin, isoniazid and pyrazinamide, rifampicin is particularly likely to cause clinically significant drug interactions as it is a potent inducer of the cytochrome P450 enzyme group, which is involved in the metabolism of many drugs, in particular oral contraceptives, corticosteroids, oral anticoagulants and cyclosproin. The use of quinolones to treat multiple drug-resistant tuberculosis and AIDS-related MAC disease raises further problems of drug interactions as, in contrast to rifampicin, these drugs inhibit some cytochrome isoenzymes, leading to reduced metabolism of certain drugs.

    Topics: Absorption; Antitubercular Agents; Biotransformation; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; Humans; Isoenzymes; Isoniazid; Quinolones; Rifabutin; Rifampin; Tissue Distribution; Tuberculosis

1994
[Results of short-term tuberculosis therapy with isoniazid, rifampicin and pyrazinamide].
    Schweizerische medizinische Wochenschrift, 1993, Jun-26, Volume: 123, Issue:25

    Short-course chemotherapy of six-month duration with an initial combination of three drugs (isoniazid [H], rifampin [R] and pyrazinamide [Z]) is recommended as the treatment of choice in tuberculosis today. Use of fixed-combination tablet (Rifater) prevents prescription errors by physicians and selective intake by noncompliant patients. It should therefore assist in the prevention of emergence of drug resistance. In a controlled study at a chest hospital in Switzerland involving 261 patients with culture proven tuberculosis, the following two regimens were compared: 1) Six-month therapy (n = 128) with daily Rifater for two months, followed by H and R for four months. 2) Nine-month therapy (n = 133) with H and R daily for nine months, supplemented by ethambutol for the first two months. The two patient groups were comparable except for initial drug resistance (16% vs 8%, p < 0.05). Overall resistance to H was 10%. Five patients had initial resistance to two or more drugs. 227 patients were re-examined 1-8, and on average 4 years after therapy: four patients relapsed after 12, 20, 36 and 90 months. Two patients with initial drug resistance to H later developed resistance to R; both of these, as well as a third relapse patient, were cured with subsequent multi-drug therapy. Despite two and a half years of chemotherapy and repeated surgery, the fourth patient with initial resistance to H and R could not be cured. All relapse patients with initial drug resistance were randomized into the six-month therapy group.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Adult; Antitubercular Agents; Drug Combinations; Drug Resistance, Microbial; Female; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Pyrazinamide; Rifampin; Time Factors; Tuberculosis

1993
Intensive short course chemotherapy for treatment of Greek children with tuberculosis.
    The Pediatric infectious disease journal, 1992, Volume: 11, Issue:12

    This prospective study with an 18-month posttreatment follow-up evaluated the efficacy of intensive short course chemotherapy in Greek children with pulmonary or extrapulmonary tuberculosis. Between November, 1988, and March 1991 a 2-month regimen of rifampin, 10 to 12 mg/kg/day, isoniazid, 10 to 12 mg/kg/day, and pyrazinamide, 30 to 35 mg/kg/day, followed by rifampin and isoniazid for the remaining 4 months, was administered orally to 36 children with tuberculosis. Twenty-three boys and 13 girls ages 8 months to 12 years (mean, 5 1/2 years) were enrolled in the study. The diagnostic criteria for establishing tuberculosis were tuberculin skin test reactivity, radiographic findings compatible with tuberculosis, epidemiological data and clinical and laboratory findings. Four children had extrapulmonary and 32 had pulmonary tuberculosis; 9 of the latter were asymptomatic. Among the pulmonary cases there were 2 children with pleural effusion. Clinical response to therapy was apparent within 7 to 14 days; the pleural effusions resolved in 2 to 6 weeks and the pulmonary infiltrates cleared in 2 to 6 months. Hilar adenopathy regressed within 18 months or longer. No serious problems with drug tolerance or toxicity were noted during the treatment period. Temporary hyperuricemia and transient elevation in serum transaminases were observed in 11 patients but no drug modification was required. There were no posttreatment relapses. These findings suggest that intensive short course chemotherapy for the treatment of Greek children with pulmonary or extrapulmonary tuberculosis appears to be effective, safe, of good patient compliance and comparable to the longer treatment regimens.

    Topics: Anti-Bacterial Agents; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Greece; Humans; Infant; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis

1992
A randomized trial of fully intermittent vs. daily followed by intermittent short course chemotherapy for childhood tuberculosis.
    The Pediatric infectious disease journal, 1990, Volume: 9, Issue:11

    Fully intermittent short course chemotherapy regimens have been used successfully in adults but not in children. We report the results on 76 children with tuberculosis, excluding central nervous system tuberculosis and primary pulmonary complex. Isoniazid, rifampin and pyrazinamide were used for treatment. They were randomly allocated to Regimen A (52 doses) and Regimen B (94 doses). Overall efficacy of both schedules was greater than 95% in 27 children with lymphatic, 43 with pulmonary and 6 with disseminated tuberculosis. Compliance in 10 children after 2 to 4 months of therapy was poor because rapid improvement was mistaken by parents for cure. Two children died, probably of underlying lung disease. Follow-up for up to 2 years did not reveal any case of relapse or recurrence of the disease. Therapy for 6 months involving administration of only 52 or 94 doses of drugs was found to be economical, effective and safe for treating children with tuberculosis.

    Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Infant; Isoniazid; Male; Patient Compliance; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary

1990
Treatment of extrapulmonary tuberculosis.
    Seminars in respiratory infections, 1989, Volume: 4, Issue:3

    The duration of therapy for pulmonary tuberculosis (TB) is now shortened to 6 or 9 months with the use of bactericidal drugs. There are few reports on the results of short course chemotherapy (SCC) in extrapulmonary tuberculosis (EP). It is unlikely that many controlled studies shall be forthcoming in the future because of involvement of many sites with the disease, each of which has special problems. However, available controlled studies and clinical experiences in EP indicate early success. The site of the disease appears to be less important since the bacterial population is much smaller in EP than in TB and is easily amenable to the bactericidal drugs. Present bactericidal drugs (isoniazid [INH], rifampin [RIF], pyrazinamide [PZA]) penetrate well into tissues and attain bactericidal levels to kill the organisms. Our experience with 9-month SCC consisting of INH 300 mg and RIF 600 mg daily for one month, followed by INH 900 mg and RIF 600 mg twice weekly for another 8 months in 478 cases of EP showed overall success in over 95% of those patients who completed therapy over a median follow-up of 42 months. The drugs may be given daily throughout with the same success. Thus, 9-month therapy with INH and RIF is highly effective in EP due to drug sensitive organisms. In TB, the duration may be shortened to 6-months with initial intensive four-drug therapy consisting of INH, RIF, PZA and streptomycin (SM) or ethambutol (EMB) daily for 2 months, followed by INH and RIF daily or twice weekly for another 4 months.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Isoniazid; Middle Aged; Rifampin; Tuberculosis

1989
[Pharmacokinetic interaction of ketoconazole, isoniazid and rifampicin].
    Medicina, 1989, Volume: 49, Issue:1

    Eight male tuberculous patients, between 20 and 60 years of age, were given Isoniazid 5 mg/kg and Ketoconazole 200 mg, first one at a time and then associated. Plasma concentrations were measured 0, 2 and 5 hs after taking the drugs. Isoniazid was measured by spectrophotometry and Ketoconazole by the microbiologic method with Candida albicans as test microorganism. When both drugs were given simultaneously Ketoconazole plasma concentration decreased 75% at 2 hs (p less than 0.025) and 85% at 5 hs (p less than 0.05), whereas that of Isoniazid remained unchanged (Table 1). Mean half-life of Isoniazid was 3.9 +/- 1.4 hs in 7 slow acetylators and 1.1 hs in one fast acetylator when given one at a time and 4.4 +/- 1.5 hs when given simultaneously. A similar study was conducted on 11 tuberculous patients who were given Rifampicin 10 mg/kg and Ketoconazole 200 mg, one at a time and concurrently. Rifampicin was measured by high pressure liquid chromatography. When Rifampicin and Ketoconazole were given concurrently plasma concentration of both drugs was reduced: Ketoconazole decreased 85% at 2 hs (p less than 0.025) and 98% at 5 hs (p less than 0.025) whereas Rifampicin decreased 45% at 2 hs (p less than 0.005) and 40% at 5 hs (p less than 0.005) (Table 2). Mean half-life of Rifampicin was 3.5 +/- 0.8 and 4.2 +/- 1.1 hs, respectively, when it was given alone and concurrently. Studies on chemical interactions between Isoniazid and Ketoconazole and between Rifampicin and Ketoconazole yielded negative results.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Adult; Clinical Trials as Topic; Drug Interactions; Drug Therapy, Combination; Humans; Isoniazid; Ketoconazole; Male; Middle Aged; Rifampin; Tuberculosis

1989
Long-term follow-up of a clinical trial of six-month and four-month regimens of chemotherapy in the treatment of pulmonary tuberculosis. Singapore Tuberculosis Service/British Medical Research Council.
    The American review of respiratory disease, 1986, Volume: 133, Issue:5

    In a study in Singapore, patients of Chinese, Malay, or Indian ethnic origin with sputum-smear-positive pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampin, and pyrazinamide followed by daily isoniazid and rifampin, either with or without pyrazinamide, allocated at random. Both regimens were given for a total duration of either 6 or 4 months by random allocation. As previously reported, all 330 patients with drug-susceptible strains of tubercle bacilli pretreatment had a favorable bacteriologic response during chemotherapy, and only 2 (1%) of 158 in the 6-month series, compared with 15 (10%) of 156 in the 4-month series, relapsed bacteriologically during the 30 months after the start of chemotherapy. A long-term follow-up assessment has been conducted 5 to 8 yr after admission to the study. The excellent results in the 6-month series were maintained; only 1 of the 138 patients assessed relapsed after 30 months, compared with 5 of the 131 in the 4-month series. Of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs pretreatment, 1 had an unfavorable response during treatment, and none of 9 in the 6-month series and 2 of 22 in the 4-month series relapsed bacteriologically by 30 months, but none of the nine 6-month and eighteen 4-month patients assessed relapsed subsequently.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Clinical Trials as Topic; Follow-Up Studies; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1986
Tuberculosis treated with rifampicin, ethambutol and isoniazid: Danish tuberculosis trial 1972-1974.
    European journal of respiratory diseases, 1982, Volume: 63, Issue:2

    A total of 577 Danish patients with tuberculosis were observed for a period of 5 years. A primary phase of treatment with 300 mg Isoniazid (INH), 450 mg Rifampicin (RMP) and 1200 mg Ethambutol (EMB) daily for 3 months was followed by administration of either INH+RMP or INH+EMB for 12 or 18 months after conversion. During the initial period the number of bacteria decreased rapidly, even in patients with the most severe tuberculosis, and all patients became culture negative. There was no significant difference in efficacy of RMP and EMB in the secondary phase. One of the 577 patients again became positive during the follow-up period, but there were no bona fide cases of relapse among patients who completed the treatment.

    Topics: Adolescent; Adult; Aged; Alcoholism; Clinical Trials as Topic; Denmark; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

1982
Chemotherapy of tuberculosis for the 1980's.
    Primary care, 1980, Volume: 7, Issue:3

    Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Humans; Isoniazid; Rifampin; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

1980
[Hepatoxic side-effects of rifampicin. A comparative clinical study].
    Die Medizinische Welt, 1977, Nov-25, Volume: 28, Issue:47

    Topics: Alanine Transaminase; Alcoholism; Alkaline Phosphatase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1977
Rifadin (rifampicin) in the treatment of gonorrhoea in Uganda. A controlled trial.
    The British journal of venereal diseases, 1971, Volume: 47, Issue:3

    Topics: Clinical Trials as Topic; Gonorrhea; Humans; Male; Penicillin G Procaine; Penicillin Resistance; Rifampin; Syphilis; Tuberculosis; Uganda; Urethritis

1971
Side effects of intermittent rifampicin.
    British medical journal, 1971, Oct-23, Volume: 4, Issue:5781

    Topics: Clinical Trials as Topic; Humans; Rifampin; Tuberculosis

1971
Rifampicin.
    Annals of ophthalmology, 1971, Volume: 3, Issue:8

    Topics: Adenoviridae; Administration, Oral; Animals; Bacteria; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Conjunctivitis; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Eye Diseases; Haemophilus Infections; Humans; Isoniazid; Mycobacterium; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Vaccinia; Vaccinia virus

1971
Rifampicin, myambutol, Isoxyl, and capreomycin as combination partners in animal experiments.
    Antibiotica et chemotherapia. Fortschritte. Advances. Progres, 1970, Volume: 16

    Topics: Animals; Antitubercular Agents; Capreomycin; Clinical Trials as Topic; Drug Combinations; Ethambutol; Mycobacterium Infections; Phenylthiourea; Rabbits; Rifampin; Tuberculosis

1970
Methods of clinical evaluation of rifampicin-activity.
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Aminosalicylic Acids; Clinical Trials as Topic; Ethambutol; Humans; Rifampin; Tuberculosis

1969
[Rifomycin in treatment of chronic tuberculosis with bacilli resistant to standard medications].
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Aminosalicylic Acids; Clinical Trials as Topic; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Humans; Rifampin; Tuberculosis

1969
[Our initial clinical experience with rifomycin].
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Adult; Aged; Antitubercular Agents; Chronic Disease; Clinical Trials as Topic; Cycloserine; Drug Synergism; Humans; Middle Aged; Rifampin; Tuberculosis

1969
Hospital-based ambulatory treatment of tuberculosis with capreomycin, ethambutol, and-or rifampicin.
    Scandinavian journal of respiratory diseases. Supplementum, 1969, Volume: 69

    Topics: Ambulatory Care; Anti-Bacterial Agents; Clinical Trials as Topic; Ethambutol; Finland; Humans; Physician-Patient Relations; Rifampin; Tuberculosis

1969
A comparison of rifampicin, ethambutol and PAS in short-term monotherapy. Preliminary results of the third cooperative study of the WATL.
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Aminosalicylic Acids; Clinical Trials as Topic; Ethambutol; Humans; Rifampin; Tuberculosis

1969
[Treatment of chronic tuberculosis with ethambutol and prothionamide associated with rifomycin of capreomycin].
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Adult; Antitubercular Agents; Chronic Disease; Clinical Trials as Topic; Drug Synergism; Ethambutol; Female; Humans; Isonicotinic Acids; Male; Middle Aged; Rifampin; Tuberculosis

1969

Other Studies

1885 other study(ies) available for rifampin and Tuberculosis

ArticleYear
Drug resistance profiles and related gene mutations in slow-growing non-tuberculous mycobacteria isolated in regional tuberculosis reference laboratories of Iran: a three year cross-sectional study.
    Pathogens and global health, 2023, Volume: 117, Issue:1

    There are limited studies on the antibiotic resistance patterns of slowly growing mycobacteria (SGM) species and their related gene mutations in Iran. This study aimed to elucidate the antibiotic susceptibility profiles and the mutations in some genes that are associated with the antibiotic resistance among SGM isolates from Iran. The SGM strains were isolated from sputum samples of suspected tuberculosis (TB) patients. SGM species were identified by standard phenotypic tests and were assigned to species level by amplification and sequencing of the

    Topics: Anti-Bacterial Agents; Clarithromycin; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Humans; Iran; Microbial Sensitivity Tests; Moxifloxacin; Mutation; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Rifampin; Tuberculosis

2023
Comparative Evaluation of GeneXpert MTB/RIF Ultra and GeneXpert MTB/RIF for Detecting Tuberculosis and Identifying Rifampicin Resistance in Pars Plana Vitrectomy Samples of Patients with Ocular Tuberculosis.
    Ocular immunology and inflammation, 2023, Volume: 31, Issue:5

    Xpert MTB/RIF Ultra (Ultra) was evaluated for the first time on Ocular tuberculosis (OTB) samples and compared with Xpert.. Seventy five vitreous fluid samples (3 confirmed OTB, 47 clinically suspected OTB, and 25 controls) were subjected to Ultra, Xpert and Multiplex-PCR and compared against culture, composite reference standard (CRS), and gene sequencing.. The sensitivity of Ultra was 50% in diagnosing OTB (100% against culture and 46.8% against CRS). The overall sensitivity of Xpert and MPCR was 16% and 72%, respectively. Xpert missed three culture-positive cases and MPCR detected additional 11. Ultra and Xpert missed two and four cases of RifR, respectively. A total of 13(59%) cases were reported 'trace' by Ultra in which RifR could not be evaluated.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Ocular; Vitrectomy

2023
Diagnosing osteo-articular tuberculosis and multidrug resistance using real-time polymerase chain reaction and high-resolution melt-curve analysis.
    Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2023, Volume: 41, Issue:4

    The study evaluated real-time quantitative polymerase chain reaction (qPCR) and high-resolution melt-curve analysis (HRM) for simultaneous diagnosis of osteo-articular tuberculosis (OATB) and drug resistance. Two hundred and fifty synovial fluid and pus specimens (20 confirmed OATB by culture, 130 suspected OATB, and 100 controls) processed in the Department of Medical Microbiology, PGIMER were subjected to qPCR using rpoB, MPB64, and IS6110 genes. All OATB positive specimens were subjected to HRM for detecting resistance to rifampicin and isoniazid. qPCR detected 129/150 OATB cases with a sensitivity of 86% (95% for confirmed and 84.6% for suspected OATB cases) and specificity of 100%. rpoB and MPB64 genes had higher sensitivity than IS6110 (86% vs. 74.6%). HRM reported eight multidrug resistant (MDR), two mono-rifampicin, and five mono-isoniazid resistant cases, all were concordant with gene sequencing. qPCR followed by HRM analysis offer a simple, accurate, and rapid platform for simultaneous detection of OATB and MDR.

    Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis

2023
Non-actionable Results, Accuracy, and Effect of First- and Second-line Line Probe Assays for Diagnosing Drug-Resistant Tuberculosis, Including on Smear-Negative Specimens, in a High-Volume Laboratory.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023, 02-08, Volume: 76, Issue:3

    Rapid tuberculosis (TB) drug susceptibility testing (DST) is crucial. Genotype MTBDRsl is a widely deployed World Health Organization (WHO)-endorsed assay. Programmatic performance data, including non-actionable results from smear-negative sputum, are scarce.. Sputa from Xpert MTB/RIF individuals (n = 951) were routinely-tested using Genotype MTBDRplus and MTBDRsl (both version 2). Phenotypic DST was the second-line drug reference standard. Discrepant results underwent Sanger sequencing.. 89% (849 of 951) of individuals were culture-positive (56%, 476 of 849 smear-negative). MTBDRplus had at least 1 nonactionable result (control and/or TB-detection bands absent or invalid, precluding resistance reporting) in 19% (92 of 476) of smear-negatives; for MTBDRsl, 40% (171 of 427) were nonactionable (28%, 120 of 427 false-negative TB; 17%, 51 of 427 indeterminate). In smear-negatives, MTBDRsl sensitivity for fluoroquinolones was 84% (95% confidence interval, 67%-93), 81% (54%-95%) for second-line injectable drugs, and 57% (28%-82%) for both. Specificities were 93% (89%-98%), 88% (81%-93%), and 97% (91%-99%), respectively. Twenty-three percent (172 of 746) of Xpert rifampicin-resistant specimens were MTBDRplus isoniazid-susceptible. Days-to-second-line-susceptibility reporting with the programmatic advent of MTBDRsl improved (6 [5-7] vs 37 [35-46]; P < .001).. MTBDRsl did not generate a result in 4 of 10 smear-negatives, resulting in substantial missed resistance. However, if MTBDRsl generates an actionable result, that is accurate in ruling-in resistance. Isoniazid DST remains crucial. This study provides real-world, direct, second-line susceptibility testing performance data on non-actionable results (that, if unaccounted for, cause an overestimation of test utility), accuracy, and care cascade impact.

    Topics: Antitubercular Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Dual Rifampicin and Isoniazid Mannose-Decorated Lipopolysaccharide Nanospheres for Macrophage- Targeted Lung Delivery.
    Current drug delivery, 2023, Volume: 20, Issue:10

    Currently, the treatment protocols for tuberculosis (TB) have several challenges, such as inconsistent oral bioavailability, dose-related adverse effects, and off-target drug toxicity.. This research reports the design and characterization of rifampicin (RIF) and isoniazid (INH) loaded hybrid lipid-polysaccharide nanoparticles using the solvent injection method, and demonstrated the influence of conjugated mannosyl residue on macrophage targeting and intracellular drug delivery capacity.. The nanospheres, herein called mannose-decorated lipopolysaccharide nanoparticles, were spherical in shape, exhibiting average sizes less than 120 nm (PDI<0.20) and positive zeta potentials. Drug encapsulation was greater than 50% for rifampicin and 60% for isoniazid. The pH-responsive drug release was sustained over a 48-hour period and preferentially released more rifampicin/isoniazid in a simulated acidic phagolysosomal environment (pH 4.8) than in a simulated physiological medium. TGA and FTIR analysis confirmed successful mannose-grafting on nanoparticle surface and optimal degree of mannosylation was achieved within 48-hour mannose-lipopolysaccharide reaction time. The mannosylated nanoparticles were biocompatible and demonstrated a significant improvement towards uptake by RAW 264.7 cells, producing higher intracellular RIF/INH accumulation when compared to the unmannosylated nanocarriers.. Overall, the experimental results suggested that mannose-decorated lipopolysaccharide nanosystems hold promise towards safe and efficacious macrophage-targeted delivery of anti-TB therapeutics.

    Topics: Humans; Isoniazid; Lipopolysaccharides; Macrophages; Mannose; Nanoparticles; Nanospheres; Rifampin; Tuberculosis

2023
Drug resistance profile of Mycobacterium kansasii clinical isolates before and after 2-month empirical antimycobacterial treatment.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2023, Volume: 29, Issue:3

    Mycobacterium kansasii pulmonary disease is frequently misdiagnosed and treated as tuberculosis, especially in countries with high tuberculosis burden. This study aimed to investigate the drug resistance profile of M.kansasii in patients with M.kansasii pulmonary disease in Shanghai and to determine the variations in drug resistance after 2 months of antimycobacterial treatment.. All patients with a diagnosis of M.kansasii pulmonary disease from 2017 to 2019 in Shanghai were retrospectively analysed. Whole-genome sequencing was performed, and the minimum inhibitory concentration (MIC) to antimycobacterial drugs was measured using the broth microdilution method.. In total, 191 patients had a diagnosis of M.kansasii pulmonary disease. Of them, 24.1% (46/191) had persistent positive culture after 2 months of antimycobacterial treatment. Whole-genome sequencing revealed that the 46 paired isolates had a difference of <17 single nucleotide polymorphisms, thus excluding the possibility of exogenous reinfection. More than 90% of the baseline isolates were sensitive to rifampin, clarithromycin, moxifloxacin, or amikacin, whereas a high resistance to ethambutol (118/191, 61.8%) and 4 μg/mL of isoniazid (32/191, 16.8%) were observed. Two isolates presented high resistance to rifamycin (i.e. a rifampin MIC of >8 μg/mL and a rifabutin MIC of 8 μg/mL) both containing the rpoB mutation (S454L). The increase of MIC to rifampin, ethambutol, and/or isoniazid was identified in 50.0% (23/46) of the patients.. A high prevalence of innate resistance to ethambutol and isoniazid was observed among circulating M.kansasii clinical strains in Shanghai. The increase in drug resistance under empirical antimycobacterial treatment highlighted the urgency of definitive species identification before initiating treatment.

    Topics: Anti-Bacterial Agents; Antitubercular Agents; China; Ethambutol; Humans; Isoniazid; Lung Diseases; Microbial Sensitivity Tests; Mycobacterium kansasii; Retrospective Studies; Rifampin; Tuberculosis

2023
Feasibility, Ease-of-Use, and Operational Characteristics of World Health Organization-Recommended Moderate-Complexity Automated Nucleic Acid Amplification Tests for the Detection of Tuberculosis and Resistance to Rifampicin and Isoniazid.
    The Journal of molecular diagnostics : JMD, 2023, Volume: 25, Issue:1

    Four moderate-complexity automated nucleic acid amplification tests for the diagnosis of tuberculosis are reported as having laboratory analytical and clinical performance similar to that of the Cepheid Xpert MTB/RIF assay. These assays are the Abbott RealTime MTB and RealTime MTB RIF/INH Resistance, Becton Dickinson MAX MDR-TB, the Hain Lifescience/Bruker FluoroType MTBDR, and the Roche cobas MTB and MTB RIF/INH assays. The study compared feasibility, ease of use, and operational characteristics of these assays/platforms. Manufacturer input was obtained for technical characteristics. Laboratory operators were requested to complete a questionnaire on the assays' ease of use. A time-in-motion analysis was also undertaken for each platform. For ease-of-use and operational requirements, the BD MAX MDR-TB assay achieved the highest scores (86% and 90%) based on information provided by the user and manufacturer, respectively, followed by the cobas MTB and MTB-RIF/INH assay (68% and 86%), the FluoroType MTBDR assay (67% and 80%), and the Abbott RT-MTB and RT MTB RIF/INH assays (64% and 76%). The time-in-motion analysis revealed that for 94 specimens, the RealTime MTB assay required the longest processing time, followed by the cobas MTB assay and the FluoroType MTBDR assay. The BD MAX MDR-TB assay required 4.6 hours for 22 specimens. These diagnostic assays exhibited different strengths and weaknesses that should be taken into account, in addition to affordability, when considering placement of a new platform.

    Topics: Feasibility Studies; Humans; Isoniazid; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; World Health Organization

2023
Folic acid protects against tuberculosis-drug-induced liver injury in rats and its potential mechanism by metabolomics.
    The Journal of nutritional biochemistry, 2023, Volume: 112

    Observational study indicated that folic acid (FA) supplementation may protect against tuberculosis-drug-induced liver injury (TBLI). The aim is to investigate the effect and mechanism of FA on TBLI in rats. Liver injury was induced by a daily gavage of isoniazid (INH) and rifampicin (RIF) in the model and FA groups. Rats in the FA group were also treated with 2.5 mg/kg body weight FA. Rats in the control group were not treated. Eight rats were used in each group. The severity of liver injury was measured by the serum levels of hepatic enzymes and histological score. The metabolites in serum and liver tissues were analyzed by HPLC-Q-TOF-MS/MS. FA treatment significantly reduced alanine aminotransferase and liver necrosis. Seventy-nine differential metabolites in the serum and liver tissues were identified among the three groups. N-acylethanolamines, INH and RIF metabolites, phosphatidylcholines, lysophosphatidylcholines, monoglycerides, diglycerides and bile acids were regulated by FA treatment, involving key metabolic pathways, such as N-acylethanolamine metabolism, INH and RIF metabolism, liver regeneration, inflammation alleviation and bile acid metabolism. RT-PCR and western blotting results confirmed the altered N-acylethanolamine metabolism and improved drug metabolism by FA. In conclusion, FA was protective against TBLI, which may be related to the regulation of N-acylethanolamine metabolism and drug detoxification by FA.

    Topics: Animals; Chemical and Drug Induced Liver Injury; Liver; Metabolomics; Rats; Rats, Wistar; Rifampin; Tandem Mass Spectrometry; Tuberculosis

2023
Four months of rifampicin for tuberculosis prevention treatment in children.
    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 2023, Volume: 29, Issue:2

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Child; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2023
A Quantitative Method for the Study of HIV-1 and Mycobacterium tuberculosis Coinfection.
    The Journal of infectious diseases, 2023, 03-01, Volume: 227, Issue:5

    Mycobacterium tuberculosis and human immunodeficiency virus-1 (HIV-1) syndemic interactions are a major global health concern. Despite the clinical significance of coinfection, our understanding of the cellular pathophysiology and the therapeutic pharmacodynamic impact of coinfection is limited. Here, we use single-round infectious HIV-1 pseudotyped viral particles expressing green fluorescent protein alongside M. tuberculosis expressing mCherry to study pathogenesis and treatment. We report that HIV-1 infection inhibited intracellular replication of M. tuberculosis and demonstrate the therapeutic activity of antiviral treatment (efavirenz) and antimicrobial treatment (rifampicin). The described method could be applied for detailed mechanistic studies to inform the development of novel treatment strategies.

    Topics: Coinfection; HIV Infections; HIV-1; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2023
Detection of Mycobacterium tuberculosis Complex Using the Xpert MTB/RIF Ultra Assay on the Stool of Pediatric Patients in Dushanbe, Tajikistan.
    Microbiology spectrum, 2023, 02-14, Volume: 11, Issue:1

    We report the findings of a prospective laboratory diagnostic accuracy study to evaluate the sensitivity, specificity, and predictive values of the Xpert MTB/RIF Ultra assay for Mycobacterium tuberculosis detection in fresh stool specimens from children under 15 years of age with confirmed tuberculosis (TB) disease from Dushanbe, Tajikistan. Six hundred eighty-eight (688) participants were enrolled from April 2019 to October 2021. We identified 16 participants (2.3%) with confirmed TB disease, defined as ≥1 TB sign/symptom plus microbiologic confirmation. With the Xpert MTB/RIF Ultra assay for stool, we found a sensitivity of 68.8% (95% CI, 46.0 to 91.5) and a specificity of 98.7% (95% CI, 97.8 to 99.5) in confirmed TB disease. Our results are comparable to other published studies; however, our cohort was larger and our confirmed TB disease rate lower than most. We also demonstrated that this assay was feasible to implement in a centralized hospital laboratory in a low-middle-income Central Asian country. However, we encountered obstacles such as lack of staffing, material ruptures, outdated government protocols, and decreased case presentation due to COVID-19. We found eight patients whose only positive test was an Xpert Ultra stool assay. None needed treatment during the study; however, three were treated later, suggesting such cases require close observation. Our report is the first from Central Asia and one of a few from a low-middle-income country. We believe our study demonstrates the generalizability of the Xpert MTB/RIF Ultra assay on fresh stool specimens from children and provides further evidence supporting WHO's approval of this diagnostic strategy.

    Topics: Antibiotics, Antitubercular; Child; COVID-19; Humans; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tajikistan; Tuberculosis; Tuberculosis, Pulmonary

2023
Large-scale genomic analysis of Mycobacterium tuberculosis reveals extent of target and compensatory mutations linked to multi-drug resistant tuberculosis.
    Scientific reports, 2023, 01-12, Volume: 13, Issue:1

    Resistance to isoniazid (INH) and rifampicin (RIF) first-line drugs in Mycobacterium tuberculosis (Mtb), together called multi-drug resistance, threatens tuberculosis control. Resistance mutations in katG (for INH) and rpoB (RIF) genes often come with fitness costs. To overcome these costs, Mtb compensatory mutations have arisen in rpoC/rpoA (RIF) and ahpC (INH) loci. By leveraging the presence of known compensatory mutations, we aimed to detect novel resistance mutations occurring in INH and RIF target genes. Across ~ 32 k Mtb isolates with whole genome sequencing (WGS) data, there were 6262 (35.7%) with INH and 5435 (30.7%) with RIF phenotypic resistance. Known mutations in katG and rpoB explained ~ 99% of resistance. However, 188 (0.6%) isolates had ahpC compensatory mutations with no known resistance mutations in katG, leading to the identification of 31 putative resistance mutations in katG, each observed in at least 3 isolates. These putative katG mutations can co-occur with other INH variants (e.g., katG-Ser315Thr, fabG1 mutations). For RIF, there were no isolates with rpoC/rpoA compensatory mutations and unknown resistance mutations. Overall, using WGS data we identified putative resistance markers for INH that could be used for genotypic drug-resistance profiling. Establishing the complete repertoire of Mtb resistance mutations will assist the clinical management of tuberculosis.

    Topics: Antitubercular Agents; Bacterial Proteins; Genomics; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Navigating a Path to Rifampicin Resistance in Tuberculosis.
    mBio, 2023, 02-28, Volume: 14, Issue:1

    For model bacteria, genetic drug resistance usually arises from antibiotic-tolerant subpopulations, but whether this is true for the globally important pathogen Mycobacterium tuberculosis-the cause of tuberculosis-is not known. Here, we discuss a recent article by Sebastian et al. (J. Sebastian, A. Thomas, C. Levine, R. Shrestha, et al., mBio 14:e0279522, 2023, 10.1128/mbio.02795-22) which leverages a robotic transwell microtiter experimental system coupled with deep sequencing of a barcoded library of M. tuberculosis to answer this question for rifampicin resistance. The authors investigate two distinct forms of antibiotic-tolerant subpopulations-classical tolerance, characterized by prolonged minimum duration of killing, and "differentially detectable" (DD) bacilli that are viable but can be recovered only in liquid medium as opposed to plating. They demonstrate that, indeed, resistance arises preferentially from both rifampicin-tolerant subpopulations, though earlier in the DD population. Use of barcoded libraries and parallel culture systems shows promise in investigating phenotypes mediated by minority subpopulations of bacteria such as development of antibiotic resistance.

    Topics: Anti-Bacterial Agents; Antitubercular Agents; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2023
Biocompatible and biodegradable copper-protocatechuic metal-organic frameworks as rifampicin carrier.
    Biomaterials advances, 2023, Volume: 146

    Topics: Animals; Antitubercular Agents; Copper; Drug Carriers; Metal-Organic Frameworks; Mice; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2023
The clinician, the lab and the patient: Understanding lab diagnostics to eradicate tuberculosis.
    The Indian journal of tuberculosis, 2023, Volume: 70, Issue:1

    Diagnostic modalities for diagnosing Tuberculosis caused by Mycobacterium group of organisms include mainly AFB smear by Ziehl Neelsen carbol fuchsin smear microscopy, GeneXpert (CB NAAT) molecular method, Line probe assay (Molecular method) and AFB culture (Liquid automated systems and solid media) methods.. This study was initiated to understand and prioritize TB lab diagnosis, with reference to selection of lab diagnostic tests and its order of preference for MTC and NTM/MOTT closely associating it with the TB irradication program initiated by the Government of India.. The results and discussion bring to light the importance of each test and the purpose of their requisition. When diagnosis is handled half heartedly eradication of TB becomes a challenge. All the efforts including planning, resources in the form of manpower, infrastructure, finances, education, time etc., would be hampered. This challenge is not only for India but the globe. For countries harboring TB, Correct diagnostic request and timely diagnosis and treatment is the key to eradication of tuberculosis.

    Topics: Humans; Microscopy; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2023
A host blood transcriptional signature differentiates multi-drug/rifampin-resistant tuberculosis (MDR/RR-TB) from drug susceptible tuberculosis: a pilot study.
    Molecular biology reports, 2023, Volume: 50, Issue:4

    Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis is one of the top thirteen causes of death worldwide. The major challenge to control TB is the emergence of drug-resistant tuberculosis (DR-TB); specifically, multi-drug resistant TB which are resistant to the most potent drugs; rifampin and isoniazid. Owing to the inconsistencies of the current diagnostic methods, a single test cannot identify the whole spectrum of DR-TB associated mutations. Recently, host blood transcriptomics has gained attention as a promising technique that develops disease-specific RNA signatures/biomarkers. However, studies on host transcriptomics infected with DR-TB is limited. Herein, we intended to identify genes/pathways that are differentially expressed in multi-drug/rifampin resistant TB (MDR/RR-TB) in contrast to drug susceptible TB.. We conducted blood RNA sequencing of 10 pulmonary TB patients (4; drug susceptible and 6; DR-TB) and 55 genes that were differentially expressed in MDR/RR-TB from drug-susceptible/mono-resistant TB were identified. CD300LD, MYL9, VAMP5, CARD17, CLEC2B, GBP6, BATF2, ETV7, IFI27 and FCGR1CP were found to be upregulated in MDR/RR-TB in all comparisons, among which CLEC2B and CD300LD were not previously linked to TB. In comparison pathway analysis, interferon alpha/gamma response was upregulated while Wnt/beta catenin signaling, lysosome, microtubule nucleation and notch signaling were downregulated.. Up/down-regulation of immunity related genes/pathways speculate the collective effect of hosts' attempt to fight against continuously multiplying DR-TB bacteria and the bacterial factors to fight against the host defense. The identified genes/pathways could act as MDR/RR-TB biomarkers, hence, further research on their clinical use should be encouraged.

    Topics: Antitubercular Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pilot Projects; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
The human proton pump inhibitors inhibit
    Proceedings of the National Academy of Sciences of the United States of America, 2023, 02-14, Volume: 120, Issue:7

    Tuberculosis treatment requires months-long combination chemotherapy with multiple drugs, with shorter treatments leading to relapses. A major impediment to shortening treatment is that

    Topics: Antitubercular Agents; Bacterial Proteins; Drug Tolerance; Humans; Macrophages; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Proton Pump Inhibitors; Rifampin; Tuberculosis; Verapamil

2023
Genomic Sequencing from Sputum for Tuberculosis Disease Diagnosis, Lineage Determination, and Drug Susceptibility Prediction.
    Journal of clinical microbiology, 2023, 03-23, Volume: 61, Issue:3

    Topics: Antitubercular Agents; Genomics; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Development of population pharmacokinetics model and Bayesian estimation of rifampicin exposure in Indonesian patients with tuberculosis.
    Tuberculosis (Edinburgh, Scotland), 2023, Volume: 139

    Interindividual variability in the pharmacokinetics (PK) of anti-tuberculosis (TB) drugs is the leading cause of treatment failure. Herein, we evaluated the influence of demographic, clinical, and genetic factors that cause variability in RIF PK parameters in Indonesian TB patients.. In total, 210 Indonesian patients with TB (300 plasma samples) were enrolled in this study. Clinical data, solute carrier organic anion transporter family member-1B1 (SLCO1B1) haplotypes *1a, *1b, and *15, and RIF concentrations were analyzed. The population PK model was developed using a non-linear mixed effect method.. A one-compartment model with allometric scaling adequately described the PK of RIF. Age and SLCO1B1 haplotype *15 were significantly associated with variability in apparent clearance (CL/F). For patients in their 40s, each 10-year increase in age was associated with a 10% decrease in CL/F (7.85 L/h). Patients with the SLCO1B1 haplotype *15 had a 24% lower CL/F compared to those with the wild-type. Visual predictive checks and non-parametric bootstrap analysis indicated good model performance.. Age and SLCO1B1 haplotype *15 were significant covariates of RIF CL/F. Geriatric patients with haplotype *15 had significantly greater exposure to RIF. The model could optimize TB pharmacotherapy through its application in therapeutic drug monitoring (clinical trial no. NCT05280886).

    Topics: Aged; Antitubercular Agents; Bayes Theorem; Humans; Indonesia; Liver-Specific Organic Anion Transporter 1; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2023
The Dysbiosis Triggered by First-Line Tuberculosis Antibiotics Fails to Reduce Their Bioavailability.
    mBio, 2023, 04-25, Volume: 14, Issue:2

    Antituberculosis therapy (ATT) causes a rapid and distinct alteration in the composition of the intestinal microbiota that is long lasting in both mice and humans. This observation raised the question of whether such antibiotic-induced changes in the microbiome might affect the absorption or gut metabolism of the tuberculosis (TB) drugs themselves. To address this issue, we utilized a murine model of antibiotic-induced dysbiosis to assay the bioavailability of rifampicin, moxifloxacin, pyrazinamide, and isoniazid in mouse plasma over a period of 12 h following individual oral administration. We found that 4-week pretreatment with a regimen of isoniazid, rifampicin, and pyrazinamide (HRZ), a drug combination used clinically for ATT, failed to reduce the exposure of any of the four antibiotics assayed. Nevertheless, mice that received a pretreatment cocktail of the broad-spectrum antibiotics vancomycin, ampicllin, neomycin, and metronidazole (VANM), which are known to deplete the intestinal microbiota, displayed a significant decrease in the plasma concentration of rifampicin and moxifloxacin during the assay period, an observation that was validated in germfree animals. In contrast, no major effects were observed when similarly pretreated mice were exposed to pyrazinamide or isoniazid. Thus, the data from this animal model study indicate that the dysbiosis induced by HRZ does not reduce the bioavailability of the drugs themselves. Nevertheless, our observations suggest that more extreme alterations of the microbiota, such as those occurring in patients on broad-spectrum antibiotics, could directly or indirectly affect the exposure of important TB drugs and thereby potentially influencing treatment outcome.

    Topics: Animals; Antitubercular Agents; Biological Availability; Dysbiosis; Humans; Isoniazid; Mice; Moxifloxacin; Pyrazinamide; Rifampin; Tuberculosis

2023
Factors associated with prevalent Mycobacterium tuberculosis infection and disease among adolescents and adults exposed to rifampin-resistant tuberculosis in the household.
    PloS one, 2023, Volume: 18, Issue:3

    Understanding factors associated with prevalent Mycobacterium tuberculosis infection and prevalent TB disease in household contacts of patients with drug-resistant tuberculosis (TB) may be useful for TB program staff conducting contact investigations.. Using data from a cross-sectional study that enrolled index participants with rifampin-resistant pulmonary TB and their household contacts (HHCs), we evaluated HHCs age ≥15 years for factors associated with two outcomes: Mycobacterium tuberculosis infection and TB disease. Among HHCs who were not already diagnosed with current active TB disease by the TB program, Mycobacterium tuberculosis infection was determined by interferon-gamma release assay (IGRA). TB disease was adjudicated centrally. We fitted logistic regression models using generalized estimating equations.. Seven hundred twelve HHCs age ≥15 years enrolled from 279 households in eight high-TB burden countries were a median age of 34 years, 63% female, 22% current smokers and 8% previous smokers, 8% HIV-positive, and 11% previously treated for TB. Of 686 with determinate IGRA results, 471 tested IGRA positive (prevalence 68.8% (95% Confidence Interval: 64.6%, 72.8%)). Multivariable modeling showed IGRA positivity was more common in HHCs aged 25-49 years; reporting prior TB treatment; reporting incarceration, substance use, and/or a period of daily alcohol use in the past 12 months; sharing a sleeping room or more evenings spent with the index participant; living with smokers; or living in a home of materials typical of low socioeconomic status. Forty-six (6.5% (95% Confidence Interval: 4.6%, 9.0%)) HHCs age ≥15 years had prevalent TB disease. Multivariable modeling showed higher prevalence of TB disease among HHCs aged ≥50 years; reporting current or previous smoking; reporting a period of daily alcohol use in the past 12 months; and reporting prior TB treatment.. We identified overlapping and distinct characteristics associated with Mycobacterium tuberculosis infection and TB disease that may be useful for those conducting household TB investigations.

    Topics: Adolescent; Adult; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; Humans; Male; Mycobacterium tuberculosis; Rifampin; Risk Factors; Tuberculin Test; Tuberculosis; Tuberculosis, Pulmonary

2023
[Progress in research of prophylactic therapy in contacts of rifampicin-resistant tuberculosis patients].
    Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi, 2023, Mar-10, Volume: 44, Issue:3

    Tuberculosis (TB) prophylactic therapy for latent infection, which can reduce the risk for the development of active TB, is an important measure in TB control. China recommends prophylactic therapy for latent tuberculosis infection (LTBI) in some key populations to reduce the risk for TB. Contacts of patients with multi-drug and rifampicin-resistant TB (MDR/RR-TB) are at high risk for the infection with drug-resistant pathogen, however, no unified prophylactic therapy regimen has been recommended for LTBI due to exposure to MDR/RR-TB patients. This paper summarizes the current MDR/RR-TB prophylactic therapy regimen and its protection effect based on the results of the retrieval of literature, guidelines, expert consensus and technical specifications to provide reference for the prevention and control of LTBI.. 对结核潜伏感染者开展预防性治疗可减少感染人群发生结核病的机会,是控制结核病的一项重要措施。我国推荐对部分重点人群的结核潜伏感染者开展预防性治疗,从而减少结核病发病的风险。耐多药/利福平耐药结核病患者接触者感染耐药病原体的风险高,但是目前对于接触耐多药/利福平耐药结核病患者的感染者还没有推荐的预防性治疗方案,本文检索文献、指南、专家共识和技术规范,对目前耐多药/利福平耐药结核病患者接触者预防性治疗方案和保护效果进行综述,为结核潜伏感染防控提供参考依据。.

    Topics: Antitubercular Agents; China; Humans; Latent Tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Detection of antigen Ag85B expression is useful for the diagnosis of tuberculosis, especially for those with an antituberculosis treatment history.
    American journal of clinical pathology, 2023, 07-05, Volume: 160, Issue:1

    The present study used immunohistochemistry (IHC) to detect antigen Ag85B in tissue sections and aimed to evaluate its validity in histopathologic diagnosis of tuberculosis (TB).. In total, 204 patients with confirmed TB and 40 other diseases were included in the present study. Ziehl-Neelsen (Z-N) stains, IHC (anti-Ag85B), and quantitative fluorescence polymerase chain reaction were used to detect acid-fast bacilli, Mycobacterium tuberculosis (MTB) antigen, and MTB DNA.. Immunohistochemistry was significantly more sensitive than Z-N stains (93.1% vs 67.2%; P < .001). The sensitivity of Z-N stains significantly correlated with anti-TB treatment history. The sensitivity of Z-N stains was lower in rifampicin (RIF)-resistant TB compared with RIF-sensitive TB (52.8% vs 69.0%; P = .091) and those without treatment history (52.8% vs 84.0%; P = .015). However, IHC was not significantly affected by treatment history (P = .410). Moreover, expression patterns of Ag85B were dependent on treatment history and commonly showed weak scattered spots in RIF-susceptible TB. Conversely, strong brown rods were often found in those with RIF-resistant TB.. Immunohistochemistry is a simple, sensitive technique for the diagnosis of TB, especially for those patients with treatment history. The expression pattern of Ag85B is a potential marker for evaluating anti-TB treatment response.

    Topics: Antitubercular Agents; Coloring Agents; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2023
Oral anticoagulants and concurrent rifampin administration in tuberculosis patients with non-valvular atrial fibrillation.
    BMC cardiovascular disorders, 2023, 04-04, Volume: 23, Issue:1

    Evidence and guidelines for Non-vitamin K antagonist oral anticoagulants (NOACs) use when prescribing concurrent rifampin for tuberculosis treatment in patients with non-valvular atrial fibrillation (NVAF) are limited.. Using the Korean National Health Insurance Service database from January 2009 to December 2018, we performed a population-based retrospective cohort study to assess the net adverse clinical events (NACE), a composite of ischemic stroke or systemic embolism and major bleeding, of NOACs compared with warfarin among NVAF patients taking concurrent rifampin administration for tuberculosis treatment. After a propensity matching score (PSM) analysis, Cox proportional hazards regression was performed in matched cohorts to investigate the clinical outcomes.. Of the 735 consecutive patients selected, 465 (63.3%) received warfarin and 270 (36.7%) received NOACs. Among 254 pairs of patients after PSM, the crude incidence rate of NACE was 25.6 in NOAC group and 32.8 per 100 person-years in warfarin group. There was no significant difference between NOAC and warfarin use in NACE (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.48-1.14; P = 0.172). Major bleeding was the main driver of NACE, and NOAC use was associated with a statistically significantly lower risk of major bleeding than that with warfarin use (HR, 0.63; 95% CI, 0.40-1.00; P = 0.0499).. In our population-based study, there was no statically significant difference in the occurrence of NACE between NOAC and warfarin use. NOAC use may be associated with a lower risk of major bleeding than that with warfarin use.

    Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Retrospective Studies; Rifampin; Rivaroxaban; Stroke; Tuberculosis; Warfarin

2023
Cubosome Lipid Nanocarriers As a Drug Delivery Vehicle for Intracellular
    ACS applied materials & interfaces, 2023, May-10, Volume: 15, Issue:18

    Topics: Antitubercular Agents; Humans; Lipids; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2023
Laryngeal tuberculosis in patients treated with adalimumab: a casual or causal connection?
    BMJ case reports, 2023, Apr-11, Volume: 16, Issue:4

    This article presents two consecutive cases of laryngeal tuberculosis in patients treated with a specific anti-tumour necrosis factor-alpha (adalimumab), with a focus on their diagnostic process and therapeutic management. Both patients presented with aspecific chronic laryngeal symptoms that had been worsening for a few months in one case and for almost 1 year in the other one. They were both studied with fibreoptic laryngoscopy and contrast-enhanced CT and MRI scans. In both cases, the laryngeal biopsy proved negative to Ziehl-Neelsen test, while positive to Koch's bacillus sensitive to rifampicin at PCR test. Both patients completely responded to standard antitubercular antibiotic therapy with rifampicin, isoniazid, pyrazinamide and etambutol protocol.In the differential diagnosis of such patients, laryngeal tuberculosis should be considered due to the reasonable linkage between the immunosuppressant therapy with adalimumab and the tuberculosis infection/reactivation.

    Topics: Adalimumab; Antitubercular Agents; Humans; Rifampin; Tuberculosis; Tuberculosis, Laryngeal

2023
Variation in Treatment of Pediatric Tuberculosis Infection in Different Provider Settings.
    The Journal of pediatrics, 2023, Volume: 259

    To evaluate implementation of rifamycin-based regimens (RBR) for pediatric tuberculosis infection (TBI) treatment among 3 provider settings in a high-incidence county.. A multicenter, retrospective observational study was performed across 3 sites in Los Angeles County: an academic center (AC), a general pediatrics federally qualified health center (FQHC), and department of public health (DPH) tuberculosis clinics. Patients initiated on TBI treatment age 1 months to 17 years between 2018 and 2020 were included. RBRs were defined as regimens: 3 months of weekly rifapentine and isoniazid, 4 months of daily rifampin, and 3 months of daily isoniazid and rifampin.. We included 424 patients: 51 from AC, 327 from DPH, and 46 from FQHC. RBR use nearly doubled during the study period (from 43% in 2018 to 82% in 2020; P < .001). FQHC had the shortest time to chest radiograph and treatment initiation; however, AC and DPH were 4 times as likely to prescribe an RBR compared to FQHC (95% CI, 2.1-7.8). AC and DPH had similar completion rates (74%) and were 2.6 times as likely to complete treatment compared to FQHC (95% CI, 1.4-4.9).. The use of RBRs for pediatric TBI varies significantly by clinical setting but is improving over time. Strategies are needed to improve RBR uptake, standardize care, and increase treatment completion, particularly among general pediatricians.

    Topics: Antitubercular Agents; Child; Drug Therapy, Combination; Humans; Infant; Isoniazid; Latent Tuberculosis; Pediatrics; Rifampin; Tuberculosis

2023
High rifampicin peak plasma concentrations accelerate the slow phase of bacterial decline in tuberculosis patients: Evidence for heteroresistance.
    PLoS computational biology, 2023, Volume: 19, Issue:4

    Antibiotic treatments are often associated with a late slowdown in bacterial killing. This separates the killing of bacteria into at least two distinct phases: a quick phase followed by a slower phase, the latter of which is linked to treatment success. Current mechanistic explanations for the in vitro slowdown are either antibiotic persistence or heteroresistance. Persistence is defined as the switching back and forth between susceptible and non-susceptible states, while heteroresistance is defined as the coexistence of bacteria with heterogeneous susceptibilities. Both are also thought to cause a slowdown in the decline of bacterial populations in patients and therefore complicate and prolong antibiotic treatments. Reduced bacterial death rates over time are also observed within tuberculosis patients, yet the mechanistic reasons for this are unknown and therefore the strategies to mitigate them are also unknown.. We analyse a dose ranging trial for rifampicin in tuberculosis patients and show that there is a slowdown in the decline of bacteria. We show that the late phase of bacterial killing depends more on the peak drug concentrations than the total drug exposure. We compare these to pharmacokinetic-pharmacodynamic models of rifampicin heteroresistance and persistence. We find that the observation on the slow phase's dependence on pharmacokinetic measures, specifically peak concentrations are only compatible with models of heteroresistance and incompatible with models of persistence. The quantitative agreement between heteroresistance models and observations is very good ([Formula: see text]). To corroborate the importance of the slowdown, we validate our results by estimating the time to sputum culture conversion and compare the results to a different dose ranging trial.. Our findings indicate that higher doses, specifically higher peak concentrations may be used to optimize rifampicin treatments by accelerating bacterial killing in the slow phase. It adds to the growing body of literature supporting higher rifampicin doses for shortening tuberculosis treatments.

    Topics: Anti-Bacterial Agents; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2023
[Investigation of Efflux Pump Genes in Resistant Mycobacterium tuberculosis Complex Clinical Isolates Exposed to First Line Antituberculosis Drugs and Verapamil Combination].
    Mikrobiyoloji bulteni, 2023, Volume: 57, Issue:2

    Tuberculosis (TB) is caused by Mycobacterium tuberculosis, still one of the most common life-threatening infectious diseases worldwide. Although drug resistance in M.tuberculosis is mainly due to spontaneous chromosomal mutations in genes encoding drug target or drug activating enzymes, the resistance cannot be explained only by these mutations. Low permeability of the cell wall, drug inactivating enzymes and especially efflux pumps (EPs) are other mechanisms of drug resistance in mycobacteria. Efflux pump inhibitors (EPIs) binding to M.tuberculosis EPs were shown to inhibit efflux of anti-TB drugs, to enhance M.tuberculosis killing, to reduce drug resistance and to produce synergistic effects with first line anti-TB drugs. In this study, we aimed to determine the minimum inhibitory concentration (MIC) of first-line anti-TB drugs in the presence of verapamil (VER) and the expression of 21 putative EP genes belonged to the ATP-binding cassette (ABC), major facilitator superfamily (MFS) and resistance-nodulation-division (RND) families which might have caused the resistance in nine M.tuberculosis complex clinical isolates resistant to all of the first line anti-TB drugs. MIC values of the isolates were determined in 96-well U-bottom plates by the resazurin microtiter test (REMA) method based on the color change principle. According to the determined MIC values of each isolate, freshly grown cultures in Middlebrook 7H9 broth were exposed to first-line anti-TB drugs and MIC of first-line anti-TB drugs in the presence of VER (½ MIC) at 37°C for 48 hours for RNA extraction. The non-drug exposed cultures were used as control. Total RNA was extracted using the RNeasy Mini Kit (Qiagen GmbH, Hilden, Germany) and then treated with DNase I (Thermo Fischer Scientific Inc., Waltham, MA). Complementary DNA (cDNA) from the extracted RNAs was synthesized with the "First strand cDNA synthesis kit" (Thermo Fischer Scientific Inc., Waltham, MA) using oligo primers. The expression levels of efflux pump genes by quantitative realtime polymerase chain reaction (qRt-PCR) were performed using the QuantiTect SYBR Green Rt-PCR Kit (Qiagen, Germany). The housekeeping sigma factor gene sigA (Rv2703) was used as internal control in qRt‑PCR assays. Relative quantification of the clinical isolates was determined by the 2-∆∆Ct method by comparing the expression levels of efflux genes in cultures exposed to primary anti-TB drugs and VER with those of non-drug exposed cultures. MIC values

    Topics: Antitubercular Agents; Bacterial Proteins; DNA, Complementary; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Verapamil

2023
Undiagnosed and missed active pulmonary tuberculosis during mass gatherings: a prospective cross-sectional study from the Hajj pilgrimage.
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2023, Volume: 42, Issue:6

    Mass gatherings increase the risk of infectious diseases transmission including tuberculosis (TB). The Hajj pilgrimage to Mecca, Saudi Arabia, is attended by over 2 million pilgrims many of whom are from high TB-burden countries, and has been linked to increased risk of TB acquisition among travellers. We investigated the burden of undiagnosed and missed active pulmonary TB (PTB) among Hajj pilgrims symptomatic for cough. The study was conducted among hospitalised and non-hospitalised travellers attending the Hajj pilgrimage in 2016 and 2017. Questionnaires were used to collect relevant data and sputum samples were collected from participants and processed using the Xpert MTB-RIF assay. Non-hospitalised pilgrims (n = 1510) originating from 16 high and medium TB-burden countries were enrolled. Undiagnosed, rifampicin-sensitive, active PTB was identified in 0.7%. Comorbidities (adjOR = 5.9 [95% CI = 1.2-27.8]), close contact with a TB case (adjOR = 5.9 [95% CI = 1.2-27.8]), cough in household (adjOR = 4.46 [95% CI = 1.1-19.5]), and previous TB treatment (adjOR = 10.1 [95% CI = 4.1-98.1]) were independent risk factors for TB. Of the hospitalised pilgrims (n = 304), 2.9% were positive for PTB, and 2.3% were missed, including a rifampicin-resistant case. History of TB treatment was associated with increased risk of TB (adjOR = 8.1 [95% CI = 1.3-48.7]). International mass gatherings may play an important role in the global epidemiology of TB. Preventive measures should be directed to reducing the risk of TB importation and transmission during Hajj and other similar events.

    Topics: Cough; Cross-Sectional Studies; Humans; Mass Gatherings; Prospective Studies; Rifampin; Saudi Arabia; Travel; Tuberculosis; Tuberculosis, Pulmonary

2023
Comparison of conventional diagnostic methods with molecular method for the diagnosis of pulmonary tuberculosis.
    The Indian journal of tuberculosis, 2023, Volume: 70, Issue:2

    Tuberculosis remains one of the deadliest communicable diseases. Prompt diagnosis of active tuberculosis cases facilitates timely therapeutic intervention and minimizes the community transmission. Although conventional microscopy has low sensitivity, still it remains the corner stone for the diagnosis of pulmonary tuberculosis in high burden countries like India. On the other hand, Nucleic acid amplification techniques due to their rapidity and sensitivity, not only help in early diagnosis and management of tuberculosis but also curtail the transmission of the disease. This study therefore was aimed at assessing the diagnostic performance of Microscopy by Ziehl Neelsen (ZN) and Auramine Staining (AO) with Gene Xpert/CBNAAT (Cartridge based nucleic acid amplification test) in the diagnosis of Pulmonary Tuberculosis.. A prospective comparative study was done on the sputum samples of 1583 adult patients from November 2018 to May 2020 suspected of having pulmonary tuberculosis as per NTEP criteria visiting the Designated Microscopic Centre of SGT Medical College, Budhera, Gurugram. Each sample was subjected to ZN staining, AO staining, and was run on CBNAAT as per National Tuberculosis Elimination Program (NTEP) guidelines. The sensitivity, specificity, PPV and NPV and Area under the curve of ZN microscopy and Fluorescent Microscopy were calculated taking CBNAAT as reference in absence of culture.. Out of the 1583 samples studied, 145 (9.15%) and 197 (12.44%) were positive by ZN and AO staining methods respectively. By CBNAAT 246 (15.54%) samples were positive for M. tuberculosis. AO was also able to detect more pauci-bacillary cases than ZN. While CBNAAT detected M. tuberculosis in 49 sputum samples which were missed by both methods of microscopy. On the other hand there were 9 samples which were positive for AFB by both the smear microscopy techniques but M. tuberculosis was not detected by CBNAAT, these were considered as Non-Tuberculous Mycobacteria. Seventeen samples were resistant to rifampicin.. Auramine Staining technique is more sensitive and less time consuming for the diagnosis of pulmonary tuberculosis as compared to the conventional ZN Staining. CBNAAT can be a useful tool for early diagnosis of patients with high clinical suspicion of pulmonary tuberculosis and detecting rifampicin resistance.

    Topics: Adult; Benzophenoneidum; Coloring Agents; Humans; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2023
Factors associated with adverse drug reactions or death in very elderly hospitalized patients with pulmonary tuberculosis.
    Scientific reports, 2023, 04-26, Volume: 13, Issue:1

    The aging of patients with tuberculosis and better therapeutic management for them are recent concerns. This study aimed to identify risk factors for adverse drug reactions (ADRs) or death in very elderly patients with pulmonary tuberculosis and to assess the association between the dosage of antituberculosis drugs and outcomes. We conducted a multicenter retrospective study at two hospitals. Hospitalized patients (≥ 80 years old) with pulmonary tuberculosis who were treated with antituberculosis drugs were enrolled. Multivariate analysis was performed to assess factors associated with ADRs or death within 60 days after treatment initiation. In total, 632 patients were included. The primary endpoint occurred in 268 patients (190 ADRs and 78 deaths). A serum albumin level < 2.5 g/dL, respiratory failure, and dependent activities of daily living were independent risk factors for ADRs or death. However, a low dosage (< 8 mg/kg/day) of rifampicin was associated with a lower risk of the primary outcomes. Delayed time to negative sputum culture conversion was not observed in the lower dosage of rifampicin group. Very elderly hospitalized tuberculosis patients with the aforementioned risk factors should be carefully monitored to receive safer treatment. Rifampicin dosage reduction may be considered for very elderly tuberculosis patients to prevent ADRs/death.

    Topics: Activities of Daily Living; Aged; Aged, 80 and over; Antitubercular Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2023
Molecular Epidemiology of Rifampicin-Resistant Mycobacterium tuberculosis by GeneXpert MTB/RIF Assay in Renal Transplant Recipients: A Single-Center Experience.
    Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation, 2023, Volume: 21, Issue:4

    There are scarce data on the incidence and resistance pattern of rifampicin-resistant Mycobacterium tuberculosis among kidney transplant recipients.. This is a retrospective, single- center study of kidney transplantrecipients suspected of M. tuberculosis infection. The GeneXpert assay we used detected mutations in the rpoB gene that confer rifampicin resistance using 5 overlapping probes (A, B, C, D, and E). The probes can detect mutations in the codons 507 to 511 (probe A), 511 to 518 (probe B), 518 to 523 (probe C), 523 to 529 (probe D), and 529 to 533 (probe E).We also detailed the treatment protocol and outcomes of kidney transplantrecipients infected with rifampicin-resistant M. tuberculosis.. In total, 2700 samples were processed during the period from October 2018 to February 2022 with successful results in 2640 samples (97.04%). One hundred and ninety (7.19%) samples were positive for M.tuberculosis, and rifampicin resistance was detected in 12 (0.45%) cases (11 pulmonary, 1 genitourinary). The most common rpoB mutation was located in the region of probe E (75.0%), followed by probe A (16.6%) and in 1 combination probe DE (8.33%). The rpoB mutations were not observed in probe B and probe C. Six patients received bedaquiline-based treatmentfor a short course of 11 months, whereas the other 6 patients required a long course of 18 to 20 months. Three patients died, 2 were lost to follow-up, and 7 were cured. During treatment, 4 patients experienced acute rejection, and 1 graft loss was reported.. We report for the first time the incidence and pattern of rifampicin resistance among kidney transplant recipients with tuberculosis infection. Further investigations are required for exploring the molecular and clinical phenotypes.

    Topics: Drug Resistance, Bacterial; Humans; Kidney; Kidney Transplantation; Molecular Epidemiology; Mutation; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Ability of the MeltPro MTB/PZA Assay to Detect Susceptibility to Pyrazinamide in Rifampin-Resistant Tuberculosis Patients.
    Microbiology spectrum, 2023, 06-15, Volume: 11, Issue:3

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Rifampin urinary excretion to predict serum targets in children with tuberculosis: a prospective diagnostic accuracy study.
    Archives of disease in childhood, 2023, Volume: 108, Issue:8

    Pharmacokinetic variability drives tuberculosis (TB) treatment outcomes but measurement of serum drug concentrations for personalised dosing is inaccessible for children in TB-endemic settings. We compared rifampin urine excretion for prediction of a serum target associated with treatment outcome.. Prospective diagnostic accuracy study.. Inpatient wards and outpatient clinics, northern Tanzania.. Children aged 4-17 years were consecutively recruited on initiation of WHO-approved treatment regimens.. Samples were collected after directly observed therapy at least 2 weeks after initiation in the intensive phase: serum at pre-dose and 1, 2 and 6 hours post-dose, later analysed by liquid chromatography-tandem mass spectrometry for calculation of rifampin total exposure or area under the concentration time curve (AUC. Urine spectrophotometry correlated with a clinically relevant serum target for rifampin, representing a step toward personalised dosing for children in TB-endemic settings.

    Topics: Antitubercular Agents; Child; Female; Humans; Male; Prospective Studies; Rifampin; Treatment Outcome; Tuberculosis

2023
Effects of second-line anti-tuberculosis drugs on the intestinal microbiota of patients with rifampicin-resistant tuberculosis.
    Frontiers in cellular and infection microbiology, 2023, Volume: 13

    To determine the effects of second-line anti-tuberculosis (TB) drugs on the composition and functions of intestinal microbiota in patients with rifampicin-resistant TB (RR-TB).. In this cross-sectional study, stool samples and relevant clinical information were collected from patients with RR-TB admitted to the Drug-resistant Specialty Department at Hunan Chest Hospital (Hunan Institute For Tuberculosis Control). The composition and functions of intestinal microbiota were analyzed using metagenomic sequencing and bioinformatics methods.. Altered structural composition of the intestinal microbiota was found when patients from the control, intensive phase treatment, and continuation phase treatment groups were compared (P<0.05). Second-line anti-TB treatment resulted in a decrease in the relative abundance of species, such as. Second-line anti-TB drug treatment caused changes in the structural composition of the intestinal microbiota in patients with RR-TB. In particular, this treatment induced a significant increase in the relative abundance of 11 conditionally pathogenic species, including

    Topics: Antitubercular Agents; Cross-Sectional Studies; Gastrointestinal Microbiome; Humans; Mycobacterium tuberculosis; Rifampin; Tryptophan; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Pooling sputum testing to diagnose tuberculosis using xpert MTB/RIF and xpert ultra: a cost-effectiveness analysis.
    BMC infectious diseases, 2023, May-22, Volume: 23, Issue:1

    The World Health Organization (WHO) recommends the diagnosis of tuberculosis (TB) using molecular tests, such as Xpert MTB/RIF (MTB/RIF) or Xpert Ultra (Ultra). These tests are expensive and resource-consuming, and cost-effective approaches are needed for greater coverage.. We evaluated the cost-effectiveness of pooling sputum samples for TB testing by using a fixed amount of 1,000 MTB/RIF or Ultra cartridges. We used the number of people with TB detected as the indicator for cost-effectiveness. Cost-minimization analysis was conducted from the healthcare system perspective and included the costs to the healthcare system using pooled and individual testing.. There was no significant difference in the overall performance of the pooled testing using MTB/RIF or Ultra (sensitivity, 93.9% vs. 97.6%, specificity 98% vs. 97%, p-value > 0.1 for both). The mean unit cost across all studies to test one person was 34.10 international dollars for the individual testing and 21.95 international dollars for the pooled testing, resulting in a savings of 12.15 international dollars per test performed (35.6% decrease). The mean unit cost per bacteriologically confirmed TB case was 249.64 international dollars for the individual testing and 162.44 international dollars for the pooled testing (34.9% decrease). Cost-minimization analysis indicates savings are directly associated with the proportion of samples that are positive. If the TB prevalence is ≥ 30%, pooled testing is not cost-effective.. Pooled sputum testing can be a cost-effective strategy for diagnosis of TB, resulting in significant resource savings. This approach could increase testing capacity and affordability in resource-limited settings and support increased testing towards achievement of WHO End TB strategy.

    Topics: Antibiotics, Antitubercular; Cost-Effectiveness Analysis; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2023
1-Year Incidence of Tuberculosis Infection and Disease Among Household Contacts of Rifampin- and Multidrug-Resistant Tuberculosis.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023, 09-18, Volume: 77, Issue:6

    Tuberculosis infection (TBI) and TB disease (TBD) incidence remains poorly described following household contact (HHC) rifampin-/multidrug-resistant TB exposure. We sought to characterize TBI and TBD incidence at 1 year in HHCs and to evaluate TB preventive treatment (TPT) use in high-risk groups.. We previously conducted a cross-sectional study of HHCs with rifampin-/multidrug-resistant TB in 8 high-burden countries and reassessed TBI (interferon-gamma release assay, HHCs aged ≥5 years) and TBD (HHCs all ages) at 1 year. Incidence was estimated across age and risk groups (<5 years; ≥5 years, diagnosed with human immunodeficiency virus [HIV]; ≥5 years, not diagnosed with HIV/unknown, baseline TBI-positive) by logistic or log-binomial regression fitted using generalized estimating equations.. Of 1016 HHCs, 850 (83.7%) from 247 households were assessed (median, 51.4 weeks). Among 242 HHCs, 52 tested interferon-gamma release assay-positive, yielding a 1-year 21.6% (95% confidence interval [CI], 16.7-27.4) TBI cumulative incidence. Sixteen of 742 HHCs developed confirmed (n = 5), probable (n = 3), or possible (n = 8) TBD, yielding a 2.3% (95% CI, 1.4-3.8) 1-year cumulative incidence (1.1%; 95% CI, .5-2.2 for confirmed/probable TBD). TBD relative risk was 11.5-fold (95% CI, 1.7-78.7), 10.4-fold (95% CI, 2.4-45.6), and 2.9-fold (95% CI, .5-17.8) higher in age <5 years, diagnosed with HIV, and baseline TBI high-risk groups, respectively, vs the not high-risk group (P = .0015). By 1 year, 4% (21 of 553) of high-risk HHCs had received TPT.. TBI and TBD incidence continued through 1 year in rifampin-/multidrug-resistant TB HHCs. Low TPT coverage emphasizes the need for evidence-based prevention and scale-up, particularly among high-risk groups.

    Topics: Cross-Sectional Studies; HIV Infections; Humans; Incidence; Latent Tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Dolutegravir once daily with rifampicin for HIV and tuberculosis.
    The lancet. HIV, 2023, Volume: 10, Issue:7

    Topics: Anti-HIV Agents; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Oxazines; Rifampin; Tuberculosis

2023
Implementation of Bedaquiline, Pretomanid, and Linezolid in the United States: Experience Using a Novel All-Oral Treatment Regimen for Treatment of Rifampin-Resistant or Rifampin-Intolerant Tuberculosis Disease.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023, 10-05, Volume: 77, Issue:7

    Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring.. Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring.. Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months.. BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

    Topics: Antitubercular Agents; Diarylquinolines; Humans; Linezolid; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; United States

2023
Rapid Detection of Extensive Drug Resistance by Xpert MTB/XDR Optimizes Therapeutic Decision-Making in Rifampin-Resistant Tuberculosis Patients.
    Journal of clinical microbiology, 2023, 06-20, Volume: 61, Issue:6

    The Xpert MTB/XDR assay met the critical need for etiologic diagnosis of tuberculosis and rifampin resistance in previous studies. However, its benefits in tailoring the treatment regimen and improving the outcome for patients with rifampin-resistant tuberculosis (RR-TB) require further investigation. In this study, the Xpert MTB/XDR assay was used to determine the resistance profile of second-line drugs for RR-TB patients in two registered multicenter clinical trials, TB-TRUST (NCT03867136) and TB-TRUST-plus (NCT04717908), with the aim of testing the efficacy of all-oral shorter regimens in RR-TB patients in China. Patients would receive the fluoroquinolone-based all-oral shorter regimen, the injectable-containing regimen, or the bedaquiline-based regimen depending on fluoroquinolone susceptibility by using Xpert MTB/XDR. Among the 497 patients performed with Xpert MTB/XDR, 128 (25.8%) had infections resistant to fluoroquinolones and/or second-line injectable drugs (SLIDs). A total of 371 participants were recruited for the trials, and whole-genome sequencing (WGS) was performed on all corresponding culture-positive baseline strains. Taking the WGS results as the standard, the accuracy of the Xpert MTB/XDR assay in terms of resistance detection was 95.2% to 99.0% for all drugs. A total of 33 cases had inconsistent results, 9 of which were due to resistance heterogeneity. Most of the patients (241/281, 85.8%) had sputum culture conversion at 2 months. In conclusion, the Xpert MTB/XDR assay has the potential to serve as a quick reflex test in patients with RR-TB, as detected via Xpert MTB/RIF, to provide a reliable drug susceptibility profile of the infecting Mycobacterium tuberculosis strain and to initiate optimized treatment promptly.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Rifampicin-induced hypertensive urgency: eyes see what the mind knows.
    BMJ case reports, 2023, May-31, Volume: 16, Issue:5

    A man had poor control of hypertension throughout 9 months of antituberculosis treatment. He consulted multiple physicians, who kept increasing this blood pressure medicine. Despite that, it was not controlled and he visited emergency many times with hypertensive urgency. When admitted in our care, he was off antituberculosis treatment for 5 days and his blood pressure was back to normal. We attributed it secondary to rifamipicin-induced enzyme induction. Tuberculosis and hypertension both being very common diseases, we report this case to highlight lack of awareness about these important and easily preventable drug interactions.

    Topics: Antitubercular Agents; Blood Pressure; Humans; Hypertension; Hypertensive Encephalopathy; Male; Rifampin; Tuberculosis

2023
In TB, an 8-wk, 5-drug regimen was noninferior to a standard 24-wk, 4-drug regimen for clinical outcomes at 96 wk.
    Annals of internal medicine, 2023, Volume: 176, Issue:6

    Paton NI, Cousins C, Suresh C, et al; TRUNCATE-TB Trial Team.

    Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Rifampin; Tuberculosis

2023
Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis.
    Pharmacogenetics and genomics, 2023, 08-01, Volume: 33, Issue:6

    In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC 0-8h ). We characterized the pharmacogenetics of these interactions.. Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters.. Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC 0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC 0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC 0-8h values similar to controls, while NAT2 slow acetylators had AUC 0-8h values 36% higher than controls.. CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

    Topics: Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Contraception, Postcoital; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Female; Genotype; HIV Infections; Humans; Isoniazid; Levonorgestrel; Pharmacogenetics; Rifampin; Tuberculosis

2023
Effect of
    Microbiology spectrum, 2023, 08-17, Volume: 11, Issue:4

    Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Stenotrophomonas maltophilia; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Treatment Strategy for Rifampin-Susceptible Tuberculosis.
    The New England journal of medicine, 2023, Jun-15, Volume: 388, Issue:24

    Topics: Humans; Rifampin; Tuberculosis

2023
Treatment Strategy for Rifampin-Susceptible Tuberculosis.
    The New England journal of medicine, 2023, Jun-15, Volume: 388, Issue:24

    Topics: Humans; Rifampin; Tuberculosis

2023
Treatment Strategy for Rifampin-Susceptible Tuberculosis.
    The New England journal of medicine, 2023, Jun-15, Volume: 388, Issue:24

    Topics: Humans; Rifampin; Tuberculosis

2023
Treatment Strategy for Rifampin-Susceptible Tuberculosis. Reply.
    The New England journal of medicine, 2023, Jun-15, Volume: 388, Issue:24

    Topics: Humans; Rifampin; Tuberculosis

2023
Design, synthesis and biological evaluation of 3-substituted-2-thioxothiazolidin-4-one (rhodanine) derivatives as antitubercular agents against Mycobacterium tuberculosis protein tyrosine phosphatase B.
    European journal of medicinal chemistry, 2023, Oct-05, Volume: 258

    Mycobacterium tuberculosis infections still pose a serious threat to human health. Combination therapies are effective medical solutions to the problem. Mycobacterium tuberculosis is an intracellular pathogen that mainly depends on a virulence factor (Mycobacterium tuberculosis protein tyrosine phosphatase B, MptpB) for its survival in the host. Therefore, MptpB inhibitors are potential components of tuberculosis combination treatments. Herein, a new series of MptpB inhibitors bearing a rhodanine group were developed using a structure-based strategy based on the virtual screening hit. The new MptpB inhibitors displayed potent MptpB inhibitory activities and great improvements in cell membrane permeability. The optimal compounds reduced the bacterial burden in a dose-dependent manner in a macrophage infection model, especially, a combination of compound 20 and rifampicin led to a bacterial burden reduction of more than 95%, greater than the reductions achieved with compound 20 or rifampicin alone. This research provides new insights into the rational design of new MptpB inhibitors and verifies that the MptpB inhibitor has a promising potential as a component of tuberculosis treatment.

    Topics: Antitubercular Agents; Bacterial Proteins; Humans; Mycobacterium tuberculosis; Protein Tyrosine Phosphatases; Rhodanine; Rifampin; Tuberculosis

2023
Diagnostic Approach to Extrapulmonary Tuberculosis by Cartridge-based Nucleic Acid Amplification Test.
    The Journal of the Association of Physicians of India, 2023, Volume: 71, Issue:6

    Tuberculosis (TB) is a highly infectious disease causing millions of cases worldwide. Though pulmonary TB is the most common form of infection, extrapulmonary cases are also very rampant and are responsible for a large number of cases. But the diagnosis of extrapulmonary cases is quite difficult because of varied manifestations and the paucibacillary nature of the infection. Cartridge-based nucleic acid amplification test (CBNAAT) is a simple, rapid test that is very efficient in the early diagnosis of these extrapulmonary cases [extrapulmonary TB (EPTB)].. A study was done to establish the usefulness of CBNAAT in the early diagnosis of EPTB cases.. A comparative study was conducted in a rural tertiary care hospital in West Bengal, India, for 8 months (July 2021-February 2022). Samples were collected from different sites like pleural fluid, lymph nodes, cerebrospinal fluid (CSF), pus, ascitic fluid, and tissue aspirate and subjected to both CBNAAT and smear staining and examination under a fluorescent microscope. Positive samples were cultured, examined, and compared.. From 593 samples collected from different sites in suspected cases of EPTB-52 samples were positive by CBNAAT, and six cases showed rifampicin resistance (RIF resistant). Smear staining of the samples by auramine-rhodamine stains and examined under the fluorescent microscope for acid-fast bacilli identifying 33 samples; the rest were negative. Slides showing acid-fast bacilli were cultured on Lowenstein-Jensen media.. Cartridge-based nucleic acid amplification test (CBNAAT) is a very useful assay for the early diagnosis of extrapulmonary cases as it can accurately identify false negative samples by smear microscopy.

    Topics: Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Extrapulmonary; Tuberculosis, Pulmonary

2023
Evaluation of Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis in Southwest China.
    PLoS neglected tropical diseases, 2023, Volume: 17, Issue:6

    The purpose of this study was to determine the diagnostic efficacy of Xpert MTB/RIF assay for rapid diagnosis of Tuberculosis (TB) and detection of rifampicin (RIF) resistance in patients suspected of having EPTB, assessing it against traditional culture and drug susceptibility test (DST) by proportional method, and the ability to predict multidrug resistance TB by Xpert MTB/RIF assay. In this study, the Xpert MTB/RIF assay was applied to 1,614 extrapulmonary specimens. Compared with TB culture and Composite Reference Standard (CRS), the Xpert MTB/RIF assay had a high sensitivity and specificity for detection of EPTB. Depending on the culture method or CRS as the standard, sensitivity of the Xpert MTB/RIF assay for detection of MTB in pleural effusion, cerebrospinal fluid, thoracic drainage fluid and throat swabs specimens were lower than that of other specimens. According to the experimental results, we have reason to believe that Xpert MTB/RIF assay is a rapid and simple technique with high sensitivity and specificity for diagnosing EPTB and detecting drug resistance in variety of specimens. Xpert MTB/RIF assay combined with DST maybe identify more cases of multi-drug resistant tuberculosis (MDR-TB).

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Extrapulmonary; Tuberculosis, Multidrug-Resistant

2023
The Use of Xpert MTB/RIF Ultra Testing for Early Diagnosis of Tuberculosis: A Retrospective Study from a Single-Center Database.
    Genes, 2023, 06-07, Volume: 14, Issue:6

    Topics: Antibiotics, Antitubercular; Early Diagnosis; Humans; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Pulmonary

2023
A physiologically-based pharmacokinetic model for tuberculosis drug disposition at extrapulmonary sites.
    CPT: pharmacometrics & systems pharmacology, 2023, Volume: 12, Issue:9

    Tuberculosis (TB) is a leading cause of mortality attributed to an infectious agent. TB primarily targets the lungs, but in about 16% cases can affect other organs as well, giving rise to extrapulmonary TB (EPTB). However, an optimal regimen for EPTB treatment is not defined. Although the recommended treatment for most forms of EPTB is the same as pulmonary TB, the pharmacokinetics of EPTB therapy are not as well studied. To address this gap, we formulate a whole-body physiologically-based pharmacokinetic (PBPK) model for EPTB that for the first time includes the ability to simulate drug concentrations in the pleura and lymph node, the most commonly affected sites of EPTB. Using this model, we estimate the time-dependent concentrations, at potential EPTB infection sites, of the following four first-line anti-TB drugs: rifampicin, ethambutol, isoniazid, and pyrazinamide. We use reported plasma concentration kinetics data to estimate model parameters for each drug and validate our model using reported concentration data not used for model formulation or parameter estimation. Model predictions match the validation data, and reported pharmacokinetic parameters (maximum plasma concentration, time to reach maximum concentration) for the drugs. The model also predicts ethambutol, isoniazid, and pyrazinamide concentrations in the pleura that match reported experimental values from an independent study. For each drug, the predicted drug concentrations at EPTB sites are compared with their critical concentration. Simulations suggest that although rifampicin and isoniazid concentrations are greater than critical concentration values at most EPTB sites, the concentrations of ethambutol and pyrazinamide are lower than their critical concentrations at most EPTB sites.

    Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2023
Estimating the prevalence of poor-quality anti-TB medicines: a neglected risk for global TB control and resistance.
    BMJ global health, 2023, Volume: 8, Issue:7

    Tuberculosis (TB) remains a major global public health problem, especially with the recent emergence of multidrug-resistant TB and extensively drug-resistant TB. There has been little consideration of the extent of substandard and falsified (SF) TB medicines as drivers of resistance. We assessed the evidence on the prevalence of SF anti-TB medicines and discussed their public health impact.. We searched Web of Science, Medline, Pubmed, Google Scholar, WHO, US Pharmacopeia and Medicines Regulatory Agencies websites for publications on anti-TB medicines quality up to 31 October 2021. Publications reporting on the prevalence of SF anti-TB drugs were evaluated for quantitative analysis.. Of the 530 screened publications, 162 (30.6%) were relevant to anti-TB medicines quality; of those, 65 (40.1%) described one or more TB quality surveys in a specific location or region with enough information to yield an estimate of the local prevalence of poor-quality TB medicines. 7682 samples were collected in 22 countries and of those, 1170 (15.2%) failed at least one quality test. 14.1% (879/6255) of samples failed in quality surveys, 12.5% (136/1086) in bioequivalence studies and 36.9% (87/236) in accelerated biostability studies. The most frequently assessed were rifampicin monotherapy (45 studies, 19.5%) and isoniazid monotherapy (33, 14.3%), rifampicin-isoniazid-pyrazinamide-ethambutol fixed dose combinations (28, 12.1%) and rifampicin-isoniazid (20, 8.6%). The median (IQR) number of samples collected per study was 12 (1-478).. SF, especially substandard, anti-TB medicines are present worldwide. However, TB medicine quality data are few and are therefore not generalisable that 15.2% of global anti-TB medicine supply is SF. The evidence available suggests that the surveillance of the quality of TB medicines needs to be an integral part of treatment programmes. More research is needed on the development and evaluation of rapid, affordable and accurate portable devices to empower pharmacy inspectors to screen for anti-TB medicines.

    Topics: Antitubercular Agents; Humans; Isoniazid; Prevalence; Rifampin; Tuberculosis

2023
Selective Pressure by Rifampicin Modulates Mutation Rates and Evolutionary Trajectories of Mycobacterial Genomes.
    Microbiology spectrum, 2023, 08-17, Volume: 11, Issue:4

    Resistance to the frontline antibiotic rifampicin constitutes a challenge to the treatment and control of tuberculosis. Here, we analyzed the mutational landscape of Mycobacterium smegmatis during long-term evolution with increasing concentrations of rifampicin, using a mutation accumulation assay combined with whole-genome sequencing. Antibiotic treatment enhanced the acquisition of mutations, doubling the genome-wide mutation rate of the wild-type cells. While antibiotic exposure led to extinction of almost all wild-type lines, the hypermutable phenotype of the Δ

    Topics: Anti-Bacterial Agents; Antitubercular Agents; Bacterial Proteins; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mutation Rate; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2023
Standardization and validation of a novel UPLC-MS/MS method to quantify first line anti-tuberculosis drugs in plasma and dried blood spots.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2023, Aug-01, Volume: 1228

    Topics: Antitubercular Agents; Bayes Theorem; Chromatography, High Pressure Liquid; Chromatography, Liquid; Ethambutol; Humans; Isoniazid; Reference Standards; Rifampin; Tandem Mass Spectrometry; Tuberculosis

2023
Favourable outcomes in RR-TB patients using BPaL and other WHO-recommended second-line anti-TB drugs.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2023, 08-01, Volume: 27, Issue:8

    Topics: Antitubercular Agents; Diarylquinolines; HIV Infections; HIV Seropositivity; Humans; Linezolid; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; World Health Organization

2023
Inadequate Lopinavir Concentrations With Modified 8-Hourly Lopinavir/Ritonavir 4:1 Dosing During Rifampicin-based Tuberculosis Treatment in Children Living With HIV.
    The Pediatric infectious disease journal, 2023, 10-01, Volume: 42, Issue:10

    Lopinavir/ritonavir plasma concentrations are profoundly reduced when co-administered with rifampicin. Super-boosting of lopinavir/ritonavir is limited by nonavailability of single-entity ritonavir, while double-dosing of co-formulated lopinavir/ritonavir given twice-daily produces suboptimal lopinavir concentrations in young children. We evaluated whether increased daily dosing with modified 8-hourly lopinavir/ritonavir 4:1 would maintain therapeutic plasma concentrations of lopinavir in children living with HIV receiving rifampicin-based antituberculosis treatment.. Children with HIV/tuberculosis coinfection weighing 3.0 to 19.9 kg, on rifampicin-based antituberculosis treatment were commenced or switched to 8-hourly liquid lopinavir/ritonavir 4:1 with increased daily dosing using weight-band dosing approach. A standard twice-daily dosing of lopinavir/ritonavir was resumed 2 weeks after completing antituberculosis treatment. Plasma sampling was conducted during and 4 weeks after completing antituberculosis treatment.. Of 20 children enrolled; 15, 1-7 years old, had pharmacokinetics sampling available for analysis. Lopinavir concentrations (median [range]) on 8-hourly lopinavir/ritonavir co-administered with rifampicin (n = 15; area under the curve 0-24 55.32 mg/h/L [0.30-398.7 mg/h/L]; C max 3.04 mg/L [0.03-18.6 mg/L]; C 8hr 0.90 mg/L [0.01-13.7 mg/L]) were lower than on standard dosing without rifampicin (n = 12; area under the curve 24 121.63 mg/h/L [2.56-487.3 mg/h/L]; C max 9.45 mg/L [0.39-26.4 mg/L]; C 12hr 3.03 mg/L [0.01-17.7 mg/L]). During and after rifampicin cotreatment, only 7 of 15 (44.7%) and 8 of 12 (66.7%) children, respectively, achieved targeted pre-dose lopinavir concentrations ≥1mg/L.. Modified 8-hourly dosing of lopinavir/ritonavir failed to achieve adequate lopinavir concentrations with concurrent antituberculosis treatment. The subtherapeutic lopinavir exposures on standard dosing after antituberculosis treatment are of concern and requires further evaluation.

    Topics: Anti-HIV Agents; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; HIV Infections; Humans; Infant; Lopinavir; Rifampin; Ritonavir; Tuberculosis

2023
Prevalence of tuberculosis and associated factors among presumptive TB refugees residing in refugee camps in Ethiopia.
    BMC infectious diseases, 2023, Jul-28, Volume: 23, Issue:1

    Tuberculosis (TB) causes significant morbidity and mortality in refugee populations. Although Ethiopia is the third largest refugee-hosting country in Africa, there is limited published data on the prevalence and associated factors of TB in refugees. The objective of this study was to estimate the prevalence of bacteriologically confirmed pulmonary TB (PTB) and explore associated factors in presumptive TB refugees residing in refugee camps in Ethiopia.. A facility-based cross-sectional study was conducted between February and August 2021 in refugee camps in Ethiopia. Data were collected consecutively from 610 presumptive TB refugees who attended for TB diagnosis in selected refugee camp clinics in Ethiopia. A pre-tested questionnaire was used to collect data, and sputum samples were collected from eligible study participants. The Xpert Mycobacterium tuberculosis (MTB)/Rifampicin (RIF) assay was performed on direct spot sputum samples, whereas morning sputum samples were processed and inoculated for bacteriological culture using Mycobacterium Growth Indicator Tube (MGIT) and Lowsteen Jensen (LJ) methods. The statistical software package (STATA version 14) was used for statistical analysis. A logistic regression model was used for the evaluation of the association between bacteriologically confirmed TB cases and the associated factors. Descriptive statistics were used for the expression of the results, and statistical significance was assumed at p < 0.05.. Out of 610 study participants, more than half were female (54.9%), and the mean age was 37.9 years (SD, 16.64). The prevalence of bacteriologically confirmed PTB cases among refugees residing in refugee camps in Ethiopia was 13.3% (95% CI, 10.7-16.2%) using the Xpert MTB/RIF assay and/or culture. MTB was detected in 12.8% (95% CI, 10.2-15.7%) of the individuals using the Xpert MTB/RIF assay, while culture positivity was observed in 11.6% (95% CI, 9.2-14.5%). The multivariable logistic regression model showed South Sudan origins (adjusted odds ratio, AOR = 7.74; 95% CI, 3.05-19.64), age group, 19-38 years old (AOR = 5.66; 95% CI, 1.86-17.28), and male sex (AOR = 2.69; 95% CI, 1.58-4.56) were significantly associated with the bacteriologically confirmed TB among refugees residing in refugee camps in Ethiopia.. The prevalence of bacteriologically confirmed PTB among presumptive TB refugees residing in refugee camps in Ethiopia was high. The national TB program should strengthen TB prevention and control activities in the refugee camps of Ethiopia. Moreover, an active TB survey program should be implemented in refugee camps in Ethiopia.

    Topics: Adult; Cross-Sectional Studies; Ethiopia; Female; Humans; Male; Mycobacterium tuberculosis; Prevalence; Refugee Camps; Refugees; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Young Adult

2023
[Recommendations for contact tracing for tuberculosis - update 2023].
    Pneumologie (Stuttgart, Germany), 2023, Volume: 77, Issue:9

    The aim of contact tracing for tuberculosis is in addition to active case finding the detection of chains of infection and the prevention of the further spread of the disease. In this context, a careful selection of contact persons is necessary, depending on the type and duration of contact, to identify persons who are recently infected and therefore to increase the benefit of a preventive therapy and to avoid unnecessary testing of persons who are not at risk of infection. Since the last update of the recommendations on contact tracing, data on the use of interferon-y release assays (IGRAs) in children has been improved markedly. These are the preferred test in contact tracing of adults. For children, both IGRAs and the tuberculin skin test can be used equivalently. Rifampicin for 4 months, rifampicin and isoniazid for 3 months, or isoniazid for 9 months are recommended as preventive therapy in cases of confirmed infection.The implementation of the contact tracing in different age groups as well as legal framework conditions and socio-medical aspects and challenges are dealt with in detail. In addition, special cases, such as environmental screening in day-care centers, schools, or other community facilities, are discussed separately.. Ziel der Umgebungsuntersuchung bei Tuberkulose ist neben der aktiven Fallfindung das Aufdecken von Infektionsketten sowie die Verhütung der Weiterverbreitung der Erkrankung. Dabei ist eine sorgfältige Auswahl der Kontaktpersonen notwendig, die sich nach Art und Dauer des Kontaktes richtet, um möglichst frisch Infizierte zu identifizieren und so den Nutzen einer anschließenden präventiven Therapie zu erhöhen und unnötige Testungen von Personen ohne Ansteckungsrisiko zu vermeiden. Seit der letzten Überarbeitung der Empfehlungen zur Umgebungsuntersuchung hat sich die Datenlage zum Einsatz von Interferon-y release-Assays (IGRAs) bei Kindern weiterhin verbessert. Diese werden bevorzugt in der Umgebungsuntersuchung von erwachsenen Kontaktpersonen eingesetzt. Für Kinder unter 15 Jahren können sowohl IGRAs wie auch weiterhin der Tuberkulin-Hauttest gleichwertig verwendet werden. Als präventive Therapie bei nachgewiesener Infektion werden Rifampicin für 4 Monate, Rifampicin und Isoniazid für 3 Monate oder aber Isoniazid für 9 Monate empfohlen.Ausführlich wird auf die Durchführung der Umgebungsuntersuchung in verschiedenen Altersgruppen sowie rechtliche Rahmenbedingungen und sozialmedizinische Aspekte und Herausforderungen eingegangen. Zusätzlich werden Sonderfälle, wie die Umgebungsuntersuchung in Kitas, Schulen oder in anderen Gemeinschaftseinrichtungen, separat dargestellt.

    Topics: Adult; Child; Contact Tracing; Humans; Isoniazid; Rifampin; Tuberculin Test; Tuberculosis

2023
Frequency of rifampicin-resistant mycobacterium tuberculosis by GeneXpert MTB/RIF assay and its correlates among 2605 probable tuberculosis patients in upper Egypt.
    The Indian journal of tuberculosis, 2023, Volume: 70, Issue:3

    GeneXpert MTB/RIF (Mycobacterium tuberculosis/rifampicin) assay is a method for detecting rifampicin resistance (RR-MTB) in suspected samples in less than 2 hours with high sensitivity and specificity yield. This study aimed to use the GeneXpert MTB/RIF assay to determine the frequency of RR-MTB and to study the possible influencing correlates associated with positive results.. This is a retrospective cross-sectional study of patients who visited TB clinic in 5 years (2016-2021). According to the data sheet of the patients, all the collected specimens were divided into 2 parts one for diagnosis by Ziehl-Neelsen stain and the other part for GeneXpert analysis. GeneXpert was also used to look for evidence of RR.. Out of the 2605 total samples screened, 718 (27.6%) tested positive for MTB on GeneXpert assay; of them 633 (88.4%) were sensitive to Rifampicin, 83 (11.6%) were resistant to Rifampicin and 2 cases were undetermined. Factors contributing to RR-MTB were: smoker/ex-smoker, with 2.5 times more risk (p = 0.013.0, p = 0.001); recurrence cases had a 4-fold increased risk (p < 0.001); patients with very low M. tuberculosis detected on the GeneXpert MTB/RIF test were 8 times more likely to have RR-TB (P = 0.004).. This study disclosed a high-rate MTB in Egyptian probable TB cases. Smoking, recurrence and cases with a very low M. tuberculosis burden noticed on the GeneXpert MTB/RIF test had augmented risk of RR-TB.

    Topics: Cross-Sectional Studies; Egypt; Humans; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Newer TB diagnostics: An update.
    The Indian journal of tuberculosis, 2023, Volume: 70, Issue:3

    In recent years, nucleic-acid amplification tests (NAATs), which are highly specific and sensitive, have helped to transform the TB diagnostic landscape. According to the WHO 2021 Guidelines on Diagnostics, the NAATs used in TB diagnosis at the point of care (POC) include Xpert MTB/RIF a cartridge-based test manufactured by Cepheid, and Truenat a chip-based test manufactured by Molbio. Other POC tests that are expected to be implemented in near future include Xpert Omni and Xpert MTB/XDR. The use of line probe assay is involved at the level of reference labs for the detection of MTB and its resistance to first-line (Isoniazid and Rifampicin) and second-line (fluoroquinolones and second-line injectables) drugs. When the currently available NAATs detect mutations for drug resistance at a particular region of MTB sequence, the Whole genome sequencing (WGS) platform demonstrates the exceptional potential for reliable and comprehensive resistance prediction for MTB isolates, by multiple gene regions or whole genome sequence analysis allowing for accurate clinical decisions.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Characteristics and treatment outcomes of co-infected tuberculosis patients with human immunodeficiency virus in Southeast China, 2012-2021.
    BMC infectious diseases, 2023, Aug-10, Volume: 23, Issue:1

    Tuberculosis (TB) is a chronic respiratory infection. Co-infection with human immunodeficiency virus (HIV) has been a significant obstacle to TB control. Insufficient attention has been given to TB/HIV, and more information is needed to address this issue. We conducted an observational study to investigate the epidemiological characteristics, treatment outcomes and its associated factors of HIV-positive TB patients in Southeast China.. An observational study was conducted based on data collected directly from China National TB Surveillance System during 2012-2021. Epidemiological characteristics, drug resistance and outcomes were described as frequency (n) and percentage (%). Risk factors for unsuccessful outcomes were determined using univariate (chi-squared) and multivariate logistic regression analysis.. A total of 347 TB/HIV cases were included, and the proportion of HIV-positive cases among all TB cases increased significantly from 0.06% to 2012 to 0.40% in 2021. The majority of cases were males (86.5%), non-local household registers (139, 40.1%), farmers or workers (179, 51.6%), and aged 40-59 (142, 40.9%). Of 347 cases, 290 (83.6%) had pulmonary TB (PTB), 10 (2.9%) had extra pulmonary TB (EPTB) and 47(13.5%) had both PTB and EPTB. A total A total of 258 (74.4%) were HIV positive prior to TB diagnosis. 8.0% (4/50) of cases were resistant to rifampicin (RIF) and 274 patients (83.8%) had successful outcomes. Being non-local (AOR = 2.193, 95% CI = 1.196-4.022, P = 0.011) and diagnosed HIV infection after TB (AOR = 2.365, 95% CI = 1.263-4.430, P = 0.007) were independent risk factors for unsuccessful outcomes of anti-TB treatment.. During 2012-2021, the proportion of HIV-positive cases among all TB cases increased significantly in Southeast China. HIV-positive TB patients were significantly more likely to develop resistance to RIF and INH and unsuccessful anti-TB treatment. Non-local registration and becoming HIV positive after TB diagnosis were independent risk factors associated with unsuccessful outcomes.

    Topics: Antitubercular Agents; China; Coinfection; Female; HIV; HIV Infections; HIV Seropositivity; Humans; Male; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis

2023
Rifampin-induced flu-like syndrome with shock in a patient with tuberculosis infection.
    CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 2023, 09-05, Volume: 195, Issue:34

    Topics: Humans; Latent Tuberculosis; Patients; Rifampin; Shock; Tuberculosis

2023
Xpert MTB/RIF Ultra on contaminated liquid cultures for tuberculosis and rifampicin-resistance detection: a diagnostic accuracy evaluation.
    The Lancet. Microbe, 2023, Volume: 4, Issue:10

    Xpert MTB/RIF Ultra (Ultra) is a widely used rapid front-line tuberculosis and rifampicin-susceptibility testing. Mycobacterium Growth Indicator Tube (MGIT) 960 liquid culture is used as an adjunct but is vulnerable to contamination. We aimed to assess whether Ultra can be used on to-be-discarded contaminated cultures.. We stored contaminated MGIT960 tubes (growth-positive, acid-fast bacilli [AFB]-negative) originally inoculated at a high-volume laboratory in Cape Town, South Africa, to diagnose patients with presumptive pulmonary tuberculosis. Patients who had no positive tuberculosis results (smear, Ultra, or culture) at contamination detection and had another, later specimen submitted within 3 months of the contaminated specimen were selected. We evaluated the sensitivity and specificity of Ultra on contaminated growth from the first culture for tuberculosis (next-available non-contaminated culture result reference standard) and rifampicin resistance (vs MTBDRplus on a later isolate). We calculated potential time-to-diagnosis improvements and also evaluated the immunochromatographic MPT64 TBc assay.. Between June 1 and Aug 31, 2019, 36 684 specimens from 26 929 patients were processed for diagnostic culture. 2402 (7%) cultures from 2186 patients were contaminated. 1068 (49%) of 2186 patients had no other specimen submitted. After 319 exclusions, there were 799 people with at least one repeat specimen submitted; of these, we included in our study 246 patients (31%) with a culture-positive repeat specimen and 429 patients (54%) with a culture-negative repeat specimen. 124 patients (16%) with a culture-contaminated repeat specimen were excluded. When Ultra was done on the initial contaminated growth, sensitivity was 89% (95% CI 84-94) for tuberculosis and 95% (75-100) for rifampicin-resistance detection, and specificity was 95% (90-98) for tuberculosis and 98% (93-100) for rifampicin-resistance detection. If our approach were used the day after contamination detection, the time to tuberculosis detection would improve by a median of 23 days (IQR 13-45) and provide a result in many patients who had none. MPT64 TBc had a sensitivity of 5% (95% CI 0-25).. Ultra on AFB-negative growth from contaminated MGIT960 tubes had high sensitivity and specificity, approximating WHO criteria for sputum test target product performance and exceeding drug susceptibility testing. Our approach could mitigate negative effects of culture contamination, especially when repeat specimens are not submitted.. The European & Developing Countries Clinical Trials Partnership, National Institutes of Health.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; South Africa; Tuberculosis; United States

2023
Low rifampicin levels in plasma associated with a poor clinical response in patients with abdominal TB.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2023, 10-01, Volume: 27, Issue:10

    Topics: Humans; Rifampin; Tuberculosis

2023
Genotypic and phenotypic comparison of drug resistance profiles of clinical multidrug-resistant Mycobacterium tuberculosis isolates using whole genome sequencing in Latvia.
    BMC infectious diseases, 2023, Sep-28, Volume: 23, Issue:1

    Multidrug-resistant tuberculosis (MDR-TB) remains a major public health problem in many high tuberculosis (TB) burden countries. Phenotypic drug susceptibility testing (DST) take several weeks or months to result, but line probe assays and Xpert/Rif Ultra assay detect a limited number of resistance conferring gene mutations. Whole genome sequencing (WGS) is an advanced molecular testing method which theoretically can predict the resistance of M. tuberculosis (Mtb) isolates to all anti-TB agents through a single analysis.. Here, we aimed to identify the level of concordance between the phenotypic and WGS-based genotypic drug susceptibility (DS) patterns of MDR-TB isolates. Overall, data for 12 anti-TB medications were analyzed.. In total, 63 MDR-TB Mtb isolates were included in the analysis, representing 27.4% of the total number of MDR-TB cases in Latvia in 2012-2014. Among them, five different sublineages were detected, and 2.2.1 (Beijing group) and 4.3.3 (Latin American-Mediterranean group) were the most abundant. There were 100% agreement between phenotypic and genotypic DS pattern for isoniazid, rifampicin, and linezolid. High concordance rate (> 90%) between phenotypic and genotypic DST results was detected for ofloxacin (93.7%), pyrazinamide (93.7%) and streptomycin (95.4%). Phenotypic and genotypic DS patterns were poorly correlated for ethionamide (agreement 56.4%), ethambutol (85.7%), amikacin (82.5%), capreomycin (81.0%), kanamycin (85.4%), and moxifloxacin (77.8%). For capreomycin, resistance conferring mutations were not identified in several phenotypically resistant isolates, and, in contrary, for ethionamide, ethambutol, amikacin, kanamycin, and moxifloxacin the resistance-related mutations were identified in several phenotypically sensitive isolates.. WGS is a valuable tool for rapid genotypic DST for all anti-TB agents. For isoniazid and rifampicin phenotypic DST potentially can be replaced by genotypic DST based on 100% agreement between the tests. However, discrepant results for other anti-TB agents limit their prescription based solely on WGS data. For clinical decision, at the current level of knowledge, there is a need for combination of genotypic DST with modern, validated phenotypic DST methodologies for those medications which did not showed 100% agreement between the methods.

    Topics: Amikacin; Antitubercular Agents; Capreomycin; Drug Resistance, Multiple, Bacterial; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Latvia; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing

2023
Global burden of disease due to rifampicin-resistant tuberculosis: a mathematical modeling analysis.
    Nature communications, 2023, 10-04, Volume: 14, Issue:1

    In 2020, almost half a million individuals developed rifampicin-resistant tuberculosis (RR-TB). We estimated the global burden of RR-TB over the lifetime of affected individuals. We synthesized data on incidence, case detection, and treatment outcomes in 192 countries (99.99% of global tuberculosis). Using a mathematical model, we projected disability-adjusted life years (DALYs) over the lifetime for individuals developing tuberculosis in 2020 stratified by country, age, sex, HIV, and rifampicin resistance. Here we show that incident RR-TB in 2020 was responsible for an estimated 6.9 (95% uncertainty interval: 5.5, 8.5) million DALYs, 44% (31, 54) of which accrued among TB survivors. We estimated an average of 17 (14, 21) DALYs per person developing RR-TB, 34% (12, 56) greater than for rifampicin-susceptible tuberculosis. RR-TB burden per 100,000 was highest in former Soviet Union countries and southern African countries. While RR-TB causes substantial short-term morbidity and mortality, nearly half of the overall disease burden of RR-TB accrues among tuberculosis survivors. The substantial long-term health impacts among those surviving RR-TB disease suggest the need for improved post-treatment care and further justify increased health expenditures to prevent RR-TB transmission.

    Topics: Antitubercular Agents; Global Burden of Disease; Humans; Models, Theoretical; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Macrophage targeted iron oxide nanodecoys augment innate immunological and drug killings for more effective Mycobacterium Tuberculosis clearance.
    Journal of nanobiotechnology, 2023, Oct-10, Volume: 21, Issue:1

    Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, is still one of the top killers worldwide among infectious diseases. The escape of Mtb from immunological clearance and the low targeting effects of anti-TB drugs remain the substantial challenges for TB control. Iron is particularly required for Mtb growth but also toxic for Mtb in high dosages, which makes iron an ideal toxic decoy for the 'iron-tropic' Mtb. Here, a macrophage-targeted iron oxide nanoparticles (IONPs)-derived IONPs-PAA-PEG-MAN nanodecoy is designed to augment innate immunological and drug killings against intracellular Mtb. IONPs-PAA-PEG-MAN nanodecoy exhibits preferential uptake in macrophages to significantly increase drug uptake with sustained high drug contents in host cells. Moreover, it can serve as a specific nanodecoy for the 'iron-tropic' Mtb to realize the localization of Mtb contained phagosomes surrounding the drug encapsulated nanodecoys and co-localization of Mtb with the drug encapsulated nanodecoys in lysosomes, where the incorporated rifampicin (Rif) can be readily released under acidic lysosomal condition for enhanced Mtb killing. This drug encapsulated nanodecoy can also polarize Mtb infected macrophages into anti-mycobacterial M1 phenotype and enhance M1 macrophage associated pro-inflammatory cytokine (TNF-α) production to trigger innate immunological responses against Mtb. Collectively, Rif@IONPs-PAA-PEG-MAN nanodecoy can synergistically enhance the killing efficiency of intracellular Mtb in in vitro macrophages and ex vivo monocyte-derived macrophages, and also significantly reduce the mycobacterial burdens in the lung of infected mice with alleviated pathology. These results indicate that Rif@IONPs-PAA-PEG-MAN nanodecoy may have a potential for the development of more effective therapeutic strategy against TB by manipulating augmented innate immunity and drug killings.

    Topics: Animals; Humans; Iron; Macrophages; Mice; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2023
Protein binding investigation of first-line and second-line antituberculosis drugs.
    International journal of antimicrobial agents, 2023, Volume: 62, Issue:6

    Data on protein binding are incomplete for first-line antituberculosis drugs, and lacking for second-line antituberculosis drugs that are used extensively for multi-drug-resistant tuberculosis (levofloxacin, linezolid and moxifloxacin). Thus, the main purposes of this study were to investigate: (i) the relationship between carrier protein concentration and drug binding; and (ii) the feasibility of predicting free drug concentration using in-vitro and in-vivo results. In-vitro experiments were performed on spiked plasma mimicking real-case samples (drug combinations from clinical practice). Median in-vivo protein binding was 1.5% for ethambutol, 9.7% for isoniazid, 0.7% for pyrazinamide and 88.2% for rifampicin; and median in-vitro protein binding was 26.2% for levofloxacin, 12.8% for linezolid and 46.3% for moxifloxacin. Albumin concentration (<30 g/L) had a moderate impact on moxifloxacin binding and a strong impact on levofloxacin, linezolid and rifampicin binding. Determination of the free drug concentration seems to be of little value for ethambutol, isoniazid, moxifloxacin and pyrazinamide; limited value for linezolid because of its low binding; and major value for rifampicin in hypoalbuminaemic patients with tuberculosis, and levofloxacin because total concentration was an inaccurate reflection of free concentration. The free concentration predicted by the mathematical model was suitable for levofloxacin and linezolid, whereas the real free concentration should be measured for rifampicin. Further investigations should be carried out to investigate the benefit of using free concentration for levofloxacin, linezolid and rifampicin, particularly in the critical period of active tuberculosis associated with hypoalbuminaemia.

    Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Levofloxacin; Linezolid; Moxifloxacin; Protein Binding; Pyrazinamide; Rifampin; Tuberculosis

2023
Tuberculosis Variant with Rifampin Resistance Undetectable by Xpert MTB/RIF, Botswana.
    Emerging infectious diseases, 2023, Volume: 29, Issue:11

    GeneXpert MTB/RIF, a tool widely used for diagnosing tuberculosis, has limitations for detecting rifampin resistance in certain variants. We report transmission of a pre-extensively drug-resistant variant in Botswana that went undetected by GeneXpert. The public health impact of misdiagnosis emphasizes the need for comprehensive molecular testing to identify resistance and guide treatment.

    Topics: Antibiotics, Antitubercular; Botswana; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
The clinical impact of rifampicin-based anti-TB therapy and tenofovir alafenamide-containing ARV regimen drug Interaction in people living with HIV: Case series report.
    Journal of infection and public health, 2023, Volume: 16, Issue:12

    People living with HIV (PLWH) are prone to developing tuberculosis (TB). Since tenofovir alafenamide (TAF) is the recommended tenofovir (TFV) prodrug and rifampicin is a key component of TB therapy, thus complicating HIV and TB coinfection management. However, there is little data regarding the impact of this drug-drug Interaction in PLWH, which makes health care providers reluctant to prescribe them together.. This was an observational, retrospective case series carried out at King Faisal Specialist Hospital & Research Center (KFSH&RC), Jeddah, Saudi Arabia. PLWH (≥18 years old) who received the TAF-containing ARV regimen and rifampicin-based anti-TB therapy together for ≥ 4 weeks were included. The objective of this study was to report the clinical impact of this drug-drug interaction (rifampicin + TAF-containing antiretroviral (ARV) regimen) on HIV viral load control in PLWH.. A total of 7 PLWH who met the inclusion criteria, 5 (71 %) out of 7, were males. All patients received dolutegravir 50 mg twice daily (DTG) plus the combination of TAF 25 mg and emtricitabine 200 mg (FTC) once daily as their ARV regimen. Four patients had suppressed viral load levels at baseline, which was maintained throughout TB treatment. Three patients had unsuppressed viral load levels at baseline and attained viral load suppression throughout the TB treatment course CONCLUSION: Overall, the TAF-containing ARV regimen maintained it's efficacy in presence of rifampicin.

    Topics: Adenine; Adolescent; Anti-HIV Agents; Anti-Retroviral Agents; Drug Interactions; Female; HIV Infections; Humans; Male; Retrospective Studies; Rifampin; Tuberculosis

2023
Evaluation of the Cepheid 3-gene host response blood test for tuberculosis diagnosis and treatment response monitoring in a primary-level clinic in rural China.
    Journal of clinical microbiology, 2023, Nov-21, Volume: 61, Issue:11

    A rapid, accurate, non-sputum-based triage test for diagnosing tuberculosis (TB) is a high-priority need. Cepheid developed a novel prototype blood test, Xpert

    Topics: Antibiotics, Antitubercular; Case-Control Studies; China; Humans; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2023
    CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 2023, 11-06, Volume: 195, Issue:43

    Topics: Humans; Latent Tuberculosis; Patients; Rifampin; Shock; Tuberculosis

2023
Tuberculosis among children and adolescents with rheumatic diseases - case series.
    Pediatric rheumatology online journal, 2023, Nov-10, Volume: 21, Issue:1

    Rheumatic patients have a higher frequency of tuberculosis(TB) than the general population. This study aimed to describe children and adolescents with TB and rheumatic diseases(RD) who were being treated in a reference center.. A series of TB cases were investigated in a reference center for childhood TB in Rio de Janeiro, Brazil, from 1995 to 2022.. Fifteen patients with underlying RD and TB were included with 8(53%) being female. The mean age at RD diagnosis was 7.10years (SD ± 0,57 years), and the mean age at TB diagnosis was 9.81 years(SD ± 0.88 years). A total of 9 cases of pulmonary TB(PTB) and 6 cases of extrapulmonary TB-pleural(2), joint/osteoarticular(1), cutaneous(1), ocular(1), and peritoneal(1)- were described. The RD observed in the 15 patients included juvenile idiopathic arthritis(9), juvenile systemic lupus erythematosus(3), juvenile dermatomyositis(1), polyarteritis nodosa(1), and pyoderma gangrenosum(1). Among the immunosuppressants/immunobiologics, methotrexate(8) was the most commonly used, followed by corticosteroids(6), etanercept(2), mycophenolate mofetil(1), cyclosporine A(1), adalimumab(1), and tocilizumab(1). The most common symptoms were fever and weight loss, and a predominance of PTB cases was noted. GeneXpert MTB/RIF® was performed in six patients and was detectable in two without rifampicin resistance; Xpert Ultra® was performed in five patients, and traces with indeterminate rifampicin resistance were detected in three. One female patient discontinued treatment, and another passed away.. The case series demonstrated the importance of suspecting and investigating TB in RD affected patients who are using immunosuppressants/ immunobiologics, particularly in countries with high rates of TB such as Brazil.

    Topics: Adolescent; Brazil; Child; Female; Humans; Immunosuppressive Agents; Male; Mycobacterium tuberculosis; Rheumatic Diseases; Rifampin; Sensitivity and Specificity; Tuberculosis

2023
[Recommendations for Contact Tracing for Tuberculosis - Update 2023].
    Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany)), 2023, Volume: 85, Issue:11

    The aim of contact tracing for tuberculosis is in addition to active case finding the detection of chains of infection and the prevention of the further spread of the disease. In this context, a careful selection of contact persons is necessary, depending on the type and duration of contact, to identify persons who are recently infected and therefore to increase the benefit of a preventive therapy and to avoid unnecessary testing of persons who are not at risk of infection. Since the last update of the recommendations on contact tracing, data on the use of interferon-y release assays (IGRAs) in children has been improved markedly. These are the preferred test in contact tracing of adults. For children, both IGRAs and the tuberculin skin test can be used equivalently. Rifampicin for 4 months, rifampicin and isoniazid for 3 months, or isoniazid for 9 months are recommended as preventive therapy in cases of confirmed infection.The implementation of the contact tracing in different age groups as well as legal framework conditions and socio-medical aspects and challenges are dealt with in detail. In addition, special cases, such as environmental screening in day-care centers, schools, or other community facilities, are discussed separately.. Ziel der Umgebungsuntersuchung bei Tuberkulose ist neben der aktiven Fallfindung das Aufdecken von Infektionsketten sowie die Verhütung der Weiterverbreitung der Erkrankung. Dabei ist eine sorgfältige Auswahl der Kontaktpersonen notwendig, die sich nach Art und Dauer des Kontaktes richtet, um möglichst frisch Infizierte zu identifizieren und so den Nutzen einer anschließenden präventiven Therapie zu erhöhen und unnötige Testungen von Personen ohne Ansteckungsrisiko zu vermeiden. Seit der letzten Überarbeitung der Empfehlungen zur Umgebungsuntersuchung hat sich die Datenlage zum Einsatz von Interferon-y release-Assays (IGRAs) bei Kindern weiterhin verbessert. Diese werden bevorzugt in der Umgebungsuntersuchung von erwachsenen Kontaktpersonen eingesetzt. Für Kinder unter 15 Jahren können sowohl IGRAs wie auch weiterhin der Tuberkulin-Hauttest gleichwertig verwendet werden. Als präventive Therapie bei nachgewiesener Infektion werden Rifampicin für 4 Monate, Rifampicin und Isoniazid für 3 Monate oder aber Isoniazid für 9 Monate empfohlen.Ausführlich wird auf die Durchführung der Umgebungsuntersuchung in verschiedenen Altersgruppen sowie rechtliche Rahmenbedingungen und sozialmedizinische Aspekte und Herausforderungen eingegangen. Zusätzlich werden Sonderfälle, wie die Umgebungsuntersuchung in Kitas, Schulen oder in anderen Gemeinschaftseinrichtungen, separat dargestellt.

    Topics: Adult; Child; Contact Tracing; Germany; Humans; Isoniazid; Rifampin; Tuberculosis

2023
Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.
    PLoS medicine, 2023, Volume: 20, Issue:11

    The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children.. We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies.. Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance.. ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

    Topics: Adolescent; Adult; Antitubercular Agents; Child; Child, Preschool; Female; HIV; HIV Infections; Humans; Infant; Infant, Newborn; Isoniazid; Lopinavir; Male; Pyrazinamide; Rifampin; Ritonavir; Tuberculosis

2023
Insight into the on/off switch that regulates expression of the MSMEG-3762/63 efflux pump in Mycobacterium smegmatis.
    Scientific reports, 2023, Nov-21, Volume: 13, Issue:1

    Drug resistance is one of the most difficult challenges facing tuberculosis (TB) control. Drug efflux is among the mechanisms leading to drug resistance. In our previous studies, we partially characterized the ABC-type MSMEG-3762/63 efflux pump in Mycobacterium smegmatis, which shares high percentage of identity with the Mycobacterium tuberculosis Rv1687/86c pump. MSMEG-3762/63 was shown to have extrusion activity for rifampicin and ciprofloxacin, used in first and second-line anti-TB treatments. Moreover, we described the functional role of the TetR-like MSMEG-3765 protein as a repressor of the MSMEG_3762/63/65 operon and orthologous Rv1687/86/85c in M. tuberculosis. Here we show that the operon is upregulated in the macrophage environment, supporting a previous observation of induction triggered by acid-nitrosative stress. Expression of the efflux pump was also induced by sub-inhibitory concentrations of rifampicin or ciprofloxacin. Both these drugs also prevented the binding of the MSMEG-3765 TetR repressor protein to its operator in the MSMEG_3762/63/65 operon. The hypothesis that these two drugs might be responsible for the induction of the efflux pump operon was assessed by bioinformatics analyses. Docking studies using a structural model of the regulator MSMEG-3765 showed that both antibiotics abolished the ability of this transcriptional repressor to recognize the efflux pump operon by interacting with the homodimer at different binding sites within the same binding pocket. Reduced binding of the repressor leads to induction of the efflux pump in M. smegmatis, and reduced efficacy of these two anti-mycobacterial drugs.

    Topics: Bacterial Proteins; Ciprofloxacin; Humans; Mycobacterium smegmatis; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2023
Phenotypic drug susceptibility characterization and clinical outcomes of tuberculosis strains with A-probe mutation by GeneXpert MTB/RIF.
    BMC infectious diseases, 2023, Nov-27, Volume: 23, Issue:1

    GeneXpert MTB/RIF (Xpert) assay was applied widely to detect Mycobacterium tuberculosis (MTB) and rifampicin resistance.. Retrospectively investigated the association among treatment histories, phenotypic drug susceptibility testing (pDST) results, and clinical outcomes of patients infected with probe A absent mutation isolate confirmed by Xpert.. 63 patients with only probe A absent mutation and 40 with additional pDST results were analyzed. 24 (60.0%) patients had molecular-phenotypic discordant rifampicin (RIF) susceptibility testing results, including 12 (12/13, 92.3%) new tuberculosis (TB) patients and 12 (12/27, 44.4%) retreated ones. 28 (28/39, 71.8%) retreated patients received first-line treatment regime within two years with failed outcomes. New patients had better treatment outcomes than retreated ones (successful: 83.3% VS. 53.8%; P value = 0.02). The clinical results of RIF-susceptible TB confirmed by pDST were not better than RIF-resistant TB (successful: 62.5% VS. 50.0%; P value = 0.43). INH-resistant TB and INH-susceptible TB had similar treatment outcomes too (successful: 61.5% VS. 50.0%; P value = 0.48). 11 (11/12, 91.7%) new patients treated with the short treatment regimen (STR) had successful outcomes.. More than half of mono probe A absent isolates had RIF molecular-phenotypic discordance results, especially in new patients. Probe A mutations were significantly associated with unsuccessful clinical outcomes, whether the pDST results were RIF susceptible or not. STR was the best choice for new patients.. retrospectively registered in Wuhan Jinyintan Hospital (No. 2021-KY-16).

    Topics: Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2023
Repurposing of Tuberculosis Drug Candidates for the Treatment of Mycobacterium ulcerans Disease.
    Chimia, 2023, Sep-20, Volume: 77, Issue:9

    Buruli ulcer (BU) is a chronic necrotizing skin disease caused by Mycobacterium ulcerans. Historically, the disease was treated by surgical excision of the skin lesions, until an 8-week combination therapy of rifampicin and streptomycin was introduced in 2004. This treatment modality was effective and reduced recurrence rates. Rifampicin is the most efficacious antibiotic for the treatment of BU and, should rifampicin-resistant M. ulcerans strains emerge, there is currently no replacement for it. As for mycobacterial diseases in general, there is a pressing need for the development of novel, fast-acting drugs. Under market economy conditions, repurposing of new tuberculosis drug candidates is the most promising avenue for alternative BU treatments. Our drug repurposing activities have led to the identification of several actives against M. ulcerans. In particular, the cytochrome bc1 complex inhibitor telacebec (Q203) is a promising drug candidate for the treatment of BU in Africa and Australia. While an active cytochrome-bd oxidase bypass limits the potency of the cytochrome-bc1-specific inhibitor telacebec against M. tuberculosis, classical lineage M. ulcerans strains rely exclusively on cytochrome-bc1 to respire. Hence, telacebec is effective at nanomolar concentration against M. ulcerans, and a high treatment efficacy in an experimental mouse infection model indicates that treatment of BU could be substantially shortened and simplified by telacebec.

    Topics: Animals; Buruli Ulcer; Cytochromes; Disease Models, Animal; Drug Repositioning; Mice; Mycobacterium ulcerans; Rifampin; Tuberculosis

2023
Mycobactin Analogues with Excellent Pharmacokinetic Profile Demonstrate Potent Antitubercular Specific Activity and Exceptional Efflux Pump Inhibition.
    Journal of medicinal chemistry, 2022, 01-13, Volume: 65, Issue:1

    In this study, we have designed and synthesized pyrazoline analogues that partially mimic the structure of mycobactin, to address the requirement of novel therapeutics to tackle the emerging global challenge of antimicrobial resistance (AMR). Our investigation resulted in the identification of novel lead compounds

    Topics: Animals; Antitubercular Agents; Bacterial Proteins; Calcium Channel Blockers; Ion Transport; Iron Chelating Agents; Male; Membrane Transport Proteins; Mycobacterium tuberculosis; Oxazoles; Rats; Rats, Sprague-Dawley; Tissue Distribution; Tuberculosis; Verapamil

2022
A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen).
    European journal of medicinal chemistry, 2022, Feb-15, Volume: 230

    There is a pressing need for new drugs against tuberculosis (TB) to combat the growing resistance to current antituberculars. Herein a novel strategy is described for hit generation against promising TB targets involving X-ray crystallographic screening in combination with phenotypic screening. This combined approach (XP Screen) affords both a validation of target engagement as well as determination of in cellulo activity. The utility of this method is illustrated by way of an XP Screen against CYP121A1, a cytochrome P450 enzyme from Mycobacterium tuberculosis (Mtb) championed as a validated drug discovery target. A focused screening set was synthesized and tested by such means, with several members of the set showing promising activity against Mtb strain H37Rv. One compound was observed as an X-ray hit against CYP121A1 and showed improved activity against Mtb strain H37Rv under multiple assay conditions (pan-assay activity). Data obtained during X-ray crystallographic screening were utilized in a structure-based campaign to design a limited number of analogues (less than twenty), many of which also showed pan-assay activity against Mtb strain H37Rv. These included the benzo[b][1,4]oxazine derivative (MIC

    Topics: Antitubercular Agents; Drug Design; Humans; Mycobacterium tuberculosis; Tuberculosis; X-Rays

2022
Identification of nitrofuranylchalcone tethered benzoxazole-2-amines as potent inhibitors of drug resistant Mycobacterium tuberculosis demonstrating bactericidal efficacy.
    Bioorganic & medicinal chemistry, 2022, 06-15, Volume: 64

    Ever increasing drug resistance has become an impeding threat that continues to hamper effective tackling of otherwise treatable tuberculosis (TB). Such dismal situation necessitates identification and exploration of multitarget acting newer chemotypes with bactericidal efficacy as a priority, that could efficiently hinder uncontrolled spread of TB. In this context, herein we present design, synthesis and bio-evaluation of chalcone tethered bezoxazole-2-amines as promising anti-TB chemotypes. Preliminary screening of 24 compounds revealed initial hits 3,4,5-trimethoxyphenyl and 5-nitrofuran-2-yl derivative exhibiting selective inhibition of Mycobacterium tuberculosis (Mtb) H37Rv. Further, structural optimization of hit compounds generated 12 analogues, amongst which 5-nitrofuran-2-yl derivatives displayed potent inhibition of not only drug-susceptible (DS) Mtb but also clinical isolates of drug-resistant (DR) Mtb strains equipotently. Moreover, cell viability test against Vero cells found these compounds with favourable selectivity. Time kill analysis led to the identification of the lead compound (E)-1-(4-((5-chlorobenzo[d]oxazol-2-yl)amino)phenyl)-3-(5-nitrofuran-2-yl)prop-2-en-1-one, that demonstrated bactericidal killing of Mtb bacilli. Together with acceptable microsomal stability, the lead compound of the series manifested all desirable traits of a promising antitubercular agent.

    Topics: Amines; Animals; Antitubercular Agents; Benzoxazoles; Chlorocebus aethiops; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitrofurans; Tuberculosis; Tuberculosis, Multidrug-Resistant; Vero Cells

2022
Nitroimidazopyrazinones with Oral Activity against Tuberculosis and Chagas Disease in Mouse Models of Infection.
    Journal of medicinal chemistry, 2022, 10-13, Volume: 65, Issue:19

    Tuberculosis and parasitic infections continue to impose a significant threat to global public health and economic growth. There is an urgent need to develop new treatments to combat these diseases. Here, we report the

    Topics: Animals; Chagas Disease; Disease Models, Animal; Mice; Mycobacterium tuberculosis; Nitroimidazoles; Nitroreductases; Trypanosoma cruzi; Tuberculosis

2022
Discovery of biphenyls bearing thiobarbiturate fragment by structure-based strategy as Mycobacterium tuberculosis protein tyrosine phosphatase B inhibitors.
    Bioorganic & medicinal chemistry, 2022, 11-01, Volume: 73

    Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) is an important virulence factor that blocks the host immune response and facilitates M. tuberculosis growth in host cells. MptpB inhibitors are potential components of tuberculosis combination treatment. Herein, we present the development of new biphenyls MptpB inhibitors with greatly improved MptpB inhibition based on our reported thiobarbiturate lead 6 by rational design with the structure-based strategy. The eight biphenyls bearing thiobarbiturate fragment target compounds showed more potent MptpB inhibition (IC

    Topics: Animals; Antitubercular Agents; Bacterial Proteins; Biphenyl Compounds; Enzyme Inhibitors; Mice; Molecular Docking Simulation; Mycobacterium tuberculosis; Protein Tyrosine Phosphatases; Thiobarbiturates; Tuberculosis; Virulence Factors

2022
Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study.
    The Lancet. Infectious diseases, 2022, Volume: 22, Issue:2

    The WHO End TB Strategy requires drug susceptibility testing and treatment of all people with tuberculosis, but second-line diagnostic testing with line-probe assays needs to be done in experienced laboratories with advanced infrastructure. Fewer than half of people with drug-resistant tuberculosis receive appropriate treatment. We assessed the diagnostic accuracy of the rapid Xpert MTB/XDR automated molecular assay (Cepheid, Sunnyvale, CA, USA) to overcome these limitations.. We did a prospective study involving individuals presenting with pulmonary tuberculosis symptoms and at least one risk factor for drug resistance in four sites in India (New Delhi and Mumbai), Moldova, and South Africa between July 31, 2019, and March 21, 2020. The Xpert MTB/XDR assay was used as a reflex test to detect resistance to isoniazid, fluoroquinolones, ethionamide, amikacin, kanamycin, and capreomycin in adults with positive results for Mycobacterium tuberculosis complex on Xpert MTB/RIF or Ultra (Cepheid). Diagnostic performance was assessed against a composite reference standard of phenotypic drug-susceptibility testing and whole-genome sequencing. This study is registered with ClinicalTrials.gov, number NCT03728725.. Of 710 participants, 611 (86%) had results from both Xpert MTB/XDR and the reference standard for any drug and were included in analysis. Sensitivity for Xpert MTB/XDR detection of resistance was 94% (460 of 488, 95% CI 92-96) for isoniazid, 94% (222 of 235, 90-96%) for fluoroquinolones, 54% (178 of 328, 50-61) for ethionamide, 73% (60 of 82, 62-81) for amikacin, 86% (181 of 210, 81-91) for kanamycin, and 61% (53 of 87, 49-70) for capreomycin. Specificity was 98-100% for all drugs. Performance was equivalent to that of line-probe assays. The non-determinate rate of Xpert MTB/XDR (ie, invalid M tuberculosis complex detection) was 2·96%.. The Xpert MTB/XDR assay showed high diagnostic accuracy and met WHO's minimum target product profile criteria for a next-generation drug susceptibility test. The assay has the potential to diagnose drug-resistant tuberculosis rapidly and accurately and enable optimum treatment.. German Federal Ministry of Education and Research through KfW, Dutch Ministry of Foreign Affairs, and Australian Department of Foreign Affairs and Trade.

    Topics: Adult; Amikacin; Australia; Capreomycin; Cross-Sectional Studies; Drug Resistance, Bacterial; Ethionamide; Fluoroquinolones; Humans; Isoniazid; Kanamycin; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Optimizing Dosing and Fixed-Dose Combinations of Rifampicin, Isoniazid, and Pyrazinamide in Pediatric Patients With Tuberculosis: A Prospective Population Pharmacokinetic Study.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022, 08-24, Volume: 75, Issue:1

    In 2010, the World Health Organization (WHO) revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) tablet of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg, and suggest a new FDC with revised weight bands.. Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modeling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9), isoniazid (11.6-26.3), and pyrazinamide (233-429 mg ∙ h/L).. In total, 180 children (42% female; 13.9% living with human immunodeficiency virus [HIV]; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children < 6, 6-13, 13-20. and 20-25 kg, and 0.5 tablet in < 3-month-olds with immature metabolism, improved exposures to all 3 drugs.. Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight bands.

    Topics: Adult; Antitubercular Agents; Child; Drug Combinations; Ethambutol; Female; Humans; Infant; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Tablets; Tuberculosis

2022
No implication of HIV coinfection on the plasma exposure to rifampicin, pyrazinamide, and ethambutol in tuberculosis patients.
    Clinical and translational science, 2022, Volume: 15, Issue:2

    Topics: Adult; Antitubercular Agents; Ethambutol; HIV Infections; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2022
Safety of latent tuberculosis infection treatment in older patients with immune-mediated inflammatory diseases.
    Clinical rheumatology, 2022, Volume: 41, Issue:3

    Screening and treatment of latent tuberculosis infections (LTBI) are required before starting biologics in patients with immune-mediated inflammatory diseases (IMIDs). This study aimed to assess the safety of LTBI treatment in older patients with IMIDs.. The medical records of 916 patients treated for LTBI before the start of biologics for IMIDs between January 2004 and December 2018 were reviewed. The safety profiles of LTBI treatment were retrospectively compared according to age.. Among the 916 patients, 201 were aged > 60 years (older age group). The older age group showed female predominance, more frequent history of previous tuberculosis, and more comorbidities, and received biologics mainly for rheumatoid arthritis. Most patients (74.0%) took isoniazid and rifampicin daily for 3 months. The treatment completion rate was 90.4% in the overall population and was lower in the older age group (91.9% vs. 85.1%, P = 0.005). Adverse drug events were more frequent in the older age group (22.9% vs. 9.8%, P < 0.001); however, differences were mainly observed for nausea (5.5% vs. 2.1%, P = 0.016) and flu-like syndrome (6.5% vs. 1.7%, P = 0.001), but not hepatotoxicity.. LTBI treatment is generally safe in older patients with IMIDs, especially with respect to hepatotoxicity. Key points • The older age group had significantly more nausea and flu-like syndrome but not hepatotoxicity, compared to the younger age group. • LTBI treatment was acceptable and generally safe in the older age group.

    Topics: Aged; Antitubercular Agents; Female; Humans; Isoniazid; Latent Tuberculosis; Middle Aged; Retrospective Studies; Rifampin; Tuberculosis

2022
Detection of pulmonary tuberculosis in children using the Xpert MTB/RIF Ultra assay on sputum: a multicenter study.
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2022, Volume: 41, Issue:2

    Microbiological confirmation is rare in children with active tuberculosis; therefore, a more accurate test is needed to detect pulmonary tuberculosis in children. In this multicenter study, we evaluated the utility of the Xpert MTB/RIF Ultra (Ultra) on sputum, an assay recommended by the World Health Organization to test for childhood tuberculosis in high-burden settings. Children with symptoms suggestive of tuberculosis were enrolled at three hospitals in China and categorized as having active tuberculosis or nontuberculosis. The sensitivity and specificity of Ultra were 42.1% (48/114) and 99.0% (208/210), respectively. Using three MTB culture results as the reference, the sensitivity of Ultra in the subset of 38 children with culture-positive and 76 children with culture-negative was 68.4% (26/38) and 28.9% (22/76), respectively(p < 0.001). A single MTB culture combined with a single Ultra could detect 54 (54/114,47.4%) cases with active TB, while repeated MTB culture combined with a single Ultra detected 60 (60/114, 52.6%) cases with active TB(p = 0.427). Among 155 children (58 with TB and 97 with RTIs) simultaneously tested with the Ultra and Xpert MTB/RIF (Xpert), the sensitivity of the Xpert (24.1%, 14/58) was lower than that of the Ultra (41.4%, 24/58; p = 0.048). Eight children were found to have rifampin-resistant MTB strains. The Xpert MTB/RIF Ultra assay should be implemented to test for pulmonary tuberculosis in children to achieve higher confirmation rates.

    Topics: Adolescent; Antibiotics, Antitubercular; Child; Child, Preschool; China; Diagnostic Tests, Routine; Drug Resistance, Bacterial; Humans; Infant; Infant, Newborn; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2022
Retrospective evaluation of routine whole genome sequencing of
    Acta clinica Belgica, 2022, Volume: 77, Issue:5

    In all cases, the WGS-based procedure was able to identify correctly the MTB species. Compared to MGIT drug susceptibility testing (DST), the sensitivity and specificity of genetic prediction of resistance to first-line antibiotics were respectively 100 and 99% (rifampicin, RIF), 90.5 and 100% (isoniazid, INH), 100 and 98% (ethambutol, EMB) and 61.1 and 100% (pyrazinamide, PZA). The negative predictive value was above 95% for these four first-line drugs. A positive predictive value of 100% was calculated for INH and PZA, 80% for RIF and 45% for EMB.. Our study confirms the effectiveness of WGS for the rapid detection of

    Topics: Antitubercular Agents; Belgium; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing

2022
Pharmacokinetic features of dolutegravir with rifampicin and rifabutin among patients coinfected with human immunodeficiency virus and tuberculosis/mycobacterium avium complex.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2022, Volume: 116

    Rifamycins are the cornerstone of anti-tuberculosis therapy while they are potent inducers of drug metabolizing enzymes. For the first time, we evaluated the effect of rifampicin (RIF) and rifabutin (RBT) on the pharmacokinetics (PK) of dolutegravir (DTG) in patients with HIV and tuberculosis (TB)/ mycobacterium avium complex (MAC) co-infection.. Both HIV/TB (or MAC) co-infected patients and HIV infected patients without TB/MAC were enrolled. Patients in the RIF group received DTG 50 mg twice daily together with 600mg of RIF, while patients in the RBT group received DTG 50 mg once daily together with 300 mg of RBT. The DTG pharmacokinetic profiles in different groups were assessed.. A total of 13 subjects in the RIF group, 12 subjects in the RBT group, and 10 subjects in non-TB/MAC group were enrolled. The geometric mean ratio (GMR) of the trough concentration (Ctr) of DTG in the RIF group to non-TB/MAC group was 1.33 [90% confidence interval (CI):0.97 to 1.81], while the GMR of the maximum concentration (Cmax) of DTG was 1.29 (90% CI: 1.23 to 1.36). The GMR of the Ctr of DTG in the RBT group to non-TB/MAC group was 0.41 (90% CI: 0.30 to 0.57), while the GMR of the Cmax of DTG was 0.55 (90% CI: 0.52 to 0.57).. Due to the relatively low trough concentrations of DTG with RBT, DTG 50mg once daily together with RBT could only serve as an alternative option for HIV/TB (or MAC) co-infected patients.

    Topics: Coinfection; Heterocyclic Compounds, 3-Ring; HIV; HIV Infections; Humans; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Oxazines; Piperazines; Pyridones; Rifabutin; Rifampin; Tuberculosis

2022
Importance of asking a social history: atypical pulmonary infections and occupational hazards.
    BMJ case reports, 2022, Jan-17, Volume: 15, Issue:1

    Non-tuberculous mycobacteria (NTM) are ubiquitous in the environment, but NTM infection is limited to individuals with risk factors. We present a case of a 62-year-old man who presented with a 1 year history of cough and shortness of breath. History was notable for significant tobacco use and work as a sandblaster without the use of personal protective equipment. His chest X-ray showed bilateral upper lobe cavitary lesions, which were redemonstrated on chest CT. A sputum Gram stain was positive for acid-fast bacilli, but his tuberculosis QuantiFERON was negative. He was started on empiric tuberculosis treatment. Sputum cultures ultimately returned for

    Topics: Ethambutol; Humans; Male; Middle Aged; Mycobacterium avium Complex; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Rifampin; Tuberculosis

2022
Determinants, risk factors and spatial analysis of multi-drug resistant pulmonary tuberculosis in Jodhpur, India.
    Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, 2022, Jan-18, Volume: 92, Issue:4

    This study was planned to estimate the proportion of confirmed multi-drug resistance pulmonary tuberculosis (TB) cases out of the presumptive cases referred to DTC (District Tuberculosis Center) Jodhpur for diagnosis; to identify clinical and socio-demographic risk factors associated with the multidrug-resistant pulmonary TB and to assess the spatial distribution to find out clustering and pattern in the distribution of pulmonary TB with the help of Geographic Information System (GIS). In the Jodhpur district, 150 confirmed pulmonary multi-drug resistant tuberculosis (MDR-TB) cases, diagnosed by probe-based molecular drug susceptibility testing method and categorized as MDR in DTC's register (District Tuberculosis Center), were taken. Simultaneously, 300 control of confirmed non-MDR or drug-sensitive pulmonary TB patients were taken. Statistical analysis was done with logistic regression. In addition, for spatial analysis, secondary data from 2013-17 was analyzed using Global Moran's I and Getis and Ordi (Gi*) statistics. In 2012-18, a total of 12563 CBNAAT (Cartridge-based nucleic acid amplification test) were performed. 2898 (23%) showed M. TB positive but rifampicin sensitive, and 590 (4.7%) showed rifampicin resistant. Independent risk factors for MDR TB were ≤60 years age (AOR 3.0, CI 1.3-7.1); male gender (AOR 3.4, CI 1.8-6.7); overcrowding (AOR 1.6, CI 1.0-2.7); using chulha (smoke appliance) for cooking (AOR 2.5, CI 1.2-4.9), past TB treatment (AOR 5.7, CI 2.9-11.3) and past contact with MDR patient (AOR 10.7, CI 3.7-31.2). All four urban TUs (Tuberculosis Units) had the highest proportion of drug-resistant pulmonary TB. There was no statistically significant clustering, and the pattern of cases was primarily random. Most of the hotspots generated were present near the administrative boundaries of TUs, and the new ones mostly appeared in the area near the previous hotspots. A random pattern seen in cluster analysis supports the universal drug testing policy of India. Hotspot analysis helps cross administrative border initiatives with targeted active case finding and proper follow-up.

    Topics: Humans; India; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Risk Factors; Smoke; Spatial Analysis; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2022
The feasibility of rifampicin Re-administration in patients with tuberculosis and Clostridioides difficile infection.
    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 2022, Volume: 28, Issue:4

    The effects of a rifampicin (RIF) on the evolution of Clostridioides difficile infection (CDI) have not previously been investigated and there is currently no consensus on whether RIF re-administration is feasible.. This retrospective observational study included consecutive tuberculosis (TB) patients diagnosed with comorbid RIF-associated CDI (RA-CDI) using strict diagnostic criteria. We investigated the association between RA-CDI and clinical outcomes, and also examined the feasibility of re-administering RIF.. Out of the 11,230 patients were admitted to TB ward at our hospital, 156 TB patients (1.4%) were diagnosed with CDI and the overall incidence of CDI was calculated as 2.1 cases per 10,000 patient-days. Of 156 patients with CDI, 86 were diagnosed with RA-CDI, of whom 28 (32.6%) were re-administered with RIF. In the re-administration group, time to initial sputum smear conversion was significantly shorter than for patients who were not re-administered with RIF (42 days [interquartile range, IQR: 35-65] vs. 55 days [IQR: 44-70], p = 0.041). Further, RIF re-administration significantly reduced length of hospital stay (69 days [IQR: 66-82] vs. 81 days [IQR: 72-89], p = 0.014). Ten patients (35.7%) had recurrent CDI after RIF re-administration. On the other hand, 15 patients (53.6%) were able to continue their TB treatment, including the RIF regimen.. The present study strengthens the argument for including RIF in the list of antibiotics that can induce CDI, particularly in elderly men suffering from underlying conditions. Although careful attention must be paid to the possibility of CDI recurrence, a strategy of re-administration of RIF is feasible.

    Topics: Aged; Clostridium Infections; Feasibility Studies; Humans; Male; Rifampin; Sputum; Tuberculosis

2022
Estimating tuberculosis drug resistance amplification rates in high-burden settings.
    BMC infectious diseases, 2022, Jan-24, Volume: 22, Issue:1

    Antimicrobial resistance develops following the accrual of mutations in the bacterial genome, and may variably impact organism fitness and hence, transmission risk. Classical representation of tuberculosis (TB) dynamics using a single or two strain (DS/MDR-TB) model typically does not capture elements of this important aspect of TB epidemiology. To understand and estimate the likelihood of resistance spreading in high drug-resistant TB incidence settings, we used epidemiological data to develop a mathematical model of Mycobacterium tuberculosis (Mtb) transmission.. A four-strain (drug-susceptible (DS), isoniazid mono-resistant (INH-R), rifampicin mono-resistant (RIF-R) and multidrug-resistant (MDR)) compartmental deterministic Mtb transmission model was developed to explore the progression from DS- to MDR-TB in The Philippines and Viet Nam. The models were calibrated using data from national tuberculosis prevalence (NTP) surveys and drug resistance surveys (DRS). An adaptive Metropolis algorithm was used to estimate the risks of drug resistance amplification among unsuccessfully treated individuals.. The estimated proportion of INH-R amplification among failing treatments was 0.84 (95% CI 0.79-0.89) for The Philippines and 0.77 (95% CI 0.71-0.84) for Viet Nam. The proportion of RIF-R amplification among failing treatments was 0.05 (95% CI 0.04-0.07) for The Philippines and 0.011 (95% CI 0.010-0.012) for Viet Nam.. The risk of resistance amplification due to treatment failure for INH was dramatically higher than RIF. We observed RIF-R strains were more likely to be transmitted than acquired through amplification, while both mechanisms of acquisition were important contributors in the case of INH-R. These findings highlight the complexity of drug resistance dynamics in high-incidence settings, and emphasize the importance of prioritizing testing algorithms which allow for early detection of INH-R.

    Topics: Antitubercular Agents; Drug Resistance; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
[A Case of Intra-abdominal Tuberculosis Due to Mycobacterium bovis Mimicking Ovarian Cancer: Importance of Microbiological Diagnosis].
    Mikrobiyoloji bulteni, 2022, Volume: 56, Issue:1

    Mycobacterium bovis causes gastrointestinal tuberculosis by being transmitted through consumption of infected milk and dairy products, mostly in developing countries, and can spread to the other neighbourhood intra-abdominal tissues and organs. In addition to the symptoms such as weight loss, weakness, abdominal pain, and chronic diarrhea in female patients with abdominal tuberculosis, findings such as pelvic mass, ascites and CA-125 elevation may be encountered. Patients with these symptoms usually preliminary diagnosed as having ovarian cancer. It is very important to distinguish between these two diseases quickly, which have different treatment protocols. In this case report, a case of intra-abdominal tuberculosis caused by M.bovis, whose diagnosis was confirmed by microbiological methods with the findings mimicking ovarian cancer such as weight loss, ascites, pelvic mass and increased CA-125 was presented. Tuberculosis was considered in the differential diagnosis of a 23-yearold female patient with abdominal pain, weight loss, ascites, pelvic mass, and elevated CA-125 (643.9 U/ml) findings and a mass in the left tubaovarian region on abdominal CT. The ileum biopsy sample taken during colonoscopy and ascitic fluid sample taken with paracentesis were sent to our laboratory for acid-fast bacilli (AFB) staining and tuberculosis culture. In our laboratory, samples were incubated in both liquid culture system [BACTEC MGIT 320 Mycobacteria Culture System (Becton Dickinson,USA)] and solid culture medium [Lowenstein-Jensen Medium (Becton Dickinson,USA)] and AFB smears were performed. While AFB smears were negative, ileum biopsy material showed growth on day 14 and ascitic fluid sample on day 11 in liquid culture medium. AFB smear was prepared from broth and red bacilli were seen on a blue background that formed cord factor. The bacillus was identified as Mycobacterium tuberculosis complex by the immunochromatographic rapid test [BD MGIT TBc Identification Test (BD,USA)]. The anti-tuberculosis drug treatment was initiated with the diagnosis of intra-abdominal tuberculosis. The isolated bacillus was found to be sensitive to isoniazid, rifampicin, ethambutol and resistant to streptomycin, according the drug susceptibility test results. Subspecies identification of M.tuberculosis complex was investigated by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) but could not be determined by this method. Genotyping was performe

    Topics: Adult; Female; Humans; Mycobacterium bovis; Mycobacterium tuberculosis; Ovarian Neoplasms; Rifampin; Tuberculosis; Young Adult

2022
ANALYSIS OF THE EFFECTIVENESS OF DIFFERENT TREATMENT REGIMENS FOR DRUG-RESISTANT TUBERCULOSIS IN PRYKARPATTIA. CHALLENGES OF OUR TIME.
    Wiadomosci lekarskie (Warsaw, Poland : 1960), 2022, Volume: 75, Issue:1

    The aim: To study the structure of adverse drug reactions and the effectiveness of treatment among patients with drug-resistant tuberculosis who follow the modified short-term and individualized treatment regimens.. Materials and methods: The analysis of 138 inpatient medical records, outpatient health cards and electronic database of the patient register was conducted. Resistant strains of MTB were microbiologically verified in all the patients. All the patients underwent clinical-laboratory, instrumental microbiological, genetic-molecular (GeneXpert MTB / RIF) methods of examination, both for diagnosis and monitoring of the effectiveness of treatment. In order to prevent complications and control adverse reactions, all the patients were briefly screened for peripheral neuropathy, basic audiometry, the QTc interval was determined, visual acuity and color perception were checked.. Results: At individualized treatment regimen of tuberculosis, adverse reactions were 3.5 times more common than in patients with modified short-term therapy, in 65 (68.4%) cases and in 8 (18.6%) cases, respectively. Accordingly, the effectiveness of treatment differed in both groups. Prevailing in long-term treatment were: treatment interruption treatment gap, treatment failure, continued treatment. In patients receiving short-term regimens, the cured rate was almost twice as common as in the second group.. Conclusions: Timely detection cases of resistant tuberculosis and using linear probe analysis (LPA) - GenoType MTBDRplus for diagnosis of fluoroquinolone resistance, will allow the use of modified short-term treatment regimens for tuberculosis. Which in turn will reduce the number of side effects and improve the outcome of treatment.

    Topics: Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Tuberculosis/COVID-19 co-infection detected in a single sputum sample using a rapid molecular test.
    Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology], 2022, Volume: 53, Issue:2

    Tuberculosis (TB) and COVID-19 affect the lungs and are transmitted mainly by aerosols or particles of saliva from infected persons. Clinical similarities between diseases can affect correct diagnosis. Individuals belonging to the population deprived of liberty (PDL) are at increased risk of contagion due to precarious sanitary conditions and overcrowded environments. A variety of specimens may be suitable for the diagnosis of COVID-19, using molecular diagnostic techniques; however, there is little data on the analysis of sputum samples with the Xpert Xpress SARS-CoV-2® for the diagnosis of COVID-19, especially in this population group. The present study reports a case of TB and COVID-19 co-infection detected in sputum from an individual belonging to the PDL. For the detection, it used the GeneXpert platform (Cepheid, USA). Mycobacterium tuberculosis complex (MTC) was detected using the Xpert MTB/RIF Ultra® cartridge and SARS-CoV-2 was detected using the Xpert Xpress SARS-CoV-2® cartridge. The genes IS6110 and IS1081 were detected within 80 min indicating the presence of MTC, with no mutations related to resistance to rifampicin. The SARS-CoV-2 E and N2 genes were detected within 45 min. The result was confirmed by RT-qPCR with detection of E, N, and RdRP/S genes in the sputum and nasopharyngeal (NP) specimens. Rapid diagnoses that allow the identification and differentiation of such diseases are important for adequate epidemiological surveillance, isolation of infected individuals, and interruption of the transmission chain. Using the GeneXpert platform, specimens can be tested as soon as they are received, without the need for prior preparation. The US Food and Drug Administration has issued emergency authorization for the use of the Cepheid Xpert Xpress SARS-CoV-2 for the rapid detection of SARS-CoV-2 using specimens from a NP or nasal wash/aspirate. The case presented here gains an innovation with the use of the sputum to COVID-19 diagnosis.

    Topics: Coinfection; COVID-19; COVID-19 Testing; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; SARS-CoV-2; Sensitivity and Specificity; Sputum; Tuberculosis

2022
Surface-enhanced Raman spectroscopy of polymerase chain reaction (PCR) products of Rifampin resistant and susceptible tuberculosis patients.
    Photodiagnosis and photodynamic therapy, 2022, Volume: 38

    Raman spectroscopy is an effective tool for detecting and discriminating microorganisms that is robust, reliable, and rapid.. To develop a polymerase chain reaction technique (PCR) based on Surface Enhanced Raman Spectroscopy (SERS) technique with principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were used to assess diagnostic capability of SERS for distinguishing between tuberculosis (TB) positive rifampin resistant and tuberculosis (TB) positive rifampin susceptible samples.. Silver nanoparticles (Ag NPs) were used as SERS substrates and technique was used to distinguish TB positive rifampin (RIF) resistant and TB positive rifampin (RIF) susceptible patients on the basis of characteristic SERS spectral features of their respective PCR products. SERS spectra were acquired from 52 samples of PCR products including 22 samples of TB positive rifampin susceptible, 30 samples of TB positive rifampin resistant and negative control samples. All these samples were collected from individuals of same age. Furthermore, multivariate data analyses techniques such as PCA and PLS-DA were used to assess diagnostic capability of SERS for distinguishing between TB positive rifampin resistant and TB positive rifampin susceptible samples.. PCA is found helpful for successful differentiation among these two groups of spectral data sets. Moreover, PLS-DA provides this classification quantitatively by predicting the class of SERS spectral data set with 73% area under curve, 96% sensitivity, 95.6% specificity and 95% accuracy.. SERS can be employed for the rapid distinguishing between TB positive rifampin resistant and TB positive rifampin susceptible samples.

    Topics: Humans; Metal Nanoparticles; Mycobacterium tuberculosis; Photochemotherapy; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Silver; Spectrum Analysis, Raman; Tuberculosis

2022
The Structural Basis of
    Molecules (Basel, Switzerland), 2022, Jan-28, Volume: 27, Issue:3

    Tuberculosis (TB), caused by the

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Models, Molecular; Mycobacterium tuberculosis; Point Mutation; Rifampin; Tuberculosis

2022
Pooled testing of sputum with Xpert MTB/RIF and Xpert Ultra during tuberculosis active case finding campaigns in Lao People's Democratic Republic.
    BMJ global health, 2022, Volume: 7, Issue:2

    Active case finding (ACF) of individuals with tuberculosis (TB) is a key intervention to find the 30% of people missed every year. However, ACF requires screening large numbers of individuals who have a low probability of positive results, typically <5%, which makes using the recommended molecular tests expensive.. We conducted two ACF surveys (in 2020 and 2021) in high TB burden areas of Lao PDR. Participants were screened for TB symptoms and received a chest X-ray. Sputum samples of four consecutive individuals were pooled and tested with Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF) (Xpert-MTB/RIF) (2020) or Xpert-Ultra (2021). The agreement of the individual and pooled samples was compared and the reasons for discrepant results and potential cartridge savings were assessed.. Each survey included 436 participants, which were tested in 109 pools. In the Xpert-MTB/RIF survey, 25 (sensitivity 89%, 95% CI 72.8% to 96.3%) of 28 pools containing MTB-positive samples tested positive and 81 pools containing only MTB-negative samples tested negative (specificity 100%, 95% CI 95.5% to 100%). In the Xpert-Ultra survey, all 32 (sensitivity 100%, 95% CI 89.3% to 100%) pools containing MTB-positive samples tested positive and all 77 (specificity 100%, 95% CI 95.3% to 100%) containing only MTB-negative samples tested negative. Pooling with Xpert-MTB/RIF and Xpert-Ultra saved 52% and 46% (227/436 and 199/436, respectively) of cartridge costs alone.. Testing single and pooled specimens had a high level of agreement, with complete concordance when using Xpert-Ultra. Pooling samples could generate significant cartridge savings during ACF campaigns.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Laos; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2022
Drug-Resistant Characteristics, Genetic Diversity, and Transmission Dynamics of Rifampicin-Resistant Mycobacterium tuberculosis in Hunan, China, Revealed by Whole-Genome Sequencing.
    Microbiology spectrum, 2022, 02-23, Volume: 10, Issue:1

    To gain a deep insight into the additional drug-resistant profiles, genetic diversity, and transmission dynamics of rifampicin-resistant tuberculosis (RR-TB) circulating in Hunan province, drug susceptibility testing and whole-genome-sequencing were performed among RR-TB strains collected from Jan. 2013 to Jun. 2018 in Hunan province. A total of 124 RR-TB strains were recovered successfully and included into the final analysis. Lineage 2.2.1 was the dominant sublineage, accounting for 72.6% (90/124), followed by lineage 4.5 (11.3%, 14/124), lineage 4.4 (8.1%, 10/124), lineage 4.2 (6.5%, 8/124) and lineage 2.2.2 (1.6%, 2/124). Overall, 83.1% (103/124) and 3.2% (4/124) of RR-TB were MDR-TB and XDR-TB, respectively. Nearly 30% of RR-TB isolates were resistant to fluoroquinolones, and 26.6% (33/124) were pre-XDR-TB. Moreover, 30.6% (38/124) of RR-TB strains were identified as phenotypically resistance to pyrazinamide. Totally, 17 clusters containing 48 (38.7%, 48/124) RR-TB strains were identified, ranging in size from 2 to 10 isolates. No significant difference was detected in clustering rate between lineage 2 and lineage 4 (

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; China; Drug Resistance, Multiple, Bacterial; Female; Genetic Variation; Genome, Bacterial; Genotype; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Epidemiology; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Whole Genome Sequencing; Young Adult

2022
Characterization of probes associated with rifampicin resistance in M.tuberculosis detected by GenXpert from a national reference laboratory at Chennai.
    Tuberculosis (Edinburgh, Scotland), 2022, Volume: 133

    With increasing use of Xpert MTB/RIF a point of care molecular test for simultaneous detection of TB and resistance to rifampicin, a growing number of rifampicin resistant cases are being detected and notified. Insights into the variation and frequencies in the probe mutations obtained through Xpert testing in the RRTB case will form the baseline information for further investigation on drug resistance. In this study we did a retrospective analysis of the GeneXpert data obtained from patient samples received at a National reference laboratory in Chennai between the years 2014 and 2020 to look at the probe distribution, the variation in the mutation and explore its significance. Probe E mutation was most commonly identified followed by Probe D, Probe A, Probe B and Probe C. Coexistence of multiple probe mutations in low bacillary load samples could be related to prolonged amplification cycle leading to delayed hybridization of probes. In such instances reporting false RR in xpert testing is possible. The probe mutations of RR should be monitored in depth with inclusion of codon specific targets for management of drug sensitive TB. In addition, heteroresistance needs to be further tested by alternative genotypic methods to avoid false resistance.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; India; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
High Prevalence of Tuberculosis Infection and Disease in Child Household Contacts of Adults With Rifampin-resistant Tuberculosis.
    The Pediatric infectious disease journal, 2022, 05-01, Volume: 41, Issue:5

    Household contact (HHC) investigation is an important strategy to identify individuals with tuberculosis (TB) exposure, infection and disease, including those who may benefit from tuberculosis preventive therapy (TPT). Data in children exposed to rifampin-resistant TB are limited.. In preparation for and to inform the feasibility of an interventional trial, HHC of adults with pulmonary rifampin-resistant TB from high TB-burden countries were evaluated in a cross-sectional study. Using interferon-gamma release assay and study-specific and 2015 international consensus definitions of intrathoracic TB in children, we evaluated the prevalence and predictors of TB infection and disease in child (<15 years) HHCs.. Of 303 child HHCs, median age (range) 7 years (0-14), 57% [95% confidence interval (CI): 50%-64%] had a positive interferon-gamma release assay result (TB infected). TB infection was associated with the index case smoking (P = 0.034), being the parent or sleeping in the same room (P = 0.002) and the child HHC being age ≥5 years and having attended school (P = 0.013). Four had study-defined confirmed TB and 9 had probable TB, a prevalence of 4.3% (95% CI: 2.6%-7.1%). Using the international consensus definitions, 4 had confirmed TB and 49 had unconfirmed TB, a prevalence of 17.2% (95% CI: 12.9%-22.4%). Twenty (7%) children had received TPT.. The prevalence of TB infection and disease was high in child HHC exposed to rifampin-resistant TB. Few children had routinely received TPT. High-quality evidence is needed to inform strong recommendations for and access to TPT in children exposed to TB resistant to rifampin.

    Topics: Adult; Child; Child, Preschool; Cross-Sectional Studies; Humans; Latent Tuberculosis; Prevalence; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2022
A cost-benefit algorithm for rapid diagnosis of tuberculosis and rifampicin resistance detection during mass screening campaigns.
    BMC infectious diseases, 2022, Mar-04, Volume: 22, Issue:1

    Active tuberculosis (TB) case finding is important as it helps detect pulmonary TB cases missed by the other active screening methods. It requires periodic mass screening in risk population groups such as prisoners and refugees. Unfortunately, in these risk population groups periodic mass screening can be challenging due to lengthy turnaround time (TAT), cost and implementation constraints. The aim of this study was to evaluate a diagnostic algorithm that can reduce the TAT and cost for TB and Rifampicin resistance (RR) detection. The algorithm involves testing with TB-LAMP followed by Xpert MTB/RIF for positive TB-LAMP cases to diagnose TB during mass campaigns in prisons and refugee camps.. The National Tuberculosis Control Program (NTCP) organized routine TB mass-screening campaigns in 34 prisons and 3 villages with refugees camps in Cameroon in 2019. TB LAMP was used for initial TB diagnosis and all TB-LAMP positive cases tested with the Xpert MTB/RIF assay to determine RR. TAT and cost benefits analysis of the combined use of TB-LAMP and Xpert MTB/RIF assays was determined and compared to the Xpert MTB/RIF assay when used only.. A total of 4075 sputum samples were collected from TB presumptive, 3672 cases in 34 prisons and 403 samples in 3 villages. Of the 4,075 samples screened with TB-LAMP, 135 were TB positive (3.31%) and run on the Xpert MTB/RIF. Of the 135 positives cases, Xpert MTB/RIF revealed 3 were RR (2.22%). The use of TB-LAMP followed by testing with Xpert MTB/RIF for TB and RR detection reduced the TAT by 73.23% in prisons and 74.92% in villages. In addition to a reduced TAT, the two molecular tests used in synergy is cost benefit from year 2 onwards.. This study demonstrates the advantages of a diagnostic algorithm based on an initial testing with TB-LAMP followed by testing with Xpert MTB/RIF for TB diagnosis. This approach improved early and rapid TB detection with an added advantage of providing RR status. The proposed algorithm is effective and less costly from the second year of implementation and should be used by TB control programs.

    Topics: Algorithms; Antibiotics, Antitubercular; Cost-Benefit Analysis; Humans; Mass Screening; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2022
Time to start of tuberculosis treatment in penitentiary system of Kyrgyz Republic: A retrospective cohort study.
    PloS one, 2022, Volume: 17, Issue:3

    Tuberculosis burden among the incarcerated population is generally higher than that of general population. Early diagnosis and prompt initiation of treatment are key strategies to contain disease transmission. The aim of this study was to determine the time to treatment initiation among inmates with new smear or Xpert MTB/RIF positive pulmonary tuberculosis and explore risk factors associated with delayed treatment initiation in prison settings.. We conducted a retrospective cohort study using routine health care data from prison settings in Kzrgyz Republic on new pulmonary tuberculosis patients confirmed by smear microscopy or GeneXpert MTB/RIF during 2014-2019. We computed delay in start of treatment-days from specimen collection to treatment initiation-for exposure variables. We dichotomized treatment delay using 10-day cut-off point,and used logistic regression to identify factors associated with treatment delay.. Among 406 cases included into analysis, the median delay to treatment initiation was 7 days [IQR: 2-16 days]. Using 10-day cut-off, 189 (46.6%) patients had delayed treatment initiation. Treatment delay was negatively associated with smear positivity [adjusted OR (aOR) = 0.44, 95% CI 0.29-0.68] compared to smear negative patients, while patients with isoniazid resistant (aOR = 2.61, 95%CI 1.49-4.56) and rifampicin resistant tuberculosis (aOR = 4.14, 95%CI 2.56-6.77) had increased delay compared to patients who were sensitive for both rifampicin and isoniazid.. Timely diagnosis and effective treatment remain the cornerstone of TB control program populations in the general and in prison settings in particular. Prison authorities need to address all potential areas of delay in TB diagnosis and treatment to strengthen their TB control efforts so that prisons remain free of TB for detainees, prison staff and visitors. These include improved supply of TB drugs, early detection of TB cases and improved collaboration with the health authorities outside the prison system.

    Topics: Humans; Isoniazid; Kyrgyzstan; Mycobacterium tuberculosis; Prisons; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2022
Four-Month Rifapentine Regimens for Tuberculosis.
    The New England journal of medicine, 2022, 03-17, Volume: 386, Issue:11

    Topics: Humans; Rifampin; Tuberculosis

2022
Four-Month Rifapentine Regimens for Tuberculosis. Reply.
    The New England journal of medicine, 2022, 03-17, Volume: 386, Issue:11

    Topics: Humans; Rifampin; Tuberculosis

2022
Assessment of the efficacy of clofazimine alone and in combination with primary agents against Mycobacterium tuberculosis in vitro.
    Journal of global antimicrobial resistance, 2022, Volume: 29

    The chemotherapeutic regimens of patients with drug-susceptible (DS)- tuberculosis (TB) comprise four primary anti-TB drugs: rifampicin (RMP), isoniazid (INH), ethambutol (EMB) and pyrazinamide (PZA), administered for six-to-nine months. These drug regimens target the various microbial populations that include actively replicating (AR), slow-replicating (SR) and non-replicating (NR) organisms. Clofazimine (CFZ) has showed benefit in shortening DS-TB treatment in vivo from six to four months when used in combination with this regimen in murine models of experimental infection. However, its antimicrobial efficacy when used in combination with the primary drugs against the various microbial populations of Mycobacterium tuberculosis has not been demonstrated.. In the current in vitro study, the inhibitory and bactericidal activities of CFZ in combination with the primary anti-TB drugs, RMP, INH and EMB against the AR and SR organisms in planktonic and biofilm-forming cultures, respectively, were evaluated by fractional inhibitory concentration index (FICI) and fractional bactericidal concentration index (FBCI) determinations, using the Loewe Additivity Model.. In planktonic cultures, CFZ demonstrated synergistic growth inhibitory activity in combination with RMP and INH individually and collectively. With respect to bactericidal activity, CFZ exhibited synergistic activity only in a two-drug combination with RMP. However, in biofilm-forming cultures, all CFZ-containing anti-TB drug combinations exhibited synergistic inhibitory and bactericidal effects, particularly in combination with RIF and INH.. Clofazimine exhibited synergistic effects in combination with primary anti-TB drugs against both planktonic and biofilm-forming cultures, showing potential benefit in augmenting treatment outcome when used during standard TB chemotherapy.

    Topics: Animals; Antitubercular Agents; Clofazimine; Ethambutol; Humans; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

2022
Performance of Xpert Ultra nasopharyngeal swab for identification of tuberculosis deaths in northern Tanzania.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2022, Volume: 28, Issue:8

    Numerous tuberculosis (TB) deaths remain undetected in low-resource endemic settings. With autopsy-confirmed tuberculosis as our standard, we assessed the diagnostic performance of Xpert MTB/RIF Ultra (Ultra; Cepheid) on nasopharyngeal specimens collected postmortem.. From October 2016 through May 2019, we enrolled pediatric and adult medical deaths to a prospective autopsy study at two referral hospitals in northern Tanzania with next-of-kin authorization. We swabbed the posterior nasopharynx prior to autopsy and tested the samples later by Ultra. At autopsy we collected lung, liver, and, when possible, cerebrospinal fluid for mycobacterial culture and histopathology. Confirmed tuberculosis was defined as Mycobacterium tuberculosis complex recovery by culture with consistent tissue histopathology findings; decedents with only histopathology findings, including acid-fast staining or immunohistochemistry, were defined as probable tuberculosis.. Of 205 decedents, 78 (38.0%) were female and median (range) age was 45 (0,96) years. Twenty-seven (13.2%) were found to have tuberculosis at autopsy, 22 (81.5%) confirmed and 5 (18.5%) probable. Ultra detected M. tuberculosis complex from the nasopharynx in 21 (77.8%) of 27 TB cases (sensitivity 70.4% [95% confidence interval {CI} 49.8-86.2%], specificity 98.9% [95% CI 96.0-99.9%]). Among confirmed TB, the sensitivity increased to 81.8% (95% CI 59.7-94.8%). Tuberculosis was not included as a death certificate diagnosis in 14 (66.7%) of the 21 MTBc detections by Ultra.. Nasopharyngeal Ultra was highly specific for identifying in-hospital tuberculosis deaths, including unsuspected tuberculosis deaths. This approach may improve tuberculosis death enumeration in high-burden countries.

    Topics: Adult; Child; Female; Humans; Male; Mycobacterium tuberculosis; Nasopharynx; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tanzania; Tuberculosis; Tuberculosis, Pulmonary

2022
Lack of reactivation of tuberculosis in patients with psoriasis treated with secukinumab in a real-world setting of latent tuberculosis infection.
    The Journal of dermatological treatment, 2022, Volume: 33, Issue:5

    Some biologics for psoriasis, especially anti-tumor necrosis factor (TNF)-α therapies, may re-activate latent tuberculosis (TBC) infection with consequent morbidity and mortality. However, there is a low reported incidence of conversion to positive TBC status among patients with psoriasis treated with second-generation biologic therapies, particularly anti-interleukin (IL)-17 therapies such as secukinumab.. To evaluate the safety profile of secukinumab in psoriasis patients with latent TBC infection.. Real-life data were collected by retrospective chart review on patients with moderate-to-severe psoriasis who showed positivity for TBC screening at baseline and underwent secukinumab treatment for psoriasis at six Italian centers. Patients received secukinumab 300 mg at week 0/1/2/3/4, then every 4 weeks.. Fifty-nine patients were enrolled; 30.5% also had psoriatic arthritis and other comorbidities were common. At baseline, the mean psoriasis duration was 14.5 years. Ten (17%) patients did not undergo prophylaxis before starting secukinumab. Conversely, isoniazid ± rifampicin or rifampicin alone prophylaxis was administered in 49/59 (83.1%) patients. After a mean treatment duration of 84 weeks, there were no cases of TBC reactivation and no unexpected safety signals.. Secukinumab use over an extended period was safe in psoriasis patients with latent TBC, even in patients who did not receive chemoprophylaxis.

    Topics: Antibodies, Monoclonal, Humanized; Humans; Isoniazid; Latent Tuberculosis; Psoriasis; Retrospective Studies; Rifampin; Severity of Illness Index; Treatment Outcome; Tuberculosis

2022
Tuberculosis Co-Infection Is Common in Patients Requiring Hospitalization for COVID-19 in Belarus: Mixed-Methods Study.
    International journal of environmental research and public health, 2022, 04-05, Volume: 19, Issue:7

    A significant drop in tuberculosis (TB) case-finding has been widely reported during the period of the COVID-19 pandemic. To address a decrease in TB notification, Belarus introduced laboratory TB testing in patients with the laboratory-confirmed coronavirus disease 2019 (COVID-19). We conducted a secondary analysis of health records among 844 patients with laboratory-confirmed COVID-19 diagnosis who were admitted to repurposed departments at TB hospitals and who were tested by Xpert MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) in five Belarus regions between April and October 2021. Quantitative analysis followed by 13 individual interviews with health managers, physicians, and nurses participating in the intervention. Most patients were male (64%) and mean age was 43.5 ± 16 years. One in twenty (n = 47, 5.6%) patients were co-infected with active pulmonary TB, and over one-third of them (n = 18) had rifampicin resistance. In-hospital mortality was comparable in patients with and without TB co-infection (2.1% and 2.3% respectively, p > 0.99). Laboratory TB testing among patients with COVID-19 at repurposed departments of TB hospitals is feasible in Belarus and may improve TB case-finding.

    Topics: Adult; Antibiotics, Antitubercular; Coinfection; COVID-19; COVID-19 Testing; Hospitalization; Humans; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; Pandemics; Republic of Belarus; Rifampin; Sensitivity and Specificity; Tuberculosis

2022
Elevated Levels of Three Reactive Oxygen Species and Fe(II) in the Antibiotic-Surviving Population of Mycobacteria Facilitate
    Antimicrobial agents and chemotherapy, 2022, 05-17, Volume: 66, Issue:5

    Topics: Anti-Bacterial Agents; Ferrous Compounds; Humans; Hydrogen Peroxide; Hydroxyl Radical; Mycobacterium smegmatis; Mycobacterium tuberculosis; Reactive Oxygen Species; Rifampin; Superoxides; Tuberculosis

2022
Whole genome sequencing of multidrug-resistant Mycobacterium tuberculosis isolates collected in the Czech Republic, 2005-2020.
    Scientific reports, 2022, 05-03, Volume: 12, Issue:1

    The emergence and spread of resistant tuberculosis (TB) pose a threat to public health, so it is necessary to diagnose the drug-resistant forms in a clinically short time frame and closely monitor their transmission. In this study, we carried out a first whole genome sequencing (WGS)-based analysis of multidrug resistant (MDR) M. tuberculosis strains to explore the phylogenetic lineages diversity, drug resistance mechanisms, and ongoing transmission chains within the country. In total, 65 isolates phenotypically resistant to at least rifampicin and isoniazid collected in the Czech Republic in 2005-2020 were enrolled for further analysis. The agreement of the results obtained by WGS with phenotypic drug susceptibility testing (pDST) in the determination of resistance to isoniazid, rifampicin, pyrazinamide, streptomycin, second-line injectables and fluoroquinolones was more than 80%. Phylogenetic analysis of WGS data revealed that the majority of MDR M. tuberculosis isolates were the Beijing lineage 2.2.1 (n = 46/65; 70.8%), while the remaining strains belonged to Euro-American lineage. Cluster analysis with a predefined cut-off distance of less than 12 single nucleotide polymorphisms between isolates showed 19 isolates in 6 clusters (clustering rate 29.2%), located mainly in the region of the capital city of Prague. This study highlights the utility of WGS as a high-resolution approach in the diagnosis, characterization of resistance patterns, and molecular-epidemiological analysis of resistant TB in the country.

    Topics: Antitubercular Agents; Czech Republic; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Phylogeny; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing

2022
Cationic inhalable particles for enhanced drug delivery to M. tuberculosis infected macrophages.
    Biomaterials advances, 2022, Volume: 133

    Inhalable microparticle-based drug delivery platforms are being investigated extensively for Tuberculosis (TB) treatment as they offer efficient deposition in lungs and improved pharmacokinetics of the encapsulated cargo. However, the effect of physical parameters of microcarriers on interaction with Mycobacterium tuberculosis (Mtb) infected mammalian cells is underexplored. In this study, we report that Mtb-infected macrophages are highly phagocytic and microparticle surface charge plays a major role in particle internalization by infected cells. Microparticles of different sizes (0.5-2 μm) were internalized in large numbers by Mtb-infected THP-1 macrophages and murine primary Bone Marrow Derived Macrophages in vitro. Drastic improvement in particle uptake was observed with cationic particles in vitro and in mice lungs. Rapid uptake of rifampicin-loaded cationic microparticles allowed high intracellular accumulation of the drug and led to enhanced anti-bacterial function when compared to non-modified rifampicin-loaded microparticles. Cytocompatibility assay and histological analysis in vivo confirmed that the formulations were safe and did not elicit any adverse reaction. Additionally, pulmonary delivery of cationic particles in mice resulted in two-fold higher uptake in resident alveolar macrophages compared to non-modified particles. This study provides a framework for future design of drug carriers to improve delivery of anti-TB drugs inside Mtb-infected cells.

    Topics: Animals; Antitubercular Agents; Macrophages; Mammals; Mice; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2022
Oral Swab Specimens Tested With Xpert MTB/RIF Ultra Assay for Diagnosis of Pulmonary Tuberculosis in Children: A Diagnostic Accuracy Study.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022, 12-19, Volume: 75, Issue:12

    Microbiologic diagnosis of childhood tuberculosis may be difficult. Oral swab specimens are a potential noninvasive alternative to sputum specimens for diagnosis.. This was a prospective diagnostic accuracy study of oral swab specimens (buccal and tongue) for pulmonary tuberculosis diagnosis in children (aged ≤ 15 years) in 2 South African hospital sites. Children with cough of any duration as well as a positive tuberculin skin test result, tuberculosis contact, loss of weight, or chest radiograph suggestive of pulmonary tuberculosis were enrolled. Two induced sputum specimens were tested with Xpert MTB/RIF (or Xpert MTB/RIF Ultra) assay and liquid culture. Oral swab specimens were obtained before sputum specimens, frozen, and later tested with Xpert MTB/RIF Ultra. Children were classified as microbiologically confirmed tuberculosis, unconfirmed tuberculosis (receipt of tuberculosis treatment), or unlikely tuberculosis according to National Institutes of Health consensus definitions based on sputum microbiologic results.. Among 291 participants (median age [interquartile range], 32 [14-73] months), 57 (20%) had human immunodeficiency virus (HIV), and 87 (30%) were malnourished; 90 (31%) had confirmed pulmonary tuberculosis (rifampicin resistant in 6 [7%] ), 157 (54%), unconfirmed pulmonary tuberculosis, and 44 (15%), unlikely tuberculosis. A single oral swab specimen was obtained from 126 (43%) of the participants (tongue in 96 and buccal in 30) and 2 swab specimens from 165 (57%) (tongue in 110 and buccal in 55). Sensitivity was low (22% [95% confidence interval, 15%-32%]) for all swab specimens combined (with confirmed pulmonary tuberculosis as reference), but specificity was high (100% [91%-100%]). The highest sensitivity was 33% (95% confidence interval, 15%-58%) among participants with HIV. The overall yield was 6.9% with 1 oral swab specimen and 7.2% with 2.. Use of the Xpert MTB/RIF Ultra assay with oral swab specimens provides poor yield for microbiologic pulmonary tuberculosis confirmation in children.

    Topics: Child; Child, Preschool; HIV Infections; Humans; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2022
Prioritising attributes for tuberculosis preventive treatment regimens: a modelling analysis.
    BMC medicine, 2022, 05-18, Volume: 20, Issue:1

    Recent years have seen important improvements in available preventive treatment regimens for tuberculosis (TB), and research is ongoing to develop these further. To assist with the formulation of target product profiles for future regimens, we examined which regimen properties would be most influential in the epidemiological impact of preventive treatment.. Following expert consultation, we identified 5 regimen properties relevant to the incidence-reducing impact of a future preventive treatment regimen: regimen duration, efficacy, ease-of-adherence (treatment completion rates in programmatic conditions), forgiveness to non-completion and the barrier to developing rifampicin resistance during treatment. For each regimen property, we elicited expert input for minimally acceptable and optimal (ideal-but-feasible) performance scenarios for future regimens. Using mathematical modelling, we then examined how each regimen property would influence the TB incidence reduction arising from full uptake of future regimens according to current WHO guidelines, in four countries: South Africa, Kenya, India and Brazil.. Of all regimen properties, efficacy is the single most important predictor of epidemiological impact, while ease-of-adherence plays an important secondary role. These results are qualitatively consistent across country settings; sensitivity analyses show that these results are also qualitatively robust to a range of model assumptions, including the mechanism of action of future preventive regimens.. As preventive treatment regimens against TB continue to improve, understanding the key drivers of epidemiological impact can assist in guiding further development. By meeting these key targets, future preventive treatment regimens could play a critical role in global efforts to end TB.

    Topics: Antitubercular Agents; Clinical Protocols; Humans; Incidence; India; Rifampin; Tuberculosis

2022
Primary psoas tuberculosis abscess with an iliac bone lytic lesion: a case report.
    Journal of medical case reports, 2022, May-18, Volume: 16, Issue:1

    Primary psoas tuberculosis is the presence of "Koch's bacillus'' within the iliopsoas muscle caused by hematogenous or lymphatic seeding from a distant site. Muscular tuberculosis has relatively low prevalence in comparison with other cases of extrapulmonary tuberculosis, which explains the difficulties in establishing the diagnosis.. In this report, we present a challenging diagnostic case of primary psoas tuberculosis in a 38-year-old middle eastern female from southern Syria. The diagnosis was based on the clinical orientation, the observation of pulmonary lesions on the computed tomography scan, and the necrotic signs in the vicinity of the infected area. Despite the misleading primary false-negative results, the final diagnosis was reached after sufficient repetition of tuberculosis-specific testing. The patient was treated with isoniazid-rifampin-pyrazinamide-ethambutol for 2 months, then isoniazid and rifampin for 7 months, with full recovery in follow-up.. This case highlights the importance of a clinical-based approach in the treatment of patients with psoas abscesses, especially in areas with high tuberculosis prevalence.

    Topics: Adult; Antitubercular Agents; Female; Humans; Isoniazid; Psoas Abscess; Pyrazinamide; Rifampin; Tuberculosis

2022
Gene-Based Diagnosis of Tuberculosis from Oral Swabs with a New Generation Pathogen Enrichment Technique.
    Microbiology spectrum, 2022, 06-29, Volume: 10, Issue:3

    Topics: Humans; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Pulmonary

2022
Diagnostic Accuracy of Therapeutic Drug Monitoring During Tuberculosis Treatment.
    Journal of clinical pharmacology, 2022, Volume: 62, Issue:10

    Topics: Antitubercular Agents; Drug Monitoring; Ethambutol; HIV Infections; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2022
Rifapentine access in Europe: growing concerns over key tuberculosis treatment component.
    The European respiratory journal, 2022, Volume: 59, Issue:5

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Europe; Humans; Rifampin; Tuberculosis

2022
The global impact of household contact management for children on multidrug-resistant and rifampicin-resistant tuberculosis cases, deaths, and health-system costs in 2019: a modelling study.
    The Lancet. Global health, 2022, Volume: 10, Issue:7

    Estimates suggest that at least 30 000 children develop multidrug-resistant or rifampicin-resistant tuberculosis each year. Despite household contact management (HCM) being widely recommended, it is rarely done.. We used mathematical modelling to evaluate the potential country-level and global effects and cost-effectiveness of multidrug-resistant or rifampicin-resistant tuberculosis HCM for children younger than 15 years who are living with a person with newly diagnosed multidrug-resistant or rifampicin-resistant tuberculosis. We compared a baseline of no HCM with several HCM strategies and tuberculosis preventive therapy regimens, calculating the effect on multidrug-resistant or rifampicin-resistant tuberculosis cases, deaths, and health-system costs. All HCM strategies involved the screening of children for prevalent tuberculosis disease but with tuberculosis preventive therapy either not given or targeted dependent on age, HIV status, and result of tuberculin skin test. We evaluated the use of fluoroquinolones (ie, levofloxacin and moxifloxacin), delamanid, and bedaquiline as tuberculosis preventive therapy.. Compared with a baseline without HCM, HCM for all adults diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in 2019 would have entailed screening 227 000 children (95% uncertainty interval [UI]: 205 000-252 000) younger than 15 years globally, and averted 2350 tuberculosis deaths (1940-2790), costing an additional US$63 million (74-95 million). If all the children within the household who had been in contact with the person with multidrug-resistant or rifampicin-resistant tuberculosis received tuberculosis preventive therapy with levofloxacin, 5620 incident tuberculosis cases (95% UI 4540-6890) and an additional 1240 deaths (970-1540) would have been prevented. Incremental cost-effectiveness ratios were lower than half of per-capita gross domestic product for most interventions in most countries. Targeting only children younger than 5 years and those living with HIV reduced the number of incident cases and deaths averted, but improved cost-effectiveness. Tuberculosis preventive therapy with delamanid increased the effect, in terms of reduced incidence and mortality, compared with levofloxacin.. HCM for patients with multidrug-resistant or rifampicin-resistant tuberculosis is cost-effective in most settings and could avert a substantial proportion of multidrug-resistant or rifampicin-resistant tuberculosis cases and deaths in children globally.. UK Medical Research Council.

    Topics: Adult; Antitubercular Agents; Child; HIV Infections; Humans; Levofloxacin; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
GeneXpert Based Confirmed Cases among Suspected Cases of Tuberculosis in a Tertiary Care Centre: A Descriptive Cross-sectional Study.
    JNMA; journal of the Nepal Medical Association, 2022, Mar-11, Volume: 60, Issue:247

    Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis mostly affecting the lungs. Due to the low sensitivity of conventional microscopy and time-consuming culture method, Nucleic acid Amplification Assay Technique is preferred because of its rapidity and sensitivity. This test also helps in finding drug resistance to Rifampicin and also curtails the transmission of disease. The study is aimed to find the prevalence of GeneXpert confirmed cases among suspected cases of tuberculosis in a tertiary care centre.. A descriptive cross-sectional study in 104 patients was conducted in a tertiary care centre from 30th Dec 2021 to 3rd Feb 2022. Ethical clearance was taken from the Institutional Review Committee (Reference number: 464/078/079). Sputum samples were collected from patients and were processed for GeneXpert under biological safety standards. GeneXpert Mycobacterium tuberculosis/rifampicin assay, sample processing, deoxyribonucleic acid extraction, and deoxyribonucleic acid amplification occurred in a fully automated cartridge-based real-time Polymerase chain reaction. A convenience sampling method was done. Collected data were coded as per variables and entered in Statistical Package for the Social Sciences version 25. Point estimate at 95% Confidence Interval was calculated along with frequency and percentage for binary data.. In all 104 patients, GeneXpert detected 10 (9.62%) (3.94-15.26 at 95% Confidence Interval) positive tuberculosis cases. Out of total positive cases, there were 6 (60%) males and 4 (40%) females and there was 1 (10%) rifampicin-resistant case.. The prevalence of pulmonary tuberculosis among presumptive cases in our study was found to be similar to reported literature.. multidrug-resistant; nucleic acid amplification test; pulmonary tuberculosis.

    Topics: Cross-Sectional Studies; DNA; Female; Humans; Male; Mycobacterium tuberculosis; Rifampin; Tertiary Care Centers; Tuberculosis; Tuberculosis, Pulmonary

2022
Intelligence Classification Algorithm-Based Drug-Resistant Pulmonary Tuberculosis Computed Tomography Imaging Features and Influencing Factors.
    Computational intelligence and neuroscience, 2022, Volume: 2022

    The drug resistance and influencing factors of patients with pulmonary tuberculosis were investigated, and a dual attention dilated residual network (DADRN) algorithm was proposed. The algorithm was applied to process and analyze lung computed tomography (CT) images of 400 included patients with pulmonary tuberculosis. Besides, sparse code book algorithm and bag of visual word (BOVW) algorithms were introduced and compared, and the influencing factors of pulmonary tuberculosis drug resistance were analyzed. The results demonstrated that the localization precision of lung consolidation, nodules, and cavities by the DADRN algorithm reached 91.2%, 92.5%, and 93.8%, respectively. The recall rate of the three algorithms amounted to 83.55%, 84.5%, and 86.4%, respectively. Both localization precision and recall rate of the DADRN algorithm were higher than those of other two algorithms (

    Topics: Adult; Algorithms; Antitubercular Agents; Humans; Intelligence; Isoniazid; Lung; Middle Aged; Rifampin; Streptomycin; Tomography, X-Ray Computed; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2022
Enteropathogen spectrum and effect on antimycobacterial pharmacokinetics among children with tuberculosis in rural Tanzania: a prospective cohort study.
    The Lancet. Microbe, 2022, Volume: 3, Issue:6

    Enteropathy is prevalent in tuberculosis-endemic areas, and it has been shown to impair intestinal absorptive function; therefore, enteropathogen burden might negatively affect antimycobacterial pharmacokinetics, particularly among malnourished children. We sought to quantify enteropathogen burden among children initiating tuberculosis treatment in rural Tanzania and determine the effect of enteropathogen burden on serum antimycobacterial pharmacokinetics.. We performed a prospective cohort study at one site in rural Tanzania as an exploratory substudy of a large multicountry cohort study. We included children younger than 15 years of age with confirmed or probable tuberculosis undergoing treatment with first-line tuberculosis therapy; children were excluded from the study if they were unable to undergo sample collection. Participants were consecutively recruited from the inpatient paediatric wards or the outpatient tuberculosis clinic at Haydom Lutheran Hospital, Tanzania. The main outcome was to quantify symptomatic enteropathogen burden and the effect on serum antimycobacterial pharmacokinetics. We quantified enteropathogen burden (defined as the sum of distinct enteropathogens detected in stool) using a multipathogen PCR capable of simultaneous detection of 37 bacterial, viral, and parasitic species or species groups from stool collected within 72 h of treatment initiation. Comprehensive clinical assessment, including presence of gastrointestinal symptoms, was performed at baseline, and serum was collected approximately 2 weeks after treatment initiation at steady state and throughout the dosing interval with concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol measured by liquid chromatography with a tandem mass spectrometry assay to quantify peak (C. 58 children were assessed for eligibilty and enrolled between June 25, 2016, and Feb 6, 2018; 44 had complete stool testing and serum pharmacokinetic data, and they were included in the analyses. 20 (45%) were female, and 24 (55%) were male. 37 (84%) had moderate or severe malnutrition. A mean of 2·1 (SD 1·3) enteropathogens were detected per participant. Target peak concentrations of rifampicin were reached in eight (18%) of 44 participants, isoniazid in 24 (54%) of 44 participants, pyrazinamide in 28 (74%) of 38 participants, and ethambutol in six (15%) of 39 participants. Compared with controlled comparisons, each summative additional bacterial enteropathogen detected was associated with a 40% lower rifampicin C. Tanzanian children undergoing tuberculosis treatment rarely attained pharmacokinetic targets; enteropathogen carriage was common and enteropathogen burden was associated with significant reductions in the concentrations of some antimycobacterial drugs. Further research should explore mechanistic relationships of individual pathogens and antimycobacterial pharmacokinetics in larger cohorts, or determine if screening for and treating enteropathogens at tuberculosis treatment initiation improves pharmacokinetic target attainment.. National Institute of Allergy and Infectious Diseases, National Institutes of Health.. For the Swahili translation of the abstract see Supplementary Materials section.

    Topics: Antitubercular Agents; Child; Cohort Studies; Ethambutol; Female; Humans; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Tanzania; Tuberculosis; United States

2022
Prevalence and Drug Resistance Pattern of
    Polish journal of microbiology, 2022, May-31, Volume: 71, Issue:2

    Drug-resistant

    Topics: Adolescent; Adult; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Ethambutol; Humans; Iraq; Isoniazid; Mycobacterium tuberculosis; Prevalence; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2022
Fluorescence Aptasensor of Tuberculosis Interferon-γ in Clinical Samples Regulated by Steric Hindrance and Selective Identification.
    Analytical chemistry, 2022, 06-28, Volume: 94, Issue:25

    Topics: Copper; DNA; Humans; Interferon-gamma; Rifampin; Tuberculosis

2022
High-Throughput Variant Detection Using a Color-Mixing Strategy.
    The Journal of molecular diagnostics : JMD, 2022, Volume: 24, Issue:8

    Many diseases are related to multiple genetic alterations within a single gene. Probing for highly multiple (>10) variants in a single quantitative PCR tube is impossible because of a limited number of fluorescence channels and the limited ability to test one variant per channel, increasing the need for tubes. Herein, a novel color-mixing strategy was experimentally validated that uses fluorescence combinations as digital color codes to probe multiple variants simultaneously. The color-mixing strategy relies on a simple intratube assay that can probe for 15 variants as part of an intertube assay that can probe for an exponentially increased number of variants. This strategy is achieved by using multiplex double-stranded toehold probes modified with fluorophores and quenchers; the probes are designed to be quenched or remain luminous after binding to wild-type or variant templates. The color-mixing strategy was used to probe for 21 pathogenic variants in thalassemia and to distinguish between heterozygous and homozygous variants in six tubes, with a specificity of 99% and a sensitivity of 94%. To support tuberculosis diagnosis, the same strategy was applied to simultaneously probe in Mycobacterium tuberculosis for rifampicin-resistance mutations occurring within one 81-bp region and one 48-bp region in the rpoB gene, plus five isoniazid-resistance mutations in the inhA and katG genes.

    Topics: Antitubercular Agents; Bacterial Proteins; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2022
Whole genome sequencing analysis to evaluate the influence of T2DM on polymorphisms associated with drug resistance in M. tuberculosis.
    BMC genomics, 2022, Jun-24, Volume: 23, Issue:1

    Type 2 diabetes mellitus (T2DM) has been associated with treatment failure, and the development of drug resistance in tuberculosis (TB). Also, whole-genome sequencing has provided a better understanding and allowed the growth of knowledge about polymorphisms in genes associated with drug resistance. Considering the above, this study analyzes genome sequences to evaluate the influence of type 2 diabetes mellitus in the development of mutations related to tuberculosis drug resistance. M. tuberculosis isolates from individuals with (n = 74), and without (n = 74) type 2 diabetes mellitus was recovered from online repositories, and further analyzed.. The results showed the presence of 431 SNPs with similar proportions between diabetics, and non-diabetics individuals (48% vs. 52%), but with no significant relationship. A greater number of mutations associated with rifampicin resistance was observed in the T2DM-TB individuals (23.2% vs. 16%), and the exclusive presence of rpoBQ432L, rpoBQ432P, rpoBS441L, and rpoBH445L variants. While these variants are not private to T2DM-TB cases they are globally rare highlighting a potential role of T2DM. The phylogenetic analysis showed 12 sublineages, being 4.1.1.3, and 4.1.2.1 the most prevalent in T2DM-TB individuals but not differing from those most prevalent in their geographic location. Four clonal complexes were found, however, no significant relationship with T2DM was observed. Samples size and potential sampling biases prevented us to look for significant associations.. The occurrence of globally rare rifampicin variants identified only in isolates from individuals with T2DM could be due to the hyperglycemic environment within the host. Therefore, further studies about the dynamics of SNPs' generation associated with antibiotic resistance in patients with diabetes mellitus are necessary.

    Topics: Antitubercular Agents; Diabetes Mellitus, Type 2; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phylogeny; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing

2022
Accuracy of Tongue Swab Testing Using Xpert MTB-RIF Ultra for Tuberculosis Diagnosis.
    Journal of clinical microbiology, 2022, 07-20, Volume: 60, Issue:7

    Tongue dorsum swabs have shown promise as alternatives to sputum for detecting Mycobacterium tuberculosis (MTB) in patients with pulmonary tuberculosis (TB). Some of the most encouraging results have come from studies that used manual quantitative PCR (qPCR) to analyze swabs. Studies using the automated Cepheid Xpert MTB/RIF Ultra qPCR test (Xpert Ultra) have exhibited less sensitivity with tongue swabs, possibly because Xpert Ultra is optimized for testing sputum, not tongue swab samples. Using two new sample preprocessing methods that demonstrated good sensitivity in preliminary experiments, we assessed diagnostic accuracy and semi-quantitative signals of Xpert Ultra performed on tongue swabs collected from 183 adults with presumed TB in Kampala, Uganda. Relative to a sputum Xpert Ultra reference standard, the sensitivity of tongue swab Xpert Ultra was 77.8% (95% confidence interval [CI] 64.4-88.0) and specificity was 100.0% (95% CI, 97.2-100.0). When compared to a microbiological reference standard (MRS) incorporating both sputum Xpert Ultra and sputum mycobacterial culture, sensitivity was 72.4% (95% CI, 59.1-83.3) and specificity remained the same. Semi-quantitative Xpert Ultra results were generally lower with tongue swabs than with sputum, and cycle threshold values were higher. None of the eight sputum Xpert Ultra "trace" or "very low" results were detected using tongue swabs. Tongue swabs should be considered when sputum cannot be collected for Xpert Ultra testing, or in certain mass-screening settings. Further optimization of tongue swab analysis is needed to achieve parity with sputum-based molecular testing for TB.

    Topics: Adult; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Uganda

2022
Detection of M. tuberculosis in the environment as a tool for identifying high-risk locations for tuberculosis transmission.
    The Science of the total environment, 2022, Oct-15, Volume: 843

    Tuberculosis (TB) remains a leading cause of infectious mortality globally, yet most cases cannot be epidemiologically linked even with extensive contact investigations and whole genome sequencing. Consequently, there remain major gaps in our understanding of where and when M. tuberculosis (Mtb) exposures occur. We aimed to investigate whether Mtb can be detected in environments where TB patients were recently present, which could serve as a tool for characterizing exposure risk. We collected 389 environment surface (ES) swabs from two high TB burden prisons in Brazil, sampling 41 (n = 340) cells occupied by individuals with active TB and 7 (n = 49) cells from individuals without TB. In a subset of pooled swabs (n = 6) and a swab from a cigarette lighter from the cell with active TB patients, we enriched Mtb DNA using RNA-bait hybrid capture assays and performed whole genome sequencing. In prison cells, Mtb DNA was detected in 55/340 (16 %) of ES swabs from cells occupied by active TB patients and none (0/49) from cells in which no active TB patients were present. Mtb was detected in 13/16 (81 %) prison cells occupied by the individuals with high/medium sputum Xpert Mtb load and 8/25 (32 %) with low/very low sputum Mtb load (p = 0.003). Seven hybrid capture samples had a median genomic coverage of 140×. rpoB mutations conferring high-level rifampin resistance were detected in 3/7 ES swabs. Mtb was frequently detectable in environments recently occupied by individuals with active TB. This approach could be applied in congregate environments to identify and characterize high-risk settings for Mtb exposure.

    Topics: Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2022
Optimization of Benzoxazinorifamycins to Minimize hPXR Activation for the Treatment of Tuberculosis and HIV Coinfection.
    ACS infectious diseases, 2022, 08-12, Volume: 8, Issue:8

    Tuberculosis (TB) is one of the most significant world health problems, responsible for 1.5 M deaths in 2020, and yet, current treatments rely largely on 40 year old paradigms. Although the rifamycins (RIFs), best exemplified by the drug rifampin (RMP), represent a well-studied and therapeutically effective chemotype that targets the bacterial RNA polymerase (RNAP), these agents still suffer from serious drawbacks including the following: 3-9 month treatment times; cytochrome P450 (Cyp450) induction [particularly problematic for human immunodeficiency virus-

    Topics: Adult; HIV Infections; Humans; Pregnane X Receptor; Rifampin; Rifamycins; Tuberculosis

2022
Optimization of Benzoxazinorifamycins to Improve
    ACS infectious diseases, 2022, 08-12, Volume: 8, Issue:8

    Rifampin (RMP), a very potent inhibitor of the

    Topics: Animals; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Mice; Mycobacterium tuberculosis; Rifampin; Rifamycins; Tuberculosis

2022
Wider access to quality-assured rifapentine-based regimens is needed to accelerate tuberculosis prevention and care globally.
    The European respiratory journal, 2022, Volume: 60, Issue:2

    Topics: Europe; Humans; Isoniazid; Rifampin; Tuberculosis

2022
Accuracy of Xpert MTB/RIF Ultra for the diagnosis of tuberculosis in adult patients: a retrospective cohort study.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2022, Volume: 122

    The value of the "trace" result in Xpert Ultra for diagnosing active tuberculosis (TB) remains unclear. Our study evaluated the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) (Cepheid, Sunnyvale, USA) over Xpert MTB/RIF (Xpert) (Cepheid, Sunnyvale, USA) and mycobacterial culture when compared with a composite reference standard (CRS).. A retrospective single-center observational study was conducted in a tertiary care hospital in South India. Over three months, patients (aged ≥15 years) data on Xpert Ultra tests and mycobacterial culture of pulmonary and extrapulmonary samples were extracted from their electronic medical records. Patients were defined as TB cases based on the CRS criteria. Sensitivity, specificity, positive and negative predictive values of diagnostic tests were calculated by comparing them to the CRS.. Xpert Ultra was more sensitive (87.8%) than Xpert (72.1%) and culture (44.1%). The specificity of Xpert Ultra was lower (98.1%) than those of Xpert (100%) and culture (100%). The sensitivity (92%) and specificity (100%) of Xpert Ultra were highest when performed on pus samples.. Xpert Ultra with the trace category is superior to the conventional Xpert, and mycobacterial culture in identifying TB.

    Topics: Adult; Humans; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2022
Hierarchical true prevalence, risk factors and clinical symptoms of tuberculosis among suspects in Bangladesh.
    PloS one, 2022, Volume: 17, Issue:7

    The study was aimed to estimate the true prevalence of human tuberculosis (TB); identify risk factors and clinical symptoms of TB; and detect rifampicin (RIF) sensitivity in three study areas of Bangladesh.. The cross-sectional study was conducted in three Bangladesh districts during 2018. Potential risk factors, clinical symptoms, and comorbidities were collected from 684 TB suspects. Sputum specimens were examined by LED microscopy. TB hierarchical true prevalence, risk factors and clinical symptoms were estimated and identified using a Bayesian analysis framework. Rifampicin sensitivity of M. tuberculosis (MTB) was detected by GeneXpert MTB/RIF assay.. The median TB true prevalence was 14.2% (3.8; 34.5). Although overall clustering of prevalence was not found, several DOTS centers were identified with high prevalence (22.3% to 43.7%). Risk factors for TB identified (odds ratio) were age (> 25 to 45 years 2.67 (1.09; 6.99), > 45 to 60 years 3.43 (1.38; 9.19) and individuals in families/neighborhoods where a TB patient(s) has (ve) already been present (12.31 (6.79; 22.60)). Fatigue, night sweat, fever and hemoptysis were identified as important clinical symptoms. Seven of the GeneXpert MTB/RIF positive sputum specimens (65) were resistant to rifampicin.. About one in every seven TB suspects was affected with TB. A number of the TB patients carry multi drug resistant MTB. Hierarchical true prevalence estimation allowed identifying DOTS centers with high TB burden. Insights from this study will enable more efficient use of DOTScenters-based TB surveillance to end the TB epidemic in Bangladesh by 2035.

    Topics: Adult; Bangladesh; Bayes Theorem; Cross-Sectional Studies; Humans; Middle Aged; Mycobacterium tuberculosis; Rifampin; Risk Factors; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2022
Real-world use and outcomes of dolutegravir-containing antiretroviral therapy in HIV and tuberculosis co-infection: a site survey and cohort study in sub-Saharan Africa.
    Journal of the International AIDS Society, 2022, Volume: 25, Issue:7

    Dolutegravir is being scaled up globally as part of antiretroviral therapy (ART), but for people with HIV and tuberculosis co-infection, its use is complicated by a drug-drug interaction with rifampicin requiring an additional daily dose of dolutegravir. This represents a disadvantage over efavirenz, which does not have a major drug-drug interaction with rifampicin. We sought to describe HIV clinic practices for prescribing concomitant dolutegravir and rifampicin, and characterize virologic outcomes among patients with tuberculosis co-infection receiving dolutegravir or efavirenz.. Within the four sub-Saharan Africa regions of the International epidemiology Databases to Evaluate AIDS consortium, we conducted a site survey (2021) and a cohort study (2015-2021). The cohort study used routine clinical data and included patients newly initiating or already receiving dolutegravir or efavirenz at the time of tuberculosis diagnosis. Patients were followed from tuberculosis diagnosis until viral suppression (<1000 copies/ml), a competing event (switching ART regimen; loss to program/death) or administrative censoring at 12 months.. In the survey, 86 of 90 (96%) HIV clinics in 18 countries reported prescribing dolutegravir to patients who were receiving rifampicin as part of tuberculosis treatment, with 77 (90%) reporting that they use twice-daily dosing of dolutegravir, of which 74 (96%) reported having 50 mg tablets available to accommodate twice-daily dosing. The cohort study included 3563 patients in 11 countries, with 67% newly or recently initiating ART. Among patients receiving dolutegravir (n = 465), the cumulative incidence of viral suppression was 58.9% (95% confidence interval [CI]: 54.3-63.3%), switching ART regimen was 4.1% (95% CI: 2.6-6.2%) and loss to program/death was 23.4% (95% CI: 19.7-27.4%). Patients receiving dolutegravir had improved viral suppression compared with patients receiving efavirenz who had a tuberculosis diagnosis before site dolutegravir availability (adjusted subdistribution hazard ratio [aSHR]: 1.47, 95% CI: 1.28-1.68) and after site dolutegravir availability (aSHR 1.28, 95% CI: 1.08-1.51).. At a programmatic level, dolutegravir was being widely prescribed in sub-Saharan Africa for people with HIV and tuberculosis co-infection with a dose adjustment for the drug-drug interaction with rifampicin. Despite this more complex regimen, our cohort study revealed that dolutegravir did not negatively impact viral suppression.

    Topics: Africa South of the Sahara; Anti-HIV Agents; Benzoxazines; Cohort Studies; Coinfection; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Oxazines; Piperazines; Pyridones; Rifampin; Tuberculosis

2022
Impact of Xpert MTB/RIF in the Diagnosis of Childhood Tuberculosis in Rural Ethiopia.
    Journal of tropical pediatrics, 2022, 06-06, Volume: 68, Issue:4

    This study assesses the impact of the Xpert MTB/RIF in the diagnosis of childhood tuberculosis (TB) in a rural hospital in a resource-constrained setting.. Retrospective cross-sectional study in children evaluated for presumptive TB from 1 June 2016 to 31 May 2017 at the Gambo General Hospital in rural Southern Ethiopia. Children were evaluated according to a defined protocol based on national guidelines. Samples were submitted for Xpert MTB/RIF assay to the nearest reference laboratory.. Of the 201 children assessed for presumptive TB, 46.3% (93/201) were diagnosed with TB. Of these, 49.5% (46/93) were microbiologically confirmed, mostly by Xpert MTB/RIF (only one patient was diagnosed by smear alone). The rest were clinically diagnosed. Microbiologically confirmed patients had a higher mean age, longer duration of fever and cough and lymphadenopathy more frequently than those clinically diagnosed. Gastric aspirates were Xpert MTB/RIF-positive in 18.2% of the samples (26/143); none were smear-positive (0/140). Sputum samples were Xpert MTB/RIF-positive in 27.1% (13/35) of the samples and smear-positive in 8.6% (3/35). There were no HIV-positive patients and just one case of rifampicin-resistant TB. A long delay (median 15 days) was detected in returning the results.. Xpert MTB/RIF serves as an important adjunctive test for diagnosing childhood TB in rural settings, with microbiological confirmation in up to half the TB cases. Processes need to be optimized to achieve an early diagnosis. The diagnosis of childhood TB in high-burden countries such as Ethiopia still relies largely upon diagnostic algorithms and the clinician's skills.Lay summaryWorld Health Organization recommends the use of Xpert MTB/RIF to improve the microbiological diagnosis of childhood tuberculosis (TB) since 2014, but the impact of this test under real conditions in rural areas of low-income countries is not clear. We conducted a cross-sectional study in children evaluated for presumptive TB from 1 June 2016 to 31 May 2017 at the Gambo General Hospital in rural Southern Ethiopia. Children were evaluated according to a clinical protocol based on national guidelines and samples were submitted for Xpert MTB/RIF assay to the nearest reference laboratory.Of the 201 children assessed, 46.3% (93/201) were diagnosed with tuberculosis. Of these, 48.4% (45/93) were microbiologically confirmed by Xpert MTB/RIF [smear microscopy only diagnosed the 5.4% (5/93)]. Patients with microbiologically confirmed tuberculosis had a higher mean age, longer duration of fever and cough and had lymphadenopathy more frequently than those clinically diagnosed. A long delay in returning the results (median 15 days) was detected. Xpert MTB/RIF serves as an important test for diagnosing childhood TB in rural settings, with microbiological confirmation in up to half the cases. Processes need to be optimized to achieve an early diagnosis. The diagnosis of childhood TB in high-burden countries still relies largely upon diagnostic algorithms and the clinician's skills.

    Topics: Child; Cough; Cross-Sectional Studies; Ethiopia; Humans; Lymphadenopathy; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2022
A Comparative Analysis of Physiologically Based Pharmacokinetic Models for Human Immunodeficiency Virus and Tuberculosis Infections.
    Antimicrobial agents and chemotherapy, 2022, 09-20, Volume: 66, Issue:9

    Physiologically based pharmacokinetic (PBPK) models have gained in popularity in the last decade in both drug development and regulatory science. PBPK models differ from classical pharmacokinetic models in that they include specific compartments for tissues involved in exposure, toxicity, biotransformation, and clearance processes connected by blood flow. This study aimed to address the gaps between the mathematics and pharmacology framework observed in the literature. These gaps included nonconserved systems of equations and compartment concentration that were not biologically relatable to the tissues of interest. The resulting system of nonlinear differential equations is solved numerically with various methods for benchmarking and comparison. Furthermore, a sensitivity analysis of all parameters were conducted to elucidate the critical parameters of the model. The resulting model was fit to clinical data as a performance benchmark. The clinical data captured the second line of antiretroviral treatment, lopinavir and ritonavir. The model and clinical data correlate well for coadministration of lopinavir/ritonavir with rifampin. Drug-drug interaction was captured between lopinavir and rifampin. This article provides conclusions about the suitability of physiologically based pharmacokinetic models for the prediction of drug-drug interaction and antiretroviral and anti-TB pharmacokinetics.

    Topics: Anti-Retroviral Agents; HIV; HIV Infections; Humans; Latent Tuberculosis; Lopinavir; Models, Biological; Rifampin; Ritonavir; Tuberculosis

2022
Diagnostic Accuracy of the Truenat MTB Plus Assay and Comparison with the Xpert MTB/RIF Assay to Detect Tuberculosis among Hospital Outpatients in Cameroon.
    Journal of clinical microbiology, 2022, 08-17, Volume: 60, Issue:8

    The Truenat MTB Plus assay is a rapid molecular test that has been recommended by the World Health Organization since 2020 as an initial test to detect tuberculosis (TB). The WHO highlighted the need to further evaluate assay performance to inform future recommendations, including in people living with HIV and compared to the Xpert MTB/RIF assay. We conducted a prospective evaluation of the diagnostic accuracy of the Truenat assay in Cameroon, a country with a high burden of HIV/TB. Adult outpatients were recruited at four hospitals; demographic information and medical history were collected, and participants produced two sputum specimens. Truenat and Xpert testing was performed on the same specimen, and performance was compared to TB culture as the reference standard. From November 2019 to December 2020, 945 participants were enrolled and included in the analysis. Among 251 participants with culture-positive TB, the sensitivity of Truenat MTB Plus was 91% (95% confidence interval [CI], 86 to 94%), similar to Xpert (90%; 95% CI, 86 to 93%). Among 74 HIV-positive participants with culture-positive TB, the sensitivity of Truenat MTB Plus was 85% (95% CI, 75 to 92%) compared to 81% for Xpert (95% CI, 70 to 89%). Among 47 participants with smear-negative TB, the sensitivity of Truenat MTB Plus was 55% (95% CI, 40 to 70%), similar to Xpert (53%; 95% CI, 38 to 68%). The specificity of Truenat MTB Plus was 96% (95% CI, 94 to 97%) compared to 99% (95% CI, 97 to 99%) for Xpert. For TB detection compared to the reference standard of TB culture, the performance of the Truenat MTB Plus assay was similar to that of Xpert in this population, including among people living with HIV.

    Topics: Adult; Cameroon; Drug Resistance, Bacterial; HIV Infections; Hospitals; Humans; Mycobacterium tuberculosis; Outpatients; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2022
Isoniazid and rifapentine treatment effectively reduces persistent M. tuberculosis infection in macaque lungs.
    The Journal of clinical investigation, 2022, 09-15, Volume: 132, Issue:18

    A once-weekly oral dose of isoniazid and rifapentine for 3 months (3HP) is recommended by the CDC for treatment of latent tuberculosis infection (LTBI). The aim of this study is to assess 3HP-mediated clearance of M. tuberculosis bacteria in macaques with asymptomatic LTBI. Twelve Indian-origin rhesus macaques were infected with a low dose (~10 CFU) of M. tuberculosis CDC1551 via aerosol. Six animals were treated with 3HP and 6 were left untreated. The animals were imaged via PET/CT at frequent intervals. Upon treatment completion, all animals except 1 were coinfected with SIV to assess reactivation of LTBI to active tuberculosis (ATB). Four of 6 treated macaques showed no evidence of persistent bacilli or extrapulmonary spread until the study end point. PET/CT demonstrated the presence of significantly more granulomas in untreated animals relative to the treated group. The untreated animals harbored persistent bacilli and demonstrated tuberculosis (TB) reactivation following SIV coinfection, while none of the treated animals reactivated to ATB. 3HP treatment effectively reduced persistent infection with M. tuberculosis and prevented reactivation of TB in latently infected macaques.

    Topics: Animals; Antitubercular Agents; Isoniazid; Latent Tuberculosis; Lung; Macaca mulatta; Mycobacterium tuberculosis; Positron Emission Tomography Computed Tomography; Rifampin; Tuberculosis

2022
Altered drug exposures of first-line TB drugs in a moxifloxacin-containing treatment regimen.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2022, 08-01, Volume: 26, Issue:8

    Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Moxifloxacin; Pregnanes; Pyrazinamide; Rifampin; South Africa; Tuberculosis

2022
Mycobacterium abscessus HelR interacts with RNA polymerase to confer intrinsic rifamycin resistance.
    Molecular cell, 2022, 09-01, Volume: 82, Issue:17

    Rifampicin (RIF), the frontline drug against M. tuberculosis, is completely ineffective against M. abscessus, partially due to the presence of an ADP-ribosyltransferase (Arr) that inactivates RIF. Using RNA-seq, we show that exposure of M. abscessus to sublethal doses of RIF and Rifabutin (RBT), a close analog of RIF, results in an ∼25-fold upregulation of Mab_helR in laboratory and clinical isolates. An isogenic deletion in Mab_helR results in RIF/RBT hypersensitivity, and overexpression of Mab_helR confers RIF tolerance in M. tuberculosis. We demonstrate an increased HelR-RNAP association in RIF-exposed bacteria and a MabHelR-mediated dissociation of RNAP from stalled initiation complexes in vitro. Finally, we show that the tip of the PCh-loop of Mab_helR, present in proximity to RIF, is critical for conferring RIF resistance but dispensable for dissociation of stalled RNAP complexes, suggesting that HelR-mediated RIF resistance requires a step in addition to displacement of RIF-stalled RNAP.

    Topics: DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium abscessus; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins; Tuberculosis

2022
HelR is a helicase-like protein that protects RNA polymerase from rifamycin antibiotics.
    Molecular cell, 2022, 09-01, Volume: 82, Issue:17

    Rifamycin antibiotics such as rifampin are potent inhibitors of prokaryotic RNA polymerase (RNAP) used to treat tuberculosis and other bacterial infections. Although resistance arises in the clinic principally through mutations in RNAP, many bacteria possess highly specific enzyme-mediated resistance mechanisms that modify and inactivate rifamycins. The expression of these enzymes is controlled by a 19-bp cis-acting rifamycin-associated element (RAE). Guided by the presence of RAE sequences, we identify a helicase-like protein, HelR, in Streptomyces venezuelae that confers broad-spectrum rifamycin resistance. We show that HelR also promotes tolerance to rifamycins, enabling bacterial evasion of the toxic properties of these antibiotics. HelR forms a complex with RNAP and rescues transcription inhibition by displacing rifamycins from RNAP, thereby providing resistance by target protection . Furthermore, HelRs are broadly distributed in Actinobacteria, including several opportunistic Mycobacterial pathogens, offering yet another challenge for developing new rifamycin antibiotics.

    Topics: Anti-Bacterial Agents; DNA-Directed RNA Polymerases; Humans; Rifampin; Rifamycins; Streptomyces; Tuberculosis

2022
Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study.
    The Lancet. Microbe, 2022, Volume: 3, Issue:9

    Whole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce.. In a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS.. Considering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5-99·0]; specificity 96·6% [95% CI 95·2-97·9]), levofloxacin (sensitivity 94·8% [93·3-97·6]; specificity 97·1% [96·7-97·6]), kanamycin (sensitivity 96·1% [95·4-96·8]; specificity 95·0% [94·4-95·7]), amikacin (sensitivity 97·2% [96·4-98·1]; specificity 98·6% [98·3-98·9]), and capreomycin (sensitivity 93·1% [90·0-96·3]; specificity 98·3% [98·0-98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0-67·1], 83·8% [81·0-86·5], and 40·1% [37·4-42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations.. The combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background).. Bill & Melinda Gates Foundation, German Centre for Infection Research, German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG.

    Topics: Antitubercular Agents; Genomics; Humans; Mycobacterium tuberculosis; Phenotype; Prospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Superior Efficacy of a TBI-166, Bedaquiline, and Pyrazinamide Combination Regimen in a Murine Model of Tuberculosis.
    Antimicrobial agents and chemotherapy, 2022, 09-20, Volume: 66, Issue:9

    TBI-166, derived from riminophenazine analogues, shows more potent anti-TB activity than clofazimine and is being assessed against tuberculosis (TB) in a phase IIa clinical trial in China. Preclinical regimen studies containing TBI-166 will support the phase IIb clinical trials of TBI-166. In the present study, we compared the efficacy in three murine TB models of an all-oral drug-resistant TB drug regimen of TBI-166 with bedaquiline (BDQ) and pyrazinamide (PZA) with the first-line regimen of isoniazid (INH) with rifampin (RFP) and PZA (HRZ regimen), the most effective reported TBI-166-containing regimen of TBI-166 with BDQ and linezolid (LZD), and the Nix-TB clinical trial regimen of BDQ with pretomanid and LZD (BPaL regimen). In the C3HeB/FeJ murine TB model, for the TBI-166+BDQ+PZA regimen, the lungs of mice were culture negative at 4 weeks, and there were no relapses at 8 weeks of treatment. The reduction in bacterial burden and relapse rate were greater than those of the HRZ regimen and the TBI-166+BDQ+LZD regimen. Compared with the BPaL regimen, the TBI-166+BDQ+PZA regimen had similar or stronger early bactericidal activity, bactericidal activity, and sterilizing activity in the BALB/c murine TB model. The bacterial burden in the TBI-166+BDQ+PZA regimen group decreased significantly more than that in the BPaL regimen group and was almost or totally relapse free (<13.33% after 8 weeks). In conclusion, oral short-course three-drug regimens, including TBI-166 with high efficacy, were identified. The TBI-166+BDQ+PZA regimen is recommended for further study in a TBI-166 phase IIb clinical trial.

    Topics: Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Isoniazid; Linezolid; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Determinants of stock-outs of first line anti-tuberculosis drugs: the case of public health facilities of Addis Ababa city administration health bureau, Addis Ababa, Ethiopia.
    BMC health services research, 2022, Aug-17, Volume: 22, Issue:1

    The health sectors success has been determined by consistent and reasonably priced health commodities supply. Despite possible death from the disease, Tuberculosis (TB) can be prevented with early diagnosis and appropriate treatment for which enough, effective, and qualified medicines need to be available. However, studies revealed stock of anti-TB drugs in health facilities. Here we present the recent finding on determinants of stock out of Anti-TB drug at public health facilities of Addis Ababa.. This study aimed to identify determinants of stock outs of first line anti TB drugs at public health facilities under Addis Ababa City Administration Health Bureau.. Mixed study design were employed. A total of 106 facilities were included in the sampling frame and data were collected from the study population such as drug store managers of health facilities providing TB treatment using semi structured questionnaire and through in-depth interview with Addis Ababa hubs of the Ethiopian Pharmaceuticals Supply Agency (EPSA), Addis Ababa City Administration Health Bureau and selected heads of pharmacy departments of health facilities from May 1-30, 2020 considering one year back retrospective data from March 20,2019 to March 20,2020. Structured record review of data from Logistics Management Information System (LMIS) tools having TB drugs was done using structured observation checklist. Data were entered, cleaned, and analyzed using SPSS Version 20. Both descriptive and multiple logistic regression analysis were performed.. 52(62.7%) of health facilities encountered stock out for at least one of these drugs during the past 1 year. Rifampicin 75 mg + Isoniazid 50 mg (RH 75/50 mg) were most stocked out first line anti-TB drug from 33(39.8%) of facilities with 17 mean stocks out days while Rifampicin 75 mg + Isoniazid 50 mg + Pyrazinamide 150 mg (RHZ 75/50/150 mg) were the least first line anti-TB drug stocked out from facilities with mean 5 days of stock out. Delayed supply of anti TB drug from EPSA, delivery of reduced quantity of anti TB drugs by EPSA and stocked out of anti TB Drugs at EPSA were significant determinate factors of stock out of first line anti-TB drug from facilities with 95%CI of 10.34(2.167-49.329), 11.452(2.183-60.079) and 5.646(1.240-25.707) respectively.. Above median of health facilities encountered stock out of first line anti-TB drug in Addis Ababa. Delayed supply of anti TB drug from EPSA, delivery of reduced quantity of anti TB drugs by EPSA and stocked out of anti TB Drugs at EPSA were significant determinate factor of stocked out of first line anti-TB drug from facilities. EPSA and other responsible bodies shall work collaboratively to improve their service and ensure availability of adequate amount of Anti TB drug in health facilities.

    Topics: Antitubercular Agents; Ethiopia; Health Facilities; Humans; Isoniazid; Retrospective Studies; Rifampin; Tuberculosis

2022
Investigation of 3-year inpatient TB cases in Zunyi, China: Increased TB burden but improved bacteriological diagnosis.
    Frontiers in public health, 2022, Volume: 10

    As one of the top three high tuberculosis (TB) burden countries, China is a country where the overall TB incidence continues to decline. However, due to its large population and area, the increased TB burden exists in regional areas.. This retrospective study analyzed local inpatient pulmonary TB cases in the Affiliated Hospital of Zunyi Medical University (AHZMU) from January 2016 to December 2018 in a high TB incidence and economically-less-developed area of China. Four methods, acid-fast bacilli stain, culture, Xpert and LAMP, were used to detect. Total 3,910 local inpatient cases with pulmonary TB were admitted to AHZMU during this study period. The annual numbers of total TB cases increased 26.4% (from 1,173 to 1,483), while new cases increased 29.6% (from 936 to 1,213) and RR-TB cases increased 2.7 times (from 31 to 84). Meanwhile, the percentage of previously treated cases declined from 20.2 to 18.2% and the. The elevated

    Topics: Humans; Inpatients; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2022
Xpert
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2022, 09-01, Volume: 26, Issue:9

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2022
Use of 3HP for TB preventive treatment in prisons.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2022, 09-01, Volume: 26, Issue:9

    Topics: Antitubercular Agents; Humans; Isoniazid; Prisons; Rifampin; Tuberculosis

2022
SLCO1B1 and SLC10A1 polymorphism and plasma rifampin concentrations in patients with co-morbidity tuberculosis-diabetes mellitus in Baja California, Mexico.
    Tuberculosis (Edinburgh, Scotland), 2022, Volume: 136

    Rifampicin is one of the most important drugs for the treatment of tuberculosis (TB). Polymorphisms in SLCO1B1 and SLC10A1 genes are associated with impaired transporter function of drug compounds such as rifampicin. The relationship between genetic variation, clinical comorbidities, and rifampicin exposures in TB patients has not been completely elucidated. The aim of this study was to investigate the prevalence of SLCO1A1 and SLCO1B1 polymorphisms in TB and TB-DM patients and to determine their relationship with rifampicin pharmacokinetics on patients from México. Blood samples were collected in two hospitals in Baja California, Mexico from February through December 2017. Sampling included 19 patients with TB, 11 with T2DM and 17 healthy individuals. Polymorphisms genotype rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs72559746,rs2291075 and rs4603354 of SLCO1B1 and rs4646285 and rs138880008 of SLC10A1 were analyzed by Sanger's sequencing. None of the SLCO1B1 and SLC10A1 variants were significantly associated with rifampicin C

    Topics: Diabetes Mellitus, Type 2; Genotype; Humans; Liver-Specific Organic Anion Transporter 1; Mexico; Morbidity; Mycobacterium tuberculosis; Organic Anion Transporters, Sodium-Dependent; Polymorphism, Single Nucleotide; Rifampin; Symporters; Tuberculosis

2022
Effects of Enzyme Induction and Polymorphism on the Pharmacokinetics of Isoniazid and Rifampin in Tuberculosis/HIV Patients.
    Antimicrobial agents and chemotherapy, 2022, 10-18, Volume: 66, Issue:10

    Tuberculosis is the most common cause of death in HIV-infected individuals. Rifampin and isoniazid are the backbones of the current first-line antitubercular therapy. The aim of the present study was to describe the time-dependent pharmacokinetics and pharmacogenetics of rifampin and isoniazid and to quantitatively evaluate the drug-drug interaction between rifampin and isoniazid in patients coinfected with HIV. Plasma concentrations of isoniazid, acetyl-isoniazid, isonicotinic acid, rifampin, and 25-desacetylrifampin from 40 HIV therapy-naive patients were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after the first dose and at steady state of antitubercular therapy. Patients were genotyped for determination of acetylator status and CYP2C19 phenotype. Nonlinear mixed-effects models were developed to describe the pharmacokinetic data. The model estimated an autoinduction of both rifampin bioavailability (0.5-fold) and clearance (2.3-fold). 25-Desacetylrifampin clearance was 2.1-fold higher at steady state than after the first dose. Additionally, ultrarapid CYP2C19 metabolizers had a 2-fold-higher rifampin clearance at steady state than intermediate or extensive metabolizers. An induction of isonicotinic acid formation from isoniazid dependent on total rifampin dose was estimated. Simulations indicated a 30% lower isoniazid exposure at steady state during administration of standard rifampin doses than isoniazid exposure in noninduced individuals. Rifampin exposure was correlated with CYP2C19 polymorphism, and rifampin administration may increase exposure to toxic metabolites by isoniazid in patients. Both findings may influence the risk of treatment failure, resistance development, and toxicity and require further investigation, especially with regard to ongoing high-dose rifampin trials.

    Topics: Antitubercular Agents; Chromatography, Liquid; Cytochrome P-450 CYP2C19; Enzyme Induction; HIV Infections; Humans; Isoniazid; Rifampin; Tandem Mass Spectrometry; Tuberculosis

2022
Evaluation of thoracic surgery as a treatment approach in patients with rifampin-resistant chronic tuberculous empyema.
    Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia, 2022, 09-05, Volume: 48, Issue:4

    Topics: Empyema; Empyema, Tuberculous; Humans; Rifampin; Thoracic Surgery; Tuberculosis

2022
Tuberculosis: Common Questions and Answers.
    American family physician, 2022, Volume: 106, Issue:3

    Approximately 10 million people worldwide were infected with tuberculosis (TB) in 2019, resulting in 1.4 million deaths. In the United States that same year, there were nearly 9,000 reported cases of TB disease and up to 13 million people were living with latent TB infection (LTBI), which is an asymptomatic, noncommunicable infection caused by Mycobacterium tuberculosis. Without treatment, LTBI will progress to active TB disease in approximately 5% to 10% of affected people. Individuals with symptoms of TB disease warrant testing. The U.S. Preventive Services Task Force recommends testing individuals at increased risk of LTBI with an interferon-gamma release assay or tuberculin skin testing. Because the incidence of LTBI in health care professionals is similar to that of the general population, periodic retesting is not recommended. After a positive test result, chest radiography should be performed and, in patients with suspected pulmonary TB disease, sputum collected for diagnosis. Both suspected and confirmed cases of LTBI and TB disease must be reported to local or state health departments. Preferred treatment regimens for LTBI include isoniazid in combination with rifapentine or rifampin, or rifampin alone for a duration of three and four months, respectively. Treatment of drug-susceptible TB disease includes an eight-week intensive phase with four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol), followed by a continuation phase lasting 18 weeks or more, with two drugs based on susceptibility testing results. Consultation with a TB expert is necessary if there is suspicion or confirmation of drug-resistant TB.

    Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Latent Tuberculosis; Pyrazinamide; Rifampin; Tuberculin; Tuberculosis; United States

2022
Pyrazinamide resistance in rifampicin discordant tuberculosis.
    PloS one, 2022, Volume: 17, Issue:9

    Mycobacterium tuberculosis strains with phenotypically susceptible rpoB mutations (rifampicin discordant) have emerged following implementation of rapid molecular drug resistance testing for tuberculosis. Whilst rifampicin resistance is known to be associated with resistance to other rifamycins (rifapentine and rifabutin) as well as isoniazid and pyrazinamide, rifampicin discordant strains have shown high rates of susceptibility to isoniazid and rifabutin. However, pyrazinamide susceptibly testing results have not been reported.. We evaluated pyrazinamide resistance in 80 rifampicin discordant and 25 rifampicin and isoniazid susceptible isolates from KwaZulu-Natal in South Africa using Mycobacteria Growth Indicator Tube method and sequencing of the pncA. We also compared susceptibility of pyrazinamide with that of isoniazid.. Pyrazinamide resistance was found in 6/80 (7.5%) rifampicin discordant isolates. All pyrazinamide resistant isolates were also resistant to isoniazid and pyrazinamide resistance was found to be associated with isoniazid resistance. No pyrazinamide resistance was found among the isoniazid susceptible isolates.. Given the low prevalence of pyrazinamide resistance in rifampicin discordant TB, this anti-TB drug still has a significant role in the treatment of these patients. Performing pyrazinamide susceptibility testing remains a challenge, our findings show that isoniazid susceptible isolates are unlikely to be resistant to pyrazinamide among the discordant TB isolates.

    Topics: Antitubercular Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Rifabutin; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Patient and health-care provider experience of a person-centred, multidisciplinary, psychosocial support and harm reduction programme for patients with harmful use of alcohol and drug-resistant tuberculosis in Minsk, Belarus.
    BMC health services research, 2022, Sep-30, Volume: 22, Issue:1

    Tuberculosis (TB) often concentrates in groups of people with complex health and social issues, including alcohol use disorders (AUD). Risk of TB, and poor TB treatment outcomes, are substantially elevated in people who have AUD. Médecins sans Frontières and the Belarus Ministry of Health have worked to improve treatment adherence in patients with multi-drug or rifampicin resistant (MDR/RR)-TB and harmful use of alcohol. In 2016, a person-centred, multidisciplinary, psychosocial support and harm reduction programme delivered by TB doctors, counsellors, psychiatrists, health-educators, and social workers was initiated. In 2020, we described patient and provider experiences within the programme as part of a wider evaluation.. We recruited 12 patients and 20 health-care workers, using purposive sampling, for in-depth individual interviews and focus group discussions. We used a participant-led, flexible, exploratory approach, enabling participants and the interviewer to shape topics of conversation. Qualitative data were coded manually and analysed thematically. As part of the analysis process, identified themes were shared with health-care worker participants to enable their reflections to be incorporated into the findings.. Key themes related to the patients' and practitioners experience of having and treating MDRTB with associated complex health and social issues were: fragility and despair and guidance, trust and health. Prejudice and marginalisation were global to both themes. Counsellors and other health workers built a trusting relationship with patients, enabling guidance through a multi-disciplinary approach, which supported patients to achieve their vision of health. This guidance was achieved by a team of social workers, counsellors, doctors and health-educators who provided professional and individualised help for patients' illnesses, personal or interpersonal problems, administrative tasks, and job searches.. Patients with MDR/RR-TB and harmful use of alcohol faced complex issues during treatment. Our findings describe how person-centred, multi-disciplinary, psychosocial support helped patients in this setting to cope with these challenges and complete the treatment programme. We recommend that these findings are used to: i) inform programmatic changes to further boost the person-centred care nature of this program; and ii) advocate for this type of person-centred care approach to be rolled out across Belarus, and in contexts that face similar challenges.

    Topics: Alcoholism; Antitubercular Agents; Harm Reduction; Humans; Psychosocial Support Systems; Qualitative Research; Republic of Belarus; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Performance of Xpert MTB/RIF for Diagnosis of Tuberculosis in HIV-Infected People in China: A Retrospective, Single-Center Study.
    Medical science monitor : international medical journal of experimental and clinical research, 2022, Oct-05, Volume: 28

    BACKGROUND There are few studies of GeneXpert MTB/RIF (hereafter referred to as Xpert) detection technology in HIV-infected people in China. Therefore, this study aimed to evaluate the value of Xpert in HIV/TB co-infected patients and to provide reference and guidance for the diagnosis of TB in HIV-infected populations. MATERIAL AND METHODS This study reviewed medical records of human immunodeficiency virus (HIV) patients hospitalized at the Infection Center of Beijing Ditan Hospital affiliated to Capital Medical University from January 2018 to May 2020, and patients diagnosed with pulmonary and extrapulmonary tuberculosis were screened as study subjects. Sensitivity and specificity of Xpert were analyzed using ROC curves. RESULTS Of the 413 HIV patients, 177 patients met the entry criteria, of which the diagnosis was active pulmonary tuberculosis (PTB): 145 and extrapulmonary tuberculosis (EPTB): 32. The sensitivity of Xpert for PTB and EPTB was 82.0% and 100%, higher than that of acid-fast bacilli (AFB) (61.0% and 58.3%), and slightly lower than that of T-SPOT.TB (91.0% and 100%); the specificity was 83.7% and 93.5%, higher than that of AFB (72.6%, 87.1%) and T-SPOT.TB (16.6%, 21.2%). The sensitivity of Xpert was 100% in bronchoalveolar lavage fluid (BALF) and 80.0% in sputum; in patients with CD4⁺ <200 cells/mm³, the sensitivity of Xpert was 90.0% and specificity was 84.8%, higher than that of AFB (60.0%, 75.5%) and T-SPOT.TB (90.0%, 21.5%). CONCLUSIONS Xpert has a high accuracy in HIV/TB co-infected patients, and Xpert still shows a high sensitivity and specificity even in HIV patients with CD4⁺ <200 cells/mm³. Xpert is recommended for the diagnosis of tuberculosis in HIV-infected patients.

    Topics: HIV Infections; Humans; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2022
A Mycobacterium tuberculosis-Infected Patient Who Could Not Tolerate Oral Intake Successfully Treated Using an Intravenous Tedizolid-Containing Regimen.
    The American journal of case reports, 2022, Oct-10, Volume: 23

    BACKGROUND Mycobacterium tuberculosis (M. tuberculosis) is usually treated by oral antimycobacterial agents, including rifampicin, ethambutol, and pyrazinamide, but the treatment regimen with intravenous and/or intramuscular antimycobacterial agents for patients who cannot take medications orally remains unclear. CASE REPORT A 77-year-old man with chronic renal failure had an esophageal-skin fistula after he had surgeries for removal of esophageal and gastric cancers and reconstruction using jejunum, and he showed a cavity, tree-in-bud formation, and pleural effusions in his left upper lung fields on his chest X-ray after treatment of cellulitis and bacteremia/candidemia by meropenem, teicoplanin, and micafungin. M. tuberculosis was isolated from his sputum and exudate fluid from the reconstructed esophageal-skin fistula. Although he could not take antimycobacterial agents orally, treatment was started with intravenous agents combining levofloxacin (LVFX) every other day, isoniazid (INH), and linezolid (LZD). However, his platelets were decreased 21 days after treatment started, and it was thought to be an adverse effect of LZD and/or INH. After changing LZD to tedizolid (TZD), in addition to changing from INH to intramuscular streptomycin twice per week, his platelet counts increased. Intravenous TZD could be continued, and it maintained his condition without exacerbations of thrombocytopenia and renal failure. The M. tuberculosis disappeared, and the abnormal chest X-ray shadows were improved 2 months after the start of treatment. CONCLUSIONS Administration of intravenous TZD, in addition to intravenous LVFX and intramuscular SM in combination, might be a candidate regimen for M. tuberculosis patients who cannot take oral medications.

    Topics: Aged; Anti-Bacterial Agents; Antitubercular Agents; Cutaneous Fistula; Ethambutol; Humans; Isoniazid; Levofloxacin; Linezolid; Male; Meropenem; Micafungin; Mycobacterium tuberculosis; Oxazolidinones; Pyrazinamide; Rifampin; Streptomycin; Teicoplanin; Tetrazoles; Tuberculosis

2022
A facile one-step jet-milling approach for the preparation of proliposomal dry powder for inhalation as effective delivery system for anti-TB therapeutics.
    Drug development and industrial pharmacy, 2022, Volume: 48, Issue:10

    Physicochemical characterization and assessment of aerosol dispersion performance of anti-TB proliposome dry powders for inhalation (DPIs) prepared using a single-step jet-milling (JM) approach.. The DPIs exhibited consistent, spherically shaped, smooth particles. Drug particles were evenly distributed with acceptable content uniformity. Drug crystallinity was not significantly affected by milling and the formulations had minimal (<2.0%) water content. After reconstitution of the DPIs, the hydrodynamic size was about 370.9-556.2 nm and charge was -12.3 to -47.3 mV. Furthermore, the proliposome DPIs presented emitted dose (69.04-89.03%), fine particle fraction, <4.4 µm (13.7 - 57.8%), and mass median aerodynamic diameter (<3.0 µm), which satisfied the requirements for deep lung delivery.. The proposed approach was suitable for preparation of proliposome DPIs that could be deployed for local targeting of the lower respiratory tract for the treatment of TB.

    Topics: Administration, Inhalation; Aerosols; Dry Powder Inhalers; Humans; Isoniazid; Liposomes; Particle Size; Powders; Rifampin; Tuberculosis

2022
Comparison of tests done, and tuberculosis cases detected by Xpert® MTB/RIF and Xpert® MTB/RIF-Ultra in Uganda.
    PloS one, 2022, Volume: 17, Issue:10

    Uganda introduced Xpert® MTB/RIF assay into its TB diagnostic algorithm in January 2012. In July 2018, this assay was replaced with Xpert® MTB/RIF Ultra assay. We set out to compare the tests done and tuberculosis cases detected by Xpert® MTB/RIF and Xpert® MTB/RIF Ultra assay in Uganda.. This was a before and after study, with the tests done and TB cases detected between Jan-June 2019 when using Xpert® MTB/RIF Ultra assay compared to those done between Jan-June 2018 while using Xpert® MTB/RIF assay. This data was analyzed using Stata version 13, it was summarized into measures of central tendency and the comparison between Xpert® MTB/RIF Ultra and Xpert® MTB/RIF was explored using a two-sided T-test which was considered significant if p <0.05.. One hundred and twelve (112) GeneXpert sites out of a possible 239 were included in the study. 128,476 (M: 1147.11, SD: 842.88) tests were performed with Xpert® MTB/RIF Ultra assay, with 9693 drug-susceptible TB (DS-TB) cases detected (M: 86.54, SD: 62.12) and 144 (M: 1.28, SD: 3.42) Rifampicin Resistant TB cases (RR-TB). Whilst 107, 890 (M: 963.30, SD: 842.88) tests were performed with Xpert® MTB/RIF assay between, 8807 (M: 78.63, SD: 53.29) DS-TB cases were detected, and 147 (M: 1.31, SD: 2.39) RR-TB cases. The Number Need to Test (NNT) to get one TB case was 12 for Xpert® MTB/RIF and 13 for Xpert ®MTB/RIF Ultra. On comparing the two assays in terms of test performance (p = 0.75) and case detection both susceptible TB (p = 0.31) and RR-TB (p = 0.95) were not found statistically significant.. This study found no significant difference in test performance and overall detection of DS-TB and RR-TB when using Xpert® MTB/RIF Ultra and Xpert® MTB/RIF assays. The health systems approach should be used to elucidate all the probable potential of Xpert® MTB/RIF Ultra.

    Topics: Antibiotics, Antitubercular; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Uganda

2022
Anti-Mycobacterial Activity of Flavonoid and Pyrimidine Compounds.
    Molecules (Basel, Switzerland), 2022, Oct-09, Volume: 27, Issue:19

    We evaluated the anti-mycobacterial effect of a flavonoid 5,7-dihydroxy-2-(4-hydroxyphenyl) 4

    Topics: Antitubercular Agents; Clarithromycin; Cycloserine; Drug Combinations; Flavonoids; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium avium; Mycobacterium tuberculosis; Pyrimidines; Rifampin; Tuberculosis

2022
Applications of machine learning tools for ultra-sensitive detection of lipoarabinomannan with plasmonic grating biosensors in clinical samples of tuberculosis.
    PloS one, 2022, Volume: 17, Issue:10

    Tuberculosis is one of the top ten causes of death globally and the leading cause of death from a single infectious agent. Eradicating the Tuberculosis epidemic by 2030 is one of the top United Nations Sustainable Development Goals. Early diagnosis is essential to achieving this goal because it improves individual prognosis and reduces transmission rates of asymptomatic infected. We aim to support this goal by developing rapid and sensitive diagnostics using machine learning algorithms to minimize the need for expert intervention.. A single molecule fluorescence immunosorbent assay was used to detect Tuberculosis biomarker lipoarabinomannan from a set of twenty clinical patient samples and a control set of spiked human urine. Tuberculosis status was separately confirmed by GeneXpert MTB/RIF and cell culture. Two machine learning algorithms, an automatic and a semiautomatic model, were developed and trained by the calibrated lipoarabinomannan titration assay data and then tested against the ground truth patient data. The semiautomatic model differed from the automatic model by an expert review step in the former, which calibrated the lower threshold to determine single molecules from background noise. The semiautomatic model was found to provide 88.89% clinical sensitivity, while the automatic model resulted in 77.78% clinical sensitivity.. The semiautomatic model outperformed the automatic model in clinical sensitivity as a result of the expert intervention applied during calibration and both models vastly outperformed manual expert counting in terms of time-to-detection and completion of analysis. Meanwhile, the clinical sensitivity of the automatic model could be improved significantly with a larger training dataset. In short, semiautomatic, and automatic Gaussian Mixture Models have a place in supporting rapid detection of Tuberculosis in resource-limited settings without sacrificing clinical sensitivity.

    Topics: Biomarkers; Biosensing Techniques; Humans; Immunosorbents; Machine Learning; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2022
Development and Optimization of a New UPLC-UV/MS Method through DoE and MLR for Detecting Substandard Drug Products to Treat Tuberculosis.
    Molecules (Basel, Switzerland), 2022, Oct-21, Volume: 27, Issue:20

    Drug products used for treating tuberculosis are one of the most widely reported medicines to be classified as falsified or substandard in low- and middle-income countries, representing a major hazard to health. The aim of this study was, firstly, to develop an ultra-performance liquid chromatography (UPLC) method which is able to analyze fixed combination tablets with up to four active pharmaceutical ingredients, including isoniazid, pyrazinamide, rifampicin, and ethambutol. Secondly, we aimed to optimize it through the design of experiments and multi-linear regression based on a central composite design and to validate it according to the guidelines of the International Conference on Harmonization. The application of this tools enabled the identification of the influential factors (flow rate, formic acid, and temperature) and their effects on the studied responses (retention factor and percentage for each drug) as part of the quality by design approach. The method proved to be to be linear in the range from 5.0 to 15 µg/mL for isoniazid, pyrazinamide, and rifampicin, being precise (<1%) and accurate (97−101%). In addition, the method validated for ethambutol proved to be linear from 1.4 to 4.2 µg/mL, as well as precise (0.54%) and accurate (97.3%). The method was stability indicated for all the active pharmaceutical ingredients studied and was able to detect two substandard formulations sampled on the African market.

    Topics: Antitubercular Agents; Chromatography, Liquid; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Substandard Drugs; Tablets; Tuberculosis

2022
[An atypical presentation of tuberculosis].
    Nederlands tijdschrift voor geneeskunde, 2022, 09-08, Volume: 166

    In 2020 there were 623 known TB infections in the Netherlands according to the Dutch ministry of health (RIVM). About 4% were located in bones and joints. The incidence of Multi Drug Resistant (MDR) TB in The Netherlands is about 1%.. We describe the case of a 46-year-old female with a painful and swelling of the mid phalangeal bone of the fourth left digit. Quantiferon was positive and PCR of the biopsy for Mycobacterium tuberculosis complex (MTC) in Ziehl-Neelsen staining confirmed tuberculous osteomyelitis. The strain was resistant for rifampicin, isoniazid, ethambutol and pyrazinamid classifying it as MDR. Treatment in a specialized center with second line drugs was indicated due to rare resistance.. Tuberculosis may manifest anywhere throughout the body, also as an (atypical) swelling of the hand. The golden diagnostic standard for bone and joint TB is biopsy with Ziehl-Neelsen staining.

    Topics: Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Origin and Dynamics of Mycobacterium tuberculosis Subpopulations That Predictably Generate Drug Tolerance and Resistance.
    mBio, 2022, 12-20, Volume: 13, Issue:6

    Initial responses to tuberculosis treatment are poor predictors of final therapeutic outcomes in drug-susceptible disease, suggesting that treatment success depends on features that are hidden within a small minority of the overall infecting Mycobacterium tuberculosis population. We developed a multitranswell robotic system to perform numerous parallel cultures of genetically barcoded M. tuberculosis exposed to steady-state concentrations of rifampicin to uncover these difficult-to-eliminate minority populations. We found that tolerance emerged repeatedly from at least two subpopulations of barcoded cells, namely, one that could not grow on solid agar media and a second that could form colonies, but whose kill curves diverged from the general bacterial population within 4 and 16 days of drug exposure, respectively. These tolerant subpopulations reproducibly passed through a phase characterized by multiple unfixed resistance mutations followed by emergent drug resistance in some cultures. Barcodes associated with drug resistance identified an especially privileged subpopulation that was rarely eliminated despite 20 days of drug treatment even in cultures that did not contain any drug-resistant mutants. The association of this evolutionary scenario with a defined subset of barcodes across multiple independent cultures suggested a transiently heritable phenotype, and indeed,

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Drug Tolerance; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2022
Dose optimization with population pharmacokinetics of ritonavir-boosted lopinavir for Thai people living with HIV with and without active tuberculosis.
    Drug metabolism and pharmacokinetics, 2022, Volume: 47

    Prior to dolutegravir availability, ritonavir-boosted lopinavir (LPV/r) was an alternative recommendation when first-line drugs could not be used. A high concentration of protease inhibitors was observed in the Thai people living with HIV (PLWH). Thus, dose reduction of LPV/r may be possible. However, the pharmacokinetics and dose optimization of LPV/r have never been investigated. This study aimed to develop a population pharmacokinetic model of LPV/r and provide dosage optimization in Thai PLWH.. LPV and RTV trough concentrations from Thai PLWH were combined with intensive data. The data were analyzed by the nonlinear mixed-effects modeling approach. The influence of RTV concentration on LPV oral clearance (CL/F) was investigated.. Rifampicin (RIF) use increased LPV and RTV CL/F by 2.16-fold and 1.99-fold, respectively. The reduced dose of 300/75 and 200/150 mg twice daily provided a comparable percentage of patients achieving LPV target trough concentration to the standard dose for PI-naïve patients. For HIV/TB co-infected patients receiving RIF who could not tolerate the recommended dose, the reduced dose of 600/150 mg twice daily was recommended.. The population pharmacokinetic model was developed by integrating the interaction between LPV and RTV. The reduced LPV/r dosage offers sufficient LPV exposure for Thai PLWH.

    Topics: Anti-HIV Agents; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Rifampin; Ritonavir; Thailand; Tuberculosis

2022
Detection of multidrug and extensively drug-resistance and mutation pattern in geriatric patients from North Indian referral institute.
    The Indian journal of tuberculosis, 2022, Volume: 69 Suppl 2

    Geriatric population are predisposed to reactivation to tuberculosis (TB) and multi-drug resistance (MDR) due to deteriorated immune system. Limited data is available in this population hence present study is undertaken to study drug resistance and associated mutations among geriatric presumptive DR-TB patients by genotypic methods METHODS: From October 2011 to December 2018, demographic characteristics of enrolled patients was collected. Smear-positive processed sputum samples were subjected directly while cultures positive for Mycobacterium Tuberculosis (MTB) from smear-negative pulmonary and all extra-pulmonary samples were subjected to LPA. The LPA used were Genotype MTBDR plus (1st line LPA) for detection of susceptibility to rifampicin (RIF) and isoniazid (INH) and Genotype MTBDR sl (2nd line LPA), for susceptibility to fluoroquinolones (FQ) and aminoglycosides (AG).. Total of 2041 samples were received from presumptive MDR-TB patients above 60 years of age during study period, of which 1406; 68.9% were within 60-70 year followed by 495; 24.3% within 71-80 year and 140; 6.9% more than 80 years. Total of 1055 MTB were detected, of which those diagnosed as RIF resistant were 117/1055; 11.2% including 89/1055; 8.5% MDR-TB and resistance to INH was in 84/1055; 8%. Total 67, 2nd line LPA gave valid results, of which 19/67 (28.4%) isolates were resistant to only FQ, and one isolate was resistant to AG.. Study finding highlights need for dedicated efforts for diagnosis, and treatment of geriatric tuberculosis. Suitable intervention at programmatic country level at country will help in strengthening tuberculosis control strategies in this population.

    Topics: Aged; Drug Resistance; Humans; Mutation; Referral and Consultation; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Enhancement of Antimycobacterial Activity of Rifampicin Using Mannose-Anchored Lipid Nanoparticles against Intramacrophage Mycobacteria.
    ACS applied bio materials, 2022, 12-19, Volume: 5, Issue:12

    Tuberculosis treatment requires a multidrug combination for the long-term, associated with adverse effects which lead to nonpatient compliance and the emergence of drug-resistant strains. Thus, mannose-anchored rifampicin-loaded solid lipid nanoparticles (M-RIF-SLNs) were developed to enhance the effect of rifampicin by selectively delivering to the macrophage, which led to the high intracellular killing of mycobacteria. The synthesized M-RIF-SLNs show a particle size of ∼100 nm and a drug loading of ∼8%. Cytotoxicity assay confirms that M-RIF-SLNs are not toxic up to 16 μg/mL (equivalent to incorporated rifampicin in SLN) toward THP-1-differentiated macrophages. An antimicrobial assay exhibits a reduction of minimum inhibitory concentration by 4-fold and 8-fold against wild-type and laboratory drug-resistant strains of

    Topics: Antitubercular Agents; Humans; Mannose; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2022
Algorithms for Screening for Active Tuberculosis among Individuals with Latent Tuberculosis Infection in a Rural Community in China.
    Microbiology spectrum, 2022, 12-21, Volume: 10, Issue:6

    Topics: Algorithms; Humans; Latent Tuberculosis; Mycobacterium tuberculosis; Rifampin; Rural Population; Sensitivity and Specificity; Tuberculosis

2022
Using the Food and Drug Administration´s Sentinel System for surveillance of TB infection.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2022, 12-01, Volume: 26, Issue:12

    Topics: Antitubercular Agents; Drug Prescriptions; Humans; Isoniazid; Rifampin; Tuberculosis; United States; United States Food and Drug Administration

2022
Tuberculosis treatment without rifampin in kidney/kidney-pancreas transplantation: A case series report.
    Transplant infectious disease : an official journal of the Transplantation Society, 2022, Volume: 24, Issue:6

    The best approach to tuberculosis (TB) treatment in transplanted patients is still unknown. Current guidelines are based on evidence either extrapolated from other populations or observational. Rifampin-containing regimens have strong pharmacokinetic interactions with immunosuppressive regimens, with high rates of organ dysfunction and ∼20% mortality. This report describes the results obtained using non-rifampin-containing regimens to treat confirmed TB in adult patients with kidney/kidney-pancreas transplantation.. Retrospective data analysis from confirmed TB cases in adult kidney/kidney-pancreas transplant recipients (2006-2019), treated "de novo" with non-rifampin-containing regimens.. Fifty-seven patients had confirmed TB. Thirty patients were treated "de novo" with non-rifampin-containing regimens. These patients' mean age was 49.24 (±11.50) years. Induction immunosuppression was used in 22 patients. Maintenance immunosuppression was tacrolimus-mycophenolate-steroids in 13 (43%), sirolimus-mycophenolate-steroids in 6 (20%), and other immunosuppressive regimens in 11 (36%). Belatacept was used in four patients. TB localizations: pulmonary 43%; disseminated 23%; extrapulmonary 33%. Twenty-seven (90%) patients completed treatment with isoniazid, ethambutol, and levofloxacin (12 months, 23; 9 months, 3; 6 months, 1); 12 of these patients also received pyrazinamide for the first 2 months and were cured with functioning grafts. One patient (3%) lost the graft while on treatment. Two patients (7%) died while on TB treatment. Median (range) follow-up after completion of TB treatment was 32 (8-150) months. No TB relapses were observed.. Results with non-rifampin-containing TB treatments in this case series were better (in terms of mortality and graft dysfunction) than those previously described with rifampin-containing regimens in transplanted patients.

    Topics: Adult; Antitubercular Agents; Humans; Immunosuppressive Agents; Isoniazid; Kidney; Middle Aged; Pancreas Transplantation; Retrospective Studies; Rifampin; Tuberculosis

2022
Drug resistance patterns and dynamics of tuberculosis in Zhejiang Province, China: Results from five periodic longitudinal surveys.
    Frontiers in public health, 2022, Volume: 10

    As one of the high multi-drug resistance tuberculosis countries, it is critical for China to understand patterns of drug resistance to better formulate effective treatment regimens.. The anti-TB Drug resistance surveillance has been conducted in Zheijang Province in years 1999, 2004, 2008, 2013, and 2018 respectively. We compared the prevalence of DR-TB from the latest survey with that of the previous four surveys in terms of all four first-line anti-TB drugs. We also examined the prevalence of rifampin-resistant TB (RR-TB) between the last two surveys and routine surveillance data.. Among 996 patients surveyed in 2018, the prevalence of RR-TB in new and previously treated TB cases was 2.5 and 4.3%, respectively. The prevalence of RR-TB among previously treated cases was much higher than for new cases in the four surveys from 1999 to 2013, while there was no significant difference between these groups in the 2018 survey. The percentage of TB cases resistant to fluoroquinolones in new patients was 3.8%. The prevalence of non-tuberculous mycobacteria increased over time; the prevalence of RR-TB among new cases slowly decreased. The prevalence of RR-TB in both new and previously treated TB cases from the latest two surveys was consistent with routine surveillance data.. This consistency between routine surveillance and periodic surveys for TB cases implies that with universal testing in Zhejiang Province, data from routine surveillance could be used instead of periodic surveys to improve access to timely and appropriate treatment for DR-TB. Levels of resistance were lower than whole-country and global estimates, further indicating the value of universal drug susceptibility testing.

    Topics: Antitubercular Agents; China; Drug Resistance; Humans; Longitudinal Studies; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2022
Xpert MTB/RIF Ultra in the auxiliary diagnosis of tuberculosis among people living with human immunodeficiency virus.
    Drug discoveries & therapeutics, 2022, Dec-26, Volume: 16, Issue:6

    Clinical diagnosis of tuberculosis (TB) in people living with the human immunodeficiency virus (HIV) poses a challenge. The Xpert MTB/RIF Ultra (Ultra) has displayed greater sensitivity at diagnosing tuberculosis and rifampicin resistance compared to the Xpert MTB/RIF (Xpert). However, whether Ultra is able to facilitate an auxiliary diagnosis of TB in patients with an HIV-TB co-infection remains unclear. Accordingly, the current study evaluated the use of Ultra in patients with an HIV-TB co-infection by summarizing relevant studies. The sensitivity and specificity of Ultra and Xpert at diagnosing patients with an HIV-TB co-infection have been summarized and compared. The performance of Ultra in diagnosing extrapulmonary tuberculosis was also summarized. Although a large-cohort, multi-center study needs to be conducted to assess Ultra's ability to detect TB in AIDS patients in the future, the current evidence supports the use of Ultra for the assessment of patients with an HIV-TB co-infection.

    Topics: Antibiotics, Antitubercular; Coinfection; HIV; HIV Infections; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Pulmonary

2022
Evaluation Study of xMAP TIER Assay on a Microsphere-Based Platform for Detecting First-Line Anti-Tuberculosis Drug Resistance.
    International journal of environmental research and public health, 2022, 12-19, Volume: 19, Issue:24

    Early diagnosis of drug susceptibility for tuberculosis (TB) patients could guide the timely initiation of effective treatment. We evaluated a novel multiplex xMAP TIER (Tuberculosis-Isoniazid-Ethambutol-Rifampicin) assay based on the Luminex xMAP system to detect first-line anti-tuberculous drug resistance. Deoxyribonucleic acid samples from 353 Mycobacterium tuberculosis clinical isolates were amplified by multiplex polymerase chain reaction, followed by hybridization and analysis through the xMAP system. Compared with the broth microdilution method, the sensitivity and specificity of the xMAP TIER assay for detecting resistance was 94.9% (95%CI, 90.0-99.8%) and 98.9% (95%CI, 97.7-100.0%) for rifampicin; 89.1% (95%CI, 83.9-94.3%) and 100.0% (95%CI, 100.0-100.0%) for isoniazid; 82.1% (95% CI, 68.0-96.3%) and 99.7% (95% CI, 99.0-100.0%) for ethambutol. With DNA sequencing as the reference standard, the sensitivity and specificity of xMAP TIER for detecting resistance were 95.0% (95% CI, 90.2-99.8%) and 99.6% (95% CI, 98.9-100.0%) for rifampicin; 96.9% (95% CI, 93.8-99.9%) and 100.0% (95% CI, 100.0-100.0%) for isoniazid; 86.1% (95% CI, 74.8-97.4%) and 100.0% (95% CI, 100.0-100.0%) for ethambutol. The results achieved showed that the xMAP TIER assay had good performance for detecting first-line anti-tuberculosis drug resistance, and it has the potential to diagnose drug-resistant tuberculosis more accurately due to the addition of more optimal design primers and probes on open architecture xMAP system.

    Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Microspheres; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2022
Detection and factors associated with tuberculosis and rifampicin resistance among presumptive patients at the Thailand-Myanmar border.
    Tropical biomedicine, 2022, Dec-01, Volume: 39, Issue:4

    Tuberculosis (TB) continues to be a major public health problem in Thailand and many countries. Endemic TB and outbreaks of TB drug resistance in the borderlands are particularly important. The Thailand-Myanmar border has extensive cross-border travel that may accelerate TB's spread. This cross-sectional study aimed to determine the frequency and factors associated with TB, and rifampicinresistant TB (RR-TB) among presumptive tuberculosis patients in Mae Sot Hospital. Sputum was processed by microscopic examination and Xpert MTB/RIF assay. Laboratory results and socio-demographic characteristics were collected and analyzed. Univariate and multivariate analyses were performed to assess the association of the risk factors with TB and RR-TB. The significant variables at p-values < 0.05 in univariate analysis were selected for multivariate analysis. Of 365 presumptive patients enrolled, 244 (66.85%) were males and 199 (54.52%) were Burmese. Of these, 314 (86.03%) were registered as new cases and 183 (50.14%) worked as laborers. Sputum microscopy was positive in 132 (36.16%) cases. Based on Xpert MTB/RIF, the frequency of TB was 136 (37.26%) and RR-TB was 15 (11.03%). TB was more common in males than females. The majority of the cases belonged to the 26-50-year-old age group and migrant workers. In RR-TB detection, the rpoB mutations covered by probe E were the most frequently observed. Sequencing showed that the most highly mutated codon was codon 531 and Ser531Thr was the most common mutation. For risk factor analysis, working as laborers was significantly (p-value < 0.05) associated with TB (aOR 2.83; 95% CI 1.43-5.63) and previously treated cases were significantly associated with RR-TB (aOR 12.33; 95% CI 2.29-66.49). The high frequency of TB and RR-TB in migrants highlights the problem and factors associated with TB at the border and the need for efforts in TB control programs in this setting.

    Topics: Adult; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Myanmar; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Thailand; Tuberculosis

2022
Tuberculosis Monitoring Encouragement Adherence Drive (TMEAD): Toward improving the adherence of the patients with drug-sensitive tuberculosis in Nashik, Maharashtra.
    Frontiers in public health, 2022, Volume: 10

    Adherence to tuberculosis (TB) medication is one of the critical challenges to tuberculosis elimination in India. Digital adherence technologies (DAT) have the potential to facilitate medication adherence and monitor it remotely. Tuberculosis Monitoring Encouragement Adherence Drive (TMEAD) is one such DAT piloted in Nasik, Maharashtra, from April 2020 to December 2021. The study aims to assess the adherence and cost-effectiveness of TMEAD compared to the standard of care among patients with drug-sensitive tuberculosis (DSTB) residing in the urban areas of Nasik, Maharashtra, India.. A quasi-experimental study was conducted among new cases of TB as per the National TB Elimination Programme (NTEP) residing in the urban geography of Nasik. The intervention and control arms were purposively selected from non-contaminating TB units (TUs). A total of 400 DSTB patients (200 in the intervention group and 200 in the control group) were enrolled. After enrolment, patients in the intervention arm were provided with the TMEAD device and followed for 24 weeks to assess treatment outcomes. Adherence was measured as those patients who have completed 80% of prescribed doses, as reported during patient follow-up, and further validated by analyzing the trace of rifampicin in urine among 20% of patients from both arms. A budget impact analysis was done to assess the impact of the TMEAD program on the overall state health budget.. Out of 400 enrolled DSTB patients, 261 patients completed treatment, 108 patients were on treatment, 15 patients died, and 16 patients were defaulters over the study period. The study reported overall treatment adherence of 94% among those who completed treatment. Patient reports indicated high levels of treatment adherence in the intervention group (99%) as compared to the control group (90%). Adherence assessed through analyzing trace of rifampicin in the urine sample for the intervention arm was 84% compared to the control arm (80%). Per beneficiary (discounted) cost for TMEAD was Indian rupees (INR) 6,573 (USD 83). The incremental cost-effectiveness ratio of the intervention is INR 11,599 (USD 146), which shows that the intervention is highly cost-effective.. This study revealed that patient-reported treatment adherence was high in TMEAD when compared to standard therapy of care for DSTB patients and the intervention is cost-effective. TMEAD could complement the national strategy to end TB by improving adherence to the treatment regimen in India.

    Topics: Antitubercular Agents; Humans; India; Medication Adherence; Rifampin; Tuberculosis

2022
Polymorphisms of SLCO1B1 Gene in Sundanese Ethnic Population of Tuberculosis Patients in Indonesia.
    Acta medica Indonesiana, 2022, Volume: 54, Issue:4

    The blood level of rifampicin, one of the tuberculosis (TB) drugs, depends on the organic anion transporting polypeptide 1B1 (OATP1B1) in hepatocytes. This protein is encoded by the solute carrier organic anion 1B1 (SLCO1B1) gene. Its genetic variation has been reported to have an impact on clinical outcomes and drug efficacy. However, the polymorphism in the SLCO1B1 gene has not been examined in Indonesia yet. We aimed to identify the frequency of polymorphism in SLCO1B1 gene among pulmonary TB patients in Bandung, Indonesia.. Cross-sectional study was conducted in West Java. 145 pulmonary TB patients who were treated with first-line drugs treatment (including rifampicin 450 mg daily) were analyzed for polymorphism in SLCO1B1 gene. Patients aged between 18-64 years old and mainly came from Sundanese ethnic group (92.4%). Genetic variants were detected using Polymerase Chain Reaction (PCR) and Sanger sequencing.. Polymorphism of c.463C>A(rs11045819) was not identified, while heterozygous and homozygous polymorphism of c.85-7793C>T(rs4149032) were identified in 74 (51.0%) and 56 (38.6%) patients, respectively. The minor allele frequency (MAF) of T (mutant) allele of c.85-7793C>T(rs4149032) was 64.13% (186/209), higher than in the general population, which the MAF of rs4149032 is 53.6% based on 1000 genome database.. This study highlights the presence of different allele frequencies of polymorphisms within the population, which might affect treatment outcomes.

    Topics: Adolescent; Adult; Cross-Sectional Studies; Ethnicity; Gene Frequency; Genotype; Humans; Indonesia; Liver-Specific Organic Anion Transporter 1; Middle Aged; Organic Anion Transporters; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis; Young Adult

2022
Evaluation of Five User-Friendly Whole Genome Sequencing Software for
    Journal of Korean medical science, 2022, Nov-28, Volume: 37, Issue:46

    Whole genome sequencing (WGS) is an increasingly useful tool for tuberculosis (TB) diagnosis and disease management. In this study, we evaluated the utility of user-friendly WGS tools in reporting resistance profiles and identifying lineages of clinical TB isolates from South Korea.. Forty clinical samples from TB patients showing discrepancies between their rapid molecular and conventional drug susceptibility tests were used in this study. Among these clinical isolates, 37 strains were successfully evaluated via WGS software, using the GenTB, TB Profiler, PhyResSE, CASTB, and Mykrobe.. More accurate and faster susceptibility results could be obtained with isoniazid than with rifampin. Using the phenotypic test as the gold standard, the isoniazid concordance rate between phenotypic drug susceptibility test (DST) and WGS (GenTB: 45.9%, TB profiler: 40.5%, PhyResSE: 40.5%, CASTB: 48.6%, and Mykrobe: 43.2%) was much higher than between phenotypic DST and rapid molecular genotypic DST (18.9%) among the 37 strains. In contrast, the rifampin concordance rate between phenotypic DST and WGS and that between phenotypic DST and rapid molecular genotypic DST was similar (81.1-89.2%). We also found novel mutations associated with INH in. WGS may play a pivotal role in TB diagnosis and the detection of drug resistance, genetic diversity, and transmission dynamics in the near future because of its accuracy, speed, and extensibility.

    Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Software; Tuberculosis; Tuberculosis, Multidrug-Resistant; Whole Genome Sequencing

2022
An efficient CRISPR interference-based prediction method for synergistic/additive effects of novel combinations of anti-tuberculosis drugs.
    Microbiology (Reading, England), 2022, Volume: 168, Issue:12

    Tuberculosis (TB) is treated by chemotherapy with multiple anti-TB drugs for a long period, spanning 6 months even in a standard course. In perspective, to prevent the emergence of antimicrobial resistance, novel drugs that act synergistically or additively in combination with major anti-TB drugs and, if possible, shorten the duration of TB therapy are needed. However, their combinatorial effect cannot be predicted until the lead identification phase of the drug development. Clustered regularly interspaced short palindromic repeats interference (CRISPRi) is a powerful genetic tool that enables high-throughput screening of novel drug targets. The development of anti-TB drugs promises to be accelerated by CRISPRi. This study determined whether CRISPRi could be applicable for predictive screening of the combinatorial effect between major anti-TB drugs and an inhibitor of a novel target. In the checkerboard assay, isoniazid killed

    Topics: Antitubercular Agents; Clustered Regularly Interspaced Short Palindromic Repeats; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2022
Pattern of rifampicin resistance and gene xpert based molecular typing of tuberculosis patients in tertiary care hospitals.
    Pakistan journal of pharmaceutical sciences, 2022, Volume: 35, Issue:6(Special)

    Mycobacterium tuberculosis associated morbidity, mortality and drug resistance is a global health issue. The Gene Xpert is used for early diagnosis of TB and simultaneous detection of Rifampicin (RIF) resistance. We aimed to determine situation analysis of clinical TB in tertiary care hospitals of Faisalabad and to find out frequency of TB and drug resistance pattern by Gene Xpert. A total of 220 samples from suspected patients of TB were included in this study and 214 samples were detected as positive by Gene Xpert. Samples were classified on the basis of gender, age group (<30, 30-50 and >50 years), type of sample (sputum and pleural) and number of M. tuberculosis by ct value (cycle threshold). The results of present study showed high positive frequency of TB in male patients and in 30-50 years of age groups by Gene Xpert. High number of M. tuberculosis was found in low and medium category in TB patients. Out of 214 positive TB patients, rifampicin resistance was detected in 16 patients. In conclusion, our study identified that Gene Xpert is an effective approach for diagnosing TB by detection of M. tuberculosis and rifampicin resistance in <2 hours for rapid diagnosis and management of TB.

    Topics: Humans; Male; Middle Aged; Molecular Typing; Mycobacterium tuberculosis; Rifampin; Tertiary Care Centers; Tuberculosis

2022
Predictive Modeling to Study the Treatment-Shortening Potential of Novel Tuberculosis Drug Regimens, Toward Bundling of Preclinical Data.
    The Journal of infectious diseases, 2022, 06-01, Volume: 225, Issue:11

    Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling.. Mycobacterium tuberculosis-infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator.. Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively.. This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models.

    Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

2022
Evaluation of screening strategies for pulmonary tuberculosis among hospitalized patients in a low-burden setting: cost-effectiveness of GeneXpert MTB/RIF compared to smear microscopy.
    Infection control and hospital epidemiology, 2022, Volume: 43, Issue:7

    We conducted a retrospective cohort study of hospitalized adults evaluated for pulmonary TB at a large academic medical center in New York from 2010 to 2017. Using propensity score matching, we compared hospital length-of-stay among patients undergoing conventional smear-based TB evaluation to a control group with non-TB pneumonia. We performed a probabilistic cost-effectiveness analysis to compare Xpert-based versus conventional TB evaluation.. In total 1,421 patients were evaluated for TB with airborne isolation and sputum testing; mycobacterial culture was positive for MTB in 49 (3.4%). Conventional TB evaluation was associated with an increase of 4.4 hospital days compared to propensity-matched controls. Xpert-based testing strategies dominated conventional TB evaluation with a cost savings of $5,947 (95% CI, $1,156-$12,540) and $4,445 (95% CI, $696-$9,526) per patient depending on the number of Xpert tests performed (1 vs 2, respectively) and assumptions about the reduction of length of stay achieved.. In the evaluation of hospitalized patients for pulmonary TB, Xpert-based testing has superior diagnostic performance and is likely cost-effective compared to smear microscopy due to reduced hospital length-of-stay associated with more rapid test results.

    Topics: Adult; Cost-Benefit Analysis; Humans; Microscopy; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2022
The performance of the Xpert MTB/RIF Version G4 in a low tuberculosis incidence setting.
    Pathology, 2022, Volume: 54, Issue:1

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; Benchmarking; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Mutation; Mycobacterium tuberculosis; Phenotype; Predictive Value of Tests; Retrospective Studies; Rifampin; Staining and Labeling; Tuberculosis

2022
Moxifloxacin Pharmacokinetics, Cardiac Safety, and Dosing for the Treatment of Rifampicin-Resistant Tuberculosis in Children.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022, 04-28, Volume: 74, Issue:8

    Moxifloxacin is a recommended drug for rifampin-resistant tuberculosis (RR-TB) treatment, but there is limited pediatric pharmacokinetic and safety data, especially in young children. We characterize moxifloxacin population pharmacokinetics and QT interval prolongation and evaluate optimal dosing in children with RR-TB.. Pharmacokinetic data were pooled from 2 observational studies in South African children with RR-TB routinely treated with oral moxifloxacin once daily. The population pharmacokinetics and Fridericia-corrected QT (QTcF)-interval prolongation were characterized in NONMEM. Pharmacokinetic simulations were performed to predict expected exposure and optimal weight-banded dosing.. Eighty-five children contributed pharmacokinetic data (median [range] age of 4.6 [0.8-15] years); 16 (19%) were aged <2 years, and 8 (9%) were living with human immunodeficiency virus (HIV). The median (range) moxifloxacin dose on pharmacokinetic sampling days was 11 mg/kg (6.1 to 17). Apparent clearance was 6.95 L/h for a typical 16-kg child. Stunting and HIV increased apparent clearance. Crushed or suspended tablets had faster absorption. The median (range) maximum change in QTcF after moxifloxacin administration was 16.3 (-27.7 to 61.3) ms. No child had QTcF ≥500 ms. The concentration-QTcF relationship was nonlinear, with a maximum drug effect (Emax) of 8.80 ms (interindividual variability = 9.75 ms). Clofazimine use increased Emax by 3.3-fold. Model-based simulations of moxifloxacin pharmacokinetics predicted that current dosing recommendations are too low in children.. Moxifloxacin doses above 10-15 mg/kg are likely required in young children to match adult exposures but require further safety assessment, especially when coadministered with other QT-prolonging agents.

    Topics: Adult; Child; Child, Preschool; Electrocardiography; Fluoroquinolones; HIV Infections; Humans; Moxifloxacin; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2022
Vikela Ekhaya: A Novel, Community-based, Tuberculosis Contact Management Program in a High Burden Setting.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022, 05-03, Volume: 74, Issue:9

    The prevention of tuberculosis (TB) in child contacts of TB cases and people living with human immunodeficiency virus (HIV) is a public health priority, but global access to TB preventive therapy (TPT) remains low. In 2019, we implemented Vikela Ekhaya, a novel community-based TB contact management program in Eswatini designed to reduce barriers to accessing TPT.. Vikela Ekhaya offered differentiated TB and HIV testing for household contacts of TB cases by using mobile contact management teams to screen contacts, assess their TPT eligibility, and initiate and monitor TPT adherence in participants' homes.. In total, 945 contacts from 244 households were screened for TB symptoms; 72 (8%) contacts reported TB symptoms, and 5 contacts (0.5%) were diagnosed with prevalent TB. A total of 322 of 330 (98%) eligible asymptomatic household contacts initiated TPT. Of 322 contacts initiating TPT, 248 children initiated 3 months of isoniazid and rifampicin and 74 children and adults living with HIV initiated 6 months of isoniazid; 298 (93%) completed TPT. In clustered logistic regression analyses, unknown HIV status (adjusted odds ratio [aOR] 5.7, P = .023), positive HIV status (aOR 21.1, P = .001), urban setting (aOR 5.6, P = .006), and low income (aOR 5.9, P = .001) predicted loss from the cascade of care among TPT-eligible contacts.. Vikela Ekhaya demonstrated that community-based TB household contact management is a feasible, acceptable, and successful strategy for TB screening and TPT delivery. The results of this study support the development of novel, differentiated, community-based interventions for TB prevention and control.

    Topics: Adult; Child; Contact Tracing; HIV Infections; Humans; Isoniazid; Levonorgestrel; Rifampin; Tuberculosis

2022
Utility of plasma cell-free DNA detection using homobifunctional imidoesters using a microfluidic system for diagnosing active tuberculosis.
    Infectious diseases (London, England), 2022, Volume: 54, Issue:1

    It is difficult to diagnose tuberculosis (TB), particularly sputum-scarce pulmonary TB and extrapulmonary TB, using conventional diagnostic tests. Since these cases require additional invasive procedures to obtain appropriate specimens, new non-invasive diagnostic tests are needed. Plasma cell-free DNA (cfDNA) detection has gained interest as a novel diagnostic test for TB as it is convenient and less invasive. Therefore, we investigated the performance of enriched cfDNA for diagnosing pulmonary TB and extrapulmonary TB.. All patients suspected to have TB, who consented to the use of blood for detecting cfDNA, were prospectively enrolled from January 2019 to June 2020. We categorised the patients as confirmed, probable, possible TB, and not-TB. We compared the performance of cfDNA with those of conventional diagnostic tests.. Among the 96 patients enrolled, 40 (41.7%) had TB, including 34 with confirmed TB and six probable TB, and 41 (42.7%) did not have TB. Acid-fast bacilli microscopy, Xpert MTB/RIF, and mycobacterial culture results were positive in 12 (31.6%), 22 (61.1%), and 25 (65.8%) patients, respectively. The sensitivity and specificity of cfDNA were 80.0% and 78.1%, respectively. While the sensitivity and specificity of cfDNA were similar to those of interferon-gamma releasing assay (IGRA) (sensitivity 80.6% and specificity 71.4%), the combined sensitivity and specificity of the two assays were 94.4% and 64.3%, respectively, which can be used to rule out TB.. Plasma cfDNA assay seems to be a useful adjunct to the current tests for diagnosing TB, especially when used in combination with IGRA for ruling out TB.AbbreviationsTBtuberculosiscfDNAcell-free DNAPCRpolymerase chain reactionAFBacid-fast bacilliIGRAinterferon-gamma releasing assayCTcomputed tomographyHIVhuman immunodeficiency virus.

    Topics: Cell-Free Nucleic Acids; Humans; Microfluidics; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2022
Pharmacokinetics of First-Line Drugs in Children With Tuberculosis, Using World Health Organization-Recommended Weight Band Doses and Formulations.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022, 05-30, Volume: 74, Issue:10

    Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization-recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial.. Children weighing 4.0-7.9, 8.0-11.9, 12.0-15.9, or 16.0-24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0-36.9 kg received doses recommended for adults <37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment.. In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4-6.6) years; 40 (52%) were male and 20 (26%) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1-45.1), 16.7 (9.2-25.9), 317 (263-399), and 9.5 (7.5-11.5) mg⋅h/L, respectively, and lower in children than in adults for rifampicin in the 4.0-7.9-, 8-11.9-, and ≥25-kg weight bands, isoniazid in the 4.0-7.9-kg and ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults.. Recommended weight band-based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization-recommended doses requires further evaluation.

    Topics: Adult; Antitubercular Agents; Child; Child, Preschool; Ethambutol; Female; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Tuberculosis; World Health Organization

2022
Surveillance of tuberculosis in Switzerland and the Principality of Liechtenstein, 2009 to 2019.
    Swiss medical weekly, 2021, 08-30, Volume: 151

    To describe the epidemiology of tuberculosis in Switzerland from 2009 to 2019.METHODS: Analysis of Swiss notification data.. Tuberculosis cases declined from 553 (7.1/100,000) in 2009 to 437 (5.1/100,000) in 2019. The male-to-female ratio was 3:2. Although the number of tuberculosis cases of Swiss origin has steadily declined, the number of tuberculosis cases of foreign origin was rather stable but peaked in 2016. Overall, three quarters of tuberculosis cases were among people of foreign origin; of these, around half were from East Africa, Southern East Europe, and Southern Asia. Forty-nine percent had extrapulmonary manifestations. Every year, with little variation, 7-16 cases with rifampicin resistance were reported (2.9% overall). Independent risk factors for rifampicin resistance were prior anti-tuberculosis treatment, with an adjusted odds ratio (aOR) of 5.5 and a 95% confidence interval (CI) from 3.7 to 8.1, and foreign origin (aOR 3.6, 95% CI 2.0-7.0), particularly Georgia (aOR 10.0, 95% CI 4.0-23.1), Ethiopia (aOR 9.4, 95% CI 3.5-24.2), Tibet (aOR 6.9; 95% CI 2.9-16.6) and Somalia (aOR 8.1, 95% CI 4.0-17.2), together with Eritrea (aOR 2.6, 95% CI 1.1-5.9), accounting for more than half of all 134 cases . From 2016 to 2018, applying the World Health Organization definitions, overall treatment success in culture-confirmed pulmonary cases was 78%, and thus below the target of 85%. Since most cases with unsuccessful outcome are due to missing information, the proportion of unsuccessful outcome are overestimated.. Autochthonous tuberculosis has become rare in Switzerland and the new diagnoses are increasingly attributable to immigration. Rifampicin resistance remains rare. Switzerland currently fails to achieve international targets for treatment success.

    Topics: Antitubercular Agents; Female; Humans; Liechtenstein; Male; Rifampin; Switzerland; Tuberculosis

2021
Flow cytometry method for absolute counting and single-cell phenotyping of mycobacteria.
    Scientific reports, 2021, 09-20, Volume: 11, Issue:1

    Detection and accurate quantitation of viable Mycobacterium tuberculosis is fundamental to understanding mycobacterial pathogenicity, tuberculosis (TB) disease progression and outcomes; TB transmission; drug action, efficacy and drug resistance. Despite this importance, methods for determining numbers of viable bacilli are limited in accuracy and precision owing to inherent characteristics of mycobacterial cell biology-including the tendency to clump, and "differential" culturability-and technical challenges consequent on handling an infectious pathogen under biosafe conditions. We developed an absolute counting method for mycobacteria in liquid cultures using a bench-top flow cytometer, and the low-cost fluorescent dyes Calcein-AM (CA) and SYBR-gold (SG). During exponential growth CA + cell counts are highly correlated with CFU counts and can be used as a real-time alternative to simplify the accurate standardisation of inocula for experiments. In contrast to CFU counting, this method can detect and enumerate cell aggregates in samples, which we show are a potential source of variance and bias when using established methods. We show that CFUs comprise a sub-population of intact, metabolically active mycobacterial cells in liquid cultures, with CFU-proportion varying by growth conditions. A pharmacodynamic application of the flow cytometry method, exploring kinetics of fluorescent probe defined subpopulations compared to CFU is demonstrated. Flow cytometry derived Mycobacterium bovis bacillus Calmette-Guérin (BCG) time-kill curves differ for rifampicin and kanamycin versus isoniazid and ethambutol, as do the relative dynamics of discrete morphologically-distinct subpopulations of bacilli revealed by this high-throughput single-cell technique.

    Topics: Colony Count, Microbial; Flow Cytometry; Humans; Immunologic Tests; Isoniazid; Kanamycin; Mycobacterium; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2021
[Evaluation of the molecular assays for detection of Mycobacterium tuberculosis complex in extrapulmonary specimens].
    Tuberkuloz ve toraks, 2021, Volume: 69, Issue:3

    Tuberculosis, one of the most common and deadly infectious diseases, mainly affects the lungs, but can involve all tissues and organs. Diagnosis of extrapulmonary tuberculosis may be more challenging than pulmonary tuberculosis, which may lead to delay in starting treatment. In our study, it was aimed to determine the diagnostic value of FluoroType MTB, GeneXpert MTB/RIF, GeneXpert MTB/RIF Ultra molecular tests in extrapulmonary specimens.. Extrapulmonary clinical materials were subjected to Kinyoun staining for acid fast bacilli and cultivation was done on Lowenstein Jensen media and BACTEC MGIT 960 automated culture system (BD). Results were compared with FluoroType MTB and GeneXpert MTB/RIF test results (2018) and with FluoroType MTB and GeneXpert MTB/RIF Ultra tests results (2019).. A total number of 892 extrapulmonary specimens were enrolled in the study. In 2018, positivity was detected in 16 (3.4%) of 467 specimens by molecular methods. Compared with culture; the sensitivity and specifity of the FluoroType MTB were 76.92%, 98.88% respectively; the sensitivity and specifity of GeneXpert MTB/RIF were 100%, 98.96% respectively. In 2019, positivity was detected in 15 (3.5%) of 425 specimens by molecular methods. The sensitivity and specifity of the FluoroType MTB was 62.5%, 98.05% respectively; the sensitivity and specificity of GeneXpert MTB/RIF Ultra was 100%, 99.36% respectively.. Although culture is the gold standard method in the diagnosis of tuberculosis, the patients were diagnosed only with polymerase chain reaction positivity, supported by the patient's clinical, radiology and pathology results in seven cases. The diagnosis of tuberculosis in extrapulmonary specimens is more challenging than in pulmonary specimens due to low bacillary burden and requiring invasive procedures for sampling. It should be considered that molecular methods have a critical role in diagnosis.

    Topics: Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Pulmonary

2021
Diagnostic performance of the Abbott RealTime MTB assay for tuberculosis diagnosis in people living with HIV.
    Scientific reports, 2021, 09-29, Volume: 11, Issue:1

    Strengthening tuberculosis diagnosis is an international priority and the advocacy for multi-disease testing devices raises the possibility of improving laboratory efficiency. However, the advantages of centralized platforms might not translate into real improvements under operational conditions. This study aimed to evaluate the field use of the Abbott RealTime MTB (RT-MTB) and Xpert MTB/RIF assays, in a large cohort of HIV-positive and TB presumptive cases in Southern Mozambique. Over a 6-month period, 255 HIV-positive TB presumptive cases were consecutively recruited in the high TB/HIV burden district of Manhiça. The diagnostic performance of both assays was evaluated against two different reference standards: a microbiological gold standard (MGS) and a composite reference standard (CRS). Results from the primary analysis (MGS) showed improved sensitivity (Se) and reduced specificity (Sp) for the Abbott RT-MTB assay compared to the Xpert MTB/RIF (RT-MTB Se: 0.92 (95% CI: 0.75;0.99) vs Xpert Se: 0.73 (95% CI: 0.52;0.88) p value = 0.06; RT-MTB Sp: 0.80 (0.72;0.86) vs Xpert Sp: 0.96 (0.92;0.99) p value < 0.001). The lower specificity may be due to cross-reactivity with non-tuberculous mycobacteria (NTMs), the detection of non-viable MTBC, or the identification of true TB cases missed by the gold standard.

    Topics: Adult; DNA, Bacterial; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Isoniazid; Male; Mozambique; Mycobacterium tuberculosis; Prospective Studies; Reagent Kits, Diagnostic; Real-Time Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis; Young Adult

2021
Real-life isoniazid and rifampicin plasma concentrations in children: a tool for therapeutic drug monitoring of tuberculosis.
    BMC infectious diseases, 2021, Oct-21, Volume: 21, Issue:1

    Low plasma levels of first-line antitubercular drugs can be counted among the main causes of poor response to antitubercular therapy, and therapeutic drug monitoring has been proposed as a method to promote tailored treatments for both child and adult patients. The main aim of the study was to evaluate serum concentrations of isoniazid (INH) and rifampicin (RIF) and to investigate reasons for sub-therapeutic plasma concentrations in order to fix dosages.. Children with TB were prospectively enrolled from January to August 2019. Two venous blood samples were collected (the first at least 15 days after the beginning of antitubercular treatment, and the second between 1 and 8 weeks later). Plasma concentrations were determined by a validated high-performance liquid chromatography method.. In all, 45 children were included. Seventy blood samples for INH plasma concentration were collected between 120 and 240 min after drug intake. Adjusting for dose (mg/kg/day) and time of INH administration, when considering three different age groups (≤ 2 years, 2-12 years, > 12 years), a statistically significant lower INH plasma concentration was observed in younger children compared to the older age groups in the multivariate analysis (p < 0.001 and p < 0.001). A total of 68 blood samples were evaluated for RIF concentrations. Both for INH and RIF a statistically significant lower plasma concentration was also observed in adolescents (p < 0.001). Fifteen children (15/45, 33%) presented drug concentrations under the referral therapeutic range.. Based on our findings, monitoring patients' drug plasma concentrations in children under 2 years of age and in adolescents can make treatment more patient-tailored.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Child, Preschool; Drug Monitoring; Humans; Infant; Isoniazid; Rifampin; Tuberculosis

2021
LC-MS/MS method for simultaneous quantification of the first-line anti-tuberculosis drugs and six primary metabolites in patient plasma: Implications for therapeutic drug monitoring.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2021, Nov-15, Volume: 1185

    The pharmacokinetic profiling of drug substances and corresponding metabolites in the biological matrix is one of the most informative tools for the treatment efficacy assessment. Therefore, to satisfy the need for comprehensive monitoring of anti-tuberculosis drugs in human plasma, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous quantification of first-line anti-tuberculosis drugs (ethambutol, isoniazid, pyrazinamide, and rifampicin) along with their six primary metabolites. Simple single-step protein precipitation with methanol was chosen as the most convenient sample pre-treatment method. Chromatographic separation of the ten analyte mixture was achieved within 10 minutes on a reverse-phase C8 column using mobile phase gradient mode. The multiple reaction monitoring mode (MRM) was used for analyte detection and quantification in patient samples. The chosen quantification ranges fully covered expected plasma concentrations. The method exhibited acceptable selectivity; the within- and between-run accuracy ranged from 87.2 to 113.6%, but within- and between-run precision was between 1.6 and 14.9% (at the LLOQ level CV < 20%). Although the response of the isonicotinic acid varied depending on the matrix source (CV 21.8%), validation results proved that such inconsistency does not affect the accuracy and precision of results. If stored at room temperature plasma samples should be processed within 4 h after collection, temporary storage at -20 °C up to 24 h is acceptable due to stability issues of analytes. The developed method was applied for the patient sample analysis (n = 34) receiving anti-tuberculosis treatment with the first-line drugs.

    Topics: Antitubercular Agents; Chromatography, High Pressure Liquid; Drug Monitoring; Ethambutol; Humans; Isoniazid; Plasma; Pyrazinamide; Rifampin; Tandem Mass Spectrometry; Tuberculosis

2021
Potential contribution of HIV during first-line tuberculosis treatment to subsequent rifampicin-monoresistant tuberculosis and acquired tuberculosis drug resistance in South Africa: a retrospective molecular epidemiology study.
    The Lancet. Microbe, 2021, Volume: 2, Issue:11

    South Africa has a high burden of rifampicin-resistant tuberculosis (including multidrug-resistant [MDR] tuberculosis), with increasing rifampicin-monoresistant (RMR) tuberculosis over time. Resistance acquisition during first-line tuberculosis treatment could be a key contributor to this burden, and HIV might increase the risk of acquiring rifampicin resistance. We assessed whether HIV during previous treatment was associated with RMR tuberculosis and resistance acquisition among a retrospective cohort of patients with MDR or rifampicin-resistant tuberculosis.. In this retrospective cohort study, we included all patients routinely diagnosed with MDR or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa, between Jan 1, 2008, and Dec 31, 2017. Patient-level data were obtained from a prospective database, complemented by data on previous tuberculosis treatment and HIV from a provincial health data exchange. Stored MDR or rifampicin-resistant tuberculosis isolates from patients underwent whole-genome sequencing (WGS). WGS data were used to infer resistance acquisition versus transmission, by identifying genomically unique isolates (single nucleotide polymorphism threshold of five). Logistic regression analyses were used to assess factors associated with RMR tuberculosis and genomic uniqueness.. The cohort included 2041 patients diagnosed with MDR or rifampicin-resistant tuberculosis between Jan 1, 2008, and Dec 31, 2017; of those, 463 (22·7%) with RMR tuberculosis and 1354 (66·3%) with previous tuberculosis treatment. In previously treated patients, HIV positivity during previous tuberculosis treatment versus HIV negativity (adjusted odds ratio [OR] 2·07, 95% CI 1·35-3·18), and three or more previous tuberculosis treatment episodes versus one (1·96, 1·21-3·17) were associated with RMR tuberculosis. WGS data showing MDR or rifampicin-resistant tuberculosis were available for 1169 patients; 360 (30·8%) isolates were identified as unique. In previously treated patients, RMR tuberculosis versus MDR tuberculosis (adjusted OR 4·96, 3·40-7·23), HIV positivity during previous tuberculosis treatment (1·71, 1·03-2·84), and diagnosis in 2013-17 (1·42, 1·02-1·99) versus 2008-12, were associated with uniqueness. In previously treated patients with RMR tuberculosis, HIV positivity during previous treatment (adjusted OR 5·13, 1·61-16·32) was associated with uniqueness as was female sex (2·50 [1·18-5·26]).. These data suggest that HIV contributes to rifampicin-resistance acquisition during first-line tuberculosis treatment and that this might be driving increasing RMR tuberculosis over time. Large-scale prospective cohort studies are required to further quantify this risk.. Swiss National Science Foundation, South African National Research Foundation, and Wellcome Trust.

    Topics: Drug Resistance; Female; HIV Infections; Humans; Molecular Epidemiology; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design.
    International journal of molecular sciences, 2021, Nov-21, Volume: 22, Issue:22

    Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against

    Topics: Anti-Bacterial Agents; Antitubercular Agents; DNA-Directed RNA Polymerases; Drug Design; Drug Resistance, Bacterial; Humans; Molecular Docking Simulation; Molecular Structure; Mycobacterium tuberculosis; Rifampin; Triterpenes; Tuberculosis

2021
How to Effectively Identify Patients With Rifampin-Resistant Tuberculosis in China: Perspectives of Stakeholders Among Service Providers.
    Frontiers in public health, 2021, Volume: 9

    To evaluate China's current rifampin-resistant tuberculosis (RR-TB) screening strategy from stakeholders' perspectives, the perceptions, attitudes, and interests of 245 stakeholders from three eastern, central, and western China provinces on RR-TB screening strategies, were investigated through stakeholder survey and interview. The attitudes toward three RR-TB screening strategies were statistically different: inclination to choose who to screen (

    Topics: Humans; Mass Screening; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
Isoniazid or rifampicin preventive therapy with and without screening for subclinical TB: a modeling analysis.
    BMC medicine, 2021, 12-14, Volume: 19, Issue:1

    Short-course, rifamycin-based regimens could facilitate scale-up of tuberculosis preventive therapy (TPT), but it is unclear how stringently tuberculosis (TB) disease should be ruled out before TPT use.. We developed a state-transition model of a TPT intervention among two TPT-eligible cohorts: adults newly diagnosed with HIV in South Africa (PWH) and TB household contacts in Pakistan (HHCs). We modeled two TPT regimens-4 months of rifampicin [4R] or 6 months of isoniazid [6H]-comparing each to a reference of no intervention. Before initiating TPT, TB disease was excluded either through symptom-only screening or with additional radiographic screening that could detect subclinical TB but might limit access to the TPT intervention. TPT's potential curative effects on both latent and subclinical TB were modeled, as were both acquisitions of resistance and prevention of drug-resistant disease. Although all eligible individuals received the screening and/or TPT interventions, the modeled TB outcomes comprised only those with latent or subclinical TB that would have progressed to symptomatic disease if untreated.. When prescribed after only symptom-based TB screening (such that individuals with subclinical TB were included among TPT recipients), 4R averted 45 active (i.e., symptomatic) TB cases (95% uncertainty range 24-79 cases or 40-89% of progressions to active TB) per 1000 PWH [17 (9-29, 43-94%) per 1000 HHCs]; 6H averted 37 (19-66, 52-73%) active TB cases among PWH [13 (7-23, 53-75%) among HHCs]. With this symptom-only screening, for each net rifampicin resistance case added by 4R, 12 (3-102) active TB cases were averted among PWH (37 [9-580] among HHCs); isoniazid-resistant TB was also reduced. Similarly, 6H after symptom-only screening increased isoniazid resistance while reducing overall and rifampicin-resistant active TB. Screening for subclinical TB before TPT eliminated this net increase in resistance to the TPT drug; however, if the screening requirement reduced TPT access by more than 10% (the estimated threshold for 4R among HHCs) to 30% (for 6H among PWH), it was likely to reduce the intervention's overall TB prevention impact.. All modeled TPT strategies prevent TB relative to no intervention, and differences between TPT regimens or between screening approaches are small relative to uncertainty in the outcomes of any given strategy. If most TPT-eligible individuals can be screened for subclinical TB, then pairing such screening with rifamycin-based TPT maximizes active TB prevention and does not increase rifampicin resistance. Where subclinical TB cannot be routinely excluded without substantially reducing TPT access, the choice of TPT regimen requires weighing 4R's efficacy advantages (as well as its greater safety and shorter duration that we did not directly model) against the consequences of rifampicin resistance in a small fraction of recipients.

    Topics: Adult; Antitubercular Agents; Humans; Isoniazid; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
Genomic signatures of pre-resistance in Mycobacterium tuberculosis.
    Nature communications, 2021, 12-15, Volume: 12, Issue:1

    Recent advances in bacterial whole-genome sequencing have resulted in a comprehensive catalog of antibiotic resistance genomic signatures in Mycobacterium tuberculosis. With a view to pre-empt the emergence of resistance, we hypothesized that pre-existing polymorphisms in susceptible genotypes (pre-resistance mutations) could increase the risk of becoming resistant in the future. We sequenced whole genomes from 3135 isolates sampled over a 17-year period. After reconstructing ancestral genomes on time-calibrated phylogenetic trees, we developed and applied a genome-wide survival analysis to determine the hazard of resistance acquisition. We demonstrate that M. tuberculosis lineage 2 has a higher risk of acquiring resistance than lineage 4, and estimate a higher hazard of rifampicin resistance evolution following isoniazid mono-resistance. Furthermore, we describe loci and genomic polymorphisms associated with a higher risk of resistance acquisition. Identifying markers of future antibiotic resistance could enable targeted therapy to prevent resistance emergence in M. tuberculosis and other pathogens.

    Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Genome, Bacterial; Genomics; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phylogeny; Rifampin; Tuberculosis

2021
Nanostructured polyelectrolyte complexes based on chitosan and sodium alginate containing rifampicin for the potential treatment of tuberculosis.
    Drug development and industrial pharmacy, 2021, Volume: 47, Issue:12

    Nanostructured polyelectrolyte complexes (nano PECs) were obtained by polyelectrolyte complexation technique from chitosan (CS) and sodium alginate (SA). Different polymer proportions were tested, as well as the addition order and homogenization type, to assess the influence on the nano PECs characteristics. The spherical shape and nanometric scale of the systems were observed by scanning electron microscopy (SEM). Nano PECs size, PDI, and zeta potential (ZP) ranged from 252 to 616 nm, from 0.22 to 0.73 and -50 to 30 mV, respectively. The increase of polymer proportion and the ultra-turrax homogenization led to the enlargement of particles size and PDI. However, no influence was observed on the ZP. The NP1s-Rb and NP4s-Rb, obtained through the sonicator with rifampicin (RIF) added before the CS and SA complexation, were selected due to the most promising characteristics of diameter (301 and 402 nm), PDI (0.27 and 0.26), and RIF incorporation (78 and 69%). The release profiles of RIF incorporated in both nano PECs were similar, with a sustained release of the drug for 180 min in phosphate buffer pH 7.2. The Weibull and the Korsmeyer-Peppas models better describe the RIF release from NP1s-Rb and NP4s-Rb, respectively, demonstrating that the release process was driven by different mechanism according to the particle composition. The nano PECs were lyophilized to prolong it stability and for possible nebulization. The addition of dextrose to the system allowed for resuspension after lyophilization. Therefore, with the results obtained, the incorporation of RIF in nano PECs based on CS and SA presents a promising system for the treatment of tuberculosis.

    Topics: Alginates; Chitosan; Drug Carriers; Humans; Polyelectrolytes; Polymers; Rifampin; Tuberculosis

2021
Comparative analysis of the drug-drug interaction between immunosuppressants, safety and efficacy of rifabutin from rifampicin-based Anti-TB treatment in living donor liver transplant recipients with active tuberculosis.
    Biomedical journal, 2021, Volume: 44, Issue:6 Suppl 2

    The Interaction between anti-tuberculous and immunosuppressive drugs which may increase the risk of graft rejections is a major challenge in managing transplant recipients with tuberculosis (TB). Instead of rifampicin (RFM), most guidelines recommended the use of rifabutin (RFB) because of its reduced capacity to induce immunosuppressant metabolism while maintaining the same efficacy as RFM against TB. However, there has been no available data directly comparing the outcome of RFB from RFM-based anti-TB regimens in liver transplant patients with TB. This study aimed to compare the effects of RFB from RFM-based treatment in terms of the drug interaction with immunosuppressants, as well as the safety, efficacy and clinical outcomes of living donor liver transplant (LDLT) recipients with active TB.. A retrospective study was conducted on all adult LDLT recipients diagnosed with active TB from June 1994 to May 2016 that had concurrently and continuously received either RFB or RFM-based treatment and immunosuppressants.. Twenty-two patients were included. Twelve (55%) patients were in the RFM group. Ten (45%) patients were in the RFB group. RFB group showed a lesser rate of immunosuppressant trough level reduction (20% vs 50%, p = 0.009) during TB treatment. There was no TB recurrence and no significant change in platelet or leukocyte count in either group. Acute cellular rejection (ACR), rate of TB-treatment completion and overall survival, rates were excellent and statistically similar in both groups.. The use of RFB in LDLT recipients with active TB, had a lesser drug interaction than when RFM was used. However, RFB did not significantly reduced the rate of ACR. RFB and RFM are both effective and safe to use in LDLT recipients with active TB.

    Topics: Adult; Drug Interactions; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Retrospective Studies; Rifabutin; Rifampin; Transplant Recipients; Tuberculosis

2021
Inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection: a prospective cohort study and immunological network analysis.
    The Lancet. Microbe, 2021, Volume: 2, Issue:8

    HIV-1 mediated dysregulation of the immune response to tuberculosis and its effect on the response to antitubercular therapy (ATT) is incompletely understood. We aimed to analyse the inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection undergoing ATT, with specific focus on the effect of ART and HIV-1 viraemia in those co-infected with HIV-1.. In this prospective cohort study and immunological network analysis, a panel of 38 inflammatory markers were measured in the plasma of a prospective patient cohort undergoing ATT at Khayelitsha Site B clinic, Cape Town, South Africa. We recruited patients with sputum Xpert MTB/RIF-positive rifampicin-susceptible pulmonary tuberculosis. Patients were excluded from the primary discovery cohort if they were younger than 18 years, unable to commence ATT for any reason, pregnant, had unknown HIV-1 status, were unable to consent to study participation, were unable to provide baseline sputum samples, had more than three doses of ATT, or were being re-treated for tuberculosis within 6 months of their previous ATT regimen. Plasma samples were collected at baseline (1-5 days after commencing ATT), week 8, and week 20 of ATT. We applied network and multivariate analysis to investigate the dynamic inflammatory profile of these patients in relation to ATT and by HIV status. In addition to the discovery cohort, a validation cohort of patients with HIV-1 admitted to hospital with CD4 counts less than 350 cells per μL and a high clinical suspicion of new tuberculosis were recruited.. Between March 1, 2013, and July 31, 2014, we assessed a cohort of 129 participants (55 [43%] female and 74 [57%] male, median age 35·1 years [IQR 30·1-43·7]) and 76 were co-infected with HIV-1. HIV-1 status markedly influenced the inflammatory profile regardless of ATT duration. HIV-1 viral load emerged as a major factor driving differential inflammatory marker expression and having a strong effect on correlation profiles observed in the HIV-1 co-infected group. Interleukin (IL)-17A emerged as a key correlate of HIV-1-induced inflammation during HIV-tuberculosis co-infection.. Our findings show the effect of HIV-1 co-infection on the complexity of plasma inflammatory profiles in patients with tuberculosis. Through network analysis we identified IL-17A as an important node in HIV-tuberculosis co-infection, thus implicating this cytokine's capacity to correlate with, and regulate, other inflammatory markers. Further mechanistic studies are required to identify specific IL-17A-related inflammatory pathways mediating immunopathology in HIV-tuberculosis co-infection, which could illuminate targets for future host-directed therapies.. National Institutes of Health, The Wellcome Trust, UK Research and Innovation, Cancer Research UK, European and Developing Countries Clinical Trials Partnership, and South African Medical Research Council.

    Topics: Adult; Antitubercular Agents; Biomarkers; Cohort Studies; Coinfection; Female; HIV Infections; HIV Seropositivity; HIV-1; Humans; Interleukin-17; Latent Tuberculosis; Male; Prospective Studies; Rifampin; South Africa; Tuberculosis

2021
Maternal and Infant Outcomes Among Pregnant Women Treated for Multidrug/Rifampicin-Resistant Tuberculosis in South Africa.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021, 04-08, Volume: 72, Issue:7

    Data on safety and efficacy of second-line tuberculosis drugs in pregnant women and their infants are severely limited due to exclusion from clinical trials and expanded access programs.. Pregnant women starting treatment for multidrug/rifampicin-resistant (MDR/RR)-tuberculosis at King Dinuzulu Hospital in KwaZulu-Natal, South Africa, from 1 January 2013 to 31 December 2017, were included. We conducted a record review to describe maternal treatment and pregnancy outcomes, and a clinical assessment to describe infant outcomes.. Of 108 pregnant women treated for MDR/RR-tuberculosis, 88 (81%) were living with human immunodeficiency virus.. Favorable MDR/RR-tuberculosis treatment outcomes were reported in 72 (67%) women. Ninety-nine (91%) of the 109 babies were born alive, but overall, 52 (48%) women had unfavorable pregnancy outcomes. Fifty-eight (54%) women received bedaquiline, and 49 (45%) babies were exposed to bedaquiline in utero. Low birth weight was reported in more babies exposed to bedaquiline compared to babies not exposed (45% vs 26%; P = .034). In multivariate analyses, bedaquiline and levofloxacin, drugs often used in combination, were both independently associated with increased risk of low birth weight. Of the 86 children evaluated at 12 months, 72 (84%) had favorable outcomes; 88% of babies exposed to bedaquiline were thriving and developing normally compared to 82% of the babies not exposed.. MDR/RR-tuberculosis treatment outcomes among pregnant women were comparable to nonpregnant women. Although more babies exposed to bedaquiline were of low birth weight, over 80% had gained weight and were developing normally at 1 year.

    Topics: Antitubercular Agents; Child; Female; Humans; Infant; Pregnancy; Pregnant Women; Rifampin; South Africa; Tuberculosis

2021
Determination of Rifampin Concentrations by Urine Colorimetry and Mobile Phone Readout for Personalized Dosing in Tuberculosis Treatment.
    Journal of the Pediatric Infectious Diseases Society, 2021, Mar-26, Volume: 10, Issue:2

    Individual pharmacokinetic variability is a driver of poor tuberculosis (TB) treatment outcomes. We developed a method for measurement of rifampin concentrations by urine colorimetry and a mobile phone photographic application to predict clinically important serum rifampin pharmacokinetic measurements in children treated for TB.. Among spiked urine samples, colorimetric assay performance was tested with conventional spectrophotometric and the mobile phone/light box methods under various environmental and biologic conditions. Urine rifampin absorbance (Abs) was then determined from timed specimens from children treated for TB in Tanzania, and compared to serum pharmacokinetic measurements collected throughout the dosing interval.. Both the mobile phone/light box and spectrophotometry demonstrated excellent correlation across a wide range of urine rifampin concentrations (7.8-1000 mg/L) in intra- and interday trials, 24-hour exposure to ambient light or darkness, and varying urinalysis profiles (all r ≥ 0.98). In 12 Tanzanian children, the urine mobile phone/light box measurement and serum peak concentration (Cmax) were significantly correlated (P = .004). Using a Cmax target of 8 mg/L, the area under the receiver operating characteristic curve was 80.1% (range, 47.2%-100%). A urine mobile phone/light box threshold of 50 Abs correctly classified all patients (n = 6) with serum measurements below target.. The urine colorimetry with mobile phone/light box assay accurately measured rifampin absorbance in varying environmental and biological conditions that may be observed clinically. Among children treated for TB, the assay was sensitive for detection of low rifampin serum concentrations. Future work will identify the optimal timing for urine collection, and operationalize use in TB-endemic settings.

    Topics: Antitubercular Agents; Cell Phone; Child; Colorimetry; Humans; Rifampin; Tuberculosis

2021
Safety and Efficacy of Rifampin or Isoniazid Among People With Mycobacterium tuberculosis Infection and Living With Human Immunodeficiency Virus or Other Health Conditions: Post Hoc Analysis of 2 Randomized Trials.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021, 11-02, Volume: 73, Issue:9

    The safety and efficacy of rifampin among people living with human immunodeficiency virus (PLHIV) or other health conditions is uncertain. We assessed completion, safety, and efficacy of 4 months of rifampin vs 9 months of isoniazid among PLHIV or other health conditions.. We conducted post hoc analysis of 2 randomized trials that included 6859 adult participants with Mycobacterium tuberculosis infection. Participants were randomized 1:1 to 10 mg/kg/d rifampin or 5 mg/kg/d isoniazid. We report completion, drug-related adverse events (AE), and active tuberculosis incidence among people living with HIV; with renal failure or receiving immunosuppressants; using drugs or with hepatitis; with diabetes mellitus; consuming >1 alcoholic drink per week or current/former smokers; and with no health condition.. Overall, 270 (3.9%) people were living with HIV (135 receiving antiretroviral therapy), 2012 (29.3%) had another health condition, and 4577 (66.8%) had no condition. Rifampin was more often or similarly completed to isoniazid in all populations. AEs were less common with rifampin than isoniazid among PLHIV (risk difference, -2.1%; 95% confidence interval [CI], -5.9 to 1.6). This was consistent for others except people with renal failure or on immunosuppressants (2.1%; 95% CI, -7.2 to 11.3). Tuberculosis incidence was similar among people receiving rifampin or isoniazid. Among participants receiving rifampin living with HIV, incidence was comparable to those with no health condition (rate difference, 4.1 per 1000 person-years; 95% CI, -6.4 to 14.7).. Rifampin appears to be safe and as effective as isoniazid across many populations with health conditions, including HIV.. NCT00170209; NCT00931736.

    Topics: Adult; Antitubercular Agents; Drug Administration Schedule; HIV; HIV Infections; Humans; Isoniazid; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis

2021
Anti-tuberculosis site-specific oral delivery system that enhances rifampicin bioavailability in a fixed-dose combination with isoniazid.
    Drug delivery and translational research, 2021, Volume: 11, Issue:3

    The in vivo release segregation of rifampicin (RIF) and isoniazid (INH) has been proposed as a strategy to avoid RIF acid degradation, which is known as one of the main factors for reduced RIF bioavailability and can result in drug-resistant tuberculosis. So far, this strategy has been scarcely explored. The aims of this study were to investigate the stability and bioavailability of RIF after combination of a very fast release matrix of RIF with a sustained delivery system of INH. A series of INH-alginic acid complexes (AA-INH) was obtained and characterized. Independent and sequential release profile of AA-INH at biorrelevant media of pH 1.20 and 6.80 was explored. In addition, AA-INH was combined with a RIF-carboxymethylcellulose very fast release complex (CMC-RIF) obtained previously and subjected to acid dissolution assays to evaluate RIF acid stability and determine RIF and INH dissolution efficiencies. Finally, a pharmacokinetic study in dogs was carried out. The AA-INH was easily obtained in solid-state. Their characterization revealed its ionic nature, with a loading capacity of around 30%. The dissolution efficiencies (15 min) confirmed release segregation in acid media with 7.8 and 65.6% for AA-INH and CMC-RIF, respectively. INH release rate from the AA-INH system was slow in acid media and increased in simulated intestinal media. The complete release of INH was achieved after 2 h in simulated intestinal media in the sequential release experiments. The acid degradation of RIF was significantly reduced (36.7%) when both systems were combined and oral administration to dogs revealed a 42% increase in RIF bioavailability. In conclusion, CMC-RIF and AA-INH may be useful for the formulation of a site-specific solid dosage form to overcome some of the main obstacles in tuberculosis treatment. Graphical abstract.

    Topics: Animals; Antitubercular Agents; Biological Availability; Dogs; Isoniazid; Rifampin; Tuberculosis

2021
Rifabutin for treating tuberculosis in solid organ transplant recipients: A retrospective observational study and literature review.
    Transplant infectious disease : an official journal of the Transplantation Society, 2021, Volume: 23, Issue:2

    The treatment of tuberculosis (TB) in solid organ transplant (SOT) recipients is challenging owing to interactions between rifampin and immunosuppressive drugs. Rifabutin, a rifamycin with excellent activity against Mycobacterium tuberculosis and that induces cytochrome p450 less, may facilitate treatment. We report our experience with rifabutin for treating TB in SOT recipients and review the available literature.. A retrospective observational study of all SOT recipients with TB between January 2000 and December 2019. The clinical characteristics and outcomes of patients treated with and without rifabutin-containing regimens were compared and a literature review was conducted.. We included 31 SOT recipients with TB, among whom 22 (71%) were men and the median age was 62 years (interquartile range 50-20). There were no significant differences between patients treated with rifabutin (n = 12), rifampin (n = 14), and non-rifamycins (n = 5) in clinical cure rates (83.3%, 64.3%, and 100%, respectively; P = .21), side effects (25%, 37.5%, and 20%, respectively; P = .74), or mortality (16.7%, 35.7%, and 0%, respectively; P = .21). Only one patient, treated with rifampin, suffered graft rejection. The literature review identified 59 SOT recipients with TB treated with rifabutin-containing regimens from 8 publications. Overall, the clinical cure, graft rejection, and mortality rates were 93.2%, 5.1%, and 6.8%, respectively.. Rifabutin-containing regimens offer a reliable alternative to rifampin when treating TB in SOT recipients.

    Topics: Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Observational Studies as Topic; Organ Transplantation; Rifabutin; Rifampin; Transplant Recipients; Tuberculosis

2021
Community-based active tuberculosis case finding using a symptom-based screening tool in the Volta Region, Ghana.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2021, Volume: 102

    Early tuberculosis case detection is important for early commencement of treatment to improve treatment outcomes and also to prevent community spread of the disease. However, there is a paucity of data in Ghana on the efficiency of the symptom-based screening tool (SBS tool) to detect Mycobacterium tuberculosis in the communities. Therefore, this study assessed the usefulness of the SBS tool for community-based active case finding in the Volta Region of Ghana.. This cross-sectional study used house-to-house and durbar screening approaches for active tuberculosis (TB) case searching from six communities, three each from the Ketu South (high TB risk) and Akatsi North (low TB risk) districts in the Volta Region of Ghana. Random eligible participants were screened with the SBS tool to identify presumptive TB cases. One sputum sample was collected from each person with presumptive TB for detection of M. tuberculosis by the GeneXpert real-time technique.. A total of 1,025 people were screened from a population of 40,462, from which 332 (32.4%) were presumed to have M. tuberculosis infection. Of the 332 presumptive TB cases, 63.9% were obtained through house-to-house screening, while 36.1% were obtained through community durbar screening. Six M. tuberculosis-positive cases (with one rifampicin resistance) were detected by house-to-house screening but not from community durbar samples, yielding an overall prevalence of 15 per 100,000 population. Among TB symptoms screened and analysed, association existed only between night sweat and TB case detection (χ. Although cumbersome and capital intensive, community-based active case searching through house-to-house screening using the SBS tool proved effective in detecting M. tuberculosis in the communities.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Cross-Sectional Studies; Drug Resistance, Bacterial; Early Diagnosis; Female; Ghana; Humans; Male; Mass Screening; Middle Aged; Mycobacterium tuberculosis; Prevalence; Rifampin; Tuberculosis; Young Adult

2021
Type I interferon signaling mediates Mycobacterium tuberculosis-induced macrophage death.
    The Journal of experimental medicine, 2021, 02-01, Volume: 218, Issue:2

    Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN-mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.

    Topics: Animals; Autocrine Communication; Cell Death; Cell Line; CRISPR-Cas Systems; HEK293 Cells; Humans; Interferon Type I; Macrophages; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Paracrine Communication; RAW 264.7 Cells; Rifampin; Signal Transduction; Tuberculosis

2021
Performance of Xpert MTB/RIF Ultra assay on respiratory and extra-respiratory samples in a high-resource setting with a low tuberculosis prevalence.
    Diagnostic microbiology and infectious disease, 2021, Volume: 99, Issue:2

    The Xpert MTB/RIF assay is a molecular assay that has improved the detection of tuberculosis and rifampicin resistance. However, its sensitivity is limited in patients with paucibacillary disease. Xpert MTB/RIF Ultra has been developed to resolve this limitation. We compared the performance of Xpert Ultra with that of culture for detection of Mycobacterium tuberculosis and rifampicin resistance. We reviewed laboratory records for 848 respiratory and 419 extrarespiratory samples that were processed between April 2018 and October 2019. The sensitivity, specificity, negative predictive value, and positive predictive value of Xpert Ultra were 94.8%, 98%, 98.8%, and 91.3% for respiratory samples and 83.8%, 96.9%, 98.4% and 72.1% for nonrespiratory ones. We found 26 culture-negative/Ultra-positive samples. Most of them have low bacillary burden and more than half belonged to patients with history of tuberculosis. Xpert Ultra demonstrates excellent diagnostic accuracy for tuberculosis detection, including paucibacillary specimens. In patients with history of tuberculosis, PCR results should be interpreted carefully.

    Topics: Antibiotics, Antitubercular; Bacterial Load; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Specimen Handling; Tuberculosis

2021
Tuberculosis in the intensive care unit: alternative treatment regimens and association with mortality.
    Tropical medicine & international health : TM & IH, 2021, Volume: 26, Issue:1

    Adequate anti-tuberculosis (TB) treatment is an important factor that can affect the patient's outcome. Higher mortality is found in patients who do not receive optimal treatment that includes isoniazid and rifampicin. The objective of this study is to evaluate the association of use of alternative TB treatment regimens (without rifampicin and isoniazid) and mortality among patients requiring intensive care.. Retrospective cohort study, from January 2010 to December 2018. Patients aged > 18 years with a TB diagnosis, admitted to the ICU of a general, tertiary care, university-affiliated hospital (Hospital de Clínicas de Porto Alegre - HCPA) were included. Data on TB treatment used and outcomes of treatment were collected.. 462 patients met the inclusion criteria and were included in the analysis; 284 used the usual treatment regimen (rifampicin, isoniazid, pyrazinamide and ethambutol - all orally), and 178 used alternative treatment regimens (IV levofloxacin plus oral ethambutol plus IM streptomycin or IV amikacin, without rifampicin and isoniazid). The mortality was higher among users of alternative treatment regimens (63.5%) than among usual treatment regimen users (51.4%) (P = 0.011). In a multivariate analysis, age, albumin and death were independently associated with alternative treatment regimens use.. TB programmes in which IV rifampicin is not widely available should consider including it, especially for critically ill TB patients, for whom there may be improved survival.. Un traitement antituberculeux (TB) adéquat est un facteur important pouvant influencer les résultats du patient. Une mortalité plus élevée est observée chez les patients qui ne reçoivent pas un traitement optimal comprenant de l'isoniazide et de la rifampicine. L'objectif de cette étude est d'évaluer l'association entre l'utilisation d'autres schémas thérapeutiques anti-TB (sans rifampicine ni isoniazide) et la mortalité chez les patients nécessitant des soins intensifs. MÉTHODES: Etude de cohorte rétrospective, de janvier 2010 à décembre 2018. Les patients âgés de >18 ans avec un diagnostic de TB, admis à l'unité de soins intensifs d'un hôpital général, avec des soins tertiaires, affilié à l'Université (Hôpital de Clínicas de Porto Alegre-HCPA) ont été inclus. Des données sur le traitement anti-TB utilisé et les résultats du traitement ont été collectés. RÉSULTATS: 462 patients répondaient aux critères d'inclusion et ont été inclus dans l'analyse; 284 ont utilisé le schéma thérapeutique habituel (rifampicine, isoniazide, pyrazinamide et éthambutol - tous par voie orale) et 178 ont utilisé des schémas thérapeutiques alternatifs (lévofloxacine IV plus éthambutol oral plus streptomycine IM ou amikacine IV, sans rifampicine ni isoniazide). La mortalité était plus élevée chez les utilisateurs de schémas thérapeutiques alternatifs (63,5%) que chez les utilisateurs de schémas thérapeutiques habituels (51,4%) (P = 0,011). Dans l'analyse multivariée, l’âge, l'albumine et le décès ont été indépendamment associés à l'utilisation de schémas thérapeutiques alternatifs.. Les programmes de lutte contre la TB dans lesquels la rifampicine IV n'est pas largement disponible devraient envisager de l'inclure, en particulier pour les patients atteints de TB et sévèrement malades, pour lesquels la survie peut être améliorée.

    Topics: Adult; Amikacin; Antibiotics, Antitubercular; APACHE; Brazil; Drug Administration Routes; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Intensive Care Units; Isoniazid; Logistic Models; Male; Middle Aged; Multivariate Analysis; Pyrazinamide; Retrospective Studies; Rifampin; Streptomycin; Tuberculosis

2021
Lipid nanoparticles coated with chitosan using a one-step association method to target rifampicin to alveolar macrophages.
    Carbohydrate polymers, 2021, Jan-15, Volume: 252

    This work proposes the development and characterization of solid lipid nanoparticles (SLNs) loaded with rifampicin (RIF) aiming to enhance mucoadhesion of the SLNs and consequently internalization by the alveolar macrophages (AMs). The lipid nanoparticles (NPs) were characterized and the results showed that the NPs obtained present a spherical or a starry shape with diameter around 250-500 nm, a monodisperse population, with zeta potential between -31 mV for uncoated SLNs and +33 mV for coated SLNs. The drug EE was approximately 90 % and the loading capacity (LC) 4.5 %. The SLNs coated with chitosan by the association method (aC-SLNs) show an effective mucoadhesive profile, verified by the turdimetry and surface loading method, corroborated with the cellular assays. The presence of chitosan in the aC-SLNs promotes higher mucoadhesive properties to the NPs and permeability in A549, suggesting that the safe aC-SLNs-RIF can be used as a promising drug delivery system for improving tuberculosis treatment.

    Topics: A549 Cells; Antibiotics, Antitubercular; Chitosan; Drug Carriers; Drug Liberation; Humans; Lipids; Macrophages, Alveolar; Nanoparticles; Particle Size; Rifampin; Tuberculosis

2021
Quantification of pyrazinamide, isoniazid, acetyl-isoniazid, and rifampicin by a high-performance liquid chromatography method in human plasma from patients with tuberculosis.
    Journal of separation science, 2021, Volume: 44, Issue:2

    Topics: Adult; Aged; Chromatography, High Pressure Liquid; Female; Humans; Isoniazid; Male; Middle Aged; Pilot Projects; Prospective Studies; Pyrazinamide; Quality Control; Rifampin; Tuberculosis

2021
Dual antitubercular drug loaded liposomes for macrophage targeting: development, characterisation,
    Journal of microencapsulation, 2021, Volume: 38, Issue:2

    The present study was conducted to formulate and investigate liposomes for the dual drug delivery based on anti-tubercular drug(s) combination i.e. Isoniazid (INH) and Rifampicin (RIF).. Mannosylated and non mannosylated liposomes were prepared by lipid thin film hydration method, using DSPC: Chol at a molar ratio 6:4 while in case of mannosylated liposomes DSPC: Chol: Man-C4-Chol at a molar ratio 6.0:3.5:0.5 were used and extensively characterised. The particle size and zeta potential were recorded to be 1.29 ± 0.24 µm and -9.1 ± 0.11 mV. The drug entrapment (%) was recorded to be 84.7 ± 1.25% for Rifampicin and 31.8 ± 0.12% for Isoniazid.. The antitubercular activity studied in Balb/C mice was maximum in the case of mannosylated liposomes. The biodistribution studies also revealed higher drug(s) concentration (accumulation) maintained over a protracted period.. The liposomal preparations are passively as well as actively uptaken by the alveolar macrophages which are the cellular tropics of infection. The mannosylated liposomes appear to be a potential carrier for dual drug delivery and targeted antitubercular therapy.

    Topics: Animals; Antitubercular Agents; Cell Line; Drug Delivery Systems; Humans; Isoniazid; Liposomes; Macrophages, Alveolar; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Tissue Distribution; Tuberculosis

2021
The Spectrum of Tuberculosis Disease in an Urban Ugandan Community and Its Health Facilities.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021, 06-15, Volume: 72, Issue:12

    New, sensitive diagnostic tests facilitate identification and investigation of milder forms of tuberculosis (TB) disease. We used community-based TB testing with the Xpert MTB/RIF Ultra assay ("Ultra") to characterize individuals with previously undiagnosed TB and compare them to those from the same community who were diagnosed with TB through routine care.. We offered community-based sputum Ultra testing to adult residents of a well-defined area (population 34 000 adults) in Kampala, Uganda, via door-to-door screening and venue-based testing, then used detailed interview and laboratory testing to characterize TB-positive individuals. We compared these individuals to residents diagnosed with pulmonary TB at local health facilities and a representative sample of residents without TB (controls).. Of 12 032 residents with interpretable Ultra results, 113 (940 [95% confidence interval {CI}, 780-1130] per 100 000) tested positive, including 71 (63%) positive at the lowest (trace) level. A spectrum of TB disease was observed in terms of chronic cough (93% among health facility-diagnosed cases, 77% among residents with positive community-based Ultra results at levels above trace, 33% among trace-positive community participants, and 18% among TB-negative controls), TB symptom prevalence (99%, 87%, 60%, and 38%, respectively), and C-reactive protein (75th percentile: 101 mg/L, 28 mg/L, 6 mg/L, and 4 mg/L, respectively). Community-diagnosed cases were less likely than health facility-diagnosed cases to have human immunodeficiency virus coinfection or previous TB. The specificity of Ultra was 99.4% (95% CI, 99.2%-99.5%) relative to a single spot sputum culture.. People with undiagnosed prevalent TB in the community have different characteristics than those diagnosed with pulmonary TB in health facilities. Newer diagnostic tests may identify a group of people with early or very mild disease.

    Topics: Adult; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Health Facilities; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Uganda

2021
Improving tuberculosis management in prisons: Impact of a rapid molecular point-of-care test.
    The Journal of infection, 2021, Volume: 82, Issue:2

    We first validated Xpert use on raw sputum at the referent laboratory. Secondly, trained physicians at the prison hospital performed Xpert tests for each patient presenting TB symptoms. The results were compared with Xpert, microscopic examination, culture and drug susceptibility testing on the corresponding decontaminated specimens.. 76 inmates were included in 15 months and 21 were diagnosed with TB. The overall sensitivity, specificity, positive and negative predictive values of Xpert were respectively: 92.3%, 100%, 100% and 98.7% on raw sputum. The efficiency of the molecular POC was confirmed by a concordance of 97% between Xpert findings from the prison hospital and culture results. Delay of microbiological diagnosis was reduced by about 18 days for 13 inmates with smear-negative sputum that avoid the mobilization of major means (escort, transport) to perform fibroscopic samples. Repeated Xpert negative results helped to speed the lifting of inmate isolation.. The implementation of Xpert in prison could optimize the management of incarcerated patients and thus limit the spread of TB among inmates, carers and other staff.

    Topics: Antibiotics, Antitubercular; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Point-of-Care Testing; Prisons; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2021
Cost of Delivering 12-Dose Isoniazid and Rifapentine Versus 6 Months of Isoniazid for Tuberculosis Infection in a High-Burden Setting.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021, 09-07, Volume: 73, Issue:5

    Successful delivery and completion of tuberculosis preventive treatment are necessary for tuberculosis elimination. Shorter preventive treatment regimens currently have higher medication costs, but patients spend less time in care and are more likely to complete treatment. It is unknown how economic costs of successful delivery differ between longer and shorter regimens in high-tuberculosis-burden settings.. We developed survey instruments to collect costs from program and patient sources, considering costs incurred from when household contacts first entered the health system. We compared the cost per completed course of preventive treatment with either 6 months of daily isoniazid (6H) or 3 months of weekly isoniazid and rifapentine (3HP), delivered by the Indus Health Network tuberculosis program in Karachi, Pakistan, between October 2016 and February 2018.. During this period, 459 individuals initiated 6H and 643 initiated 3HP; 39% and 61% completed treatment, respectively. Considering costs to both the program and care recipients, the cost per completed course was 394 US dollars (USD) for 6H and 333 USD for 3HP. Using a new 2020 price for rifapentine reduced the cost per completed course of 3HP to 290 USD. Under varying assumptions about drug prices and costs incurred by care recipients, the cost per completed course was lower for 3HP in all scenarios, and the largest cost drivers were the salaries of clinical staff.. In a high-burden setting, the cost of successful delivery of 3HP was lower than that of 6H, driven by higher completion.

    Topics: Antitubercular Agents; Cost-Benefit Analysis; Drug Therapy, Combination; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Tuberculosis

2021
Diagnostic Accuracy Study of a Novel Blood-Based Assay for Identification of Tuberculosis in People Living with HIV.
    Journal of clinical microbiology, 2021, 02-18, Volume: 59, Issue:3

    Topics: Diagnostic Tests, Routine; HIV Infections; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2021
Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.
    The Journal of antimicrobial chemotherapy, 2021, 02-11, Volume: 76, Issue:3

    Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered.. To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated.. We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575.. The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10).. Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups.

    Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Carboxylic Ester Hydrolases; Humans; Liver-Specific Organic Anion Transporter 1; Pharmaceutical Preparations; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2021
Accuracy of molecular drug susceptibility testing amongst tuberculosis patients in Karakalpakstan, Uzbekistan.
    Tropical medicine & international health : TM & IH, 2021, Volume: 26, Issue:4

    In this retrospective study, we evaluated the diagnostic accuracy of molecular tests (MT) for the detection of DR-TB, compared to the gold standard liquid-based drug susceptibility testing (DST) in Karakalpakstan.. A total of 6670 specimens received in the Republican TB No 1 Hospital Laboratory of Karakalpakstan between January and July 2017 from new and retreatment patients were analysed. Samples were tested using Xpert MTB/RIF and line probe assays (LPA) for the detection of mutations associated with resistance. The sensitivity and specificity of MTs were calculated relative to results based on DST.. The accuracy of MT for detection of rifampicin resistance was high, with sensitivity and specificity over 98%. However, we observed reduced sensitivity of LPA for detection of resistance; 86% for isoniazid (95% CI 82-90%), 86% for fluoroquinolones (95% CI 68-96%), 70% for capreomycin (95% CI 46-88%) and 23% for kanamycin (95% CI 13-35%).. We show that MTs are a useful tool for rapid and safe diagnosis of DR-TB; however, clinicians should be aware of their limitations. Although detection of rifampicin resistance was highly accurate, our data suggest that resistance mutations circulating in the Republic of Karakalpakstan for other drugs were not detected by the methods used here. This merits further investigation.

    Topics: Antibiotics, Antitubercular; Capreomycin; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Isoniazid; Kanamycin; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Reproducibility of Results; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Uzbekistan

2021
Detection of Mycobacterium tuberculosis complex in pulmonary and extrapulmonary samples with the FluoroType MTBDR assay.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2021, Volume: 27, Issue:10

    Rifampicin (RIF) and isoniazid (INH) are the two most effective first-line antibiotic drugs for the treatment of tuberculosis (TB). The new FluoroType MTBDR (FT-MTBDR) real-time PCR is intended to detect INH and RIF resistance mutations as a second step following a primary Mycobacterium tuberculosis complex (MTBC) PCR. Here we evaluate the feasibility of the FT-MTBDR assay to detect simultaneously MTBC-specific DNA as well as to detect potential INH and RIF resistance through analysing inhA promotor, katG and rpoB sequences in one PCR reaction.. We analysed 3885 consecutive primary samples with FT-MTBDR and compared the results with microscopy and culture: 978 were from sputum, 2007 from other respiratory tract locations plus gastric lavages, and 875 from extrapulmonary locations, respectively.. Overall, 176 samples were MTBC culture positive and 139 FT-MTBDR positive, providing a FT-MTBDR sensitivity of 0.714 (95% confidence interval 0.640-0.779) and specificity of 0.996 (0.994-0.998), respectively. For the 978 sputum, 96 were MTBC culture positive and 89 FT-MTBDR positive, sensitivity 0.854 (0.764-0.915) and specificity 0.992 (0.983-0.997). Of the 139 MTBC positive, 99 (71%) had interpretable genotypic resistance results for at least one drug, 92 (66%) for both drugs.. The ability of FT-MTBDR to detect MTBC is adequate with the significant added feature of simultaneous genotypic resistance detection of both INH and RIF in a single PCR reaction.

    Topics: Antitubercular Agents; Bacterial Proteins; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis

2021
Modelling the global burden of drug-resistant tuberculosis avertable by a post-exposure vaccine.
    Nature communications, 2021, 01-18, Volume: 12, Issue:1

    There have been notable advances in the development of vaccines against active tuberculosis (TB) disease for adults and adolescents. Using mathematical models, we seek to estimate the potential impact of a post-exposure TB vaccine, having 50% efficacy in reducing active disease, on global rifampicin-resistant (RR-) TB burden. In 30 countries that together accounted for 90% of global RR-TB incidence in 2018, a future TB vaccine could avert 10% (95% credible interval: 9.7-11%) of RR-TB cases and 7.3% (6.6-8.1%) of deaths over 2020-2035, with India, China, Indonesia, Pakistan, and the Russian Federation having the greatest contribution. This impact would increase to 14% (12-16%) and 31% (29-33%) respectively, when combined with improvements in RR-TB diagnosis and treatment relative to a scenario of no vaccine and no such improvements. A future TB vaccine could have important implications for the global control of RR-TB, especially if implemented alongside enhancements in management of drug resistance.

    Topics: Adolescent; Adult; Antitubercular Agents; Computer Simulation; Drug Resistance, Bacterial; Global Burden of Disease; Humans; Incidence; Models, Statistical; Mycobacterium tuberculosis; Post-Exposure Prophylaxis; Rifampin; Tuberculosis; Tuberculosis Vaccines

2021
Do catastrophic costs impact treatment outcomes in people with rifampicin-resistant tuberculosis in the Republic of Moldova?
    Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, 2021, Jan-14, Volume: 91, Issue:1

    The Republic of Moldova is among the 30 Rifampicin-Resistant and/or Multidrug-Resistant (RR/MDR) Tuberculosis (TB) high burden countries in the world. Despite free TB diagnostics and treatment, TB patients face substantial economic losses and this may impact overall treatment outcomes. We assessed if there is an association between TB-related catastrophic costs and TB treatment outcomes. We conducted a cohort study using data from patient records and a survey that quantified catastrophic costs among RR/MDR-TB affected households in the Republic of Moldova in 2016. We included adult patients (age ≥18 years) with RR/MDR-TB who had been in inpatient (intensive phase) or outpatient (continuous phase) treatment for at least 2 months. Unfavourable treatment outcome, such as failure, death or lost to follow-up, was the primary outcome variable. The definition of catastrophic TB-related costs followed the World Health Organisation (WHO) guidelines: costs due to TB ≥20% of annual household income. Log-binomial regression was used to assess association between the outcome and catastrophic TB-related costs adjusting for other socio-demographic, behavioural and clinical covariates.  In total 287 RR/MDR-TB patients (78% males, mean age 42 years) were included. Of them, 30% experienced catastrophic TB-related costs. Overall, one in five patients (21%) had unfavourable treatment outcome, such as treatment failure (5%), death (8%) or lost to follow-up (8%). The experience of catastrophic TB-related costs was not associated with unfavourable treatment outcome [adjusted relative risk (aRR)=0.88, 95% CI: 0.50-1.50]. Major factors independently associated with unfavourable TB treatment outcomes were poverty (aRR=2.07; 95% CI: 1.06-4.07), urban residence (aRR=1.99; 95% CI: 1.12-3.52) and positive HIV (Human Immunodeficiency Virus) status (aRR=2.61; 95% CI: 1.31-4.89). As a result, we failed to find an association between catastrophic costs and treatment outcomes of RR/MDR-TB patients in the Republic of Moldova. However, we found that patients from poor households and urban areas were twice more likely to achieve unfavourable TB treatment outcomes disregarding whether they experienced catastrophic costs or not. Also, TB/HIV patients and urban residents were identified as the most vulnerable groups with higher risk of unfavourable treatment outcome and TB-related costs.

    Topics: Adolescent; Adult; Cohort Studies; Female; HIV Infections; Humans; Male; Moldova; Rifampin; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
Incidence rate and time to serious adverse events among rifampicin resistant tuberculosis patients in Georgia treated with new and repurposed anti-tuberculosis drugs, 2016-2018.
    Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, 2021, Jan-14, Volume: 91, Issue:1

    Considering the complexity of second-line anti-tuberculosis (TB) treatment regimens, the management of drug-resistant TB (DR-TB) in Georgia remains a major challenge. Since the introduction of new and repurposed anti-TB medications, the implementation of active TB Drug Safety Monitoring (aDSM) was a critical program component to help establish safety and manage all treatment related Serious Adverse Events (SAEs). In our study, we aimed to describe the occurrence, characteristics and timing of SAE among patients with Rifampicin Resistant and Multi-Drug Resistant TB (RR/MDR-TB) receiving new and/or repurposed anti-TB medications (bedaquiline, delamanid, linezolid, clofazimine, imipenem) during the period of 2016-2018 in Georgia and identify predictors of SAE. The data were obtained from the medical charts, electronic database and standardized aDSM reports During 2016-2018 period in total 970 people with RR/MDR-TB were notified in Georgia and 388 of them received new and/or repurposed TB drugs as part of their treatment regimen and all were included into the study. The results showed a total of 73 SAEs registered among 49 (12.6%) patients receiving new and/or repurposed drugs. The overall SAE incidence rate per 100 person-months was 1.16. The severity of the majority of the SAEs (46.6%) was grade III and 21.9% were grade IV. The most common SAE reported was hepatotoxicity, with an incidence of 0.26 per 100 person-month (n=16, 21.9%) followed by cardiotoxicity with an incidence of 0.16 per 100 person-month (n=10, 13.7%). Median time to SAE occurrence was 183 days (IQR 84 - 334) after treatment initiation. Resistance profile was the only predictor associated with occurrence of a SAEs. There was increased hazard of SAEs among patients with XDR-TB (adjusted HR=2.18, 95% CI: 1.12-4.23). Our findings on SAEs among patients treated with new or repurposed anti-TB drugs are echoing the findings available in the literature. They highlight the need for close monitoring of patients and underlines the importance of the aDSM during the whole treatment. Safety profile of the medications and combinations used are yet to be established and larger datasets comprised of patients receiving same treatment regimens need to be utilized.

    Topics: Antitubercular Agents; Georgia; Humans; Incidence; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
The Outcome of Accidental Bacille Calmette-Guérin Overdose During Routine Neonatal Immunization.
    The Pediatric infectious disease journal, 2021, 06-01, Volume: 40, Issue:6

    We report a retrospective study on outcome of 14 newborn infants who received 62.5 times the recommended dose of Bacille Calmette-Guérin for immunization. All infants then received high-dose isoniazid and rifampicin (20 mg/kg/d each) as preventive therapy for 6 months. All had mild local adverse reactions, a third resolving within 16 weeks and all by 6 months.

    Topics: Accidents; Anti-Bacterial Agents; BCG Vaccine; Drug-Related Side Effects and Adverse Reactions; Humans; Infant, Newborn; Isoniazid; Retrospective Studies; Rifampin; Tuberculosis; Vaccination

2021
Diagnostic accuracy of a liquid chromatography-tandem mass spectrometry assay in small hair samples for rifampin-resistant tuberculosis drug concentrations in a routine care setting.
    BMC infectious diseases, 2021, Jan-22, Volume: 21, Issue:1

    Treatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging. We developed a multi-analyte assay for eleven anti-TB drugs in small hair samples as an objective metric of drug exposure.. Small hair samples were collected from participants at various timepoints during directly observed RR-TB treatment at an inpatient tertiary referral facility in South Africa (DR-TB cohort). We assessed qualitative determination (i.e., detection above limit of detection) of bedaquiline, linezolid, clofazimine, pretomanid, levofloxacin, moxifloxacin, pyrazinamide, isoniazid, ethambutol, ethionamide, and prothionamide in an LC-MS/MS index panel assay against a reference standard of inpatient treatment records. Because treatment regimens prior to hospitalization were not available, we also analyzed specificity (for all drugs except isoniazid) using an external cohort of HIV-positive patients treated for latent TB infection with daily isoniazid (HIV/LTBI cohort) in Uganda.. Among the 57 DR-TB patients (58% with pre-XDR/XDR-TB; 70% HIV-positive) contributing analyzable hair samples, the sensitivity of the investigational assay was 94% or higher for all drugs except ethionamide (58.5, 95% confidence interval [CI], 40.7-99.9). Assay specificity was low across all tested analytes within the DR-TB cohort; conversely, assay specificity was 100% for all drugs in the HIV/LTBI cohort.. Hair drug concentrations reflect long-term exposure, and multiple successive regimens commonly employed in DR-TB treatment may result in apparent false-positive qualitative and falsely elevated quantitative hair drug levels when prior treatment histories within the hair growth window are not known.

    Topics: Adult; Antitubercular Agents; Chromatography, Liquid; Drug Monitoring; Female; Hair; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tandem Mass Spectrometry; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
Integrating Xpert MTB/RIF for TB diagnosis in the private sector: evidence from large-scale pilots in Patna and Mumbai, India.
    BMC infectious diseases, 2021, Jan-28, Volume: 21, Issue:1

    Xpert MTB/RIF (Xpert) has been recommended by WHO as the initial diagnostic test for TB and rifampicin-resistance detection. Existing evidence regarding its uptake is limited to public health systems and corresponding resource and infrastructure challenges. It cannot be readily extended to private providers, who treat more than half of India's TB cases and demonstrate complex diagnostic behavior.. We used routine program data collected from November 2014 to April 2017 from large-scale private sector engagement pilots in Mumbai and Patna. It included diagnostic vouchers issued to approximately 150,000 patients by about 1400 providers, aggregated to 18,890 provider-month observations. We constructed three metrics to capture provider behavior with regards to adoption of Xpert and studied their longitudinal variation: (i) Uptake (ordering of test), (ii) Utilization for TB diagnosis, and (iii) Non-adherence to negative results. We estimated multivariate linear regression models to assess heterogeneity in provider behavior based on providers' prior experience and Xpert testing volumes.. Uptake of Xpert increased considerably in both Mumbai (from 36 to 60.4%) and Patna (from 12.2 to 45.1%). However, utilization of Xpert for TB diagnosis and non-adherence to negative Xpert results did not show systematic trends over time. In regression models, cumulative number of Xpert tests ordered was significantly associated with Xpert uptake in Patna and utilization for diagnosis in Mumbai (p-value< 0.01). Uptake of Xpert and its utilization for diagnosis was predicted to be higher in high-volume providers compared to low-volume providers and this gap was predicted to widen over time.. Private sector engagement led to substantial increase in uptake of Xpert, especially among high-volume providers, but did not show strong evidence of Xpert results being integrated with TB diagnosis. Increasing availability and affordability of a technically superior diagnostic tool may not be sufficient to fundamentally change diagnosis and treatment of TB in the private sector. Behavioral interventions, specifically aimed at, integrating Xpert results into clinical decision making of private providers may be required to impact patient-level outcomes.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; India; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Pilot Projects; Practice Patterns, Physicians'; Private Sector; Rifampin; Tuberculosis

2021
Relationship among genetic polymorphism of SLCO1B1, rifampicin exposure and clinical outcomes in patients with active pulmonary tuberculosis.
    British journal of clinical pharmacology, 2021, Volume: 87, Issue:9

    Rifampicin is a key drug for the treatment of tuberculosis (TB). Little is known for the relationship between the rifampicin pharmacokinetics and genetic polymorphisms in the Asian population. We aimed to investigate relationship between genetic polymorphism of SLCO1B1 and rifampicin exposure and its impact on clinical outcomes in Korean patients with active pulmonary TB.. From February 2016 to December 2019, patients with active pulmonary TB who were taking rifampicin for >1 week were prospectively enrolled. Serial or 1-time blood sampling was conducted to determine rifampicin concentrations. The genotype of 4 single nucleotide polymorphisms of SLCO1B1 was determined. To estimate the drug clearance and exposure, population pharmacokinetics analysis was conducted. Clinical outcomes such as time to acid-fast bacteria culture conversion, chest radiograph score changes from baseline, and all-cause mortality were also evaluated. The exposure among different SLCO1B1 genotype was compared and relationship between drug exposure and clinical outcomes were explored.. A total of 105 patients (70 males and 35 females) were included in the final analysis. The mean age of patients was 55.4 years. The mean drug clearance and exposure were 13.6 L/h and 57.9 mg h/L, respectively. The genetic polymorphisms of SLCO1B1 were not related to rifampicin clearance or exposure. As the rifampicin exposure increased, the chest radiographs improved significantly, but the duration of acid-fast bacteria culture conversion was not related to the drug exposure.. SLCO1B1 gene polymorphisms did not influence rifampicin concentrations and clinical outcomes in Korean patients with active pulmonary TB.

    Topics: Female; Humans; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2021
Decreased classical monocytes and CD163 expression in TB patients: an indicator of drug resistance.
    Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology], 2021, Volume: 52, Issue:2

    Tuberculosis (TB) is a disease instigated by Mycobacterium tuberculosis. Peripheral blood monocytes represent highly efficient effector cells of innate immunity against TB. Little is known about monocyte subsets and their potential involvement in the development of M. tuberculosis drug resistance in patients with TB. This study was conducted to investigate alterations in monocyte subsets, CD163 expression on monocytes, and its serum level in patients without and with rifampicin resistance TB (RR-TB) and healthy controls. A total of 164 patients with TB (84 without RR-TB and 80 patients with RR-TB) and 85 healthy controls were enrolled in this study. The percentages of various monocyte subsets and surface expression of CD163 on monocytes were quantitatively determined using flow cytometry. The serum level of CD163 was determined by commercially available ELISA kits. Decreased frequency of classical monocytes was detected in patients with RR-TB. Non-classical monocytes were decreased in patients without RR-TB; however, intermediate monocytes were raised in patients with RR-TB. The serum level of CD163 was decreased in patients of RR-TB that showsed a positive correlation with the frequency of CD14

    Topics: Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antitubercular Agents; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Monocytes; Mycobacterium tuberculosis; Receptors, Cell Surface; Rifampin; Tuberculosis

2021
Evaluation of the effect of temperature on the stability and antimicrobial activity of rifampicin quinone.
    Journal of pharmaceutical and biomedical analysis, 2021, Apr-15, Volume: 197

    Rifampicin is an antibiotic used as a first line treatment for tuberculosis, as well as in the treatment of other infectious diseases. Drug quality is essential for drug efficacy. Determining the stability and activity of Rifampicin Quinone in solution is important in its role as a standard against which to determine Rifampicin quality and in its effect on treatment and AMR development. Poor quality medicines, such as antimicrobials not only increase mortality and morbidity, but can also contribute to the development of antimicrobial resistance (AMR). One common marker of poor quality in Rifampicin samples is the presence of the degradation product Rifampicin Quinone. In this study we have found that Rifampicin Quinone in solution undergoes a chemical conversion to Rifampicin that is temperature dependent. This conversion occurs in physiologically relevant temperatures (30-50 °C) and time scales (24-120 h) and was verified using HPLC and LC-MS methods. Additionally, the conversion of Rifampicin Quinone to Rifampicin results in an increase in antimicrobial activity. We believe that ours is the first study reporting the instability of Rifampicin Quinone, and this instability in solution at these temperatures and time scales raises concerns for its use as a standard in quality testing using liquid chromatography methods and in studies of the effect of Rifampicin Quinone on AMR. Due to the use of Rifampicin Quinone as a standard in determining Rifampicin quality, the instability of Rifampicin Quinone also poses public health concerns, as the incorrect determination of medicine quality risks patient health and may promote the development of AMR.

    Topics: Anti-Bacterial Agents; Humans; Rifampin; Temperature; Tuberculosis

2021
Fidaxomicin has high
    Journal of medical microbiology, 2021, Volume: 70, Issue:3

    This study aimed to evaluate whether the antibiotic fidaxomicin has

    Topics: Antitubercular Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Fidaxomicin; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy.
    Scientific reports, 2021, 02-18, Volume: 11, Issue:1

    Alternative ways to prevent and treat infectious diseases are needed. Previously, we identified a fungal peptide, NZX, that was comparable to rifampicin in lowering M. tuberculosis load in a murine tuberculosis (TB) infection model. Here we assessed the potential synergy between this cationic host defence peptide (CHDP) and the current TB drugs and analysed its pharmacokinetics. We found additive effect of this peptide with isoniazid and ethambutol and confirmed these results with ethambutol in a murine TB-model. In vivo, the peptide remained stable in circulation and preserved lung structure better than ethambutol alone. Antibiotic resistance studies did not induce mutants with reduced susceptibility to the peptide. We further observed that this peptide was effective against nontuberculous mycobacteria (NTM), such as M. avium and M. abscessus, and several Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In conclusion, the presented data supports a role for this CHDP in the treatment of drug resistant organisms.

    Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Ethambutol; Female; Humans; Isoniazid; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Rifampin; Tuberculosis

2021
Fabrication and Characterization of Surface Engineered Rifampicin Loaded Lipid Nanoparticulate Systems for the Potential Treatment of Tuberculosis: An In Vitro and In Vivo Evaluation.
    Journal of pharmaceutical sciences, 2021, Volume: 110, Issue:5

    The main aim of the present investigation highlights the development of mannose appended rifampicin containing solid lipid nanoparticles (Mn-RIF-SLNs) for the management of pulmonary TB. The developed Mn-RIF-SLNs showed particle size of Mn-RIF-SLNs (479 ± 13 nm) which was found to be greater than that of unconjugated SLNs (456 ± 11 nm), with marginal reduction in percentage entrapment efficiency (79.41 ± 2.42%). The in vitro dissolution studies depicted an initial burst release followed by sustained release profile indicating biphasic release pattern, close-fitting Weibull model having least F-value. The cytotoxicity studies using J774A.1 cell line represented that the developed SLNs were non-toxic and safe as compared to free drug. Fluorescence imaging and flow cytometric (FACS) analysis depicted significant (1.79-folds) intracellular uptake of coumarin-6 (fluorescent marker) loaded Mn-C6-SLNs. The in vivo pharmacokinetic studies in sprague-dawley rats were performed and Mn-RIF-SLNs showed remarkable enhancement in terms of relative bioavailability (~17-folds) as compared to its drug solution via oral administration. The biodistribution studies revealed higher lung accumulation (1.8-folds) of Mn-RIF-SLNs as compared to the Un-RIF-SLNs. In conclusion, the developed Mn-RIF-SLNs could serve as a promising tool for delivering the drug cargo to the site of infection (lungs) in the treatment of TB.

    Topics: Animals; Drug Carriers; Lipids; Nanoparticles; Particle Size; Rats; Rifampin; Tissue Distribution; Tuberculosis

2021
Performance of Xpert MTB/RIF for the Diagnosis of Extrapulmonary Tuberculosis.
    Clinical laboratory, 2021, Feb-01, Volume: 67, Issue:2

    Mycobacterial burden is low in extrapulmonary specimens, making diagnosis and treatment difficult. Xpert MTB/RIF is a real-time PCR assay for the detection of Mycobacterium tuberculosis and rifampin resistance. This study evaluated the performance of the Xpert MTB/RIF assay in extrapulmonary specimens.. Acid-Fast Bacilli (AFB) smear, culture, and Xpert MTB/RIF were performed on extrapulmonary specimens. Mycobacterial culture was performed on BACTEC MGIT liquid for 6 weeks and 2% Ogawa medium for 8 weeks. Overall sensitivity and specificity of Xpert MTB/RIF was estimated using culture as a gold standard. Xpert MTB/RIF sensitivity and cycle-threshold (Ct) values according to AFB smear grade were evaluated. The sensitivity, specificity, and concordance of rifampin resistance compared to the phenotypic drug sensitivity test were evaluated.. A total of 1,289 specimens were included in the study. The overall sensitivity and specificity of the Xpert MTB/RIF assay were 59.4% (41/69, 95% CI 46.9 - 70.9%) and 99.3% (1,212/1,220, 95% CI 98.7 - 99.7), respectively. Positive predictive value of Xpert MTB/RIF was 83.7% (41/49, 95% CI 69.8 - 92.2) and negative predictive value was 97.7% (1,212/1,240, 95% CI 96.7 - 98.5%). Xpert MTB/RIF assay sensitivity significantly increased with increases in AFB smear grade (p < 0.001). AFB smear grades and Xpert MTB/RIF Ct values were negatively correlated. Rifampin resistance results of Xpert MTB/RIF and culture showed a concordance rate of 97.2%.. The Xpert MTB/RIF assay could be used to replace the AFB smear for the diagnosis of extrapulmonary tuberculosis, and has high specificity for the detection of rifampin resistance.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2021
Tale of compounding oddities.
    BMJ case reports, 2021, Mar-04, Volume: 14, Issue:3

    We present a case of a 59-year-old man, who on being evaluated for abdominal pain and headache, was found to have a pancreatic head mass and inflammatory hypophysitis. Xpert MTB/Rif of the pancreatic mass biopsy showed the presence of tuberculosis (TB) with a very low load, and rifampicin resistance was detected with absence of probes A and B. Pyrosequencing (a novel genotypic test for TB) of the Xpert MTB/Rif isolate detected a single, rare, high-confidence mutation (S512T) in the rpoB region (rifampicin resistance determining region in the MTB genome). The TB mycobacteria growth indicator tube (TBMGIT) phenotypic drug susceptibility test (DST), however, showed rifampicin susceptibility. Incidentally, he was unable to tolerate rifampicin and responded well to a non-rifampicin-based regimen. We discuss a possible hypothesis of the Xpert-DST discordance in accordance with a recent literature review on phenotypic DST methods. We also discuss the utility of pyrosequencing in clinical practice for the diagnosis of TB and its resistance patterns.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Male; Middle Aged; Mutation; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
Phenotypic and genotypic drug sensitivity profiles of Mycobacterium tuberculosis infection and associated factors in northeastern Ethiopia.
    BMC infectious diseases, 2021, Mar-12, Volume: 21, Issue:1

    Tuberculosis is a devastating and a deadly disease despite the novel advances in its diagnostic tools and drug therapy. Drug resistant Mycobacterium contributes a great share to tuberculosis mortality. Status of drug resistance and patients' awareness toward the disease is unknown in northeastern Ethiopia. Thus, the aim of this study was to determine the phenotypic and genotypic drug sensitivity patterns and associated factors in Oromia Special Zone and Dessie Town, northeastern Ethiopia.. In a cross-sectional study, 384 smear positive tuberculosis cases were recruited and Löwenstein-Jensen culture was done. The performance of GenoTypic MTBDRplus assay using the conventional BACTEC MGIT 960 as a "gold standard" was determined. Drug resistant strains were identified using spoligotyping. Pearson Chi-square test was used to determine the association of drug sensitivity test and tuberculosis type, lineages, dominant strains and clustering of the isolates.. The 384 smear positive Mycobacterium samples were cultured on LJ media of which 29.2% (112/384) as culture positive. A fair agreement was found between MTBDRplus assay and the conventional MGIT test in detecting the Mycobacterium tuberculosis with sensitivity, specificity, positive and negative predictive value of 94.2, 30.2, 68.4 and 76.5%, respectively. Among LJ culture positive samples 95 of them gave valid result for MTBDRplus assay and 16.8% (16/95) as drug resistant. Similarly, MGIT subculture was made for the 112 isolates and 69 of them gave positive result with 15.9% (11/69) as drug resistant. Cohen's kappa value showed almost a perfect agreement between the two testing methods in detecting rifampicin (sensitivity 100% and specificity 98.3%) and multi-drug resistance (sensitivity 83.3% and specificity 100%). Spoligotyping identified 76.5% (13/17) of the drug resistant isolates as Euro-American and family 33 as the predominant family. Significant association was observed between drug resistant isolates and the dominant strains (χ2: 34.861; p = 0.040) of the Mycobacterium.. Higher magnitude of drug resistance was found in the study area. The GenoTypic MDRTBplus assay had an acceptable drug sensitivity testing performance.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Cross-Sectional Studies; Drug Resistance, Bacterial; Ethiopia; Female; Genotype; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Phenotype; Reagent Kits, Diagnostic; Rifampin; Tuberculosis; Young Adult

2021
Development and performance of CUHAS-ROBUST application for pulmonary rifampicin-resistance tuberculosis screening in Indonesia.
    PloS one, 2021, Volume: 16, Issue:3

    Diagnosis of Pulmonary Rifampicin Resistant Tuberculosis (RR-TB) with the Drug-Susceptibility Test (DST) is costly and time-consuming. Furthermore, GeneXpert for rapid diagnosis is not widely available in Indonesia. This study aims to develop and evaluate the CUHAS-ROBUST model performance, an artificial-intelligence-based RR-TB screening tool.. A cross-sectional study involved suspected all type of RR-TB patients with complete sputum Lowenstein Jensen DST (reference) and 19 clinical, laboratory, and radiology parameter results, retrieved from medical records in hospitals under the Faculty of Medicine, Hasanuddin University Indonesia, from January 2015-December 2019. The Artificial Neural Network (ANN) models were built along with other classifiers. The model was tested on participants recruited from January 2020-October 2020 and deployed into CUHAS-ROBUST (index test) application. Sensitivity, specificity, and accuracy were obtained for assessment.. A total of 487 participants (32 Multidrug-Resistant/MDR 57 RR-TB, 398 drug-sensitive) were recruited for model building and 157 participants (23 MDR and 21 RR) in prospective testing. The ANN full model yields the highest values of accuracy (88% (95% CI 85-91)), and sensitivity (84% (95% CI 76-89)) compare to other models that show sensitivity below 80% (Logistic Regression 32%, Decision Tree 44%, Random Forest 25%, Extreme Gradient Boost 25%). However, this ANN has lower specificity among other models (90% (95% CI 86-93)) where Logistic Regression demonstrates the highest (99% (95% CI 97-99)). This ANN model was selected for the CUHAS-ROBUST application, although still lower than the sensitivity of global GeneXpert results (87.5%).. The ANN-CUHAS ROBUST outperforms other AI classifiers model in detecting all type of RR-TB, and by deploying into the application, the health staff can utilize the tool for screening purposes particularly at the primary care level where the GeneXpert examination is not available.. NCT04208789.

    Topics: Adult; Antibiotics, Antitubercular; Area Under Curve; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; Humans; Indonesia; Logistic Models; Male; Middle Aged; Mycobacterium tuberculosis; Neural Networks, Computer; Rifampin; ROC Curve; Sensitivity and Specificity; Tuberculosis

2021
Safety and feasibility of 1 month of daily rifapentine plus isoniazid to prevent tuberculosis in children and adolescents: a prospective cohort study.
    The Lancet. Child & adolescent health, 2021, Volume: 5, Issue:5

    Shorter regimens for tuberculosis prevention can improve completion rates and protection against developing active tuberculosis disease after tuberculosis exposure. We aimed to assess the safety and feasibility of 1 month of daily isoniazid and rifapentine (1HP) in children and adolescents in a low-resource setting in south Asia with low prevalence of HIV.. This prospective cohort study was done in eight tuberculosis facilities in Karachi, Pakistan. Eligible participants were aged 2-19 years and were household contacts of patients with drug-susceptible tuberculosis infection. After clinical, radiological, and laboratory evaluation to rule out tuberculosis disease, participants were prescribed 1HP as a preventive regimen. Isoniazid was administered as 100 mg or 300 mg oral tablets and rifapentine was administered as 150 mg oral tablets. Dosing was according to participant bodyweight. The primary endpoints were the cumulative probability of a household contact completing all stages of the preventive care cascade, assessed in all eligible participants, and the proportion of household contacts completing 1HP, assessed among all those who initiated the regimen. Safety was assessed in all household contacts who initiated the 1HP regimen.. Between Dec 21, 2019, and March 20, 2020, 1395 household contacts of 253 patients with tuberculosis were identified, including 678 household contacts who were eligible to participate. 628 (93%) completed evaluation, of whom ten (2%) had active tuberculosis disease. Of the 618 individuals eligible for tuberculosis prevention, 408 (66%) initiated 1HP, 385 (94%) of whom completed the regimen. The median duration of 1HP was 31 days (IQR 30-32) in those who completed the regimen. The cumulative probability of completing all steps of the tuberculosis prevention cascade was 58%. A girl aged 11 years developed tuberculosis disease within 6 months of completing 1HP. A boy aged 14 years developed a burning sensation during 1HP therapy and discontinued the regimen. No other adverse events were observed.. 1HP can be safely and feasibly implemented as tuberculosis prevention in children and adolescents in programmatic settings.. The Global Fund to Fight AIDS, Tuberculosis and Malaria.

    Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Cohort Studies; Duration of Therapy; Female; Humans; Isoniazid; Male; Pakistan; Prospective Studies; Rifampin; Treatment Adherence and Compliance; Tuberculosis; Young Adult

2021
Compensatory effects of
    Emerging microbes & infections, 2021, Volume: 10, Issue:1

    Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Evolution, Molecular; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium smegmatis; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2021
Universal Access to Xpert MTB/RIF Testing for Diagnosis of Tuberculosis in Uzbekistan: How Well Are We Doing?
    International journal of environmental research and public health, 2021, 03-12, Volume: 18, Issue:6

    As per national guidelines in Uzbekistan, all presumptive tuberculosis patients should be tested using the Xpert MTB/RIF assay for diagnosing tuberculosis. There is no published evidence how well this is being implemented. In this paper, we report on the Xpert coverage among presumptive tuberculosis patients in 2018 and 2019, factors associated with non-testing and delays involved. Analysis of national aggregate data indicated that Xpert testing increased from 24% in 2018 to 46% in 2019, with variation among the regions: 21% in Tashkent region to 100% in Karakalpakstan. In a cohort (January-March 2019) constituted of 40 randomly selected health facilities in Tashkent city and Bukhara region, there were 1940 patients of whom 832 (43%, 95% confidence interval (CI): 41-45%) were not Xpert-tested. Non-testing was significantly higher in Bukhara region (73%) compared to Tashkent city (28%). In multivariable analysis, patient's age, distance between primary health centre (PHC) and Xpert laboratory, diagnostic capacity and site of PHC were associated with non-testing. The median (interquartile range) duration from date of initial visit to PHC to receiving results was 1 (1-2) day in Tashkent city compared to 3 (1-6) days in Bukhara region (

    Topics: Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary; Uzbekistan

2021
Is deployement of diagnostic test alone enough? Comprehensive package of interventions to strengthen TB laboratory network: three years of experience in Burkina Faso.
    BMC infectious diseases, 2021, Apr-13, Volume: 21, Issue:1

    The laboratory plays a critical role in tuberculosis (TB) control by providing testing for diagnosis, treatment monitoring, and surveillance at each level of the health care system. Weak accessibility to TB diagnosric services still represents a big concern in many limited resources' countries. Here we report the experience of Burkina Faso in implementing a comprehensive intervention packages to strengthen TB laboratory capacity and diagnostic accessibility.. The intervention lasted from October 2016 to December 2018 and focused on two main areas: i) development of strategic documents and policies; ii) implementation of TB diagnostic technology. National TB laboratory data were collected between 2016 and 2018 and evaluated according to five programmatic TB laboratory indicators: i) Percentage of notified new and relapse TB cases with bacteriological confirmation; ii) Percentage of notified new and relapse TB cases tested by Xpert MTB/RIF; iii) Percentage of notified, bacteriologically confirmed TB cases with a drug susceptibility testing (DST) result for rifampin; iv) Percentage of notified MDR-TB cases on the estimated number of MDR-TB cases; v) The ration between the number of smear microscopy and Xpert MTB/RIF tests. We compared these indicators between a 1 year (2016-2017) and 2 years (2016-2018) timeframe.. From 2016 to 2018, the percentage of bacteriologically confirmed cases increased from 67 to 71%. The percentage of new and relapse TB cases notified tested by Xpert MTB/RIF increased from 18% in 2016 to 46% in 2018 and the percentage of bacteriologically confirmed cases with an available DST result for rifampicin increased from 27% in 2016 to 66% in 2018.. The percentage of notified MDR-TB cases on the estimated number of MDR-TB cases in 2018 increased from 43% in 2016 to 78% in 2018. In 2018, the ratio between the number of smear microscopy and Xpert MTB/RIF tests decreased from 53% in 2016 to 21% in 2018.. We demonstrated that the implementation of a comprehensive package of laboratory strengthening interventions led to a significant improvement of all indicators. External technical assistance played a key role in speeding up the TB laboratory system improvement process.

    Topics: Antibiotics, Antitubercular; Burkina Faso; Humans; International Cooperation; Laboratories; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Recurrence; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
Diagnostic accuracy of the FluoroType MTB and MTBDR VER 2.0 assays for the centralized high-throughput detection of Mycobacterium tuberculosis complex DNA and isoniazid and rifampicin resistance.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2021, Volume: 27, Issue:9

    To evaluate the accuracy of two new molecular diagnostic tests for the detection of drug-resistant tuberculosis, the FluoroType MTB and MTBDR VER 2.0 assays, in combination with manual and automated DNA extraction methods.. Sputa from 360 Xpert Ultra Mycobacterium tuberculosis complex (MTBC)-positive patients and 250 Xpert Ultra MTBC-negative patients were tested. GenoType MTBDRplus served as reference for MTBC and drug resistance detection. Sanger sequencing was used to resolve discrepancies.. FluoroType MTB VER 2.0 showed similar MTBC sensitivity compared with FluoroType MTBDR VER 2.0 (manual DNA extraction: 91.6% (294/321) versus 89.8% (291/324); p 0.4); automated DNA extraction: 92.1% (305/331) versus 87.7% (291/332); p 0.05)). FluoroType MTBDR VER2.0 showed comparable diagnostic accuracy to FluoroType MTBDR VER1.0 as previously reported for the detection of MTBC and rifampicin and isoniazid resistance.. The FluoroType MTB and MTBDR VER 2.0 assays together with an automated DNA extraction and PCR set-up platform may improve laboratory operational efficiency for the diagnosis of MTBC and resistance to rifampicin and isoniazid and show promise for the implementation in a centralized molecular drug susceptibility testing model.

    Topics: Antitubercular Agents; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2021
Shortening the Short Course of Tuberculosis Treatment.
    The New England journal of medicine, 2021, 05-06, Volume: 384, Issue:18

    Topics: Humans; Moxifloxacin; Rifampin; Tuberculosis

2021
TB-QUICK: CRISPR-Cas12b-assisted rapid and sensitive detection of Mycobacterium tuberculosis.
    The Journal of infection, 2021, Volume: 83, Issue:1

    Tuberculosis (TB) remains one of the public health problems worldwide. Rapid, sensitive and cost-effective diagnosis of Mycobacterium tuberculosis (M.tb) is critical for TB control.. We developed a novel M.tb DNA detection platform (nominated as TB-QUICK) which combined loop-mediated isothermal amplification (LAMP) and CRISPR-Cas12b detection. TB-QUICK was performed on pulmonary or plasma samples collected from 138 pulmonary TB (PTB) patients, 21 non-TB patients and 61 close contacts to TB patients. Acid-fast bacillus (AFB) smear, M.tb culture and GeneXpert MTB/RIF (Xpert) assays were routinely conducted in parallel.. By targeting M.tb IS6110, TB-QUICK platform could detect as low as 1.3 copy/μL M.tb DNA within 2 h. In pulmonary TB samples, TB-QUICK exhibited improved overall sensitivity of 86.8% over M.tb culture (66.7%) and Xpert (70.4%), with the specificity of 95.2%. More significantly, TB-QUICK exhibited a superior sensitivity in AFB-negative samples (80.5%) compared to Xpert (57.1%) and M.tb culture (46.2%). In the detection of plasma M.tb DNA by TB-QUICK, 41.2% sensitivity for AFB-positive and 31.7% for AFB-negative patients were achieved.. In conclusion, TB-QUICK exhibits rapidity and sensitivity for M.tb DNA detection with the superiority in smear-negative paucibacillary TB patients. The clinical application of TB-QUICK in TB diagnosis needs to be further validated in larger cohort.

    Topics: Clustered Regularly Interspaced Short Palindromic Repeats; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2021
A positive COVID-19 test is associated with high mortality in RR-TB-HIV patients.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2021, May-01, Volume: 25, Issue:5

    Topics: COVID-19; HIV Infections; Humans; Rifampin; SARS-CoV-2; Tuberculosis

2021
Prevalence of rifampicin resistance tuberculosis among HIV/TB coinfected patients in Benue State, Nigeria.
    The Pan African medical journal, 2021, Volume: 38

    the emergence of HIV/TB co-infection has changed the global health landscape globally, particularly in sub-Saharan Africa and Asia with a high prevalence rate. It has further worsened and compound patient diagnosis, treatment/management approach and infection control. Rifampicin resistance TB (RR-TB) is a good indicator of treatment failure and infection control in the community. This study determines the prevalence of RR-TB among HIV/TB coinfected patients in Benue State, Nigeria.. the case-control study was carried out at Federal Medical Centre, Makurdi and General Hospital, Otupko, between January 2017 and February 2018. One thousand and ten suspected tuberculosis and HIV patients were enrolled in the study, diagnosed according to WHO guidelines. Sputum samples were collected and then analyzed by acid-fast bacilli smear test and GeneXpert MTB/RIF assay.. the relatively high prevalence of HIV/TB co-infection and RR-TB is a tremendous public health threat, considering society's attendant implication. Further surveillance studies are needed to evaluate the situation in Benue State better.

    Topics: Adolescent; Adult; Antitubercular Agents; Case-Control Studies; Child; Child, Preschool; Coinfection; Female; HIV Infections; Humans; Infant; Infant, Newborn; Male; Middle Aged; Nigeria; Prevalence; Rifampin; Rural Population; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant; Urban Population; Young Adult

2021
Performance of Real-Time Semi-Quantitative Polymerase Chain Reaction Assay for Optimum Diagnosis of Extrapulmonary Tuberculosis and Sensitivity to Rifampin in a Tertiary Care Center.
    Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion, 2021, 11-05, Volume: 73, Issue:6

    Tuberculosis represents a public health problem, with extrapulmonary disease occurring in 15% of incident cases annually. Early diagnosis is a challenge due to its paucibacillary nature. Recently, a molecular real-time semi-quantitative assay (GeneXpert Ultra) was developed to overcome limitations of the previous assay version (Xpert MTB/RF).. The objective of the study was to assess the usefulness of the novel next-generation GeneXpert assay in extrapulmonary samples from different anatomic sites under routine diagnostic conditions at a university medical center.. A total of 519 samples from patients with presumptive diagnosis of extrapulmonary TB were subjected to smear microscopy, culture, and molecular assay. Univariate analyses for demographic and microbiological characteristics were performed. The sensitivity, specificity, and Kappa index with a 95% confidence interval were determined.. Molecular assay was positive in 53 samples (10.2%), of which 38 (71.6%) belonged to the "low" and "trace" semi-quantitative categories. The overall sensitivity and specificity were 86.4% (95% confidence intervals [CI]: 74.1-98.8) and 95.6% (95% CI: 93.7-97.6), respectively. Phenotypic drug susceptibility testing for rifampin was 100% concordant.. Molecular assay showed significant results when compared to other standard tests, making it a useful tool that could lead in the improvement to a rapid diagnosis of extrapulmonary disease.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tertiary Care Centers; Tuberculosis

2021
Expression profiling of TRIM gene family reveals potential diagnostic biomarkers for rifampicin-resistant tuberculosis.
    Microbial pathogenesis, 2021, Volume: 157

    The epidemic of pulmonary tuberculosis (TB), especially rifampin-resistant tuberculosis (RR-TB) presents a major challenge for TB control today. However, there is a lack of reliable and specific biomarkers for the early diagnosis of RR-TB. We utilized reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to profile the transcript levels of 72 tripartite motif (TRIM) genes from a discovery cohort of 10 drug-sensitive tuberculosis (DS-TB) patients, 10 RR-TB patients, and 10 healthy controls (HCs). A total of 35 differentially expressed genes (DEGs) were screened out, all of which were down-regulated. The bio functions and pathways of these DEGs were enriched in protein ubiquitination, regulation of the viral process, Interferon signaling, and innate immune response, etc. A protein-protein interaction network (PPI) was constructed and analyzed using STRING and Cytoscape. Twelve TRIM genes were identified as hub genes, and seven (TRIM1, 9, 21, 32, 33, 56, 66) of them were verified by RT-qPCR in a validation cohort of 95 subjects. Moreover, we established the RR-TB decision tree models based on the 7 biomarkers. The receiver operating characteristic (ROC) analyses showed that the models exhibited the areas under the curve (AUC) values of 0.878 and 0.868 in discriminating RR-TB from HCs and DS-TB, respectively. Our study proposes potential biomarkers for RR-TB diagnosis, and also provides a new experimental basis to understand the pathogenesis of RR-TB.

    Topics: Biomarkers; Gene Expression Profiling; Humans; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2021
STEPS: A Solution for Ensuring Standards of TB Care for Patients Reaching Private Hospitals in India.
    Global health, science and practice, 2021, 06-30, Volume: 9, Issue:2

    In India, the private sector diagnoses and treats more patients with TB than the public sector. Gaps in the TB care cascade were observed more among the patients diagnosed in the private sector.. The System for TB Elimination in Private Sector (STEPS) model evolved as a solution to address gaps in the quality of care for patients in the private sector by ensuring standards of TB care. STEPS has 3 components: a consortium of private hospitals, a coalition of all professional medical associations, and a STEPS center in each private hospital. STEPS centers act as a single window for notification, linkage for social welfare measures, contact investigation, chemoprophylaxis, direct benefit transfers, and treatment adherence support.. STEPS was piloted in 14 districts in the state of Kerala. All 14 districts formed consortiums of private hospital management for policy support and a coalition of professional medical associations for advocacy with doctors. STEPS centers were established in 318 private hospitals.. Notification to National TB Elimination Program from the private sector improved by 26% when compared to the previous year. Among the patients notified from the private sector, microbiologically confirmed cases increased by 81%, rifampicin resistance testing at baseline increased by 56%, and the percentage of those informed of their HIV status increased by 95%. The percentage of patients notified from the private sector with their treatment outcome reported improved from 39% (2018) to 99% (2019).. The STEPS model demonstrated that a low-cost locally customized private sector engagement model is feasible and is beneficial to society. STEPS could be one of the major solutions for supporting patients reaching the private sector.

    Topics: Hospitals, Private; Humans; India; Private Sector; Public Sector; Rifampin; Tuberculosis

2021
Drug Resistance of Mouse Somatic Cells to Rifampicin in Experimental Tuberculosis.
    Bulletin of experimental biology and medicine, 2021, Volume: 171, Issue:1

    We have demonstrated that long-term exposure of intact mice to rifampicin (6 months) induces resistance to this drug, which manifested in inability of rifampicin to suppress the growth of Mycobacterium tuberculosis in the lungs and spleen during subsequent infection. It the same time, isoniazid is still effective in these mice. In this case, the phenomenon of somatic resistance to rifampicin in mice was observed if the treatment was started in a short period (within 4 days) after infection with M. tuberculosis. If the interval between infection and rifampicin administration was longer (3 weeks), the resistance disappeared.

    Topics: Animals; Antitubercular Agents; Drug Resistance; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2021
A high-throughput screening assay based on automated microscopy for monitoring antibiotic susceptibility of Mycobacterium tuberculosis phenotypes.
    BMC microbiology, 2021, 06-05, Volume: 21, Issue:1

    Efficient high-throughput drug screening assays are necessary to enable the discovery of new anti-mycobacterial drugs. The purpose of our work was to develop and validate an assay based on live-cell imaging which can monitor the growth of two distinct phenotypes of Mycobacterium tuberculosis and to test their susceptibility to commonly used TB drugs.. Both planktonic and cording phenotypes were successfully monitored as fluorescent objects using the live-cell imaging system IncuCyte S3, allowing collection of data describing distinct characteristics of aggregate size and growth. The quantification of changes in total area of aggregates was used to define IC. Our results emphasize the efficiency of using automated live-cell imaging and its potential in high-throughput whole-cell screening to evaluate existing and search for novel antimycobacterial drugs.

    Topics: Antitubercular Agents; Automation; High-Throughput Screening Assays; Humans; Isoniazid; Linezolid; Microbial Sensitivity Tests; Microscopy; Mycobacterium tuberculosis; Phenotype; Rifampin; Tuberculosis

2021
Early and Midterm Outcomes of Endovascular Repair of Tuberculous Infected Native (Mycotic) Aortic Aneurysms.
    European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery, 2021, Volume: 62, Issue:2

    Topics: Aged; Antitubercular Agents; Aortic Aneurysm; Blood Vessel Prosthesis; Drug-Eluting Stents; Endovascular Procedures; Female; Humans; Isoniazid; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Rifampin; Survival Rate; Treatment Outcome; Tuberculosis

2021
A Semimechanistic Pharmacokinetic Model for Depot Medroxyprogesterone Acetate and Drug-Drug Interactions With Antiretroviral and Antituberculosis Treatment.
    Clinical pharmacology and therapeutics, 2021, Volume: 110, Issue:4

    Depot medroxyprogesterone acetate is an injectable hormonal contraceptive, widely used by women of childbearing potential living with HIV and/or tuberculosis. As medroxyprogesterone acetate is a cytochrome P450 (CYP3A4) substrate, drug-drug interactions (DDIs) with antiretroviral or antituberculosis treatment may lead to subtherapeutic medroxyprogesterone acetate concentrations (< 0.1 ng/mL), resulting in contraception failure, when depot medroxyprogesterone is dosed at 12-week intervals. A pooled population pharmacokinetic analysis with 744 plasma medroxyprogesterone acetate concentrations from 138 women treated with depot medroxyprogesterone and antiretroviral/antituberculosis treatment across three clinical trials was performed. Monte Carlo simulations were performed to predict the percentage of participants with subtherapeutic medroxyprogesterone acetate concentrations and to derive alternative dosing strategies. Medroxyprogesterone acetate clearance increased by 24.7% with efavirenz coadministration. Efavirenz plus antituberculosis treatment (rifampicin + isoniazid) increased clearance by 52.4%. Conversely, lopinavir/ritonavir and nelfinavir decreased clearance (28.7% and 15.8%, respectively), but lopinavir/ritonavir also accelerated medroxyprogesterone acetate's appearance into the systemic circulation, thus shortening the terminal half-life. A higher risk of subtherapeutic medroxyprogesterone acetate concentrations at Week 12 was predicted on a typical 60-kg woman on efavirenz (4.99%) and efavirenz with antituberculosis treatment (6.08%) when compared with medroxyprogesterone acetate alone (2.91%). This risk increased in women with higher body weight. Simulations show that re-dosing every 8 to 10 weeks circumvents the risk of subtherapeutic medroxyprogesterone acetate exposure associated with these DDIs. Dosing depot medroxyprogesterone every 8 to 10 weeks should eliminate the risk of subtherapeutic medroxyprogesterone acetate exposure caused by coadministered efavirenz and/or antituberculosis treatment, thus reducing the risk of contraceptive failure.

    Topics: Alkynes; Anti-Retroviral Agents; Antitubercular Agents; Benzoxazines; Contraceptive Agents, Hormonal; Contraceptive Effectiveness; Cyclopropanes; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Delayed-Action Preparations; Drug Administration Schedule; Drug Combinations; Drug Interactions; Female; HIV Infections; Humans; Isoniazid; Lopinavir; Medroxyprogesterone Acetate; Nelfinavir; Rifampin; Ritonavir; Tuberculosis

2021
Rifampicin exposure reveals within-host Mycobacterium tuberculosis diversity in patients with delayed culture conversion.
    PLoS pathogens, 2021, Volume: 17, Issue:6

    Mycobacterium tuberculosis (Mtb) genetic micro-diversity in clinical isolates may underline mycobacterial adaptation to tuberculosis (TB) infection and provide insights to anti-TB treatment response and emergence of resistance. Herein we followed within-host evolution of Mtb clinical isolates in two cohorts of TB patients, either with delayed Mtb culture conversion (> 2 months), or with fast culture conversion (< 2 months). We captured the genetic diversity of Mtb isolates obtained in each patient, by focusing on minor variants detected as unfixed single nucleotide polymorphisms (SNPs). To unmask antibiotic tolerant sub-populations, we exposed these isolates to rifampicin (RIF) prior to whole genome sequencing (WGS) analysis. Thanks to WGS, we detected at least 1 unfixed SNP within the Mtb isolates for 9/15 patients with delayed culture conversion, and non-synonymous (ns) SNPs for 8/15 patients. Furthermore, RIF exposure revealed 9 additional unfixed nsSNP from 6/15 isolates unlinked to drug resistance. By contrast, in the fast culture conversion cohort, RIF exposure only revealed 2 unfixed nsSNP from 2/20 patients. To better understand the dynamics of Mtb micro-diversity, we investigated the variant composition of a persistent Mtb clinical isolate before and after controlled stress experiments mimicking the course of TB disease. A minor variant, featuring a particular mycocerosates profile, became enriched during both RIF exposure and macrophage infection. The variant was associated with drug tolerance and intracellular persistence, consistent with the pharmacological modeling predicting increased risk of treatment failure. A thorough study of such variants not necessarily linked to canonical drug-resistance, but which are prone to promote anti-TB drug tolerance, may be crucial to prevent the subsequent emergence of resistance. Taken together, the present findings support the further exploration of Mtb micro-diversity as a promising tool to detect patients at risk of poorly responding to anti-TB treatment, ultimately allowing improved and personalized TB management.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis

2021
A Case of Colonic Tuberculosis Revealed by Polymerase Chain Reaction.
    Clinical laboratory, 2021, Jul-01, Volume: 67, Issue:7

    The authors report a case of tumor-like colonic tuberculosis revealed by PCR in a 32-year-old patient with a low-level peritoneal effusion on CT scan with negative histological study on colonic biopsy.. The colonic biopsy received at the laboratory after grinding in a porcelain mortar, was the object of a molecular study by GeneXpert MT/RIF (Cepheid, Sunnyvale, CA, USA) using the automated real-time PCR technique and a conventional study based on Ziehl-Nielsen staining and culture on Lowenstein-Jensen® solid medium (LJ) and Mycobacteria Growth Indicator Tube (MGIT®) liquid medium.. The patient was a 32-year-old male without any personal or family history of tuberculosis and without signs of tuberculosis impregnation. He had a story of ingestion of non-pasteurized dairy products including milk and cheese. For 45 days he had constipation with abdominal pain and feeling of heaviness. Physical examination of the patient revealed abdominal tenderness without adenopathy. The laboratory workup showed a normal blood count, CRP, liver and kidney function tests. The HIV test was negative. Medical imaging revealed a low-level peritoneal effusion that could not be punctured. Colonoscopy showed a thickening of the colon. The colonic biopsy, after crushing and sonication, was searched for the Mycobacterium tuberculosis complex by both molecular biology and conventional methods. Molecular research by GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) using the automated real-time PCR technique, revealed the presence of the Mycobacterium tuberculosis complex without detection of rifampicin resistance. On the other hand, the direct examination after special Ziehl-Nielsen staining was positive (Figure 2) and the cultures on Lowenstein-Jensen® solid medium (LJ) and Mycobacteria Growth Indicator Tube (MGIT®) liquid medium were also positive after two and three weeks, confirming the molecular diagnosis. The histology study showed moderate non-specific chronic colitis with no histological arguments for tuberculosis or malignancy. The patient was placed on curative tuberculosis treatment according to the national protocol, with a favorable clinical-radiological course.. Colonic tuberculosis is a disease that may mimic many other diseases; therefore, a correct approach is necessary for the correct diagnosis and treatment.

    Topics: Adult; Bacteriological Techniques; Colon; Humans; Male; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis

2021
Characteristics of rifampicin-resistant tuberculosis detection in China, 2015-2019.
    Infectious diseases of poverty, 2021, Jul-17, Volume: 10, Issue:1

    The very high burden of rifampicin resistance tuberculosis (RR-TB) and the very low detection of RR-TB cases are a major challenge that China has been facing. This study analyzed the characteristics of RR-TB detection in China after the change of RR-TB detection strategy since 2015, aiming to provide reference and evidence for the development of more precise national drug resistance tuberculosis prevention and control policy.. We extracted data related to rifampicin resistance screening from the national Tuberculosis Information Management System (TBIMS) from 2015 to 2019, and used descriptive research methods to analyze the screening rate of presumptive RR-TB, the number and duration of RR-TB patients detected and drug resistance testing methods in each year. Chi-square test was used to compare the differences in component ratio or rate between years, and Kruskal Wallis test was used to compare the differences in median days for detection of RR-TB patients in each year.. A total of 68,200 RR-TB cases were detected during 2015-2019, of which 48.1% were new cases. The number and detection rate of RR-TB cases increased year by year, from 10 019 and 14.3% in 2015 to 18 623 and 28.7% in 2019, respectively. Of the bacteriologically confirmed TB cases, 81.9% were tested for RR in 2019, a considerable increase from 29.5% in 2015. In 2019, only 41.0% of RR-TB cases had fluoroquinolones (FQs) susceptibility testing performed, and this proportion has been declining year by year since 2016. The proportion of application of rapid molecular tools increased from 24.0% in 2015 to 67.1% in 2019, and the median days to obtain RR results was significantly shortened. In 2019, 76.0% of RR-TB cases were diagnosed as presumptive RR-TB in county-level hospitals.. After China modified the RR-TB detection strategy, the screening rate of RR and the number of RR-TB cases increased significantly. The RR testing methods now predominantly utilize rapid molecular tools. However, comprehensive measures should be implemented to close the gap in the detection of RR-TB cases. It is imperative to take FQs susceptibility testing seriously and effectively strengthen the laboratory capacity of county-level hospitals.

    Topics: China; Humans; Mass Screening; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2021
Impact of the GeneXpert® MTB/RIF rapid molecular test on tuberculosis detection: temporal trends and vulnerable territories.
    Revista latino-americana de enfermagem, 2021, Volume: 29

    to assess the impact of the GeneXpert® MTB/RIF rapid molecular test on tuberculosis detection, to analyze the temporal trend of the event and to identify vulnerable territories in a Brazilian municipality.. an ecological study carried out in Ribeirão Preto, São Paulo, Brazil, a municipality considered a priority in tuberculosis control due to the high number of cases. To classify the temporal trend, the Prais-Winsten method and the Interrupted Time Series were used to identify changes in the disease incidence. Kernel intensity analysis was applied to identify vulnerable areas.. the temporal trend of tuberculosis decreased by 18.1%/year and by 6.9%/year for children under 15 years old. The North District decreased by 6.67%/year and the East District increased by 17.5%/year in the incidence of tuberculosis. Resistant tuberculosis, after the implementation of the Rapid Molecular Test, increased by 0.6% per year. The South and West Districts showed a higher density of cases, with a range from 45 to 79 tuberculosis cases per square kilometer (km2).. although resistant tuberculosis is not a problem in the scenario, the study showed an increase in its incidence, which puts it on alert. The use of spatial analysis enabled the identification of priority areas, putting them in evidence for health surveillance actions.

    Topics: Adolescent; Brazil; Child; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2021
Effect of efavirenz-based ART on the pharmacokinetics of rifampicin and its primary metabolite in patients coinfected with TB and HIV.
    The Journal of antimicrobial chemotherapy, 2021, 10-11, Volume: 76, Issue:11

    To evaluate the effects of concomitant efavirenz-based ART and genetic polymorphism on the variability in rifampicin and 25-desacetylrifampicin pharmacokinetics.. Plasma concentrations of rifampicin and 25-desacetylrifampicin from 63 patients coinfected with TB and HIV were analysed by LC-MS/MS followed by non-linear mixed-effects modelling. Patients were genotyped for SLCO1B1 (463 C>A, 388 A>G, 11187 G>A, rs4149015, 521 T>C and 1436 G>C) and SLCO1B3 (334 T>G).. One-compartment disposition models described the observations adequately. The oral clearances of rifampicin and 25-desacetylrifampicin were 140% and 110% higher, respectively, in patients on concomitant efavirenz-based ART. Rifampicin bioavailability was also lower in patients on concomitant ART. Further, although not included in the final model, a lower relative bioavailability in carriers of WT SLCO1B3 334 T>G compared with carriers of mutations in the genotype was estimated.. The results presented indicate both pre-systemic and systemic induction by efavirenz-based ART affecting rifampicin pharmacokinetics. The described drug-drug interaction has a clinical impact on rifampicin exposure prior to steady state and may impact the early bactericidal activity in patients on efavirenz-based ART.

    Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Chromatography, Liquid; Coinfection; Cyclopropanes; HIV Infections; Humans; Liver-Specific Organic Anion Transporter 1; Rifampin; Tandem Mass Spectrometry; Tuberculosis

2021
Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis.
    Antimicrobial agents and chemotherapy, 2021, 10-18, Volume: 65, Issue:11

    Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2, and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used noncompartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 to 2,540 ng/ml in plasma and 16.2 to 5,478 ng/ml in PBMCs, and concentrations of M2 over the 6-month treatment period ranged from 34.3 to 496 ng/ml in plasma and 109.2 to 16,764 ng/ml in PBMCs. Plasma concentrations of bedaquiline were higher than those of M2, but intracellular concentrations of M2 were considerably higher than those of bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratios 1 and 2 months after start of treatment were 0.61 (95% confidence interval [CI]: 0.42 to 0.92) and 1.10 (95% CI: 0.74 to 1.63) for bedaquiline and 12.4 (95% CI: 8.8 to 17.8) and 22.2 (95% CI: 15.6 to 32.3) for M2. The intracellular-plasma ratios for both bedaquiline and M2 were decreased by 54% (95% CI: 24 to 72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting

    Topics: Antitubercular Agents; Chromatography, Liquid; Diarylquinolines; Humans; Leukocytes, Mononuclear; Rifampin; Tandem Mass Spectrometry; Tuberculosis

2021
Age and sex distribution of Mycobacterium tuberculosis infection and rifampicin resistance in Myanmar as detected by Xpert MTB/RIF.
    BMC infectious diseases, 2021, Aug-09, Volume: 21, Issue:1

    Detection of tuberculosis disease (TB) and timely identification of Mycobacterium tuberculosis (Mtb) strains that are resistant to treatment are key to halting tuberculosis transmission, improving treatment outcomes, and reducing mortality.. We used 332,657 Xpert MTB/RIF assay results, captured as part of the Myanmar Data Utilization Project, to characterize Mtb test positivity and rifampicin resistance by both age and sex, and to evaluate risk factors associated with rifampicin resistance.. Overall, 70% of individuals diagnosed with TB were males. Test positivity was higher among males (47%) compared to females (39%). The highest positivity by age occurred among individuals aged 16-20, with test positivity for females (65%) higher than for males (57%). Although a greater absolute number of males were rifampicin resistant, a greater proportion of females (11.4%) were rifampicin resistant as compared to males (9.3%). In the multivariate model, history of previous treatment, age less than 30, testing in the Yangon region, and female sex were significantly positively associated with rifampicin resistance after adjusting for HIV status and year test was performed.. Our results indicate that young adults were more likely to test positive for TB and be identified as rifampicin resistant compared to older adults.

    Topics: Aged; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; Humans; Male; Myanmar; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sex Distribution; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

2021
A novel agar base medium for drug susceptibility testing of
    Future microbiology, 2021, Volume: 16

    Topics: Agar; Antitubercular Agents; Culture Media; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

2021
Inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection: a prospective cohort study and immunological network analysis.
    The Lancet. Microbe, 2021, Volume: 2, Issue:8

    HIV-1 mediated dysregulation of the immune response to tuberculosis and its effect on the response to antitubercular therapy (ATT) is incompletely understood. We aimed to analyse the inflammatory profile of patients with tuberculosis with or without HIV-1 co-infection undergoing ATT, with specific focus on the effect of ART and HIV-1 viraemia in those co-infected with HIV-1.. In this prospective cohort study and immunological network analysis, a panel of 38 inflammatory markers were measured in the plasma of a prospective patient cohort undergoing ATT at Khayelitsha Site B clinic, Cape Town, South Africa. We recruited patients with sputum Xpert MTB/RIF-positive rifampicin-susceptible pulmonary tuberculosis. Patients were excluded from the primary discovery cohort if they were younger than 18 years, unable to commence ATT for any reason, pregnant, had unknown HIV-1 status, were unable to consent to study participation, were unable to provide baseline sputum samples, had more than three doses of ATT, or were being re-treated for tuberculosis within 6 months of their previous ATT regimen. Plasma samples were collected at baseline (1-5 days after commencing ATT), week 8, and week 20 of ATT. We applied network and multivariate analysis to investigate the dynamic inflammatory profile of these patients in relation to ATT and by HIV status. In addition to the discovery cohort, a validation cohort of patients with HIV-1 admitted to hospital with CD4 counts less than 350 cells per μL and a high clinical suspicion of new tuberculosis were recruited.. Between March 1, 2013, and July 31, 2014, we assessed a cohort of 129 participants (55 [43%] female and 74 [57%] male, median age 35·1 years [IQR 30·1-43·7]) and 76 were co-infected with HIV-1. HIV-1 status markedly influenced the inflammatory profile regardless of ATT duration. HIV-1 viral load emerged as a major factor driving differential inflammatory marker expression and having a strong effect on correlation profiles observed in the HIV-1 co-infected group. Interleukin (IL)-17A emerged as a key correlate of HIV-1-induced inflammation during HIV-tuberculosis co-infection.. Our findings show the effect of HIV-1 co-infection on the complexity of plasma inflammatory profiles in patients with tuberculosis. Through network analysis we identified IL-17A as an important node in HIV-tuberculosis co-infection, thus implicating this cytokine's capacity to correlate with, and regulate, other inflammatory markers. Further mechanistic studies are required to identify specific IL-17A-related inflammatory pathways mediating immunopathology in HIV-tuberculosis co-infection, which could illuminate targets for future host-directed therapies.. National Institutes of Health, The Wellcome Trust, UK Research and Innovation, Cancer Research UK, European and Developing Countries Clinical Trials Partnership, and South African Medical Research Council.

    Topics: Adult; Antitubercular Agents; Biomarkers; Cohort Studies; Coinfection; Female; HIV Infections; HIV Seropositivity; HIV-1; Humans; Interleukin-17; Latent Tuberculosis; Male; Prospective Studies; Rifampin; South Africa; Tuberculosis; United States

2021
Adoption of evidence-informed guidelines in prescribing protease inhibitors for HIV-Tuberculosis co-infected patients on rifampicin and effects on HIV treatment outcomes in Uganda.
    BMC infectious diseases, 2021, Aug-16, Volume: 21, Issue:1

    We aimed to determine how emerging evidence over the past decade informed how Ugandan HIV clinicians prescribed protease inhibitors (PIs) in HIV patients on rifampicin-based tuberculosis (TB) treatment and how this affected HIV treatment outcomes.. We reviewed clinical records of HIV patients aged 13 years and above, treated with rifampicin-based TB treatment while on PIs between1st-January -2013 and 30th-September-2018 from twelve public HIV clinics in Uganda. Appropriate PI prescription during rifampicin-based TB treatment was defined as; prescribing doubled dose lopinavir/ritonavir- (LPV/r 800/200 mg twice daily) and inappropriate PI prescription as prescribing standard dose LPV/r or atazanavir/ritonavir (ATV/r).. Of the 602 patients who were on both PIs and rifampicin, 103 patients (17.1% (95% CI: 14.3-20.34)) received an appropriate PI prescription. There were no significant differences in the two-year mortality (4.8 vs. 5.7%, P = 0.318), loss to follow up (23.8 vs. 18.9%, P = 0.318) and one-year post TB treatment virologic failure rates (31.6 vs. 30.7%, P = 0.471) between patients that had an appropriate PI prescription and those that did not. However, more patients on double dose LPV/r had missed anti-retroviral therapy (ART) days (35.9 vs 21%, P = 0.001).. We conclude that despite availability of clinical evidence, double dosing LPV/r in patients receiving rifampicin-based TB treatment is low in Uganda's public HIV clinics but this does not seem to affect patient survival and viral suppression.

    Topics: Adolescent; Adult; Aged; Anti-HIV Agents; Coinfection; Drug Therapy, Combination; Female; Guidelines as Topic; HIV Infections; HIV Protease Inhibitors; Humans; Inappropriate Prescribing; Lopinavir; Middle Aged; Protease Inhibitors; Rifampin; Ritonavir; Treatment Outcome; Tuberculosis; Uganda; Young Adult

2021
Synthesis and efficacy of pyrvinium-inspired analogs against tuberculosis and malaria pathogens.
    Bioorganic & medicinal chemistry letters, 2020, 04-15, Volume: 30, Issue:8

    Herein, we report the synthesis and evaluation of pyrvinium-based antimalarial and antitubercular compounds. Pyrvinium is an FDA approved drug for the treatment of pinworm infection, and it has been reported to have antiparasitic and antimicrobial activities. Pyrvinium contains quinoline core coupled with pyrrole. We replaced the pyrrole with various aryl or heteroaryl substituents to generate pyrvinium analogs. The profiling of these compounds against malaria parasite P. falciparum 3D7 revealed analogs with better antimalarial activity than pyrvinium pamoate. Compound 14 and 16 showed IC

    Topics: Antimalarials; Antitubercular Agents; Dose-Response Relationship, Drug; Malaria, Falciparum; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Parasitic Sensitivity Tests; Plasmodium falciparum; Pyrvinium Compounds; Structure-Activity Relationship; Tuberculosis

2020
Design, synthesis, and evaluation of new 2-(quinoline-4-yloxy)acetamide-based antituberculosis agents.
    European journal of medicinal chemistry, 2020, Apr-15, Volume: 192

    Using a classical molecular simplification approach, a series of 36 quinolines were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (M. tuberculosis) growth. Structure-activity relationship (SAR) studies leaded to potent antitubercular agents, with minimum inhibitory concentration (MIC) values as low as 0.3 μM against M. tuberculosis H37Rv reference strain. Furthermore, the lead compounds were active against multidrug-resistant strains, without cross-resistance with some first- and second-line drugs. Testing the molecules against a spontaneous mutant strain containing a single mutation in the qcrB gene (T313A) indicated that the synthesized quinolines targeted the cytochrome bc

    Topics: Animals; Antitubercular Agents; Cell Survival; Cells, Cultured; Chlorocebus aethiops; Dose-Response Relationship, Drug; Drug Design; Hep G2 Cells; Humans; Macrophages; Mice; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; RAW 264.7 Cells; Structure-Activity Relationship; Tuberculosis; Vero Cells

2020
Indole chalcones: Design, synthesis, in vitro and in silico evaluation against Mycobacterium tuberculosis.
    European journal of medicinal chemistry, 2020, Jul-15, Volume: 198

    Topics: Amino Acid Sequence; Animals; Antitubercular Agents; Cell Line; Cell Survival; Chalcones; Drug Evaluation, Preclinical; Enzyme Inhibitors; Fatty Acid Synthase, Type II; Humans; Indoles; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis

2020
Structure-activity relationship analyses of fusidic acid derivatives highlight crucial role of the C-21 carboxylic acid moiety to its anti-mycobacterial activity.
    Bioorganic & medicinal chemistry, 2020, 07-01, Volume: 28, Issue:13

    Fusidic acid (FA) is a potent congener of the fusidane triterpenoid class of antibiotics. Structure-activity relationship (SAR) studies suggest the chemical structure of FA is optimal for its antibacterial activity. SAR studies from our group within the context of a drug repositioning approach in tuberculosis (TB) suggest that, as with its antibacterial activity, the C-21 carboxylic acid group is indispensable for its anti-mycobacterial activity. Further studies have led to the identification of 16-deacetoxy-16β-ethoxyfusidic acid (58), an analog which exhibited comparable activity to FA with an in vitro MIC

    Topics: Animals; Anti-Bacterial Agents; Cricetulus; Drug Evaluation, Preclinical; Drug Repositioning; Fusidic Acid; Humans; Microbial Sensitivity Tests; Mycobacterium; Structure-Activity Relationship; Tuberculosis

2020
Synthesis and biological evaluation of anti-tubercular activity of Schiff bases of 2-Amino thiazoles.
    Bioorganic & medicinal chemistry letters, 2020, 12-15, Volume: 30, Issue:24

    Topics: Amination; Antitubercular Agents; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Schiff Bases; Thiazoles; Tuberculosis

2020
Antituberculosis drug resistance in isolates of Mycobacterium tuberculosis complex in southeast Spain.
    Journal of global antimicrobial resistance, 2020, Volume: 20

    The aim of this study was to determine resistance to antituberculosis (anti-TB) drugs in Mycobacterium tuberculosis complex isolates from patients diagnosed with Tuberculosis (TB) in southeast Spain and to study related epidemiological factors.. This retrospective study analysed 5-year data (2012-2016) obtained in southeast Spain for a total equivalent population of 1 735 608 inhabitants. Clinical samples were examined from 557 patients with suspected pulmonary TB (n=470; 84.4%) or extrapulmonary TB (n=87; 15.6%), taking into account patient age, sex, human immunodeficiency virus (HIV) infection, country of birth and prior anti-TB treatment.. TB was found more frequently in men than in women (66.6% vs. 33.4%), and the age group with the most cases (43.7%) was 36-55 years. Among the first-line anti-TB drugs, 7.0% of patients harboured isolates resistant to isoniazid (INH) and 1.6% to rifampicin (RIF); moreover, 1.4% of isolates were multidrug-resistant TB (MDR-TB) and 0.7% were extensively drug-resistant TB. There was a statistically significant relationship (P=0.028) between MDR-TB isolates and non-Spanish-born patients, but not between the latter and INH resistance.. Resistance to INH and RIF was observed at levels similar to those published nationwide, with rates of MDR-TB being somewhat lower. Rates of HIV/TB co-infection have decreased considerably between 2012 and 2016.

    Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antitubercular Agents; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sex Characteristics; Spain; Tuberculosis; Young Adult

2020
Pancreatic tuberculosis diagnosed by endoscopic ultrasound-guided fine needle aspiration in a 14-year-old adolescent.
    Medecine et maladies infectieuses, 2020, Volume: 50, Issue:1

    Topics: Abdominal Pain; Adolescent; Antitubercular Agents; Cote d'Ivoire; Drug Therapy, Combination; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Humans; Isoniazid; Male; Pancreatitis; Pyrazinamide; Rifampin; Travel-Related Illness; Tuberculosis

2020
Isoniazid and Rifapentine Treatment Eradicates Persistent
    American journal of respiratory and critical care medicine, 2020, 02-15, Volume: 201, Issue:4

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Isoniazid; Latent Tuberculosis; Macaca; Models, Animal; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis

2020
Association of ABCC Gene Polymorphism With Susceptibility to Antituberculosis Drug-Induced Hepatotoxicity in Western Han Patients With Tuberculosis.
    Journal of clinical pharmacology, 2020, Volume: 60, Issue:3

    Six-month combination regimens could lead to serious hepatotoxicity, which may limit the clinical use of antituberculosis drugs. ABCC transporters are critical to the influx and efflux of compounds into and out of cells. The aim of this study was to explore whether the genetic variants in ABCC genes were related to the development of antituberculosis drug-induced hepatotoxicity. Here, we screened and genotyped 39 single-nucleotide polymorphisms of 13 ABCC genes in 746 eligible patients treated by first-line antituberculosis drugs in Western China Hospital. Genomic DNA was extracted from a peripheral blood sample of each patient, and clinical symptoms and laboratory results were recorded regularly. We found that the incidence rate of hepatotoxicity was 15.8% in the western Chinese Han population. As a result, the ABCC2 rs3740065 genotype, sex, and the baseline level of alanine aminotransferase are independent risk factors of antituberculosis drug-induced hepatotoxicity, with P values of .008, .014, and <.001, respectively. Our findings revealed a fraction of the underlying mechanism of hepatotoxicity, and larger validation studies on different populations are warranted to confirm these findings.

    Topics: Adult; Alanine Transaminase; Antitubercular Agents; Asian People; ATP-Binding Cassette Transporters; Chemical and Drug Induced Liver Injury; China; Drug Therapy, Combination; Ethambutol; Female; Genetic Predisposition to Disease; Genotype; Humans; Isoniazid; Male; Middle Aged; Multidrug Resistance-Associated Protein 2; Polymorphism, Single Nucleotide; Pyrazinamide; Rifampin; Risk Factors; Sex Factors; Tuberculosis; Young Adult

2020
Adjunctive Immunotherapeutic Efficacy of N-Formylated Internal Peptide of Mycobacterial Glutamine Synthetase in Mouse Model of Tuberculosis.
    Protein and peptide letters, 2020, Volume: 27, Issue:3

    Host-directed therapies are a comparatively new and promising method for the treatment of tuberculosis. A variety of host pathways, vaccines and drugs have the potential to provide novel adjunctive therapies for the treatment of tuberculosis. In this connection, we have earlier reported the immunotherapeutic potential of N-formylated N-terminal peptide of glutamine synthetase of Mycobacterim tuberculosis H37Rv (Mir SA and Sharma S, 2014). Now in the present study, we investigated the immunotherapeutic effect of N-terminally formylated internal-peptide 'f- MLLLPD' of mycobacterial glutamine synthetase (Rv2220) in mouse model of tuberculosis.. The N-terminally formylated peptide, f-MLLLPD was tested for its potential to generate Reactive Oxygen Species (ROS) in murine neutrophils. Further, its therapeutic effect alone or in combination with anti-tubercular drugs was evaluated in mouse model of tuberculosis.. The f-MLLLPD peptide treatment alone and in combination with ATDs reduced the bacterial load (indicated as colony forming units) in lungs of infected mice by 0.58 (p<0.01) and 2.92 (p<0.001) log10 units respectively and in their spleens by 0.46 (p<0.05) and 2.46 (p<0.001) log10 units respectively. In addition, the observed histopathological results correlated well with the CFU data.. The results of the current study show that f-MLLLPD peptide confers an additional therapeutic efficacy to the anti-tuberculosis drugs.

    Topics: Animals; Bacterial Load; Bacterial Proteins; Disease Models, Animal; Drug Therapy, Combination; Female; Glutamate-Ammonia Ligase; Isoniazid; Lung; Mice; Mycobacterium tuberculosis; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Reactive Oxygen Species; Rifampin; Spleen; Tuberculosis

2020
Tuberculosis Following Lung Transplantation. A 27-Year Spanish Multicenter Experience. Incidence, Presentation, Prevention and Treatment with Rifampicin.
    Archivos de bronconeumologia, 2020, Volume: 56, Issue:8

    Tuberculosis (TB) represents a diagnostic and therapeutic challenge for solid organ transplant recipients, particularly after lung transplant (LT). Our aim was to determine the impact of TB in LT patients in Spain, considering prevalence, clinical presentation, prevention and therapeutic management. In addition, differences in outcome between rifampicin (RIF) versus non-RIF containing regimens were analyzed.. Multicenter, observational retrospective study, including all cases of TB diagnosed in recipients after LT, in five pulmonary transplant units in Spain, between January 1990 and December 2017.. Among 2962 LT recipients, 45 cases of TB were diagnosed, resulting in a prevalence of 1.52%. Most of them (88.89%) were diagnosed during the first year posttransplantation, 86.67% with pulmonary presentation. Screening for latent TB infection (LTBI) was done in 36 of the 45 patients and LTBI was detected pretransplant in 12 (33.33%). Less than half of the patients with disease (42.22%) received rifampicin (RIF). Lower probability of TB worsening was found in RIF-containing regimens (p=0.049), as well as longer survival (p=0.001). RIF use was not associated with an increased risk in rejection (p=0.99), but doses of calcineurin inhibitors (CNI) had to be raised an average of 215%.. Risk of TB after LT was lower in our series than previously reported. TB should be searched during the first year posttransplant in patients with TB risk factors. Pulmonary presentation was predominant. More sensitive algorithms for detecting LTBI before LT are crucial. It is reasonable to use RIF-containing regimens over non-RIF regimens based on the tendency toward better outcome in our series. RIF regimen requires close monitoring of CNI trough level for 2-3 weeks, until stability is achieved.

    Topics: Humans; Incidence; Lung Transplantation; Retrospective Studies; Rifampin; Spain; Tuberculosis

2020
Clinical Characteristics of Active Tuberculosis Diagnosed After Starting Treatment for Latent Tuberculosis Infection.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020, 08-22, Volume: 71, Issue:5

    Although rare, subclinical tuberculosis disease can be missed during evaluations for latent tuberculosis infection, and can manifest with symptoms during latent tuberculosis treatment. Among over 8000 patients treated for latent tuberculosis we found no evidence of acquired drug resistance, underscoring the safety of rifampin monotherapy for latent tuberculosis.

    Topics: Antitubercular Agents; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Tuberculosis

2020
Rifampicin Can Be Given as Flat-Dosing Instead of Weight-Band Dosing.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020, 12-15, Volume: 71, Issue:12

    The weight-band dosing in tuberculosis treatment regimen has been implemented in clinical practice for decades. Patients will receive different number of fixed dose combination tablets according to their weight-band. However, some analysis has shown that weight was not the best covariate to explain variability of rifampicin exposure. Furthermore, the rationale for using weight-band dosing instead of flat-dosing becomes questionable. Therefore, this study aimed to compare the average and the variability of rifampicin exposure after weight-band dosing and flat-dosing.. Rifampicin exposure were simulated using previously published population pharmacokinetics model at dose 10-40 mg/kg for weight-band dosing and dose 600-2400 mg for flat-dosing. The median area under the curve (AUC0-24 h) after day 7 and 14 were compared as well as the variability of each dose group between weight-band and flat-dosing.. The difference of median AUC0-24 h of all dose groups between flat-dosing and weight-band dosing were considered low (< 20%) except for the lowest dose. At the dose of 10 mg/kg (600 mg for flat-dosing), flat-dosing resulted in higher median AUC0-24h compared to the weight-band dosing. A marginal decrease in between-patient variability was predicted for weight-band dosing compared to flat-dosing.. Weight-band dosing yields a small and non-clinically relevant decrease in variability of AUC0-24h.

    Topics: Body Weight; Dose-Response Relationship, Drug; Humans; Rifampin; Tablets; Tuberculosis

2020
Rapid and highly sensitive quantification of the anti-tuberculosis agents isoniazid, ethambutol, pyrazinamide, rifampicin and rifabutin in human plasma by UPLC-MS/MS.
    Journal of pharmaceutical and biomedical analysis, 2020, Feb-20, Volume: 180

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Calibration; Chromatography, High Pressure Liquid; Drug Monitoring; Ethambutol; Humans; Isoniazid; Pyrazinamide; Reference Standards; Reproducibility of Results; Rifabutin; Rifampin; Sensitivity and Specificity; Tandem Mass Spectrometry; Tuberculosis

2020
Aryl Hydrocarbon Receptor Modulation by Tuberculosis Drugs Impairs Host Defense and Treatment Outcomes.
    Cell host & microbe, 2020, 02-12, Volume: 27, Issue:2

    Antimicrobial resistance in tuberculosis (TB) is a public health threat of global dimension, worsened by increasing drug resistance. Host-directed therapy (HDT) is an emerging concept currently explored as an adjunct therapeutic strategy for TB. One potential host target is the ligand-activated transcription factor aryl hydrocarbon receptor (AhR), which binds TB virulence factors and controls antibacterial responses. Here, we demonstrate that in the context of therapy, the AhR binds several TB drugs, including front line drugs rifampicin (RIF) and rifabutin (RFB), resulting in altered host defense and drug metabolism. AhR sensing of TB drugs modulates host defense mechanisms, notably impairs phagocytosis, and increases TB drug metabolism. Targeting AhR in vivo with a small-molecule inhibitor increases RFB-treatment efficacy. Thus, the AhR markedly impacts TB outcome by affecting both host defense and drug metabolism. As a corollary, we propose the AhR as a potential target for HDT in TB in adjunct to canonical chemotherapy.

    Topics: Animals; Antitubercular Agents; Basic Helix-Loop-Helix Transcription Factors; Humans; Immunity, Cellular; Mycobacterium marinum; Mycobacterium tuberculosis; Phagocytosis; Receptors, Aryl Hydrocarbon; Rifabutin; Rifampin; THP-1 Cells; Treatment Outcome; Tuberculosis; Zebrafish

2020
Characteristics of compensatory mutations in the rpoC gene and their association with compensated transmission of Mycobacterium tuberculosis.
    Frontiers of medicine, 2020, Volume: 14, Issue:1

    The aim of this study was to characterize rpoC gene mutations in Mycobacterium tuberculosis (MTB) and investigate the factors associated with rpoC mutations and the relation between rpoC mutations and tuberculosis (TB) transmission. A total of 245 MTB clinical isolates from patients with TB in six provinces and two municipalities in China were characterized based on gene mutations through DNA sequencing of rpoC and rpoB genes, phenotyping via standard drug susceptibility testing, and genotypic profiling by mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing. Approximately 36.4% of the rifampin-resistant isolates harbored nonsynonymous mutations in the rpoC gene. Twenty-nine nonsynonymous single mutations and three double mutations were identified. The rpoC mutations at locus 483 (11.3%) were predominant, and the mutations at V483G, W484G, I491V, L516P, L566R, N698K, and A788E accounted for 54.5% of the total detected mutations. Fifteen new mutations in the rpoC gene were identified. Rifampin resistance and rpoB mutations at locus 531 were significantly associated with rpoC mutations. MIRU-VNTR genotype results indicated that 18.4% of the studied isolates were clustered, and the rpoC mutations were not significantly associated with MIRU-VNTR clusters. A large proportion of rpoC mutation was observed in the rifampicin-resistant MTB isolates. However, the findings of this study do not support the association of rpoC mutation with compensated transmissibility.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Proteins; China; DNA-Directed RNA Polymerases; Drug Resistance, Multiple, Bacterial; Female; Genotype; Humans; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Minisatellite Repeats; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sequence Analysis, DNA; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2020
Migrations do not modify Mycobacterium tuberculosis resistance rates: a 20-year retrospective study.
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2020, Volume: 39, Issue:6

    Tuberculosis (TB) caused by resistant strains is becoming a public health concern also in high-income countries. In Pavia province, Northern Italy, the prevalence of foreign-born has increased in recent years. Nevertheless, it is unclear if this has modified epidemiology and resistance patterns of Mycobacterium tuberculosis. We retrospectively collected data on all the Mycobacterium tuberculosis strains isolated by culture in the microbiology reference laboratory of the province of Pavia from 01/01/1998 to 31/12/2017. Overall, 919 patients were identified, 320 were foreign-born (34.8%). The proportion of cases due to foreign-born patients increased during the study period as did resistance to isoniazid (INH) (p = 0.01), while resistance to rifampicin (RIF) did not (p = 0.8). INH and RIF resistance were comparable among Italian and foreign-born patients (7.9% vs 9.7% for INH and 4% vs 5% for RIF, respectively). Twenty-height (3.05%) patients harboured MDR strains. Prevalence of MDR strains was not different between Italians and foreign-born patients (2.8% vs 3.4%, p = 0.6). During the study period the proportion of TB cases due to foreign-born patients and INH resistance increased. This increase was equal among Italian and foreign-born patients. Migrants in our area are not a driver of resistance to anti-mycobacterial drugs.

    Topics: Adult; Aged; Antitubercular Agents; Female; Humans; Isoniazid; Italy; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Prevalence; Retrospective Studies; Rifampin; Transients and Migrants; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
Genotypic characterization of 'inferred' rifampin mutations in GenoType MTBDRplus assay and its association with phenotypic susceptibility testing of Mycobacterium tuberculosis.
    Diagnostic microbiology and infectious disease, 2020, Volume: 96, Issue:4

    In GenoType MTBDRplus assay [line probe assay (LPA)], when Mycobacterium tuberculosis (M. tuberculosis) sample DNA fails to hybridize to at least 1 rpoB wild-type probe and any mutation probe, it is inferred as rifampin (RIF)-resistant. In this study, we sought to identify such 'inferred' mutations in M. tuberculosis isolates (n = 203) by rpoB gene sequencing and determined their association with phenotypic resistance. D516Y, H526N, L511P mutations were associated with both phenotypically sensitive (59%, n = 38/64) and resistant (23.7%, n = 33/139) antimicrobial susceptibility testing (AST) results, whereas S531W mutation was associated with only RIF-resistant isolates (33%, n = 46/139). These results demonstrated that, at standard drug concentrations, some 'inferred' mutations may be missed by RIF-AST (phenotypically sensitive). The use of LPA permits identification of these RIF-resistant isolates, and incorporation of additional mutation probes (e.g., S531W) could further increase LPA specificity. Further studies are needed to establish the significance of the type of 'inferred' mutation with clinical/treatment outcomes.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Phenotype; Rifampin; Sputum; Tuberculosis

2020
Determination of minimum bactericidal concentration, in single or combination drugs, against
    Future microbiology, 2020, Volume: 15

    Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Isoniazid; Levofloxacin; Linezolid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2020
Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.
    Nature medicine, 2020, Volume: 26, Issue:4

    Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure

    Topics: Adult; Animals; Antitubercular Agents; Biological Availability; Drug Therapy, Combination; Female; Humans; Lung; Male; Mycobacterium tuberculosis; Positron Emission Tomography Computed Tomography; Rabbits; Rifampin; Tissue Distribution; Tuberculosis; Tuberculosis, Pulmonary

2020
Antitubercular nanocarrier monotherapy: Study of In Vivo efficacy and pharmacokinetics for rifampicin.
    Journal of controlled release : official journal of the Controlled Release Society, 2020, 05-10, Volume: 321

    Tuberculosis represents a major global health problem for which improved approaches are needed to shorten the course of treatment and to combat the emergence of resistant strains. The development of effective and safe nanobead-based interventions can be particularly relevant for increasing the concentrations of antitubercular agents within the infected site and reducing the concentrations in the general circulation, thereby avoiding off-target toxic effects. In this work, rifampicin, a first-line antitubercular agent, was encapsulated into biocompatible and biodegradable polyester-based nanoparticles. In a well-established BALB/c mouse model of pulmonary tuberculosis, the nanoparticles provided improved pharmacokinetics and pharmacodynamics. The nanoparticles were well tolerated and much more efficient than an equivalent amount of free rifampicin.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Drug Carriers; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nanostructures; Rifampin; Tuberculosis

2020
Evaluation of the BD MAX™ MDR-TB assay in a real-world setting for the diagnosis of pulmonary and extra-pulmonary TB.
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2020, Volume: 39, Issue:7

    Tuberculosis in London occurs at a rate of 19 cases per 100,000 population, with a significant proportion diagnosed as extra-pulmonary infection. At Barts Health NHS Trust, our TB rates are much higher than the London average and approximately 60% cases are extra-pulmonary in nature. We evaluated the BD MAX™ MDR-TB assay as a molecular tool for rapid diagnosis of TB. One hundred twenty-eight specimens, encompassing pulmonary (70) and extra-pulmonary (58) infection, were tested using the BD MAX™ MDR-TB assay and compared with smear and liquid culture results, to determine PCR performance. The BD MAX™ MDR-TB assay was also compared with the Xpert MTB/RIF assay, where applicable. TB was successfully detected in 50/66 Mycobacterium tuberculosis culture positive specimens, with additional detections in 2 of the culture negative specimens. The BD MAX™ MDR-TB assay demonstrated higher sensitivity with the pulmonary samples (92%) compared with the extra-pulmonary samples (52%), although the performance with fluids and biopsies demonstrated greater potential than the remaining extra-pulmonary samples. Rifampicin and/or isoniazid resistance was successfully detected by the BD MAX™ in 2/3 samples, where WGS susceptibility results were available. The BD MAX™ MDR-TB assay was comparable with the performance of the Xpert MTB/RIF assay. TB can successfully be diagnosed, in both pulmonary and extra-pulmonary samples, using the BD MAX™ MDR-TB assay.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

2020
Translational Model-Informed Approach for Selection of Tuberculosis Drug Combination Regimens in Early Clinical Development.
    Clinical pharmacology and therapeutics, 2020, Volume: 108, Issue:2

    The development of optimal treatment regimens in tuberculosis (TB) remains challenging due to the need of combination therapy and possibility of pharmacodynamic (PD) interactions. Preclinical information about PD interactions needs to be used more optimally when designing early bactericidal activity (EBA) studies. In this work, we developed a translational approach which can allow for forward translation to predict efficacy of drug combination in EBA studies using the Multistate Tuberculosis Pharmacometric (MTP) and the General Pharmacodynamic Interaction (GPDI) models informed by in vitro static time-kill data. These models were linked with translational factors to account for differences between the in vitro system and humans. Our translational MTP-GPDI model approach was able to predict the EBA

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Bacterial Load; Clinical Trials, Phase II as Topic; Drug Development; Drug Dosage Calculations; Drug Therapy, Combination; Humans; Isoniazid; Microbial Sensitivity Tests; Models, Biological; Mycobacterium tuberculosis; Rifampin; Translational Research, Biomedical; Tuberculosis

2020
Isolation and Immunological Detection of
    Ethiopian journal of health sciences, 2020, Volume: 30, Issue:1

    Immunological techniques are important tools for tuberculosis epidemiology; although its use is underutilized in Nigeria. In this study, we report the epidemiological outlook of Mycobacterium tuberculosis among HIV patients in Benue State, Nigeria.. Sputum samples were collected from 425 suspected TB patients from July 2016 to February 2018 and subjected to acid-fast microscopy, GeneXpert MTB/RIF, processed using NALC-NaOH and cultured on Lowenstein-Jensen media. The isolates obtained were identified by SD-Bioline® assay.. The prevalence of TB by acid-fast microscopy was 35(15.9%). The prevalence of TB by acid-fast bacilli was significantly (χ. The study revealed that Mycobacterium tuberculosis infection is still a major public health problem, with relatively high prevalence rate of rifampicin resistance among HIV positive patients. Further studies are needed for early detection and treatment intervention necessary for infection control.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Case-Control Studies; Child; Child, Preschool; Coinfection; Drug Resistance, Bacterial; Female; HIV; HIV Infections; Humans; Infant; Infant, Newborn; Male; Middle Aged; Mycobacterium tuberculosis; Nigeria; Rifampin; Tuberculosis; Young Adult

2020
High-Dose First-Line Treatment Regimen for Recurrent Rifampicin-Susceptible Tuberculosis.
    American journal of respiratory and critical care medicine, 2020, 06-15, Volume: 201, Issue:12

    Topics: Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
Reply to Decroo
    American journal of respiratory and critical care medicine, 2020, 06-15, Volume: 201, Issue:12

    Topics: Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
Drug-Induced Liver Injury from Anti-Tuberculosis Treatment: A Retrospective Cohort Study.
    Medical science monitor : international medical journal of experimental and clinical research, 2020, Mar-07, Volume: 26

    BACKGROUND The aim of this study was to investigate the clinical characteristics and the risk factors associated with anti-tuberculosis (anti-TB) drug-induced liver injury (DILI). MATERIAL AND METHODS This retrospective study enrolled 140 hospitalized patients diagnosed with anti-TB DILI during January 2009 to December 2015. We assessed the baseline characteristics and performed regular follow-up up to the 24th week to assess the possible risk factors associated with the condition. RESULTS The study population was 58.6% male and 41.4% female patients; 20.7% were diagnosed with grades 4-5 DILI and 79.3% with grades 1-3 DILI. Female patients were significantly more likely to be diagnosed with grades 4-5 DILI than with grades 1-3 DILI (58.6% vs. 36.9%, p=0.036). Patients treated with a multidrug anti-TB regimen were more commonly affected with grades 4-5 DILI (86.2% vs. 68.5%, p=0.045). A significant number of patients who reinitiated anti-TB therapy suffered severe liver injury in comparison to patients with grades 1-3 DILI (41.4% vs. 10.8%, P<.001). Laboratory examinations revealed significantly higher values for total bilirubin (TBL), International normalized ratio (INR), and Hy's law (P<.001) in the grades 4-5 group compare to the grades 1-3 group. CONCLUSIONS Female gender, combination therapy for antitubercular drugs (isoniazid, rifampicin and pyrazinamide), re-challenge were the risk factors associated with the severity of anti-TB DILI.

    Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors; Tuberculosis; Young Adult

2020
Effect of Xpert MTB/RIF testing introduction and favorable outcome predictors for tuberculosis treatment among HIV infected adults in rural southern Mozambique. A retrospective cohort study.
    PloS one, 2020, Volume: 15, Issue:3

    Global roll out of Xpert MTB/RIF technology has resulted in dramatic changes in TB diagnosis. However, benefits in resource-limited, high-burden TB/HIV settings, remain to be verified. In this paper we describe the characteristics of a large cohort of TB patients in a rural hospital in Southern Mozambique before and after Xpert MTB/RIF introduction, together with some determinants of favorable treatment outcome.. We conducted a retrospective cohort study of TB infected patients ≥15 years of age, diagnosed and treated at Carmelo Hospital of Chókwè between January 1, 2006 and December 31, 2017. Patient demographic and clinical characteristics, and treatment outcomes were recorded and compared before and after Xpert MTB/RIF, which was introduced in the second semester of 2012.. 9,655 patients were analyzed, with 44.1% females. HIV testing was conducted in 99.9% of patients, with 82.8% having TB/HIV co-infection. 73.2% of patients had a favorable treatment outcome. No increase was observed in the number of TB patients identified after introduction of Xpert MTB/RIF testing.. Upon introduction, Xpert testing seemed to have a punctual beneficial effect on TB treatment outcomes, however this effect apparently disappeared shortly afterwards. Challenges remain for integration of TB and HIV care, as worse outcomes are reported for those patients diagnosed with TB shortly after starting ART, and also for those never starting ART. The need of reasonably excluding TB disease before ART start should be highlighted to every health care provider engaged in HIV care.

    Topics: Adolescent; Adult; Aged; Female; HIV Infections; Humans; Male; Middle Aged; Mozambique; Retrospective Studies; Rifampin; Rural Population; Survival Analysis; Treatment Outcome; Tuberculosis; Young Adult

2020
Cost-effectiveness of IGRA/QFT-Plus for TB screening of migrants in Oman.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2020, Volume: 92S

    To estimate the cost of a screening program for identifying latent tuberculosis (TB) infections in migrants to Oman.. A Markov model was used to estimate the cost of screening using an interferon-gamma release assay (IGRA) applied to all migrants from high TB endemic countries, followed by preventive TB treatment.. The model compared seven different scenarios, with a comparison of the direct cost and the quality-adjusted life-years (QALYs) saved.. IGRA testing followed by 3 months of preventive treatment with rifapentine/isoniazid (3HP) was the most cost-effective intervention.

    Topics: Cost-Benefit Analysis; Female; Humans; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Markov Chains; Mass Screening; Oman; Quality-Adjusted Life Years; Rifampin; Transients and Migrants; Tuberculosis

2020
Evolving therapies for rifampicin-resistant tuberculosis: balancing efficacy and toxicity.
    The Lancet. Respiratory medicine, 2020, Volume: 8, Issue:4

    Topics: Cohort Studies; HIV Infections; Humans; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
Dosing of Dolutegravir in TB/HIV Coinfected Patients on Rifampicin: Twice Is (Always) Better Than Once.
    Journal of acquired immune deficiency syndromes (1999), 2020, 07-01, Volume: 84, Issue:3

    Topics: Adult; Aged; Coinfection; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Rifampin; Tuberculosis

2020
The potential deployment of a pan-tuberculosis drug regimen in India: A modelling analysis.
    PloS one, 2020, Volume: 15, Issue:3

    There is increasing interest in future, highly-potent 'pan-TB' regimens against tuberculosis (TB), that may be equally effective in both drug-susceptible and rifampicin-resistant (RR) forms of TB. Taking the example of India, the country with the world's largest burden of TB, we show that adoption of these regimens could be: (i) epidemiologically impactful, and (ii) cost-saving to the national TB programme, even if the regimen itself is more costly than current TB treatment. Mathematical modelling suggests that deployment of a pan-TB regimen in 2022 would reduce the annual incidence of TB in 2030 by 23.9% [95% Bayesian credible intervals [CrI] 17.6-30.8%] if used to treat all TB cases, and by 2.30% [95% CrI 1.57-3.48%] if used to treat only RR-TB. Notably, with a regimen costing less than USD 359 (95% CrI 287-441), treating all diagnosed TB cases with the pan-TB regimen yielded greater cost-savings than treating just those diagnosed with RR-TB. One limitation of our approach is that it does not capture the risk of resistance to the new regimen. We discuss ways in which this risk could be mitigated using modern adherence support mechanisms, as well as drug sensitivity testing at the point of TB diagnosis, to prevent new resistant forms from becoming established. A combination of such approaches would be important for maximising the useful lifetime of any future regimen.

    Topics: Antitubercular Agents; Drug Discovery; Humans; India; Models, Statistical; Rifampin; Tuberculosis

2020
Prevention of tuberculosis in HIV infection with novel drugs.
    The lancet. HIV, 2020, Volume: 7, Issue:6

    Topics: Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Isoniazid; Oxazines; Piperazines; Pyridones; Rifampin; Tuberculosis

2020
Association of ABO blood group and antituberculosis drug-induced liver injury: A case-control study from a Chinese Han population.
    Journal of clinical pharmacy and therapeutics, 2020, Volume: 45, Issue:4

    Antituberculosis drug-induced liver injury (ATLI) is a serious adverse drug reaction, and its pathogenic mechanism is still largely unknown. Rifampin (RIF) has been reported to cause haemolysis due to the production of drug-dependent antibodies, and haemolysis results in an increased level of free haem, which affects the function of hepatocytes. Blood group determinants can act as specific receptor sites for drug-antibody complexes, causing erythrocyte destruction in the presence of RIF. RIF-induced immune haemolysis may be a potential mechanism for ATLI. Thus, the study aimed to explore the role of ABO blood group systems in Chinese ATLI patients.. A 1:4 matched case-control study was conducted among 146 ATLI cases and 584 controls. Multivariable conditional logistic regression and Cox proportional regression were used to estimate the association between ABO blood group and risk of ATLI by odds ratio (OR), hazards ratio (HR) and 95% confidence intervals (CIs), and liver disease history and taking hepatoprotectant were used as covariates.. Patients in the A, B, AB and non-O blood groups had a significantly higher risk of ATLI than those in the O blood group (OR = 1.832, 95% CI: 1.126-2.983, P = .015; OR = 1.751, 95% CI: 1.044-2.937, P = .034; OR = 2.059, 95% CI: 1.077-3.938, P = .029; OR = 1.822, 95% CI: 1.173-2.831, P = .007, respectively). After considering the time of ALTI occurrence, similar results were found in the A, B, AB and non-O blood groups (HR = 1.676, 95% CI: 1.072-2.620, P = .024; HR = 1.620, 95% CI: 1.016-2.584, P = .043; HR = 2.010, 95% CI: 1.130-3.576, P = .018; HR = 1.701, 95% CI: 1.138-2.542, P = .010, respectively). Furthermore, subgroup analysis also detected a significant association between ABO blood group and ATLI in patients taking RIF (P < .05). However, no significant difference was observed in patients not taking RIF (P > .05).. The present study is the first to evaluate the role of ABO blood group systems in Chinese ATLI cases. Based on the present matched case-control study, the ABO blood group may be associated with susceptibility to ATLI in the Chinese antituberculosis population, especially in patients with blood groups A, B and AB who are taking RIF.

    Topics: ABO Blood-Group System; Antitubercular Agents; Asian People; Case-Control Studies; Chemical and Drug Induced Liver Injury; Female; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis

2020
Accuracy of a reverse dot blot hybridization assay for simultaneous detection of the resistance of four anti-tuberculosis drugs in Mycobacterium tuberculosis isolated from China.
    Infectious diseases of poverty, 2020, Apr-16, Volume: 9, Issue:1

    Drug resistant tuberculosis poses a great challenge for tuberculosis control worldwide. Timely determination of drug resistance and effective individual treatment are essential for blocking the transmission of drug resistant Mycobacterium tuberculosis. We aimed to establish and evaluate the accuracy of a reverse dot blot hybridization (RDBH) assay to simultaneously detect the resistance of four anti-tuberculosis drugs in M. tuberculosis isolated in China.. In this study, we applied a RDBH assay to simultaneously detect the resistance of rifampicin (RIF), isoniazid (INH), streptomycin (SM) and ethambutol (EMB) in 320 clinical M. tuberculosis isolates and compared the results to that from phenotypic drug susceptibility testing (DST) and sequencing. The RDBH assay was designed to test up to 42 samples at a time. Pearson's chi-square test was used to compute the statistical measures of the RDBH assay using the phenotypic DST or sequencing as the gold standard method, and Kappa identity test was used to determine the consistency between the RDBH assay and the phenotypic DST or sequencing.. The results showed that the concordances between phenotypic DST and RDBH assay were 95% for RIF, 92.8% for INH, 84.7% for SM, 77.2% for EMB and the concordances between sequencing and RDBH assay were 97.8% for RIF, 98.8% for INH, 99.1% for SM, 93.4% for EMB. Compared to the phenotypic DST results, the sensitivity and specificity of the RDBH assay for resistance detection were 92.4 and 98.5% for RIF, 90.3 and 97.3% for INH, 77.4 and 91.5% for SM, 61.4 and 85.7% for EMB, respectively; compared to sequencing, the sensitivity and specificity of the RDBH assay were 97.7 and 97.9% for RIF, 97.9 and 100.0% for INH, 97.8 and 100.0% for SM, 82.6 and 99.1% for EMB, respectively. The turnaround time of the RDBH assay was 7 h for testing 42 samples.. Our data suggested that the RDBH assay could serve as a rapid and efficient method for testing the resistance of M. tuberculosis against RIF, INH, SM and EMB, enabling early administration of appropriate treatment regimens to the affected drug resistant tuberculosis patients.

    Topics: Antitubercular Agents; China; Drug Resistance, Bacterial; Ethambutol; Humans; Immunoblotting; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Streptomycin; Tuberculosis

2020
Decision making to discharge patients from airborne infection isolation rooms: The role of a single GeneXpert MTB/RIF strategy in Brazil.
    Infection control and hospital epidemiology, 2020, Volume: 41, Issue:7

    Tuberculosis (TB) transmission in healthcare facilities is still a concern in low-income countries, where airborne isolation rooms are scarce due to high costs. We evaluated the use of single GeneXpert MTB/RIF, the molecular Mycobacterium tuberculosis (MTB) DNA and resistance to rifampicin (RIF) test, as an accurate and faster alternative to the current criteria of 3 negative acid-fast bacilli (AFB) smears to remove patients from airborne isolation.. In this real-world investigation, we evaluated the impact of a single GeneXpert MTB/RIF on the decision making for discharging patients from respiratory isolation. We enrolled patients with suspected pulmonary TB in a public hospital that provides care for high-complexity patients in Brazil. We studied the performance, costs, and time saved comparing the GeneXpert MTB/RIF with AFB smears.. We enrolled 644 patients in 3 groups based on the number of AFB smears performed (1, 2, and 3, respectively) on respiratory specimens. GeneXpert MTB/RIF demonstrated good performance compared to AFB smear to rule out TB in all groups. The negative predictive value for AFB smear was 94% (95% confidence interval [CI], 0.90-0.97) and 98% (95% CIs, 0.94-0.99) for GeneXpert MTB/RIF in G3. The isolation discharge based on 3 AFB smears took 84 hours compared to 24 hours with GeneXpert MTB/RIF, which represents 560 patient-days saved in the isolation rooms.. A single GeneXpert MTB/RIF is a fast and strong predictor for TB absence in a high-complexity hospital, which is quite similar to results obtained in recent studies in low-burden settings. This molecular test may also increase patient rotation through isolation rooms, with a positive impact in the emergency room and infectious diseases wards.

    Topics: Brazil; Clinical Decision-Making; Cross Infection; Humans; Mycobacterium tuberculosis; Patient Discharge; Patient Isolation; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2020
Use of whole-genome sequencing to predict Mycobacterium tuberculosis drug resistance in Shanghai, China.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2020, Volume: 96

    To evaluate the performance of whole-genome sequencing (WGS) for predicting Mycobacterium tuberculosis (MTB) drug resistance.. 276 rifampin-resistance tuberculosis (RR-TB) and 30 rifampicin-sensitive clinical isolates were randomly selected from patients with tuberculosis in Shanghai Pulmonary Hospital (SPH). Phenotypic drug susceptibility testing (DST) against six anti-TB drugs was performed, and WGS was used to predict the drug resistance using an online 'TB-Profiler' tool.. Using phenotypic susceptibility as the gold standard, the overall sensitivities and specificities for WGS were 94.53% and 92.00% for isoniazid, 97.10% and 100.00% for rifampicin, 97.46% and 64.36% for ethambutol, 97.14% and 95.83% or streptomycin, 93.02% and 98.87% for ofloxacin, and 75.00% and 100.00% for amikacin, respectively. The concordances of WGS-based DST and phenotypic DST were: isoniazid (94.12%), rifampicin (97.39%), ethambutol (77.12%), streptomycin (96.73%), ofloxacin (96.41%) and amikacin (97.06%).. WGS could be a promising approach to predict resistance to isoniazid, rifampicin, ethambutol, streptomycin, ofloxacin, and amikacin.

    Topics: Adult; Amikacin; Antitubercular Agents; China; Drug Resistance, Bacterial; Ethambutol; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Ofloxacin; Rifampin; Streptomycin; Tuberculosis; Whole Genome Sequencing

2020
Dose optimisation of first-line tuberculosis drugs using therapeutic drug monitoring in saliva: feasible for rifampicin, not for isoniazid.
    The European respiratory journal, 2020, Volume: 56, Issue:4

    Topics: Antitubercular Agents; Drug Monitoring; Humans; Isoniazid; Mycobacterium tuberculosis; Pharmaceutical Preparations; Rifampin; Saliva; Tuberculosis

2020
No significant influence of diabetic mellitus on isoniazid plasma levels in patients under treatment for tuberculosis.
    Infectious diseases (London, England), 2020, Volume: 52, Issue:8

    Topics: Antitubercular Agents; Diabetes Mellitus; Humans; Isoniazid; Patients; Plasma; Rifampin; Tuberculosis

2020
Targeted Theranostics for Tuberculosis: A Rifampicin-Loaded Aggregation-Induced Emission Carrier for Granulomas Tracking and Anti-Infection.
    ACS nano, 2020, 07-28, Volume: 14, Issue:7

    Tuberculosis (TB) causes a global burden with its high rates of infection and death, especially the irrepressible threats of latent infection and drug resistance. Therefore, it is important to construct efficient theranostics for the prevention and control of TB. Herein, we created a targeted theranostic strategy for TB with a rifampicin-loaded aggregation-induced emission (AIE) carrier and performed testing in laboratory animals. The AIE carrier was constructed to localize in the granulomas and emit fluorescent signals at the early stage of infection, enabling the early diagnosis of TB. Subsequently, reactive oxygen species (ROS) were generated to eradicate infection, and the loaded rifampicin (RIF) was released for the synergistic treatment of persistent bacteria. Furthermore, targeted TB therapy was performed with the light-controlled release of ROS and accurate delivery of RIF, which realizes an anti-infection effect, providing an especially important treatment for drug-resistant TB. Thus, targeted theranostics for TB in laboratory animals possess the potential to become granulomas-tracking and anti-infection strategies for the diagnosis and treatment of TB.

    Topics: Animals; Granuloma; Mycobacterium tuberculosis; Precision Medicine; Rifampin; Tuberculosis

2020
The risk of multidrug- or rifampicin-resistance in males
    The European respiratory journal, 2020, Volume: 56, Issue:3

    Males are at an increased risk of tuberculosis (TB) disease compared to females. Additionally, several risk factors for multidrug-resistant (MDR) or rifampicin-resistant (RR) TB disease are more common in males, hence male TB patients may have a higher relative risk of MDR/RR-TB than female TB patients.We used sex-disaggregated data of TB patients reported to the World Health Organization for 106 countries to calculate male-to-female (M:F) risk ratios of having MDR/RR-TB.There was no evidence of either sex being more at risk of MDR/RR-TB in 81% (86 out of 106) of countries, with an overall random-effects weighted M:F risk ratio of 1.04 (95% CI 0.97-1.11). In 12% (13 out of 106) of countries there was evidence that males were more at risk, while in 7% (seven out of 106), females were more at risk. The risk of having TB that was MDR/RR increased for males compared to females as MDR/RR-TB incidence increased, and was higher for males than females in the former Soviet Union, where the risk ratio was 1.16 (1.06-1.28). Conversely, the risk increased for females compared to males as gross domestic product purchase power parity increased, and was higher for females than males in countries where the majority of TB burden was found in the foreign-born population, where the risk ratio was 0.84 (0.75-0.94).In general, the risk of MDR/RR-TB, among those with TB, is the same for males as for females. However, males in higher MDR/RR-TB burden countries, particularly the former Soviet Union, face an increased risk that their infection is MDR/RR-TB, highlighting the need for a sex-differentiated approach to TB case-finding and care.

    Topics: Antitubercular Agents; Female; Humans; Male; Mycobacterium tuberculosis; Odds Ratio; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; World Health Organization

2020
Twice-Daily vs. Once-Daily Dolutegravir in Patients With Human Immunodeficiency Virus-Tuberculosis Coinfection Receiving Rifampicin-Based Tuberculosis Therapy.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020, 06-24, Volume: 71, Issue:1

    Topics: Coinfection; Heterocyclic Compounds, 3-Ring; HIV; HIV Infections; Humans; Oxazines; Pharmacology, Clinical; Piperazines; Pyridones; Rifampin; Tuberculosis

2020
Clinically relevant mutations in mycobacterial LepA cause rifampicin-specific phenotypic resistance.
    Scientific reports, 2020, 05-21, Volume: 10, Issue:1

    Although all wild-type bacterial populations exhibit antibiotic tolerance, bacterial mutants with higher or lower tolerant subpopulation sizes have been described. We recently showed that in mycobacteria, phenotypically-resistant subpopulations can grow in bulk-lethal concentrations of rifampicin, a first-line anti-tuberculous antibiotic targeting RNA polymerase. Phenotypic resistance was partly mediated by paradoxical upregulation of RNA polymerase in response to rifampicin. However, naturally occurring mutations that increase tolerance via this mechanism had not been previously described. Here, we used transposon insertional mutagenesis and deep sequencing (Tnseq) to investigate rifampicin-specific phenotypic resistance using two different in vitro models of rifampicin tolerance in Mycobacterium smegmatis. We identify multiple genetic factors that mediate susceptibility to rifampicin. Disruption of one gene, lepA, a translation-associated elongation factor, increased rifampicin tolerance in all experimental conditions. Deletion of lepA increased the subpopulation size that is able to grow in bulk-lethal rifampicin concentrations via upregulation of basal rpoB expression. Moreover, homologous mutations in lepA that are found in clinical Mycobacterium tuberculosis (Mtb) isolates phenocopy lepA deletion to varying degrees. Our study identifies multiple genetic factors associated with rifampicin tolerance in mycobacteria, and may allow correlation of genetic diversity of clinical Mtb isolates with clinically important phenotypes such as treatment regimen duration.

    Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Humans; Mutagenesis; Mutation; Mycobacterium smegmatis; Peptide Initiation Factors; Phenotype; Rifampin; Tuberculosis

2020
Severe Rifampicin-induced Vitamin K Deficiency Coagulopathy in a Child.
    The Pediatric infectious disease journal, 2020, Volume: 39, Issue:9

    An 8-month-old child under tuberculosis treatment presented with multiple ecchymotic lesions. A severe coagulopathy was evidenced compatible with vitamin K deficiency [II (3%), VII (2%), IX (3%) and X (1%)]. It was reversed with vitamin K and plasma administration. Rifampicin-induced vitamin K deficiency is very rare, reported only once before, possibly related to an inhibition of vitamin K cycle.

    Topics: Antibiotics, Antitubercular; Blood Coagulation Disorders; Child; Humans; Infant; Male; Plasma; Rifampin; Treatment Outcome; Tuberculosis; Vitamin K; Vitamin K Deficiency

2020
Identification of Substituted Amino Acid Hydrazides as Novel Anti-Tubercular Agents, Using a Scaffold Hopping Approach.
    Molecules (Basel, Switzerland), 2020, May-21, Volume: 25, Issue:10

    Discovery and development of new therapeutic options for the treatment of

    Topics: Amino Acid Substitution; Antitubercular Agents; Cell Proliferation; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Organic Chemicals; Rifampin; Structure-Activity Relationship; Tuberculosis

2020
Tuberculosis sepsis after tocilizumab treatment.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2020, Volume: 26, Issue:11

    Topics: Antibodies, Monoclonal, Humanized; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Middle Aged; Multiple Organ Failure; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Sepsis; Treatment Outcome; Tuberculosis

2020
Ocular adverse events in drug sensitive TB patients on daily fixed dose combination anti-TB drugs: A record review study from Kerala, India.
    The Indian journal of tuberculosis, 2020, Volume: 67, Issue:2

    Government of India's Revised National TB Control Programme (RNTCP) has begun implementing daily fixed dose combination (FDC) anti-TB treatment regimen for drug sensitive TB patients in which ethambutol is given for six months. Prolonged ethambutol use is known to cause ocular adverse drug events (ADE).. To assess the magnitude of ocular ADEs in adult drug sensitive TB patients initiated on daily FDCs and to describe the demographic and clinical profile of patients with ocular ADEs.. We conducted a retrospective cohort study involving review of RNTCP records of all adult (age >14 years) drug sensitive TB patients initiated on daily FDCs between1. 714 patients were initiated on daily FDCs during the study period. It was unknown whether all patients had undergone assessment for ocular ADEs. However, of these 714 patients, 8 patients (1.1%) were documented to have had ocular ADEs. Seven of these 8 patients had received ethambutol more than 15 mg/kg body weight and had developed ocular symptoms (decreased/blurring of vision) 3 months after TB treatment initiation. Ethambutol was stopped in all these 8 patients. In 5 patients it was recorded that ocular ADEs had resolved following stoppage of ethambutol and in the remaining it was unknown.. The study confirms the occurrence of ocular ADEs among drug sensitive TB patients on daily FDCs and recommends strengthening of systems for assessing, documenting and managing ocular ADE.

    Topics: Adult; Aged; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Combinations; Ethambutol; Eye Diseases; Female; Humans; India; Isoniazid; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Tuberculosis; Vision Disorders

2020
Human mesenchymal stem cell based intracellular dormancy model of Mycobacterium tuberculosis.
    Microbes and infection, 2020, Volume: 22, Issue:9

    Understanding the biology of the tuberculosis pathogen during dormant asymptomatic infection, called latent tuberculosis is crucial to decipher a resilient therapeutic strategy for the disease. Recent discoveries exhibiting presence of pathogen's DNA and bacilli in mesenchymal stem cells (MSCs) of human and mouse despite completion of antitubercular therapy, indicates that these specific cells could be one of the niches for dormant Mycobacterium tuberculosis in humans. To determine if in vitro infection of human MSCs could recapitulate the in vivo characteristics of dormant M. tuberculosis, we examined survival, phenotype, and drug susceptibility of the pathogen in MSCs. When a very low multiplicity of infection (1:1) was used, M. tuberculosis could survive in human bone marrow derived MSCs for more than 22 days without any growth. At this low level of infection, the pathogen did not cause any noticeable host cell death. During the later phase of infection, MSC-residing M. tuberculosis exhibited increased expression of HspX (a 16-kDa alpha-crystallin homolog) with a concurrent increase in tolerance to the frontline antitubercular drugs Rifampin and isoniazid. These results present a human MSC-based intracelllular model of M. tuberculosis infection to dissect the mechanisms through which the pathogen acquires and maintains dormancy in the host.

    Topics: Animals; Anti-Infective Agents; Antigens, Bacterial; Antitubercular Agents; Bacterial Proteins; Bone Marrow; Cell Survival; Drug Tolerance; Host-Pathogen Interactions; Humans; Isoniazid; Latent Tuberculosis; Mesenchymal Stem Cells; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenotype; Rifampin; Tuberculosis

2020
Potentiation of rifampin activity in a mouse model of tuberculosis by activation of host transcription factor EB.
    PLoS pathogens, 2020, Volume: 16, Issue:6

    Efforts at host-directed therapy of tuberculosis have produced little control of the disease in experimental animals to date. This is not surprising, given that few specific host targets have been validated, and reciprocally, many of the compounds tested potentially impact multiple targets with both beneficial and detrimental consequences. This puts a premium on identifying appropriate molecular targets and subjecting them to more selective modulation. We discovered an aminopyrimidine small molecule, 2062, that had no direct antimycobacterial activity, but synergized with rifampin to reduce bacterial burden in Mtb infected macrophages and mice and also dampened lung immunopathology. We used 2062 and its inactive congeners as tool compounds to identify host targets. By biochemical, pharmacologic, transcriptomic and genetic approaches, we found that 2062's beneficial effects on Mtb control and clearance in macrophages and in mice are associated with activation of transcription factor EB via an organellar stress response. 2062-dependent TFEB activation led to improved autophagy, lysosomal acidification and lysosomal degradation, promoting bacterial clearance in macrophages. Deletion of TFEB resulted in the loss of IFNγ-dependent control of Mtb replication in macrophages. 2062 also targeted multiple kinases, such as PIKfyve, VPS34, JAKs and Tyk2, whose inhibition likely limited 2062's efficacy in vivo. These findings support a search for selective activators of TFEB for HDT of TB.

    Topics: Animals; Antitubercular Agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Disease Models, Animal; Female; Mice; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2020
Factors associated with catastrophic total costs due to tuberculosis under a designated hospital service model: a cross-sectional study in China.
    BMC public health, 2020, Jun-26, Volume: 20, Issue:1

    Certain districts and counties in China designated local general hospital as the designated hospital for tuberculosis (TB) management after the promulgation of the Law of Practicing Physicians in 2009. To our knowledge, there is limited research on catastrophic payments of TB patients under this service model, often with inconsistent conclusions. In addition, there has been no published studies from China using the updated 2018 World Health Organization (WHO) definition of catastrophic total costs due to TB. This study used the latest criterion recommended by the WHO to analyze the incidence of catastrophic total costs for households affected by TB under the designated hospital model and explore its influencing factors.. A cross-sectional analysis was carried out in all ten designated hospitals in Ningbo, China. Eligible pulmonary TB cases confirmed by sputum culture of Mycobacterium tuberculosis were recruited and surveyed from September 2018 to October 2018. We evaluated catastrophic total costs using total costs for TB treatment exceeding 20% of the household's annual pre-TB income. A sensitivity analysis was performed while varying the thresholds. The least absolute shrinkage and selection operator (LASSO) regression were applied to select variables, and multiple logistic regression analysis were used to identify the determinants of catastrophic total costs.. A total of 672 patients were included, with a median age of 41 years old. The rate of catastrophic total costs of surveyed households was 37.1%, and that of households affected by MDR was 69.6%. Medical cost accounted for more than 60% of the total cost. 57.7% cases were hospitalized. The hospitalization rates of patients with no comorbidities, no severe adverse drug reactions, and rifampin-sensitive TB were 53.9, 54.9, and 55.3%, respectively. Patients in the poorest households had the highest hospitalization rates (Q1:54.8%, Q2:61.4%, Q3:52.2%, Q4:49.5%, Q5:69.7%, P = 0.011) and the highest incidence of severe adverse drug reactions (Q1:29.6%, Q2:19.6%, Q3:28.0%, Q4:33.7%, Q5:35.3%, P = 0.034). Factors such as elderly, minimum living security, unemployed before or after illness, poor economic status, seeking medical care outside the city, hospitalization, absence of local basic medical insurance coverage and MDR were positively associated with catastrophic costs.. Substantial proportions of patients and households affected by pulmonary TB faced catastrophic economic risks in Ningbo, China. The existing policies that focus on expanding the coverage of basic medical insurance and economic protection measures (such as cash transfers to compensate low-income households for direct non-medical costs and income loss) might be insufficient. Tailored program that mitigate inappropriate healthcare and address equity of care delivery are worthy of attention.

    Topics: Adult; Aged; Antibiotics, Antitubercular; Catastrophic Illness; China; Cost of Illness; Cross-Sectional Studies; Family Characteristics; Female; Health Care Costs; Hospitalization; Humans; Incidence; Income; Male; Middle Aged; Rifampin; Socioeconomic Factors; Tuberculosis

2020
Evaluation of Xpert MTB/RIF for the Diagnosis of Lymphatic Tuberculosis.
    BioMed research international, 2020, Volume: 2020

    We searched four databases for the relevant literature published from May 2007 to December 2019. The quality of the literature was evaluated with reference to the evaluation criteria. Data that were extracted from the literature on Xpert MTB/RIF diagnosis of lymphatic tuberculosis were used to plot the summary receiver operating characteristic (SROC) curve, after which the software was used to combine and analyze the accuracy of these data.. A total of 27 studies were included. The sensitivity of Xpert MTB/RIF for detecting lymphatic tuberculosis was 0.79 (95% CI (0.77, 0.81)), the specificity was 0.88 (95% CI (0.87, 0.90)), and the positive likelihood ratio (PLR) was 7.21 (95% CI (4.93, 10.55)). In addition, the negative likelihood ratio (NLR) was 0.25 (95% CI (0.19, 0.32)) and the diagnostic odds ratio (DOR) was 40.23 (95% CI (24.53, 65.98)). At the same time, we used the extracted data to make the SROC curve, obtaining the following parameters: area under the curve (AUC) = 0.9144,. Xpert MTB/RIF has high accuracy in detecting lymphatic tuberculosis, and it can be used to quickly and easily diagnose lymphatic tuberculosis at an early stage as a general method.

    Topics: Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Publication Bias; Rifampin; ROC Curve; Tuberculosis

2020
Primary breast tuberculosis in an HIV-infected patient.
    International journal of STD & AIDS, 2020, Volume: 31, Issue:9

    The presentation of tuberculosis can be nonspecific and atypical in patients with human immunodeficiency virus infection, especially in the extrapulmonary forms. The incidence of breast tuberculosis is very low. We report a case of primary breast tuberculosis: a 26-year-old woman with a 5-month history of a left-sided breast lump associated with pain. Biopsy of the breast lump for histological examination suggested granulomatous inflammation, secretions tested with GeneXpert for

    Topics: Adult; Antitubercular Agents; Biopsy; Breast; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2020
Prevalence and management of tuberculosis among people who use drugs in Abidjan, Ivory Coast.
    The International journal on drug policy, 2020, Volume: 83

    Background Although people who use drugs (PWUD) are a high-risk group for tuberculosis (TB), there is practically no data on TB prevalence in Ivory Coast. The aim of the study was to estimate pulmonary TB prevalence and assess the cascade of care with confirmed pulmonary TB (TB+) among PWUD in Abidjan. Methods The study targeted adult people who had used heroin and/or cocaine/crack in the previous six months. A first part consisted in a cross-sectional prevalence estimation survey using mobile facility testing in smoking spots. A multivariable logistic regression was performed to determine the factors associated with TB infection. In a second part, all participants who tested positive for pulmonary TB were offered follow-up for the duration of their treatment and invited to participate in a community-based support program (e.g. family mediation visits or self-support groups). Results Between October 2016 and May 2017, 545 PWUD were informed about the survey and 532 agreed to participate. Most of them were male (n = 484; 91.0%) single (n = 434; 81.6%), with an average age of 34.9 (SD 8.3) years. Drugs most commonly consumed were heroin and crack (n = 530; 99.6% and n = 353; 66.4% respectively) and were inhaled (i.e. smoked). Out of the 531 participants with an Xpert MTB/RIF® test result, 52 were diagnosed with pulmonary TB, i.e. a prevalence of 9.8%, 95% CI [7.5%-12.7%]. Among them, 17.3% had rifampicin-resistant TB. Factors significantly associated with TB infection in the multivariable analysis were: having been recruited in Treichville smoking spot (OR=2.0 [1.1 - 3.7]; p = 0.03), being unemployed (OR = 1.8 [1.0 - 3.4]; p = 0.05), and being co-infected with HIV (OR=3.3 [1.2 - 8.1]; p = 0.01); 60.0% of the patients were successfully treated. Conclusion TB prevalence among the PWUD is high. The community-based support model enables good treatment efficacy among this usually hard-to-reach population.

    Topics: Adult; Cote d'Ivoire; Cross-Sectional Studies; Drug Resistance, Bacterial; Humans; Male; Mycobacterium tuberculosis; Pharmaceutical Preparations; Prevalence; Rifampin; Tuberculosis

2020
Correlation of drug resistance with single nucleotide variations through genome analysis and experimental validation in a multi-drug resistant clinical isolate of M. tuberculosis.
    BMC microbiology, 2020, 07-25, Volume: 20, Issue:1

    Genome sequencing and genetic polymorphism analysis of clinical isolates of M. tuberculosis is carried out to gain further insight into molecular pathogenesis and host-pathogen interaction. Therefore the functional evaluation of the effect of single nucleotide variation (SNV) is essential. At the same time, the identification of invariant sequences unique to M. tuberculosis contributes to infection detection by sensitive methods. In the present study, genome analysis is accompanied by evaluation of the functional implication of the SNVs in a MDR clinical isolate VPCI591.. By sequencing and comparative analysis of VPCI591 genome with 1553 global clinical isolates of M. tuberculosis (GMTV and tbVar databases), we identified 141 unique strain specific SNVs. A novel intergenic variation in VPCI591 in the putative promoter/regulatory region mapping between embC (Rv3793) and embA (Rv3794) genes was found to enhance the expression of embAB, which correlates with the high resistance of the VPCI591 to ethambutol. Similarly, the unique combination of three genic SNVs in RNA polymerase β gene (rpoB) in VPCI591 was evaluated for its effect on rifampicin resistance through molecular docking analysis. The comparative genomics also showed that along with variations, there are genes that remain invariant. 173 such genes were identified in our analysis.. The genetic variation in M. tuberculosis clinical isolate VPCI591 is found in almost all functional classes of genes. We have shown that SNV in rpoB gene mapping outside the drug binding site along with two SNVs in the binding site can contribute to quantitative change in MIC for rifampicin. Our results show the collective effect of SNVs on the structure of the protein, impacting the interaction between the target protein and the drug molecule in rpoB as an example. The study shows that intergenic variations bring about quantitative changes in transcription in embAB and in turn can lead to drug resistance.

    Topics: Antitubercular Agents; Bacterial Proteins; Binding Sites; DNA-Directed RNA Polymerases; Drug Resistance, Multiple, Bacterial; Gene Expression Regulation, Bacterial; High-Throughput Nucleotide Sequencing; Humans; Models, Molecular; Molecular Docking Simulation; Mycobacterium tuberculosis; Pentosyltransferases; Polymorphism, Single Nucleotide; Protein Structure, Tertiary; Rifampin; Tuberculosis; Whole Genome Sequencing

2020
[Using of the Sensititre MycoTB Plate Method for the Detection of Anti-tuberculous Drug Susceptibility of Rifampin Resistant Mycobacterium tuberculosis Complex Isolates].
    Mikrobiyoloji bulteni, 2020, Volume: 54, Issue:2

    Members of the Mycobacterium tuberculosis complex (MTBC) are the causative agents of tuberculosis (TB). Rifampin resistance in the clinical isolates of MTBC is an important indicator for multidrug resistant-TB (MDR-TB) cases. In this study, it was aimed to evaluate whether the Sensititre MycoTB plaque method is suitable for the routine use in determining drug susceptibility of rifampin resistant MTBC strains. Xpert MTBC/ RIF positive rifampin resistant 100 MTBC isolates were included in the study. Xpert MTBC/RIF (Cepheid, USA) test were performed after the samples were processed by homogenization and decontamination and acid-fast staining. Rifampin resistant clinical samples were cultured in automated MGIT/BACTEC 960 (Becton Dickinson, USA) system and acid fast bacteria (AFB) were investigated. The anti-TB drug susceptibility tests of all culture positive AFB and cord factor identified as MTBC by using a cart test (MPB64, Capilla TB-Neo, Tauns Laboratories, Inc., Numazu, Japan) were performed with the Löwenstein-Jensen proportion method (LJPM) and Sensititre MycoTB (Trek Diagnostic Systems, Cleveland, OH, USA) methods. For the comparison of the methods used, the tests were performed simultaneously. The standard LJPM was performed according to the previously described procedures by World Health Organization and the Sensititre MycoTB plate method was performed as defined by the manufacturer. The final concentrations of isoniazide, rifampin, rifabutin, ethambutol, ofloxacin, moxifloxacin amikacin, kanamycin, cycloserine, ethionamide and p-aminosalicylic acid in Löwenstein-Jensen media for LJPM were 0.2 µg/ml, 40.0 µg/ml, 20.0 µg/ml, 2.0 µg/ml, 2.0 µg/ml, 1.0 µg/ml, 4.0 µg/ml, 30.0 µg/ml, 30.0 µg/ml, 40.0 µg/ml, 40.0 µg/ml and 1.0 µg/ ml, respectively. The results were obtained in 14 days for all of the drugs in the Sensititre MycoTB plate method and in 28-42 days in the LJPM. In this study, the sensitivity and specificity percentages of the Sensititre MycoTB method and the categorical agreement between the two methods were calculated. The sensitivity and specificity percentages of the Sensititre MycoTB plate method were between 84.4-100% and 95.6- 100%, respectively. The categorical agreements between the two methods were 92-100% for the drugs tested in the study. Ethambutol was found to have the lowest sensitivity (84.4%) and specificity (95.6%). The sensitivities of isoniazide, ofloxacin, streptomycin, kanamycin, ethionamide and p-aminosalicylic acid were

    Topics: Antitubercular Agents; Ethambutol; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2020
Machine learning reveals that Mycobacterium tuberculosis genotypes and anatomic disease site impacts drug resistance and disease transmission among patients with proven extra-pulmonary tuberculosis.
    BMC infectious diseases, 2020, Jul-31, Volume: 20, Issue:1

    There is a general dearth of information on extrapulmonary tuberculosis (EPTB). Here, we investigated Mycobacterium tuberculosis (Mtb) drug resistance and transmission patterns in EPTB patients treated in the Tshwane metropolitan area, in South Africa.. Consecutive Mtb culture-positive non-pulmonary samples from unique EPTB patients underwent mycobacterial genotyping and were assigned to phylogenetic lineages and transmission clusters based on spoligotypes. MTBDRplus assay was used to search mutations for isoniazid and rifampin resistance. Machine learning algorithms were used to identify clinically meaningful patterns in data. We computed odds ratio (OR), attributable risk (AR) and corresponding 95% confidence intervals (CI).. Of the 70 isolates examined, the largest cluster comprised 25 (36%) Mtb strains that belonged to the East Asian lineage. East Asian lineage was significantly more likely to occur within chains of transmission when compared to the Euro-American and East-African Indian lineages: OR = 10.11 (95% CI: 1.56-116). Lymphadenitis, meningitis and cutaneous TB, were significantly more likely to be associated with drug resistance: OR = 12.69 (95% CI: 1.82-141.60) and AR = 0.25 (95% CI: 0.06-0.43) when compared with other EPTB sites, which suggests that poor rifampin penetration might be a contributing factor.. The majority of Mtb strains circulating in the Tshwane metropolis belongs to East Asian, Euro-American and East-African Indian lineages. Each of these are likely to be clustered, suggesting on-going EPTB transmission. Since 25% of the drug resistance was attributable to sanctuary EPTB sites notorious for poor rifampin penetration, we hypothesize that poor anti-tuberculosis drug dosing might have a role in the development of resistance.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Genotype; Humans; Infant; Isoniazid; Machine Learning; Male; Middle Aged; Mutation; Mycobacterium tuberculosis; Phylogeny; Rifampin; South Africa; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

2020
Upfront Xpert MTB/RIF for diagnosis of pediatric TB-Does it work? Experience from India.
    PloS one, 2020, Volume: 15, Issue:8

    Diagnosis of TB in pediatric population poses several challenges. A novel initiative was implemented in several major cities of India aimed at providing upfront access to free-of-cost Xpert MTB/RIF to presumptive pediatric TB cases. This paper aims to describe the experience of implementing this large initiative and assess feasibility of the intervention in high TB burden settings.. Data were drawn from the pediatric TB project implemented in 10 major cities of India between April 2014 and March 2018. In each city, providers, both public and private, were engaged and linked with a high throughput Xpert MTB/RIF lab (established in that city) through rapid specimen transportation and electronic reporting system. Rates and proportions were estimated to describe the characteristics of this cohort.. Of the total 94,415 presumptive pediatric TB cases tested in the project, 6,270 were diagnosed positive for MTB (6.6%) on Xpert MTB/RIF (vs 2% on smear microscopy). Among MTB positives, 545 cases were rifampicin resistant (8.7%). The median duration between collection of specimens and reporting of results was 0 days (same day) and >89% cases were initiated on treatment. Approximately 50% of the specimens tested were non-sputum. The number of providers/facilities engaged under the project increased >10-fold (from 124 in Q2'14 to 1416 in Q1'18).. This project, which was one of the largest initiatives globally among pediatric population, demonstrated the feasibility of sustaining rapid and upfront access to free-of-cost Xpert MTB/RIF testing. The project underscores the efficiency of this rapid diagnostic assay in tackling several challenges in pediatric TB diagnosis, identifies opportunities for further interventions as well as brings to light scope for effective engagement with healthcare providers. The findings have facilitated a policy decision by National TB Programme mandating the use of Xpert MTB/RIF as a primary diagnostic tool for TB diagnosis in children, which is being scaled-up.

    Topics: Adolescent; Antibiotics, Antitubercular; Child; Child, Preschool; Female; Health Personnel; Humans; India; Infant; Male; Mass Screening; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2020
[IManagement of patients with relapsed primary naso-sinusal tuberculosis].
    The Pan African medical journal, 2020, Volume: 36

    Primary naso-sinusal tuberculosis (TB) is a relatively rare or exceptional disorder characterized by polymorphic or non-specific clinical manifestation. Diagnosis is based on anatomo-pathological examination and mycobacteriology test of biopsy specimen. Predictor of good outcome is early conventional anti-tuberculous antibiotic therapy. However, our study reports recurrence at this rare site in an immunocompetent patient despite early suitable TB treatment and good adherence with therapy. Relapse was correlated with underdosing of rifampicin. This study highlights the diagnostic, etiological and therapeutic management of this relapse. Our experience could help clinicians to better manage this uncommon condition.

    Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Female; Humans; Medication Adherence; Middle Aged; Paranasal Sinus Diseases; Recurrence; Rifampin; Tuberculosis

2020
A population approach of rifampicin pharmacogenetics and pharmacokinetics in Mexican patients with tuberculosis.
    Tuberculosis (Edinburgh, Scotland), 2020, Volume: 124

    Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; ATP Binding Cassette Transporter, Subfamily B; Bayes Theorem; Biological Availability; Drug Administration Schedule; Drug Dosage Calculations; Female; Humans; Liver-Specific Organic Anion Transporter 1; Male; Mexico; Middle Aged; Models, Biological; Pharmacogenetics; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Prospective Studies; Reproducibility of Results; Rifampin; Treatment Outcome; Tuberculosis; Young Adult

2020
Injectables' key role in rifampicin-resistant tuberculosis shorter treatment regimen outcomes.
    PloS one, 2020, Volume: 15, Issue:8

    Since a meta-analysis showed little or no effect of second-line injectables on treatment success, and using injectables may induce ototoxicity, injectable-free rifampicin-resistant tuberculosis (RR-TB) treatment regimens are recommended. However, acquired resistance preventing activity was overlooked. No previous study assessed the effect of shortening the duration of kanamycin administration to 2 months during the intensive phase of the RR-TB shorter treatment regimen (STR).. Retrospective cohort study of the effect of using 2 months of kanamycin instead of the standard 4(+) months (extension if lack of smear conversion at 4 months) on recurrence (either treatment failure or relapse) and fluoroquinolone acquired drug resistance, in patients treated with a gatifloxacin-based STR in Damien Foundation supported clinics in Bangladesh. Logistic regression was used to estimate associations.. Five of 52 (9.6%) treated with a STR containing two months of kanamycin had recurrence, compared to 21 of 738 (2.8%) patients treated with the standard STR containing 4(+) months of kanamycin (OR 3.7; 95%CI:1.5-10.3). In those with initially fluoroquinolone-susceptible TB, acquired resistance to fluoroquinolone was detected in none of 639 patients treated with 4(+) months of kanamycin and two (4.5%) of 44 treated with two months of kanamycin (OR 75.2; 95%CI:3.6-1592.1).. Two months of kanamycin was insufficient to prevent recurrence with acquired resistance to gatifloxacin, the core drug of the most effective RR-TB STR. Injectable mediated resistance prevention is important to reach high effectiveness, to safeguard all treatment options after recurrence, and to prevent the spread of resistant TB. Studies on all-oral regimens should also assess the effect of regimen composition on resistance acquisition. Until evidence shows that other drugs can assure at least the same strong resistance preventing activity of the injectables, it seems wise to continue using this group of drugs, and adapt the regimen if any ototoxicity is detected.

    Topics: Adolescent; Adult; Cohort Studies; Drug Resistance, Bacterial; Female; Humans; Injections; Kanamycin; Male; Middle Aged; Retrospective Studies; Rifampin; Time Factors; Treatment Outcome; Tuberculosis; Young Adult

2020
In vitro anti-mycobacterial activity of novel benzo(c)thiophene-1,3-dione: A novel scaffold against Mycobacterium tuberculosis.
    Microbial pathogenesis, 2020, Volume: 148

    Tuberculosis (TB) an infectious disease with very high mortality claims approximately 1.5 million lives and infects 2 billion people annually. The present study evaluated anti-tuberculosis activity of benzo(c)thiophene-1,3-dione against Mycobacterial tuberculosis H37RV in vitro and in vivo in tuberculosis mice model. The MIC of benzo(c)thiophene-1,3-dione, rifampicin and isoniazid were found to be 4.0, 2.0 and 1.0 μg/ml, respectively. Benzo(c)thiophene-1,3-dione showed MIC in the range of 8-14 μg/ml against four drug-resistant isolates of M. tuberculosis and MBC 14 μg/ml against M. tuberculosis H37RV. Interaction of benzo(c)thiophene-1,3-dione with rifampicin led to 2-fold increase in anti-TB activity whereas with isoniazid improvement showed 4-fold enhancement. Fractional inhibitor concentration index suggested additive interaction with rifampicin and synergism with isoniazid. Treatment with benzo(c)thiophene-1,3-dione at 1X MIC indicated bacteriostatic activity whereas at 2X, 4X and 4X MIC doses significant reduction in M. tuberculosis load was observed. The benzo(c)thiophene-1,3-dione administration to mice at doses of 5000 and 1000 mg/kg caused no changes in behaviour nor any death. Benzo(c)thiophene-1,3-dione treatment of tuberculosis mice model effectively inhibited pulmonary CFU compared to model group. Data obtained from MTT assay showed negligible cytotoxicity of benzo(c)thiophene-1,3-dione against CMMT, MB 157, CL-S1, normal breast cells in 5-320 μg/ml concentration range. Thus, benzo(c)thiophene-1,3-dione exhibits promising anti-mycobacterial activity against Mycobacterium tuberculosis H37RV and other drug resistant strains. In Mycobacterium tuberculosis mice model benzo(c)thiophene-1,3-dione significantly suppressed bacterial load and showed synergism with isoniazid. Therefore, benzo(c)thiophene-1,3-dione has potential to be evaluated further for development of anti-tuberculosis treatment.

    Topics: Animals; Antitubercular Agents; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Thiophenes; Tuberculosis

2020
Retrospective record review of pregnant women treated for rifampicin-resistant tuberculosis in South Africa.
    PloS one, 2020, Volume: 15, Issue:9

    Tuberculosis (TB) is amongst the top five causes of death in women of childbearing age (15-≤44 years). Little is known about treatment of pregnant women with drug-resistant TB (DR-TB). Treatment for pregnant women remains challenging and more complex in DR-TB/HIV co-infection, where an evidence-based guide to clinical practice is limited. The study reviewed treatment and pregnancy outcomes and birth outcomes of their new-born in a cohort of pregnant women with DR-TB from three MDR-TB hospitals during 2010 and 2018.. Data were extracted from: TB register and patient clinic notes using a standardized case record form. Information on DR-TB treatment, pregnancy and Adverse Drug Events (ADEs) of twenty-six pregnant women treated with individualized second-line TB medications were captured. The frequency of favourable and adverse outcomes regarding disease and pregnancy were evaluated.. The mean age was 29 years (SD ±5.1), with the minimum and maximum age of 21 and 40 years, respectively. Eleven (42.3%) were previously treated with first-line TB drugs, 11 (42.3%) never treated before and 4 (15.4%) were previously treated for DR-TB. Of the 26 women, 15 (57.7%) had at least one ADE, but most had more than one ADE. Seventeen women were successfully treated, and 22 live births recorded. Live birth outcome was significantly associated with trimester of initiation of DR-TB treatment (p = 0.036). The proportion of live births for the pregnancy trimester when DR-TB treatment was initiated, were 60.0%, 90.9% and 100.0%, for first, second and third trimester, respectively.. DR-TB treatment should be delayed until after the first trimester. Routine pharmacovigilance surveillance integrated antenatal and delivery services with an integrated record of DR-TB treatment during pregnancy is recommended. Prospective studies using standardised case record forms for DR-TB treatment for pregnant women could provide more insight on the effect of DR-TB treatment on the birth outcome.

    Topics: Adult; Antitubercular Agents; Cohort Studies; Coinfection; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Middle Aged; Pregnancy; Pregnancy Outcome; Retrospective Studies; Rifampin; South Africa; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
Hemophagocytic syndrome associated with Mycobacterium bovis in a patient with X-SCID: a case report.
    BMC infectious diseases, 2020, Sep-29, Volume: 20, Issue:1

    Mycobacterium bovis could infect patients with immunodeficiency or immunosuppressive conditions via Bacillus Calmette-Guérin (BCG) vaccination. Tuberculosis-related hemophagocytic syndrome (HPS) is reported, but not HPS caused by Mycobacterium bovis in children.. A boy with X-SCID was diagnosed with M. bovis-associated HPS, emphasizing that X-SCID should be considered when M. bovis is detected in a male infant with low lymphocyte counts.

    Topics: Antibiotics, Antitubercular; High-Throughput Nucleotide Sequencing; Humans; Infant; Interleukin Receptor Common gamma Subunit; Isoniazid; Lymphohistiocytosis, Hemophagocytic; Male; Mutation; Mycobacterium bovis; Mycobacterium tuberculosis; Patient Discharge; Polymerase Chain Reaction; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis; X-Linked Combined Immunodeficiency Diseases

2020
Tuberculosis drug resistance in Canakkale, Turkey.
    Central European journal of public health, 2020, Volume: 28, Issue:3

    Topics: Antitubercular Agents; Bacterial Proteins; Catalase; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Turkey

2020
The use of Gene-Xpert MTB RIF in the diagnosis of extrapulmonary tuberculosis in childhood and adolescence.
    Revista da Sociedade Brasileira de Medicina Tropical, 2020, Volume: 53

    Gene-Xpert MTB RIF (Xpert) is based on nucleic acid amplification by real-time polymerase chain reaction, which allows for the identification of Mycobacterium tuberculosis and rifampin resistance. We describe the use of Xpert for extrapulmonary tuberculosis (EPTB) in children and adolescents.. A case series of two reference centers in Rio de Janeiro from 2014-2019.. The final diagnosis of EPTB was established in 11/36 (31%) patients, with five cases detectable by Xpert. For lymph node evaluation (9/11), diagnosis by Xpert occurred in 5/9 patients, all with caseous aspects.. Xpert can facilitate the rapid diagnosis of lymph node tuberculosis.

    Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Tuberculosis

2020
Rifampicin resistance patterns and dynamics of tuberculosis and drug-resistant tuberculosis in Enugu, South Eastern Nigeria.
    Journal of infection in developing countries, 2020, 09-30, Volume: 14, Issue:9

    Tuberculosis (TB) continues to be a public health problem globally. The burden is further exacerbated in developing countries like Nigeria, by poor diagnosis, management and treatment, as well as rapid emergence of drug-resistant TB. This study was conducted to evaluate the prevalence of drug-resistant TB, determine the rpoB gene mutation patterns of Mycobacterium tuberculosis (MTB) and model the dynamics of multidrug resistant TB (MDR-TB) in Enugu, Nigeria.. A total of 868 samples, from patients accessing DOTS services in designated centres within the zone, were screened by sputum-smear microscopy, while 207 samples were screened by Nucleic Acid Amplification (Xpert® MTB/Rif) Test (NAAT). A deterministic model was formulated to study the transmission dynamics of TB and MDR-TB, using live data generated through epidemiological study.. The results showed TB prevalence values of 22.1% and 21.3% by sputum-smear and NAAT assays, respectively. Analysis of the rifampicin resistance patterns showed the highest occurrence of mutations (50%) along codons 523 - 527. Factors such as combination therapy, multiple therapy and compliance to treatment had influence on both prevalence and development of TB drug resistance in the population.. This first documentation of Rifampicin resistance patterns in MTB from Nigeria shows that a majority of rpoB gene mutations occurred along codons 523 to 527, contrary to the widely reported codon 531 mutation and that multiple interventions such as combination therapy, with good compliance to treatment are needed to reduce both prevalence and development of TB drug resistance in the population.

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; Bacteriological Techniques; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Models, Theoretical; Mutation; Mycobacterium tuberculosis; Nigeria; Nucleic Acid Amplification Techniques; Prevalence; Reagent Kits, Diagnostic; Rifampin; RNA, Ribosomal, 16S; Sputum; Tuberculosis

2020
Tuberculous Spondylodiscitis after Lumbar Microdiscectomy.
    Journal of the College of Physicians and Surgeons--Pakistan : JCPSP, 2020, Volume: 30, Issue:9

    Postoperative spondylodiscitis (PSD) and postoperative osteomyelitis (POM) are known complications of lumbar disc surgery. Many infectious agents play a role in its etiology and it is mostly bacterial. A 55-year male patient underwent lumbar microdiscectomy (LMD) for left L4-5 disc hernia. Lumbar magnetic resonance images of the patient in the postoperative eighth week showed an infection, thought to be due to tuberculosis (TB) in the operation site and adjacent vertebrae. The patient who was positive for the QuantiFERON-TB Gold In-Tube (QFT-GIT) test was diagnosed with TB-induced PSD. The patient received anti-TB treatment consisting of ethambutol, isoniazid, pyrazinamide, and rifampin. We report a very rare case of PSD due to TB infection after LMD. Clinical results and management of the patient was compared with other patients with similar characteristics in the literature. Key Words: Discectomy, Osteomyelitis, Spondylodiscitis, Tuberculosis.

    Topics: Discitis; Diskectomy; Humans; Interferon-gamma Release Tests; Isoniazid; Male; Rifampin; Tuberculin Test; Tuberculosis

2020
Cost-effectiveness of one month of daily isoniazid and rifapentine versus three months of weekly isoniazid and rifapentine for prevention of tuberculosis among people receiving antiretroviral therapy in Uganda.
    Journal of the International AIDS Society, 2020, Volume: 23, Issue:10

    Preventive therapy is essential for reducing tuberculosis (TB) burden among people living with HIV (PLWH) in high-burden settings. Short-course preventive therapy regimens, such as three-month weekly rifapentine and isoniazid (3HP) and one-month daily rifapentine and isoniazid (1HP), may help facilitate uptake of preventive therapy for latently infected patients, but the comparative cost-effectiveness of these regimens under different conditions is uncertain.. We used a Markov state-transition model to estimate the incremental costs and effectiveness of 1HP versus 3HP in a simulated cohort of patients attending an HIV clinic in Uganda, as an example of a low-income, high-burden setting in which TB preventive therapy might be prescribed to PLWH. Our primary outcome was the incremental cost-effectiveness ratio, expressed as 2019 US dollars per disability-adjusted life year (DALY) averted. We estimated cost-effectiveness under different conditions of treatment completion and efficacy of 1HP versus 3HP, latent TB prevalence and rifapentine price.. Assuming equivalent clinical outcomes using 1HP and 3HP and a rifapentine price of $0.21 per 150 mg, 1HP would cost an additional $4.66 per patient treated. Assuming equivalent efficacy but 20% higher completion with 1HP versus 3HP, 1HP would cost $1,221 per DALY averted relative to 3HP. This could be reduced to $18 per DALY averted if 1HP had 5% greater efficacy than 3HP and the price of rifapentine were 50% lower. At a rifapentine price of $0.06 per 150 mg, 1HP would become cost-neutral relative to 3HP.. 1HP has the potential to be cost-effective under many realistic circumstances. Cost-effectiveness depends on rifapentine price, relative completion and efficacy, prevalence of latent TB and local willingness-to-pay.

    Topics: Anti-HIV Agents; Antitubercular Agents; Cost-Benefit Analysis; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Latent Tuberculosis; Male; Quality-Adjusted Life Years; Rifampin; Tuberculosis; Uganda

2020
GeneXpert for the diagnosis of COVID-19 in LMICs.
    The Lancet. Global health, 2020, Volume: 8, Issue:12

    Topics: COVID-19; Developing Countries; Health Resources; Humans; Madagascar; Mycobacterium tuberculosis; Pandemics; Polymerase Chain Reaction; Rifampin; SARS-CoV-2; Sensitivity and Specificity; Tuberculosis

2020
Prediction of rifampicin resistance beyond the RRDR using structure-based machine learning approaches.
    Scientific reports, 2020, 10-22, Volume: 10, Issue:1

    Rifampicin resistance is a major therapeutic challenge, particularly in tuberculosis, leprosy, P. aeruginosa and S. aureus infections, where it develops via missense mutations in gene rpoB. Previously we have highlighted that these mutations reduce protein affinities within the RNA polymerase complex, subsequently reducing nucleic acid affinity. Here, we have used these insights to develop a computational rifampicin resistance predictor capable of identifying resistant mutations even outside the well-defined rifampicin resistance determining region (RRDR), using clinical M. tuberculosis sequencing information. Our tool successfully identified up to 90.9% of M. tuberculosis rpoB variants correctly, with sensitivity of 92.2%, specificity of 83.6% and MCC of 0.69, outperforming the current gold-standard GeneXpert-MTB/RIF. We show our model can be translated to other clinically relevant organisms: M. leprae, P. aeruginosa and S. aureus, despite weak sequence identity. Our method was implemented as an interactive tool, SUSPECT-RIF (StrUctural Susceptibility PrEdiCTion for RIFampicin), freely available at https://biosig.unimelb.edu.au/suspect_rif/ .

    Topics: Antitubercular Agents; Bacterial Proteins; Drug Resistance, Bacterial; Humans; Leprosy; Machine Learning; Mutation, Missense; Mycobacterium leprae; Mycobacterium tuberculosis; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Tuberculosis

2020
Finding the right balance between efficacy and tolerability for TB treatment.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2020, 11-01, Volume: 24, Issue:11

    Topics: Humans; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
The antibiotic sorangicin A inhibits promoter DNA unwinding in a
    Proceedings of the National Academy of Sciences of the United States of America, 2020, 12-01, Volume: 117, Issue:48

    Rifampicin (Rif) is a first-line therapeutic used to treat the infectious disease tuberculosis (TB), which is caused by the pathogen

    Topics: Aminoglycosides; Antibiotics, Antitubercular; Binding Sites; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Models, Molecular; Molecular Conformation; Mycobacterium tuberculosis; Promoter Regions, Genetic; Protein Binding; Rifampin; Structure-Activity Relationship; Tuberculosis

2020
Bacillus Calmette-GuÉrin-Associated Cervical Spondylitis in a 3-Year-Old Immunocompetent Girl.
    The Pediatric infectious disease journal, 2020, Volume: 39, Issue:12

    Bacillus Calmette-Guérin (BCG)-associated osteomyelitis is a rare adverse event following BCG vaccination, and there have been no previous reports of BCG-associated cervical spondylitis. Here, we describe the case of a 3-year-old immunocompetent girl who developed BCG-associated cervical spondylitis and was successfully treated by prompt surgical drainage of the abscess and administration of isoniazid and rifampicin for 9 months without sequelae.

    Topics: Abscess; Antitubercular Agents; BCG Vaccine; Cervical Vertebrae; Child, Preschool; Female; Humans; Immunocompetence; Isoniazid; Mycobacterium bovis; Osteomyelitis; Rifampin; Spondylitis; Tuberculosis

2020
Lymphocyte stimulation test in the diagnostics of adverse reactions to antituberculouse line 1 and 2 drugs.
    Klinicheskaia laboratornaia diagnostika, 2020, Sep-16, Volume: 65, Issue:9

    Adverse drug reactions to anti-TB drugs (ADR) are found in 6-20% of patients and have various clinical manifestations and are detected in the lymphocyte stimulation test (LST), recorded by the incorporation on H3 thymidine, but nowadays it has significant limitations. We used LST with WST-1 reagent to detect ADR to the main 1-st and 2-nd line antituberculosis drugs in 11 tuberculosis patients who had ADR (6 - hepatotoxic reaction, 3 - blood eosinophilia and 2 - with joint pain syndrome). 6 people with tuberculosis contacts made up the control group. LST evaluation with WST-1 showed that in patients with a hepatotoxic reaction, the SI index was>2 and exceeded the values in the control group (3.28±0.59, 95% CI-1.16 and 0, 74±0.16, 95% CI - 0.31, respectively) upon stimulation of cell cultures with rifampicin alone but not with other drugs. Cell cultures stimulated with the PHA mitogen have SI >2 in ADR patients (mainly with hepatotoxic reactions). Control group SI was <2 (4,93±0.53, 95% CI - 1, 04 and 1.97±0.3, 95% CI - 0.59, respectively). We have not detected PPD-L cell cultures stimulation with WST-1 reagent both in the group of patients with ADR and the control group. In patients with eosinophilia and joint pain syndrome SI was low for all studied drugs and did not differ from the control group. The sensitivity of the LST test with WST-1 reagent is not sufficient to determine ADR to anti-TB drugs.

    Topics: Antitubercular Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Lymphocyte Activation; Pharmaceutical Preparations; Rifampin; Tuberculosis

2020
Point-of-Care Ultrasound Image of Intra-Abdominal Lymphadenopathy in Tuberculosis.
    The American journal of tropical medicine and hygiene, 2020, Volume: 103, Issue:6

    Topics: Abdomen; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Lymph Nodes; Lymphadenopathy; Mycobacterium tuberculosis; Point-of-Care Systems; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis; Ultrasonography; Young Adult

2020
A retrospective cohort study of early mortality among patients with HIV/TB co-infection in Shanghai municipality.
    HIV medicine, 2020, Volume: 21, Issue:11

    Tuberculosis (TB) is the most common and fatal opportunistic co-infection among HIV-infected individuals. While TB-associated mortality predominantly occurs in the first 90 days after admission, such a correlation remains unclear in HIV/TB co-infected patients. Thus, we aimed to investigate the 90-day mortality and associated risk factors among HIV/TB co-infected patients in China.. Adult patients with HIV and a newly confirmed TB diagnosis admitted to the Shanghai Public Health Clinical Center between September 2009 and August 2017 were enrolled. Clinical and laboratory characteristics, key treatments and outcomes were collected retrospectively. The associations between different factors and early mortality were analysed.. Of the 485 laboratory-confirmed HIV/TB patients [median (range) age = 39 (19-79) years], 413 (85.15%) were male. Diagnosis was confirmed by culture, pathology and acid-fast bacilli smear alone in 362 (74.6%), 6 (1.2%) and 117 (24.1%) patients, respectively. Multiple drug-/rifampin-resistant TB was detected in 21 (5.8%) of the 367 patients with a positive culture. Rifampin or rifabutin was administered to 402 (82.9%) patients. Additionally, 66 (13.6%) and 86 (17.7%) died within 90 days and 1 year of admission, respectively. Of the 64 TB-related deaths, 59 (92.2%) occurred within 90 days of admission. In Cox regression, central nervous system (CNS) TB [odds ratio (OR) = 2.49, 95% confidence interval (CI): 1.46-4.23, P < 0.001], no antiretroviral therapy (ART) within 3 months after admission (OR = 11, 95% CI: 6.4-18.9, P < 0.001), and plasma albumin level < 25 g/L (OR = 1.91, 95% CI: 1.07-3.40, P = 0.021) were associated with early death.. Tuberculosis co-infection was prevalent and fatal in HIV-infected patients, with most deaths occurring within 90 days of admission. Early mortality was associated with CNS-TB, no ART, and serum albumin level < 25 g/L.

    Topics: Adult; Aged; Antibiotics, Antitubercular; China; Coinfection; Female; HIV Infections; Hospitalization; Humans; Male; Middle Aged; Prevalence; Regression Analysis; Retrospective Studies; Rifabutin; Rifampin; Risk Factors; Tuberculosis; Young Adult

2020
Pharmacokinetics of First-Line Drugs Among Children With Tuberculosis in Rural Tanzania.
    Journal of the Pediatric Infectious Diseases Society, 2020, Feb-28, Volume: 9, Issue:1

    Dosing recommendations for treating childhood tuberculosis (TB) were revised by the World Health Organization, yet so far, pharmacokinetic studies that have evaluated these changes are relatively limited. We evaluated plasma drug concentrations of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) among children undergoing TB treatment in Tanzania when these dosing recommendations were being implemented.. At the end of intensive-phase TB therapy, blood was obtained 2 hours after witnessed medication administration to estimate the peak drug concentration (C2h), measured using high-performance liquid chromatography or liquid chromatography-tandem mass spectrometry methods. Differences in median drug concentrations were compared on the basis of the weight-based dosing strategy using the Mann-Whitney U test. Risk factors for low drug concentrations were analyzed using multivariate regression analysis.. We enrolled 51 human immunodeficiency virus-negative children (median age, 5.3 years [range, 0.75-14 years]). The median C2hs were below the target range for each TB drug studied. Compared with children who received the "old" dosages, those who received the "revised" WHO dosages had a higher median C2h for RIF (P = .049) and PZA (P = .015) but not for INH (P = .624) or EMB (P = .143); however, these revised dosages did not result in the target range for RIF, INH, and EMB being achieved. A low starting dose was associated with a low C2h for RIF (P = .005) and PZA (P = .005). Malnutrition was associated with a low C2h for RIF (P = .001) and INH (P = .001).. Among this cohort of human immunodeficiency virus-negative Tanzanian children, use of the revised dosing strategy for treating childhood TB did not result in the target drug concentration for RIF, INH, or EMB being reached.

    Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Ethambutol; Female; HIV Seronegativity; Humans; Infant; Isoniazid; Longitudinal Studies; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Rural Population; Tanzania; Tuberculosis

2020
Feasibility of Identifying Household Contacts of Rifampin-and Multidrug-resistant Tuberculosis Cases at High Risk of Progression to Tuberculosis Disease.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020, 01-16, Volume: 70, Issue:3

    We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial.. We conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing.. From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy.. The majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.

    Topics: Adult; Child, Preschool; Cross-Sectional Studies; Family Characteristics; Feasibility Studies; Female; Humans; Male; Rifampin; Tuberculin Test; Tuberculosis; Tuberculosis, Multidrug-Resistant

2020
Subtherapeutic Rifampicin Concentration Is Associated With Unfavorable Tuberculosis Treatment Outcomes.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020, 03-17, Volume: 70, Issue:7

    The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood.. We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models.. Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-μg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01-1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05-1.28]). A 1-μg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01-1.11]).. Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.

    Topics: Antitubercular Agents; Humans; India; Isoniazid; Prospective Studies; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2020
Rifampin-resistant Tuberculosis in the United States, 1998-2014.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020, 04-10, Volume: 70, Issue:8

    Monoresistance to rifamycins necessitates longer and more toxic regimens for tuberculosis (TB). We examined characteristics and mortality associated with rifampin-monoresistant (RMR) TB in the United States.. We analyzed Mycobacterium tuberculosis culture-positive cases reported to the National TB Surveillance System (excluding California) between 1998 and 2014. We defined RMR TB found on initial drug susceptibility testing and possible acquired rifampin-resistant (ARR) TB. We assessed temporal trends in RMR TB. For both classifications of rifampin resistance, we calculated adjusted risk ratios (adjRRs) and 95% confidence intervals (CIs) for characteristics associated with mortality when compared with drug-susceptible TB in multivariable models using backward selection.. Of 180 329 TB cases, 126 431 (70%) were eligible for analysis, with 359 (0.28%) of eligible cases reported as RMR. The percentage of RMR TB cases with HIV declined 4% annually between 1998 and 2014. Persons with HIV and prior TB were more likely to have RMR TB (adjRR, 25.9; 95% CI, 17.6-38.1), as were persons with HIV and no prior TB (adjRR, 3.1; 95% CI, 2.4-4.1) vs those without either characteristic, controlling for other statistically significant variables. RMR cases had greater mortality (adjRR, 1.4; 95% CI, 1.04-1.8), controlling for HIV and other variables. Persons with HIV had greater risk of ARR than persons without HIV (adjRR, 9.6; 95% CI, 6.9-13.3), and ARR was also associated with increased mortality, controlling for HIV and other variables.. All forms of rifampin resistance were positively associated with HIV infection and increased mortality.

    Topics: Antitubercular Agents; HIV Infections; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; United States

2020
Phenolic N-monosubstituted carbamates: Antitubercular and toxicity evaluation of multi-targeting compounds.
    European journal of medicinal chemistry, 2019, Nov-01, Volume: 181

    The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N-monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis H

    Topics: Antitubercular Agents; Carbamates; Hep G2 Cells; Humans; Isocitrate Lyase; Mycobacterium tuberculosis; Phenols; Salicylanilides; Tuberculosis

2019
Identification of benzothiazinones containing an oxime functional moiety as new anti-tuberculosis agents.
    European journal of medicinal chemistry, 2019, Nov-01, Volume: 181

    A series of benzothiazinones (BTZs) containing an oxime moiety, based on the structure of ZR-10 discovered in our lab, were designed and synthesized. Most of the compounds with alkoxyimino groups attached to the piperazine or cyclohexyl ring of PBTZ169, exhibit excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016-0.037 μg/mL) and low cell cytotoxicity. Two close PBTZ169-analogues 3a and 3b with proper ADME/T and PK properties show potent in vivo efficacy in an acute mouse model of tuberculosis. Compound 3a is under evaluation as a potential clinical candidate for treatment of tuberculosis.

    Topics: Animals; Antitubercular Agents; Drug Design; Female; Humans; Mice, Inbred ICR; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oximes; Piperazines; Thiazines; Tuberculosis

2019
Factors associated with isoniazid resistant tuberculosis among human immunodeficiency virus positive patients in Swaziland: a case-control study.
    BMC infectious diseases, 2019, Aug-20, Volume: 19, Issue:1

    Isoniazid resistant tuberculosis is the most prevalent type of resistance in Swaziland and over two-thirds of the isoniazid resistant tuberculosis patients are tuberculosis and human immunodeficiency virus co-infected. The study aimed to determine risk factors associated with isoniazid resistant tuberculosis among human immunodeficiency virus positive patients in Swaziland.. This was a case-control study conducted in nine healthcare facilities across Swaziland. Cases were patients with isoniazid resistant tuberculosis (including 78 patients with isoniazid mono-resistant tuberculosis, 42 with polydrug-resistant tuberculosis, and 77 with multidrug-resistant tuberculosis). Controls were presumed drug-susceptible tuberculosis patients (n = 203). Multinomial logistic regression was used to determine related factors.. The median time lag from diagnosis to tuberculosis treatment initiation was 50 days for isoniazid mono or poly drug-resistant tuberculosis, 17 days for multidrug-resistant tuberculosis compared to 1 day for drug-susceptible tuberculosis patients. History of previous tuberculosis treatment was positively associated with either isoniazid mono or poly drug-resistant tuberculosis (OR = 7.91, 95% CI: 4.14-15.11) and multidrug-resistant tuberculosis (OR = 12.20, 95% CI: 6.07-24.54). Isoniazid mono or poly resistant tuberculosis patients were more likely to be from rural areas (OR = 2.05, 95% CI: 1.23-3.32) and current heavy alcohol drinkers compared to the drug-susceptible tuberculosis group. Multi drug-resistant tuberculosis patients were more likely to be non-adherent to tuberculosis treatment compared to drug-susceptible tuberculosis group (OR = 3.01, 95% CI: 1.56-5.82).. To prevent and control isoniazid resistant tuberculosis among HIV-positive patients in Swaziland, the tuberculosis program should strengthen the use of rapid diagnostic tests, detect resistance early, promptly initiate supervised tuberculosis treatment and decentralize quality tuberculosis services to the rural areas. Adherence to tuberculosis treatment should be improved.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Case-Control Studies; Eswatini; Female; HIV Infections; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Rifampin; Risk Factors; Socioeconomic Factors; Tuberculosis; Tuberculosis, Multidrug-Resistant

2019
High mortality during tuberculosis retreatment at a Ghanaian tertiary center: a retrospective cohort study.
    The Pan African medical journal, 2019, Volume: 33

    High mortality among individuals receiving retreatment for tuberculosis (RT-TB) persists, although reasons for these poor outcomes remain unclear.. We retrospectively reviewed 394 RT-TB patients diagnosed between January 2010 and June 2016 in Accra, Ghana.. Of RT-TB patients, 161 (40.9%) were treated empirically (negative/absent smear, culture or Xpert), of whom 30.4% (49/161) had only extrapulmonary TB signs or symptoms. Mortality during treatment was 19.4%; 15-day mortality was 10.8%. In multivariable proportional hazards regression, living with HIV (aHR=2.69 [95 CI: 1.51, 4.80], p<0.01) and previous loss-to-follow up (aHR=8.27 (95 CI: 1.10, 62.25), p=0.04) were associated with mortality, while drug susceptibility testing (DST, aHR=0.36 (95 CI: 0.13, 1.01), p=0.052) was protective. Isoniazid resistance was observed in 40% (23/58 tested) and rifampin resistance in 19.1% (12/63 tested).. High rates of extrapulmonary TB and smear/culture negative disease highlight the barriers to achieving DST-driven RT-TB regimens and the need for improved diagnostics. Our finding of poly-drug resistance in rifampin-susceptible cases supports access to comprehensive first line DST. Additionally, interventions to reduce mortality, especially in HIV co-infected RT-TB patients, are urgently needed.

    Topics: Adult; Antitubercular Agents; Cohort Studies; Drug Resistance, Multiple, Bacterial; Female; Ghana; HIV Infections; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Proportional Hazards Models; Retreatment; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2019
Estimating the impact of a novel drug regimen for treatment of tuberculosis: a modeling analysis of projected patient outcomes and epidemiological considerations.
    BMC infectious diseases, 2019, Sep-09, Volume: 19, Issue:1

    Regimens that could treat both rifampin-resistant (RR) and rifampin-susceptible tuberculosis (TB) while shortening the treatment duration have reached late-stage clinical trials. Decisions about whether and how to implement such regimens will require an understanding of their likely clinical impact and how this impact depends on local epidemiology and implementation strategy.. A Markov state-transition model of 100,000 representative South African adults with TB was used to simulate implementation of the regimen BPaMZ (bedaquiline, pretomanid, moxifloxacin, and pyrazinamide), either for RR-TB only or universally for all patients. Patient outcomes, including cure rates, time with active TB, and time on treatment, were compared to outcomes under current care. Sensitivity analyses varied the drug-resistance epidemiology, rifampin susceptibility testing practices, and regimen efficacy.. Using BPaMZ exclusively for RR-TB increased the proportion of all RR-TB that was cured by initial treatment from 60 ± 1% to 67 ± 1%. Expanding use of BPaMZ to all patients increased cure of RR-TB to 89 ± 1% and cure of all TB from 87.3 ± 0.1% to 89.5 ± 0.1%, while shortening treatment by 1.9 months/person. In sensitivity analyses, reducing the coverage of rifampin susceptibility testing resulted in lower projected proportions of patients cured under all regimen scenarios (current care, RR-only BPaMZ, and universal BPaMZ), compared to the proportions projected using South Africa's high coverage; however, this reduced coverage resulted in greater expected incremental benefits of universal BPaMZ implementation, both when compared to RR-only BPaMZ implementation and when compared to to current care under the same low rifampin susceptibility testing coverage. In settings with higher RR-TB prevalence, the benefits of BPaMZ were magnified both for RR-specific and universal BPaMZ implementation.. Novel regimens such as BPaMZ could improve RR-TB outcomes and shorten treatment for all patients, particularly with universal use. Decision-makers weighing early options for implementing such regimens at scale will want to consider the expected impact on patient outcomes and on the burden of treatment in their local context.

    Topics: Adult; Antitubercular Agents; Diarylquinolines; Humans; Markov Chains; Nitroimidazoles; Prevalence; Pyrazinamide; Rifampin; South Africa; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2019
A Shorter Regimen for Rifampin-Resistant Tuberculosis.
    The New England journal of medicine, 2019, 09-12, Volume: 381, Issue:11

    Topics: Humans; Isoniazid; Rifampin; Tuberculosis

2019
A Shorter Regimen for Rifampin-Resistant Tuberculosis.
    The New England journal of medicine, 2019, 09-12, Volume: 381, Issue:11

    Topics: Humans; Isoniazid; Rifampin; Tuberculosis

2019
A Shorter Regimen for Rifampin-Resistant Tuberculosis. Reply.
    The New England journal of medicine, 2019, 09-12, Volume: 381, Issue:11

    Topics: Humans; Isoniazid; Rifampin; Tuberculosis

2019
One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis.
    The New England journal of medicine, 2019, 09-12, Volume: 381, Issue:11

    Topics: HIV; Humans; Isoniazid; Rifampin; Tuberculosis

2019
One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis. Reply.
    The New England journal of medicine, 2019, 09-12, Volume: 381, Issue:11

    Topics: HIV; Humans; Isoniazid; Rifampin; Tuberculosis

2019
Comparison of Xpert MTB/RIF with AFB smear and AFB culture in suspected cases of paediatric tuberculosis in a tertiary care hospital, Karachi.
    JPMA. The Journal of the Pakistan Medical Association, 2019, Volume: 69, Issue:9

    To evaluate the sensitivity, specificity, positive predictive and negative predictive values of Xpert mycobacterium tuberculosis and resistance to rifampicin by comparing it with acid-fast bacilli smear and culture in suspected tuberculosis patients.. The retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised patient data from January 2013 to December 2016. Data related to children with clinical suspicion of pulmonary and extra-pulmonary tuberculosis based on Modified Kenneth Jones criteria, aged 1 month to 18 years whose samples (respiratory or non-respiratory) were sent for Xpert mycobacterium tuberculosis and resistance to rifampicin and acid-fast bacilli smear and culture con currently. Analysis was carried out by STATA 12 and Med Calc softwares .. Of the 91 cases, 50(54.9%) related to females. The overall median age of the patients was 12.5 years (interquartile range: 8 years). Overall, 42(46.2%) cases had extra-pulmonary tuberculosis. The Xpert test had 66.7% sensitivity compared to smear microscopy 47.6%. Overall sensitivity, specificity, positive predictive value and negative predictive value were 95.7%, 72%, 51.2% and 98.3% respectively when the two tests were compared.. Xpert mycobacterium tuberculosis was found to be more sensitive than acid-fast bacilli smear and culture in both pulmonary and extra-pulmonar y tuberculosis in children.

    Topics: Adolescent; Antibiotics, Antitubercular; Child; Child, Preschool; Culture Techniques; Drug Resistance, Bacterial; Female; Humans; Infant; Male; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Pakistan; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tertiary Care Centers; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2019
Potential impact of efflux pump genes in mediating rifampicin resistance in clinical isolates of Mycobacterium tuberculosis from India.
    PloS one, 2019, Volume: 14, Issue:9

    Despite the consideration of chromosomal mutations as the major cause of rifampicin (RIF) resistance in M. tuberculosis, the role of other mechanisms such as efflux pumps cannot be ruled out. We evaluated the role of four efflux pumps viz., MmpL2 (Rv0507), MmpL5 (Rv0676c), Rv0194 and Rv1250 in providing RIF resistance in M. tuberculosis. The real time expression of the efflux pumps was analyzed in 16 RIF resistant and 11 RIF susceptible clinical isolates of M. tuberculosis after exposure to RIF. Expression of efflux pumps in these isolates was also correlated with mutations in the rpoB gene and MICs of RIF in the presence and absence of efflux pump inhibitors. Under RIF stress, Rv0194 was induced in 8/16 (50%) RIF resistant and 2/11 (18%) RIF susceptible isolates; mmpL5 in 7/16 (44%) RIF resistant and 1/11 (9%) RIF susceptible isolates; Rv1250 in 4/16 (25%) RIF resistant and 2/11 (18%) RIF susceptible isolates; and mmpL2 was upregulated in 2/16 (12.5%) RIF resistant and 1/11 (9%) RIF susceptible isolates. This preliminary study did not find any association between Rv0194, MmpL2, MmpL5 and Rv1250 and RIF resistance. However, the overexpression of Rv0194 and mmpL5 in greater number of RIF resistant isolates as compared to RIF susceptible isolates and expression of Rv0194 in wild type (WT) resistant isolates suggests a need for further investigations.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA Mutational Analysis; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Humans; India; Membrane Transport Proteins; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2019
Assessing the Utility of GeneXpert MTB/Rif Assay in a Tertiary Care Centre in Southern India with Established Microscopy and Liquid Culture Facilities.
    The Journal of the Association of Physicians of India, 2019, Volume: 67, Issue:8

    To evaluate the diagnostic accuracy of the Xpert MTB/RIF assay for the detection of M. tuberculosis in pulmonary and extra pulmonary specimens and to compare it with conventional techniques.. A prospective study was conducted with the introduction of GeneXpert in a tertiary care hospital which relied on microscopy and culture for diagnosis of tuberculosis. All patients for whom geneXpert was ordered by the physician were included in the study. Samples which did not have accompanying microscopy or MGIT culture requests were excluded from the analysis of the results. Sensitivity and specificity of GeneXpert was calculated using liquid culture as the reference test.. Xpert MTB/RIF assay was performed on 742 samples of which 116 were positive for Mycobacterium tuberculosis. Rifampicin resistance was seen in 6 samples. The pulmonary samples showed a positivity rate of 16.8% while 17.1% of the extrapulmonary samples were positive by GeneXpert. A comparative analysis of microscopy, liquid culture and GeneXpert could be done for 88 samples. Of the 88 geneXpert positive samples, 42 were positive by smear microscopy and MGIT culture while 46 showed discordant results. Of these, 18 samples were positive by geneXpert but showed no growth in MGIT culture. 15 of these patients had undergone anti-tuberculous treatment (ATT) within the past 12 months. The sensitivity of geneXpert was 89.7% and specificity was 95.1% when compared to liquid culture as a gold standard. Sensitivity for extrapulmonary samples was 85.7% and specificity was 98.05%.. To conclude, though GeneXpert detects tuberculosis within the shortest possible time, it still suffers from intermediate level sensitivity, which makes culture facilities relevant even in settings that offer an Xpert/Rif assay.

    Topics: Biological Assay; Drug Resistance, Bacterial; Humans; India; Microscopy; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tertiary Care Centers; Tuberculosis

2019
Determinants of serum concentration of first-line anti-tuberculosis drugs from China.
    Medicine, 2019, Volume: 98, Issue:41

    Therapeutic drug monitoring has been employed in anti-tuberculosis (TB) drugs to assess optimal dose for maximum therapeutic effects and minimal toxicity. But the determinants of serum concentration need further evidences.In a retrospective case-control study, clinical and laboratory data were collected from 717 in-patients with TB at Xi'an Chest Hospital, China. Two hours serum concentrations of isoniazid, rifampicin, pyrazinamide as well as ethambutol were obtained and analyzed by liquid chromatography-tandem mass spectrometry.The month 2 culture conversion group had lower concentration of isoniazid, pyrazinamide, and ethambutol than month 1 group. Statistical analysis showed that serum concentrations of isoniazid, rifampicin, pyrazinamide, and ethambutol revealed a positive relationship with dose (mg/kg) (P < .001, P < .001, P < .001, and P = .003, respectively). Furthermore, isoniazid concentration was related to smoking (P = .009) and prior TB (P = .011), while rifampicin and pyrazinamide concentrations were correlated to sex (P = .004 and 0.025, respectively). Ethambutol concentration was associated with creatinine clearance (Ccr, P = .002).It is necessary to optimize drug doses using therapeutic drug monitoring while considering the following determinants: weight, smoking status, prior TB, sex, and Ccr. Furthermore, low 2 hours serum concentrations can be associated with longer culture conversion.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Case-Control Studies; China; Chromatography, Liquid; Creatinine; Dose-Response Relationship, Drug; Drug Monitoring; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Sex Factors; Smoking; Tuberculosis; Young Adult

2019
High prevalence of DR-TB (drug-resistant tuberculosis): An Indicator of public health negligence.
    Pakistan journal of pharmaceutical sciences, 2019, Volume: 32, Issue:4

    Tuberculosis (TB) is among the 10 most common worldwide causes of mortality. In Pakistan, estimated 510,000 tuberculosis patients had been diagnosed with an occurrence of 276/100,000. As per most recent global TB report 2018, Pakistan is amongst the 30 countries high TB with drug-resistant Mycobacterium tuberculosis particularly MDR (multi-drug resistant strains). A retrospective study had been designed using DR-TB patients' records from January 2013 to the December 2017 year from a public sector hospital in Karachi. Overall 315 drug-resistant tuberculosis patient's data had been incorporated in the study. All data had been analyzed using SPSS version 16 software. Chi-square test had been used to analyze the data with CI (confidence interval) 95% and level of significance 5%. The study result showed that 64.1% MDR patients, 27.9% MTB rifampicin resistance, 4.8% mono-drug resistant , XDR(1.6%), 1% poly-drug resistant and only 0.6% are MDR suspects showing no association of DR-TB with gender (p-value 0.787), age group (p-value 0.757), treatment outcomes (p-value 0.549), year of registration( p-value 0.206), first line treatment history(p-value 0.643) with a 95% confidence interval. The drug resistance TB cases have been periodically rising every year. Early identification is required to reduce the percent mortality and inhibit the disease transmission.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Pakistan; Prevalence; Public Health; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2019
SHORT COMMUNICATION-Pattern of anti-tuberculosis drugs susceptibility in new and previously treated tuberculosis patients and environmental risk factors investigation.
    Pakistan journal of pharmaceutical sciences, 2019, Volume: 32, Issue:4

    Resistance pattern both in newly and previously treated-TB patients and risk factors associated in spread of tuberculosis are investigated in the current study. A total 244 Mycobacterium tuberculosis isolates were used for drug-susceptibility test against four drugs. Environmental risk factors were assessed by using self-designed history proforma. Among 244 TB-isolates, 64% were categorized as MDR-TB in drug-susceptibility test. Male proportion was 51% while 32% belonged to 15-34 years age group and 49% were from city Lahore whereas majority of people (31%) was working on daily wages. Divergent drug-resistance pattern was obtained; RIF (68%), SM (52%), EMB (51%). INH showed only (27%) resistance against first-line anti-TB drug. Drug-resistance prevalence for two drug combination was highest (50%) for (INH+SM) and (INH+EMB) followed by (RIF+SM) (49%) whereas for three drugs combination (INH+RIF+EMB) and (INH+RIF+SM) the prevalence was almost same 50% and 49% respectively while 66% patients were categorized as previously treated and 34% as new TB cases. In drug susceptibility test, 71% were identified as MDR-TB among New TB cases, while 63% were identified as MDR-TB from previously treated cases. Surprisingly DST results displayed that percentage prevalence of MDR-TB both in newly and previously treated cases was almost same.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Environment; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pakistan; Prevalence; Rifampin; Risk Factors; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2019
Comparison of GeneXpert and line probe assay for detection of Mycobacterium tuberculosis and rifampicin-mono resistance at the National Tuberculosis Reference Laboratory, Kenya.
    BMC infectious diseases, 2019, Oct-15, Volume: 19, Issue:1

    The dual challenge of low diagnostic sensitivity of microscopy test and technical challenge of performing a TB culture test poses a problem for case detection and initiation of Tuberculosis (TB) second-line treatment. There is thus need for a rapid, reliable and easily accessible assay. This comparative analysis was performed to assess diagnostic performance characteristics of GeneXpert MTB/RIF and Line Probe Assay (LPA).. Three hundred twenty nine sputum samples of patients across the 47 counties in Kenya suspected to have drug resistant TB were picked and subjected to GeneXpert, LPA and Culture MGIT at the National TB Reference Laboratory. Sensitivity, specificity and predictive values were then determined to assess the performance characteristics of the various assays.. Against culture MGIT as the gold standard for TB diagnosis, GeneXpert had a sensitivity, specificity, positive predictive value, and negative predictive value of 78.5, 64.9, 59.4 and 82.2% respectively while LPA had 98.4, 66.0, 65.4 and 98.4%. For diagnosis of rifampicin mono-resistance GeneXpert had a moderate agreement (Kappa 0.59, P < 0.01) (sensitivity 62.50%, specificity 96.50%) while LPA that had almost perfect agreement (Kappa = 0.89, p < 0.01) with a (sensitivity 90.0% and specificity 99.1%).. LPA has a better performance characteristic to GeneXpert and an alternative to culture with regards to detection of RIF's mono-resistance.

    Topics: Bacterial Proteins; Drug Resistance, Bacterial; Female; Humans; Kenya; Male; Multiplex Polymerase Chain Reaction; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Oxidoreductases; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2019
[Tuberculosis].
    Der Internist, 2019, Volume: 60, Issue:11

    Tuberculosis is a bacterial infectious disease that is usually transmitted by inhalation of droplets containing the bacteria. The World Health Organization (WHO) estimates that approximately 10 million patients were newly diagnosed with tuberculosis in 2017. Rapid diagnosis relies on a combination of imaging and microbiological, molecular, and, rarely, immunological tests. Genotypic methods enable early diagnosis and allow highly accurate prediction of drug resistance. Phenotypic (culture-based) methods are the diagnostic gold standard. Standard management of patients with pan drug-susceptible pulmonary tuberculosis includes a combination of rifampicin, isoniazid, ethambutol and pyrazinamide for 2 months followed by rifampicin and isoniazid for additional 4 months, which leads to cure rates of >80%. With individualized treatment schemes, similar cure rates can be achieved for patients with multidrug-resistant tuberculosis.

    Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2019
Genotyping of Mycobacterium tuberculosis Rifampin Resistance-Associated Mutations by Use of Data from Xpert MTB/RIF Ultra Enables Large-Scale Tuberculosis Molecular Epidemiology Studies.
    Journal of clinical microbiology, 2019, 12-23, Volume: 58, Issue:1

    Molecular epidemiology studies of tuberculosis have been empowered in recent years by the availability of whole-genome sequencing, which has allowed a new focus on the adaptive significance of drug resistance mutations. Genome sequencing technology remains expensive, however, limiting the potential for larger studies. Conversely, during this same time the GeneXpert molecular diagnostic method has been deployed globally and now serves as a cornerstone of tuberculosis diagnosis and drug sensitivity testing. In this issue, Y. Cao, H. Parmar, A. M. Simmons, D. Kale, et al. (J Clin Microbiol 57:e00907-19, 2019, https://doi.org/10.1128/JCM.00907-19) report the development of an algorithm that can use high-resolution melting temperature data generated in the course of analysis using the next-generation Xpert MTB/RIF Ultra assay to accurately genotype rifampin resistance-associated mutations. When paired with a system to aggregate data from diagnostic laboratories, this technique has the potential to enable studies on the global scale of the epidemiology of tuberculosis drug resistance.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Genotype; Humans; Molecular Epidemiology; Mutation; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Temperature; Tuberculosis

2019
A modular paper-and-plastic device for tuberculosis nucleic acid amplification testing in limited-resource settings.
    Scientific reports, 2019, 10-25, Volume: 9, Issue:1

    We present a prototype for conducting rapid, inexpensive and point-of-care-compatible nucleic acid amplification tests (NAATs) for tuberculosis (TB). The fluorescent isothermal paper-and-plastic NAAT (FLIPP-NAAT) uses paper-based loop mediated isothermal amplification (LAMP) for DNA detection. The cost of materials required to build a 12-test-zone device is $0.88 and the cost of reagents per reaction is $0.43. An inexpensive imaging platform enables filter-free fluorescence detection of amplified DNA using a cell-phone camera. FLIPP-NAAT can be operated by an untrained user and only requires a regular laboratory incubator as ancillary equipment. All reagents can be dry-stored in the device, facilitating storage and transportation without cold chains. The device design is modular and the assay demonstrated high specificity to Mycobacterium tuberculosis (Mtb), analytical sensitivity of the order of 10 copies of Mtb gDNA, and tolerance to complex samples. The clinical sensitivity and specificity of sputum-based FLIPP NAAT tests were 100% (zero false negatives) and 68.75% (five false positives), respectively (N = 30), using Xpert MTB/RIF assay as the reference standard. FLIPP-NAAT has the potential to provide affordable and accessible molecular diagnostics for TB in low- and middle-income countries, when used in conjunction with an appropriate sample preparation technique. Although demonstrated for the detection of TB, FLIPP-NAAT is a platform technology for amplification of any nucleic acid sequence.

    Topics: DNA; Fluorescence; Humans; Nucleic Acid Amplification Techniques; Plastics; Reagent Kits, Diagnostic; Rifampin; Tuberculosis

2019
[CME: Extrapulmonary Tuberculosis].
    Praxis, 2019, Volume: 108, Issue:15

    Topics: Antibiotics, Antitubercular; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2019
Data quality of drug-resistant tuberculosis and antiretroviral therapy electronic registers in South Africa.
    BMC public health, 2019, Dec-05, Volume: 19, Issue:1

    To assess the quality and completeness of treatment and outcome data in the electronic tuberculosis (TB) and antiretroviral treatment (ART) registers in drug-resistant (DR-) TB patients at three treatment facilities in South Africa.. We did a retrospective cohort study using routinely-collected data from DR-TB registers of rifampicin resistant adults (≥18 years old), on ART, initiating DR-TB treatment between January 2012 and December 2013. We linked patient information from the DR-TB register to the ART register using patient identifiers and an algorithm based on string edit distance and date of birth. We describe data gaps and discrepancies found.. Overall, 2852 DR-TB patients met our inclusion criteria based on the DR-TB register data, and of these, 1685 (59%) could be matched to the ART registers. An additional 253 patients from the DR-TB registers were found in the ART registers, having initiated ART, despite the DR-TB register indicating that they were not on ART (or this data was missing). 11% of matched patients did not have TB treatment status recorded in the ART register despite being recorded as being on TB treatment in the DR-TB register, and 78% did not have an ART start date recorded in DR-TB register despite being on ART treatment as per the ART register. 11% of matched patients had a death recorded in one register but not the other, and of those with death recorded in both, 15% of dates differed by > 1 month.. The underreporting of death and the lack of ART or TB status in the electronic DR-TB and ART registers could negatively impact monitoring efforts by downplaying the state of the TB/HIV epidemic. Improved recording of these data sources, and data integration across systems, could improve the accuracy of reporting for the national HIV/ART and TB programs.

    Topics: Adult; Anti-Retroviral Agents; Data Accuracy; Female; HIV Infections; Humans; Male; Registries; Retrospective Studies; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant

2019
Low diagnostic accuracy of Xpert MTB/RIF assay for extrapulmonary tuberculosis: A multicenter surveillance.
    Scientific reports, 2019, 12-06, Volume: 9, Issue:1

    Diagnostic accuracy of Xpert MTB/RIF assay for pulmonary tuberculosis (PTB) and extrapulmonary TB (EPTB) has not been investigated in Iran. This study was aimed to assess the diagnostic accuracy of Xpert MTB/RIF assay for both PTB and EPTB. A total of 2111 clinical samples (1218 pulmonary and 838 extra-pulmonary) were collected from 16 medical centers during the study period and were analyzed for detection of PTB and EPTB by both Xpert MTB/RIF assay and standard conventional methods (culture and direct smear microscopy). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of Xpert MTB/RIF assay for PTB were found to be 95.5%, 96.7%, 83.8%, and 99.1% respectively. For EPTB, the sensitivity, specificity, PPV and NPV of Xpert MTB/RIF assay counted for 76.5%, 95.9%, 62%, and 97.9% respectively. Xpert MTB/RIF assay found to be highly sensitive, specific and comparable to standard conventional methods for the diagnosis of PTB. However, the sensitivity and specificity of Xpert MTB/RIF for EPTB specimens were highly variable; thus, Xpert MTB/RIF cannot be recommended to replace standard conventional tests for diagnosis of EPTB.

    Topics: Antibiotics, Antitubercular; Cross-Sectional Studies; Drug Resistance, Bacterial; Humans; Iran; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Predictive Value of Tests; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2019
Realizing the "40 by 2022" Commitment from the United Nations High-Level Meeting on the Fight to End Tuberculosis: What Will It Take to Meet Rapid Diagnostic Testing Needs?
    Global health, science and practice, 2019, 12-23, Volume: 7, Issue:4

    The potential gains from full adoption of World Health Organization (WHO)-recommended rapid diagnostics (WRDs) for tuberculosis (TB) are significant, but there is no current analysis of the additional investment needed to reach this goal. We sought to estimate the necessary investment in instruments, tests, and money, using Xpert MTB/RIF (Xpert), which detects

    Topics: Algorithms; Antitubercular Agents; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis; United Nations

2019
Multicenter evaluation of TB-SPRINT 59-Plex Beamedex®: accuracy and cost analysis.
    BMC infectious diseases, 2019, Dec-10, Volume: 19, Issue:1

    Molecular tests can allow the rapid detection of tuberculosis (TB) and multidrug-resistant TB (MDR-TB). TB-SPRINT 59-Plex Beamedex® is a microbead-based assay developed for the simultaneous spoligotyping and detection of MDR-TB. The accuracy and cost evaluation of new assays and technologies are of great importance for their routine use in clinics and in research laboratories. The aim of this study was to evaluate the performance of TB-SPRINT at three laboratory research centers in Brazil and calculate its mean cost (MC) and activity-based costing (ABC).. TB-SPRINT data were compared with the phenotypic and genotypic profiles obtained using Bactec™ MGIT™ 960 system and Genotype® MTBDRplus, respectively.. Compared with MGIT, the accuracies of TB-SPRINT for the detection of rifampicin and isoniazid resistance ranged from 81 to 92% and 91.3 to 93.9%, respectively. Compared with MTBDRplus, the accuracies of TB-SPRINT for rifampicin and isoniazid were 99 and 94.2%, respectively. Moreover, the MC and ABC of TB-SPRINT were USD 127.78 and USD 109.94, respectively.. TB-SPRINT showed good results for isoniazid and rifampicin resistance detection, but still needs improvement to achieve In Vitro Diagnostics standards.

    Topics: Antitubercular Agents; Bacterial Proteins; Catalase; Costs and Cost Analysis; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Flow Cytometry; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Promoter Regions, Genetic; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Tuberculosis

2019
Evaluation of GeneXpert MTB/RIF system performances in the diagnosis of extrapulmonary tuberculosis.
    BMC infectious diseases, 2019, Dec-19, Volume: 19, Issue:1

    Tuberculosis represents a serious public health problem and a significant diagnostic and therapeutic challenge worldwide. Molecular diagnostic techniques are crucial in the World Health Organization's new tuberculosis control strategy. This study aims to evaluate the performance of GeneXpert MTB/RIF (Cepheid Sunnyvale, CA, United States) in diagnosis of extra-pulmonary tuberculosis then compare it's performance in detecting Rifampicin resistance to GenoType MTBDRplus (HAIN Life Sciences, Nehren, Germany).. Samples from pulmonary and/or extra-pulmonary origins were analysed in a 21 months retrospective study. Samples were sent to the bacteriology laboratory for Mycobacterium tuberculosis detection using conventional bacteriological and molecular methods (GeneXpert MTB/RIF and MTBDRplus). Sensitivity and specificity were calculated for the stained smear and GeneXpert according to culture (Gold Standard) as well as for GeneXpert MTB/RIF in both negative and positive microscopy tuberculosis cases. Data's statistical analysis was performed with SPSS13.0 software.. Seven hundred fourteen patients' samples were analysed; the average age was 47.21 ± 19.98 years with a male predominance (66.4%). Out of 714 samples: 285 were from pulmonary and 429 were from extra-pulmonary origins. The positivity rates for microscopy, GeneXpert MTB/RIF and culture were 12.88, 20.59 and 15.82%, respectively. These rates were 18.9, 23.85 and 20.35% for pulmonary samples and 9.71, 18.41 and 12.82% for extra-pulmonary samples, respectively. The sensitivity and specificity of GeneXpert MTB/RIF were almost the same in both pulmonary and extra-pulmonary samples (78.2 and 90.4%) and (79,3 and 90.3%) respectively. Rifampicin resistance rate found by GeneXpert MTB/RIF was 0.84%. Comparison of Rifampicin resistance obtained by GeneXpert MTB/RIF and Genotype MTBDRplus, showed 100% agreement between the two techniques for studied samples.. This confirms GeneXpert MTB/RIF advantage for tuberculosis diagnosis, particularly extra-pulmonary tuberculosis with negatively stained smear. The performance of GeneXpert and Genotype MTBDRplus are similar in detection of Rifampicin resistance. However, variability of detection performance according to tuberculosis endemicity deserves more attention in the choice of screening techniques of Rifampicin resistance, hence the interest of conducting comparative studies of detection performance under low and medium endemicity on large samples of tuberculosis populations.

    Topics: Adolescent; Adult; Aged; Diagnostic Tests, Routine; Drug Resistance, Multiple, Bacterial; Female; Genotype; Humans; Incidence; Male; Microscopy; Middle Aged; Molecular Diagnostic Techniques; Morocco; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis; Young Adult

2019
Performance of Xpert MTB/RIF Ultra and Xpert MTB/RIF for the Diagnosis of Tuberculosis through Testing of Formalin-fixed Paraffin-embedded Tissues.
    Biomedical and environmental sciences : BES, 2019, Volume: 32, Issue:12

    Topics: Adult; Drug Resistance, Bacterial; Female; Formaldehyde; Humans; Male; Mycobacterium tuberculosis; Paraffin Embedding; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tissue Fixation; Tuberculosis

2019
Evaluation of Xpert MTB/RIF Assay for Diagnosis of Tuberculosis in Children.
    Journal of tropical pediatrics, 2019, 02-01, Volume: 65, Issue:1

    Childhood tuberculosis (TB) is now a global priority. With the advent of Xpert MTB/RIF, more TB cases in children are being reported. This study was undertaken to evaluate the performance of Xpert in diagnosis of pulmonary and extra-pulmonary TB in children.. Specimens from 171 suspected TB cases in children aged <15 years were tested with Xpert, culture and smear microscopy in the Department of Microbiology, Institute of Medical Sciences, India.. The specimens included 106 gastric aspirates, 51 cerebrospinal fluids, 8 induced sputum and 6 lymph node aspirates. Xpert detected Mycobacterium tuberculosis in 19 cases (14 pulmonary and 5 extra-pulmonary), 7 of which were rifampicin-resistant. Sensitivity, specificity, positive predictive value and negative predictive value of Xpert compared with culture were 88.89, 98.04, 84.21 and 98.68%, respectively. The sensitivity was 100% in children aged 1-5 years and 6-10 years and in gastric aspirates.. Xpert is an efficient diagnostic tool in childhood tuberculosis.

    Topics: Child; Child, Preschool; DNA, Bacterial; Female; Gastric Juice; Humans; India; Male; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2019
Therapeutic Drug Monitoring: The Need for Practical Guidance.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2019, 03-05, Volume: 68, Issue:6

    Topics: Coinfection; Drug Monitoring; HIV; HIV Infections; Humans; Isoniazid; Rifampin; Sputum; Tuberculosis

2019
Rifampicin Alters Metformin Plasma Exposure but Not Blood Glucose Levels in Diabetic Tuberculosis Patients.
    Clinical pharmacology and therapeutics, 2019, Volume: 105, Issue:3

    The pharmacokinetic (PK) and clinical implications of combining metformin with rifampicin are relevant to increasing numbers of patients with diabetic tuberculosis (TB) across the world and are yet unclear. We assessed the impact of rifampicin on metformin PKs and its glucose-lowering effect in patients with diabetic TB by measuring plasma metformin and blood glucose during and after TB treatment. Rifampicin increased metformin exposure: plasma area under the plasma concentration-time curve from time point 0 to the end of the dosing interval (AUC

    Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Blood Glucose; Cohort Studies; Diabetes Mellitus, Type 2; Drug Interactions; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Rifampin; Tuberculosis; Young Adult

2019
A Case Series of Acute Kidney Injury During Anti-tuberculosis Treatment.
    Internal medicine (Tokyo, Japan), 2019, Feb-15, Volume: 58, Issue:4

    Objective The standard anti-tuberculosis (TB) regimen occasionally causes acute kidney injury (AKI). The major etiology is rifampicin-induced acute interstitial nephritis. However, the standard management of AKI induced by anti-TB drugs has yet to be established. Methods We retrospectively reviewed patients with TB who developed AKI after starting standard anti-TB treatment between 2006 and 2016 at a single TB center. The clinical characteristics and the management are described. Results Among 1,430 patients with active TB, 15 (1.01%) developed AKI. The mean age (standard deviation) was 61 years (18). The median (interquartile range) time to AKI development was 45 days (21-54 days). The median serum creatinine level before anti-TB treatment was 0.7 mg/dL (0.5-1.4 mg/dL), whereas the median peak serum creatinine level after AKI onset was 4.0 mg/dL (3.08-5.12 mg/dL). Five patients (33.3%) were pathologically confirmed as having acute interstitial nephritis (AIN), and 7 patients (46.7%) had a clinical diagnosis of the disease. All anti-TB drugs were stopped, and steroids were administered to 5 (100%) patients with pathologically confirmed AIN and 3 (42.8%) patients with clinically diagnosed AIN. The renal function was normalized in 12 patients (80.0%) after restarting anti-TB treatment without rifampicin (n=12) or isoniazid (n=1). Two patients died due to severe renal failure after restarting rifampicin. Conclusion Rifampicin is the leading cause of AKI. Levofloxacin may be an alternative to rifampicin thanks to its safety and potency. Restarting anti-TB treatment without rifampicin and short-term steroid administration may be a feasible management for AKI.

    Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Female; Humans; Japan; Male; Middle Aged; Nephritis, Interstitial; Retrospective Studies; Rifampin; Tuberculosis

2019
Comment on: The potential use of rifabutin for treatment of patients diagnosed with rifampicin-resistant tuberculosis.
    The Journal of antimicrobial chemotherapy, 2019, 03-01, Volume: 74, Issue:3

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Rifabutin; Rifampin; Treatment Outcome; Tuberculosis

2019
Revised Antituberculosis Drug Doses and Hepatotoxicity in HIV Negative Children.
    Indian journal of pediatrics, 2019, Volume: 86, Issue:3

    To compare the incidence of anti tuberculosis drug-induced hepatotoxicity (ATDH) with those on old vs. revised WHO doses in human immunodeficiency virus (HIV) negative children. The secondary objective was to determine the overall incidence of hepatitis in children on Anti tubercular treatment (ATT) and isoniazid prophylactic therapy (IPT).. Children attending pediatric outpatient / admitted in wards, on ATT/ IPT between January 2007 and December 2017 (11 y) were included. Children were divided into Group 1 (treated based on old doses, from January 2007 to December 2011) and Group 2 (treated based on revised doses from January 2012 to December 2017). Children with multi drug resistant tuberculosis (MDRTB) and pre-existing liver disease were excluded.. A total of 515 children were enrolled. Twelve children developed ATDH with an overall incidence of 2.3%. Five out of 260 (1.9%) developed hepatitis with old doses vs. 7 of the 255 (2.7%) with revised doses; this difference was not statistically significant. When calculated only for active TB (excluding children on IPT), overall incidence of hepatitis was 2.7%. Comparison between group 1 (2.04%) and group 2 (3.5%) was again not statistically significant. Ten out of 12 children who developed hepatitis were restarted on ATT without recurrence. No child on IPT developed hepatitis. There was no mortality.. Revised WHO dosing does not increase incidence of hepatitis compared to old dosing in HIV negative children. Overall incidence was 2.3%. Hepatitis did not occur with IPT.

    Topics: Adolescent; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Coinfection; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis; HIV; HIV Infections; Humans; Incidence; India; Infant; Isoniazid; Liver; Liver Function Tests; Male; Prospective Studies; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2019
Evaluation of the culture-enhanced Xpert MTB/RIF assay for the diagnosis of smear-negative tuberculosis.
    Medecine et maladies infectieuses, 2019, Volume: 49, Issue:6

    To evaluate a new tool for the early diagnosis of tuberculosis.. A total of 374 smear-negative clinical specimens from patients with suspected tuberculosis were evaluated using a new procedure consisting of a preliminary step of culture in broth bottles followed by the detection of Mycobacterium tuberculosis complex (Mtb) and rifampicin resistance by the Xpert MTB/RIF assay (XMTB-RIF).. A total of 30 Mtb strains were isolated, all susceptible to rifampicin. When broth cultures were subjected to XMTB-RIF analysis after 15 days of incubation, sensitivity, specificity, PPV, and NPV were each 100% when compared with liquid culture.. The XMTB-RIF assay used in 15-day broth cultures may provide a final culture result for smear-negative specimens. This process, combined with clinical signs, may contribute to rapidly diagnosing tuberculosis and also to the early reevaluation of empirical antituberculosis treatment.

    Topics: Antitubercular Agents; Bacterial Typing Techniques; Biopsy; Cytodiagnosis; Diagnosis, Differential; Drug Resistance, Bacterial; Early Diagnosis; False Negative Reactions; Humans; Microbiological Techniques; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2019
Bacteriologically confirmed extra pulmonary tuberculosis and treatment outcome of patients consulted and treated under program conditions in the littoral region of Cameroon.
    BMC pulmonary medicine, 2019, Jan-17, Volume: 19, Issue:1

    Extra-pulmonary tuberculosis (EPTB) is defined as any bacteriologically confirmed or clinically diagnosed case of TB involving organs other than the lungs. It is frequently a diagnostic and therapeutic challenge with paucity of data available. The aim of this study was to assess the prevalence of bacteriologically confirmed EPTB; to determine the most affected organs and to evaluate the therapeutic outcome of EPTB patients treated under program conditions in the littoral region of Cameroon.. A descriptive cross-sectional laboratory-based epidemiological survey was conducted from January 2016 to December 2017 and 109 specimens from 15 of the 39 diagnosis and treatment centers in the littoral region were obtained. Two diagnostic methods (Gene Xpert MTB and culture (LJ and MGIT) were used for EPTB diagnosis. Determine HIV1/2 and SD Biolinewere used for HIV diagnosis. Confirmed EPTB cases were treated following the national tuberculosis guide.. The prevalence of bacteriologically confirmed EPTB was 41.3% (45). All 45 cases were sensitive to rifampicin. Males were predominately more infected [26 (57.8%)] likewise the age group 31-45 years with 15 (33.3%) cases. The overall prevalence for HIV was 33.6% (36). HIV infection was present in 28.9% (13) of patients with EPTB. The most affected sites with EPTB were: Lymph nodes (66.5%), pleural cavity (15.6%), abdominal organs (11.1%), neuromeningeal (2.2%), joints (2.2%) and heart (2.2%). Overall, 84.4% of the study participants had a therapeutic success with males responding better 57.9% (p = 0.442). Therapeutic success was better (71.7%) in HIV negative EPTB patients (p = 0.787).. The prevalence of bacteriologically confirmed EPTB patients treated under program conditions in the littoral region of Cameroon is high with a therapeutic success of 84.4% and the lymph nodes is the most affected site.

    Topics: Adolescent; Adult; Antitubercular Agents; Cameroon; Coinfection; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Prevalence; Rifampin; Sex Factors; Treatment Outcome; Tuberculosis; Tuberculosis, Cardiovascular; Tuberculosis, Central Nervous System; Tuberculosis, Lymph Node; Tuberculosis, Osteoarticular; Tuberculosis, Pleural; Young Adult

2019
Advantages of the AdvanSure MDR-TB GenoBlot assay containing disputed rpoB mutation-specific probes in a routine clinical laboratory setting.
    Respiratory medicine, 2019, Volume: 146

    The AdvanSure MDR-TB GenoBlot Assay detects isoniazid- and rifampin-resistant tuberculosis using mutation-specific probes, including probes to disputed rpoB mutations. The aim of this study was to evaluate the clinical usefulness of molecular drug susceptibility testing (DST) using the AdvanSure assay with weekly batch testing in routine clinical laboratory settings in a country with an intermediate tuberculosis burden.. The AdvanSure assay was evaluated against an absolute concentration (AC) method and the Mycobacterial Growth Indicator Tube (MGIT) 960 System, which are phenotypic DST methods, using 496 Mycobacterium tuberculosis (MTB) isolates. We retrospectively reviewed and compared DST results and turnaround times (TATs), the time intervals from MTB culture identification to final reporting, for these methods.. For rifampin, the AdvanSure assay showed 99.2% (492/496) concordance with both the AC and MGIT methods. AdvanSure also detected an rpoB mutation (D516Y) conferring low-level resistance in three isolates categorized as rifampin-susceptible by both phenotypic DST methods. For isoniazid, AdvanSure concordance rates with the AC method and MGIT DST were 96.6% (479/496) and 95.4% (473/496), respectively. The median TAT of AdvanSure in weekly batch testing was 5.8 days, shorter than the times for the phenotypic DST methods, which were 35.1 days for the AC method and 8.9 days for MGIT DST.. AdvanSure shows promising clinical usefulness for rapid detection of rifampin- and/or isoniazid-resistant tuberculosis when used as a complementary method to phenotypic DST assays in weekly batch testing. Furthermore, MTB isolates with disputed mutations for rifampin resistance were detectable by the AdvanSure assay.

    Topics: Bacterial Proteins; Diagnostic Tests, Routine; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Tertiary Healthcare; Time Factors; Tuberculosis

2019
Personalized Tuberculosis Treatment Through Model-Informed Dosing of Rifampicin.
    Clinical pharmacokinetics, 2019, Volume: 58, Issue:6

    This study proposes a model-informed approach for therapeutic drug monitoring (TDM) of rifampicin to improve tuberculosis (TB) treatment.. Two datasets from pulmonary TB patients were used: a pharmacokinetic study (34 patients, 373 samples), and TDM data (96 patients, 391 samples) collected at Radboud University Medical Center, The Netherlands. Nine suitable population pharmacokinetic models of rifampicin were identified in the literature and evaluated on the datasets. A model developed by Svensson et al. was found to be the most suitable based on graphical goodness of fit, residual diagnostics, and predictive performance. Prediction of individual area under the concentration-time curve from time zero to 24 h (AUC. A sampling strategy using 2- and 4-h blood collection was selected to be the most suitable. The bias and precision of the two strategies were comparable, except that the linear regression strategy was more biased in prediction of the AUC. Blood sampling at 2 and 4 h, combined with model-based prediction, can be used instead of the currently used linear regression strategy, shortening the sampling by 2 h and one sampling point without performance loss while simultaneously offering flexibility in sampling times.

    Topics: Antitubercular Agents; Area Under Curve; Datasets as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Humans; Linear Models; Models, Biological; Precision Medicine; Rifampin; Tuberculosis

2019
Efficacy and tolerability of desensitization in the treatment of delayed drug hypersensitivities to anti-tuberculosis medications.
    Respiratory medicine, 2019, Volume: 147

    Delayed drug hypersensitivity to first-line anti-tuberculosis medication is a major challenge in tuberculosis treatment.. This study was performed to investigate the efficacy/tolerability of desensitization therapy in treatment of first-line anti-tuberculosis medication hypersensitivity and the usefulness of immunologic evaluation therein.. This study was conducted as a prospective, observational cohort study. Subjects who experienced hypersensitivity reactions, including maculopapular exanthema (MPE) and drug reaction with eosinophilia and systemic symptoms (DRESS), to first-line anti-tuberculosis medications (isoniazid [INH], ethambutol [EMB], rifampin [RFP], and pyrazinamide [PZA]) were enrolled. Patch, intradermal, lymphocyte transformation, and oral provocation tests were performed to determine culprit drugs, which were desensitized with rapid and graded challenge protocols. Breakthrough reactions (BTRs) during or after desensitization were assessed.. In total, 31 desensitization treatments (INH, 8; EMB, 8; RFP, 11; PZA, 4) to 12 patients (8 with MPE and 4 with DRESS) were performed. The overall success rate of desensitization was 80.7%. All the study subjects except one completed the full course of anti-tuberculosis treatment. The overall BTR free rate was 64.5%. Sixteen (80%) treatments for MPE and four (36.4%) for DRESS were BTR free (P = 0.023). Drugs that were positive on any two of three immunologic studies showed significantly high BTR rates (P = 0.014), although this was not correlated with desensitization failure rate.. Rapid desensitization therapy to multiple anti-tuberculosis medications for delayed drug hypersensitivity was safe and successful. Combination of multiple immunologic evaluations may predict BTR although it needs validation in larger studies.

    Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Desensitization, Immunologic; Drug Hypersensitivity; Ethambutol; Female; Humans; Incidence; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis

2019
Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis.
    Pharmacogenomics, 2019, Volume: 20, Issue:4

    We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin.. Genotypes for SLCO1B1, NAT2, PXR, ABCB1 and UGT1A genes were determined using a TaqMan. Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively. Of the 58 patients contributing drug concentrations, rapid and intermediate acetylators had 2.3- and 1.6-times faster isoniazid clearance than slow acetylators. No association was observed between rifampicin pharmacokinetics and SLCO1B1, ABCB1, UGT1A or PXR genotypes.. Clinical relevance of the effects of genetic variation on isoniazid concentrations and low first-line tuberculosis drug exposures observed require further investigation.

    Topics: Adult; Arylamine N-Acetyltransferase; ATP Binding Cassette Transporter, Subfamily B; Female; Genotype; Glucuronosyltransferase; Humans; Isoniazid; Liver-Specific Organic Anion Transporter 1; Male; Polymorphism, Single Nucleotide; Recurrence; Rifampin; Tuberculosis

2019
The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study.
    Clinical pharmacology and therapeutics, 2019, Volume: 106, Issue:2

    Unsatisfactory treatment outcomes have been reported in patients coinfected with HIV/tuberculosis (TB). The aim of this study was to assess the influence of single-nucleotide polymorphisms (SNPs) in genes encoding for proteins involved in antitubercular drug disposition or effect. A pharmacogenetic study was conducted in Kampala, Uganda, where all analysis was performed. The impact of SNPs on antitubercular drug exposure, adverse events, and treatment outcomes was evaluated in patients coinfected with HIV/TB receiving treatments for both conditions. In 221 participants, N-acetyltransferase 2 (NAT2; rs1799930), solute carrier organic anion transporter family member 1B1 (SLCO1B1; rs4149032), and pregnane X receptor (PXR; rs2472677) variants affected isoniazid exposure in multivariate analysis. Most patients were deemed cured (163; 73.8%), yet PXR 63396TT carriers had a higher probability of death (P = 0.007) and of worsening peripheral neuropathy (P = 0.018). In this exploratory study in Ugandan patients coinfected with HIV/TB, genetic variants in PXR, SLCO1B1, and NAT2 were moderately associated with isoniazid exposure, whereas PXR 63396TT carriers showed worse outcomes.

    Topics: Adult; Antitubercular Agents; Arylamine N-Acetyltransferase; Correlation of Data; Female; HIV Infections; Humans; Isoniazid; Liver-Specific Organic Anion Transporter 1; Male; Outcome Assessment, Health Care; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Pregnane X Receptor; Rifampin; Tuberculosis; Uganda

2019
Rifampicin Nanoformulation Enhances Treatment of Tuberculosis in Zebrafish.
    Biomacromolecules, 2019, 04-08, Volume: 20, Issue:4

    Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of alveolar macrophages. These cells avidly take up nanoparticles, even without the use of specific targeting ligands, making the use of nanotherapeutics ideal for the treatment of such infections. Methoxy poly(ethylene oxide)- block-poly(ε-caprolactone) nanoparticles of several different polymer blocks' molecular weights and sizes (20-110 nm) were developed and critically compared as carriers for rifampicin, a cornerstone in tuberculosis therapy. The polymeric nanoparticles' uptake, consequent organelle targeting and intracellular degradation were shown to be highly dependent on the nanoparticles' physicochemical properties (the cell uptake half-lives 2.4-21 min, the degradation half-lives 51.6 min-ca. 20 h after the internalization). We show that the nanoparticles are efficiently taken up by macrophages and are able to effectively neutralize the persisting bacilli. Finally, we demonstrate, using a zebrafish model of tuberculosis, that the nanoparticles are well tolerated, have a curative effect, and are significantly more efficient compared to a free form of rifampicin. Hence, these findings demonstrate that this system shows great promise, both in vitro and in vivo, for the treatment of tuberculosis.

    Topics: Animals; Disease Models, Animal; Drug Carriers; Humans; Macrophages; Mice; Mycobacterium tuberculosis; Nanoparticles; RAW 264.7 Cells; Rifampin; Tuberculosis; Zebrafish

2019
Rifampicin and rifabutin resistance in 1003 Mycobacterium tuberculosis clinical isolates.
    The Journal of antimicrobial chemotherapy, 2019, 06-01, Volume: 74, Issue:6

    Drug-resistant TB remains a public health challenge. Rifamycins are among the most potent anti-TB drugs. They are known to target the RpoB subunit of RNA polymerase; however, our understanding of how rifamycin resistance is genetically encoded remains incomplete. Here we investigated rpoB genetic diversity and cross-resistance between the two rifamycin drugs rifampicin and rifabutin.. We performed WGS of 1003 Mycobacterium tuberculosis clinical isolates and determined MICs of both rifamycin agents on 7H10 agar using the indirect proportion method. We generated rpoB mutants in a laboratory strain and measured their antibiotic susceptibility using the alamarBlue reduction assay.. Of the 1003 isolates, 766 were rifampicin resistant and 210 (27%) of these were rifabutin susceptible; 102/210 isolates had the rpoB mutation D435V (Escherichia coli D516V). Isolates with discordant resistance were 17.2 times more likely to harbour a D435V mutation than those resistant to both agents (OR 17.2, 95% CI 10.5-27.9, P value <10-40). Compared with WT, the D435V in vitro mutant had an increased IC50 of both rifamycins; however, in both cases to a lesser degree than the S450L (E. coli S531L) mutation.. The observation that the rpoB D435V mutation produces an increase in the IC50 of both drugs contrasts with findings from previous smaller studies that suggested that isolates with the D435V mutation remain rifabutin susceptible despite being rifampicin resistant. Our finding thus suggests that the recommended critical testing concentration for rifabutin should be revised.

    Topics: Antitubercular Agents; Bacterial Proteins; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifabutin; Rifampin; Tuberculosis

2019
Metformin induced autophagy in diabetes mellitus - Tuberculosis co-infection patients: A case study.
    The Indian journal of tuberculosis, 2019, Volume: 66, Issue:1

    Metformin (MET) is a potential combination drug to elevate anti-TB efficacy. However, the clinical effect, especially smear reversion, during metformin applied with anti-tuberculosis and insulin in patients with type 2 DM newly TB co-infection were remain unknown. An observational clinical study was done in DM newly TB co-infection outpatients at Surabaya Paru Hospital. This study evaluated MET therapy, at least 2 months, accompanying with insulin and anti-TB regimens and compared to comparison group. The smear, microtubule-associated Protein1 Light Chain 3B (MAP1LC3B) level, as the presentation of autophagy, Superoxide Dismutase (SOD) level, Interferon (IFN)-γ and Interleukin (IL)-10 levels were evaluated twice. From 42 participants in this study, 22 participants of observation group that received additional MET therapy, 100% had sputum smear reversion after 2-months intensive phase of anti-TB therapy. Whereas 25% of 20 participants of comparison group did not undergo reversion inserts sputum smear. As conclusion, MET has the potential of being an additive combination therapy to enhance the bactericidal effect of anti-TB on DM-TB coinfection patients. Metformin enhances the effects of anti-TB and insulin therapy in increasing the smear reversion by increasing autophagy.

    Topics: Adult; Antitubercular Agents; Autophagy; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Ethambutol; Humans; Hypoglycemic Agents; Insulin; Interferon-gamma; Interleukin-10; Isoniazid; Leukocytes, Mononuclear; Metformin; Microtubule-Associated Proteins; Middle Aged; Pyrazinamide; Rifampin; Sputum; Superoxide Dismutase; Tuberculosis

2019
Mycobacterium tuberculosis infection and resistance to rifampicin with GeneXpert®MTB/RIF: a single-center experience on bronchoalveolar lavage samples in renal failure patients.
    JPMA. The Journal of the Pakistan Medical Association, 2019, Volume: 69, Issue:2

    Patients with end-stage renal disease (ESRD) are immunocompromised and are more at risk to develop and acquire Mycobacterium tuberculosis (MTB) infection. However, risk assessment is uncertain. The objective of current research was to study the frequency of MTB infection in ESRD patients . For this purpose, bronchoalveolar lavage (BAL) samples were evaluated for the presence of MTB by using GeneXpert®MTB/RIF test. We analysed 350 clinical samples of BAL collected from a tertiary care hospital in Pakistan, from September, 2015 to July, 2016. We performed the GeneXpert®test on each sample. According to our results prevalence of MTB was observed in 1.7% of bronchoalveolar lavage (BAL) samples taken from patients with chronic kidney diseases. All the positive samples were susceptible to rifampicin. There is a low prevalence of MTB infec tion (pulmonar y tuberculosis) in patients with chronic kidney disease in our setup. Suspected patients can be diagnosed by using GeneXpert®MTB/RIF testing on bronchoalveolar lavage samples.

    Topics: Antibiotics, Antitubercular; Bronchoalveolar Lavage Fluid; Female; Humans; Immunocompromised Host; Kidney Failure, Chronic; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pakistan; Prevalence; Rifampin; Risk Assessment; Tertiary Care Centers; Tuberculosis

2019
Rapid direct drug susceptibility testing of
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2019, 02-01, Volume: 23, Issue:2

    Early diagnosis and drug susceptibility testing are important for anti-tuberculosis treatment.. To develop a rapid method for detecting. The sensitivity and specificity of. Culture ddPCR could detect

    Topics: Antitubercular Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Streptomycin; Tuberculosis

2019
A Short Regimen for Rifampin-Resistant Tuberculosis.
    The New England journal of medicine, 2019, 03-28, Volume: 380, Issue:13

    Topics: Humans; Pyrazinamide; Rifampin; Tuberculosis

2019
Ending Tuberculosis through Prevention.
    The New England journal of medicine, 2019, 03-14, Volume: 380, Issue:11

    Topics: HIV; Humans; Isoniazid; Rifampin; Tuberculosis

2019
High-dose rifampicin in tuberculosis: Experiences from a Dutch tuberculosis centre.
    PloS one, 2019, Volume: 14, Issue:3

    Recent evidence suggests that higher rifampicin doses may improve tuberculosis (TB) treatment outcome.. In this observational cohort study we evaluated all TB patients who were treated with high-dose rifampicin (> 10 mg/kg daily) in our reference centre, from January 2008 to May 2018. Indications, achieved plasma rifampicin exposures, safety and tolerability were evaluated.. Eighty-eight patients were included. The main indications were low plasma concentrations (64.7%) and severe illness (29.5%), including central nervous system TB. Adjusted rifampicin dosages ranged from 900 mg to a maximum of 2400 mg (corresponding to 32 mg/kg) per day. Patients with severe illness received high-dose rifampicin immediately, the others had a higher dosage guided by therapeutic drug monitoring. Four patients developed hepatotoxicity, of which two were proven due to isoniazid. Re-introduction of high-dose rifampicin was successful in all four. Eighty-seven patients tolerated high-dose rifampicin well throughout treatment. Only one patient required a dose reduction due to gastro-intestinal disturbance.. High-dose rifampicin, used in specific groups of patients in our clinical setting, is safe and well-tolerated for the whole treatment duration. Measurement of drug exposures could be used as a tool/guide to increase rifampicin dosage if a reduced medication absorption or a poor treatment outcome is suspected. We suggest to administer high-dose rifampicin to patients with severe manifestations of TB or low rifampicin exposure to improve treatment outcome.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Area Under Curve; Central Nervous System; Cohort Studies; Drug Administration Schedule; Drug Monitoring; Female; Humans; Isoniazid; Liver; Male; Middle Aged; Netherlands; Patient Safety; Rifampin; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

2019
Sequencing of the entire rpob gene and characterization of mutations in isolates of Mycobacterium tuberculosis circulating in an endemic tuberculosis setting.
    Journal of global antimicrobial resistance, 2019, Volume: 19

    To evaluate the use of a sequencing procedure for the entire rpoB gene of Mycobacterium tuberculosis to identify mutations pre-rifampicin resistance determining region (RRDR), within RRDR, and post-RRDR in isolates circulating in a region affected by tuberculosis (TB).. Five primers were designed, with which five DNA fragments of rpoB were obtained, sequenced by Sanger, and analysed in silico in order to identify mutations over the entire rpoB gene in rifampicin-sensitive and rifampicin-resistant TB.. It was possible to analyse the entire rpoB gene in five rifampicin-sensitive and 15 rifampicin-resistant isolates. Thirty-six mutations were identified. Two mutations were found pre-RRDR, nine within-RRDR and 25 post-RRDR. The most frequent mutations within RRDR were S531L (53%), followed by S512T (20%), all of which were found in rifampicin-resistant isolates. Of the 25 mutations found post-RRDR, 14 were only in resistant isolates, and the most frequent was D853N, which was present in 85% of isolates. Mutations E818K, D836N and T882P were observed in 80% of the rifampicin-resistant and rifampicin-sensitive isolates.. The proposed sequencing method allowed identification of mutations in the entire rpoB gene. This procedure represents a useful tool for diagnosing rifampicin resistance. The number of mutations that were found raises new questions about the diversity of mutations in the rpoB gene and their role in rifampicin resistance in regions where TB is endemic.

    Topics: Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Endemic Diseases; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifampin; Sequence Analysis, DNA; Tuberculosis

2019
Genetic polymorphisms of long noncoding RNA RP11-37B2.1 associate with susceptibility of tuberculosis and adverse events of antituberculosis drugs in west China.
    Journal of clinical laboratory analysis, 2019, Volume: 33, Issue:5

    Little knowledge about the biological functions of RP11-37B2.1, a newly defined long noncoding RNA (lncRNA) molecule, is currently available. Previous studies have shown rs160441, located in the RP11-37B2.1 gene, is significantly associated with tuberculosis (TB) in a Ghanaian and the Gambian populations.. We investigated the influence of single-nucleotide polymorphisms (SNPs) within lncRNA RP11-37B2.1 on the risk of TB and the possible correlation with adverse drug reactions (ADRs) from TB treatment in a Western Chinese population. Four SNPs within lncRNA RP11-37B2.1 were genotyped in 554 TB cases and 561 healthy subjects using the improved multiplex ligation detection reaction method, and the patients were followed up monthly to monitor the development of ADRs.. No significant association between the SNPs of lncRNA RP11-37B2.1 and TB susceptibility was observed (all P > 0.05). Surprisingly, significant association was observed between two SNPs (rs218916 and rs160441) and thrombocytopenia development during anti-TB therapy under the dominant model (P = 0.003 and 0.014, respectively).. Our findings firstly exhibit that rs218916 and rs160441 within lncRNA RP11-37B2.1 significantly associate with the occurrence of thrombocytopenia and suggest RP11-37B2.1 genetic variants are potential biosignatures for thrombocytopenia during anti-TB treatment.

    Topics: Adult; Anemia; Antitubercular Agents; Asian People; Case-Control Studies; China; Female; Genetic Predisposition to Disease; Humans; Isoniazid; Leukopenia; Male; Middle Aged; Polymorphism, Single Nucleotide; Prospective Studies; Rifampin; RNA, Long Noncoding; Thrombocytopenia; Tuberculosis

2019
Successfully Engaging Private Providers to Improve Diagnosis, Notification, and Treatment of TB and Drug-Resistant TB: The EQUIP Public-Private Model in Chennai, India.
    Global health, science and practice, 2019, 03-22, Volume: 7, Issue:1

    Private physicians in India see and treat more than half of all people with tuberculosis (TB) each year and thus have potential to make significant contributions to TB control. The EQUIP project was designed as a prospective cohort study to assess the potential of private providers to diagnose and appropriately treat drug-resistant TB (DR-TB) in the Central and South districts of Chennai, India.. The private-sector engagement model consisted of free access to rapid diagnostics; choice of free daily or thrice-weekly treatment regimens; support for notification of patients; and patient support including directly observed therapy through EQUIP centers staffed by a community-based interface agency. Data were collected on provider participation; referral results; treatment regimens prescribed; and treatment outcomes.. From October 2015 through June 2017, 227 of the 466 (48.7%) private providers approached referred at least 1 patient to an EQUIP center for evaluation. A total of 2,621 patients received testing and 1,232 (47.0%) were diagnosed with TB. Of those, 727 (59.0%) were bacteriologically confirmed, including 694 (56.3%) using GeneXpert and 33 (2.7%) using smear microscopy. A total of 26 (3.7% of GeneXpert diagnosed) patients were confirmed as rifampicin-resistant cases. EQUIP-related notifications comprised approximately 10% of TB and DR-TB notifications in Chennai during the project period. The project initiated 1,167 (96.8%) drug-sensitive TB patients on treatment. Of those, 691 (59.2%) received standard daily regimens with EQUIP support and 288 (24.7%) received standard intermittent regimens. At the time of writing, 89.4% of 868 drug-susceptible TB patients receiving EQUIP support had treatment success. Of the 26 rifampicin-resistant TB cases notified, 20 (77%) started and continued on second-line treatment; 2 died and 4 were lost to follow-up prior to treatment initiation.. Private providers can make a substantial contribution to detection and appropriate treatment of patients with TB and DR-TB in India when provided with access to rapid diagnostics, support for notification and patient treatment through interface agencies, and free, quality anti-TB drugs.

    Topics: Communication; Diagnostic Services; Disclosure; Drug Resistance, Multiple; Humans; India; Physicians; Private Practice; Private Sector; Program Evaluation; Prospective Studies; Public Health; Public-Private Sector Partnerships; Quality Improvement; Referral and Consultation; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2019
Treatment-Shortening Effect of a Novel Regimen Combining Clofazimine and High-Dose Rifapentine in Pathologically Distinct Mouse Models of Tuberculosis.
    Antimicrobial agents and chemotherapy, 2019, Volume: 63, Issue:6

    Clofazimine and high-dose rifapentine have each separately been associated with treatment-shortening activity when incorporated into tuberculosis (TB) treatment regimens. We hypothesized that both modifications, i.e., the addition of clofazimine and the replacement of rifampin with high-dose rifapentine, in the first-line regimen for drug-susceptible TB would significantly shorten the duration of treatment necessary for cure. We tested this hypothesis in a well-established BALB/c mouse model of TB chemotherapy and also in a C3HeB/FeJ mouse model in which mice can develop caseous necrotic lesions, an environment where rifapentine and clofazimine may individually be less effective. In both mouse models, replacing rifampin with high-dose rifapentine and adding clofazimine in the first-line regimen resulted in greater bactericidal and sterilizing activity than either modification alone, suggesting that a rifapentine- and clofazimine-containing regimen may have the potential to significantly shorten the treatment duration for drug-susceptible TB. These data provide preclinical evidence supporting the evaluation of regimens combining high-dose rifapentine and clofazimine in clinical trials.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Clofazimine; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Rifampin; Tuberculosis

2019
Anthropometric and Genetic Factors Associated With the Exposure of Rifampicin and Isoniazid in Mexican Patients With Tuberculosis.
    Therapeutic drug monitoring, 2019, Volume: 41, Issue:5

    Tuberculosis (TB) remains a critical infectious, contagious disease worldwide with high prevalence and mortality rate. The directly observed treatment short-course therapy includes rifampicin (RMP) and isoniazid (INH) for at least 6 months. The purposes of this scheme are to interrupt the transmissibility of the Mycobacterium tuberculosis complex and to avoid secondary complications. Low plasma concentrations of these anti-TB drugs have been associated with extended treatment duration, therapeutic failure, and relapse. The determination of anthropometric, genetic, and clinical variables that may affect plasma concentrations of RMP and INH might facilitate the detection of patients at increased risk of therapeutic failure.. A prospective observational study was performed in patients with TB diagnosis. A fixed-dose combined formulation was administered following clinical guidelines, and 12 venous blood samples were collected within 24 hours after dose for the quantification of plasma levels of RMP and INH by high-performance liquid chromatography-ultraviolet. The plasma concentrations versus time for each drug in each patient were assessed by a noncompartmental approach to obtain Cmax, and the area under the concentration-time curve to the last observation point (AUC0-24 h) was calculated by the linear trapezoidal rule. Genetic polymorphisms of the enzyme involved in INH metabolism (NAT2) and proteins involved in RMP transport (glycoprotein-P and OATP1B1) were determined.. A total of 34 patients aged between 18 and 72 years with the diagnosis of TB were included in the current study. A multivariate analysis was performed to determine the anthropometric and genetic characteristics that modified the Cmax and AUC0-24 h of RMP and INH. Results indicated that RMP Cmax and AUC0-24 h were affected by sex, dose/weight, and single nucleotide polymorphism of MDR1. In addition, age, body mass index, and NAT2 acetylator genotype were shown to determine the Cmax and AUC0-24 h for INH.. Anthropometric, genetic, and dosage characteristics of Mexican patients with TB are an important source of risk for subtherapeutic plasma concentrations of anti-TB drugs. Factors such as lower-than-recommended RMP dose, male patients with TB, and MDR1 3435 genotype, in addition to age group, body mass index, and INH acetylator phenotype based on NAT2 genotype, should be considered during treatment.

    Topics: Adolescent; Adult; Aged; Anthropometry; Antibiotics, Antitubercular; Antitubercular Agents; Arylamine N-Acetyltransferase; ATP Binding Cassette Transporter, Subfamily B, Member 1; Chromatography, High Pressure Liquid; Female; Genotype; Humans; Isoniazid; Male; Mexico; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Prospective Studies; Rifampin; Tuberculosis; Young Adult

2019
Xpert MTB/RIF Ultra for Detection of Mycobacterium tuberculosis in Cerebrospinal Fluid.
    Journal of clinical microbiology, 2019, Volume: 57, Issue:6

    Topics: Antibiotics, Antitubercular; Coinfection; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2019
Prevalence of rifampicin resistant Mycobacterium tuberculosis among presumptive tuberculosis patients in selected governmental hospitals in Addis Ababa, Ethiopia.
    BMC infectious diseases, 2019, Apr-04, Volume: 19, Issue:1

    Rapid detection of rifampicin resistance is essential for early management and prevention of transmission of multidrug-resistant tuberculosis (MDR-TB). We studied the prevalence of rifampicin resistance of Mycobacterium tuberculosis (MTB) among presumptive TB patients in Addis Ababa, Ethiopia.. A retrospective cross sectional study was conducted in three referral hospitals and the regional laboratory in Addis Ababa city from March 2015 to October 2017. Data was collected by data-extraction sheet from registration books. It was analyzed using SPSS version 20. Statistically significant association was taken with P < 0.05.. A total of 12,414 (11,672 adults and 742 paediatrics) TB presumptive patients were included in the study. The overall prevalence of TB was 15.11% (1876/12414) in all age groups and 13.6%(101/742) among paediatric population. Rifampicin resistant TB was 9.9% (186/1876) in all TB confirmed cases and 7.9% (8/101) in paediatric TB patients. The prevalence of rifampicin resistant TB among new and previously treated was 7.6 and 27.4%, respectively. Sex (being female) and previous TB treatment were significantly associated with rifampicin resistant TB.. Rifampicin-resistant TB is prevalent both among adult and paediatric TB patients. The strong association of rifampicin resistance with previous treatment in this study suggests the need to improve and monitor the treatment to limit the emergence of drug resistant TB.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Child; Child, Preschool; Cross-Sectional Studies; Drug Resistance, Bacterial; Ethiopia; Female; Hospitals, Public; Humans; Infant; Male; Middle Aged; Prevalence; Retrospective Studies; Rifampin; Sex Factors; Tuberculosis; Young Adult

2019
Outlook for tuberculosis elimination in California: An individual-based stochastic model.
    PloS one, 2019, Volume: 14, Issue:4

    As part of the End TB Strategy, the World Health Organization calls for low-tuberculosis (TB) incidence settings to achieve pre-elimination (<10 cases per million) and elimination (<1 case per million) by 2035 and 2050, respectively. These targets require testing and treatment for latent tuberculosis infection (LTBI).. To estimate the ability and costs of testing and treatment for LTBI to reach pre-elimination and elimination targets in California.. We created an individual-based epidemic model of TB, calibrated to historical cases. We evaluated the effects of increased testing (QuantiFERON-TB Gold) and treatment (three months of isoniazid and rifapentine). We analyzed four test and treat targeting strategies: (1) individuals with medical risk factors (MRF), (2) non-USB, (3) both non-USB and MRF, and (4) all Californians. For each strategy, we estimated the effects of increasing test and treat by a factor of 2, 4, or 10 from the base case. We estimated the number of TB cases occurring and prevented, and net and incremental costs from 2017 to 2065 in 2015 U.S. dollars. Efficacy, costs, adverse events, and treatment dropout were estimated from published data. We estimated the cost per case averted and per quality-adjusted life year (QALY) gained.. In the base case, 106,000 TB cases are predicted to 2065. Pre-elimination was achieved by 2065 in three scenarios: a 10-fold increase in the non-USB and persons with MRF (by 2052), and 4- or 10-fold increase in all Californians (by 2058 and 2035, respectively). TB elimination was not achieved by any intervention scenario. The most aggressive strategy, 10-fold in all Californians, achieved a case rate of 8 (95% UI 4-16) per million by 2050. Of scenarios that reached pre-elimination, the incremental net cost was $20 billion (non-USB and MRF) to $48 billion. These had an incremental cost per QALY of $657,000 to $3.1 million. A more efficient but somewhat less effective single-lifetime test strategy reached as low as $80,000 per QALY.. Substantial gains can be made in TB control in coming years by scaling-up current testing and treatment in non-USB and those with medical risks.

    Topics: Algorithms; Antitubercular Agents; Calibration; California; Computer Simulation; Cost-Benefit Analysis; Disease Eradication; Epidemics; Humans; Incidence; Isoniazid; Mass Screening; Quality-Adjusted Life Years; Rifampin; Risk Factors; Stochastic Processes; Tuberculin Test; Tuberculosis; World Health Organization

2019
Rifampin Induces Expression of P-glycoprotein on the THP1 Cell-Derived Macrophages, Causing Decrease Intramacrophage Concentration of Prothionamide.
    Journal of pharmaceutical sciences, 2019, Volume: 108, Issue:9

    Rifampin (RIF) has been widely used for the treatment of bacterial infections, including tuberculosis (TB). Treatment of drug-resistant TB is a global problem because of reduced drug efficacy. The present study determined the effect of RIF on MDR1 gene (P-glycoprotein, P-gp) expression in THP1 macrophages and analyzed the intracellular concentration of the anti-TB drug prothionamide in the presence of RIF. RIF treatment significantly induced MDR1 protein and mRNA levels in phorbol 12-myristate 13-acetate-stimulated THP1 macrophages (p < 0.001 and 0.01, respectively). The pregnane X receptor inhibitors resveratrol and ketoconazole significantly suppressed RIF-induced P-gp expression in THP1 macrophages (p < 0.05). RIF-treated THP1 macrophages also exhibited strong efflux of P-gp substrate, resulting in a reduced intracellular concentration of rhodamine-123 and prothionamide (p < 0.01 and 0.05, respectively). By contrast, the P-gp inhibitor cyclosporine A significantly increased intracellular concentration of rhodamine-123 and prothionamide (p < 0.001 and 0.05, respectively). The present results suggest that the usage of RIF together with P-gp-substrate drugs to treat TB may lead to deteriorated treatment efficacy because of the lower intracellular drug concentration. Further studies would be necessary to know the influence of RIF-induced P-gp induction on the treatment outcome of patients with TB.

    Topics: Antitubercular Agents; ATP Binding Cassette Transporter, Subfamily B; Cell Line, Tumor; Drug Antagonism; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Intracellular Fluid; Macrophages; Prothionamide; Rifampin; Tuberculosis; Up-Regulation

2019
The Combination Rifampin-Nitazoxanide, but Not Rifampin-Isoniazid-Pyrazinamide-Ethambutol, Kills Dormant Mycobacterium tuberculosis in Hypoxia at Neutral pH.
    Antimicrobial agents and chemotherapy, 2019, Volume: 63, Issue:7

    The activities of rifampin, nitazoxanide, PA-824, and sutezolid were tested against dormant

    Topics: Antitubercular Agents; Drug Combinations; Drug Therapy, Combination; Ethambutol; Humans; Hydrogen-Ion Concentration; Hypoxia; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazolidinones; Pyrazinamide; Rifampin; Tuberculosis

2019
Limited Sampling Strategies Using Linear Regression and the Bayesian Approach for Therapeutic Drug Monitoring of Moxifloxacin in Tuberculosis Patients.
    Antimicrobial agents and chemotherapy, 2019, Volume: 63, Issue:7

    Therapeutic drug monitoring (TDM) of moxifloxacin is recommended to improve the response to tuberculosis treatment and reduce acquired drug resistance. Limited sampling strategies (LSSs) are able to reduce the burden of TDM by using a small number of appropriately timed samples to estimate the parameter of interest, the area under the concentration-time curve. This study aimed to develop LSSs for moxifloxacin alone (MFX) and together with rifampin (MFX+RIF) in tuberculosis (TB) patients. Population pharmacokinetic (popPK) models were developed for MFX (

    Topics: Adult; Antitubercular Agents; Area Under Curve; Bayes Theorem; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Linear Models; Male; Middle Aged; Moxifloxacin; Reproducibility of Results; Rifampin; Tuberculosis

2019
Studies on the interaction of antibiotic drug rifampin with DNA and influence of bivalent metal ions on binding affinity.
    Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy, 2019, Aug-05, Volume: 219

    In this paper, the interaction between rifampin, a known antibiotic used against tuberculosis, and DNA helix is investigated by applying multiple biophysical and molecular modelling approaches in an aqueous solution at pH 7.4 and 5. It was proved that the fluorescence quenching of labeled probe DNA by rifampin is a result of the complex formation of rifampin in groove of DNA. Binding parameters were calculated using the logarithmic Hill equation to provide a quantitative term of the binding affinity between rifampin and DNA sites. The resulting ΔH

    Topics: Antibiotics, Antitubercular; Binding Sites; DNA; Humans; Hydrogen Bonding; Metals; Molecular Docking Simulation; Nucleic Acid Conformation; Rifampin; Tuberculosis

2019
Pharmacokinetics of adjusted-dose 8-hourly lopinavir/ritonavir in HIV-infected children co-treated with rifampicin.
    The Journal of antimicrobial chemotherapy, 2019, 08-01, Volume: 74, Issue:8

    To evaluate the proportion of children with lopinavir Cmin ≥1 mg/L when receiving a novel 8-hourly lopinavir/ritonavir dosing strategy during rifampicin co-treatment.. HIV-infected children on lopinavir/ritonavir and rifampicin were enrolled in a prospective pharmacokinetic study. Children were switched from standard-of-care lopinavir/ritonavir-4:1 with additional ritonavir (1:1 ratio) twice daily to 8-hourly lopinavir/ritonavir-4:1 using weight-banded dosing. Rifampicin was dosed at 10-20 mg/kg/day. After 2 weeks, plasma samples were collected ∼2, 4, 6, 8 and 10 h after the morning lopinavir/ritonavir-4:1 dose, ALT was obtained to assess safety and treatment was switched back to standard of care. ClinicalTrials.gov registration number: NCT01637558.. We recruited 11 children in two weight bands: 5 (45%) were 10-13.9 kg and received 20-24 mg/kg/dose of lopinavir and 6 (55%) children weighed 6-9.9 kg and received 20-23 mg/kg/dose of lopinavir. The median age was 15 months (IQR = 12.6-28.8 months). The median (IQR) lopinavir Cmin was 3.0 (0.1-5.5) mg/L. Seven (63.6%) of the 11 children had Cmin values ≥1 mg/L. Children with a lopinavir mg/kg dose below the median 21.5 were more likely to have Cmin <1 mg/L (P = 0.02). There was a strong positive correlation between lopinavir and ritonavir concentrations. No associations were found between lopinavir AUC2-10 and age, sex, weight, nutritional status or mg/kg/dose of lopinavir.. These data do not support the use of 8-hourly lopinavir/ritonavir at studied doses. Evaluation of higher doses is needed to optimize treatment outcomes of TB and HIV in young children.

    Topics: Alanine Transaminase; Anti-HIV Agents; Antibiotics, Antitubercular; Child; Child, Preschool; Drug Combinations; Female; HIV Infections; Humans; Infant; Infant, Newborn; Lopinavir; Male; Plasma; Prospective Studies; Rifampin; Ritonavir; Treatment Outcome; Tuberculosis

2019
Impact of selective immune-cell depletion on growth of Mycobacterium tuberculosis (Mtb) in a whole-blood bactericidal activity (WBA) assay.
    PloS one, 2019, Volume: 14, Issue:5

    We investigated the contribution of host immune cells to bacterial killing in a whole-blood bactericidal activity (WBA) assay, an ex vivo model used to test efficacy of drugs against mycobacterium tuberculosis (Mtb). We performed WBA assays with immuno-magnetic depletion of specific cell types, in the presence or absence of rifampicin. Innate immune cells decreased Mtb growth in absence of drug, but appeared to diminish the cidal activity of rifampicin, possibly attributable to intracellular bacterial sequestration. Adaptive immune cells had no effect with or without drug. The WBA assay may have potential for testing adjunctive host-directed therapies acting on phagocytic cells.

    Topics: Antitubercular Agents; Biological Assay; Blood Bactericidal Activity; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2019
Fabrication of bioactive rifampicin loaded κ-Car-MA-INH/Nano hydroxyapatite composite for tuberculosis osteomyelitis infected tissue regeneration.
    International journal of pharmaceutics, 2019, Jun-30, Volume: 565

    Biocompatible polymers and ceramic materials have been identified as vital components to fabricate drug delivery and tissue engineering applications because of their high drug loading capability, sustained release and higher mechanical strength with remarkable in-vivo bioavailability. In the present work, initially we designed κ-carrageenan grafted with maleic anhydride and then reacted it with isoniazid drug (κ-Car-MA-INH). The polymeric system was cross linked with nanohydroxyapatite (NHAP) via electrostatic interaction followed by the addition of rifampicin (RF) and loaded to fabricate κ -Car-MA-INH/NHAP/RF nanocomposites. The chemical modification and interaction of drug with the polymeric-ceramic system were characterised by Fourier Transform Infrared spectroscopy (FT-IR). The zeta potential of the κ -Car-MA-INH/NHAP/RF nanocomposite was observed to be -20.04 mV using Zetasizer. The in vitro drug release studies demonstrated that the nanocomposite releases 76% of RF and 82% of INH in 12 days at pH 5.5. Scanning Electron Microscope analysis revealed the structural deformation of Staphylococcus aureus and Klebsiella pneumoniae upon treatment with this nanocomposite. By using ex-vivo studies combined with physio-chemical characterization methods on the erythrocytes, L929 and MG-63 cell lines, this composite was found to be biocompatible, non-cytotoxic and inducing cell proliferation with less significant hemolysis. Thus, our modified drug delivery nanocomposites afforded higher drug bioavailability with large potential for fabrication as long-acting drug delivery nanocomposites, especially with hydrophobic drugs inducing the growth of osteoblastic bone cells.

    Topics: Animals; Antitubercular Agents; Carrageenan; Cell Line; Drug Delivery Systems; Drug Liberation; Durapatite; Erythrocytes; Hemolysis; Humans; Isoniazid; Klebsiella pneumoniae; Macrophages; Maleic Anhydrides; Mice; Nanocomposites; Osteoblasts; Osteomyelitis; Regeneration; Rifampin; Staphylococcus aureus; Tuberculosis

2019
Screening and treatment for tuberculosis in a cohort of unaccompanied minor refugees in Berlin, Germany.
    PloS one, 2019, Volume: 14, Issue:5

    In 2015, 4062 unaccompanied minor refugees were registered in Berlin, Germany. According to national policies, basic clinical examination and tuberculosis (TB) screening is a prerequisite to admission to permanent accommodation and schooling for every refugee. This article evaluates the use of an interferon-γ-release-assay (IGRA) during the initial examination and TB screening of 970 unaccompanied minor refugees.. IGRA test were obtained during TB screening for 301 (31.0%) of 970 adolescents not previously screened for TB. Positive IGRA results were obtained in 13.9% (42/301). Most of the 42 IGRA-positive refugees originated from Afghanistan or Syria (n?20 and 10 respectively). Two IGRA-positive adolescents were lost to follow-up, 2 were diagnosed with TB and the remaining 38 diagnosed with latent TB infection (LTBI). Demographic features of the 40 patients with positive IGRA result were as follows: 39 male, median age 16.8 years (IQR 16.0-17.2y), none meeting underweight criteria (median BMI 21.3kg/m2). On initial chest X-ray 2/40 participants had signs of active TB, while in 38 active disease was excluded and the diagnosis of latent TB infection (LTBI) made. Active hepatitis B-co-infection was diagnosed in 3/38 patients. All patients with LTBI received Isoniazid and Rifampicin for 3 months without occurrence of severe adverse events. The most frequently observed side effect was transient upper abdominal pain (n = 5). Asymptomatic elevation of liver transaminases was seen in 2 patients. 29 patients completed treatment with no signs of TB disease at the end of chemoprevention and 9 were lost to follow up.. Screening for TB infection in minor refugees was feasible in our setting with a relatively high rate of TB infection detected. Chemopreventive treatment was tolerated well regardless of underlying hepatitis-B-status. Minor refugees migrating to Germany should be screened for TB infection, instead of TB disease only, regardless of the background TB incidence.

    Topics: Adolescent; Berlin; Chemoprevention; Female; Germany; Hepatitis B; Humans; Isoniazid; Latent Tuberculosis; Male; Mass Screening; Minors; Refugees; Rifampin; Tuberculosis

2019
Application of serial tests for Mycobacterium tuberculosis detection to active lung tuberculosis cases in Indonesia.
    BMC research notes, 2019, Jun-03, Volume: 12, Issue:1

    Rapid detection and accurate diagnosis are very important in managing active tuberculosis because they provide an advantage in preventing further disease transmission. In accordance with the recommendation of the World Health Organization, the Indonesian Tuberculosis Control Program uses the acid fast bacilli (AFB) smear and Chest X-ray methods as the primary methods for detecting tuberculosis, especially in new cases of suspected tuberculosis. The genus Mycobacterium has many species, strains, and variants, and their natural differences may affect the clinical outcome of the diseases they induce. The purpose of this study was to assess different tuberculosis detection methods as part of serial tests and determine the best diagnostic approach for detecting active lung tuberculosis in Indonesia.. This study used clinical samples from tuberculosis patients and assessed them using a series of tests, aiming to increase the sensitivity of active tuberculosis detection. Some samples that yielded negative results in the AFB smear test were detected as positive for Mycobacterium tuberculosis using the nucleic acid amplification test, with a sensitivity of 83.1%. Additionally, nucleic acid amplification also detected positive results among samples assessed as M. tuberculosis-negative using the culture method, this method yielded the same results as the Gene Xpert test.

    Topics: Adult; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; Humans; Indonesia; Male; Middle Aged; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2019
Tuberculosis treatment in the private healthcare sector in India: an analysis of recent trends and volumes using drug sales data.
    BMC infectious diseases, 2019, Jun-19, Volume: 19, Issue:1

    There is a pressing need for systematic approaches for monitoring how much TB treatment is ongoing in the private sector in India: both to cast light on the true scale of the problem, and to help monitor the progress of interventions currently being planned to address this problem.. We used commercially available data on the sales of rifampicin-containing drugs in the private sector, adjusted for data coverage and indication of use. We examined temporal, statewise trends in volumes (patient-months) of TB treatment from 2013 to 2016. We additionally analysed the proportion of drugs that were sold in combination packaging (designed to simplify TB treatment), or as loose pills.. Drug sales suggest a steady trend of TB treatment dispensed by the private sector, from 18.4 million patient-months (95% CI 17.3-20.5) in 2013 to 16.8 patient-months (95% CI 15.5-19.0) in 2016. Overall, seven of 29 states in India accounted for more than 70% of national-level TB treatment volumes, including Uttar Pradesh, Maharashtra and Bihar. The overwhelming majority of TB treatment was dispensed not as loose pills, but in combination packaging with other TB drugs, accounting for over 96% of private sector TB treatment in 2017.. Our findings suggest consistent levels of TB treatment in the private sector over the past 4 years, while highlighting specific states that should be prioritized for intervention. Drug sales data can be helpful for monitoring a system as large, disorganised and opaque as India's private sector.

    Topics: Antibiotics, Antitubercular; Health Care Sector; Humans; India; Rifampin; Tuberculosis

2019
Mycobacterium tuberculosis detection from oral swabs with Xpert MTB/RIF ULTRA: a pilot study.
    BMC research notes, 2019, Jun-20, Volume: 12, Issue:1

    Diagnostic testing for tuberculosis depends on microbiological detection of Mycobacterium tuberculosis (Mtb) in sputum. For patients unable to expectorate sputum, such as children and individuals living with HIV, this poses barriers to rapid diagnosis and treatment initiation. Therefore, this study aimed to use oral swabs as an alternative sample type for Mtb detection via molecular testing.. In a pilot study, we aimed to evaluate sensitivity of Mtb detection via oral swabs using Xpert MTB/RIF ULTRA. We enrolled 33 TB cases and 30 controls from Lima, Peru, and detected Mtb from oral swabs with a sensitivity of 45% (95% confidence interval (CI) 29-62%) and specificity of 100% (95% CI 89-100%) using liquid culture of sputum as reference test. Our current protocol will need optimization, but these results support future exploration of the use of oral swabs for Mtb detection.

    Topics: Adult; Humans; Mouth; Mycobacterium tuberculosis; Pilot Projects; Reagent Kits, Diagnostic; Rifampin; Tuberculosis

2019
Evolution of rifampicin treatment for tuberculosis.
    Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2019, Volume: 74

    Rifampicin was discovered in 1965 and remains one of the most important drugs in tuberculosis treatment that is valued for its sterilizing activity and ability to shorten treatment. Antimicrobial activity of rifampicin was initially proved in vitro; subsequently numerous in vivo studies showed the bactericidal properties and dose-dependent effect of rifampicin. Rifampicin was first during the late 1960s to treat patients suffering from chronic drug-resistant pulmonary TB. Decades later, rifampicin continues to be studied with particular emphasis on whether higher doses could shorten the duration of treatment without increasing relapse or having adverse effects. Lesion-specific drug penetration and pharmacokinetics of rifampicin are improving our understanding of effective concentration while potentially refining drug regimen designs. Another prospective aspect of high-dose rifampicin is its potential use in treating discrepant mutation thereby eliminating the need for MDR treatment. To date, several clinical trials have shown the safety, efficacy, and tolerability of high-dose rifampicin. Currently, high-dose rifampicin has been used successfully in a routine clinical setting for the treatment of high-risk patients. However, the WHO and other relevant policy makers have not committed to implementing a controlled rollout thereof. This review describes the course that rifampicin has travelled to the present-day exploration of high-dose rifampicin treatment.

    Topics: Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Humans; Rifampin; Tuberculosis; World Health Organization

2019
Rapid, point-of-care diagnosis of tuberculosis with novel Truenat assay: Cost-effectiveness analysis for India's public sector.
    PloS one, 2019, Volume: 14, Issue:7

    Truenat is a novel molecular assay that rapidly detects tuberculosis (TB) and rifampicin-resistance. Due to the portability of its battery-powered testing platform, it may be valuable in peripheral healthcare settings in India.. Using a microsimulation model, we compared four TB diagnostic strategies for HIV-negative adults with presumptive TB: (1) sputum smear microscopy in designated microscopy centers (DMCs) (SSM); (2) Xpert MTB/RIF in DMCs (Xpert); (3) Truenat in DMCs (Truenat DMC); and (4) Truenat for point-of-care testing in primary healthcare facilities (Truenat POC). We projected life expectancy, costs, incremental cost-effectiveness ratios (ICERs), and 5-year budget impact of deploying Truenat POC in India's public sector. We defined a strategy "cost-effective" if its ICER was

    Topics: Adult; Cost-Benefit Analysis; Drug Resistance, Bacterial; Female; Health Care Costs; HIV Infections; Humans; India; Male; Microscopy; Mycobacterium tuberculosis; Point-of-Care Systems; Public Sector; Rifampin; Sputum; Tuberculosis

2019
Outcome of inadvertent high dose BCG administration in newborns at a tertiary care hospital, Karachi- Case series.
    PloS one, 2019, Volume: 14, Issue:7

    Bacillus Calmette-Guérin (BCG) vaccine is given to newborns soon after birth. BCG vaccine overdose has been rarely reported. Here we report the outcome of newborns who accidently received high dose BCG at a tertiary care hospital, Karachi. We reviewed records of 26 newborns, who accidentally received intradermal high dose BCG, used for the treatment of urinary bladder cancers and 80 times higher dose than the BCG used for routine vaccination. The incident happened from 14-16th April, 2016 at Aga Khan University Hospital, Karachi. Analysis was carried out using SPSS. A total of 23/26(88.5%) newborns were followed for atleast 3 months and 11/26 (42.3%) were followed for atleast one year. 13/26 (50%) were male. All 26 patients were prescribed isoniazid and rifampicin for 3 months. 3/26 (11.5%) were lost to follow-up before completion of anti-tuberculous drugs (ATT). Lesions at the BCG site were observed in 16/26 (61.5%) infants, of which 15 (93.8%) had a papule, 3 (18.8%) developed a pustule, 3 (18.8%) had skin induration and 2 (12.5%) had skin erythema. Axillary lymphadenopathy was observed in 1/26 (3.8%) patient. Coagulation was deranged in 3/26 (11.5%) of babies. Intracranial bleeding was observed in 1/26 (3.8%) case. Localized skin lesions were the most common adverse events. None of them developed clinical tuberculosis. Chemoprophylaxis for inadvertent high dose BCG administration should be given for atleast 3 months. Furthermore, vigilant follow-up, transparency and disclosure are the vital steps in the management of any medical error.

    Topics: Antitubercular Agents; BCG Vaccine; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Mycobacterium bovis; Pakistan; Rifampin; Tertiary Care Centers; Tuberculosis; Vaccination

2019
Cartridge-based nucleic acid amplification test: a novel rapid diagnostic tool to study the burden of tuberculosis from a tertiary care hospital.
    Tropical doctor, 2019, Volume: 49, Issue:4

    Despite efforts to limit the morbidity and mortality from tuberculosis (TB), it continues to be an important cause of death. There is an urgent need for a diagnostic test that accurately and quickly diagnoses TB, especially if it is also a near-point-of-care test. The GeneXpert polymerase chain reaction test (known in India as CBNAAT [cartridge-based nucleic acid amplification test] and is capable of diagnosing TB and rifampicin resistance within 2 h) is a promising tool. The duration of our study was two years and was carried out in the DOTS centre of a tertiary care hospital in India. A total of 5449 samples were processed using CBNAAT. Of the total samples tested, 2068 were extra-pulmonary. The following information was collected: number of extra-pulmonary samples processed; number of

    Topics: Antibiotics, Antitubercular; Bacteriological Techniques; Drug Resistance, Bacterial; Early Diagnosis; Humans; India; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Tertiary Care Centers; Tuberculosis

2019
Identification and Characterization of Genetic Determinants of Isoniazid and Rifampicin Resistance in Mycobacterium tuberculosis in Southern India.
    Scientific reports, 2019, 07-16, Volume: 9, Issue:1

    Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of Mycobacterium tuberculosis. There is an urgent need to understand the mechanisms by which the mutations confer resistance in order to identify new drug targets and to design new drugs. Previous studies have reported numerous mutations that confer resistance to anti-TB drugs, but there has been little systematic analysis to understand their genetic background and the potential impacts on the drug target stability and/or interactions. Here, we report the analysis of whole-genome sequence data for 98 clinical M. tuberculosis isolates from a city in southern India. The collection was screened for phenotypic resistance and sequenced to mine the genetic mutations conferring resistance to isoniazid and rifampicin. The most frequent mutation among isoniazid and rifampicin isolates was S315T in katG and S450L in rpoB respectively. The impacts of mutations on protein stability, protein-protein interactions and protein-ligand interactions were analysed using both statistical and machine-learning approaches. Drug-resistant mutations were predicted not only to target active sites in an orthosteric manner, but also to act through allosteric mechanisms arising from distant sites, sometimes at the protein-protein interface.

    Topics: Adult; Allosteric Regulation; Antitubercular Agents; Bacterial Proteins; Catalase; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; India; Isoniazid; Machine Learning; Models, Molecular; Mutation; Mycobacterium tuberculosis; Protein Conformation; Protein Stability; Rifampin; Tuberculosis; Whole Genome Sequencing

2019
Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study.
    The Lancet. Child & adolescent health, 2019, Volume: 3, Issue:9

    Malnourished and young children are particularly susceptible to severe forms of tuberculosis and poor treatment response. WHO dosing guidelines for drugs for tuberculosis treatment are based only on weight, which might lead to systematic underdosing and poor outcomes in these children. We aimed to assess and quantify the population effect of WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with the highest disease burden.. We used an integrated model that linked country-specific demographic data at the individual level from the 20 countries with the highest disease burden to pharmacokinetic, outcome, and epidemiological models. We estimated tuberculosis treatment outcomes in children younger than 5 years following WHO guidelines (children are dosed by weight bands corresponding to the number of fixed-dose combination tablets [75 mg rifampicin, 50 mg isoniazid, 150 mg pyrazinamide]) and two alternative dosing strategies: one based on a proposed algorithm that uses age, weight, and available formulations, in which underweight children would receive the same drug doses as would normal weight children of the same age; and another based on an individualised algorithm without dose limitations, in which derived doses results in target exposure attainment for the typical child.. We estimated that 57 234 (43%) of 133 302 children younger than 5 years who were treated for tuberculosis in 2017 were underdosed with WHO dosing and only 47% of children would reach the rifampicin exposure target. Underdosing and subtherapeutic exposures were more common among malnourished children than among age-matched healthy children. The proposed dosing approach improved estimated rifampicin target exposure attainment to 62% and equalised outcomes by nutritional status. An estimated third of unfavourable treatment outcomes might be resolved with this dosing strategy, saving the lives of a minimum of 2423 children in these countries annually. With individualised dosing approaches, almost all children could achieve adequate exposure for cure.. This work shows that a simple change in dosing procedure to include age and nutritional status, requiring no additional measurements or new drug formulations, is one approach to improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality.. Eunice Kennedy Shriver National Institute of Child Health and Human Development and UK Medical Research Council.

    Topics: Algorithms; Antitubercular Agents; Body Weight; Child Nutrition Disorders; Child, Preschool; Drug Administration Schedule; Humans; Isoniazid; Models, Statistical; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2019
Clinical Significance of the Plasma Protein Binding of Rifampicin in the Treatment of Tuberculosis Patients.
    Clinical pharmacokinetics, 2019, Volume: 58, Issue:12

    Topics: Antitubercular Agents; Blood Proteins; Humans; Protein Binding; Rifampin; Tuberculosis

2019
Mannosylated graphene oxide as macrophage-targeted delivery system for enhanced intracellular M.tuberculosis killing efficiency.
    Materials science & engineering. C, Materials for biological applications, 2019, Volume: 103

    Topics: Animals; Drug Delivery Systems; Graphite; Humans; Macaca mulatta; Macrophages; Mannose; Mycobacterium tuberculosis; Nanoparticles; Rifampin; THP-1 Cells; Tuberculosis

2019
Optimization of a paediatric fixed dose combination mini-tablet and dosing regimen for the first line treatment of tuberculosis.
    European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 2019, Oct-01, Volume: 138

    We aim to optimize the paediatric dosing regimen of isoniazid, rifampicin and pyrazinamide for the first-line treatment of tuberculosis, based on a fixed dose combination (FDC) mini-tablet using simulations. An optimization problem was set up to determine the 3 strengths of the drugs of the mini-tablet and 4 cutoff points that define the weight bands of a dosing chart, simultaneously. Using Monte Carlo simulations, first, exposure targets were determined for the 3 drugs, from published population pharmacokinetic models for adults, assuming that the approved doses for adults are de facto efficacious. Then optimal strengths and cutoff points were determined by matching children exposures generated from population pharmacokinetic models to the adults targets. The optimal dosing strengths of the FDC tablet were found to be 95 mg of rifampicin, 200 mg of pyrazinamide and 75 mg of isoniazid, and the 4 body weight bands for 1 to 4 mini-tablets, respectively were: 4 to 8 kg, 8 to 12 kg, 12 to 18 kg and 18 to 28 kg. Children with body weight ≥ 28 kg will be treated with adult dosages. The higher doses proposed were evaluated to be much closer to the adult targets compared to the existing recommended by WHO paediatric doses.

    Topics: Adult; Antitubercular Agents; Child; Humans; Isoniazid; Pyrazinamide; Rifampin; Tablets; Tuberculosis

2019
Design, synthesis and antitubercular evaluation of benzothiazinones containing a piperidine moiety.
    European journal of medicinal chemistry, 2018, May-10, Volume: 151

    We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way.

    Topics: Animals; Antitubercular Agents; Drug Design; Female; Humans; Mice, Inbred ICR; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Piperidines; Thiazines; Tuberculosis

2018
Antibacterial and anti-TB tat-peptidomimetics with improved efficacy and half-life.
    European journal of medicinal chemistry, 2018, May-25, Volume: 152

    Non-natural antimicrobial peptides are ideal as next-generation antibiotics because of their ability to circumvent the problems of drug resistance and in vivo instability. We report novel all-α- and α,γ-mixed Tat peptide analogues as potential antibacterial and anti-TB agents. These peptides have broad spectrum antibacterial activities against Gram-positive (MICs 0.61 ± 0.03 to 1.35 ± 0.21 μM with the peptide γTatM4) and Gram-negative (MICs 0.71 ± 0.005 to 1.26 ± 0.02 μM with γTatM4) bacteria and are also effective against active and dormant forms of Mycobacterium tuberculosis, including strains that are resistant to rifampicin and isoniazid. The introduction of the non-natural amino acids of the study in the Tat peptide analogues results in increased resistance to degradation by proteolysis, significantly increasing their half-life. The peptides appear to inhibit bacteria by a membrane disruption mechanism, and have only a low cytotoxic effect on mammalian cells.

    Topics: Anti-Bacterial Agents; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Erythrocytes; Gram-Negative Bacteria; Gram-Positive Bacteria; Hemolysis; Humans; Microbial Sensitivity Tests; Molecular Structure; Particle Size; Peptidomimetics; Structure-Activity Relationship; Tuberculosis

2018
Synthesis of carbohydrazides and carboxamides as anti-tubercular agents.
    European journal of medicinal chemistry, 2018, Aug-05, Volume: 156

    Topics: Antitubercular Agents; Caco-2 Cells; Drug Design; HEK293 Cells; Humans; Hydrazines; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis

2018
Evaluation of the Adequacy of the 2010 Revised World Health Organization Recommended Dosages of the First-line Antituberculosis Drugs for Children: Adequacy of Revised Dosages of TB Drugs for Children.
    The Pediatric infectious disease journal, 2018, Volume: 37, Issue:1

    The World Health Organization recommended increased dosages of the first-line antituberculosis (anti-TB) drugs for children in 2010. We examined the frequency of and factors associated with low plasma maximum concentration (Cmax) of each drug in children treated with the revised dosages.. Children on anti-TB therapy for at least 4 weeks underwent pharmacokinetic testing. Plasma Cmax below the lower limit of proposed reference range was considered low. Bivariate and multivariate analyses were used to examine the factors associated with low Cmax of each drug.. Of the 100 children, 58% were male, 50% HIV-infected and 49% younger than 5 years old. The median (interquartile range) Cmax was 5.9 (4.5-7.7) µg/mL for isoniazid, 6.5 (4.9-8.8) µg/mL for rifampin, 26.0 (21.2-33.4) µg/mL for pyrazinamide and 1.7 (0.9-2.7) µg/mL for ethambutol. There was a strong correlation between Cmax and AUC0-8h for all drugs. Low Cmax occurred in 9/100 (9.0%), 61/100 (61.0%), 17/97 (17.5%) and 60/97 (61.9%) for isoniazid, rifampin, pyrazinamide and ethambutol, respectively. In addition, 75/97 (77.3%) children had pyrazinamide Cmax < 35 µg/mL. Factors associated with low Cmax were NAT2 metabolizer phenotype status for isoniazid; height, dosage and HIV coinfection status for rifampin; height for pyrazinamide; and age, dosage and HIV coinfection status for ethambutol.. The high frequency of low rifampin and ethambutol Cmax in our study is consistent with emerging pharmacokinetic data in children treated according to the new WHO recommendations. Higher dosages than currently recommended especially for rifampin may be necessary in children.

    Topics: Adolescent; Antitubercular Agents; Arylamine N-Acetyltransferase; Child; Child, Preschool; Coinfection; Female; Ghana; HIV Infections; Humans; Infant; Male; Practice Guidelines as Topic; Prospective Studies; Rifampin; Tuberculosis; World Health Organization

2018
A 25-Year-Old Woman With a Deceptive Pancreas Cyst: All Is Not as It Appears!
    Gastroenterology, 2018, Volume: 154, Issue:5

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Ethambutol; Female; Humans; Isoniazid; Mycobacterium tuberculosis; Pancreatic Cyst; Pyrazinamide; Rifampin; Tomography, X-Ray Computed; Treatment Outcome; Tuberculosis

2018
Are fluconazole or sertraline dose adjustments necessary with concomitant rifampin?
    HIV medicine, 2018, Volume: 19, Issue:6

    Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antibiotics, Antitubercular; Antifungal Agents; Dose-Response Relationship, Drug; Drug Interactions; Fluconazole; HIV Infections; Humans; Mycoses; Rifampin; Sertraline; Tuberculosis

2018
Development of resistance to Mycobacterium tuberculosis is manageable in hidradenitis suppurativa. Response to 'Treatment of hidradenitis suppurativa with rifampicin: have we forgotten tuberculosis?'
    The British journal of dermatology, 2018, Volume: 178, Issue:1

    Topics: Biochemical Phenomena; Hidradenitis Suppurativa; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2018
Microbial sensor for drug susceptibility testing of Mycobacterium tuberculosis.
    Journal of applied microbiology, 2018, Volume: 124, Issue:1

    Drug susceptibility testing (DST) of clinical isolates of Mycobacterium tuberculosis is critical in treating tuberculosis. We demonstrate the possibility of using a microbial sensor to perform DST of M. tuberculosis and shorten the time required for DST.. The sensor is made of an oxygen electrode with M. tuberculosis cells attached to its surface. This sensor monitors the residual oxygen consumption of M. tuberculosis cells after treatment with anti-TB drugs with glycerine as a carbon source. In principle, after drug pretreatment for 4-5 days, the response differences between the sensors made of drug-sensitive isolates are distinguishable from the sensors made of drug-resistant isolates. The susceptibility of the M. tuberculosis H37Ra strain, its mutants and 35 clinical isolates to six common anti-TB drugs: rifampicin, isoniazid, streptomycin, ethambutol, levofloxacin and para-aminosalicylic acid were tested using the proposed method. The results agreed well with the gold standard method (LJ) and were determined in significantly less time. The whole procedure takes approximately 11 days and therefore has the potential to inform clinical decisions.. To our knowledge, this is the first study that demonstrates the possible application of a dissolved oxygen electrode-based microbial sensor in M. tuberculosis drug resistance testing. This study used the microbial sensor to perform DST of M. tuberculosis and shorten the time required for DST.. The overall detection result of the microbial sensor agreed well with that of the conventional LJ proportion method and takes less time than the existing phenotypic methods. In future studies, we will build an O

    Topics: Antitubercular Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2018
Deregulation of Genes Associated with Alternate Drug Resistance Mechanisms in Mycobacterium tuberculosis.
    Current microbiology, 2018, Volume: 75, Issue:4

    Alternate mechanisms of drug resistance involving intrinsic defense pathways play an important role in development of drug resistance. Deregulation of drug efflux, cellular metabolism, and DNA repair have been indicated to have effect on drug tolerance and persistence. Here we chose eight genes from these pathways to investigate their association with development of multidrug resistance (MDR). We generated mono drug resistant and MDR strains of rifampicin and isoniazid and examined the differential expression of genes belonging to efflux, DNA repair and cell wall lipid synthesis pathways. Rv1687c, recB, ppsD and embC genes showed significant (P <0.05) upregulation in mono-resistant (both rifampicin and isoniazid) as well as MDR strains. mmr showed significant upregulation with rifampicin resistance while Rv1457c showed significant upregulation only with mono-resistant strains. Highest expression change was observed with Rv1687c and ppsD. The study identified potential key genes that are significantly associated with development of drug resistance in vitro. These genes may help identify clinical strains predisposed to acquiring drug resistance in patients during the course of treatment or help in management of MDR forms of tuberculosis.

    Topics: Antitubercular Agents; Bacterial Proteins; Down-Regulation; Drug Resistance, Multiple, Bacterial; Gene Expression Regulation, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2018
Evaluation of Whole-Genome Sequencing for Mycobacterial Species Identification and Drug Susceptibility Testing in a Clinical Setting: a Large-Scale Prospective Assessment of Performance against Line Probe Assays and Phenotyping.
    Journal of clinical microbiology, 2018, Volume: 56, Issue:2

    Use of whole-genome sequencing (WGS) for routine mycobacterial species identification and drug susceptibility testing (DST) is becoming a reality. We compared the performances of WGS and standard laboratory workflows prospectively, by parallel processing at a major mycobacterial reference service over the course of 1 year, for species identification, first-line

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Genome, Bacterial; Humans; Isoniazid; Molecular Typing; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Time Factors; Tuberculosis

2018
Mucoadhesive chitosan-coated solid lipid nanoparticles for better management of tuberculosis.
    International journal of pharmaceutics, 2018, Jan-30, Volume: 536, Issue:1

    Taking into consideration the potential mucoadhesion properties of systems in lung delivery, this paper describes the preparation and characterization of chitosan-coated solid lipid nanoparticles (C-SLNs) loaded with rifampicin (RIF) as anti-tuberculosis (anti-TB) drug. The process of development and characterization of the NPs in terms of size, surface charge, encapsulation efficiency (EE), morphology, in vitro drug release, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), in vitro assessment of mucoadhesive property, cell viability and permeability studies are documented. Results showed that the SLNs had a smooth spherical shape with a size of ca. 245-344 nm and with a zeta potential around -30 mV for SLNs and +40 mV for C-SLNs. The surface charge variation from negative to positive charge and FTIR analysis demonstrated the successful process of coating the nanoparticles (NPs) surface with chitosan. The DSC thermograms were in agreement with the nanostructure of the SLNs. The EE of drug was found to be higher than 90% and the loading capacity (LC) around 4.5%. C-SLNs show higher in vitro muchoadesive properties and a higher permeability in alveolar epithelial cells A549 than uncoated SLNs, indicating that the developed C-SLNs can be used as a promising carrier for sasfer and efficient management of TB.

    Topics: Antitubercular Agents; Chitosan; Drug Carriers; Drug Liberation; Excipients; Lipids; Nanoparticles; Nanostructures; Particle Size; Rifampin; Tuberculosis

2018
Optimal doses of rifampicin in the standard drug regimen to shorten tuberculosis treatment duration and reduce relapse by eradicating persistent bacteria.
    The Journal of antimicrobial chemotherapy, 2018, 03-01, Volume: 73, Issue:3

    Although high-dose rifampicin holds promise for improving tuberculosis disease control by eradication of persistent bacteria, the optimal dose of rifampicin that kills persistent bacteria and shortens the treatment duration is unknown.. The Cornell mouse model was used to test the efficacy of rifampicin at elevated doses combined with isoniazid and pyrazinamide to kill actively growing and persistent bacilli and to measure relapse rate. Persistent bacteria were evaluated using Mycobacterium tuberculosis culture supernatant containing resuscitation-promoting factors. Pharmacokinetic parameters and dose-dependent activity for cultivable and persistent bacilli were determined.. Increasing doses of rifampicin in combination with isoniazid and pyrazinamide resulted in dose-dependent faster bacterial clearance. Evaluated both on solid media and in culture filtrate containing resuscitation-promoting factors, a regimen containing a standard dose of rifampicin at 10 mg/kg over 14 weeks failed to achieve organ sterility. In contrast, higher doses of rifampicin achieved organ sterility in a much shorter time of 8-11 weeks. Disease relapse, which occurred in 86% of mice treated with the standard regimen for 14 weeks, was completely prevented by rifampicin doses of ≥ 30 mg/kg.. In the treatment of murine tuberculosis, a rifampicin dose of 30 mg/kg was sufficient to eradicate persistent M. tuberculosis, allowing shorter treatment duration without disease relapse.

    Topics: Animals; Antitubercular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Spleen; Tuberculosis

2018
Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV-Coinfected Children in India: Recommendations for Dose Modifications.
    Clinical pharmacology and therapeutics, 2018, Volume: 104, Issue:4

    This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (P

    Topics: Adolescent; Age Factors; Antitubercular Agents; Body Weight; Child; Child, Preschool; Coinfection; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Drug Monitoring; Drug Therapy, Combination; Female; HIV Infections; Humans; India; Infant; Isoniazid; Male; Models, Biological; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

2018
Completion Rate and Safety of Tuberculosis Infection Treatment With Shorter Regimens.
    Pediatrics, 2018, Volume: 141, Issue:2

    The traditional treatment of tuberculosis (TB) infection (9 months of daily isoniazid [9H]) is safe but completion rates of <50% are reported. Shorter regimens (3 months of once-weekly isoniazid and rifapentine [3HP] or 4 months of daily rifampin [4R]) are associated with improved adherence in adults.. This was a retrospective cohort study (2014-2017) of children (0-18 years old) seen at a children's TB clinic in a low-incidence nation. We compared the frequency of completion and adverse events (AEs) in children receiving 3HP, 4R, and 9H; the latter 2 regimens could be administered by families (termed self-administered therapy [SAT]) or as directly observed preventive therapy (DOPT); 3HP was always administered under DOPT.. TB infection treatment was started in 667 children: 283 (42.4%) 3HP, 252 (37.8%) 9H, and 132 (19.8%) 4R. Only 52% of children receiving 9H via SAT completed therapy. Children receiving 3HP were more likely to complete therapy than the 9H (SAT) group (odds ratio [OR] 27.4, 95% confidence interval [CI]: 11.8-63.7). Multivariate analyses found receipt of medication under DOPT (OR: 5.72, 95% CI: 3.47-9.43), increasing age (OR: 1.09, 95% CI: 1.02-1.17), and the absence of any AE (OR: 1.70, 95% CI: 0.26-0.60) to be associated with completing therapy. AEs were more common in the 9H group (OR: 2.51, 95% CI: 1.48-4.32). Two (0.9%) children receiving 9H developed hepatotoxicity; no child receiving 3HP or 4R developed hepatotoxicity.. Shorter regimens are associated with increased completion rates and fewer AEs than 9H.

    Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Medication Adherence; Retrospective Studies; Rifampin; Texas; Tuberculosis

2018
Diagnostic validation of rapid molecular detection of Mycobacterium tuberculosis in pus samples by GeneXpert.
    JPMA. The Journal of the Pakistan Medical Association, 2018, Volume: 68, Issue:1

    To evaluate the performance of GeneXpert for detection of mycobacterium tuberculosis in pus samples and compare its results with conventional techniques in terms of validity, rapidity and rifampicin resistance.. This longitudinal, descriptive study was conducted at Jinnah Hospital, Lahore, Pakistan, from January 2012 to December 2015, and comprised pus samples of people suspected of having extra-pulmonary tuberculosis. Participants were included by using consecutive sampling technique. The pus samples were subjected to Ziehl-Neelsen smear microscopy and Lowenstein-Jensen culture as per World Health Organisation's protocol and GeneXpert as per manufacturer protocol. SPSS 17 was used for data analysis. Validity of GeneXpert and rifampicin resistance were determined and compared with Ziehl-Neelsen staining using Lowenstein-Jensen culture as the gold standard.. Of the 212 pus samples, 84(39.6%) were positive on Lowenstein-Jensen culture with mean turnaround time of 20±6 days, 77(36.3%) on GeneXpert and 22(10.4%) on Ziehl-Neelsen smear. The highest detection rate of mycobacterium tuberculosis 62(80.5%) was in lymph node samples by GeneXpert. The sensitivity and specificity of GeneXpert were 91.6% and 100% respectively, while Ziehl-Neelsen smear showed a sensitivity26.2% and specificity of 100%. Rifampicin resistance was detected in 5(6.4%) pus samples by GeneXpert.. GeneXpert had a higher validity compared to Ziehl-Neelsen smear microscopy.

    Topics: Adult; Antitubercular Agents; Drug Resistance, Bacterial; Female; Humans; Longitudinal Studies; Male; Microbial Sensitivity Tests; Microscopy; Molecular Typing; Mycobacterium tuberculosis; Pakistan; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Suppuration; Tuberculosis

2018
Pound foolish and penny wise-when will dosing of rifampicin be optimised?
    The Lancet. Respiratory medicine, 2018, Volume: 6, Issue:4

    Topics: Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Humans; Rifampin; Tuberculosis

2018
Diagnostic performances of the Xpert MTB/RIF in Brazil.
    Respiratory medicine, 2018, Volume: 134

    As for all tests, the diagnostic performances of Xpert MTB/RIF might be different in settings with different tuberculosis prevalence. Aim of the study is to evaluate the performances of Xpert MTB/RIF to diagnose tuberculosis in Brazil, where 407 culture-confirmed tuberculosis patients were retrospectively enrolled in Rio Grande do Sul, between 2015 and 2016.. Sensitivity, specificity, positive and negative predictive values of the test were calculated and a logistic regression analysis was performed to assess the role played by explanatory variables in the occurrence of true positive and negative diagnostic results.. Sensitivity of Xpert MTB/RIF was 100.0%, specificity 92.8%; positive and negative predictive values were 71.4% and 100.0%, respectively. In the HIV- infected sub-group specificity was 59.3%. In the multivariate logistic regression analysis, true positivity was associated with increasing age (1.0; p-value: 0.02) while true positivity and negativity were negatively associated with alcohol abuse.. Xpert is sensitive and specific in the Brasilian settings.

    Topics: Adult; Antibiotics, Antitubercular; Brazil; Coinfection; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Opportunistic Infections; Predictive Value of Tests; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis

2018
Automated broth-based systems versus the MYCOTB plate for antimicrobial susceptibility testing of the Mycobacterium tuberculosis complex: challenges in interpretation.
    Diagnostic microbiology and infectious disease, 2018, Volume: 91, Issue:1

    We examined categorical agreement between automated mycobacterial susceptibility testing methods (Mycobacterial Growth Indicator Tube [MGIT] 960 System and the VersaTREK Mycobacteria Detection and Susceptibility System) which are based on single critical concentration (CC) "breakpoints" and a commercial microbroth dilution method (Sensititre Mycobacterium tuberculosis MIC Plate [MYCOTB]) which provides an MIC value. Mycobacterium tuberculosis isolates (n=355) were tested against three first-line antimycobacterial agents (ethambutol [EMB], isoniazid [INH], rifampin [RIF]) using the MYCOTB plate and either the MGIT 960 (site 1, n=142) or VersaTREK (site 2, n=213) systems. Overall categorical agreement was 96.8%. When stratified by drug and CC-defined susceptible and resistant isolates, concordance ranged from 75% to 100%. Interpretation of MIC-based results versus established CC-based results was challenging for drugs whose CC was not represented by an exactly equivalent concentration in the manufacturer-defined dilutions on the MYCOTB plate (EMB, INH). We propose interpretations of MYCOTB plate MICs using the currently available plate configuration.

    Topics: Antitubercular Agents; Automation, Laboratory; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2018
Xpert MTB/RIF as add-on test to microscopy in a low tuberculosis incidence setting.
    The European respiratory journal, 2018, Volume: 51, Issue:3

    Topics: Algorithms; Decision Support Systems, Clinical; Endoscopy; Humans; Incidence; Infectious Disease Medicine; Italy; Microscopy; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Respiration Disorders; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary; World Health Organization

2018
First-line anti-tuberculosis drugs induce hepatotoxicity: A novel mechanism based on a urinary metabolomics platform.
    Biochemical and biophysical research communications, 2018, 03-04, Volume: 497, Issue:2

    Tuberculosis (TB) has become a global public health and social threat. As clinical first-line drugs, rifampicin and isoniazid used in combination with pyrazinamide and ethambutol (the HRZE regimen) usually induce hepatotoxicity. However, the mechanisms underlying this phenomenon remain unclear, and studying the metabolic impact of co-treating TB patients with the HRZE regimen can provide new hepatotoxicity evidence. In this study, urine metabolites from TB patients were profiled using a high-resolution ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) platform. The tricarboxylic acid circulation, arginine and proline metabolism and purine metabolic pathways were found to be affected by anti-TB drugs. The levels of pyroglutamate, isocitrate, citrate, and xanthine were significantly decreased after the administration of HRZE. The above mentioned pathways were also different between drug-induced liver injury (DILI) and non-DILI patients. Urate and cis-4-octenedioic acid levels in the DILI group were significantly increased compared to those in the non-DILI group, while the cis-aconitate and hypoxanthine levels were significantly decreased. These results highlight that superoxide generation can aggravate the hepatotoxic effects of the HRZE regimen. In addition, our metabolomic approach had the ability to predict hepatotoxicity for clinical applications.

    Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Ethambutol; Female; Humans; Isoniazid; Liver; Male; Mass Spectrometry; Metabolic Networks and Pathways; Metabolomics; Middle Aged; Purines; Pyrazinamide; Rifampin; Tuberculosis; Young Adult

2018
Improved Stability of Tuberculosis Drug Fixed-Dose Combination Using Isoniazid-Caffeic Acid and Vanillic Acid Cocrystal.
    Journal of pharmaceutical sciences, 2018, Volume: 107, Issue:6

    The classic fixed-dose combination (FDC) of 4 tuberculosis drugs, namely rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol dihydrochloride (EDH) has the twin issues of physical stability and RIF cross-reaction in the 4-FDC. The major reason for these quality issues is the interaction between RIF and INH to yield isonicotinyl hydrazone in drug tablets. Pharmaceutical cocrystals of INH with caffeic acid (CFA) (PZA + EDH + RIF + INH-CFA cocrystal) and vanillic acid (VLA) (PZA + EDH + RIF + INH-VLA cocrystal) are able to stabilize the FDC formulation compared with the reference batch (PZA + EDH + RIF + INH). Stability studies under accelerated humidity and temperature stress conditions of 40°C and 75% relative humidity showed that the physical stability of the cocrystal formulation was superior by powder X-ray diffraction and scanning electron microscopy analysis, and chemical purity was analyzed by high-performance liquid chromatography. Changes in the composition and structure were monitored on samples drawn at 7, 15, 22, and 30 days of storage. FDC-INH-CFA cocrystal batch exhibited greater stability compared with FDC-INH-VLA cocrystal and FDC reference drug batches. The superior stability of INH-CFA cocrystal is attributed to the presence of stronger hydrogen bonds and cyclic O-H⋯O synthon in the crystal structure.

    Topics: Antitubercular Agents; Caffeic Acids; Crystallization; Drug Combinations; Drug Stability; Drug Storage; Ethambutol; Humans; Isoniazid; Models, Molecular; Pyrazinamide; Rifampin; Tuberculosis; Vanillic Acid

2018
Tuberculosis treatment outcome and predictors in northern Ethiopian prisons: a five-year retrospective analysis.
    BMC pulmonary medicine, 2018, Feb-20, Volume: 18, Issue:1

    The prison situations are notorious for causing interruptions of tuberculosis (TB) treatment and occurrence of unfavorable outcomes. In Ethiopian prisons, though TB treatment programs exist, treatment outcome results and factors contributing to unsuccessful outcome are not well documented. In this study, we assessed the treatment outcome of TB cases and identified risk factors for unsuccessful outcome in northern Ethiopian prisons.. A retrospective record review was conducted for all prisoners diagnosed with TB between September 2011 and August 2015. Outcome variables were defined following WHO guidelines.. Out of the 496 patients, 11.5% were cured, 68% completed treatment, 2.5% were lost to follow-up, 1.6% were with a treatment failure, 1.4% died, and 15% were transferred out. All transferred out or released prisoners were not appropriately linked to health facilities and might be lost to treatment follow-up. The overall treatment success rate (TSR) of the 5 years was 94% among the patients who were not transferred out. The odds of unsuccessful outcome were 4.68 times greater among re-treatment cases compared to the newly treated cases. The year of treatment was also associated with variations in TSR; those treated during the earlier year were more likely to have unsuccessful outcome. Sputum non-conversion at the second-month check-up was strongly associated with unsuccessful outcome among the smear-positive cases.. The mean TSR of the prisoners in the study prisons was quite satisfactory when gauged against the target level set by the End TB Strategy. However, the lack of appropriate linkage and tracking systems for those prisoners transferred or released before their treatment completion would have a negative implication for the national TB control program as such patients might interrupt their treatment and develop drug-resistant TB. Being in a re-treatment regimen and sputum non-conversion at the second-month check-up were significantly associated with unsuccessful treatment outcome among the all forms of and smear-positive TB cases, respectively.

    Topics: Adolescent; Adult; Aftercare; Anti-Retroviral Agents; Antitubercular Agents; Coinfection; Directly Observed Therapy; Drug Therapy, Combination; Ethambutol; Ethiopia; Female; HIV Infections; Humans; Isoniazid; Logistic Models; Lost to Follow-Up; Male; Multivariate Analysis; Patient Discharge; Patient Transfer; Prisoners; Prisons; Pyrazinamide; Retreatment; Retrospective Studies; Rifampin; Risk Factors; Sputum; Streptomycin; Treatment Failure; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

2018
Sex differences and factors influencing the duration of the QT interval in patients on anti-tuberculosis therapy.
    The European respiratory journal, 2018, Volume: 51, Issue:2

    Topics: Antitubercular Agents; Clinical Trials as Topic; Electrocardiography; Ethambutol; Female; Gatifloxacin; Heart Rate; Humans; Isoniazid; Male; Models, Theoretical; Multivariate Analysis; Pyrazinamide; Rifampin; Sex Factors; Tuberculosis

2018
rpoB gene mutations among Mycobacterium tuberculosis isolates from extrapulmonary sites.
    APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, 2018, Volume: 126, Issue:3

    The aim of this study was to analyze mutations occurring in the rpoB gene of Mycobacterium tuberculosis (MTB) isolates from clinical samples of extrapulmonary tuberculosis (EPTB). Seventy formalin-fixed, paraffin-embedded samples and fresh tissue samples from confirmed EPTB cases were analyzed. Nested PCR based on the rpoB gene was performed on the extracted DNAs, combined with cloning and subsequent sequencing. Sixty-seven (95.7%) samples were positive for nester PCR. Sequence analysis of the 81 bp region of the rpoB gene demonstrated mutations in 41 (61.2%) of 67 sequenced samples. Several point mutations including deletion mutations at codons 510, 512, 513 and 515, with 45% and 51% of the mutations in codons 512 and 513 respectively were seen, along with 26% replacement mutations at codons 509, 513, 514, 518, 520, 524 and 531. The most common alteration was Gln → His, at codon 513, presented in 30 (75.6%) isolates. This study demonstrated sequence alterations in codon 513 of the 81 bp region of the rpoB gene as the most common mutation occurred in 75.6% of molecularly confirmed rifampin-resistant strains. In addition, simultaneous mutation at codons 512 and 513 was demonstrated in 34.3% of the isolates.

    Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Bacterial Proteins; Cells, Cultured; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Point Mutation; Rifampin; Sequence Deletion; Tuberculosis; Young Adult

2018
Evaluation of the efficacy of valproic acid and suberoylanilide hydroxamic acid (vorinostat) in enhancing the effects of first-line tuberculosis drugs against intracellular Mycobacterium tuberculosis.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2018, Volume: 69

    New tuberculosis (TB) drug treatment regimens are urgently needed. This study evaluated the potential of the histone deacetylase inhibitors (HDIs) valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to enhance the effects of first-line anti-TB drugs against intracellular Mycobacterium tuberculosis.. M. tuberculosis H37Rv cultures were exposed to VPA or SAHA over 6 days, in the presence or absence of isoniazid (INH) and rifampicin (RIF). The efficacy of VPA and SAHA against intracellular M. tuberculosis with and without INH or RIF was tested by treating infected macrophages. Bactericidal activity was assessed by counting mycobacterial colony-forming units (CFU).. VPA treatment exhibited superior bactericidal activity to SAHA (2-log CFU reduction), while both HDIs moderately improved the activity of RIF against extracellular M. tuberculosis. The bactericidal effect of VPA against intracellular M. tuberculosis was greater than that of SAHA (1-log CFU reduction) and equalled that of INH (1.5-log CFU reduction). INH/RIF and VPA/SAHA combination treatment inhibited intracellular M. tuberculosis survival in a shorter time span than monotherapy (3days vs. 6 days).. VPA and SAHA have adjunctive potential to World Health Organization-recommended TB treatment regimens. Clinical evaluation of the two drugs with regard to reducing the treatment duration and improving treatment outcomes in TB is warranted.

    Topics: Antitubercular Agents; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Isoniazid; Macrophages; Mycobacterium tuberculosis; Rifampin; THP-1 Cells; Tuberculosis; Valproic Acid; Vorinostat

2018
Exposure of Nursed Infants to Maternal Treatment with Ethambutol and Rifampicin.
    Basic & clinical pharmacology & toxicology, 2018, Volume: 123, Issue:2

    Mycobacterial diseases remain a significant cause of morbidity and mortality worldwide. Rifampicin and ethambutol are among the drugs recommended by WHO as first-line treatment. In this work, we addressed the question whether doses of the two anti-tuberculosis agents ethambutol and rifampicin transferred to a nursed infant could be of health concerns when the mother is under treatment. We used the approach of pharmacokinetic modelling using a structural model with two interconnected organisms: the first one being the organism of the nursing mother and the second one being the organism of the nursed child. Physiological data were taken from the literature. The models were parameterised by data from the literature concerning clearance, absorption and plasma/milk ratio. Distribution into the tissues was calculated by an algorithm. The predictive power of the model was tested by comparing the predicted plasma concentrations in the mothers with measured data from the literature. Comparison with measured data after direct infant treatment was performed for the rifampicin plasma concentrations predicted in the nursed infant. Both comparisons confirmed the appropriateness of the modelling results. The transfer of 0.08 mg/kg bw/day ethambutol via breast milk to the nursed infant, the dose we have estimated, when the mother received a therapeutic dose of 24.5 mg/kg bw, can be judged as being without health concern. Likewise, for rifampicin, the transferred dose of 0.4 mg/kg bw to the nursed infant resulting from a therapeutic dose of 10.9 mg/kg bw to the mother does not raise health concerns.

    Topics: Adult; Algorithms; Antitubercular Agents; Breast Feeding; Dose-Response Relationship, Drug; Ethambutol; Female; Humans; Infant; Milk, Human; Models, Biological; Rifampin; Tissue Distribution; Tuberculosis

2018
Individualizing Tuberculosis (TB) Treatment: Are TB Programs in High Burden Settings Ready for Prime Time Therapeutic Drug Monitoring?
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2018, 08-16, Volume: 67, Issue:5

    Topics: Antitubercular Agents; Coinfection; Drug Monitoring; HIV; HIV Infections; Humans; Isoniazid; Rifampin; Sputum; Tuberculosis

2018
Rapid and sensitive method for simultaneous determination of first-line anti-tuberculosis drugs in human plasma by HPLC-MS/MS: Application to therapeutic drug monitoring.
    Tuberculosis (Edinburgh, Scotland), 2018, Volume: 109

    Topics: Antitubercular Agents; Chromatography, High Pressure Liquid; Drug Monitoring; Ethambutol; Humans; Isoniazid; Predictive Value of Tests; Pyrazinamide; Reproducibility of Results; Rifampin; Spectrometry, Mass, Electrospray Ionization; Streptomycin; Tandem Mass Spectrometry; Tuberculosis

2018
Defining the best regimen to treat isoniazid-resistant tuberculosis.
    The Lancet. Respiratory medicine, 2018, Volume: 6, Issue:4

    Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2018
Functionalization of PLGA Nanoparticles with 1,3-β-glucan Enhances the Intracellular Pharmacokinetics of Rifampicin in Macrophages.
    Pharmaceutical research, 2018, Mar-29, Volume: 35, Issue:6

    Mycobacterium tuberculosis which causes tuberculosis, is primarily resident within macrophages. 1,3-β-glucan has been proposed as a ligand to target drug loaded nanoparticles (NPs) to macrophages. In this study we characterized the intracellular pharmacokinetics of the anti-tubercular drug rifampicin delivered by 1,3-β-glucan functionalized PLGA NPs (Glu-PLGA). We hypothesized that Glu-PLGA NPs would be taken up at a faster rate than PLGA NPs, and consequently deliver higher amounts of rifampicin into the macrophages.. Carbodiimide chemistry was employed to conjugate 1,3-β-glucan and rhodamine to PLGA. Rifampicin loaded PLGA and Glu-PLGA NPs as well as rhodamine functionalized PLGA and Glu-PLGA NPs were synthesized using an emulsion solvent evaporation technique. Intracellular pharmacokinetics of rifampicin and NPs were evaluated in THP-1 derived macrophages. A pharmacokinetic model was developed to describe uptake, and modelling was performed using ADAPT 5 software.. The NPs increased the rate of uptake of rifampicin by a factor of 17 and 62 in case of PLGA and Glu-PLGA, respectively. Expulsion of NPs from the macrophages was also observed, which was 3 fold greater for Glu-PLGA NPs than for PLGA NPs. However, the ratio of uptake to expulsion was similar for both NPs. After 24 h, the amount of rifampicin delivered by the PLGA and Glu-PLGA NPs was similar. The NPs resulted in at least a 10-fold increase in the uptake of rifampicin.. Functionalization of PLGA NPs with 1,3-β-glucan resulted in faster uptake of rifampicin into macrophages. These NPs may be useful to achieve rapid intracellular eradication of Mycobacterium tuberculosis.

    Topics: Antibiotics, Antitubercular; beta-Glucans; Cell Culture Techniques; Cell Line; Drug Carriers; Drug Compounding; Humans; Macrophages; Models, Biological; Mycobacterium tuberculosis; Nanoparticles; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin; Tuberculosis

2018
Cost-effectiveness of Preventive Therapy for Tuberculosis With Isoniazid and Rifapentine Versus Isoniazid Alone in High-Burden Settings.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2018, 09-14, Volume: 67, Issue:7

    A short-course regimen of 3 months of weekly rifapentine and isoniazid (3HP) has recently been recommended by the World Health Organization as an alternative to at least 6 months of daily isoniazid (isoniazid preventive therapy [IPT]) for prevention of tuberculosis (TB). The contexts in which 3HP may be cost-effective compared to IPT among people living with human immunodeficiency virus are unknown.. We used a Markov state transition model to estimate the incremental cost-effectiveness of 3HP relative to IPT in high-burden settings, using a cohort of 1000 patients in a Ugandan HIV clinic as an emblematic scenario. Cost-effectiveness was expressed as 2017 US dollars per disability-adjusted life year (DALY) averted from a healthcare perspective over a 20-year time horizon. We explored the conditions under which 3HP would be considered cost-effective relative to IPT.. Per 1000 individuals on antiretroviral therapy in the reference scenario, treatment with 3HP rather than IPT was estimated to avert 9 cases of TB and 1 death, costing $9402 per DALY averted relative to IPT. Cost-effectiveness depended strongly on the price of rifapentine, completion of 3HP, and prevalence of latent TB. At a willingness to pay of $1000 per DALY averted, 3HP is likely to be cost-effective relative to IPT only if the price of rifapentine can be greatly reduced (to approximately $20 per course) and high treatment completion (85%) can be achieved.. 3HP may be a cost-effective alternative to IPT in high-burden settings, but cost-effectiveness depends on the price of rifapentine, achievable completion rates, and local willingness to pay.

    Topics: Anti-HIV Agents; Antitubercular Agents; Cost-Benefit Analysis; Drug Therapy, Combination; HIV Infections; Humans; Isoniazid; Markov Chains; Rifampin; Tuberculosis

2018
Improving treatment outcome assessment in a mouse tuberculosis model.
    Scientific reports, 2018, 04-09, Volume: 8, Issue:1

    Preclinical treatment outcome evaluation of tuberculosis (TB) occurs primarily in mice. Current designs compare relapse rates of different regimens at selected time points, but lack information about the correlation between treatment length and treatment outcome, which is required to efficiently estimate a regimens' treatment-shortening potential. Therefore we developed a new approach. BALB/c mice were infected with a Mycobacterium tuberculosis Beijing genotype strain and were treated with rifapentine-pyrazinamide-isoniazid-ethambutol (R

    Topics: Administration, Oral; Animals; Antitubercular Agents; Disease Models, Animal; Drug Therapy, Combination; Ethambutol; Female; Genotype; Humans; Mice; Mice, Inbred BALB C; Models, Theoretical; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2018
Urgent Living-Donor Liver Transplantation in a Patient With Concurrent Active Tuberculosis: A Case Report.
    Transplantation proceedings, 2018, Volume: 50, Issue:3

    Although active tuberculosis (TB) is considered a contraindication for liver transplantation (LT), this is the only treatment in patients with liver failure and concurrent active TB. We report a case with successful urgent living-donor LT for irreversible liver failure in the presence of active TB.. A 48-year-old man, with a history of decompensated alcoholic liver cirrhosis, was presented with stupor. At admission, his consciousness had deteriorated to semi-coma, and his renal function also rapidly deteriorated to hepatorenal syndrome. A preoperative computed tomography scan of the chest revealed several small cavitary lesions in both upper lobes, and acid-fast bacillus stain from his sputum was graded 2+. Adenosine deaminase levels from ascites were elevated, suggesting TB peritonitis. A first-line anti-TB drug regimen was started immediately (rifampin, isoniazid, levofloxacin, and amikacin). An urgent living-donor LT was performed 2 days later. After LT, the regimen was changed to second-line anti-TB drugs (amikacin, levofloxacin, cycloserine, and pyridoxine). The sputum acid-fast bacillus stain tested negative on postoperative day 10. His liver function remained well preserved, even after the reversion to first-line anti-TB treatment. The patient recovered without any anti-TB medication-related complications and was discharged.. LT can be prudently performed as a life-saving option, particularly for patients with liver failure and concurrent active TB.

    Topics: Antitubercular Agents; Humans; Isoniazid; Levofloxacin; Liver Failure; Liver Transplantation; Living Donors; Male; Middle Aged; Rifampin; Tuberculosis

2018
Making up the difference: ensuring the bioequivalence of fixed-dose combinations for tuberculosis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2018, 05-01, Volume: 22, Issue:5

    Topics: Drug Combinations; Humans; Rifampin; South Africa; Therapeutic Equivalency; Tuberculosis

2018
Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis.
    PLoS pathogens, 2018, Volume: 14, Issue:4

    Mycobacterium tuberculosis (Mtb) remains a grave threat to world health with emerging drug resistant strains. One prominent feature of Mtb infection is the extensive reprogramming of host tissue at the site of infection. Here we report that inhibition of matrix metalloproteinase (MMP) activity by a panel of small molecule inhibitors enhances the in vivo potency of the frontline TB drugs isoniazid (INH) and rifampicin (RIF). Inhibition of MMP activity leads to an increase in pericyte-covered blood vessel numbers and appears to stabilize the integrity of the infected lung tissue. In treated mice, we observe an increased delivery and/or retention of frontline TB drugs in the infected lungs, resulting in enhanced drug efficacy. These findings indicate that targeting Mtb-induced host tissue remodeling can increase therapeutic efficacy and could enhance the effectiveness of current drug regimens.

    Topics: Animals; Antitubercular Agents; Granuloma, Respiratory Tract; Isoniazid; Lung; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Rifampin; Small Molecule Libraries; Tuberculosis

2018
Protein Binding of First-Line Antituberculosis Drugs.
    Antimicrobial agents and chemotherapy, 2018, Volume: 62, Issue:7

    The 4-drug regimen of rifampin, isoniazid, pyrazinamide, and ethambutol is an inexpensive, reliable option for treating patients with drug-susceptible tuberculosis (TB). Its efficacy could be further improved by determining the free drug concentrations in plasma, knowing that only the unbound drug can freely penetrate to the tissues. Using an ultrafiltration technique, we determined the protein binding (PB) extent and variability of the first-line anti-TB drugs when given simultaneously to TB patients, representing a real-life case scenario. We used clinical samples routinely received by our laboratory. Plasma proteins were also measured. A protein-free medium was used to determine the nonspecific binding. Plasma samples from 22 patients were included, of which plasma proteins were measured for 18 patients. The median PB was determined for rifampin (88%; range, 72 to 91%), isoniazid (14%; range, 0 to 34%), pyrazinamide (1%; range, 0 to 7%), and ethambutol (12%; range, 4 to 24%). Plasma proteins were not found to be significant predictors for the PB of first-line anti-TB drugs. Rifampin PB was positively correlated with its plasma concentration (

    Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Protein Binding; Pyrazinamide; Rifampin; Tuberculosis

2018
Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas.
    PloS one, 2018, Volume: 13, Issue:5

    Drug resistant tuberculosis is increasing world-wide. Resistance against isoniazid (INH), rifampicin (RIF), or both (multi-drug resistant TB, MDR-TB) is of particular concern, since INH and RIF form part of the standard regimen for TB disease. While it is known that suboptimal treatment can lead to resistance, it remains unclear how host immune responses and antibiotic dynamics within granulomas (sites of infection) affect emergence and selection of drug-resistant bacteria. We take a systems pharmacology approach to explore resistance dynamics within granulomas. We integrate spatio-temporal host immunity, INH and RIF dynamics, and bacterial dynamics (including fitness costs and compensatory mutations) in a computational framework. We simulate resistance emergence in the absence of treatment, as well as resistance selection during INH and/or RIF treatment. There are four main findings. First, in the absence of treatment, the percentage of granulomas containing resistant bacteria mirrors the non-monotonic bacterial dynamics within granulomas. Second, drug-resistant bacteria are less frequently found in non-replicating states in caseum, compared to drug-sensitive bacteria. Third, due to a steeper dose response curve and faster plasma clearance of INH compared to RIF, INH-resistant bacteria have a stronger influence on treatment outcomes than RIF-resistant bacteria. Finally, under combination therapy with INH and RIF, few MDR bacteria are able to significantly affect treatment outcomes. Overall, our approach allows drug-specific prediction of drug resistance emergence and selection in the complex granuloma context. Since our predictions are based on pre-clinical data, our approach can be implemented relatively early in the treatment development process, thereby enabling pro-active rather than reactive responses to emerging drug resistance for new drugs. Furthermore, this quantitative and drug-specific approach can help identify drug-specific properties that influence resistance and use this information to design treatment regimens that minimize resistance selection and expand the useful life-span of new antibiotics.

    Topics: Antitubercular Agents; Computer Simulation; Drug Resistance, Bacterial; Drug Resistance, Multiple; Granuloma; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2018
Evaluation of dried blood spot sampling for pharmacokinetic research and therapeutic drug monitoring of anti-tuberculosis drugs in children.
    International journal of antimicrobial agents, 2018, Volume: 52, Issue:1

    Dried blood spot (DBS) sampling for pharmacokinetic (PK) studies and therapeutic drug monitoring have unique advantages over venous sampling. This study aimed to evaluate a DBS method for first-line anti-tuberculosis drugs in children, and DBS sampling to assess PK parameters.. Paraguayan children were treated according to the revised paediatric dosing scheme of the World Health Organization. A PK curve was performed both with DBS sampling and conventional venous sampling for rifampicin, pyrazinamide and ethambutol. Passing-Bablok regression, Bland-Altman plots and predictive performance evaluation were used to assess agreement between DBS and plasma concentrations. The percentages of patients attaining population PK values for C. After use of a conversion factor, Passing-Bablok regression showed no significant proportional or systematic bias between DBS and plasma concentrations. Bland-Altman plots showed that 95% of the ratios of the DBS predicted:observed plasma concentrations lay between 0.6 and 1.4 for rifampicin, 0.5 and 1.6 for pyrazinamide and -0.4 and 2.8 for ethambutol. DBS measurements showed acceptable predictive performance for rifampicin and pyrazinamide, but not for ethambutol. Assessment of C. For rifampicin and pyrazinamide, the DBS method was accurate in predicting plasma concentrations, and was used successfully for PK parameter assessment. However, predicting ethambutol plasma concentrations with DBS measurement was associated with too much imprecision. Despite higher dosing, only 25% of the population reached average target adult rifampicin exposures.

    Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Dried Blood Spot Testing; Drug Monitoring; Ethambutol; Female; Humans; Infant; Male; Pyrazinamide; Rifampin; Tuberculosis

2018
GeneChip analysis of resistant Mycobacterium tuberculosis with previously treated tuberculosis in Changchun.
    BMC infectious diseases, 2018, 05-22, Volume: 18, Issue:1

    With the widespread use of rifampicin and isoniazid, bacterial resistance has become a growing problem. Additionally, the lack of relevant baseline information for the frequency of drug-resistant tuberculosis (TB) gene mutations is a critical issue, and the incidence of this infection in the city of Changchun has not investigated to date. However, compared with the slow traditional methods of drug susceptibility testing, recently developed detection methods, such as rifampicin and isoniazid resistance-related gene chip techniques, allow for rapid, easy detection and simultaneous testing for mutation frequency and drug resistance.. In this study, the rifampicin and isoniazid resistance-related gene mutation chip method was employed for an epidemiological investigation. To assess the gene mutation characteristics of drug-resistant TB and evaluate the chip method, we tested 2143 clinical specimens from patients from the infectious diseases hospital of Changchun city from January to December 2016. The drug sensitivity test method was used as the reference standard.. The following mutation frequencies of sites in the rifampicin resistance gene rpoB were found: Ser531Leu (52.6%), His526Tyr (12.3%), and Leu511Pro (8.8%). The multidrug-resistance (MDR)-TB mutation frequency was 34.7% for rpoB Ser531Leu and katG Ser315Thr, 26.4% for rpoB Ser531Leu and inhA promoter - 15 (C → T), and 10.7% for rpoB His526Tyr and katG Ser315Thr. In addition, drug susceptibility testing served as a reference standard. In previously treated clinical cases, the sensitivity and specificity of GeneChip were 83.1 and 98.7% for rifampicin resistance, 79.9 and 99.6% for isoniazid resistance, and 74.1 and 99.8% for MDR-TB.. Our experimental results show that the chip method is accurate and reliable; it can be used to detect the type of drug-resistant gene mutation in clinical specimens. Moreover, this study can be used as a reference for future research on TB resistance baselines.

    Topics: Antitubercular Agents; Bacterial Proteins; China; Drug Resistance, Bacterial; Gene Frequency; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Oligonucleotide Array Sequence Analysis; Rifampin; Tuberculosis

2018
Rapid molecular test for tuberculosis: impact of its routine use at a referral hospital.
    Jornal brasileiro de pneumologia : publicacao oficial da Sociedade Brasileira de Pneumologia e Tisilogia, 2018, Volume: 44, Issue:2

    To evaluate the impact of the use of the molecular test for Mycobacterium tuberculosis and its resistance to rifampin (Xpert MTB/RIF), under routine conditions, at a referral hospital in the Brazilian state of Bahia.. This was a descriptive study using the database of the Mycobacteriology Laboratory of the Octávio Mangabeira Specialized Hospital, in the city of Salvador, and georeferencing software. We evaluated 3,877 sputum samples collected from symptomatic respiratory patients, under routine conditions, between June of 2014 and March of 2015. All of the samples were submitted to sputum smear microscopy and the Xpert MTB/RIF test. Patients were stratified by gender, age, and geolocation.. Among the 3,877 sputum samples evaluated, the Xpert MTB/RIF test detected M. tuberculosis in 678 (17.5%), of which 60 (8.8%) showed resistance to rifampin. The Xpert MTB/RIF test detected M. tuberculosis in 254 patients who tested negative for sputum smear microscopy, thus increasing the diagnostic power by 59.9%.. The use of the Xpert MTB/RIF test, under routine conditions, significantly increased the detection of cases of tuberculosis among sputum smear-negative patients.

    Topics: Adult; Antibiotics, Antitubercular; Brazil; Diagnostic Tests, Routine; Drug Resistance, Bacterial; Female; Humans; Male; Microscopy; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Reference Values; Reproducibility of Results; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tertiary Care Centers; Treatment Outcome; Tuberculosis

2018
Carvacrol activity & morphological changes in Mycobacterium tuberculosis.
    Future microbiology, 2018, 06-01, Volume: 13

    Evaluating carvacrol, derivatives and carvacrol plus anti-TB (anti-tuberculous) drug combination activities in Mycobacterium tuberculosis as well as carvacrol cytotoxicity, efflux pump inhibitor activity and morphological changes in M. tuberculosis H. Carvacrol (CAR) and derivatives' activities were determined by resazurin microtiter assay and drug interaction by resazurin drug combination microtiter. Carvacrol cytotoxicity in VERO cells and efflux pumps inhibitor activity by ethidium bromide assay were determined and scanning electron microscopy performed.. Carvacrol MIC ranged from 19 to 156 μg/ml and carvacrol plus rifampicin combination showed synergistic effect in clinical isolates. No anti-M. tuberculosis activity improvement was observed with carvacrol derivatives. Carvacrol showed to be selective for M. tuberculosis, to have efflux pumps activity and to induce rough bacillary and agglomerates.. Carvacrol shows good anti-M. tuberculosis activity and synergism with rifampicin.

    Topics: Antitubercular Agents; Bacterial Proteins; Cymenes; Humans; Microbial Sensitivity Tests; Monoterpenes; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2018
Intrapatient variability in plasma rifampicin & isoniazid in tuberculosis patients.
    The Indian journal of medical research, 2018, Volume: 147, Issue:3

    Large variability in anti-tuberculosis (TB) drug concentrations between patients is known to exist. However, limited information is available on intrapatient drug levels during the course of anti-TB treatment (ATT). This study was conducted to evaluate intrapatient variability in plasma rifampicin (RMP) and isoniazid (INH) concentrations during ATT at start of the treatment, at the end of intensive phase (IP) of ATT and at the end of ATT in adult TB patients being treated in the Revised National TB Control Programme (RNTCP).. Adult TB patients (n=485), receiving thrice-weekly ATT in the RNTCP, were studied. Two-hour post-dosing concentrations of RMP and INH were determined at month 1, end of IP and end of ATT, after directly observed drug administration. Drug concentrations were estimated by high-performance liquid chromatography.. The median (inter-quartile range) RMP concentrations during the first month, at end of IP and end of ATT were 2.1 (0.4-5.0), 2.4 (0.6-5.5) and 2.2 (0.5-5.3) μg/ml, respectively. The corresponding INH concentrations were 7.1 (4.2-9.9), 7.2 (3.9-10.9) and 6.7 (3.9-9.5) μg/ml. None of the differences in drug concentrations obtained at different time points during ATT were significant. RMP and INH concentrations at different time points were significantly correlated. Age and body mass index caused significant variability in drug concentrations.. Plasma RMP and INH estimations in adult TB patients at two hours after drug administration remained unaltered during ATT. Clinicians can consider testing drug concentrations at any time point during ATT. These findings may assume significance in the context of therapeutic drug monitoring of anti-TB drug concentrations.

    Topics: Adolescent; Adult; Antitubercular Agents; Humans; India; Isoniazid; Pilot Projects; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis

2018
Xpert Ultra Can Unambiguously Identify Specific Rifampin Resistance-Conferring Mutations.
    Journal of clinical microbiology, 2018, Volume: 56, Issue:9

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Molecular Probes; Mutation; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Temperature; Tuberculosis

2018
Evaluation of the Xpert MTB/RIF Ultra Assay for Direct Detection of Mycobacterium tuberculosis Complex in Smear-Negative Extrapulmonary Samples.
    Journal of clinical microbiology, 2018, Volume: 56, Issue:9

    Topics: Adult; Antibiotics, Antitubercular; Diagnostic Tests, Routine; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Rifampin; Sensitivity and Specificity; Time Factors; Tuberculosis

2018
Co-inhibition as a strategic therapeutic approach to overcome rifampin resistance in tuberculosis therapy: atomistic insights.
    Future medicinal chemistry, 2018, 07-01, Volume: 10, Issue:14

    Amid the current global challenge of antimicrobial resistance, RNA polymerase remains a paramount therapeutic target for tuberculosis. Dual binding of rifampin (RIF) and a novel compound, DAAP1, demonstrated the suppression of RIF resistance. However, a paucity of data elucidating the structural mechanism of action of this synergistic interaction prevails. Methodology & results: Molecular dynamic simulations unraveled the synergistic inhibitory characteristics of DAAP1 and RIF. Co-binding induced a stable protein, increased the degree of compactness of binding site residues around RIF and subsequently an improved binding affinity toward RIF.. Findings established the structural mechanism by which DAAP1 stabilizes Mycobacterium tuberculosis RNA polymerase, thus possibly suppressing RIF resistance. This study will assist toward the design of novel inhibitors combating drug resistance in tuberculosis.

    Topics: Antitubercular Agents; Bacterial Proteins; Benzene Derivatives; Binding Sites; Catalytic Domain; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Molecular Dynamics Simulation; Mycobacterium tuberculosis; Phenylalanine; Rifampin; Thermodynamics; Tuberculosis

2018
Mutations of
    Ethiopian journal of health sciences, 2018, Volume: 28, Issue:3

    Drug resistance is a leading concern in control of TB. Resistance against rifampin as one of the most important drugs in the treatment of. This study was conducted on referred samples of patients who did not respond to anti-TB treatment, in Tuberculosis Regional Reference Laboratory at Shariati Hospital. Drug susceptibility of M. tuberculosis isolates was surveyed using a proportional method on LJ medium. The isolates with resistant to rifampin were reconfirmed and then the rpoB gene was amplified and sequenced.. Among 27 resistant cases, 8, 11 and 8 people were from Iran, Afghanistan, and Turkmenistan, respectively. In 26 out of 27 isolates, rpoB gene mutations were observed. The most prevalent mutations belonged to the codon 53.. The use of rpoB gene sequencing led to the lack of the need for growth of the organism in the culture medium, the direct use of clinical samples, reduction of biological risks and a detection about 96.3% of MDR TB cases lowering the cost of the treatment.

    Topics: Adult; Antitubercular Agents; Bacterial Proteins; Codon; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Female; Genes, Bacterial; Humans; Iran; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2018
Neuropsychiatric manifestations among HIV-1 infected African patients receiving efavirenz-based cART with or without tuberculosis treatment containing rifampicin.
    European journal of clinical pharmacology, 2018, Volume: 74, Issue:11

    Efavirenz-based combination antiretroviral therapy (cART) is associated with neuropsychiatric adverse events. We investigated the time to onset, duration, clinical implications, impact of pharmacogenetic variations, and anti-tuberculosis co-treatment on efavirenz-associated neuropsychiatric manifestations.. Prospective cohort study of cART naïve HIV patients with or without tuberculosis (HIV-TB) co-infection treated with efavirenz-based cART. Rifampicin-based anti-tuberculosis therapy was initiated 4 weeks prior to efavirenz-based cART in HIV-TB patients. Data on demographic, clinical, laboratory, and a 29-item questionnaire on neuropsychiatric manifestations were collected for 16 weeks after cART initiation. Genotyping for CYP2B6, CYP3A5, SLCO1B1, and ABCB1 and quantification of efavirenz plasma concentration were done on the 4th and 16th week.. Data from 458 patients (243 HIV-only and 215 HIV-TB) were analyzed. Overall incidence of neuropsychiatric manifestations was 57.6% being higher in HIV-only (66.7%) compared to HIV-TB patients (47.4%) (p < 0.01). HIV-only patients were more symptomatic, with proportionately higher grades of manifestations compared to HIV-TB patients. Median time to manifestations was 1 week after cART initiation in HIV-only and 6 weeks after anti-TB (i.e., 2 weeks after cART initiation) in HIV-TB patients. HIV-only patients had significantly higher efavirenz plasma concentrations at 4 weeks after cART compared to HIV-TB patients. No association of sex or genotype was seen in relation to neuropsychiatric manifestations. Risk for neuropsychiatric manifestations was three times more in HIV-only patients compared to HIV-TB (p < 0.01).. Incidence of neuropsychiatric manifestations during early initiation of efavirenz-based cART is high in Tanzanian HIV patients. Risk of neuropsychiatric manifestations is lower in HIV patients co-treated with rifampicin containing anti-TB compared to those treated with efavirenz-based cART only.

    Topics: Adult; Africa South of the Sahara; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Benzoxazines; Cohort Studies; Cyclopropanes; Female; Genotype; HIV Infections; HIV-1; Humans; Male; Mental Disorders; Pharmacogenetics; Prospective Studies; Rifampin; Tuberculosis

2018
Synergistic Interplay of The Co-administration of Rifampin And Newly Developed Anti-TB Drug: Could It Be a Promising New Line of TB Therapy?
    Combinatorial chemistry & high throughput screening, 2018, Volume: 21, Issue:6

    Rifampin resistance has dampened the existing efforts being made to control the global crisis of Tuberculosis and antimicrobial resistance in general. Previous studies that attempted to provide insights into the structural mechanism of Rifampin resistance did not utilize the X-ray crystal structure of Mycobacterium tuberculosis RNA polymerase due to its unavailability.. We provide an atomistic mechanism of Rifampin resistance in a single active site mutating Mycobacterium tuberculosis RNA polymerase, using a recently resolved crystal structure. We also unravel the structural interplay of this mutation upon co-binding of Rifampin with a novel inhibitor, D-AAP1. Mutation distorted the overall conformational landscape of Mycobacterium tuberculosis RNA polymerase, reduced binding affinity of Rifampin and shifted the overall residue interaction network of the enzyme upon binding of only Rifampin. Interestingly, co-binding with DAAP1, though impacted by the mutation, exhibited improved Rifampin binding interactions amidst a distorted residue interaction network.. Findings offer vital conformational dynamics and structural mechanisms of mutant enzyme-single ligand and mutant enzyme-dual ligand interactions which could potentially shift the current therapeutic protocol of Tuberculosis infections.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Molecular Dynamics Simulation; Mycobacterium tuberculosis; Protein Binding; Protein Conformation; Rifampin; Structure-Activity Relationship; Tuberculosis

2018
Ambroxol Induces Autophagy and Potentiates Rifampin Antimycobacterial Activity.
    Antimicrobial agents and chemotherapy, 2018, Volume: 62, Issue:9

    Host-directed therapy in tuberculosis is a potential adjunct to antibiotic chemotherapy directed at

    Topics: Ambroxol; Animals; Antitubercular Agents; Autophagy; Macrophages; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2018
Anti-Mycobacterium tuberculosis activity of naphthoimidazoles combined with isoniazid and rifampicin.
    Tuberculosis (Edinburgh, Scotland), 2018, Volume: 111

    Tuberculosis (TB) is the cause of more than one million deaths worldwide, and despite being a curable disease, some factors can make therapy difficult, emphasizing the need for the development of new drugs that may potentiate the action of the classic anti-TB antimicrobials. Naphthoimidazoles show a broad spectrum of biological activities, including antimycobacterial activity. The aim of this study was to evaluate the anti-Mycobacterium tuberculosis activity of nine naphthoimidazoles, alone and combined with isoniazid (INH) and rifampicin (RIF). We evaluated the minimum inhibitory concentration (MIC) of the compounds, the fractional inhibitory concentration of the combinations of the naphthoimidazoles with INH or RIF, and the cytotoxicity of these compounds. Eight compounds showed MICs ranging from 1.56 to 25 μg/mL and the presence of substituents on phenyl groups shown to be essential for antimycobacterial activity. Four compounds showed additivity with both INH and RIF and showed SI values higher than 10, indicating safety. Thus, considering the antimycobacterial activity and the absence of antagonism between naphthoimidazoles and the two main drugs for TB treatment, these compounds could be scaffolds for the development of new anti-TB drugs.

    Topics: Antitubercular Agents; Drug Discovery; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Imidazoles; Isoniazid; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Naphthoquinones; Rifampin; Structure-Activity Relationship; Tuberculosis

2018
Direct genotyping of Mycobacterium tuberculosis from Xpert
    Tuberculosis (Edinburgh, Scotland), 2018, Volume: 111

    Genotyping of Mycobacterium tuberculosis (MTB) isolates has markedly improved our knowledge of its transmission dynamics. MIRU-VNTR is considered the reference molecular tool for MTB fingerprinting. However, the dependence of this technique on cultured isolates means that we lack molecular epidemiology data from many settings where culture facilities have not been implemented. Efforts have been made to adapt the MIRU-VNTR procedure to direct analysis of clinical specimens, although implementation of these efforts has not proven successful. The large-scale roll-out of Xpert MTB/RIF (Xpert) technology, which is now in almost every TB-endemic country, including many where MTB is not cultured, provides us with a new opportunity to explore whether MTB genotyping could be performed from the remnants of the Xpert cartridge. We ran a pilot study in Mozambique in which the remnants of 24 positive Xpert assays for detection of MTB were used as template material for the 15-locus or the more discriminatory 24-locus MIRU-VNTR technique. MTB fingerprinting was possible in specimens with a high bacterial burden, according to the Xpert load categories, and within the first week after Xpert was performed. Given the wide availability, simple processing, and rapid reporting of results with Xpert, our findings suggest that MIRU-VNTR-based fingerprinting from remnants of Xpert could play a major role in extending MTB molecular epidemiology studies to settings where information on the transmission dynamics of this pathogen is lacking.

    Topics: Antibiotics, Antitubercular; Automation, Laboratory; Bacteriological Techniques; DNA, Bacterial; Drug Resistance, Bacterial; Feasibility Studies; Genotype; Humans; Microbial Sensitivity Tests; Minisatellite Repeats; Molecular Epidemiology; Mozambique; Mycobacterium tuberculosis; Phenotype; Pilot Projects; Predictive Value of Tests; Rifampin; Tuberculosis

2018
Antituberculous drugs modulate bacterial phagolysosome avoidance and autophagy in Mycobacterium tuberculosis-infected macrophages.
    Tuberculosis (Edinburgh, Scotland), 2018, Volume: 111

    Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) complex remains a deadly infectious disease worldwide. Mtb is an intracellular pathogen, and autophagy is an essential component of the immune response leading to TB clearance. Anti-TB treatment is based on classical isoniazid (INH) and rifampicin (RIF), but also new drugs, such as linezolid (LNZ) and bedaquiline (BDQ). However, little is known about these antibiotics' impact on Mtb intra-macrophagic behavior independent of their impact on host cells. We explored the effect of mycobacterial pre-treatment with these four antibiotics on the intra-macrophagic Mtb survival and trafficking, thanks to bacterial counts and microscopy confocal imaging. Our results showed that INH and BDQ impaired Mtb phagosome escape, RIF increased autolysosome formation, and LNZ and BDQ improved autophagy activation and efficacy. These data suggest that antibiotics favoring autophagy activation (LNZ and BDQ) may allowed better Mtb clearance by macrophages and could provide basis for future anti-TB strategies.

    Topics: Antitubercular Agents; Autophagy; Diarylquinolines; Host-Pathogen Interactions; Humans; Isoniazid; Linezolid; Macrophages; Mycobacterium tuberculosis; Phagosomes; Rifampin; Tuberculosis; U937 Cells

2018
Dolutegravir use in combination with rifampicin-based tuberculosis therapy: 3 years of real-world experience in a large UK teaching hospital.
    Sexually transmitted infections, 2018, Volume: 94, Issue:6

    Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Hospitals, Teaching; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Rifampin; Treatment Outcome; Tuberculosis; United Kingdom

2018
Comparison of the Purelyse® - IS6110 nested PCR with the Xpert® MTB/RIF test in clinical samples with suspected tuberculosis.
    Journal of microbiological methods, 2018, Volume: 152

    Tuberculosis (TB) has a high incidence, prevalence and mortality in the world. Due to its high level of transmission and long-term pharmacological treatment, it is important to have sensitive and specific diagnostic tests. Recently, the PureLyse® system, which is a novel DNA extraction method, was proposed to be an important tool for molecular diagnosis of TB. Here, we compare the PureLyse® system followed by an IS6110 nested PCR (PureLyse® - IS6110 nested PCR) with the Xpert® MTB/RIF test for Mycobacterium tuberculosis complex (MTBC) identification in 40 clinical samples. Among the 40 samples, 26 samples were positive and 14 negative for the Xpert® MTB/RIF test as well as for the PureLyse® - IS6110 nested PCR. According to the Xpert® MTB/RIF test, positive samples presented different bacillary concentrations from "High" to "Very low" and rifampin resistance was observed in 5 samples. The concordance of both molecular methods makes the PureLyse® - IS6110 nested PCR suitable for MTBC detection in patients for low-income resources.

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; Bacteriological Techniques; Diagnostic Tests, Routine; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2018
Formulation, optimization, and characterization of rifampicin-loaded solid lipid nanoparticles for the treatment of tuberculosis.
    Drug development and industrial pharmacy, 2018, Volume: 44, Issue:12

    Mycobacterium tuberculosis, being the causative infectious agent, is the leading cause of death worldwide amongst the infectious disease. The low bioavailability of rifampicin (RIF), one of the vital constituent of antitubercular therapy, instigates an urge to develop nanocarrier, which can prevent its degradation in the acidic pH of the stomach. Solid lipid nanoparticles (SLNs) have been proven to be promising versatile platform for oral delivery of lipophilic drugs. Therefore, the current investigation demonstrates development of RIF-loaded solid lipid nanoparticles (RIF-SLNs) using high-pressure homogenization technique by employing a three-level, three-factor Box-Behnken design. Concentration of drug, concentration of emulsifier, and homogenization pressure were selected as an independent variables, and %drug loading (%DL), %entrapment efficiency (%EE), and particle size were selected as dependent variables. The developed RIF-SLNs were characterized for particle size, polydispersity index, zeta potential, %EE, %DL, differential scanning calorimetry, X-ray diffraction, and TEM analysis. The mean diameter of RIF-SLNs was found to be 456 ± 11 nm, %EE of 84.12 ± 2.78%, and %DL of 15.68 ± 1.52%. The in vitro lipolysis experiments revealed that RIF-SLNs stabilized using poloxamer 188, exhibited antilipolytic effect. Furthermore, the in vitro GI stability studies (at pH 1.2, pH 4.5, pH 6.8, and pH 7.4) revealed that the developed system could withstand various gastrointestinal tract media. The in vitro dissolution studies depicted biphasic drug release profile for drug-loaded SLNs revealing best fit with Weibull model. The accelerated stability studies for 6 months does not revealed any significant change in characteristics of developed RIF-SLNs.

    Topics: Antitubercular Agents; Biological Availability; Chemistry, Pharmaceutical; Drug Carriers; Drug Compounding; Drug Liberation; Drug Stability; Humans; Lipids; Nanoparticles; Particle Size; Rifampin; Tuberculosis; X-Ray Diffraction

2018
Tuberculosis-related type of psoriasis.
    Medical hypotheses, 2018, Volume: 117

    Psoriasis is a multifaceted disease in terms of its pathophysiological mechanisms, inducing and aggravating factors, clinical types and clinical severity, associated comorbidities and therapeutic modalities. In recent years, an attracting perspective has emerged to identify variants of the disease with their own specific clinical course and management which could stratify the variable spectrum of the disease into different entities (such as palmo-plantar pustulosis). We hypothesize the existence of a unique Tuberculosis-related type of psoriasis that could be managed successfully with rifampicin.

    Topics: Anti-Bacterial Agents; Antitubercular Agents; Biological Therapy; Comorbidity; Humans; Models, Theoretical; Prevalence; Psoriasis; Rifampin; Tuberculosis

2018
Antimycobacterial susceptibility evaluation of rifampicin and isoniazid benz-hydrazone in biodegradable polymeric nanoparticles against
    International journal of nanomedicine, 2018, Volume: 13

    Tuberculosis (TB) is the single largest infectious disease which requires a prolonged treatment regime with multiple drugs. The present treatment for TB includes frequent administration of a combination of four drugs for a duration of 6 months. This leads to patient's noncompliance, in addition to developing drug-resistant strains which makes treatment more difficult. The formulation of drugs with biodegradable polymeric nanoparticles (NPs) promises to overcome this problem.. In this study, we focus on two important drugs used for TB treatment - rifampicin (RIF) and isoniazid (INH) - and report a detailed study of RIF-loaded poly lactic-co-glycolic acid (PLGA) NPs and INH modified as INH benz-hydrazone (IH2) which gives the same therapeutic effect as INH but is more stable and enhances the drug loading in PLGA NPs by 15-fold compared to INH. The optimized formulation was characterized using particle size analyzer, scanning electron microscopy and transmission electron microscopy. The drug release from NPs and stability of drug were tested in different pH conditions.. These results show that NP formulations will improve the efficacy of drug delivery for TB treatment.

    Topics: A549 Cells; Animals; Antitubercular Agents; Biocompatible Materials; Cell Death; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Drug Compounding; Drug Delivery Systems; Drug Liberation; Humans; Isoniazid; Lactic Acid; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nanoparticles; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Proton Magnetic Resonance Spectroscopy; RAW 264.7 Cells; Rifampin; Static Electricity; Surface Tension; Tuberculosis

2018
Cost-utility analysis of high-dose treatment for intermediate-susceptible, dose-dependent tuberculosis patients.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2018, 09-01, Volume: 22, Issue:9

    We proposed to: 1) introduce an intermediate-susceptible, dose-dependent (ISDD) category for Mycobacterium tuberculosis infection; and 2) treat patients with M. tuberculosis infection in this category with a high dose of rifampicin (RMP) and isoniazid (INH).. To examine the impact of our strategy on quality-adjusted life-years (QALY) and costs in a low-income country with a high prevalence of multidrug-resistant tuberculosis (MDR-TB) (Belarus) and a high-income, low MDR-TB prevalence country (The Netherlands).. A Markov model comprising 14 health states was used to simulate treatment outcomes and costs accrued over 5 years for a hypothetical cohort of 10 000 patients. One-way sensitivity analysis, probabilistic sensitivity analysis and a scenario analysis were also performed.. Our strategy was shown to be cost-effective for Belarus, but not for the Netherlands. At a willingness-to-pay of 50 000 euros per QALY, the probability of our strategy being cost-effective was 50% for the Netherlands and 57% for Belarus.. The study shows that our strategy could be cost-effective and more efficacious. However, more studies are needed on the outcomes of using higher doses of INH and RMP.

    Topics: Antitubercular Agents; Cohort Studies; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Costs; Humans; Isoniazid; Markov Chains; Mycobacterium tuberculosis; Netherlands; Quality-Adjusted Life Years; Rifampin; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2018
Improvement of Mycobacterium tuberculosis detection by Xpert MTB/RIF Ultra: A head-to-head comparison on Xpert-negative samples.
    PloS one, 2018, Volume: 13, Issue:8

    The new Xpert MTB/RIF Ultra assay (Ultra, Cepheid, Sunnyvale, USA) is a cartridge-based automated diagnostic test that can simultaneously identify Mycobacterium tuberculosis complex (MTB) and resistance to Rifampicin (RIF). With respect to the previous version Xpert MTB/RIF assay (Xpert), IS6110/IS1081 repetitive elements probes have been added allowing the detection of lower MTB load, defined by the new semi-quantitative category "trace" with indeterminate RIF resistance. The aim of this study was to evaluate performance of the new version Ultra on Xpert-negative, but TB culture-positive clinical samples.. The de-identified frozen samples (-20 °C) collected over a 4-year period (February 2014-October 2017), which had previously resulted smear-negative, Xpert-negative but MTB culture-positive, were analyzed with Ultra. The de-frosted samples were loaded into the cartridge using the same process as the previous version, according to manufacturer's instruction.. During the study period 382 MTB culture-positive samples were archived: 314 resulted Xpert-positive and 68 Xpert-negative. Thirty-one of the 68 Xpert-negative samples resulted positive with Ultra, with an overall improvement in MTB detection of 45.6%. Out of 36 Xpert-negative respiratory samples, 18 resulted Ultra-positive with the following semi-quantitative loads: "low"(n = 1), "very low"(n = 11), "trace"(n = 6), with an improvement in MTB detection of 50%. The best performance was achieved on bronchoalveolar lavage specimens (53.8%). Out of 32 Xpert-negative non-respiratory samples, 13 resulted Ultra-positive with the following semi-quantitative loads: "very low"(n = 7), "trace"(n = 6), with an improvement in MTB detection of 40.6%. The best performance was achieved on biopsies (55.6%) and lymph nodes (50%). The new category "trace" detected 12 out of the 31 Ultra-positive MTB samples; in the remaining 19 samples RIF susceptibility was determined with 100% concordance with the phenotypic susceptibility test. The mean time to positivity of samples found negative by Ultra was significantly longer in comparison to positive samples in liquid culture.. Our results are consistent with the few studies published so far and confirm the better performance of Ultra compared to the previous version in both respiratory and non-respiratory smear-negative samples, with an overall improvement of 45.6%.

    Topics: Antibiotics, Antitubercular; Diagnostic Tests, Routine; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Reproducibility of Results; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis

2018
Characterizing the Effects of Glutathione as an Immunoadjuvant in the Treatment of Tuberculosis.
    Antimicrobial agents and chemotherapy, 2018, Volume: 62, Issue:11

    Topics: Adjuvants, Immunologic; Anti-Bacterial Agents; Antitubercular Agents; Cell Line; Drug Therapy, Combination; Ethambutol; Glutathione; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; THP-1 Cells; Tuberculosis; Tuberculosis, Multidrug-Resistant

2018
Kasugamycin potentiates rifampicin and limits emergence of resistance in
    eLife, 2018, 08-28, Volume: 7

    Most bacteria use an indirect pathway to generate aminoacylated glutamine and/or asparagine tRNAs. Clinical isolates of

    Topics: Aminoacylation; Aminoglycosides; Animals; Drug Resistance, Bacterial; Drug Synergism; Edeine; Injections, Intraperitoneal; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Organ Specificity; Protein Biosynthesis; Rifampin; RNA, Transfer; Streptomycin; Tuberculosis

2018
Upfront Xpert MTB/RIF testing on various specimen types for presumptive infant TB cases for early and appropriate treatment initiation.
    PloS one, 2018, Volume: 13, Issue:8

    Diagnosis of tuberculosis (TB) in infants is challenging due to non-specific clinical presentations of the disease in this age-group and low sensitivity of widely available TB diagnostic tools, which in turn delays prompt access to TB treatment. Upfront access to Xpert/MTB RIF (Xpert) testing, a highly sensitive and specific rapid diagnostic tool, could potentially address some of these challenges. Under the current project, we assessed the utility and feasibility of applying upfront Xpert for diagnosis of tuberculosis in infants, including for testing of non-sputum specimens.. A high throughput lab was established in each of the four project cities, and linked to various health care providers across the city, through rapid specimen transportation and electronic reporting linkages. Free Xpert testing was offered to all infant (<2 years of age) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities.. A total of 7,994 presumptive infant TB cases were enrolled in the project from April 2014 to October 2016, detecting 465 (5.8%, CI: 5.3-6.4) TB cases. The majority (93.9%; CI: 93.4-94.4) of patient specimens were non-sputum and TB positivity was higher amongst non-sputum specimens. Further, a high proportion (5.6% CI 3.8-8.1) of infant TB cases were found to be rifampicin resistant. Covering large cities with a single lab per city over more than two years, the project demonstrated the feasibility of same-day diagnosis with upfront Xpert testing. This in turn led to prompt treatment initiation, with a two-day median turnaround time to treatment initiation. Case mortality observed in the project cohort of diagnosed TB cases was 11.0% (CI 8.4-14.1), the majority of which was pre- or early treatment mortality, in spite of prompt access to treatment for most diagnosed cases.. The current project demonstrated the feasibility of applying rapid and upfront Xpert testing for presumptive infant TB cases. Rapid TB diagnosis in turn facilitates prompt and appropriate treatment initiation. Further, levels of rifampicin resistance observed in infants TB cases highlight the additional benefit of upfront resistance testing. However, high rates of early case mortality, in spite of prompt diagnosis and treatment initiation, highlight the need for further research in infant patient pathways for overall improvement in TB care for infant populations.

    Topics: Antitubercular Agents; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2018
"Life continues": Patient, health care and community care workers perspectives on self-administered treatment for rifampicin-resistant tuberculosis in Khayelitsha, South Africa.
    PloS one, 2018, Volume: 13, Issue:9

    Self-administered treatment (SAT), a differentiated model of care for rifampicin-resistant tuberculosis (RR-TB), might address adherence challenges faced by patients and health care systems. This study explored patient, health-care worker (HCW) and community care worker (CCW) perspectives on a SAT pilot programme in South Africa, in which patients were given medication to take at home with the optional support of a CCW.. We conducted a mixed-methods study from July 2016-June 2017. The quantitative component included semi-structured questionnaires with patients, HCWs and CCWs; the qualitative component involved in-depth interviews with patients enrolled in the pilot programme. Interviews were conducted in isiXhosa, translated, transcribed and manually coded.. Overall, 27 patients, 12 HCWs and 44 CCWs were enrolled in the quantitative component; nine patients were also interviewed. Of the 27 patients who completed semi-structured questionnaires, 22 were HIV-infected and 17 received a monthly supply of RR TB treatment. Most HCWs and CCWs (10 and 32, respectively) understood the pilot programme; approximately half (n = 14) of the patients could not correctly describe the pilot programme. Overall, 11 and 41 HCWs and CCWs reported that the pilot programme promoted treatment adherence. Additionally, 11 HCWs reported that the pilot programme relieved pressure on the clinic. Key qualitative findings highlighted the importance of a support person and how the flexibility of SAT enabled integration of treatment into their daily routines and reduced time spent in clinics. The pilot programme was also perceived to allow patients more autonomy and made it easier for them to manage side-effects.. The SAT pilot programme was acceptable from the perspective of patients, HCWs and CCWs and should be considered as a differentiated model of care for RR-TB, particularly in settings with high burdens of HIV, in order to ease management of treatment for patients and health-care providers.

    Topics: Adult; Attitude to Health; Community Networks; Female; Health Knowledge, Attitudes, Practice; Health Personnel; Humans; Longitudinal Studies; Male; Middle Aged; Patient Compliance; Patients; Rifampin; Self Care; South Africa; Surveys and Questionnaires; Tuberculosis; Tuberculosis, Multidrug-Resistant

2018
Mycobacterium tuberculosis carrying a rifampicin drug resistance mutation reprograms macrophage metabolism through cell wall lipid changes.
    Nature microbiology, 2018, Volume: 3, Issue:10

    Tuberculosis is a significant global health threat, with one-third of the world's population infected with its causative agent Mycobacterium tuberculosis (Mtb). The emergence of multidrug-resistant (MDR) Mtb that is resistant to the frontline anti-tubercular drugs rifampicin and isoniazid forces treatment with toxic second-line drugs. Currently, ~4% of new and ~21% of previously treated tuberculosis cases are either rifampicin-drug-resistant or MDR Mtb infections

    Topics: Animals; Antitubercular Agents; Bacterial Proteins; Cell Wall; Cells, Cultured; DNA-Directed RNA Polymerases; Drug Resistance, Multiple, Bacterial; Female; Gene Expression; Host-Pathogen Interactions; Interferon-beta; Interleukin-1; Lipids; Macrophages; Male; Mice; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Receptors, Interleukin-1; Rifampin; Signal Transduction; Tuberculosis

2018
Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.
    The New England journal of medicine, 2018, 10-11, Volume: 379, Issue:15

    The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.. We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance.. A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted.. Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Ethambutol; Genome, Bacterial; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Phenotype; Pyrazinamide; Rifampin; Tuberculosis; Whole Genome Sequencing

2018
Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism.
    Nature communications, 2018, 10-08, Volume: 9, Issue:1

    Rifamycin antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (Rif

    Topics: Aminobenzoates; Antibiotics, Antitubercular; Bacteria; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Hydroxybenzoates; Metagenomics; Molecular Structure; Mutation; Mycobacterium tuberculosis; Rifampin; Rifamycins; Soil Microbiology; Tuberculosis

2018
High rates of death and loss to follow-up by 12 months of rifampicin resistant TB treatment in South Africa.
    PloS one, 2018, Volume: 13, Issue:10

    Treatment success rates of rifampicin resistant (RR)/multi-drug resistant (MDR) tuberculosis (TB) in South Africa range from 43-48%, falling short of the World Health Organization's target of ≥75%. We present rates and assess predictors of attrition by 12 months on treatment.. Prospective observational cohort analysis of adults (≥18 years) initiating RR/MDR-TB treatment from 01 March 2013 to 30 September 2016. Attrition was defined as a combination of death and loss to follow-up (LTFU; treatment interruption ≥2 months) by 12 months on treatment. Predictors of attrition were identified using Cox Proportional Hazards models to estimate crude (HR) and adjusted hazard ratios (aHR) with corresponding 95% confidence intervals.. By 12 months on treatment, 75/240 (31.3%) patients had either died (37/240; 15.4%) or been LTFU (38/240; 15.8%). Patients with moderate/severe anaemia (aHR: 2.10; 95% CI 1.00-4.39), and those who were smear positive at baseline (aHR: 2.04; 95% CI 1.01-4.12) were significantly more likely to die or be lost from care.. At this outpatient DR-TB treatment site, there was a high rate of attrition halfway through the standard treatment course at 12 months of 31%. High rates of attrition by 12 months on treatment may continue during the second-half of therapy.

    Topics: Adolescent; Adult; Anemia; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Bacterial; Female; Humans; Kaplan-Meier Estimate; Male; Medication Adherence; Middle Aged; Observational Studies as Topic; Proportional Hazards Models; Prospective Studies; Rifampin; Severity of Illness Index; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2018
Vitamin C and Mycobacterium tuberculosis Persisters.
    Antimicrobial agents and chemotherapy, 2018, Volume: 62, Issue:11

    Topics: Animals; Ascorbic Acid; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2018
Reply to Yew et al., "Vitamin C and Mycobacterium tuberculosis Persisters".
    Antimicrobial agents and chemotherapy, 2018, Volume: 62, Issue:11

    Topics: Animals; Ascorbic Acid; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2018
Long-term efavirenz pharmacokinetics is comparable between Tanzanian HIV and HIV/Tuberculosis patients with the same CYP2B6*6 genotype.
    Scientific reports, 2018, 11-05, Volume: 8, Issue:1

    The impact of anti-tuberculosis co-treatment on efavirenz (EFV) exposure is still uncertain as contradictory reports exist, and the relevance of CYP2B6*6 genetic polymorphism on efavirenz clearance while on-and-off anti-tuberculosis co-treatment is not well investigated. We investigated the determinants of long-term efavirenz pharmacokinetics by enrolling HIV (n = 20) and HIV/Tuberculosis (n = 36) subjects undergoing efavirenz and efavirenz/rifampicin co-treatment respectively. Pharmacokinetic samplings were done 16 weeks after initiation of efavirenz-based anti-retroviral therapy and eight weeks after completion of rifampicin-based anti-tuberculosis treatment. Population pharmacokinetic modeling was used to characterize variabilities and covariates of efavirenz pharmacokinetic parameters. CYP2B6*6 genetic polymorphism but not rifampicin co-treatment was the statistically significant covariate. The estimated typical efavirenz clearance in the HIV only subjects with the CYP2B6*1/*1 genotype was 23.6 L/h/70 kg, while it was 38% and 69% lower in subjects with the CYP2B6*1/*6 and *6/*6 genotypes, respectively. Among subjects with the same CYP2B6 genotypes, efavirenz clearances were comparable between HIV and HIV/Tuberculosis subjects. Typical efavirenz clearances before and after completion of anti-tuberculosis therapy were comparable. In conclusion, after 16 weeks of treatment, efavirenz clearance is comparable between HIV and HIV/Tuberculosis patients with the same CYP2B6 genotype. CYP2B6 genotyping but not anti-tuberculosis co-treatment should guide efavirenz dosing to optimize treatment outcomes.

    Topics: Adult; Alkynes; Benzoxazines; Coinfection; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Interactions; Female; Genotype; HIV Infections; Humans; Male; Middle Aged; Rifampin; Tanzania; Tissue Distribution; Tuberculosis

2018
Management of De Novo Mycobacterial Infection After Lung Transplantation Without Rifampicin: Case Series of a Single Institution.
    Transplantation proceedings, 2018, Volume: 50, Issue:9

    To treat organ transplant patients with mycobacterial infection, physicians need to pay attention to interaction between drugs used against mycobacteria and immunosuppressants. The purpose of this report is to describe the clinical features of and treatment for mycobacterial infection in lung transplant (LTx) recipients.. To investigate the incidence, treatment, and outcome for mycobacterial infection, we retrospectively reviewed 100 LTx recipients in our program since 2000.. Four recipients (4.0%) developed mycobacterial infection. Three recipients took tacrolimus, and 1 received cyclosporine with mycophenolate mofetil and a steroid for immunosuppression. Tuberculosis (TB) was isolated from 2 recipients, and non-tuberculous mycobacteriosis (NTM) was detected in the other 2. We treated the patients with levofloxacin + isoniazid + pyrazinamide + ethambutol (EB) for TB and clarithromycin (CLM) + EB for NTM to avoid interaction of calcineurin inhibitors (CNI: 8-10 ng/mL in trough level) with rifampicin (RFP). In treating the patients with NTM, we were able to maintain an adequate blood concentration of CNI by decreasing the dosage from one-half to one-quarter. All mycobacterial infections were controlled with treatment. In 1 patient with chronic obstructive pulmonary disease (COPD) infected with TB in the native lung, the forced expiratory volume in 1 second (FEV1) unexpectedly increased from 1890 mL before infection to 2320 mL possibly due to organization of the native lung.. We were able to manage the mycobacterial infections using drugs other than RFP without any cases of acute rejection under adequate immunosuppression. Organization of the native lung with TB infection unexpectedly resulted in improvement of FEV1 in a COPD patient.

    Topics: Adult; Anti-Bacterial Agents; Calcineurin Inhibitors; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Lung Transplantation; Male; Middle Aged; Mycobacterium Infections; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Mycophenolic Acid; Nontuberculous Mycobacteria; Postoperative Complications; Retrospective Studies; Rifampin; Tacrolimus; Tuberculosis

2018
Efficacy Versus Hepatotoxicity of High-dose Rifampin, Pyrazinamide, and Moxifloxacin to Shorten Tuberculosis Therapy Duration: There Is Still Fight in the Old Warriors Yet!
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2018, 11-28, Volume: 67, Issue:suppl_3

    One approach that could increase the efficacy and reduce the duration of antituberculosis therapy is pharmacokinetics/pharmacodynamics-based optimization of doses. However, this could increase toxicity.. We mimicked the concentration-time profiles achieved by human equivalent doses of moxifloxacin 800 mg/day, rifampin 1800 mg/day, and pyrazinamide 4000 mg/day (high-dose regimen) vs isoniazid 300 mg/day, rifampin 600 mg/day, and pyrazinamide 2000 mg/day (standard therapy) in bactericidal and sterilizing effect studies in the hollow fiber system model of tuberculosis (HFS-TB). In an intracellular Mycobacterium tuberculosis (Mtb) HFS-TB experiment, we added a 3-dimensional human organotypic liver to determine potential hepatotoxicity of the high-dose regimen, based on lactate dehydrogenase (LDH). Treatment lasted 28 days and Mtb bacterial burden was based on colony counts. We calculated the time to extinction (TTE) of the Mtb population in the HFS-TB and used morphism-based transformation and Latin hypercube sampling to identify the minimum therapy duration in patients.. The kill rate of standard therapy in the bactericidal effect and sterilizing effect experiments were 0.97 (95% confidence interval [CI], .91-.99) log10 colony-forming units (CFU)/mL/day, and 0.56 (95% CI, .49-.59) log10 CFU/mL/day, respectively. The high-dose regimen's bactericidal and sterilizing effect kill rates were 0.99 (95% CI, .96-.99) log10 CFU/mL/day and 0.72 (95% CI, .56-.79) log10 CFU/mL/day, respectively. The upper confidence bound for TTE in patients was 4.5-5 months for standard therapy vs 3.7 months on the high-dose regimen. There were no differences in LDH concentrations between the 2 regimens at any time point (P > .05).. The high-dose regimen may moderately shorten therapy without increased hepatotoxicity compared to standard therapy.

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Humans; Liver; Models, Biological; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Time Factors; Tuberculosis

2018
Mycobacterium africanum (Lineage 6) shows slower sputum smear conversion on tuberculosis treatment than Mycobacterium tuberculosis (Lineage 4) in Bamako, Mali.
    PloS one, 2018, Volume: 13, Issue:12

    Ancestral M. tuberculosis complex lineages such as M. africanum are underrepresented among retreatment patients and those with drug resistance. To test the hypothesis that they respond faster to TB treatment, we determined the rate of smear conversion of new pulmonary tuberculosis patients in Bamako, Mali by the main MTBc lineages.. Between 2015 and 2017, we conducted a prospective cohort study of new smear positive pulmonary tuberculosis patients in Bamako. Confirmed MTBc isolates underwent genotyping by spoligotyping for lineage classification. Patients were followed at 1 month (M), 2M and 5M to measure smear conversion in auramine (AR) and Fluorescein DiAcetate (FDA) vital stain microscopy.. All the first six human MTBc lineages were represented in the population, plus M. bovis in 0.8% of the patients. The most widely represented lineage was the modern Euro-American lineage (L) 4, 57%, predominantly the T family, followed by L6 (M. africanum type 2) in 22.9%. Ancestral lineages 1, 5, 6 and M. bovis combined amounted to 28.8%. Excluding 25 patients with rifampicin resistance, smear conversion, both by AR and FDA, occurred later in L6 compared to L4 (HR 0.80 (95% CI 0.66-0.97) for AR, and HR 0.81 (95%CI 0.68-0.97) for FDA). In addition we found that HIV negative status, higher BMI at day 0, and patients with smear grade at baseline ≤ 1+ were associated with earlier smear conversion.. The six major human lineages of the MTBc all circulate in Bamako. Counter to our hypothesis, we found that patients diseased with modern M. tuberculosis complex L4 respond faster to TB treatment than those with M. africanum L6.

    Topics: Adolescent; Adult; Antitubercular Agents; Bacterial Typing Techniques; Drug Resistance, Bacterial; Female; Humans; Male; Mali; Microscopy; Mycobacterium; Odds Ratio; Prospective Studies; Rifampin; Sputum; Tuberculosis; Young Adult

2018
Prevalence of rifampicin resistant tuberculosis and associated factors among presumptive tuberculosis patients in a secondary referral hospital in Lagos Nigeria.
    African health sciences, 2018, Volume: 18, Issue:3

    Nigeria is one of the 30 high burden countries for drug resistant tuberculosis (DR-TB). This study assessed the prevalence and factors associated with rifampicin resistant tuberculosis (RR-TB) in a secondary referral hospital in Lagos State Nigeria.. A total of 2497 clients were screened for MTB and RR-TB during the study period. The majority (51.4%) were between 25 - 44 years. Male: Female ratio was 1:0.8. Of the 2497 clients screened, MTB was detected in 942 (37.7%) out of which 220 (23.4%) had RR-TB. Age (AOR 1.8, 95%CI 1.3- 2.6, p = 0.001), symptomatic contact with DR-TB patients (AOR 3.3, 95%CI 2.1-5.1, p <0.001) and type of TB (AOR 2.9, 95% CI 1.7 - 5.0, <0.001) were associated with RR-TB after adjusting for age, gender, HIV status and symptomatic contacts with DR-TB patients.. The prevalence of RR-TB in new and previously treated TB patients was high in this study. Urgent steps are needed to avert an impending RR-TB epidemic.

    Topics: Adult; Aged; Antibiotics, Antitubercular; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Nigeria; Polymerase Chain Reaction; Prevalence; Retrospective Studies; Rifampin; Sequence Analysis, DNA; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

2018
Twenty years of rifampicin resistance surveillance in Bangladesh: periodic vs. continuous monitoring.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2018, 12-01, Volume: 22, Issue:12

    To analyse 20 years of tuberculosis (TB) drug resistance surveillance, comparing conventional periodic random drug resistance surveys with continuous monitoring, in Damien Foundation-supported districts of Bangladesh.. Retrospective study of data on TB drug resistance from five periodic surveys among newly registered patients vs. continuous monitoring of retreatment patients from 1996 to 2016.. Periodic surveys and continuous monitoring showed similar trends in rifampicin (RMP) resistance; with all smear-positives registered as denominator, prevalence in new cases was found to be at approximately the same level as incidence in retreatment cases. Changes in trends observed using continuous monitoring preceded those detected in periodic surveys by a few years. The accurate interpretation of trend changes requires detailed knowledge of changes in treatment regimens, referral criteria, testing methods and operational factors.. Low rates of resistance to RMP, isoniazid and the fluoroquinolones were maintained over the two decades, indicating excellent TB programme performance, including highly active standard first- and second-line treatment regimens. Continuous monitoring is feasible, but requires rigorous application of referral guidelines and data maintenance. Contrary to random surveys, continuous monitoring provides early indications of programme performance, essential for individual patient management, and is more efficient and cost-effective.

    Topics: Antitubercular Agents; Bangladesh; Developing Countries; Drug Resistance, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Molecular Epidemiology; Monitoring, Physiologic; Mycobacterium tuberculosis; Population Surveillance; Program Evaluation; Recurrence; Retreatment; Retrospective Studies; Rifampin; Risk Assessment; Treatment Outcome; Tuberculosis

2018
Discovery of Imidazo[1,2-a]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis.
    Journal of medicinal chemistry, 2017, 02-23, Volume: 60, Issue:4

    The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.

    Topics: Adenosine Triphosphate; Animals; Antitubercular Agents; Ethers; Humans; Mice; Mice, Inbred BALB C; Models, Molecular; Mycobacterium tuberculosis; Pyridines; Quinine; Tuberculosis

2017
The need for randomised controlled trials of isoniazid monoresistant tuberculosis treatment.
    The Lancet. Infectious diseases, 2017, Volume: 17, Issue:4

    Topics: Antitubercular Agents; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2017
Assessments of serum copper and zinc concentration, and the Cu/Zn ratio determination in patients with multidrug resistant pulmonary tuberculosis (MDR-TB) in Côte d'Ivoire.
    BMC infectious diseases, 2017, 04-11, Volume: 17, Issue:1

    In Côte d'Ivoire, multidrug-resistant tuberculosis (MDR-TB) is a serious public health problem with a prevalence estimated at 2.5% in 2006. Zinc and copper are essential Trace element needed to strengthen the immune system and also useful in the fight against tuberculosis. The Cu / Zn ratio is a good indicator of oxidative stress. The principal aim of this study was to evaluate the serum concentration of some trace element and determine the Cu / Zn ratio in patients with multidrug resistant pulmonary tuberculosis (MDR-TB) before and after second line treatment of TB.. Blood samples were obtained from 100 MDR-TB patients after confirmation of their status through the microscopic and molecular diagnosis of resistance to Isoniazid and Rifampicin by GeneXpert. The concentration level of zinc and copper were determined using flame air / acetylene atomic absorption spectrometer (AAS) Type Varian Spectr AA-20 Victoria, Australlia.. A significant decrease in zinc levels (P < 0.05) and an increased Cu / Zn ratio (P < 0.05) was observed in MDR-TB patients compared to controls TB free. During treatment a significant reduction in Cu / Zn ratio (P < 0.05) was observed compared to the initial result.. The decrease in serum zinc level and the high Cu / Zn ratio could explain the immune system dysfunction and the high level of oxidative stress in patients with MDR-TB. Therefore the evaluation of the zinc and copper status could represent essential parameters in monitoring of TB second line treatment for better treatment management.

    Topics: Adolescent; Adult; Antitubercular Agents; Copper; Cote d'Ivoire; Female; Humans; Isoniazid; Male; Middle Aged; Oxidative Stress; Prevalence; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Victoria; Young Adult; Zinc

2017
GeneXpert: A momentous innovation that needs a touch of prudence.
    The Indian journal of tuberculosis, 2017, Volume: 64, Issue:2

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; False Negative Reactions; False Positive Reactions; Humans; Mycobacterium tuberculosis; Predictive Value of Tests; Rifampin; Tuberculosis

2017
Prevention of TB using rifampicin plus isoniazid reduces nevirapine concentrations in HIV-exposed infants.
    The Journal of antimicrobial chemotherapy, 2017, 07-01, Volume: 72, Issue:7

    Newborns of HIV-infected mothers are given daily doses of nevirapine to prevent HIV-1 acquisition. Infants born to mothers with TB should also receive TB preventive therapy. TB preventive regimens include isoniazid for 6 months or rifampicin plus isoniazid for 3 months (RH preventive therapy). The effect of concomitant RH preventive therapy on nevirapine concentrations in infants is unknown.. Tshepiso was a prospective case-control cohort study of pregnant HIV-infected women with and without TB whose newborn infants received standard doses of nevirapine for HIV prophylaxis. Infants born to mothers with TB also received RH preventive therapy. Infant plasma nevirapine concentrations were measured at 1 and 6 weeks. The effects of RH preventive therapy on nevirapine disposition were investigated in a population pharmacokinetic model.. Of 164 infants undergoing pharmacokinetic sampling, 46 received RH preventive therapy. After adjusting for weight using allometric scaling, the model estimated a 33% reduction in nevirapine trough concentrations with RH preventive therapy compared with TB-unexposed infants not receiving concomitant rifampicin and a 30% decline in trough concentrations in a typical infant between day 7 and 35 post-partum.. Rifampicin-based TB preventative treatment reduces nevirapine concentrations significantly in HIV-exposed infants. Although the nevirapine exposures required to prevent HIV acquisition in breastfeeding infants are undefined, given the potential risks associated with underdosing nevirapine in this setting, it is prudent to avoid rifampicin-based preventive therapy in HIV-exposed children receiving prophylactic nevirapine.

    Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Breast Feeding; Case-Control Studies; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Isoniazid; Male; Mothers; Nevirapine; Post-Exposure Prophylaxis; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Rifampin; Tuberculosis

2017
BCG vaccination-induced suppurative lymphadenitis: four signs to pay attention to.
    International wound journal, 2017, Volume: 14, Issue:6

    Suppurative lymphadenitis is one of the severe complication after BCG vaccination, but its diagnostic criteria and treatment guidelines have not yet been established. In this article, we describe a case of suppurative lymphadenitis caused by BCG vaccination and propose diagnostic criteria and treatment guidelines of the disease. The lymphadenitis was presented as skin involving mass and was completely extirpated. Pathological evaluation revealed a necrotising lymphadenitis, consistent with the diagnosis of BCG lymphadenitis. The patient was administered adjuvant medical treatment with anti-TB medications (Isoniazid and Rifampicin) for 3 months. At 6 months follow-up, the disease was in complete remission without complications. We recommend focus on the following four signs when diagnosing BCG lymphadenitis: (i) previous history of vaccination on the ipsilateral side of the lesion, (ii) absence of any other infection signs, (iii) absence of fever and (iv) isolated axillary or supraclavicular/cervical lymph node enlargement proven by ultrasonography or computed tomography scan. BCG vaccination-induced suppurative lymphadenitis can easily be overlooked, but prompt, accurate diagnosis followed by appropriate surgical resection should result in complete healing as in this case.

    Topics: Adjuvants, Immunologic; Antibiotics, Antitubercular; Antitubercular Agents; BCG Vaccine; Humans; Isoniazid; Lymphadenitis; Rifampin; Treatment Outcome; Tuberculosis

2017
[Prevalence of Mycobacterium tuberculosis resistance to quinolones and injectables in Colombia, 2012-2013].
    Biomedica : revista del Instituto Nacional de Salud, 2017, Jan-24, Volume: 37, Issue:1

    Tuberculosis is a health problem worldwide. The World Health Organization estimated 9.6 million new cases and 480,000 multirresistant cases for 2014. The assessment of resistance to quinolones and injectables was implemented only a few years ago, so its prevalence is not known.. To determine the prevalence of resistance to amikacin, capreomycin and ofloxacin in cases of tuberculosis resistant to isoniazid and/or rifampin during 2012-2013.. This was a cross-sectional study of 489 isolates resistant to isoniazid and/or rifampin. We used the Bactec MGITTM technique for susceptibility tests. For analyzing the rate of resistance, we grouped cases according to the history of treatment with second line drugs.. In the 438 new cases, the drug that showed greater overall resistance was kanamycin with 7.1 % (95% CI: 4.6 to 9.6). In 51 previously treated cases, this highest resistance was 27.5 % (95% CI:14.2 to 40.7). The overall resistance was higher in cases with a history of treatment with quinolones and injectables. We found seven cases of extremely resistant tuberculosis.. This study demonstrates the presence of resistance to second line drugs in people with drug-resistant tuberculosis with and without previous treatment with quinolones and/or injectables, these latter having a higher percentage of resistance. For that reason, it is essential to perform susceptibility testing and analyze this information routinely.

    Topics: Antitubercular Agents; Colombia; Cross-Sectional Studies; Humans; Isoniazid; Mycobacterium tuberculosis; Prevalence; Quinolones; Rifampin; Tuberculosis

2017
[Characterization of clinical isolates of Mycobacterium tuberculosis from HIV positive individuals in Colombia, 2012].
    Biomedica : revista del Instituto Nacional de Salud, 2017, Jan-24, Volume: 37, Issue:1

    One third of the increase in tuberculosis cases is attributed to the spread of HIV. In 2012, 1,397 HIV-associated tuberculosis cases were reported in Colombia, i.e., 11.8% of the total cases. Molecular epidemiology tools help to understand the transmission of tuberculosis.. To characterize clinical isolates of Mycobacterium tuberculosis derived from HIV-infected individuals, received at the Laboratorio Nacional de Referencia in the Instituto Nacional de Salud.. This was a descriptive observational study. We analyzed 63 isolates of M. tuberculosis from HIV-infected individuals. Identification, drug susceptibility and genotyping assays were performed.. Of the new cases evaluated, three (5.0%) were resistant to isoniazid combined with streptomycin; two (3.3%) to rifampicin, and one (1.6%) to isoniazid. Previously treated cases were sensitive. No multidrug resistance was evident. Among the predominant genotypes, 20 isolates were (31.7%) LAM9, eight (12.7%), H1, and seven (11.1%), T1. Nineteen isolates corresponded to orphan patterns. One single grouping was observed among tested isolates. We found no statistically significantdifference between the proportions of the antituberculous drug resistance and genotypes.. We found resistant isolates to the most powerful drugs, rifampicin and isoniazid, among new cases, showing the transmission of resistant strains. Genetic families of M. tuberculosis LAM9, T1 and H1 correspond to those described in the general population. We detected no active transmission among studied isolates. More comprehensive studies are needed to assess the real situation of HIV associated tuberculosis in the country regarding sensitivity and transmission.

    Topics: Antitubercular Agents; Colombia; HIV Infections; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2017
Immunostimulatory activity of plumieride an iridoid in augmenting immune system by targeting Th-1 pathway in balb/c mice.
    International immunopharmacology, 2017, Volume: 48

    Plumieride, an iridoid glucoside isolated from Plumieria acutifolia leaves was investigated for its immunostimulatory activity on humoral, cell mediated and intracellular cytokine levels in sensitized and unsensitised balb/c mice. Plumieride restores the suppressed cell mediated, humoral immune response and also enhances the release of TNF- α, IFN-γ, and IL-2 (Th-1) in immune compromised cyclosporine and cyclophosphamide treated balb/c mice. It does not stimulate the IL-4 (Th-2) expression. Plumieride demonstrates significant augmentation of Th-1 response in immunosuppressed balb/c mice. Results of the present study suggested that plumieride can be developed as an immunostimulatory adjuvant to treat the immune suppression in various disease condition(s).

    Topics: Adjuvants, Immunologic; Animals; Antibiotics, Antitubercular; Antigens; B-Lymphocytes; Cyclosporine; Cytokines; Drug Synergism; Erythrocytes; Female; Furans; Graft Rejection; Hypersensitivity, Delayed; Macrophages, Peritoneal; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Sheep; Skin Transplantation; Spiro Compounds; Spleen; T-Lymphocytes; Tuberculosis

2017
A user-friendly mathematical modelling web interface to assist local decision making in the fight against drug-resistant tuberculosis.
    BMC infectious diseases, 2017, 05-30, Volume: 17, Issue:1

    Multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) represent an important challenge for global tuberculosis (TB) control. The high rates of MDR/RR-TB observed among re-treatment cases can arise from diverse pathways: de novo amplification during initial treatment, inappropriate treatment of undiagnosed MDR/RR-TB, relapse despite appropriate treatment, or reinfection with MDR/RR-TB. Mathematical modelling allows quantification of the contribution made by these pathways in different settings. This information provides valuable insights for TB policy-makers, allowing better contextualised solutions. However, mathematical modelling outputs need to consider local data and be easily accessible to decision makers in order to improve their usefulness. We present a user-friendly web-based modelling interface, which can be used by people without technical knowledge. Users can input their own parameter values and produce estimates for their specific setting. This innovative tool provides easy access to mathematical modelling outputs that are highly relevant to national TB control programs. In future, the same approach could be applied to a variety of modelling applications, enhancing local decision making.

    Topics: Antitubercular Agents; Decision Making; Drug Resistance, Bacterial; Humans; Models, Theoretical; Precision Medicine; Retreatment; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; User-Computer Interface

2017
In vitro and in vivo activity of biapenem against drug-susceptible and rifampicin-resistant Mycobacterium tuberculosis.
    The Journal of antimicrobial chemotherapy, 2017, 08-01, Volume: 72, Issue:8

    Biapenem, a carbapenem antibiotic, has been shown to have synergistic bactericidal anti-TB activity when combined with rifampicin both in vitro and in the mouse model of TB chemotherapy. We hypothesized that this synergy would result in biapenem/rifampicin activity against rifampicin-resistant Mycobacterium tuberculosis .. Our objective was to evaluate the synergy of biapenem/rifampicin against both low- and high-level rifampicin-resistant strains of M. tuberculosis , in vitro and in the mouse model.. Biapenem/rifampicin activity was evaluated using three strains of M. tuberculosis : strain 115R (low-level rifampicin resistance); strain 124R (high-level rifampicin resistance); and the drug-susceptible H37Rv parent strain. Biapenem/rifampicin synergy was evaluated in vitro by chequerboard titration. In vivo , we first conducted a dose-ranging experiment with biapenem against H37Rv in the mouse model. We then evaluated biapenem/rifampicin activity in mice infected with each M. tuberculosis strain.. In vitro , synergy was observed between biapenem and rifampicin against H37Rv and strain 115R. In vivo , biapenem exhibited clear dose-dependent activity against H37Rv, with all biapenem doses as active or more active than rifampicin alone. Biapenem and rifampicin had synergistic bactericidal activity against H37Rv in the mouse model; no synergy was observed in mice infected with either of the rifampicin-resistant strains. Biapenem alone was active against all three strains.. Our preclinical experiments indicate that biapenem has potential for use as an anti-TB drug, including for use against rifampicin-resistant TB. Thus, biapenem has promise for repurposing as a 'new' - and desperately needed - drug for the treatment of drug-resistant TB.

    Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Drug Resistance, Bacterial; Drug Synergism; Female; Mice, Inbred BALB C; Microbial Viability; Mycobacterium tuberculosis; Rifampin; Thienamycins; Treatment Outcome; Tuberculosis

2017
Evaluation of the Quantamatrix Multiplexed Assay Platform system for simultaneous detection of Mycobacterium tuberculosis and the rifampicin resistance gene using cultured mycobacteria.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2017, Volume: 61

    The differentiation of Mycobacterium tuberculosis complex (MTBC) from non-tuberculous mycobacteria (NTM) is of primary importance for infection control and the selection of anti-tuberculosis drugs. Up to date data on rifampicin (RIF)-resistant tuberculosis (TB) is essential for the early management of multidrug-resistant TB. The aim of this study was to evaluate the usefulness of a newly developed multiplexed, bead-based bioassay (Quantamatrix Multiplexed Assay Platform, QMAP) for the rapid differentiation of 23 Mycobacterium species including MTBC and RIF-resistant strains.. A total of 314 clinical Mycobacterium isolates cultured from respiratory specimens were used in this study.. The sensitivity and specificity of the QMAP system for Mycobacterium species were 100% (95% CI 99.15-100%, p<0.0001) and 97.8% (95% CI 91.86-99.87%, p<0.0001), respectively. The results of conventional drug susceptibility testing and the QMAP Dual-ID assay were completely concordant for all clinical isolates (100%, 95% CI 98.56-100%). Out of 223 M. tuberculosis (MTB) isolates, 196 were pan-susceptible and 27 were resistant to RIF according to QMAP results. All of the mutations in the RIF resistance-determining region detected by the QMAP system were confirmed by rpoB sequence analysis and a REBA MTB-Rifa reverse blot hybridization assay. The majority of the mutations (n=26, 96.3%), including those missing wild-type probe signals, were located in three codons (529-534, 524-529, and 514-520), and 17 (65.4%) of these mutations were detected by three mutation probes (531TTG, 526TAC, and 516GTC).. The entire QMAP system assay takes about 3h to complete, while results from the culture-based conventional method can take up to 48-72h. Although improvements to the QMAP system are needed for direct respiratory specimens, it may be useful for rapid screening, not only to identify and accurately discriminate MTBC from NTM, but also to identify RIF-resistant MTB strains in positive culture samples.

    Topics: Bacterial Typing Techniques; Drug Resistance, Microbial; Humans; Microspheres; Mutation; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2017
How should discordance between molecular and growth-based assays for rifampicin resistance be investigated?
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2017, 07-01, Volume: 21, Issue:7

    Molecular tests to detect the presence of Mycobacterium tuberculosis and genetic polymorphisms in the rpoB gene conferring resistance to rifampicin (RMP) have become integral parts of tuberculosis diagnostics worldwide. These assays are often performed sequentially or in parallel to phenotypic drug susceptibility testing. Discordances between molecular and phenotypic tests invariably occur. Root causes range from pre-, post- and analytic errors to co-existence of non-tuberculous mycobacteria, silent mutations, mutations outside the 81 base-pair RMP resistance-determining region, non-canonical mutations conferring increased minimal inhibitory concentrations below the critical concentration in some phenotypic drug susceptibility tests, and heteroresistance. Resolving discordant results is challenging. This guide aims to assist both clinicians and microbiologists in interpreting discordances by providing a structured approach to manage further investigations. Case scenarios are discussed, including the likelihood of occurrence.

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Polymorphism, Genetic; Rifampin; Tuberculosis

2017
Conjugated and Entrapped HPMA-PLA Nano-Polymeric Micelles Based Dual Delivery of First Line Anti TB Drugs: Improved and Safe Drug Delivery against Sensitive and Resistant Mycobacterium Tuberculosis.
    Pharmaceutical research, 2017, Volume: 34, Issue:9

    First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF.. HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and. Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, -19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% (p < 0.01, INH Vs PMRI; p < 0.0001, RIF Vs PMRI), respectively. MABA assay (cytotoxicity) based MIC values of PMRI formulation was observed as ≥0.0625 and ≥0.50 μg/mL (for sensitive and resistant strain). The microscopic analysis further confirmed that the delivery approach was effective than pure drugs.. RIF loaded and INH conjugated HPMA-PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis. The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.

    Topics: Antibiotics, Antitubercular; Delayed-Action Preparations; Drug Liberation; Hemolysis; Humans; Kinetics; Methacrylates; Micelles; Mycobacterium tuberculosis; Polyesters; Rifampin; Tuberculosis

2017
    mBio, 2017, 07-11, Volume: 8, Issue:4

    The

    Topics: Animals; ATP-Binding Cassette Transporters; Bacterial Proteins; Gene Expression Regulation, Bacterial; Membrane Transport Proteins; Mice; Mycobacterium tuberculosis; Phosphates; Phosphotransferases; Rifampin; Sequence Deletion; Signal Transduction; Tuberculosis

2017
The Good, the Bad and the Ugly of the Next-Generation Xpert Mtb/Rif
    Archivos de bronconeumologia, 2017, Volume: 53, Issue:12

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; False Positive Reactions; Humans; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2017
Rapid diagnosis of extrapulmonary tuberculosis with Xpert Mycobacterium tuberculosis/rifampicin assay.
    Journal of medical microbiology, 2017, Volume: 66, Issue:7

    XpertMycobacterium tuberculosis/rifampicin (Xpert MTB/RIF) assay has been endorsed by the World Health Organization (WHO) for diagnosis of extrapulmonary tuberculosis (EPTB), while the sensitivity and specificity have not been fully evaluated. We aimed to evaluate the performance of Xpert MTB/RIF assay in the detection of different extrapulmonary specimens.. A total of 420 nonrespiratory specimens were detected with acid-fast bacilli (AFB) smear microscopy, solid culture, conventional drug susceptibility testing (DST) and Xpert MTB/RIF assay. Using solid culture and conventional DST as the gold standard, we assessed the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of the Xpert MTB/RIF assay for detecting MTB and rifampin resistance, respectively.. When setting the solid culture results as the gold standard, the sensitivity, specificity, PPV, NPV and Kappa value of Xpert MTB/RIF assay and AFB smear results were 70.6 % (48/68), 91.96 % (318/346), 63.2 % (48/76), 94.1 % (318/338), 0.60, respectively. In addition, when compared with conventional DST results, the sensitivity, specificity, PPV, NPV and Kappa of the Xpert MTB/RIF assay for detecting rifampin resistance were 91.7 % (11/12), 100.0 % (47/47), 100.0 % (11/11), 97.9 % (47/48) and 0.95, respectively.. Compared with AFB smear and solid culture, Xpert MTB/RIF assay has high sensitivities and short detection time, so could be used as an alternative for the rapid diagnosis of EPTB and rifampin resistance in clinical practice.

    Topics: Adult; Aged; Antibiotics, Antitubercular; Bacteriological Techniques; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Time Factors; Tuberculosis

2017
PknB remains an essential and a conserved target for drug development in susceptible and MDR strains of M. Tuberculosis.
    Annals of clinical microbiology and antimicrobials, 2017, Aug-18, Volume: 16, Issue:1

    The Mycobacterium tuberculosis (M.tb) protein kinase B (PknB) which is now proved to be essential for the growth and survival of M.tb, is a transmembrane protein with a potential to be a good drug target. However it is not known if this target remains conserved in otherwise resistant isolates from clinical origin. The present study describes the conservation analysis of sequences covering the inhibitor binding domain of PknB to assess if it remains conserved in susceptible and resistant clinical strains of mycobacteria picked from three different geographical areas of India.. A total of 116 isolates from North, South and West India were used in the study with a variable profile of their susceptibilities towards streptomycin, isoniazid, rifampicin, ethambutol and ofloxacin. Isolates were also spoligotyped in order to find if the conservation pattern of pknB gene remain consistent or differ with different spoligotypes. The impact of variation as found in the study was analyzed using Molecular dynamics simulations.. The sequencing results with 115/116 isolates revealed the conserved nature of pknB sequences irrespective of their susceptibility status and spoligotypes. The only variation found was in one strains wherein pnkB sequence had G to A mutation at 664 position translating into a change of amino acid, Valine to Isoleucine. After analyzing the impact of this sequence variation using Molecular dynamics simulations, it was observed that the variation is causing no significant change in protein structure or the inhibitor binding.. Hence, the study endorses that PknB is an ideal target for drug development and there is no pre-existing or induced resistance with respect to the sequences involved in inhibitor binding. Also if the mutation that we are reporting for the first time is found again in subsequent work, it should be checked with phenotypic profile before drawing the conclusion that it would affect the activity in any way. Bioinformatics analysis in our study says that it has no significant effect on the binding and hence the activity of the protein.

    Topics: Antitubercular Agents; Base Sequence; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Ethambutol; Genetic Variation; Humans; India; Isoniazid; Microbial Sensitivity Tests; Mitoxantrone; Molecular Docking Simulation; Mutation; Mycobacterium tuberculosis; Ofloxacin; Phenotype; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Rifampin; Sequence Analysis; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2017
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2017, 09-01, Volume: 21, Issue:9

    National Institute of Diseases of the Chest and Hospital, Dhaka; Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders, Dhaka; and Chittagong Chest Disease Hospital, Chittagong, Bangladesh.. To present operational data and discuss the challenges of implementing FAST (Find cases Actively, Separate safely and Treat effectively) as a tuberculosis (TB) transmission control strategy.. FAST was implemented sequentially at three hospitals.. Using Xpert® MTB/RIF, 733/6028 (12.2%, 95%CI 11.4-13.0) patients were diagnosed with unsuspected TB. Patients with a history of TB who were admitted with other lung diseases had more than twice the odds of being diagnosed with unsuspected TB as those with no history of TB (OR 2.6, 95%CI 2.2-3.0, P < 0.001). Unsuspected multidrug-resistant TB (MDR-TB) was diagnosed in 89/1415 patients (6.3%, 95%CI 5.1-7.7). Patients with unsuspected TB had nearly five times the odds of being diagnosed with MDR-TB than those admitted with a known TB diagnosis (OR 4.9, 95%CI 3.1-7.6, P < 0.001). Implementation challenges include staff shortages, diagnostic failure, supply-chain issues and reliance on external funding.. FAST implementation revealed a high frequency of unsuspected TB in hospitalized patients in Bangladesh. Patients with a previous history of TB have an increased risk of being diagnosed with unsuspected TB. Ensuring financial resources, stakeholder engagement and laboratory capacity are important for sustainability and scalability.

    Topics: Bangladesh; Hospitalization; Humans; Mycobacterium tuberculosis; Prevalence; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2017
An application of competitive reporter monitored amplification (CMA) for rapid detection of single nucleotide polymorphisms (SNPs).
    PloS one, 2017, Volume: 12, Issue:8

    Single nucleotide polymorphisms (SNPs) are essential parameters in molecular diagnostics and can be used for the early detection and clinical prognosis in various diseases. Available methods for SNP detection are still labor-intensive and require a complex laboratory infrastructure, which are not suitable for the usage in resource-limited settings. Thus, there is an urgent need for a simple, reliable and rapid approach. In this paper we modified the previously developed competitive reporter monitored amplification (CMA) technique for the detection of resistance mediating SNPs in Mycobacterium tuberculosis complex (MTBC) strains. As a proof-of-principle for the application of the CMA-based SNP assay in routine molecular tuberculosis diagnostic, we show that the assay recognizes resistance mediating SNPs for rifampicin, isoniazid and ethambutol from either isolated DNA or heat inactivated M. tuberculosis cell cultures. The CMA-based SNP assay can identify the most prevalent resistance mediating mutations in the genes rpoB, katG, embB, and the promotor region of inhA within one hour.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Ethambutol; Genes, Reporter; Humans; Isoniazid; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis

2017
Activity of human beta defensin-1 and its motif against active and dormant Mycobacterium tuberculosis.
    Applied microbiology and biotechnology, 2017, Volume: 101, Issue:19

    The ineffectiveness of anti-tuberculous therapy against dormant and drug-resistant mycobacteria demands scrutiny of alternative candidates like antimicrobial peptides having different mechanisms of action. The present study was designed to explore the activity of human beta defensin-1 (HBD-1) and its in silico identified short motif Pep-B against active and dormant Mycobacterium tuberculosis (M. tb) H37Rv. Activity of HBD-1 and Pep-B was determined against actively growing M. tb in vitro, inside monocyte-derived macrophages (MDMs) and dormant bacilli in in vitro potassium deficiency and human peripheral blood mononuclear cell (PBMC) granuloma models using colony-forming unit enumeration. The minimum inhibitory concentrations (MIC) of HBD-1 and Pep-B were found to be 2 and 20 μg/ml, respectively. These peptides also inhibited intracellular mycobacterial growth at concentrations lower than in vitro MICs along with increased IFN-γ levels. Although at higher concentration, HBD-1 (× 2 MIC) and Pep-B (× 2 MIC) led to decrease in in vitro dormant mycobacterial load as compared to rifampicin (× 25 MIC) and isoniazid (× 16 MIC). Similarly, both peptides showed higher killing efficacy against dormant mycobacteria inside granuloma as compared to rifampicin. Thus, the present study indicates that HBD-1 and its motif are effective antimicrobial players against both actively growing and dormant mycobacteria.

    Topics: Antitubercular Agents; beta-Defensins; Computational Biology; Hemolysis; Humans; Isoniazid; Leukocytes, Mononuclear; Macrophages; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2017
Food significantly reduces plasma concentrations of first-line anti-tuberculosis drugs.
    The Indian journal of medical research, 2017, Volume: 145, Issue:4

    Concomitant feeding and anti-tuberculosis (TB) drug administration are likely to reduce nausea and enhance compliance to treatment. However, food could lower plasma drug concentrations. This study was undertaken to examine the effect of food on two-hour plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA), and pharmacokinetics of these drugs in adult TB patients.. Newly diagnosed adult TB patients were recruited from the Revised National Tuberculosis Control Programme (RNTCP) treatment centres in Chennai Corporation, Chennai, India. Two-hour post-dosing plasma concentrations were determined in 25 patients, and a semi-intensive pharmacokinetic study was undertaken in six patients. RMP, INH and PZA concentrations were determined by high-performance liquid chromatography.. The geometric mean two-hour concentrations with food and under fasting conditions were 2.2 and 5.5 μg/ml for RMP (P<0.001), 3.9 and 11.3 μg/ml for INH (P<0.001), and 18.0 and 28.2 μg/ml for PZA (P<0.001), respectively. Drug administration with food caused the plasma concentration to decrease by 50, 45 and 34 per cent for RMP, INH and PZA, respectively. Significant decreases in peak concentrations and exposures of drugs and delay in time to attain peak concentrations of drugs when taken with food were also observed.. Our findings showed that food lowered anti-TB drug concentrations significantly and delayed absorption. Patients may be explained the beneficial effects of taking anti-TB drugs in a fasting state and advised to do so. There is a need for more research on optimization of dosing to maximize efficacy and safety of currently used drugs.

    Topics: Adult; Antitubercular Agents; Fasting; Female; Food; Humans; India; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis

2017
Scaling-up the Xpert MTB/RIF assay for the detection of tuberculosis and rifampicin resistance in India: An economic analysis.
    PloS one, 2017, Volume: 12, Issue:9

    India is considering the scale-up of the Xpert MTB/RIF assay for detection of tuberculosis (TB) and rifampicin resistance. We conducted an economic analysis to estimate the costs of different strategies of Xpert implementation in India.. Using a decision analytical model, we compared four diagnostic strategies for TB patients: (i) sputum smear microscopy (SSM) only; (ii) Xpert as a replacement for the rapid diagnostic test currently used for SSM-positive patients at risk of drug resistance (i.e. line probe assay (LPA)); (iii) Upfront Xpert testing for patients at risk of drug resistance; and (iv) Xpert as a replacement for SSM for all patients.. The total costs associated with diagnosis for 100,000 presumptive TB cases were: (i) US$ 619,042 for SSM-only; (ii) US$ 575,377 in the LPA replacement scenario; (iii) US$ 720,523 in the SSM replacement scenario; and (iv) US$ 1,639,643 in the Xpert-for-all scenario. Total cohort costs, including treatment costs, increased by 46% from the SSM-only to the Xpert-for-all strategy, largely due to the costs associated with second-line treatment of a higher number of rifampicin-resistant patients due to increased drug-resistant TB (DR-TB) case detection. The diagnostic costs for an estimated 7.64 million presumptive TB patients would comprise (i) 19%, (ii) 17%, (iii) 22% and (iv) 50% of the annual TB control budget. Mean total costs, expressed per DR-TB case initiated on treatment, were lowest in the Xpert-for-all scenario (US$ 11,099).. The Xpert-for-all strategy would result in the greatest increase of TB and DR-TB case detection, but would also have the highest associated costs. The strategy of using Xpert only for patients at risk for DR-TB would be more affordable, but would miss DR-TB cases and the cost per true DR-TB case detected would be higher compared to the Xpert-for-all strategy. As such expanded Xpert strategy would require significant increased TB control budget to ensure that increased case detection is followed by appropriate care.

    Topics: Antibiotics, Antitubercular; Biological Assay; Humans; India; Rifampin; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

2017
[Genotyping and drug susceptibility of
    Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi, 2017, Sep-10, Volume: 38, Issue:9

    Topics: Antitubercular Agents; China; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2017
Diphenyleneiodonium chloride (DPIC) displays broad-spectrum bactericidal activity.
    Scientific reports, 2017, 09-14, Volume: 7, Issue:1

    Indiscriminate use of antibiotics globally has lead to an increase in emergence of drug-resistant pathogens under both nosocomial, as well as more worryingly, in community setting as well. Further, a decrease in the corporate interest and financial commitment has exerted increasing pressure on a rapidly dwindling antimicrobial drug discovery and developmental program. In this context, we have screened the Library of Pharmacologically Active Compounds (LOPAC, Sigma) against Staphylococcus aureus and Mycobacterium tuberculosis to identify potent novel antimicrobial molecules amongst non-antibiotic molecules. Microplate-based whole cell growth assay was performed to analyze the antimicrobial potency of the compounds against Staphylococcus aureus and Mycobacterium tuberculosis. We identified diphenyleneiodonium chloride, a potent inhibitor of NADH/NADPH oxidase, as a broad-spectrum antibiotic potently active against drug resistant strains of Staphylococcus aureus and Mycobacterium tuberculosis. Intriguingly, the diphenyleneiodonium chloride was also very effective against slow-growing non-replicating Mtb persisters. FIC index demonstrated a strongly synergistic interaction between diphenyleneiodonium chloride and Rifampicin while it did not interact with INH. The antimicrobial property of the diphenyleneiodonium chloride was further validated in vivo murine neutropenic thigh S. aureus infection model. Taken together, these findings suggest that Diphenyleneiodonium chloride can be potentially repurposed for the treatment of tuberculosis and staphylococcal infections.

    Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Repositioning; Drug Synergism; Enzyme Inhibitors; Mice; Microbial Viability; Mycobacterium tuberculosis; NADH, NADPH Oxidoreductases; Onium Compounds; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Treatment Outcome; Tuberculosis

2017
Rifampicin resistance in mycobacterium tuberculosis patients using GeneXpert at Livingstone Central Hospital for the year 2015: a cross sectional explorative study.
    BMC infectious diseases, 2017, 09-22, Volume: 17, Issue:1

    Since the recent introduction of GeneXepert for the detection of Tuberculosis (TB) drug resistance mutations in both primary resistance and acquired resistance in Zambia, little has been documented in literature on the issue of rifampicin resistance especially in the face of a high National TB burden. The study aimed to determine the prevalence of rifampicin resistance in tuberculosis patients at Livingstone Central Hospital for the year 2015.. This was a cross sectional study conducted at Livingstone Central Hospital where we reviewed 152 records (from January 1, 2015 to 31st December, 2015) involving patients who presented with clinically suspected TB or documented TB, whose samples were sent to the laboratory for GeneXpert Mycobacterium tuberculosis/rifampicin testing. Statistical evaluations used a one-sample test of proportion and Fisher's exact test.. The age of participants ranged from 8 months to 73 years old (median = 34). Of the participants with complete data on gender, 99 (66%) and 52 (34%) were males and females respectively. The TB co-infection with HIV prevalence was 98.3% (p < 0.001). Prevalence of rifampicin resistance was 5.9% and there was no statistical significant difference between being male or female (p = 0.721).. We were able to show from our study, evidence of rifampicin resistance at Livingstone Central Hospital. Hence, there was need for further in-depth research and appropriate interventions (i.e close follow-up and patient care for drug resistance positive patients).

    Topics: Adolescent; Adult; Aged; AIDS-Related Opportunistic Infections; Child; Child, Preschool; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; Hospitals; Humans; Infant; Male; Middle Aged; Mutation; Mycobacterium tuberculosis; Prevalence; Rifampin; Tuberculosis; Young Adult; Zambia

2017
Treatment outcomes of rifampin-sparing treatment in patients with pulmonary tuberculosis with rifampin-mono-resistance or rifampin adverse events: A retrospective cohort analysis.
    Respiratory medicine, 2017, Volume: 131

    Rifampin (RIF) mono-resistant tuberculosis (RMR-TB) is a rare disease. Current guidelines recommend that RMR-TB be treated as multidrug-resistant TB (MDR-TB) but the evidence is scarce.. We conducted a retrospective cohort study on pulmonary TB patients to investigate the characteristics and outcomes of RMR-TB. The characteristics of RMR-TB were compared with those with adverse events to rifampin (RAE-TB).. Forty-four RMR-TB and 29 RAE-TB patients were enrolled. RMR-TB patients showed more alcohol use, prior history of TB, and radiologically severe disease, while RAE-TB patients were older and had more comorbidities and combined extrapulmonary TB. A fluoroquinolone (FQ) was the drug most commonly added (70.5%, RMR-TB; 82.8%, RAE-TB). Median treatment duration was 453 days in RMR-TB and 371 days in RAE-TB (p = 0.001) and treatment success rates were 87.2% (34/39) and 80.0% (20/25), respectively (p = 0.586). Subanalysis of the RMR-TB group by treatment regimen (standard regimen [n = 11], standard regimen + FQ [n = 12], MDR-TB regimen [n = 21]) revealed a higher rate of radiologically severe disease in the MDR-TB subgroup, with similar treatment success rates for the subgroups (85.7% [6/7]), 91.7% [11/12], and 85.0% [17/20], respectively) despite different durations of treatment (345, 405, and 528 days, respectively). Two recurrences (33.3% [2/6]) developed only in standard regimen subgroup, suggesting that standard regimen is not enough to treat RMR-TB patients.. The treatment outcome of RMR-TB with 1

    Topics: Adult; Age Distribution; Aged; Alcohol Drinking; Aminosalicylic Acid; Antitubercular Agents; Cohort Studies; Comorbidity; Cycloserine; Ethambutol; Female; Fluoroquinolones; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Prothionamide; Pyrazinamide; Republic of Korea; Retrospective Studies; Rifampin; Severity of Illness Index; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2017
Delays in diagnosis and treatment of extrapulmonary tuberculosis in Guatemala.
    BMJ case reports, 2017, Oct-09, Volume: 2017

    A 23-year-old indigenous Guatemalan man presented in 2016 to our clinic in Sololá, Guatemala, with 10 months of recurrent neck swelling, fevers, night sweats and weight loss. Previously, he had sought care in three different medical settings, including a private physician-run clinic, a tertiary private cancer treatment centre and, finally, a rural government health post. With assistance from our institution's accompaniment staff, the patient was admitted to a public tertiary care hospital for work-up. Rifampin-susceptible tuberculosis was diagnosed, and appropriate treatment was begun. The case illustrates how low tuberculosis recognition among community health workers and health system segmentation creates obstacles to appropriate care, especially for patients with limited means. As a result, significant diagnostic and treatment delays can occur, increasing the public health burden of tuberculosis.

    Topics: Antibiotics, Antitubercular; Delayed Diagnosis; Fever; Guatemala; Humans; Male; Neck Pain; Rifampin; Tuberculosis; Young Adult

2017
Tuberculosis in recipients of solid-organ transplants during 1995-2015 in Cali, Colombia.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2017, 11-01, Volume: 21, Issue:11

    Tuberculosis (TB) in solid-organ transplants (SOTs) is an important opportunistic infection associated with mortality and graft loss. SOT recipients carry a higher risk of contracting active TB than the general population. Clinical and radiographic presentations are non-specific, and sputum smear and culture have low yields. TB patients with SOTs require standard anti-tuberculosis treatment. However, rifampicin (RMP) use is associated with a 30% rate of acute graft rejection (AGR) and a 20% rate of transplant loss.. To determine treatment outcomes in SOT recipients with active TB.. A retrospective study of clinical and microbiological data and TB treatment outcomes.. Among the 2349 transplants assessed, active TB was detected in 31 recipients; 55% had pulmonary TB and 40% were sputum smear-positive. In 32% of the patients, TB was diagnosed 30 days after symptom onset, 77% of the patients were cured and 10% died. AGR occurred in 13%.. TB was diagnosed in <30 days. Anti-tuberculosis treatment without RMP (80% vs. 67%; P = 0.48, OR 0.5, 95%CI 0.07-3.55) and with moxifloxacin yielded higher treatment success rates and a lower risk of AGR.

    Topics: Adolescent; Adult; Antitubercular Agents; Colombia; Female; Fluoroquinolones; Graft Rejection; Humans; Male; Middle Aged; Moxifloxacin; Opportunistic Infections; Organ Transplantation; Retrospective Studies; Rifampin; Risk Factors; Sputum; Transplant Recipients; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

2017
Critical physicochemical and biological attributes of nanoemulsions for pulmonary delivery of rifampicin by nebulization technique in tuberculosis treatment.
    Drug delivery, 2017, Volume: 24, Issue:1

    The study investigated aerosolization, pulmonary inhalation, intracellular trafficking potential in macrophages and pharmacokinetics profiles of rifampicin-oleic acid first-generation nanoemulsion and its respective chitosan- and chitosan-folate conjugate-decorated second and third-generation nanoemulsions, delivered via nebulization technique. The nanoemulsions were prepared by conjugate synthesis and spontaneous emulsification techniques. They were subjected to physicochemical, drug release, aerosolization, inhalation, cell culture and pharmacokinetics analysis. The nanoemulsions had average droplet sizes of 40-60 nm, with narrow polydispersity indices. They exhibited desirable pH, surface tension, viscosity, refractive index, density and viscosity attributes for pulmonary rifampicin administration. All nanoemulsions demonstrated more than 95% aerosol output and inhalation efficiency greater than 75%. The aerosol output, aerosolized and inhaled fine particle fractions were primarily governed by the size and surface tension of nanoemulsions in an inverse relationship. The nanoemulsions were found to be safe with third-generation nanoemulsion exhibiting higher cell internalization potential, reduced plasma drug concentration, and higher lung drug content.

    Topics: Administration, Inhalation; Antitubercular Agents; Cell Line; Chemistry, Pharmaceutical; Chitosan; Drug Liberation; Emulsions; Macrophages; Nanoparticles; Oleic Acid; Particle Size; Rifampin; Tuberculosis; Viscosity

2017
The South African Tuberculosis Care Cascade: Estimated Losses and Methodological Challenges.
    The Journal of infectious diseases, 2017, 11-06, Volume: 216, Issue:suppl_7

    While tuberculosis incidence and mortality are declining in South Africa, meeting the goals of the End TB Strategy requires an invigorated programmatic response informed by accurate data. Enumerating the losses at each step in the care cascade enables appropriate targeting of interventions and resources.. We estimated the tuberculosis burden; the number and proportion of individuals with tuberculosis who accessed tests, had tuberculosis diagnosed, initiated treatment, and successfully completed treatment for all tuberculosis cases, for those with drug-susceptible tuberculosis (including human immunodeficiency virus (HIV)-coinfected cases) and rifampicin-resistant tuberculosis. Estimates were derived from national electronic tuberculosis register data, laboratory data, and published studies.. The overall tuberculosis burden was estimated to be 532005 cases (range, 333760-764480 cases), with successful completion of treatment in 53% of cases. Losses occurred at multiple steps: 5% at test access, 13% at diagnosis, 12% at treatment initiation, and 17% at successful treatment completion. Overall losses were similar among all drug-susceptible cases and those with HIV coinfection (54% and 52%, respectively, successfully completed treatment). Losses were substantially higher among rifampicin- resistant cases, with only 22% successfully completing treatment.. Although the vast majority of individuals with tuberculosis engaged the public health system, just over half were successfully treated. Urgent efforts are required to improve implementation of existing policies and protocols to close gaps in tuberculosis diagnosis, treatment initiation, and successful treatment completion.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Black People; Coinfection; Community Health Services; Cost of Illness; Disease Eradication; Drug Resistance, Multiple, Bacterial; HIV Infections; Humans; Incidence; Lost to Follow-Up; Mycobacterium tuberculosis; Patient Care; Rifampin; South Africa; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2017
Rifabutin: Is it useful in the treatment of multidrug-resistant tuberculosis?
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2017, Volume: 65

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Humans; Mycobacterium tuberculosis; Rifabutin; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2017
Tuberculosis of the tonsil simulating a cancer.
    The Lancet. Infectious diseases, 2017, Volume: 17, Issue:12

    Topics: Adenoids; Adult; Antitubercular Agents; Diagnosis, Differential; Ethambutol; Female; Humans; Isoniazid; Mycobacterium tuberculosis; Pharyngeal Neoplasms; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2017
Genotyping and drug susceptibility testing of mycobacterial isolates from population-based tuberculosis prevalence survey in Ghana.
    BMC infectious diseases, 2017, 12-02, Volume: 17, Issue:1

    Mycobacterium tuberculosis complex (MTBC) and Non-tuberculosis Mycobacterium (NTM) infections differ clinically, making rapid identification and drug susceptibility testing (DST) very critical for infection control and drug therapy. This study aims to use World Health Organization (WHO) approved line probe assay (LPA) to differentiate mycobacterial isolates obtained from tuberculosis (TB) prevalence survey in Ghana and to determine their drug resistance patterns.. A retrospective study was conducted whereby a total of 361 mycobacterial isolates were differentiated and their drug resistance patterns determined using GenoType Mycobacterium Assays: MTBC and CM/AS for differentiating MTBC and NTM as well MTBDRplus and NTM-DR for DST of MTBC and NTM respectively.. Out of 361 isolates, 165 (45.7%) MTBC and 120 (33.2%) NTM (made up of 14 different species) were identified to the species levels whiles 76 (21.1%) could not be completely identified. The MTBC comprised 161 (97.6%) Mycobacterium tuberculosis and 4 (2.4%) Mycobacterium africanum. Isoniazid and rifampicin monoresistant MTBC isolates were 18/165 (10.9%) and 2/165(1.2%) respectively whiles 11/165 (6.7%) were resistant to both drugs. Majority 42/120 (35%) of NTM were M. fortuitum. DST of 28 M. avium complex and 8 M. abscessus complex species revealed that all were susceptible to macrolides (clarithromycin, azithromycin) and aminoglycosides (kanamycin, amikacin, and gentamicin).. Our research signifies an important contribution to TB control in terms of knowledge of the types of mycobacterium species circulating and their drug resistance patterns in Ghana.

    Topics: Adolescent; Adult; Aged; Clarithromycin; Drug Resistance, Bacterial; Female; Genotype; Ghana; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Prevalence; Retrospective Studies; Rifampin; Surveys and Questionnaires; Tuberculosis

2017
Comparative yielding of BACTEC MGIT 960 and GeneXpert MTB/RIF Assay for Rapid Diagnosis of Drug Resistance Tuberculosis from Sputum Specimen.
    Mymensingh medical journal : MMJ, 2017, Volume: 26, Issue:4

    Among communicable disease, tuberculosis is the second leading cause of death worldwide, killing nearly two million people each year. Several diagnostic techniques are currently used to detect mycobacteria in respiratory specimens. Therefore an alternative, rapid and most effective method is required for diagnosis of pulmonary tuberculosis which is relatively more sensitive and specific. A total of 107 sputum samples of suspected TB patients were enrolled attending the National Tuberculosis Reference Laboratory (NTRL), Mohakhali, Dhaka, Bangladesh from July 2014 to July 2015. Liquid culture of 107 sputum samples, yielded 76.63% culture positive and 1.86% contamination was observed. Antibiotic susceptibility test was done for 82 culture positive sputum samples among which 28.04% cases were resistant to both Rifampicin and Isoniazid. GeneXpert assay detected 85.04% M. tuberculosis among which 25.23% were found to be Rifampicin Resistance.

    Topics: Antibiotics, Antitubercular; Bangladesh; Drug Resistance, Bacterial; Humans; Rifampin; Sputum; Tuberculosis

2017
Characteristics of infants exposed to maternal tuberculosis and chemoprophylaxis using 3 months of isoniazid and rifampicin.
    Paediatrics and international child health, 2017, Volume: 37, Issue:2

    Although the clinical features of infants with congenital tuberculosis (TB) are well established, the features of infants exposed to TB in utero including those who are non-infected, are not well reported. TB-exposed infants are at risk of developing TB post-delivery, and chemoprophylaxis, usually isoniazid, is therefore recommended. Isoniazid/rifampicin combined is an alternative, but little is known about its effectiveness.. To determine the clinical features of infants exposed to TB in utero and the proportion who develop TB infection and disease despite chemoprophylaxis with a 3-month course of isoniazid/rifampicin.. This was a retrospective review of TB-infected women and their infants between 2007 and 2010. Features of mothers and infants at delivery, and follow-up of infants after completion of isoniazid/rifampicin are described.. Eighty-eight infants born to 86 TB-infected women were studied. TB diagnosis was made peri-partum in 24.4% of women, and only 46.2% of those diagnosed ante-partum were on anti-TB treatment for >2 months. Human immunodeficiency virus (HIV) was positive in 97.7% of the TB-infected women and in 74.6% the CD4 count was <200 cells/mm. The majority of TB-exposed infants were born to mothers with TB/HIV co-infection, and a high proportion were pre-term and of low birthweight. Although the high attrition rate made it difficult to assess the effectiveness of chemoprophylaxis with isoniazid/rifampicin, only one of the 60 infants who completed follow-up to 3 months was found to have tuberculous infection.

    Topics: Adolescent; Adult; Antitubercular Agents; Chemoprevention; Drug Therapy, Combination; Female; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Isoniazid; Male; Maternal Exposure; Pregnancy; Retrospective Studies; Rifampin; Tuberculosis; Young Adult

2017
Time to review treatment of isoniazid-resistant tuberculosis?
    The Lancet. Infectious diseases, 2017, Volume: 17, Issue:2

    Topics: Antitubercular Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2017
[First clinical isolate of Mycobacterium tuberculosis exhibiting resistance to rifampicin and sensibility to isoniazid in the Elche´s Health Department-General Hospital(1998-2015)].
    Revista espanola de quimioterapia : publicacion oficial de la Sociedad Espanola de Quimioterapia, 2017, Volume: 30, Issue:1

    Topics: Adult; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Hospitals, General; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Spain; Tuberculosis

2017
Evaluation of the GeneXpert MTB/RIF assay on extrapulmonary and respiratory samples other than sputum: a low burden country experience.
    Pathology, 2017, Volume: 49, Issue:1

    The aim of this study was to assess the performance of the GeneXpert MTB/RIF assay on extrapulmonary (EP) and respiratory (non-sputum) clinical samples of patients suspected of having tuberculosis (TB) from Queensland, Australia. A total of 269 EP and respiratory (non-sputum) clinical samples collected from Qld patients who were suspected of having TB were subjected to the GeneXpert MTB/RIF analysis, Ziehl-Neelsen (ZN) staining, Mycobacterium tuberculosis (MTB) culture and drug susceptibility testing. Phenotypic and genotypic data were compared. The overall performance analysis of the GeneXpert MTB/RIF assay for detection of MTB complex demonstrated sensitivity of 89%, specificity of 95%, PPV of 89% and NPV of 95% using culture as a reference standard. The GeneXpert MTB/RIF analysis of acid-fast bacilli (AFB) smear positive samples and AFB smear negative samples showed sensitivities of 100% and 77%, respectively. Looking at individual EP and respiratory (non-sputum) sample types, the sensitivity ranged from 60% to 100% although the specificity ranged from 33% to 100% with the specificity of lymph node tissue biopsy being the lowest. The GeneXpert MTB/RIF assay detected 11% more TB cases than culture and 27% more cases than ZN microscopy. Due to insufficient numbers of presenting rifampicin resistance cases, performance analysis of the GeneXpert MTB/RIF assay on rifampicin resistance could not be carried out. The GeneXpert MTB/RIF assay is potentially valuable for TB diagnosis in the majority of the EP and respiratory (other than sputum) samples in our setting. Although the GeneXpert MTB/RIF assay provides rapid diagnostic results, the overall sensitivity to rule out the disease is suboptimal for some specimen types. Performance varied according to specimen type and AFB smear status. The sensitivity and specificity of lymph node tissue was 63% and 33%. Care must be taken when using the GeneXpert MTB/RIF assay for detection of MTB in lymph node tissue samples. All samples should be cultured regardless of the GeneXpert MTB/RIF assay result.

    Topics: Drug Resistance, Bacterial; Genotype; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2017
Inhalation of Respirable Crystalline Rifapentine Particles Induces Pulmonary Inflammation.
    Molecular pharmaceutics, 2017, 01-03, Volume: 14, Issue:1

    Rifapentine is an anti-tuberculosis (anti-TB) drug with a prolonged half-life, but oral delivery results in low concentrations in the lungs because of its high binding (98%) to plasma proteins. We have shown that inhalation of crystalline rifapentine overcomes the limitations of oral delivery by significantly enhancing and prolonging the drug concentration in the lungs. The delivery of crystalline particles to the lungs may promote inflammation. This in vivo study characterizes the inflammatory response caused by pulmonary deposition of the rifapentine particles. The rifapentine powder was delivered to BALB/c mice by intratracheal insufflation at a dose of 20 mg/kg. The inflammatory response in the lungs and bronchoalveolar lavage (BAL) was examined at 12 h, 24 h, and 7 days post-treatment by flow cytometry and histopathology. At 12 and 24 h post-treatment, there was a significant influx of neutrophils into the lungs, and this returned to normal by day 7. A significant recruitment of macrophages occurred in the BAL at 24 h. Consistent with these findings, histopathological analysis demonstrated pulmonary vascular congestion and significant macrophage recruitment at 12 and 24 h post-treatment. In conclusion, the pulmonary delivery of crystalline rifapentine caused a transient neutrophil-associated inflammatory response in the lungs that resolved over 7 days. This observation may limit pulmonary delivery of rifapentine to once a week at a dose of 20 mg/kg or less. The effectiveness of weekly dosing with inhalable rifapentine will be assessed in murine Mycobacterium tuberculosis infection.

    Topics: Administration, Inhalation; Animals; Antibiotics, Antitubercular; Female; Half-Life; Lung; Macrophages; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Neutrophils; Pneumonia; Powders; Rifampin; Tuberculosis

2017
Analysis of discrepant results between the Genotype
    Respiratory medicine, 2017, Volume: 122

    We investigated discrepant results determined using the Genotype. Among 1373 MTBDRplus assays performed at our tertiary referral center in South Korea between August 2009 and December 2015, the results for 46 (3.4%) differed from those for ADST. KatG and inhA gene sequencing analysis results were available for 23 patients. ADSTs were carried out using the absolute concentration method with Löwenstein-Jensen media.. Results from 11 patients indicated INH susceptibility by MTBDRplus assay and INH resistance by ADST. For 5 of these patients, sequencing revealed no evidence of mutations, whereas specific mutations were detected in the remaining 6 patients. These should have been detected using the MTBDRplus assay. The other 12 patients had isolates with the opposite discrepancy, that is INH resistance by MTBDRplus assay but INH susceptibility by ADST. For 7 of these cases, sequencing results were consistent with those of the MTBDRplus assay. However, sequencing analysis did not explain the discrepancies in the remaining 5 patients. All 23 patients with discrepant results received individualized treatment regimens determined by the attending physician according to their test results and susceptibility to other drugs, such as rifampin. Good outcomes were reported for the majority.. Discrepancies between test results for INH resistance on the MTBDRplus assay and ADST appear to be infrequent. Gene sequencing analysis is useful for identifying the cause of the discrepancy.

    Topics: Adult; Aged; Antitubercular Agents; Bacterial Proteins; Catalase; Female; Genotype; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Oxidoreductases; Republic of Korea; Retrospective Studies; Rifampin; Sequence Analysis, DNA; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2017
Novel rapid PCR for the detection of Ile491Phe rpoB mutation of Mycobacterium tuberculosis, a rifampicin-resistance-conferring mutation undetected by commercial assays.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2017, Volume: 23, Issue:4

    Neither the liquid medium-based Bactec MGIT, nor commercial molecular assays such as the Xpert MTB/RIF and the MTBDRplus V2.0 assays are capable of detecting up to 30% of rifampicin-resistant Mycobacterium tuberculosis strains in Swaziland because of the large proportion of the rpoB Ile491Phe mutations. In other countries, the frequency of this mutation is thought to be low.. We designed a real-time multiplex allele-specific PCR assay to identify the rpoB Ile491Phe mutation responsible for these undetected resistant M. tuberculosis strains.. The technique showed 100% similarity with rpoB sequencing on a panel of 78 strains from Swaziland.. We propose that the detection of the rpoB Ile491Phe rpoB mutation should complement commercial assays for the diagnosis of rifampicin-resistant M. tuberculosis in routine conditions, particularly in countries where this specific mutation is frequent. The technique proposed in this paper is adapted for most reference laboratories.

    Topics: Amino Acid Substitution; Antibiotics, Antitubercular; Bacterial Proteins; Codon; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Multiplex Polymerase Chain Reaction; Mutation; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Tuberculosis

2017
Spectinamides are effective partner agents for the treatment of tuberculosis in multiple mouse infection models.
    The Journal of antimicrobial chemotherapy, 2017, 03-01, Volume: 72, Issue:3

    New drug regimens employing combinations of existing and experimental antimicrobial agents are needed to shorten treatment of tuberculosis (TB) in humans. The spectinamides are narrow-spectrum semisynthetic analogues of spectinomycin, modified to avoid intrinsic efflux by Mycobacterium tuberculosis . Spectinamides, including lead 1599, have been previously shown to exhibit a promising therapeutic profile in mice as single agents. Here we explore the in vivo activity of lead spectinamides when combined with other agents.. The efficacy of 1599 or 1810 was tested in combination in three increasingly advanced TB mouse models. Mice were infected by aerosol and allowed to establish acute or chronic infection, followed by treatment (≤4 weeks) with the spectinamides alone or in two- and three-drug combination regimens with existing and novel therapeutic agents. Bacteria were enumerated from lungs by plating for cfu.. Herein we show the following: (i) 1599 exhibits additive or synergistic activity with most of the first-line agents; (ii) 1599 in combination with rifampicin and pyrazinamide or with bedaquiline and pyrazinamide promotes significantly improved efficacy in the high-dose aerosol model; (iii) 1599 enhances efficacy of rifampicin or pyrazinamide in chronically infected BALB/c mice; and (iv) 1599 is synergistic when administered in combination with rifampicin and pyrazinamide in the C3HeB/FeJ mouse model showing caseous necrotic pulmonary lesions.. Spectinamides were effective partner agents for multiple anti-TB agents including bedaquiline, rifampicin and pyrazinamide. None of these in vivo synergistic interactions was predicted from in vitro MIC chequerboard assays. These data support further development of the spectinamides as combination partners with existing and experimental anti-TB agents.

    Topics: Animals; Antitubercular Agents; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Spectinomycin; Tuberculosis

2017
Rifampicin-resistance pattern of Mycobacterium tuberculosis and associated factors among presumptive tuberculosis patients referred to Debre Markos Referral Hospital, Ethiopia: a cross-sectional study.
    BMC research notes, 2017, Jan-03, Volume: 10, Issue:1

    Prevailing data on rifampicin-resistant M. tuberculosis is essential for early management of MDR-TB. Therefore, this study was conducted to determine the prevalence of rifampicin-resistant Mycobacterium tuberculosis and associated factors among presumptive TB cases in Debre Markos Referral Hospital, Ethiopia.. A cross-sectional study was conducted from September 2014 to March 2015. Detection of M. tuberculosis and resistance to rifampicin was performed using Gene Xpert MTB/RIF assay. Data was collected using structured questionnaire by face to face interview. Logistic regression analysis was computed to determine the associated factors of rifampicin-resistant M. tuberculosis.. A total of 505 presumptive TB patients included in the study. The prevalence of M. tuberculosis confirmed cases was 117 (23.2%) (95% CI 19.7-27%). It was higher among males (27.9%) than females (17.9%) (AOR: 2.17; CI 1.35-3.49). Of the 117 M. tuberculosis confirmed cases, 12 (10.3%) (95% CI 6.0-17.1%) were resistant to rifampicin. Rifampicin-resistant M. tuberculosis was noticed in 7 previously treated TB patients (17.1%) and 5 treatment naive patients (6.7%) (AOR: 4.16; CI 1.04-16.63). The prevalence of rifampicin-resistant M. tuberculosis was 6 (9.8%) and 6 (11.3%) in pulmonary and extra-pulmonary infections, respectively. Of the 30, MTB/HIV co-infection, 3 (10%) were rifampicin-resistant M. tuberculosis.. Rifampicin-resistant M. tuberculosis is prevalent in both pulmonary and extra-pulmonary tuberculosis patients. Previous treatment with anti-TB drugs was significantly associated with rifampicin resistance. Therefore, the use of Gene Xpert should be scaled up across the country for rapid detection and management of drug resistant M. tuberculosis.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Cross-Sectional Studies; Drug Resistance, Bacterial; Ethiopia; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Prevalence; Regression Analysis; Rifampin; Sample Size; Surveys and Questionnaires; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

2017
One-year mortality of HIV-positive patients treated for rifampicin- and isoniazid-susceptible tuberculosis in Eastern Europe, Western Europe, and Latin America.
    AIDS (London, England), 2017, 01-28, Volume: 31, Issue:3

    The high mortality among HIV/tuberculosis (TB) coinfected patients in Eastern Europe is partly explained by the high prevalence of drug-resistant TB. It remains unclear whether outcomes of HIV/TB patients with rifampicin/isoniazid-susceptible TB in Eastern Europe differ from those in Western Europe or Latin America.. One-year mortality of HIV-positive patients with rifampicin/isoniazid-susceptible TB in Eastern Europe, Western Europe, and Latin America was analysed and compared in a prospective observational cohort study. Factors associated with death were analysed using Cox regression modelsRESULTS:: Three hundred and forty-one patients were included (Eastern Europe 127, Western Europe 165, Latin America 49). Proportions of patients with disseminated TB (50, 58, 59%) and initiating rifampicin + isoniazid + pyrazinamide-based treatment (93, 94, 94%) were similar in Eastern Europe, Western Europe, and Latin America respectively, whereas receipt of antiretroviral therapy at baseline and after 12 months was lower in Eastern Europe (17, 39, 39%, and 69, 94, 89%). The 1-year probability of death was 16% (95% confidence interval 11-24%) in Eastern Europe, vs. 4% (2-9%) in Western Europe and 9% (3-21%) in Latin America; P < 0.0001. After adjustment for IDU, CD4 cell count and receipt of antiretroviral therapy, those residing in Eastern Europe were at nearly 3-fold increased risk of death compared with those in Western Europe/Latin America (aHR 2.79 (1.15-6.76); P = 0.023).. Despite comparable use of recommended anti-TB treatment, mortality of patients with rifampicin/isoniazid-susceptible TB remained higher in Eastern Europe when compared with Western Europe/Latin America. The high mortality in Eastern Europe was only partially explained by IDU, use of ART and CD4 cell count. These results call for improvement of care for TB/HIV patients in Eastern Europe.

    Topics: Adult; Antitubercular Agents; Europe; Europe, Eastern; Female; HIV Infections; Humans; Isoniazid; Latin America; Male; Prospective Studies; Rifampin; Survival Analysis; Tuberculosis

2017
Anti-TB drug concentrations and drug-associated toxicities among TB/HIV-coinfected patients.
    The Journal of antimicrobial chemotherapy, 2017, 04-01, Volume: 72, Issue:4

    Toxicities due to anti-TB treatment frequently occur among TB/HIV-coinfected patients.. To determine the association between anti-TB drug concentrations and the occurrence of hepatotoxicity and peripheral neuropathy among TB/HIV-coinfected patients.. TB/HIV-coinfected patients were started on standard dose anti-TB treatment according to WHO guidelines. Anti-TB drug concentrations were measured using HPLC 1, 2 and 4 h after drug intake at 2, 8 and 24 weeks following initiation of TB treatment. Participants were assessed for hepatotoxicity using Division of AIDS toxicity tables and for peripheral neuropathy using clinical assessment of tendon reflexes, vibration sensation or symptoms. Cox regression was used to determine the association between toxicities and drug concentrations.. Of the 268 patients enrolled, 58% were male with a median age of 34 years. Participants with no hepatotoxicity or mild, moderate and severe hepatotoxicity had a median C max of 6.57 (IQR 4.83-9.41) μg/mL, 7.39 (IQR 5.10-10.20) μg/mL, 7.00 (IQR 6.05-10.95) μg/mL and 3.86 (IQR 2.81-14.24) μg/mL, respectively. There was no difference in the median C max of rifampicin among those who had hepatotoxicity and those who did not ( P  =   0.322). There was no difference in the isoniazid median C max among those who had peripheral neuropathy 2.34 (1.52-3.23) μg/mL and those who did not 2.21 (1.45-3.11) μg/mL ( P  =   0.49).. There was no association between rifampicin concentrations and hepatotoxicity or isoniazid concentrations and peripheral neuropathy among TB/HIV-coinfected patients.

    Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Coinfection; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Peripheral Nervous System Diseases; Prospective Studies; Regression Analysis; Rifampin; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

2017
Involvement of protoporphyrin IX accumulation in the pathogenesis of isoniazid/rifampicin-induced liver injury: the prevention of curcumin.
    Xenobiotica; the fate of foreign compounds in biological systems, 2017, Volume: 47, Issue:2

    Combination of isoniazid (INH) and rifampicin (RFP) causes liver injury frequently among tuberculosis patients. However, mechanisms of the hepatotoxicity are not entirely understood. Protoporphyrin IX (PPIX) accumulation, as an endogenous hepatotoxin, resulting from isoniazid and rifampicin co-therapy (INH/RFP) has been reported in PXR-humanized mice. Aminolevulinic acid synthase1 (ALAS1), ferrochelatase (FECH) and breast cancer resistance protein (BCRP) play crucial roles in PPIX synthesis, metabolism and transport, respectively. Herein, this study focused on the role of INH/RFP in these processes. We observed PPIX accumulation in human hepatocytes (L-02) and mouse livers. FECH expression was initially found downregulated both in L-02 cells and mouse livers and expression levels of ALAS1 and BCRP were elevated in L-02 cells after INH/RFP treatment, indicating FECH inhibition and ALAS1 induction might confer a synergistic effect on PPIX accumulation. Additionally, our results revealed that curcumin alleviated INH/RFP-induced liver injury, declined PPIX levels and induced FECH expression in both L-02 cells and mice. In conclusion, our data provide a novel insight in the mechanism of INH/RFP-induced PPIX accumulation and evidence for understanding pathogenesis of INH/RFP-induced liver injury, and suggest that amelioration of PPIX accumulation might be involved in the protective effect of curcumin on INH/RFP-induced liver injury.

    Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Curcumin; Isoniazid; Liver; Mice; Photosensitizing Agents; Protoporphyrins; Rifampin; Tuberculosis

2017
Target regimen profiles for treatment of tuberculosis: a WHO document.
    The European respiratory journal, 2017, Volume: 49, Issue:1

    Topics: Anti-Retroviral Agents; Antitubercular Agents; Communicable Disease Control; Drug Interactions; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Infectious Disease Medicine; Models, Theoretical; Pulmonary Medicine; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2017
GeneXpert: A new tool for the rapid detection of rifampicin resistance in mycobacterium tuberculosis.
    JPMA. The Journal of the Pakistan Medical Association, 2017, Volume: 67, Issue:2

    To evaluate the diagnostic accuracy of GeneXpert assay for the detection of rifampicin resistance in mycobacterium tuberculosis using conventional drug susceptibility testing as gold standard.. This cross-sectional study was conducted at Jinnah Hospital, Lahore, / Allama Iqbal Medical College, Lahore, Pakistan, from January 2012 to December 2014, and comprised clinically and radiologically diagnosed tuberculosis suspected cases. Pulmonary and extra-pulmonary specimens were collected from strong tuberculosis suspects. All specimens were processed for Ziehl Neelsen staining, Lowenstein-Jensen culture and GeneXpert assay. All mycobacterium tuberculosis positive cases on Lowenstein-Jensen culture were further processed for drug susceptibility testing.. Of the 2,200 cases, 840(49.46%) were positive for mycobacterium tuberculosis on GeneXpert assay. Of them, 134(15.6%) cases showed rifampicin resistance on GeneXpert assay. The sensitivity, specificity, positive predictive value and negative predictive value of GeneXpert assay for rifampicin resistance were 127(98.3%), 704(99.1%), 127(94.7%) and 704(99.4%), respectively, by comparing the results with drug susceptibility testing.. GeneXpert assay was an extremely helpful diagnostic tool for the detection of rifampicin resistance in tuberculosis suspects with fairly high sensitivity and specificity along with short turnout time.

    Topics: Antitubercular Agents; Cross-Sectional Studies; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Typing; Mycobacterium tuberculosis; Pakistan; Rifampin; Tuberculosis

2017
The multistate tuberculosis pharmacometric model: a semi-mechanistic pharmacokinetic-pharmacodynamic model for studying drug effects in an acute tuberculosis mouse model.
    Journal of pharmacokinetics and pharmacodynamics, 2017, Volume: 44, Issue:2

    The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day). Twenty-five mice received oral rifampicin (1, 3, 9, 26 or 98 mg·kg

    Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2017
The tuberculosis taboo.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2017, 03-01, Volume: 21, Issue:3

    The treatment of latent tuberculous infection (TBI) is a productive and meaningful approach to tuberculosis (TB) control, and an important component of the World Health Organization's (WHO's) new End TB Strategy, especially in high-risk contacts. Unfortunately, although recognized and recommended by the WHO, it continues to be underutilized, and has even been ignored for decades in some high-risk groups, as though it were a taboo. Historical approaches to treating TBI in contacts of drug-susceptible and drug-resistant TB are presented and discussed as compelling experiences. In the United States, the Centers for Disease Control and Prevention have recently shown that a directly observed or even self-administered 12-month regimen to treat TBI with once-weekly isoniazid (INH) and rifapentine is as effective as 9 months of daily INH. Treating TBI in drug-susceptible cases and their contacts should not still be considered taboo-such a short, effective regimen is more akin to the Holy Grail. While not yet confirmed in a clinical trial, treating contacts of drug-resistant TB with the same drugs that are effective in the source case would be expected intuitively and practically to prevent TB in contacts and should be introduced now instead of waiting until clinical trials are completed.

    Topics: Antitubercular Agents; Contact Tracing; Drug Therapy, Combination; Global Health; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Taboo; Time Factors; Tuberculosis; World Health Organization

2017
Three year evaluation of Xpert MTB/RIF in a low prevalence tuberculosis setting: A Scottish perspective.
    The Journal of infection, 2017, Volume: 74, Issue:5

    Xpert MTB/RIF (Cepheid) is a rapid molecular assay shown to be sensitive and specific for pulmonary tuberculosis (TB) diagnosis in highly endemic countries. We evaluated its diagnostic performance in a low TB prevalence setting, examined rifampicin resistance detection and quantitative capabilities predicting graded auramine microscopy and time to positivity (TTP) of culture.. Xpert MTB/RIF was used to test respiratory samples over a 3 year period. Samples underwent graded auramine microscopy, solid/liquid culture, in-house IS6110 real-time PCR, and GenoType MTBDRplus (HAIN Lifescience) to determine rifampicin and/or isoniazid resistance.. A total of 2103 Xpert MTB/RIF tests were performed. Compared to culture sensitivity was 95.8%, specificity 99.5%, positive predictive value (PPV) 82.1%, and negative predictive value (NPV) 99.9%. A positive correlation was found between auramine microscopy grade and Xpert MTB/RIF assay load. We found a clear reduction in the median TTP as Xpert MTB/RIF assay load increased. Rifampicin resistance was detected.. Xpert MTB/RIF was rapid and accurate in diagnosing pulmonary TB in a low prevalence area. Rapid results will influence infection prevention and control and treatment measures. The excellent NPV obtained suggests further work should be carried out to assess its role in replacing microscopy.

    Topics: Antibiotics, Antitubercular; Early Diagnosis; Humans; Molecular Typing; Mycobacterium tuberculosis; Predictive Value of Tests; Retrospective Studies; Rifampin; Scotland; Tuberculosis

2017
Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase.
    Bioorganic & medicinal chemistry, 2016, Mar-01, Volume: 24, Issue:5

    Tuberculosis is a serious infectious disease caused by human pathogen bacteria Mycobacterium tuberculosis. Bacterial drug resistance is a very significant medical problem nowadays and development of novel antibiotics with different mechanisms of action is an important goal of modern medical science. Leucyl-tRNA synthetase (LeuRS) has been recently clinically validated as antimicrobial target. Here we report the discovery of small-molecule inhibitors of M. tuberculosis LeuRS. Using receptor-based virtual screening we have identified six inhibitors of M. tuberculosis LeuRS from two different chemical classes. The most active compound 4-{[4-(4-Bromo-phenyl)-thiazol-2-yl]hydrazonomethyl}-2-methoxy-6-nitro-phenol (1) inhibits LeuRS with IC50 of 6μM. A series of derivatives has been synthesized and evaluated in vitro toward M. tuberculosis LeuRS. It was revealed that the most active compound 2,6-Dibromo-4-{[4-(4-nitro-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenol inhibits LeuRS with IC50 of 2.27μM. All active compounds were tested for antimicrobial effect against M. tuberculosis H37Rv. The compound 1 seems to have the best cell permeability and inhibits growth of pathogenic bacteria with IC50=10.01μM and IC90=13.53μM.

    Topics: Amino Acid Sequence; Antitubercular Agents; Enzyme Inhibitors; Humans; Leucine-tRNA Ligase; Models, Molecular; Molecular Sequence Data; Mycobacterium tuberculosis; Nitrophenols; Protein Structure, Tertiary; Sequence Alignment; Tuberculosis

2016
Novel morpholinoquinoline nucleus clubbed with pyrazoline scaffolds: Synthesis, antibacterial, antitubercular and antimalarial activities.
    European journal of medicinal chemistry, 2016, Apr-13, Volume: 112

    A series of novel morpholinoquinoline based conjugates with pyrazoline moiety were synthesized under microwave irradiation. The newly synthesized compounds were screened for their preliminary in vitro antibacterial activity against a panel of pathogenic strains of bacteria and fungi, antituberculosis activity against Mycobacterium tuberculosis H37Rv and antimalarial activity against Plasmodium falciparum. Most of them exhibited significant antibacterial activity as compared to the first line drugs. Compounds 6a and 9d were found to possess excellent antibacterial activity potency as compared to ampicillin (286 μM), chloramphenicol (154 μM) and ciprofloxacin (150 μM). In antifungal screening, against Candida albicans, compounds 6c, 7c, 8a, 8b, 8c and 9b showed significant activity as compared to griseofulvin (1147 μM). Compounds 8b, 6b, 9d, 6a, 9b, 7b and 8a displayed brilliant activity against P. falciparum strain as compared to chloroquine (IC50 0.062 μM) as well as quinine (IC50 0.826 μM). Compounds 6d, 7b, 8b, 9c and 9d exhibited superior antitubercular activity. Among them 8b was found to be equipotent to rifampicin with 95% inhibition. The cytotoxicity of the synthesized compounds was tested using bioassay of Schizosaccharomyces pombe cells at cellular level.

    Topics: Anti-Infective Agents; Antimalarials; Antitubercular Agents; Bacteria; Bacterial Infections; Fungi; Humans; Malaria, Falciparum; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycoses; Plasmodium falciparum; Pyrazoles; Quinolines; Structure-Activity Relationship; Tuberculosis

2016
Synthesis, biological evaluation and molecular docking study of some novel indole and pyridine based 1,3,4-oxadiazole derivatives as potential antitubercular agents.
    Bioorganic & medicinal chemistry letters, 2016, Apr-01, Volume: 26, Issue:7

    A series of indole and pyridine based 1,3,4-oxadiazole derivatives 5a-t were synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra (MTB) and Mycobacterium bovis BCG both in active and dormant state. Compounds 5b, 5e, 5g and 5q exhibited very good antitubercular activity. All the newly synthesized compounds 5a-t were further evaluated for anti-proliferative activity against HeLa, A549 and PANC-1 cell lines using modified MTT assay and found to be noncytotoxic. On the basis of cytotoxicity and MIC values against Mycobacterium bovis BCG, selectivity index (SI) of most active compounds 5b, 5e, 5g and 5q was calculated (SI=GI50/MIC) in active and dormant state. Compounds 5b, 5e and 5g demonstrated SI values ⩾10 against all three cell lines and were found to safe for advance screening. Compounds 5a-t were further screened for their antibacterial activity against four bacteria strains to assess their selectivity towards MTB. In addition, the molecular docking studies revealed the binding modes of these compounds in active site of enoyl reductase (InhA), which in turn helped to establish a structural basis of inhibition of mycobacteria. The potency, low cytotoxicity and selectivity of these compounds make them valid lead compounds for further optimization.

    Topics: Animals; Antitubercular Agents; Cell Line; Humans; Indoles; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium bovis; Mycobacterium tuberculosis; Oxadiazoles; Pyridines; Structure-Activity Relationship; Tuberculosis

2016
Facile synthesis of 1,3-thiazolidin-4-ones as antitubercular agents.
    Bioorganic & medicinal chemistry letters, 2016, Apr-01, Volume: 26, Issue:7

    We have developed, highly efficient, one-pot, solvent-free, [Et3NH][HSO4] catalyzed multicomponent reaction protocol for the synthesis of 1,3-thiazolidin-4-ones in excellent yields. For the first time, the 1,3-thiazolidin-4-ones were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis dormant MTB H37Ra and Mycobacterium bovis BCG strains. Among the synthesized basic 1,3-thiazolidin-4-ones, particularly the compounds 4c, 4d, 4e, 4f, 4h, 4i and 4j displays promising antitubercular activity along with no significant cytotoxicity against the cell lines MCF-7, A549 and HCT-116.

    Topics: Animals; Antitubercular Agents; Cell Line; Combinatorial Chemistry Techniques; Green Chemistry Technology; Humans; Microbial Sensitivity Tests; Mycobacterium bovis; Mycobacterium tuberculosis; Structure-Activity Relationship; Thiazolidines; Tuberculosis

2016
Design, syntheses, and anti-tuberculosis activities of conjugates of piperazino-1,3-benzothiazin-4-ones (pBTZs) with 2,7-dimethylimidazo [1,2-a]pyridine-3-carboxylic acids and 7-phenylacetyl cephalosporins.
    Bioorganic & medicinal chemistry letters, 2016, Apr-15, Volume: 26, Issue:8

    Tuberculosis (TB) remains one of the most threatening diseases in the world and the need for development of new therapies is dire. Herein we describe the rationale for the design and subsequent syntheses and studies of conjugates between pBTZ and both the imidazopyridine and cephalosporin scaffolds. Overall some compounds exhibited notable anti-TB activity in the range of 2-0.2 μM in the Microplate Alamar Blue (MABA) Assay.

    Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Drug Design; Imidazoles; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Piperazines; Pyridines; Structure-Activity Relationship; Thiazines; Tuberculosis

2016
Investigation of 4-amino-5-alkynylpyrimidine-2(1H)-ones as anti-mycobacterial agents.
    Bioorganic & medicinal chemistry, 2016, Apr-15, Volume: 24, Issue:8

    In vitro anti-mycobacterial activities of novel 4-amino-5-alkynylpyrimidine-2(1H)-ones were investigated. 4-Amino-5-heptynylpyrimidine-2(1H)-one (3) and 4-amino-5-(2-phenylethynyl)pyrimidine-2(1H)-one (7) displayed potent in vitro activity against Mycobacterium bovis and Mycobacterium tuberculosis. Compounds 3 and 7 were also assessed for their in vivo activity in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds showed promising in vivo efficacy at a dose of 25 mg/kg for 2 weeks. Importantly, compounds 3 and 7 interacted synergistically with the front-line anti-tuberculosis drug isoniazid in vitro and in vivo. These results suggest that this class of compounds has strong anti-mycobacterial potential.

    Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Female; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium bovis; Mycobacterium tuberculosis; Pyrimidinones; Structure-Activity Relationship; Tuberculosis

2016
Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis.
    Journal of medicinal chemistry, 2016, 07-14, Volume: 59, Issue:13

    We report two series of novel cephalosporins that are bactericidal to Mycobacterium tuberculosis alone of the pathogens tested, which only kill M. tuberculosis when its replication is halted by conditions resembling those believed to pertain in the host, and whose bactericidal activity is not dependent upon or enhanced by clavulanate, a β-lactamase inhibitor. The two classes of cephalosporins bear an ester or alternatively an oxadiazole isostere at C-2 of the cephalosporin ring system, a position that is almost exclusively a carboxylic acid in clinically used agents in the class. Representatives of the series kill M. tuberculosis within macrophages without toxicity to the macrophages or other mammalian cells.

    Topics: Animals; Antitubercular Agents; Cells, Cultured; Cephalosporins; Female; Hep G2 Cells; Humans; Macrophages; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis

2016
Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection.
    Journal of medicinal chemistry, 2016, 07-14, Volume: 59, Issue:13

    Our team had previously identified certain indolecarboxamides that represented a new chemical scaffold that showed promising anti-TB activity at both an in vitro and in vivo level. Based on mutational analysis using bacteria found resistant to one of these indolecarboxamides, we identified the trehalose monomycolate transporter MmpL3 as the likely target of these compounds. In the present work, we now further elaborate on the SAR of these compounds, which has led in turn to the identification of a new analog, 4,6-difluoro-N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1H-indole-2-carboxamide (26), that shows excellent activity against drug-sensitive (MIC = 0.012 μM; SI ≥ 16000), multidrug-resistant (MDR), and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains, has superior ADMET properties, and shows excellent activity in the TB aerosol lung infection model. Compound 26 is also shown to work in synergy with rifampin. Because of these properties, we believe that indolecarboxamide 26 is a possible candidate for advancement to human clinical trials.

    Topics: Animals; Antitubercular Agents; Bacterial Proteins; Disease Models, Animal; Drug Design; Female; Humans; Indoles; Membrane Transport Proteins; Mice, Inbred BALB C; Microbial Sensitivity Tests; Models, Molecular; Molecular Docking Simulation; Molecular Targeted Therapy; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis, Multidrug-Resistant

2016
Design, development of new synthetic methodology, and biological evaluation of substituted quinolines as new anti-tubercular leads.
    Bioorganic & medicinal chemistry letters, 2016, 12-15, Volume: 26, Issue:24

    Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Drug Design; HEK293 Cells; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Quinolines; Structure-Activity Relationship; Tuberculosis

2016
Discovery of new chemical entities as potential leads against Mycobacterium tuberculosis.
    Bioorganic & medicinal chemistry letters, 2016, 12-15, Volume: 26, Issue:24

    A series of biheterocyclic (1H-indole, benzofuran, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyrimidin-5(4H)-one, imidazo[2,1-b]thiazole and pyrazolo[5,1-b]thiazole) derivatives were synthesized and evaluated for their anti-tubercular activities. The imidazo[2,1-b]thiazoles 9a-c and pyrazolo[5,1-b]thiazoles 10a-c exhibited promising anti-tubercular activity in varying degrees. Especially, the 2,6-dimethylpyrazolo[5,1-b]thiazole 10a exhibited strong suppressing function against H37Ra strain with MIC value of 0.03μg/mL. Compound 10a also displayed good pharmacokinetic profiles with oral bioavailability (F) of 41.7% and a half-life of 13.4h. Furthermore, 10a significantly reduced the bacterial burden in an autoluminescent H37Ra infected mouse model, suggesting its promising potential for development of anti-tubercular drugs.

    Topics: Administration, Oral; Animals; Antitubercular Agents; Biological Availability; Chlorocebus aethiops; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Mice; Molecular Structure; Mycobacterium tuberculosis; Rats; Structure-Activity Relationship; Tuberculosis; Vero Cells

2016
A Breast Lump in an Elderly Lady - Carcinoma or else ?.
    Indian journal of leprosy, 2016, Volume: 87, Issue:4

    Breast tuberculosis (TB) is rare form of extra-pulmonary TB. It is most commonly seen in women of reproductive age group, especially in young, multiparous women who are breast feeding. In geriatric women, breast TB in some cases simulates with breast carcinoma due to common signs which include hard breast lump with nodular surface, ulceration, fixity to skin, discharging sinus, retraction of nipple, axillary lymphadenopathy etc. Hence, it is very difficult to differentiate breast TB from breast cancer, especially in elderly women on clinical ground only, and therefore, histopathological diagnosis is mandatory. Fine needle aspiration cytology is frequently inconclusive due to very small amount of tissue material, and open biopsy or lumpectomy followed by histopathological examination is necessary to confirm the diagnosis of breast TB. Six-month course of anti-tuberculous therapy - ATT (rifampicin, isoniazid, pyrazinamide and ethambutol) is adequate for complete resolution. Here, we report a case of breast TB in an elderly women presenting with left sided breast lump with ulceration of overlying skin and ipsilateral axillary lymphadenopathy. This case of tuberculous mastitis was suspected to be carcinoma due to presence of hard, tender, breast lump with irregular margin, nodular surface, ulceration, purulent discharge and ipsilateral axillary lymphadenopathy in absence of any constitutional symptoms of TB, and heterogenous, hypoechoic mass on USG, which was confirmed by histopathological examination of resected breast lump and responded fully to ATT.

    Topics: Aged; Antitubercular Agents; Biopsy, Fine-Needle; Breast; Breast Neoplasms; Ethambutol; Female; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2016
Development and characterization of spray-dried porous nanoaggregates for pulmonary delivery of anti-tubercular drugs.
    Drug delivery, 2016, Volume: 23, Issue:3

    Tuberculosis, MTB or tubercle bacillus (TB) is a lethal, infectious disease mainly caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. In this study, guar gum-based porous nanoaggregates were formulated by precipitation technique with two frontline antitubercular drugs, i.e. isoniazid and rifampicin. The formulations were optimized on the basis of various evaluation parameters such as morphology, density, entrapment efficiency and in vitro drug release. The optimized formulations were administered by inhalable route to Wistar rats for the evaluation of drugs in different organs (lungs, liver and kidneys). High drug encapsulation efficiency was achieved in guar gum porous nanoaggregates, ranging from 50% to 60%. A single pulmonary dose resulted in therapeutic drug concentrations of 30%-50% in the lungs and in other organs (less than 5%) for 24 h. From this study, we can conclude that delivering drugs through pulmonary route is advantageous for local action in lungs. Furthermore, the formulation showed sustained drug release pattern, which could be beneficial for reducing the drug dose or frequency of dosing, thus helpful in improving patient compliance.

    Topics: Animals; Antitubercular Agents; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Carriers; Female; Galactans; Isoniazid; Lung; Male; Mannans; Mycobacterium tuberculosis; Nanoparticles; Plant Gums; Porosity; Rats; Rats, Wistar; Rifampin; Tuberculosis

2016
Incidence and Clinical Outcomes of Clostridium difficile Infection after Treatment with Tuberculosis Medication.
    Gut and liver, 2016, Volume: 10, Issue:2

    To determine the incidence and clinical characteristics of tuberculosis (TB) medication-associated Clostridium difficile infection.. This multicenter study included patients from eight tertiary hospitals enrolled from 2008 to 2013. A retrospective analysis was conducted to identify the clinical features of C. difficile infection in patients who received TB medication.. C. difficile infection developed in 54 of the 19,080 patients prescribed TB medication, representing a total incidence of infection of 2.83 cases per 1,000 adults. Fifty-one of the 54 patients (94.4%) were treated with rifampin. The patients were usually treated with oral metronidazole, which produced improvement in 47 of the 54 patients (87%). Twenty-three patients clinically improved with continuous rifampin therapy for C. difficile infection. There were no significant differences in improvement between patients treated continuously (n=21) and patients in whom treatment was discontinued (n=26).. The incidence of C. difficile infection after TB medication was not low considering the relatively low TB medication dosage compared to other antibiotics. It may not be always necessary to discontinue TB medication. Instead, decisions concerning discontinuation of TB medication should be based on TB status.

    Topics: Adult; Aged; Aged, 80 and over; Anti-Infective Agents; Antibiotics, Antitubercular; Clostridioides difficile; Enterocolitis, Pseudomembranous; Female; Humans; Incidence; Male; Metronidazole; Middle Aged; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis

2016
Spray-dried particles as pulmonary delivery system of anti-tubercular drugs: design, optimization, in vitro and in vivo evaluation.
    Pharmaceutical development and technology, 2016, Volume: 21, Issue:8

    Currently, one-third of the world's population is infected with tuberculosis (TB) mainly spread by inhalation of the tubercle bacilli, Mycobacterium tuberculosis. Patient non-compliance is the major reason for failure of anti-tubercular drugs (ATDs) chemotherapy due to multidrug administration for longer duration of time period. The main aim of current research study was to develop and characterize inhalable spray-dried particles for pulmonary delivery of ATDs, i.e., rifampicin (RIF) and isoniazid (INH). ATDs-loaded alginate particles were prepared by ionotropic gelation technique followed by spray drying and characterized on the basis of various evaluation parameters. Results showed that the optimized spray-dried particles were found to be spherical in shape with excellent flow properties. The drug release showed the biphasic pattern of release, i.e., initial burst (30-40% up to 4 h) followed by a sustained release pattern (90% up to 60 h). Optimized formulations exhibited lower cytotoxicity and excellent lung uptake up to 8 h. Optimized formulation also showed higher rate and extent of drug uptake by lungs due to preferential phagocytosis be macrophage. In future, alginate particles could be a promising carrier for targeted delivery of ATDs to alveolar macrophages for efficient management of TB.

    Topics: Administration, Inhalation; Alginates; Animals; Antitubercular Agents; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Compounding; Drug Delivery Systems; Female; Glucuronic Acid; Hexuronic Acids; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Particle Size; Rifampin; Tuberculosis

2016
Single- and multiple-dose pharmacokinetics of ethambutol and rifampicin in a tuberculosis patient with acute respiratory distress syndrome undergoing extended daily dialysis and ECMO treatment.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2016, Volume: 42

    The dosing of drugs in critically ill patients undergoing renal replacement therapy is based on limited data. We report for the first time single- and multiple-dose pharmacokinetics of ethambutol (EMB), which is cleared renally to 80%, and rifampicin (RIF), which is cleared renally to <30%, in a patient requiring both extracorporeal membrane oxygenation (ECMO) and renal replacement therapy. Extended dialysis removed a considerable amount of both EMB and RIF, with a dialyser plasma clearance ranging between 37 and 95 ml/min for EMB and between 39 and 53 ml/min for RIF. The EMB peak level (3h after a 2-h infusion) using a dose of 1000 mg/day on the first day of treatment was 2.3mg/l, which is in the low therapeutic range (2-5mg/l). Doubling the dose to 2000 mg/day resulted in peak levels slightly to markedly above the recommended range. There was no detectable effect of the ECMO membrane on the removal of both drugs. After an initial dose as for patients without renal impairment (15 mg/kg/day), therapeutic drug monitoring should be used to guide EMB dosing in patients undergoing extended daily dialysis.

    Topics: Adult; Antitubercular Agents; Ethambutol; Extracorporeal Membrane Oxygenation; Humans; Male; Renal Dialysis; Respiratory Distress Syndrome; Rifampin; Tuberculosis

2016
Thioridazine in PLGA nanoparticles reduces toxicity and improves rifampicin therapy against mycobacterial infection in zebrafish.
    Nanotoxicology, 2016, Volume: 10, Issue:6

    Encapsulating antibiotics such as rifampicin in biodegradable nanoparticles provides several advantages compared to free drug administration, including reduced dosing due to localized targeting and sustained release. Consequently, these characteristics reduce systemic drug toxicity. However, new nanoformulations need to be tested in complex biological systems to fully characterize their potential for improved drug therapy. Tuberculosis, caused by infection with the bacterium Mycobacterium tuberculosis, requires lengthy and expensive treatment, and incomplete therapy contributes to an increasing incidence of drug resistance. Recent evidence suggests that standard therapy may be improved by combining antibiotics with bacterial efflux pump inhibitors, such as thioridazine. However, this drug is difficult to use clinically due to its toxicity. Here, we encapsulated thioridazine in poly(lactic-co-glycolic) acid nanoparticles and tested them alone and in combination with rifampicin nanoparticles, or free rifampicin in macrophages and in a zebrafish model of tuberculosis. Whereas free thioridazine was highly toxic in both cells and zebrafish embryos, after encapsulation in nanoparticles no toxicity was detected. When combined with rifampicin nanoparticles, the nanoparticles loaded with thioridazine gave a modest increase in killing of both Mycobacterium bovis BCG and M. tuberculosis in macrophages. In the zebrafish, the thioridazine nanoparticles showed a significant therapeutic effect in combination with rifampicin by enhancing embryo survival and reducing mycobacterial infection. Our results show that the zebrafish embryo is a highly sensitive indicator of drug toxicity and that thioridazine nanoparticle therapy can improve the antibacterial effect of rifampicin in vivo.

    Topics: Animals; Antitubercular Agents; Cell Survival; Cells, Cultured; Disease Models, Animal; Drug Therapy, Combination; Female; Humans; Lactic Acid; Macrophages; Male; Mice, Inbred C57BL; Mycobacterium tuberculosis; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin; Thioridazine; Tuberculosis; Zebrafish

2016
Combination of anti-tuberculosis drugs with vitamin C or NAC against different Staphylococcus aureus and Mycobacterium tuberculosis strains.
    Microbial pathogenesis, 2016, Volume: 93

    Hepatotoxicity due to anti tuberculosis drugs, rifampin and isoniazid, is a major problem in tuberculosis patients. Vitamin C, an antioxidant, and N-acetyl cysteine (NAC), a scavenger of active metabolites, reduce the hepatotoxicity. The aim of present study was to investigate the effect of vitamin C and NAC individually on the antibacterial activity of anti tuberculosis drugs against Mycobacterium tuberculosis and Staphylococcus aureus strains.. The MICs of each compound against all strains were determined in 96 wells plate. Rifampin was tested at serial two fold concentrations alone or in combination with NAC or vitamin C.. The MIC of rifampin against different strains of S. aureus was 0.008-0.032 μg/ml. The MIC of rifampin and isoniazid against M. tuberculosis strains were 40 and 0.2 μg/ml, respectively. Vitamin C and NAC had no antibacterial activity against all strains. MIC of rifampin was reduced two fold by combination with vitamin C for all S. aureus strains, while NAC did not affect the antibacterial activity of rifampin. Vitamin C and NAC had remarkable effects on the antibacterial activity of anti-tuberculosis drugs against M. tuberculosis.. Synergistic effects were observed between rifampin or isoniazid and vitamin C against all tested strains. However, combination therapy of rifampin and isoniazid with NAC was not being effective. This study highlighted the advantages of combination of anti-tuberculosis drugs and vitamin C to eradicate the microbial infections.

    Topics: Acetylcysteine; Antitubercular Agents; Ascorbic Acid; Drug Synergism; Drug Therapy, Combination; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Tuberculosis

2016
A simultaneous population pharmacokinetic analysis of rifampicin in Malawian adults and children.
    British journal of clinical pharmacology, 2016, Volume: 81, Issue:4

    Low rifampicin plasma concentrations can lead to treatment failure and increased risk of developing drug resistant tuberculosis. The objectives of this study were to characterize the population pharmacokinetics (popPK) of rifampicin in Malawian children and adults with tuberculosis, simulate exposures under revised WHO dosing guidelines that aim to reduce the risk of low exposures of rifampicin and examine predicted exposures using weight- and age-based dosing bands under new dosing recommendations.. Patients were recruited at least two weeks after initiation of the intensive phase of treatment and received RIF in FDC of anti-TB drugs. A total of 5-6 rich and 1-2 sparse samples were collected. nonmem (v7.2) was used to build a population-PK model.. A 165 TB patients, 115 adults and 50 children, aged 7 months to 65 years and weighing 4.8 to 87 kg, were included in the one compartment model with first order absorption best described the data. The mean population estimate for CL/F was 23.9 (l h(-1)  70 kg(-1) ) with inter-individual variability of 46.6%. Exposure was unaffected by HIV status. Relative bioavailability in children was estimated at 49% lower compared to adults (100% relative bioavailability). Simulations showed significantly lower rifampicin exposure in children vs. adults. In children average AUC was 13.5 mg l(-1) h, which was nearly half that was observed in adults (26.3 mg l(-1)  h). Using age as a surrogate for weight in dosing bands gave similar results compared with the weight bands. Increasing dose to approximately 15 mg kg(-1) , increased AUC in children to an average of 22 mgl(-1)  h. bringing expected exposures in children closer to those predicted for adults.. The popPK model developed can be used to optimize rifampicin exposures through dosing simulations. WHO dosing recommendations may not be achieved using currently licensed fixed dose combination formulations of TB therapy.

    Topics: Adolescent; Adult; Age Factors; Aged; Antitubercular Agents; Area Under Curve; Biological Availability; Child; Child, Preschool; Dose-Response Relationship, Drug; Humans; Infant; Malawi; Middle Aged; Models, Biological; Rifampin; Tuberculosis; Young Adult

2016
Cost-benefit analysis of Xpert MTB/RIF for tuberculosis suspects in German hospitals.
    The European respiratory journal, 2016, Volume: 47, Issue:2

    Our objective was to assess the cost-benefit of enhancing or replacing the conventional sputum smear with the real-time PCR Xpert MTB/RIF method in the inpatient diagnostic schema for tuberculosis (TB).Recent data from published per-case cost studies for TB/multidrug-resistant (MDR)-TB and from comparative analyses of sputum microscopy, mycobacterial culture, Xpert MTB/RIF and drug susceptibility testing, performed at the German National Reference Center for Mycobacteria, were used. Potential cost savings of Xpert MTB/RIF, based on test accuracy and multiple cost drivers, were calculated for diagnosing TB/MDR-TB suspects from the hospital perspective.Implementing Xpert MTB/RIF as an add-on in smear-positive and smear-negative TB suspects saves on average €48.72 and €503, respectively, per admitted patient as compared with the conventional approach. In smear-positive and smear-negative MDR-TB suspects, cost savings amount to €189.56 and €515.25 per person, respectively. Full replacement of microscopy by Xpert MTB/RIF saves €449.98. In probabilistic Monte-Carlo simulation, adding Xpert MTB/RIF is less costly in 46.4% and 76.2% of smear-positive TB and MDR-TB suspects, respectively, but 100% less expensive in all smear-negative suspects. Full replacement by Xpert MTB/RIF is also consistently cost-saving.Using Xpert MTB/RIF as an add-on to and even as a replacement for sputum smear examination may significantly reduce expenditures in TB suspects.

    Topics: Bacterial Proteins; Cost-Benefit Analysis; DNA-Directed RNA Polymerases; Europe; Germany; Hospital Costs; Hospitalization; Humans; Microscopy; Models, Economic; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2016
Evaluation of molecular detection of extrapulmonary tuberculosis and resistance to rifampicin with GeneXpert® MTB/RIF.
    Medecine et maladies infectieuses, 2016, Volume: 46, Issue:1

    We aimed to evaluate the GeneXpert® MTB/RIF test for the diagnosis of extrapulmonary tuberculosis. The test simultaneously detects Mycobacterium tuberculosis complex and resistance to rifampicin.. We analyzed 153 clinical samples collected in a tertiary hospital in Sfax, Tunisia, between 2013 and 2014. We performed the GeneXpert® test, a Ziehl-Neelsen and auramine-rhodamine staining, conventional culture on MGIT 960 and LJ media, and we tested the resistance to anti-tuberculosis drugs on MGIT 960 and LJ media for each sample. Diagnosis was based on clinical, radiological, microbiological, pathological, and therapeutic data.. We considered that 59 patients out of 153 presented with tuberculosis. PCR was positive in 50 samples and all of these samples were susceptible to rifampicin. Sensitivity, specificity, positive predictive value, and negative predictive value of the GeneXpert® test were 84.7%, 96.8%, 94.3%, and 91%, respectively, compared with diagnosis. We observed a statistically significant difference between the direct test and the GeneXpert® test, and between culture and the GeneXpert® test. No statistically significant difference was observed between pathological results and the GeneXpert® test. Sensitivity of the GeneXpert® test was 87.5% in biopsies, 80% in pus and abscesses, and 66.7% in biological fluids. All strains were susceptible to rifampicin with culture and GeneXpert® test.. The GeneXpert® test helped detect a higher proportion of M. tuberculosis complex. It does not replace conventional diagnostic methods but it is a useful addition to achieve better sensitivity and obtain rapid results.

    Topics: Abscess; Antitubercular Agents; Biopsy; Body Fluids; DNA, Bacterial; Drug Resistance; Female; HIV Seronegativity; Humans; Male; Mycobacterium tuberculosis; Polymerase Chain Reaction; Predictive Value of Tests; Retrospective Studies; Rifampin; Sensitivity and Specificity; Staining and Labeling; Suppuration; Tuberculosis; Tuberculosis, Multidrug-Resistant

2016
Xpert MTB/Rif for the diagnosis of extrapulmonary tuberculosis--an experience from a tertiary care centre in South India.
    Tropical medicine & international health : TM & IH, 2016, Volume: 21, Issue:3

    The Xpert MTB/Rif, with a detection limit of 131 CFU/ml, plays a valuable role in the diagnosis of extrapulmonary tuberculosis, both susceptible and resistant. This study aims at evaluating the Xpert MTB/Rif for the same, at a tertiary care centre in south India, assessing it against both culture and a composite gold standard (CGS).. We tested consecutive samples from patients suspected of extrapulmonary tuberculosis with Xpert MTB/Rif, evaluated its sensitivity and specificity against solid and/or liquid culture and CGS. An individual analysis of different sample types (tissue biopsies, fluids, pus, lymph node biopsies and CSF) given an adequate sample size, against both culture and CGS, was also performed.. In total, 494 samples were analysed against culture. Compared to culture, the sensitivity of Xpert MTB/Rif was 89% (95% CI 0.81-0.94) and its specificity was 74% (95% CI 0.70-0.78). When Xpert MTB/Rif was compared to the CGS, pooled sensitivity was 62% (95% CI 0.56-0.67) and specificity was 100% (95% CI 0.91-1.00).. This assay performs better than the currently available conventional laboratory methods. The rapidity with which results are obtained is an added advantage, and its integration into a routine diagnostic protocol must be considered.

    Topics: Automation, Laboratory; Drug Resistance, Bacterial; Humans; India; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Sputum; Tertiary Care Centers; Tuberculosis

2016
A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro.
    The Journal of antimicrobial chemotherapy, 2016, Volume: 71, Issue:4

    Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states.. The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time-kill curves from log-phase (0.25-16 mg/L) and stationary-phase (0.5-64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure-response relationships.. The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R(2) = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively.. The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro.

    Topics: Algorithms; Antitubercular Agents; Bacterial Proteins; Colony Count, Microbial; Dose-Response Relationship, Drug; Humans; Methionine; Microbial Sensitivity Tests; Models, Biological; Mycobacterium tuberculosis; Predictive Value of Tests; Radiopharmaceuticals; Rifampin; Tuberculosis

2016
In Vitro Evaluation of Inhalable Verapamil-Rifapentine Particles for Tuberculosis Therapy.
    Molecular pharmaceutics, 2016, Mar-07, Volume: 13, Issue:3

    Recent studies have demonstrated that efflux pumps of Mycobacterium tuberculosis (M. tb) provide a crucial mechanism in the development of drug resistant to antimycobacterial drugs. Drugs that inhibit these efflux pumps, such as verapamil, have shown the potential in enhancing the treatment success. We therefore hypothesized that the combined inhaled administration of verapamil and a first-line rifamycin antibiotic will further improve the treatment efficacy. An inhalable dry powder consisting of amorphous verapamil and crystalline rifapentine with l-leucine as an excipient was produced by spray drying. The in vitro aerosol characteristic of the powder, its microbiological activity and stability were assessed. When the powder was dispersed by an Osmohaler, the total fine particle fraction (FPFtotal, wt % of particles in aerosol <5 μm) of verapamil and rifapentine was 77.4 ± 1.1% and 71.5 ± 2.0%, respectively. The combination drug formulation showed a minimum inhibitory concentration (MIC90) similar to that of rifapentine alone when tested against both M. tb H37Ra and M. tb H37Rv strains. Importantly, the combination resulted in increased killing of M. tb H37Ra within the infected macrophage cells compared to either verapamil or rifapentine alone. In assessing cellular toxicity, the combination exhibited an acceptable half maximal inhibitory concentration (IC50) values (62.5 μg/mL) on both human monocytic (THP-1) and lung alveolar basal epithelial (A549) cell lines. Finally, the powder was stable after 3 months storage in 0% relative humidity at 20 ± 3 °C.

    Topics: Adenocarcinoma; Administration, Inhalation; Aerosols; Anti-Arrhythmia Agents; Antibiotics, Antitubercular; Cell Survival; Chemistry, Pharmaceutical; Humans; In Vitro Techniques; Lung Neoplasms; Microbial Sensitivity Tests; Monocytes; Mycobacterium tuberculosis; Particle Size; Rifampin; Tuberculosis; Verapamil

2016
Comment on the case report "Limb deformity in a newborn. Is rifampicin just an innocent bystander?" by Kalayci et al.
    European review for medical and pharmacological sciences, 2016, Volume: 20, Issue:1

    Topics: Antitubercular Agents; Female; Humans; Male; Pregnancy; Pregnancy Complications, Infectious; Rifampin; Tuberculosis; Upper Extremity Deformities, Congenital

2016
Low Serum Concentrations of Rifampicin and Pyrazinamide Associated with Poor Treatment Outcomes in Children with Tuberculosis Related to HIV Status.
    The Pediatric infectious disease journal, 2016, Volume: 35, Issue:5

    To compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between HIV-infected and HIV-uninfected children with tuberculosis (TB) and correlate it with TB treatment outcome.. HIV-uninfected (n = 84) and HIV-infected (n = 77) children with TB receiving standard thrice weekly treatment were recruited from 6 hospitals in India. Semi-intensive pharmacokinetic sampling was performed during intensive phase of TB treatment after directly observed administration of drugs. Drug concentrations were measured by high performance liquid chromatography. INH acetylator status was determined, and nutritional assessment was done. Children were followed-up and treatment outcomes noted.. Children with HIV and TB had significantly lower RMP peak concentration (Cmax) (2.6 vs. 5.1 μg/mL; P < 0.001) and exposure [area under the time-concentration curve (AUC0-8); 10.4 vs. 23.4 μg/mL h; P < 0.001] than those with TB. Among HIV-infected children, a significantly higher proportion had stunting (77% vs. 29%; P < 0.001) and underweight (73% vs. 38%; P < 0.001) compared with children with TB. Combining both groups, RMP Cmax (P = 0.001; adjusted odds ratio = 1.437; 95% confidence interval: 1.157-1.784) and PZA Cmax (P = 0.027; adjusted odds ratio = 1.041; 95% confidence interval: 1.005-1.079) significantly influenced treatment outcome.. HIV infection was associated with lower Cmax of RMP and INH and AUC0-8 of RMP. Over 90% of children in both groups had subtherapeutic RMP Cmax. Cmax of RMP and PZA significantly influenced TB treatment outcome in children with TB. The findings have important clinical implications and suggest the need to increase anti-TB drug doses in children with HIV and TB.

    Topics: Antitubercular Agents; Child; Child, Preschool; Chromatography, High Pressure Liquid; Female; Follow-Up Studies; HIV Infections; Hospitals; Humans; India; Infant; Isoniazid; Male; Pyrazinamide; Rifampin; Serum; Treatment Outcome; Tuberculosis

2016
Editorial Commentary: Improving Children's Access to New Tuberculosis Diagnostic Tools Starts With the Collection of Appropriate Specimens.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2016, May-01, Volume: 62, Issue:9

    Topics: Child; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2016
Monitoring latent tuberculosis infection diagnosis and management in the Netherlands.
    The European respiratory journal, 2016, Volume: 47, Issue:5

    Targeted diagnosis and treatment of latent tuberculosis (TB) infection (LTBI) among persons with a high risk of exposure to TB or of developing TB when infected has been performed and monitored routinely in the Netherlands since 1993. We describe trends in target groups, diagnostic methods and treatment regimens, and explore determinants for treatment initiation, treatment completion and adverse events.In total, 37 729 persons were registered with LTBI from 1993 to 2013, of whom 28 931 (77%) started preventive treatment; 82% of those completed preventive treatment and 8% stopped preventive treatment due to adverse events. Two-thirds of the notified cases were detected through contact investigation.Increasing numbers of persons with immunosuppressive disorders, elderly persons and foreign-born persons were notified in recent years, due to policy changes and the introduction of the interferon-γ release assay. Children (96%) and the immunosuppressed (95%) were more likely to start preventive treatment. Children (93%) were also more likely to complete preventive treatment, as were persons treated with rifampicin or rifampicin/isoniazid regimens (91% and 92%, respectively). The latter groups were also 40% less likely to stop preventive treatment due to adverse events.Under these operational conditions, the estimated risk reduction on incident TB in the target population for LTBI management is 40-60%.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Child, Preschool; Communicable Disease Control; Female; Health Policy; Humans; Immunocompromised Host; Immunosuppressive Agents; Infant; Infant, Newborn; Infectious Disease Medicine; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Multivariate Analysis; Netherlands; Registries; Rifampin; Rural Population; Treatment Outcome; Tuberculosis; Young Adult

2016
Factors Associated with Tuberculosis and Rifampicin-Resistant Tuberculosis amongst Symptomatic Patients in India: A Retrospective Analysis.
    PloS one, 2016, Volume: 11, Issue:2

    Tuberculosis remains a major public health challenge for India. Various studies have documented different levels of TB and multi-drug resistant (MDR) TB among diverse groups of the population. In view of renewed targets set under the End TB strategy by 2035, there is an urgent need for TB diagnosis to be strengthened. Drawing on data from a recent, multisite study, we address key questions for TB diagnosis amongst symptomatics presenting for care: are there subgroups of patients that are more likely than others, to be positive for TB? In turn, amongst these positive cases, are there factors-apart from treatment history-that may be predictive for multi-drug resistance?. We used data from a multi-centric prospective demonstration study, conducted from March 2012 to December 2013 in 18 sub-district level TB programme units (TUs) in India and covering a population of 8.8 million. In place of standard diagnostic tests, upfront Xpert MTB/RIF testing was offered to all presumptive TB symptomatics. Here, using data from this study, we used logistic regression to identify association between risk factors and TB and Rifampicin-Resistant TB among symptomatics enrolled in the study.. We find that male gender; history of TB treatment; and adult age compared with either children or the elderly are risk factors associated with high TB detection amongst symptomatics, across the TUs. While treatment history is found be a significant risk factor for rifampicin-resistant TB, elderly (65+ yrs) people have significantly lower risk than other age groups. However, pediatric TB cases have no less risk of rifampicin resistance as compared with adults (OR 1.23 (95% C.I. 0.85-1.76)). Similarly, risk of rifampicin resistance among both the genders was the same. These patterns applied across the study sites involved. Notably in Mumbai, amongst those patients with microbiological confirmation of TB, female patients showed a higher risk of having MDR-TB than male patients.. Our results cast fresh light on the characteristics of symptomatics presenting for care who are most likely to be microbiologically positive for TB, and for rifampicin resistance. The challenges posed by TB control are complex and multifactorial: evidence from diverse sources, including retrospective studies such as that addressed here, can be invaluable in informing future strategies to accelerate declines in TB burden.

    Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Child; Drug Resistance, Bacterial; Female; Humans; India; Male; Middle Aged; Retrospective Studies; Rifampin; Risk Factors; Sex Factors; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2016
Clofazimine Contributes Sustained Antimicrobial Activity after Treatment Cessation in a Mouse Model of Tuberculosis Chemotherapy.
    Antimicrobial agents and chemotherapy, 2016, Volume: 60, Issue:5

    Experimental and clinical studies have indicated that the antileprosy drug clofazimine may contribute treatment-shortening activity when included in tuberculosis treatment regimens. Clofazimine accumulates to high levels in tissues, has a long half-life, and remains in the body for months after administration is stopped. We hypothesized that in tuberculosis treatment, accumulated clofazimine may contribute sustained antimicrobial activity after treatment cessation, and we used the BALB/c mouse model of chronic tuberculosis chemotherapy to address this hypothesis. Mycobacterium tuberculosis-infected mice were treated for 4 weeks or 8 weeks with either isoniazid alone, clofazimine alone, the first-line regimen rifampin-isoniazid-pyrazinamide-ethambutol, or a first-line regimen where clofazimine was administered in place of ethambutol. To evaluate posttreatment antimicrobial activity, bacterial regrowth in the lungs and spleens was assessed at the day of treatment cessation and 2, 4, 6, and 8 weeks after treatment was stopped. Bacterial regrowth was delayed in all mice receiving clofazimine, either alone or in combination, compared to the mice that did not receive clofazimine. This effect was especially evident in mice receiving multidrug therapy. In mice not receiving clofazimine, bacterial regrowth began almost immediately after treatment was stopped, while in mice receiving clofazimine, bacterial regrowth was delayed for up to 6 weeks, with the duration of sustained antimicrobial activity being positively associated with the time that serum clofazimine levels remained at or above the 0.25-μg/ml MIC for M. tuberculosis Thus, sustained activity of clofazimine may be important in the treatment-shortening effect associated with this drug.

    Topics: Animals; Antitubercular Agents; Clofazimine; Disease Models, Animal; Drug Combinations; Drug Therapy, Combination; Ethambutol; Female; Isoniazid; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Withholding Treatment

2016
Application of Fluorescent Protein Expressing Strains to Evaluation of Anti-Tuberculosis Therapeutic Efficacy In Vitro and In Vivo.
    PloS one, 2016, Volume: 11, Issue:3

    The slow growth of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), hinders development of new diagnostics, therapeutics and vaccines. Using non-invasive real-time imaging technologies to monitor the disease process in live animals would facilitate TB research in all areas. We developed fluorescent protein (FP) expressing Mycobacterium bovis BCG strains for in vivo imaging, which can be used to track bacterial location, and to quantify bacterial load in live animals. We selected an optimal FP for in vivo imaging, by first cloning six FPs: tdTomato, mCherry, mPlum, mKate, Katushka and mKeima, into mycobacteria under either a mycobacterial Hsp60 or L5 promoter, and compared their fluorescent signals in vitro and in vivo. Fluorescence from each FP-expressing strain was measured with a multimode reader using the optimal excitation and emission wavelengths for the FP. After normalizing bacterial numbers with optical density, the strain expressing L5-tdTomato displayed the highest fluorescence. We used the tdTomato-labeled M. bovis BCG to obtain real-time images of pulmonary infections in living mice and rapidly determined the number of bacteria present. Further comparison between L5-tdTomato and Hsp60-tdTomato revealed that L5-tdTomato carried four-fold more tdTomato gene copies than Hsp60-tdTomato, which eventually led to higher protein expression of tdTomato. Evaluating anti-TB efficacy of rifampicin and isoniazid therapy in vitro and in vivo using the L5-tdTomato strain demonstrated that this strain can be used to identify anti-TB therapeutic efficacy as quickly as 24 h post-treatment. These M. bovis BCG reporter strains represent a valuable new tool for evaluation of therapeutics, vaccines and virulence.

    Topics: Animals; Antitubercular Agents; Bacterial Proteins; Cell Line; Chaperonin 60; Luminescent Proteins; Mice; Mycobacterium bovis; Mycobacterium tuberculosis; Promoter Regions, Genetic; Rifampin; Tuberculosis

2016
Potential of Casiopeínas® Copper Complexes and Antituberculosis Drug Combination against Mycobacterium tuberculosis.
    Chemotherapy, 2016, Volume: 61, Issue:5

    New compounds with antituberculosis activity and their combination with classic drugs have been evaluated to determine possible interactions and antagonism. The aim of this study was to evaluate the in vitro activity of Casiopeínas® copper-based compounds (CasIIIia, CasIIIEa, and CasIIgly) alone and combined with isoniazid (INH), rifampicin, or ethambutol (EMB) against resistant and susceptible Mycobacterium tuberculosis. Seventeen clinical M. tuberculosis isolates (5 multi-drug resistant and 2 resistant to INH and/or EMB) were subjected to determination of the minimal inhibitory concentration (MIC) by the resazurin microtiter assay and combination assessment by the resazurin drug combination microtiter assay. The Casiopeínas® alone showed a remarkable effect against resistant isolates with MIC values from 0.78 to 12.50 μg/ml. Furthermore, a synergistic effect mainly with EMB is shown for both resistant and susceptible clinical isolates. Casiopeínas® are promising candidates for future investigation into the development of antituberculosis drugs, being one of the first examples of essential metal-based drugs used in this field.

    Topics: Antitubercular Agents; Coordination Complexes; Copper; Drug Resistance, Bacterial; Drug Synergism; Ethambutol; Humans; Isoniazid; Macrophages; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2016
Immune response to antituberculosis drug-loaded gelatin and polyisobutyl-cyanoacrylate nanoparticles in macrophages.
    Therapeutic delivery, 2016, Volume: 7, Issue:4

    Secondary toxicity of nanoparticles (NPs) in macrophages is a well-known phenomenon. The aim of the study was to investigate the immuneresponse of macrophages after NP treatment.. Antituberculosis drugs moxifloxacin and rifampicin were loaded into gelatin and polyisobutyl-cyanoacrylate NPs. The NPs were physicochemical characterized. Cellular immuneresponses and cellular viability were determined. The drug release kinetics vary depending on the type of NP, size and loading capacity. IC50 values of polyisobutyl-cyanoacrylate NPs were lower than for gelatin NPs. NPs treatment induced higher release of Th1 type cytokines compared with free drug.. NPs together with chemotherapeutic drugs might be able to trigger an immune response in macrophages. The combined effect might be able to overcome mycobacteria infections.

    Topics: Animals; Antitubercular Agents; Cell Line; Cell Survival; Chromatography, High Pressure Liquid; Cyanoacrylates; Cytokines; Drug Carriers; Drug Liberation; Dynamic Light Scattering; Enbucrilate; Enzyme-Linked Immunosorbent Assay; Fluoroquinolones; Gelatin; Macrophages; Mice; Microscopy, Electron, Transmission; Moxifloxacin; Nanoparticles; Rifampin; Spectrophotometry, Ultraviolet; Tuberculosis

2016
Rifabutin and rifampin resistance levels and associated rpoB mutations in clinical isolates of Mycobacterium tuberculosis complex.
    Diagnostic microbiology and infectious disease, 2016, Volume: 85, Issue:2

    Cross-resistance in rifamycins has been observed in rifampin (RIF)-resistant Mycobacterium tuberculosis complex isolates; some rpoB mutations do not confer broad in vitro rifamycin resistance. We examined 164 isolates, of which 102 were RIF-resistant, for differential resistance between RIF and rifabutin (RFB). A total of 42 unique single mutations or combinations of mutations were detected. The number of unique mutations identified exceeded that reported in any previous study. RFB and RIF MICs up to 8 μg/mL by MGIT 960 were studied; the cut-off values for susceptibility to RIF and RFB were 1 μg/mL and 0.5 μg/mL, respectively. We identified 31 isolates resistant to RIF but susceptible to RFB with the mutations D516V, D516F, 518 deletion, S522L, H526A, H526C, H526G, H526L, and two dual mutations (S522L + K527R and H526S + K527R). Clinical investigations using RFB to treat multidrug-resistant tuberculosis cases harboring those mutations are recommended.

    Topics: Antibiotics, Antitubercular; DNA-Directed RNA Polymerases; Humans; Microbial Sensitivity Tests; Mutation, Missense; Mycobacterium tuberculosis; Rifabutin; Rifampin; Tuberculosis

2016
The clinical outcomes of oldest old patients with tuberculosis treated by regimens containing rifampicin, isoniazid, and pyrazinamide.
    Clinical interventions in aging, 2016, Volume: 11

    To investigate the clinical characteristics, adverse drug reactions, and outcomes of the oldest old patients (aged ≥80 years) with tuberculosis (TB) treated with rifampicin, isoniazid, and pyrazinamide (RIP)-containing regimens.. A retrospective chart review study.. A 1,200-bed tertiary teaching hospital in southwest Taiwan.. We conducted a retrospective observational study between January 1, 2005 and December 31, 2011. Seven hundred adult patients (aged ≥18 years) with TB treated with RIP-containing anti-TB regimens were reviewed, including 161 oldest old patients.. Clinical outcomes included clinical responsiveness and microbiological eradication. Adverse outcomes included drug-induced hepatitis, and other symptoms included gastrointestinal upset (eg, abdominal pain, vomiting, diarrhea, or dyspepsia), skin rash, joint pain, and hyperuricemia.. Compared with the non-oldest old adult patients, the oldest old patients more frequently had hepatitis (P=0.014), gastrointestinal upset (P=0.029), and unfavorable outcomes (P<0.001). In a multivariate analysis, hepatitis during treatment (adjusted odds ratio: 3.482, 95% confidence interval: 1.537-7.885; P<0.003) and oldest old age (adjusted odds ratio: 5.161, 95% confidence interval: 2.294-11.613; P<0.010) were independent risk factors for unfavorable outcomes. In the oldest old patients with hepatitis, rifampicin use was more common in the favorable outcome group than in the unfavorable outcome group (100% vs 37.5%; P=0.001).. The oldest old age and hepatitis during RIP treatment were associated with unfavorable outcomes. For the oldest old patients with TB having hepatitis during treatment, rifampicin rechallenge and use might benefit the treatment outcome.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Comorbidity; Drug Therapy, Combination; Female; Hepatitis; Hospitals, Teaching; Humans; Isoniazid; Male; Middle Aged; Multivariate Analysis; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors; Taiwan; Treatment Outcome; Tuberculosis; Young Adult

2016
CYP2B6 genotype-based efavirenz dose recommendations during rifampicin-based antituberculosis cotreatment for a sub-Saharan Africa population.
    Pharmacogenomics, 2016, Volume: 17, Issue:6

    To assess genotype effect on efavirenz (EFV) pharmacokinetics, treatment outcomes and provide genotype-based EFV doses recommendations during for tuberculosis (TB)-HIV-1 cotreatment.. EFV concentrations from 158 HIV-TB co-infected patients treated with EFV/lamivudine/zidovidine and rifampicin were analyzed. Genotype and CD4 and viral load data were analyzed using a population PK model.. Simulated AUCs for 600 mg EFV dose were 1.2- and 2.4-times greater than the product label for Ugandans in general and CYP2B6*6/*6 genotypes respectively. EFV daily doses of 450 and 250 mg for Ugandans and CYP2B6*6/*6 genotypes, respectively, yielded simulated exposures comparable to the product label.. Around 450 and 250 mg daily doses might meet EFV dosing needs of HIV-TB infected Ugandans in general and CYP2B6*6/*6 genotypes, respectively.

    Topics: Adult; Africa South of the Sahara; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Coinfection; Cyclopropanes; Cytochrome P-450 CYP2B6; Female; Genotype; HIV Infections; HIV-1; Humans; Lamivudine; Male; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis; Viral Load; Zidovudine

2016
Sensititre® MYCOTB MIC plate for drug susceptibility testing of Mycobacterium tuberculosis complex isolates.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:3

    National Tuberculosis Clinical Laboratory, China.. To evaluate the accuracy and feasibility of the MYCOTB MIC plate in anti-tuberculosis drug susceptibility testing.. MYCOTB testing of Mycobacterium tuberculosis isolates, the Löwenstein-Jensen (LJ) proportion method and the resurazine microtitre assay (REMA), which is extensively used for in-house assay for minimal inhibition concentration (MIC) testing, were performed simultaneously for comparison. A total of 126 clinical isolates were tested using both MYCOTB and the LJ proportion method against 12 anti-tuberculosis drugs; 80 were also tested using REMA.. Categorical agreement between MYCOTB and the LJ proportion method was 99.2% for rifampicin, ofloxacin, amikacin, kanamycin and cycloserine, and 98.4% for isoniazid and para-aminosalicylic acid; ethambutol (EMB) had the lowest agreement (86.5%). The overall categorical agreement between MYCOTB and REMA ranged between 98.8% and 100%. MYCOTB outcomes, interpreted on day 10 and 21, were stable for all drugs except EMB.. MYCOTB is a rapid, convenient, quantitative and accurate method for testing both first- and second-line anti-tuberculosis drugs.

    Topics: Amikacin; Aminosalicylic Acid; Antitubercular Agents; China; Cycloserine; Ethambutol; Humans; Isoniazid; Kanamycin; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Ofloxacin; Rifampin; Tuberculosis

2016
School-based Study to Identify and Treat Adolescent Students at Risk for Tuberculosis Infection.
    The Pediatric infectious disease journal, 2016, Volume: 35, Issue:7

    Screening for and treating tuberculosis (TB) infection in children and adolescents is an effective way of decreasing future TB cases. However, current approaches leave many children at risk for TB unidentified.. We recruited adolescent students from 2 public high schools (a magnet and a low-income) in the Houston Independent School District. Compared with the magnet school, the student population at the low-income school was larger, primarily Hispanic and economically disadvantaged. Students were educated about TB, and parents completed a risk factor questionnaire. Students with TB risk factors were tested using 2 interferon gamma release assays (IGRAs). Those with a positive IGRA received a 12-dose regimen of weekly isoniazid/rifapentine (3HP) administered via direct observation at school.. Nine hundred twenty-five students received TB education; 73% of their parents submitted the TB questionnaire. Eighty-six percent of students (n = 415) with a TB risk factor identified on the study questionnaire agreed to IGRA testing. Sixteen students had at least one positive IGRA (1% [magnet], 4.1% [low-income]; P = 0.005). Recent student travel to a high-risk country (7) or contact with TB disease (2) were associated with IGRA positivity (P < 0.05). All students with a positive IGRA accepted, tolerated and completed 3HP treatment at school.. School-based TB education, screening, testing using IGRAs and administration of 3HP treatment is feasible to improve the identification and treatment of adolescent students at risk for TB.

    Topics: Adolescent; Antitubercular Agents; Directly Observed Therapy; Drug Combinations; Female; Humans; Isoniazid; Male; Mass Screening; Mycobacterium tuberculosis; Poverty; Rifampin; Risk Factors; School Health Services; Students; Surveys and Questionnaires; Texas; Tuberculin Test; Tuberculosis

2016
Pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in HIV-infected Indian children.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:5

    Co-infection with the human immunodeficiency virus (HIV) may lead to inadequate plasma concentrations of anti-tuberculosis drugs in children with tuberculosis (TB).. To describe the influence of HIV infection on the pharmacokinetics of isoniazid, rifampicin, pyrazinamide and ethambutol in children.. Prospective drug estimation study in two cohorts of children: HIV-infected (n = 24) and non-HIV-infected (n = 32) with TB. Dosages used were based on earlier World Health Organization recommendations. All four drugs were estimated simultaneously using liquid chromatography mass spectrometry.. The HIV-TB co-infected children had a mean age of 105.9 months (standard deviation 43.1); there were 10 girls (41.7%). The maximum plasma concentration (Cmax), time taken to achieve Cmax, area under curve from 0-4 h and 2 h concentrations of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) were not affected by the HIV status of the children. Ethambutol (EMB) concentrations were lower in HIV-TB co-infected children. Inadequate 2 h concentrations of INH, RMP and EMB were found in the majority of the children in both groups. PZA concentrations were adequate in almost all children. Younger age and lower dose were associated with lower 2 h concentrations of INH and RMP.. Inadequate concentrations of INH, RMP and EMB in both HIV-TB-infected and non-HIV-infected children provide support for the recently revised recommended doses of INH and RMP. EMB levels were lower in HIV-infected children; however, more studies are needed to validate this observation.

    Topics: Adolescent; Age Factors; Antitubercular Agents; Child; Child, Preschool; Chromatography, Liquid; Coinfection; Drug Dosage Calculations; Drug Monitoring; Ethambutol; Female; HIV Infections; Humans; India; Infant; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Spectrometry, Mass, Electrospray Ionization; Treatment Outcome; Tuberculosis

2016
Safety and Adherence for 12 Weekly Doses of Isoniazid and Rifapentine for Pediatric Tuberculosis Infection.
    The Pediatric infectious disease journal, 2016, Volume: 35, Issue:7

    Traditional treatment of tuberculosis infection (TBI) is efficacious, but adherence is low. Eighty children with TBI received a 12-dose once-weekly isoniazid/rifapentine regimen; 79 (99%) completed therapy, 94% reported no adverse events, 1 child had mildly elevated transaminases but 1 adolescent later developed pulmonary TB. Isoniazid/rifapentine is safe, is well tolerated and has much higher completion rates than traditional TBI regimens.

    Topics: Adolescent; Antibiotics, Antitubercular; Antitubercular Agents; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Isoniazid; Male; Medication Adherence; Rifampin; Skin Tests; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

2016
Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape.
    Antimicrobial agents and chemotherapy, 2016, Volume: 60, Issue:7

    Molecular diagnostic assays, with their ability to rapidly detect resistance-associated mutations in bacterial genes, are promising technologies to control the spread of drug-resistant tuberculosis (DR-TB). Sequencing assays provide detailed information for specific gene regions and can help diagnostic assay developers prioritize mutations for inclusion in their assays. We performed pyrosequencing of seven Mycobacterium tuberculosis gene regions (katG, inhA, ahpC, rpoB, gyrA, rrs, and eis) for 1,128 clinical specimens from India, Moldova, and South Africa. We determined the frequencies of each mutation among drug-resistant and -susceptible specimens based on phenotypic drug susceptibility testing results and examined mutation distributions by country. The most common mutation among isoniazid-resistant (INH(r)) specimens was the katG 315ACC mutation (87%). However, in the Eastern Cape, INH(r) specimens had a lower frequency of katG mutations (44%) and higher frequencies of inhA (47%) and ahpC (10%) promoter mutations. The most common mutation among rifampin-resistant (RIF(r)) specimens was the rpoB 531TTG mutation (80%). The mutation was common in RIF(r) specimens in Mumbai (83%) and Moldova (84%) but not the Eastern Cape (17%), where the 516GTC mutation appeared more frequently (57%). The most common mutation among fluoroquinolone-resistant specimens was the gyrA 94GGC mutation (44%). The rrs 1401G mutation was found in 84%, 84%, and 50% of amikacin-resistant, capreomycin-resistant, and kanamycin (KAN)-resistant (KAN(r)) specimens, respectively. The eis promoter mutation -12T was found in 26% of KAN(r) and 4% of KAN-susceptible (KAN(s)) specimens. Inclusion of the ahpC and eis promoter gene regions was critical for optimal test sensitivity for the detection of INH resistance in the Eastern Cape and KAN resistance in Moldova. (This study has been registered at ClinicalTrials.gov under registration number NCT02170441.).

    Topics: Bacterial Proteins; Capreomycin; Drug Resistance, Multiple, Bacterial; Isoniazid; Kanamycin; Microbial Sensitivity Tests; Moldova; Mutation; Mycobacterium tuberculosis; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant

2016
Mycobacterium tuberculosis Uganda II is more susceptible to rifampicin and isoniazid compared to Beijing and Delhi/CAS families.
    BMC infectious diseases, 2016, Apr-21, Volume: 16

    Mycobacterium tuberculosis Uganda family is the predominant cause of tuberculosis in Uganda. Reasons for this are not clear but are likely to be due to the rampant person-to-person transmission or delayed susceptibility of the organism to drugs during treatment, which may lead to continuous shedding of infectious bacilli, among others. The objective of this study was to determine in vitro, the susceptibility patterns of M. tuberculosis Uganda family compared with Beijing and Delhi/CAS, other M. tuberculosis sub-lineages that also circulate in Uganda but are not as prevalent. The comparisons were made after 10 days of exposure of the strains to Rifampicin and Isoniazid, the most important first-line anti-tuberculosis drugs.. Minimum inhibitory concentrations (MICs) for three Isoniazid- and Rifampicin-susceptible M. tuberculosis strains (Uganda II, Beijing and Delhi/CAS families) were determined by micro-dilution plate assay. Killing curves for each strain were deduced from colony forming units after exposure to Isoniazid and Rifampicin on days 0, 2, 4, 6, 8, and 10 under aerobic and oxygen-depleted conditions. Data were analyzed with GraphPad Prism 5 software.. The MIC for Isoniazid was 0.05 μg/ml for M. tuberculosis Uganda II, and 0.03 μg/ml for M. tuberculosis Beijing and Delhi/CAS. Rifampicin MIC was 1 μg/ml for M. tuberculosis Uganda II, and 0.12 μg/ml for Beijing and Delhi/CAS. At low Rifampicin (0.03-2.5 μg/ml) and Isoniazid (0.12-5 μg/ml) concentrations under aerobic conditions, there was no significant difference in susceptibility patterns between M. tuberculosis Uganda II and Beijing or Delhi/CAS. However, at high Rifampicin (5 μg/ml) and Isoniazid (1.25 μg/ml) concentrations under oxygen-depleted conditions, M. tuberculosis Uganda II was more susceptible to the drugs compared with Beijing or Delhi/CAS families.. The predominance of M. tuberculosis Uganda II family as the main causative agent of tuberculosis in Uganda is not attributed to its susceptibility behavior to Isoniazid and Rifampicin. Probably, its predominance is due to differences in the immune defenses in the general population against the strains, given that Beijing and Delhi/CAS families may have been introduced more recently. Further research beyond susceptibility to anti-tuberculosis drugs is required to fully explore tuberculosis strain predominance in Uganda.

    Topics: Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxygen; Rifampin; Tuberculosis

2016
Comparison of GeneXpert MTB/RIF and conventional methods for the diagnosis of tuberculosis in Kosovo.
    Journal of infection in developing countries, 2016, Apr-28, Volume: 10, Issue:4

    Tuberculosis (TB) is a major public health problem worldwide, with the highest mortality occurring in developing countries. The burden of TB in Kosovo is among the highest in Europe. The aim of this study was to compare Cepheid GeneXpert MTB/RIF assay for direct detection of Mycobacterium tuberculosis complex (MTBC) and rifampin (RIF) resistance with conventional methods.. A cross-sectional design to evaluate diagnostic tests was carried out at the Department of Microbiology, National Institute of Public Health of Kosovo and Lung Clinic, from January to June 2014. The detection of MTBC and RIF resistance using the Xpert MTB/RIF assay was assessed in 116 specimens received from 110 patients suspected of having TB and compared with conventional smear microscopy and culture methods.. Fifty-eight patients (52.7%) were male, and the mean age was 48.6±18.1 years. Twenty-nine patients (26.4%) had underlying lung diseases. Of the 116 specimens investigated, 28 (24.1%) were MTBC-positive by culture, while 34 (29.3%) were positive by Xpert assay. Two samples showed false-negative Xpert results. Compared with culture, the Xpert assay achieved 82.3% (95% CI: 65.5%-93.2%) sensitivity, and 97.6% (95% CI: 91.5%-99.7%) specificity. GeneXpert could detect 11.7% and 50% additional positive cases as compared to Lowenstein-Jensen culture and smear microscopy, respectively. Three cases with resistance to rifampin were detected from clinical isolates.. The GeneXpert MTB/RIF assay is a helpful tool for rapid diagnosis and prompt treatment of TB.

    Topics: Adult; Aged; Antitubercular Agents; Bacteriological Techniques; Cross-Sectional Studies; Drug Resistance, Bacterial; Europe; Female; Humans; Kosovo; Male; Microscopy; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium; Prospective Studies; Rifampin; Tuberculosis

2016
[Application of Gene Xpert Mycobacterium tuberculosis DNA and resistance to rifampicin assay in the rapid detection of tuberculosis in children].
    Zhonghua er ke za zhi = Chinese journal of pediatrics, 2016, Volume: 54, Issue:5

    To detect Mycobacterium tuberculosis (MTB) and rifampin resistance of the clinical specimens in children by Xpert MTB DNA and resistance to rifampicin(MTB/RIF) detection system, and evaluate the application value of this method in children with tuberculosis.. Data of 109 children cases of clinically suspected tuberculosis were collected (including 46 gastric lavage aspirate, 19 sputum, 10 fine needle aspiration biopsy, 4 pus, 14 cerebrospinal fluid, 11 Serous membrance fluid, 1 marrow, 3 stool, 1 urine specimens)between April 2014 and March 2015. All specimens were detected by smear fluorescence staining microscopy, MGIT 960 BACTEC liquid culture, Xpert MTB/RIF assay and T-SPOT.TB test respectively. The sensitivity and specificity of Xpert MTB/RIF assay were analyzed in those clinical specimens.. The sensitivity and specificity of the Xpert MTB/RIF assay for MTB detection in childhood tuberculosis clinical specimen were 28.6% and 87.5%. The sensitivity of 65 pulmonary tuberculosis(46 gastric lavage aspirate, 19 sputum) which included gastric lavage aspirates and sputum was 33.3% and 57.1%, the specificity of the two was 100.0%. In 44 extrapulmonary tuberculosis, the sensitivity of the pus and the puncture fluid was higher and approached 100.0%. The detection rate of the cerebrospinal fluid and serous cavity effusion was very low. The sensitivity was 100.0% in smear-positive and culture-positive samples and only 30.8% to 50.0% in smear-negative and culture-positive samples. The sensitivity and specificity of Xpert MTB/RIF assay to detect rifampin resistance were 100.0%. In clinical samples, the sensitivity of Xpert MTB/RIF assay was higher than that of smear fluorescence staining microscopy, but the difference was not statistically significant (χ(2)=0, P>0.05). The result was equivalent to that of MGIT 960 BACTEC liquid culture (28.6% vs. 27.3%, χ(2)=2.50, P>0.05), and far below that of T-SPOT.TB(28.6% vs 59.7%, χ(2)=13.92, P<0.05).. Xpert MTB/RIF assay did not show obvious advantage in childhood tuberculosis, especially in serous cavity effusion and cerebrospinal fluid, but the advantages of detecting tuberculosis rapidly and resistance to rifampin can provide help for the clinical diagnosis and treatment in childrenhood tuberculosis.

    Topics: Child; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2016
Longitudinal whole genome analysis of pre and post drug treatment Mycobacterium tuberculosis isolates reveals progressive steps to drug resistance.
    Tuberculosis (Edinburgh, Scotland), 2016, Volume: 98

    Tuberculosis (TB) is one of the leading causes of death due to an infectious disease in the world. Understanding the mechanisms of drug resistance has become pivotal in the detection and treatment of newly emerging resistant TB cases. We have analyzed three pairs of Mycobacterium tuberculosis strains pre- and post-drug treatment to identify mutations involved in the progression of resistance to the drugs rifampicin and isoniazid. In the rifampicin resistant strain, we confirmed a mutation in rpoB (S450L) that is known to confer resistance to rifampicin. We discovered a novel L101R mutation in the katG gene of an isoniazid resistant strain, which may directly contribute to isoniazid resistance due to the proximity of the mutation to the katG isoniazid-activating site. Another isoniazid resistant strain had a rare mutation in the start codon of katG. We also identified a number of mutations in each longitudinal pair, such as toxin-antitoxin mutations that may influence the progression towards resistance or may play a role in compensatory fitness. These findings improve our knowledge of drug resistance progression during therapy and provide a methodology to monitor longitudinal strains using whole genome sequencing, polymorphism comparison, and functional annotation.

    Topics: Antitubercular Agents; Bacterial Proteins; Bacterial Toxins; Catalase; DNA Mutational Analysis; Drug Resistance, Multiple, Bacterial; Genome, Bacterial; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Models, Molecular; Mutation; Mycobacterium tuberculosis; Phenotype; Polymorphism, Single Nucleotide; Protein Conformation; Rifampin; Structure-Activity Relationship; Time Factors; Treatment Outcome; Tuberculosis

2016
Efavirenz Plasma Concentrations and HIV Viral Load in HIV/AIDS-tuberculosis Infection Patients Treated with Rifampicin.
    Acta medica Indonesiana, 2016, Volume: 48, Issue:1

    to determine the effect of a rifampicin-containing tuberculosis regimen on efavirenz plasma concentrations and viral load in HIV/AIDS-Tuberculosis infection patients who received efavirenz-based antiretroviral therapy.. plasma efavirenz concentrations and HIV viral load were measured in HIV/AIDS patients treated with 600 mg efavirenz-based antiretroviral for 3 to 6 months and in HIV/AIDS-Tuberculosis infection patients treated with similar antiretroviral regimen plus rifampicin-containing antituberculosis in Sulianti Saroso Infectious disease Hospital, Jakarta. Plasma efavirenz concentration in both groups were compared using Mann-Whitney test, while proportion of patients with viral load >40 copy/mL were analyzed with chi-square test.. forty five patients (27 with HIV/AIDS and 18 with HIV/AIDS-Tuberculosis infections) were recruited during the period of February to May 2015. The median efavirenz plasma concentration obtained from HIV/AIDS group was 0,680 mg/L(range 0,24 to 5,67 mg/L and that obtained from HIV/AIDS-Tuberculosis group was 0.685 mg/L (0.12 -2.23 mg/L) which was not significantly different statistically. The proportion of patients with viral load 40 copies/mL after 3-6 months of ARV treatment in the HIV/AIDS group was 51.9%, and in the HIV/AIDS-Tuberculosis group was 72.2%, which was not significantly different statistically (Chi Square test, p=0.291).. plasma efavirenz concentration in HIV/AIDS-tuberculosis patients receiving antiretroviral and rifampicin is not significantly different from that on HIV/AIDS patients without tuberculosis. Proportion of patients with viral load of >40 copy/mL is higher in HIV/AIDS-tuberculosis patients receiving rifampicin compared to HIV/AIDS patients that not receive rifampicin. However, this difference did not reach statistical significance. Confirmatory studies with bigger sample size are needed to clarify the influence of rifampicin on plasma level of efavirenzand and on viral load.

    Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; CD4 Lymphocyte Count; Central Nervous System; Cyclopropanes; Female; Humans; Male; Middle Aged; Rifampin; Tuberculosis; Viral Load; Young Adult

2016
Chemotherapeutic Evaluation of Guar Gum Coated Chitosan Nanoparticle Against Experimental Tuberculosis.
    Journal of biomedical nanotechnology, 2016, Volume: 12, Issue:3

    The major goal of the current research was to develop and evaluate the therapeutic potential of anti-tubercular drugs (ATDs) loaded natural polysaccharide comprising of galacto mannan subunit in experimental tuberculosis (TB). Experimental formulations were prepared by ionotropic gelation technique followed by spray drying. Morphological analysis suggested that optimized nanoparticles were found to be discrete and spherical in nature with a particle size distribution range from 230 ± 4.5 nm to 310 ± 6.2 nm. The in-vitro drug release behavior indicated the biphasic pattern comprising of initial burst followed by a sustained release pattern. Guar gum coated chitosan nanoparticles (CGNPs) among the leading formulation exhibited the highest cell uptake potential confirmed by FACS analysis. Challenge study also supports the in-vivo bio-distribution illustrated by the significant reduction in CFU count in experimental TB in mice. Histopathology study demonstrated that none of the treated group shows any evidence of lung tissue abnormality. Hence, the study marked the fact that CGNPs could be a promising carrier for selective delivery of ATDs to alveolar macrophages for efficient management of TB with the interception of minimal side effects.

    Topics: Animals; Antitubercular Agents; Chitosan; Coated Materials, Biocompatible; Delayed-Action Preparations; Diffusion; Female; Galactans; Isoniazid; Mannans; Mice; Mice, Inbred BALB C; Nanocapsules; Plant Gums; Rifampin; Treatment Outcome; Tuberculosis

2016
Xpert(®) MTB/RIF for improved case detection of extra-pulmonary TB in a tertiary care setting in urban India.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:7

    Department of microbiology at a tertiary care hospital, Mumbai, India.. To determine 1) the sensitivity and specificity of the Xpert(®) MTB/RIF assay in comparison with microscopy and culture in extra-pulmonary tuberculosis (EPTB), and 2) the number of additional cases of EPTB and rifampicin (RMP) resistance detected using this assay.. The study was conducted from July 2013 to April 2015. All consecutive patients with clinically suspected EPTB referred for microscopic examination to the Department of Microbiology that were sufficient in specimen volume were included in the study.. Of the 728 specimens included in the study, respectively 5.5%, 23.5% and 20.9% were positive on smear, culture and Xpert. Compared to culture, Xpert had a sensitivity of 84.2% (95%CI 81.4-86.6) and specificity of 98.2% (95%CI 90-104). All specimens with high and medium load on assay were positive on culture; 28 (18.4%) specimens were RMP-resistant and 124 (81.6%) were Xpert-susceptible. No additional RMP-resistant cases were detected using Xpert as compared to phenotypic drug susceptibility testing.. The ability of the Xpert assay to rapidly detect a significantly greater number of bacteriologically confirmed EPTB cases, including RMP-resistant cases, makes it an important diagnostic tool in a TB-endemic country.

    Topics: Antibiotics, Antitubercular; DNA Mutational Analysis; Drug Resistance, Bacterial; Genotype; Humans; India; Microscopy; Molecular Diagnostic Techniques; Mutation; Mycobacterium tuberculosis; Phenotype; Predictive Value of Tests; Reproducibility of Results; Rifampin; Tertiary Care Centers; Time Factors; Tuberculosis; Urban Health Services; Workflow

2016
Xpert(®) MTB/RIF detection of rifampin resistance and time to treatment initiation in Harare, Zimbabwe.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:7

    Patients at elevated risk of drug-resistant tuberculosis (TB) are prioritized for Xpert(®) MTB/RIF testing; however, the clinical usefulness of the test in this population is understudied.. From November 2011 to June 2014, consecutive out-patients with a history of previous TB in high-density suburbs of Harare, Zimbabwe, were tested using Xpert, solid and liquid culture, and the microscopic observation drug susceptibility assay. Diagnostic accuracy for rifampin (RMP) resistance and time to initiation of second-line regimens were ascertained. The rpoB gene was sequenced in cases with culture-confirmed RMP resistance and genotypic susceptibility.. Among 352 retreatment patients, 71 (20%) were RMP-resistant, 98 (28%) RMP-susceptible, 64 (18%) culture-negative/Xpert-positive, and 119 (34%) culture-negative/Xpert-negative. Xpert had a sensitivity of 86% (95%CI 75-93) and a specificity of 98% (95%CI 92-100) for RMP-resistant TB. The positive predictive value of Xpert-determined RMP resistance for multidrug-resistant TB (MDR-TB) was 82% (95%CI 70-91). Of 71 (83%) participants, 59 initiated treatment with second-line drugs, with a median time to treatment initiation of 18 days (IQR 10-44).. The diagnostic accuracy of Xpert for RMP resistance is high, although the predictive value for MDR-TB was lower than anticipated. Xpert allows for faster initiation of second-line treatment than culture-based drug susceptibility testing under programmatic conditions.

    Topics: Adult; Antitubercular Agents; Bacterial Proteins; DNA Mutational Analysis; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mutation; Mycobacterium tuberculosis; Predictive Value of Tests; Prospective Studies; Reproducibility of Results; Retreatment; Rifampin; Time Factors; Time-to-Treatment; Treatment Outcome; Tuberculosis; Zimbabwe

2016
Therapeutic drug monitoring of isoniazid and rifampicin during anti-tuberculosis treatment in Auckland, New Zealand.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:7

    There is uncertainty as to the optimal therapeutic concentrations of anti-tuberculosis drugs to achieve cure.. To characterise the use of therapeutic drug monitoring (TDM), and identify risk factors and outcomes for those with concentrations below the drug interval.. Patients treated for tuberculosis (TB) who had rifampicin (RMP) or isoniazid (INH) concentrations measured between 1 January 2005 and 31 December 2012 were studied retrospectively. Matched concentrations and drug dosing time were assessed according to contemporary regional drug intervals (RMP > 6 μmol/l, INH > 7.5 μmol/l) and current international recommendations (RMP > 10 μmol/l, INH > 22 μmol/l). Outcomes were assessed using World Health Organization criteria.. Of 865 patients, 121 had concentrations of either or both medications. RMP concentrations were within the regional drug intervals in 106/114 (93%) and INH in 91/100 (91%). Concentrations were within international drug intervals for RMP in 76/114 (67%) and INH in 53/100 (53%). Low weight-based dose was the only statistically significant risk factor for concentrations below the drug interval. Of the 35 patients with low concentrations, 21 were cured, 9 completed treatment and 5 transferred out. There were no relapses during follow-up (mean 66.5 months).. There were no clinically useful characteristics to guide use of TDM. Many patients had concentrations below international therapeutic intervals, but were successfully treated.

    Topics: Adult; Antitubercular Agents; Databases, Factual; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; New Zealand; Predictive Value of Tests; Recurrence; Remission Induction; Retrospective Studies; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

2016
Design, synthesis, and In vitro antituberculosis activity of 2(5H)-Furanone derivatives.
    IUBMB life, 2016, Volume: 68, Issue:8

    A series of 2(5H)-furanone-based compounds were synthesized from commercially available mucohalic acids. From the first-generation compounds, three showed inhibitory activity (10 µg/mL) of at least 35% against Mycobacterium smegmatis mc(2) 155 growth (Bioscreen C system). In screening the active first-generation compounds for growth inhibition against Mycobacterium tuberculosis H37Rv, the most active compound was identified with a minimum inhibitory concentration (MIC99 ) of 8.07 µg/mL (15.8 µM) using BACTEC 460 system. No cross-resistance was observed with some current first-line anti-TB drugs, since it similarly inhibited the growth of multidrug resistant (MDR) clinical isolates. The compound showed a good selectivity for mycobacteria since it did not inhibit the growth of selected Gram-positive and Gram-negative bacteria. It also showed synergistic activity with rifampicin (RIF) and additive activity with isoniazid (INH) and ethambutol (EMB). Additional time-kill studies showed that the compound is bacteriostatic to mycobacteria, but cytotoxic to the Chinese Hamster Ovarian (CHO) cell line. From a second generation library, two compounds showed improved anti-TB activity against M. tuberculosis H37Rv and decreased CHO cell cytotoxicity. The compounds exhibited MIC values of 2.62 µg/mL (5.6 µM) and 3.07 µg/mL (5.6 µM) respectively. The improved cytotoxicity against CHO cell line of the two compounds ranged from IC50  = 38.24 µg/mL to IC50  = 45.58 µg/mL when compared to the most active first-generation compound (IC50  = 1.82 µg/mL). The two second generation leads with selectivity indices (SI) of 14.64 and 14.85 respectively, warrant further development as anti-TB drug candidates. © 2016 IUBMB Life, 68(8):612-620, 2016.

    Topics: Animals; Antitubercular Agents; CHO Cells; Cricetulus; Drug Synergism; Ethambutol; Furans; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2016
Down-regulation of N-acetylglucosamine-1-phosphate transferase (WecA) enhanced the sensitivity of Mycobacterium smegmatis against rifampin.
    Journal of applied microbiology, 2016, Volume: 121, Issue:4

    To construct a conditional N-acetylglucosamine-1-phosphate transferase (WecA) knockdown strain of Mycobacterium smegmatis and to investigate the biological effect of WecA on mycobacterial growth, morphology and susceptibilities against anti-tuberculosis drugs.. Mycobacterium smegmatis wecA knockdown strain was constructed by using a tetracycline-inducible expression vector pMind and the expression of WecA was regulated by antisense RNA. The results of growth curves and the colony formation unit curves showed that the growth rate of WecA down-regulation strain was decreased and the amount of live bacterial cells dropped. In addition, the wecA knockdown strain exhibited dramatically morphological alterations through scanning electron microscopy observation. The susceptibility of WecA low-expression strain to anti-tuberculosis drugs was detected by using a rapid resazurin microtitre assay as well as a traditional agar dilution method. Notably, the wecA knockdown strain was more sensitive to rifampin, compared with the wecA normal-expression strain. In addition, the sensitivity of wild type Myco. smegmatis mc(2) 155 strain against rifampin was also enhanced in the presence of a low concentration of tunicamycin, a natural WecA inhibitor.. Down-regulation of WecA enhanced the sensitivity of Myco. smegmatis against rifampin.. These results provided a possibility of combined application of rifampin together with tunicamycin or other WecA inhibitors, which could be a new approach for the treatment of tuberculosis.

    Topics: Antibiotics, Antitubercular; Down-Regulation; Gene Knockdown Techniques; Humans; Hypersensitivity; Mycobacterium smegmatis; Mycobacterium tuberculosis; Rifampin; Transferases (Other Substituted Phosphate Groups); Tuberculosis

2016
In vitro evaluation of novel inhalable dry powders consisting of thioridazine and rifapentine for rapid tuberculosis treatment.
    European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 2016, Volume: 107

    Thioridazine is an orally administered antipsychotic drug with potential for treatment of drug-resistant tuberculosis (TB). However, drug-induced adverse cardiac effects have been reported when thioridazine was used at an efficacious oral dose of 200mg/day to treat TB. Pulmonary delivery of thioridazine could be a rational approach to reduce dose-related side effects while enabling high drug concentrations at the primary site of infection. The present study compares in vitro aerosol performance, storage stability, and in vitro antimicrobial activity and cytotoxicity of two inhalable powders composed of thioridazine and a first-line anti-TB drug, rifapentine. Formulation 1 is a combination of amorphous thioridazine and crystalline rifapentine, while Formulation 2 consisted of both drugs as amorphous forms. Both thioridazine-rifapentine formulations were found suitable for inhalation with a total fine particle fraction (<5μm) of 68-76%. The two powders had similar MIC90 to rifapentine alone, being 0.000625μg/mL and 0.005μg/ml against Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv, respectively. In contrast, thioridazine alone had a MIC90 of 12.5μg/mL and 500μg/mL, against M. tuberculosis H37Ra and M. tuberculosis H37Rv, respectively, demonstrating no synergistic anti-TB activity. However, thioridazine and rifapentine in a ratio of 1:3 enhanced the killing of M. tuberculosis H37Ra within the human monocyte-derived macrophages (THP-1) compared to the single drug treatments. Both powders showed an acceptable half maximal inhibitory concentration (IC50) of 31.25μg/mL on both THP-1 and human lung epithelial (A549) cells. However, Formulation 1 showed greater chemical stability than Formulation 2 after three months of storage under low humidity (vacuum) at 20±3°C. In conclusion, we have demonstrated a novel inhalable powder consisted of amorphous thioridazine and crystalline rifapentine (Formulation 1) with a good aerosol performance, potent anti-TB activity and storage stability, which deserves further in vivo investigations.

    Topics: Administration, Inhalation; Antitubercular Agents; Humans; In Vitro Techniques; Powder Diffraction; Powders; Rifampin; Thioridazine; Tuberculosis

2016
[Experimental study of GeneXpert(®) system in the diagnosis of extra-pulmonary tuberculosis].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2016, Volume: 39, Issue:7

    To explore the application value of GeneXpert MTB/RIF for detection of extra-pulmonary tuberculosis and resistance to rifampin.. A total of 150 samples were collected, including 33 needle aspirates from lymphoid tuberculosis, 23 needle aspirates from spinal tuberculosis, 49 from tuberculous pleural effusions, 24 from cerebrospinal fluid of tuberculous cephalomeningitis, and 21 urinary sediment samples from renal tuberculosis. Smear microscopy, mycobacterium tuberculosis culture and the MTB/RIF method were used to examine these samples and their positive rates were compared. Rifampin susceptibility tests was performed for culture-positive strains using proportion method, which was compared with the result from GeneXpert MTB/RIF method.. Of the 150 cases of extra-pulmonary tuberculosis, 17 samples were smear-positive, with a sensitivity of 11.3% (17/150); 30 were culture-positive with a sensitivity of 20.0% (30/150); and 96 were positive by MTB/RIF method with a sensitivity of 64.0% (96/150). There was a significant difference between MTB/RIF method and the culture method (χ(2)=59.61, P<0.01). The differences were also significant when the MTB/RIF method was compared with the smear method (χ(2)=88.60, P<0.01) or compared with culture plus smear methods (χ(2)=4.26, P<0.05). Separately, the differences were statistically significant between GeneXpert MTB/RIF method and other 2 methods for diagnosis of lymphoid tuberculosis (n=33, χ(2)=20.56, P<0.01 vs. culture method; χ(2)=27.13, P<0.01 vs. smear results) while no difference was found between culture and smear method (χ(2)=0.67, P>0.05), spinal tuberculosis (n=23, χ(2)=12.74, P<0.01 vs. culture method; χ(2)=14.81, P< 0.01 vs. smear method), tuberculous pleurisy (n=49, χ(2)=32.34, P<0.01 vs.culture method; χ(2)=49.69, P<0.01 vs. smear method) and renal tuberculosis (n=21, χ(2)=4.20, P<0.05 vs. culture method; χ(2) =8.40, P<0.01 vs. smear results). The sensitivity for tuberculous meningitis had no difference among these 3 methods (n=24, P>0.05). Rifampicin-resistance of the strains from the 30 culture-positive cases of extra-pulmonary tuberculosis (20.0%, 6/30) exhibited agreement with GeneXpert MTB/RIF test.. The simplicity and high sensitivity of GeneXpert MTB/RIF technology make it a good diagnostic test for rapid detection of extra-pulmonary tuberculosis and resistance to rifampin.

    Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Needles; Pleural Effusion; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Renal; Tuberculosis, Spinal

2016
Impact of diabetes mellitus on tuberculosis drug resistance in new cases of tuberculosis.
    Journal of global antimicrobial resistance, 2016, Volume: 4

    The objectives of this study were to determine the impact of diabetes mellitus (DM) on antituberculosis drug resistance in new cases of tuberculosis (TB). A case-control study was conducted on all newly diagnosed pulmonary TB adult patients with DM as cases and without DM as controls who were hospitalised from May 2013 to October 2013 in Iran. A molecular resistance test for rapid detection of resistance to isoniazid and rifampicin was done. Multivariate analysis was performed to determine the impact of DM on any anti-TB drug resistance. In total, 62 TB cases with DM and 64 TB cases without DM were included. TB cases with DM were more likely to be older (59 years vs. 43 years; P=0.001). Two TB-DM patients had multidrug-resistant TB (MDR-TB) (3.2%) compared with no cases of MDR-TB in the control group, and more TB-DM cases had isolates that were resistant to at least one drug (12.9% vs. 10.9%). DM [odds ratio (OR)=4.82, 95% confidence interval (CI) 1-23.57], age <40 years (OR=5.48, 95% CI 1.19-25.29) and history of TB contact (OR=5.86, 95% CI 1.69-20.36) remained significantly associated with any drug resistance in the multivariate analysis. In conclusion, new TB patients with DM are at increased risk of anti-TB drug resistance. More studies are needed to confirm these results.

    Topics: Adult; Aged; Case-Control Studies; Diabetes Mellitus; Drug Resistance, Bacterial; Female; Humans; Iran; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis

2016
Dosage of isoniazid and rifampicin poorly predicts drug exposure in tuberculosis patients.
    The European respiratory journal, 2016, Volume: 48, Issue:4

    Topics: Antitubercular Agents; Area Under Curve; Body Weight; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Isoniazid; Rifampin; Tuberculosis

2016
SLCO1B1 gene polymorphisms do not influence plasma rifampicin concentrations in a South Indian population.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:9

    To determine the effect of SLCO1B1 gene polymorphisms (rs11045819, rs4149032 and rs4149033) on rifampicin (RMP) concentrations in adult tuberculosis (TB) patients from south India.. We genotyped adult TB patients for three SLCO1B1 gene polymorphisms-rs11045819, rs4149032 and rs4149033-and compared 2-h post-dosing RMP concentrations of the different genotypes for each of the polymorphisms. Plasma RMP was determined using high-performance liquid chromatography. Genotyping was performed using direct sequencing.. Among the 256 study patients, minor allele frequencies were respectively 0.01 (A), 0.46 (C) and 0.07 (A) for rs11045819, rs4149032 and rs4149033 polymorphisms; genotype distributions followed Hardy-Weinberg equilibrium. RMP concentrations did not significantly differ between the different genotypes of the three polymorphisms.. This is the first study to show that rs11045819, rs4149032 and rs4149033 polymorphisms in the SLCO1B1 gene did not influence RMP concentrations in Indian patients.

    Topics: Adult; Antibiotics, Antitubercular; Female; Gene Frequency; Genotype; Genotyping Techniques; Humans; India; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis; White People

2016
Pharmacokinetics of thrice-weekly rifampicin, isoniazid and pyrazinamide in adult tuberculosis patients in India.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:9

    To study the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in adult tuberculosis (TB) patients and examine factors that influence drug pharmacokinetics.. Adult TB patients (n = 101) receiving thrice-weekly anti-tuberculosis treatment in the Revised National TB Control Programme (RNTCP) were studied. The study was conducted at steady state after directly observed drug administration. RMP, INH and PZA concentrations were estimated using high-performance liquid chromatography and NAT2 genotyping by real-time polymerase chain reaction.. RMP peak concentration (Cmax) was sub-therapeutic (<8 μg/ml) in 88% of the patients. The Cmax of RMP, INH and PZA at 2 h was observed in respectively 83.2%, 97.0% and 92.1% of the patients. The Cmax and area under the curve from 0 to 8 h (AUC0-8) of PZA was lower in TB patients with diabetes mellitus than in non-diabetics. Significant associations were observed between the Cmax and the AUC0-8 of RMP, INH and PZA with drug doses; RMP with category of treatment; INH with smoking, body mass index and N-acetyl transferase 2 genotype; and PZA with sex and smoking.. Several risk factors for drug concentration variations were identified. Two-hour post-dosing drug concentrations mimicked Cmax. A high proportion of TB patients had RMP Cmax below the expected range, which is a matter of concern.

    Topics: Adult; Antitubercular Agents; Arylamine N-Acetyltransferase; Female; Genotyping Techniques; Humans; India; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Sample Size; Tuberculosis; Young Adult

2016
Comparison of a real-time polymerase chain reaction-based system and Erlich-Ziehl-Neelsen method with culture in the identification of Mycobacterium tuberculosis.
    Turkish journal of medical sciences, 2016, Jan-05, Volume: 46, Issue:1

    Mycobacterium tuberculosis is still a major health problem throughout the world, especially in developing countries. Disease control heavily depends on the establishment of early diagnosis. The aim of this study is to compare the efficacy of culture, GeneXpert MTB/RIF device, and Erlich-Ziehl-Neelsen direct microscopic method.. A total of 927 samples (243 respiratory and 684 nonrespiratory), which were sent to Ondokuz Mayıs University Medical Faculty Tuberculosis Laboratory on suspicion of M. tuberculosis, were included in the study.. When compared to standard culture, sensitivity, specificity, and positive and negative predictive values of the GeneXpert system for respiratory samples were 100%, 98.7%, 87%, and 100%, respectively; these values for nonrespiratory samples were 71%, 98.6%, 71%, and 98.6%, respectively.. New, reliable, rapid, and easy-to-use methods that display high specificity and sensitivity are required for an effective struggle against tuberculosis. According to these results, we suggest that GeneXpert MTB/RIF is a rapid and reliable system, and when used in company with conventional tests, it would make significant contributions to the diagnosis of tuberculosis.

    Topics: Humans; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Tuberculosis

2016
Identification of rifampin-regulated functional modules and related microRNAs in human hepatocytes based on the protein interaction network.
    BMC genomics, 2016, 08-22, Volume: 17 Suppl 7

    In combination with gene expression profiles, the protein interaction network (PIN) constructs a dynamic network that includes multiple functional modules. Previous studies have demonstrated that rifampin can influence drug metabolism by regulating drug-metabolizing enzymes, transporters, and microRNAs (miRNAs). Rifampin induces gene expression, at least in part, by activating the pregnane X receptor (PXR), which induces gene expression; however, the impact of rifampin on global gene regulation has not been examined under the molecular network frameworks.. In this study, we extracted rifampin-induced significant differentially expressed genes (SDG) based on the gene expression profile. By integrating the SDG and human protein interaction network (HPIN), we constructed the rifampin-regulated protein interaction network (RrPIN). Based on gene expression measurements, we extracted a subnetwork that showed enriched changes in molecular activity. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG), we identified the crucial rifampin-regulated biological pathways and associated genes. In addition, genes targeted by miRNAs that were significantly differentially expressed in the miRNA expression profile were extracted based on the miRNA-gene prediction tools. The miRNA-regulated PIN was further constructed using associated genes and miRNAs. For each miRNA, we further evaluated the potential impact by the gene interaction network using pathway analysis. RESULTS AND DISCCUSSION: We extracted the functional modules, which included 84 genes and 89 interactions, from the RrPIN, and identified 19 key rifampin-response genes that are associated with seven function pathways that include drug response and metabolism, and cancer pathways; many of the pathways were supported by previous studies. In addition, we identified that a set of 6 genes (CAV1, CREBBP, SMAD3, TRAF2, KBKG, and THBS1) functioning as gene hubs in the subnetworks that are regulated by rifampin. It is also suggested that 12 differentially expressed miRNAs were associated with 6 biological pathways.. Our results suggest that rifampin contributes to changes in the expression of genes by regulating key molecules in the protein interaction networks. This study offers valuable insights into rifampin-induced biological mechanisms at the level of miRNAs, genes and proteins.

    Topics: Antibiotics, Antitubercular; Computational Biology; Gene Expression Profiling; Gene Expression Regulation; Humans; Inactivation, Metabolic; Microarray Analysis; MicroRNAs; Pregnane X Receptor; Protein Interaction Maps; Receptors, Steroid; Rifampin; Tuberculosis

2016
The genotypic study of Mycobacterium tuberculosis complex resistant to isoniazid: Galicia, Spain (2008-2013).
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2016, Volume: 35, Issue:11

    Incorporation of rapid detection systems to identify mutations in M. tuberculosis complex that confer resistance to isoniazid and rifampicin has potentiated the knowledge of their distribution, given the geographical variability. We performed antibiograms of the 2,993 strains isolated in Galicia, Spain (2008-2013). In the strains resistant to isoniazid, a concentration of 0.4 mg/mL and MTBDRplus Genotype test (Hain Lifescience, Germany) were used. We found that 3.64 % of strains were resistant to isoniazid, while 0.43 % were resistant to isoniazid and rifampicin (multidrug resistant, MDR). The MTBDRplus test showed an overall sensitivity of 72.48 %, with 62.5 % sensitivity for non MDR isoniazid-resistant strains and 100 % sensitivity for MDR strains. The katG gene mutation was detected at codon 315 in 38.53 % of strains. The S315T mutation appeared in 61.54 % of MDR strains and 34.38 % of non-MDR strains. The 28.44 % had mutations in inhA, (93.55 % in C15T), and 38.46 % of MDR strains were mutated. In non-MDR strains, 37.50 % were wild-type, 35.42 % and 27.08 % had mutations in katG and inhA, respectively. The most frequent mutation in rpoβ was S531L (46.15 %). The 38.71 % and 41.9 % of strains with resistance to isoniazid and streptomycin had mutations in katG and inhA, respectively (2 strains with mutations in T8C and T8A). The distribution pattern of resistance among strains with high and low concentrations of isoniazid showed statistically significant differences in relation to the mutation in katG and wild-type. The sensitivity of the Genotype MTBDRplus test for non-MDR strains in our area was at the lower threshold described.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Genotype; Genotyping Techniques; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Spain; Tuberculosis

2016
Fixed-dose combination and therapeutic drug monitoring in tuberculosis: friend or foe?
    The European respiratory journal, 2016, Volume: 48, Issue:4

    Topics: Antitubercular Agents; Drug Combinations; Drug Monitoring; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2016
Gold Nanorods as Drug Delivery Vehicles for Rifampicin Greatly Improve the Efficacy of Combating Mycobacterium tuberculosis with Good Biocompatibility with the Host Cells.
    Bioconjugate chemistry, 2016, Oct-19, Volume: 27, Issue:10

    TB remains a challenging disease to control worldwide. Nanoparticles have been used as drug carriers to deliver high concentrations of antibiotics directly to the site of infection, reducing the duration of treatment along with any side effects of off-target toxicities after systemic exposure to the antibiotics. Herein we have developed a drug delivery platform where gold nanorods (AuNRs) are conjugated to rifampicin (RF), which is released after uptake into macrophage cells (RAW264.7). Due to the nature of the macrophage cells, the nanoparticles are actively internalized into macrophages and release RF after uptake, under the safety frame of the host cells (macrophage). AuNRs without RF conjugation exhibit obvious antimicrobial activity. Therefore, AuNRs could be a promising antimycobacterial agent and an effective delivery vehicle for the antituberculosis drug Rifampicin for use in tuberculosis therapy.

    Topics: Animals; Antitubercular Agents; Cell Line; Drug Delivery Systems; Drug Liberation; Gold; Host-Pathogen Interactions; Macrophages; Mice; Mycobacterium tuberculosis; Nanotubes; Rifampin; Tuberculosis

2016
Do Xpert MTB/RIF Cycle Threshold Values Provide Information about Patient Delays for Tuberculosis Diagnosis?
    PloS one, 2016, Volume: 11, Issue:9

    Early diagnosis and initiation to appropriate treatment is vital for tuberculosis (TB) control. The XpertMTB/RIF (Xpert) assay offers rapid TB diagnosis and quantitative estimation of bacterial burden through Cycle threshold (Ct) values. We assessed whether the Xpert Ct value is associated with delayed TB diagnosis as a potential monitoring tool for TB control programme performance.. This analysis was nested in a prospective study under the routine TB surveillance procedures of the National TB Control Program in Manhiça district, Maputo province, Mozambique. Presumptive TB patients were tested using smear microscopy and Xpert. We explored the association between Xpert Ct values and self-reported delay of Xpert-positive TB patients as recorded at the time of diagnosis enrolment. Patients with >60 days of TB symptoms were considered to have long delays.. Of 1,483 presumptive TB cases, 580 were diagnosed as TB of whom 505 (87.0%) were due to pulmonary TB and 302 (94.1%) were Xpert positive. Ct values (range, 9.7-46.4) showed a multimodal distribution. The median (IQR) delay was 30 (30-45) days. Ct values showed no correlation with delay (R2 = 0.001, p = 0.621), nor any association with long delays: adjusted odds ratios (AOR) (95% confidence interval [CI]) comparing to >28 cycles 0.99 (0.50-1.96; p = 0.987) for 23-28 cycles, 0.93 (0.50-1.74; p = 0.828) for 16-22 cycles; and 1.05 (0.47-2.36; p = 0.897) for <16 cycles. Being HIV-negative (AOR [95% CI]), 2.05 (1.19-3.51, p = 0.009) and rural residence 1.74 (1.08-2.81, p = 0.023), were independent predictors of long delays.. Xpert Ct values were not associated with patient delay for TB diagnosis and cannot be used as an indicator of TB control program performance.

    Topics: Adult; Delayed Diagnosis; Demography; Female; Humans; Male; Multivariate Analysis; Reagent Kits, Diagnostic; Rifampin; Tuberculosis

2016
Evaluation of Xpert MTB/RIF for the Diagnosis of Extrapulmonary Tuberculosis in China.
    Biomedical and environmental sciences : BES, 2016, Volume: 29, Issue:8

    We evaluate the performance of Xpert MTB/RIF for the diagnosis of extrapulmonary tuberculosis (EPTB) in China. The performance of Xpert was evaluated compared to the composite reference standard (CRS), drug susceptibility testing (DST), and imaging examination. The overall sensitivity and specificity of Xpert were 64.1% (195/304) and 100% (24/24), respectively, using CRS as the gold standard. The sensitivity was significantly higher than that of culture for pus (P<0.05). The proportion of EPTB-positive cases diagnosed by imaging was two times more than that diagnosed using Xpert; however, 6 out of 19 cases may have been overdiagnosed by imaging. Compared to phenotypic DST, the sensitivity and specificity of Xpert were 80% (12/15) and 100% (75/75), respectively. Considering its high sensitivity and specificity, Xpert MTB/RIF may be used as a rapid initial test for EPTB diagnosis, and may also support a quicker decision on the treatment regimen. The combination of imaging and Xpert testing could provide high efficiency and accurate diagnosis of suspected EPTB.

    Topics: Bacterial Proteins; China; Diagnostic Tests, Routine; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

2016
ISONIAZID AND RIFAMPIN PHARMACOKINETICS IN TWO ASIAN ELEPHANTS (ELEPHAS MAXIMUS) INFECTED WITH MYCOBACTERIUM TUBERCULOSIS.
    Journal of zoo and wildlife medicine : official publication of the American Association of Zoo Veterinarians, 2016, Volume: 47, Issue:3

    This report describes the pharmacokinetic profiles of chronically administered oral isoniazid and rifampin in one adult male and one adult female Asian elephant ( Elephas maximus ) that were asymptomatically infected with Mycobacterium tuberculosis . Rifampin's half-life was reduced when compared to previous single-dose pharmacokinetic profiles of healthy uninfected Asian elephants. Both elephants experienced delayed absorption of isoniazid and rifampin as compared to previous pharmacokinetic studies in this species. The altered pharmacokinetics of both drugs in repeated-dosing clinical situations underscores the need for individual therapeutic drug monitoring for tuberculosis treatment.

    Topics: Animals; Antitubercular Agents; Area Under Curve; Elephants; Female; Half-Life; Isoniazid; Male; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2016
Use and evaluation of a line probe assay in patients with tuberculosis in Peru: 2011-2013.
    Revista panamericana de salud publica = Pan American journal of public health, 2016, Volume: 39, Issue:1

    Objective To determine the use and performance of a line probe assay (LPA) compared with conventional culture and drug sensitivity testing (CDST) in patients registered with tuberculosis (TB) under routine program conditions in Peru in 2011-2013. Methods This was a descriptive, operational research, cross-sectional study of sputum specimens from patients with smear-positive pulmonary TB and mycobacterial cultures from patients with smear-negative or positive TB. Drug resistance to rifampicin and/or isoniazid detected by LPA was compared to CDST. Sensitivity, specificity, and predictive values were calculated and reliability for detecting drug resistance was assessed through kappa coefficient, with values 0.61-0.80 showing substantial correlation, and 0.81 or above showing almost-perfect correlation. Results In 2011-2013, there were 16 169 LPA tests performed, with the proportion of TB patients receiving the test increasing from 3.2% to 30.2%. In all, 2 905 LPA test results were compared to CDST. For LPA in sputum specimens, sensitivity for rifampicin was 92%; isoniazid, 94%; and MDR-TB, 88%; while specificity for rifampicin was 92%; isoniazid, 92%; and MDR-TB, 95%. For LPA in mycobacterial cultures, sensitivity for rifampicin was 95%; isoniazid, 96%; and MDR-TB, 90%; while specificity for rifampicin was 85%; isoniazid, 91%; and MDR-TB, 94%. Kappa coefficients were at 0.81 or above for all comparisons of LPA with CDST using sputum specimens and cultures, except for isoniazid in cultures, which was at 0.79. Conclusions This study suggests that LPA is a reliable and rapid screening test for drug-resistant TB and should be considered suitable for routine use and scale up in Peru.

    Topics: Antitubercular Agents; Cross-Sectional Studies; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Peru; Reproducibility of Results; Rifampin; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

2016
Severe adverse events during second-line tuberculosis treatment in the context of high HIV Co-infection in South Africa: a retrospective cohort study.
    BMC infectious diseases, 2016, Oct-21, Volume: 16, Issue:1

    According to the World Health Organization, South Africa ranks as one of the highest burden of TB, TB/HIV co-infection, and drug-resistant TB (DR-TB) countries. DR-TB treatment is complicated to administer and relies on the use of multiple toxic drugs, with potential for severe adverse drug reactions. We report the occurrence of adverse events (AEs) during a standardised DR-TB treatment regimen at two outpatient, decentralized, public-sector sites in Johannesburg, South Africa.. We reviewed medical records of the six-month intensive treatment phase for rifampicin-resistant (RR) TB patients registered May 2012 - December 2014. Patients contributed follow-up time until death, loss from treatment, censoring (6 months) or data extraction. A standardized regimen of kanamycin, moxifloxacin, ethionamide, terizidone, and pyrazinamide was used according to national guidelines. AEs were graded using the AIDS Clinical Trial Group scale. We present subhazard ratios from competing risk analysis for time to severe AE, accounting for mortality and loss from treatment.. Across the two sites, 578 eligible patient files were reviewed. 36.7 % were categorized as low weight (≤50 kg) at DR-TB initiation. 76.0 % had no history of TB treatment prior to the current episode of RR TB. 26.8 % were diagnosed with RR TB while hospitalized, indicating poor clinical condition. 82.5 % of patients were also HIV positive, of whom 43.8 % were on ART prior to RR TB treatment and 32.1 % initiated ART with or after RR TB treatment. Median CD4 count was 114.5 (IQR: 45-246.5). Overall, 578 reports of AEs were captured for 204 patients (35.3 %) and 110 patients (19.0 %) had at least one severe AE reported. Patients with at least one AE experienced a median of 3 (IQR: 2-4) AEs per patient. HIV-positive patients with CD4 counts ≤100 cells/mm. Severe AE are common during the first 6 months of RR TB treatment and HIV-positive patients newly initiating ART have the highest subdistribution hazard ratio for severe AE, accounting for the competing risks of death and loss from treatment.

    Topics: Adolescent; Adult; Anti-HIV Agents; Antitubercular Agents; CD4 Lymphocyte Count; Child; Cohort Studies; Coinfection; Female; HIV Infections; Humans; Male; Middle Aged; Retrospective Studies; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2016
Surveillance for tuberculosis in a rural community in The Philippines.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:11

    Estimates of the tuberculosis (TB) burden in the Philippines are largely dependent on prevalence surveys.. To conduct a prospective community-based survey to generate epidemiological data on TB among patients seeking care in public health centres in a rural municipality in the Philippines.. Prospective surveillance and follow-up of presumptive TB cases from May 2013 to July 2015.. Of 1622 participants with presumptive TB, 468 (28.8%) (95%CI 26.6-31.1) were diagnosed with TB. The annual TB case notification rate in San Juan was 212 (95%CI 184-242) per 100 000 population. There were nine TB-attributable deaths during the study period. Only 8.8% (95%CI 6.2-11.32) of the cases were children aged <15 years; 274 (58.5%) cases were bacteriologically confirmed. Of 210 isolates tested for antimicrobial resistance, 49 (23.3%, 95%CI 17.58-29.02) were resistant. Resistance to isoniazid (INH) was common (n = 33, 15.7%); multidrug-resistant TB was 1.9%.. TB remains an important health problem in the Philippines. We identified low case detection of TB in children and high INH resistance rates in this rural community.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Isoniazid; Kanamycin; Male; Middle Aged; Philippines; Population Surveillance; Prevalence; Prospective Studies; Public Health; Rifampin; Rural Population; Streptomycin; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2016
Tuberculosis treatment outcomes of six and eight month treatment regimens in districts of Southwestern Ethiopia: a comparative cross-sectional study.
    BMC infectious diseases, 2016, 11-08, Volume: 16, Issue:1

    A switch of continuation phase tuberculosis (TB) treatment regimen from Ethambutol (E) and Isoniazid (H) combination for 6 months (6EH) to Rifampicin (R) and Isoniazid (H) combination for 4 months (4RH) was recommended. However, the effect of the regimen switch in Ethiopian setting is not known.. A comparative cross-sectional study among 790 randomly selected new cases of TB (395 each treated with 4RH and 6EH during the continuation phase) was conducted in nine health centers and one hospital in three zones in southwestern Ethiopia. Data were abstracted from the standard unit TB register composed of standard case and treatment outcome definitions. Data were analyzed using STATA version 13 where binary logistic regression was fitted to identify independent predictors of unsuccessful treatment outcomes at 5 % significance level.. Over all, 695 (88 %) of the patients had a successful treatment outcome with statistically significant difference (85.3 % vs 90.6 %, p = 0.02) among the 6HE and 4RH regimens, respectively. After adjusting for confounders, 4RH continuation phase treatment regimen adjusted odds ratio (AOR) [(95 % confidence interval (CI)) 0.55 (0.34,0.89)], age [AOR (95 % CI 1.02 (1.001,1.022)], rural residence [AOR (95 % CI) 2.1 (1.18,3.75)] Human Immunodeficiency virus (HIV) positives [AOR (95 % CI) 2.39 (1.12,5.07)] and increased weight at the end of the second month [AOR (95 % CI 0.28 (0.11,0.72)] independently predicted treatment outcome.. The switch of continuation phase TB treatment regimen from 6EH to 4RH has brought better treatment outcomes which imply applicability of the recommendation in high prevalent and resource constrained settings. Therefore, it should be maintained and augmented through further studies on its impact among the older, rural residents and HIV positives.

    Topics: Adult; Antitubercular Agents; Cross-Sectional Studies; Drug Therapy, Combination; Ethambutol; Ethiopia; Female; HIV Seropositivity; Hospitals; Humans; Isoniazid; Logistic Models; Male; Rifampin; Socioeconomic Factors; Treatment Outcome; Tuberculosis

2016
Tuberculosis presenting as a 'swollen calf'.
    BMJ case reports, 2016, Nov-23, Volume: 2016

    We report the case of an 83-year-old man who presented with swelling of his left lower leg. Subsequent investigations revealed that the swelling was due to a Mycobacterium tuberculosis abscess in the tibialis anterior muscle.

    Topics: Abscess; Aged, 80 and over; Antibiotics, Antitubercular; Antitubercular Agents; Diagnosis, Differential; Diagnostic Imaging; Edema; Humans; Isoniazid; Leg; Male; Muscle, Skeletal; Mycobacterium tuberculosis; Recurrence; Rifampin; Tuberculosis

2016
Rapid Detection of Mycobacterium tuberculosis Strains Resistant to Isoniazid and/or Rifampicin: Standardization of Multiplex Polymerase Chain Reaction Analysis.
    The American journal of tropical medicine and hygiene, 2016, Dec-07, Volume: 95, Issue:6

    Drug susceptibility testing using molecular techniques can enhance the identification of drug-resistant Mycobacterium tuberculosis Two multiplex real-time polymerase chain reaction (qPCR) assays were developed to detect the most common resistance-associated mutations to isoniazid (katGS315T, inhA-15C → T), and rifampicin (rpoBH526Y and rpoBS531L). To assess the species specificity of the qPCR, we selected 31 nontuberculous mycobacteria (NTM) reference strains belonging to 17 species from the public collection of mycobacterial cultures (BCCM/ITM). Additionally, we tested 17 isoniazid and/or rifampicin-resistant strains with other mutations in the target genes to assess mutation specificity. The limit of detection for all the targeted mutations was 20 bacilli/reaction. Multiplex 1 showed 90%, 95%, and 100% efficiency for wild type (WT), Mut katGS315T, and Mut rpoBS531L, respectively; whereas Multiplex 2 showed 97%, 94%, and 90% efficiency for WT, Mut inhA-15, and Mut rpoBH526Y, respectively. Three of 17 strains that presented other mutations in the target genes were identified as rifampicin resistant and only 3/31 NTM showed a similar melting temperature to rpoBL531 and/or katGT315 mutants. Thus, our proposed cascade of specific tuberculosis detection followed by drug resistance testing showed sensitivities for katGS315T, rpoBS531L, rpoBH526Y, and inhA-15 detection of 100%, 100%, 100%, and 96%, respectively; and specificities of 98%, 95%, 100%, and 100, respectively.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Humans; Isoniazid; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Time Factors; Tuberculosis

2016
Drug-related hepatitis in patients treated with standard anti-tuberculosis chemotherapy over a 30-year period.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2016, Volume: 20, Issue:12

    Drug-induced hepatitis is known to occur in a proportion of patients on treatment for active tuberculosis (TB).. We prospectively examined the incidence of drug-induced hepatitis in 2070 patients treated for TB with the standard regimen based on 6 months of rifampicin (R, RMP) and isoniazid (H, INH), with 2 months of initial pyrazinamide (Z, PZA) and ethambutol (E, EMB), over a 30-year period from 1981 to 2010, in Blackburn, UK.. Of the 1031 (49.8%) males and 1039 (50.2%) females studied, 451 (21.8%) were White and 1585 (76.6%) were of South Asian origin. Only 34 (1.6%) were of African or other origins. Of the total number of patients treated, 63 (3.0%) had drug-related hepatitis, 26 (5.8%) of whom were White, 37 (2.33%) Asians and 0 other. Incidence was significantly higher in Whites than Asians (OR 2.13, P = 0.008). Incidence increased with increasing age (OR 1.16, P = 0.02). The presumed causative drug was PZA 57%, RMP 32%, INH 11%, EMB 0%. There was no trend of increased hepatitis rates over time.. Rates of drug-induced hepatitis where change of treatment is required are low in patients treated with standard RHZE-based therapy (3%). Caucasians and older patients were more likely to develop hepatitis than their counterparts.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Ethambutol; Female; Follow-Up Studies; Hepatitis; Humans; Incidence; Infant; Infant, Newborn; Isoniazid; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis; Young Adult

2016
Performance of the G4 Xpert
    BMC infectious diseases, 2016, Dec-20, Volume: 16, Issue:1

    An analytical study was performed to assess Xpert detection of mutations associated with rifampin resistance in rifampin-susceptible and -resistant isolates. A clinical study was performed in which specimens from US and non-US persons suspected of tuberculosis (TB) were tested to determine Xpert performance characteristics. All specimens underwent smear microscopy, mycobacterial culture, conventional drug-susceptibility testing and Xpert testing; DNA from isolates with discordant rifampin resistance results was sequenced.. Among 191 laboratory-prepared isolates in the analytical study, Xpert sensitivity for detection of rifampin resistance associated mutations was 97.7% and specificity was 90.8%, which increased to 99.0% after DNA sequencing analysis of the discordant samples. Of the 1,096 subjects in the four clinical studies, 49% were from the US. Overall, Xpert detected MTBc in 439 of 468 culture-positive specimens for a sensitivity of 93.8% (95% confidence interval [CI]: 91.2%-95.7%) and did not detect MTBc in 620 of 628 culture-negative specimens for a specificity of 98.7% (95% CI: 97.5%-99.4%). Sensitivity was 99.7% among smear-positive cases, and 76.1% among smear-negative cases. Non-determinate MTBc detection and false-positive RIF resistance results were low (1.2 and 0.9%, respectively).. The updated Xpert assay retained the high sensitivity and specificity of the previous assay versions and demonstrated low rates of non-determinate and RIF resistance false positive results.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Biological Assay; Case-Control Studies; Developing Countries; DNA, Bacterial; Drug Resistance, Bacterial; False Positive Reactions; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Prevalence; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis; United States; Young Adult

2016
[Performance of GeneXpert MTB / RIF
    The Pan African medical journal, 2016, Volume: 25

    The challenge facing developing countries is the availability of methods for rapid and accurate diagnosis of tuberculosis. Some molecular techniques offer this advantage, so we used GeneXpert MTB / RIF test in the diagnosis of extra-pulmonary tuberculosis to evaluate its performance compared with conventional methods.. Between 2010 and 2015, 544 extrapulmonary clinical specimens were collected and analyzed by microscopy, culture and GeneXpert. The evaluation of antitubercular susceptibility testing was performed using the MGIT 960 system. Genotype MTBDRplus was used to confirm the cases of rifampicin resistance detected by the GX system.. The study population included 544 patients, 55.15% men and 44.85% women. Patients age ranged from 1-92 years with the majority in the 18-45 age group. The sensitivity and the overall specificity of microscopy was 43.86% and 98.36%, 94.74% and 97.95% for GeneXpert. This study shows that the GeneXpert test exhibits high sensitivity for routine diagnosis of extra-pulmonary tuberculosis and should be used instead of microscopy. The cases of rifampicin resistance detected by GeneXpert should be confirmed by other molecular testing methods before initiating treatment.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Genotype; Humans; Infant; Male; Microbial Sensitivity Tests; Microscopy; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Senegal; Sensitivity and Specificity; Tuberculosis; Young Adult

2016
First line anti-tuberculosis induced hepatotoxicity: incidence and risk factors.
    The Pan African medical journal, 2016, Volume: 25

    In our days, tuberculosis, whet ever its localization, became a curable disease. The cornerstone is a 6 month course of isoniazid, rifampicine and pyrazinamide. All of the three first line antituberculosis drugs may induce hepatic damage which may have negative consequences for treatment outcome. Several risk factors were associated with the development of antituberculosis- drug-induced hepatotoxicity (ATDH). A retrospective study was conducted from July 2014 to March 2015 regarding all therapeutic drug-monitoring requests sent to the Laboratory of Poison Control and Pharmacovigilance Centre of Morocco. 142 patients diagnosed with active tuberculosis were included in study. Plasma peak levels of isoniazid, rifampicin and pyrazinamide were analyzed in plasma samples after 2 to 3 hours of administration of anti-tuberculosis treatment. Logistic regression was used to identify the ATDH risk factors. The incidence of ATDH was found 24.6% (35 patients out of 142). Intergroup differences in the plasma levels were statistically significant for isoniazid (p=0.036). ATDH was found to be associated with combined form of anti-TB drugs (p=0.002, COR=13.1, AOR= 13.5) and plasma concentration of INH superior to 2mg/l (p=0.045, COR=1.3, AOR= 1.4).age, gender, alcohol intake and smoking status were not significantly associated with ATDH. The finding of 24.6% incidence of hepatotoxicity is extremely high. Many factors can be associated with the development of ATDH such as genetic factors, combined forms of treatment and plasma peak levels.

    Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Monitoring; Female; Humans; Incidence; Isoniazid; Logistic Models; Male; Middle Aged; Morocco; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors; Tuberculosis

2016
Novel, potent, orally bioavailable and selective mycobacterial ATP synthase inhibitors that demonstrated activity against both replicating and non-replicating M. tuberculosis.
    Bioorganic & medicinal chemistry, 2015, Feb-15, Volume: 23, Issue:4

    The mycobacterial F0F1-ATP synthase (ATPase) is a validated target for the development of tuberculosis (TB) therapeutics. Therefore, a series of eighteen novel compounds has been designed, synthesized and evaluated against Mycobacterium smegmatis ATPase. The observed ATPase inhibitory activities (IC50) of these compounds range between 0.36 and 5.45μM. The lead compound 9d [N-(7-chloro-2-methylquinolin-4-yl)-N-(3-((diethylamino)methyl)-4-hydroxyphenyl)-2,3-dichlorobenzenesulfonamide] with null cytotoxicity (CC50>300μg/mL) and excellent anti-mycobacterial activity and selectivity (mycobacterium ATPase IC50=0.51μM, mammalian ATPase IC50>100μM, and selectivity >200) exhibited a complete growth inhibition of replicating Mycobacterium tuberculosis H37Rv at 3.12μg/mL. In addition, it also exhibited bactericidal effect (approximately 2.4log10 reductions in CFU) in the hypoxic culture of non-replicating M. tuberculosis at 100μg/mL (32-fold of its MIC) as compared to positive control isoniazid [approximately 0.2log10 reduction in CFU at 5μg/mL (50-fold of its MIC)]. The pharmacokinetics of 9d after p.o. and IV administration in male Sprague-Dawley rats indicated its quick absorption, distribution and slow elimination. It exhibited a high volume of distribution (Vss, 0.41L/kg), moderate clearance (0.06L/h/kg), long half-life (4.2h) and low absolute bioavailability (1.72%). In the murine model system of chronic TB, 9d showed 2.12log10 reductions in CFU in both lung and spleen at 173μmol/kg dose as compared to the growth of untreated control group of Balb/C male mice infected with replicating M. tuberculosis H37Rv. The in vivo efficacy of 9d is at least double of the control drug ethambutol. These results suggest 9d as a promising candidate molecule for further preclinical evaluation against resistant TB strains.

    Topics: Adenosine Triphosphate; Animals; Antitubercular Agents; Male; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; Mycobacterium Infections, Nontuberculous; Mycobacterium smegmatis; Mycobacterium tuberculosis; Proton-Translocating ATPases; Quinolines; Rats, Sprague-Dawley; Sulfonamides; Tuberculosis

2015
Syntheses and evaluation of substituted aromatic hydroxamates and hydroxamic acids that target Mycobacterium tuberculosis.
    Bioorganic & medicinal chemistry letters, 2015, Nov-01, Volume: 25, Issue:21

    Tuberculosis (TB) continues to remain one of the most threatening diseases in the world. With the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) strains, the need to develop new therapies is dire. The syntheses of a focused library of hydroxamates and hydroxamic acids is described, as well as anti-TB activity in the microplate alamar blue assay (MABA). A number of compounds exhibited good activity against Mtb, with notable compounds exhibiting MIC values in the range of 20-0.71 μM. This work suggests that both hydroxamates and their free acids may be incorporated into more complex scaffolds and serve as potential leads for the development of anti-TB agents.

    Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Hydrocarbons, Aromatic; Hydroxamic Acids; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis

2015
Pyrrolo[3,4-c]pyridine-1,3(2H)-diones: A Novel Antimycobacterial Class Targeting Mycobacterial Respiration.
    Journal of medicinal chemistry, 2015, Dec-10, Volume: 58, Issue:23

    High-throughput screening of a library of small polar molecules against Mycobacterium tuberculosis led to the identification of a phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing the ester moiety with a methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents was designed and executed to explore structure-activity relationships with respect to the N-benzyl substituent, leading to compounds with nanomolar activity. The frontrunner compound (5h) from these studies was well tolerated in mice. A M. tuberculosis cytochrome bd oxidase deletion mutant (ΔcydKO) was hyper-susceptible to compounds from this series, and a strain carrying a single point mutation in qcrB, the gene encoding a subunit of the menaquinol cytochrome c oxidoreductase, was resistant to compounds in this series. In combination, these observations indicate that this novel class of antimycobacterial compounds inhibits the cytochrome bc1 complex, a validated drug target in M. tuberculosis.

    Topics: Animals; Antitubercular Agents; Electron Transport Complex III; Humans; Mice; Microsomes, Liver; Molecular Targeted Therapy; Mycobacterium tuberculosis; Pyridones; Pyrroles; Rats; Tuberculosis

2015
Pyrazole clubbed triazolo[1,5-a]pyrimidine hybrids as an anti-tubercular agents: Synthesis, in vitro screening and molecular docking study.
    Bioorganic & medicinal chemistry, 2015, Dec-15, Volume: 23, Issue:24

    A series of novel pyrazole linked triazolo-pyrimidine hybrids were synthesized and evaluated for their anti-tuberculosis activity against M.tb H37Rv strain. Some of the screened entities rendered promising anti-tb activity (MIC: 0.39μg/mL) and were found non toxic against Vero cells (IC50: ⩾20μg/mL). Further, the docking study against wild type InhA enzyme of Mycobacterium tuberculosis using Glide reproduced the most active inhibitors (J21 and J27) with lowest binding energies and highest Glide XP scores demonstrating efficient binding to the active pocket. Additionally, the enzyme inhibition assay and ADME prediction of the active proved to be an attest to the possibility of developing compound J27 as a potent anti-tubercular lead.

    Topics: Animals; Antitubercular Agents; Bacterial Proteins; Chlorocebus aethiops; Humans; Molecular Docking Simulation; Mycobacterium tuberculosis; Oxidoreductases; Pyrazoles; Pyrimidines; Triazoles; Tuberculosis; Vero Cells

2015
Formulation of novel sustained release rifampicin-loaded solid lipid microparticles based on structured lipid matrices from Moringa oleifera.
    Pharmaceutical development and technology, 2015, Volume: 20, Issue:5

    To formulate sustained release rifampicin-loaded solid lipid microparticles (SLMs) using structured lipid matrices based on Moringa oil (MO) and Phospholipon 90G (P90G).. Rifampicin-loaded and unloaded SLMs were formulated by melt homogenization and characterized in terms of particle morphology and size, percentage drug content (PDC), pH stability, stability in simulated gastric fluid (SGF, pH 1.2), minimum inhibitory concentration (MIC) and in vitro release. In vivo release was studied in Wistar rats.. Rifampicin-loaded SLMs had particle size range of 32.50 ± 2.10 to 34.0 ± 8.40 μm, highest PDC of 87.6% and showed stable pH. SLMs had good sustained release properties with about 77.1% release at 12 h in phosphate buffer (pH 6.8) and 80.3% drug release at 12 h in simulated intestinal fluid (SIF, pH 7.4). SLMs exhibited 48.51% degradation of rifampicin in SGF at 3 h, while rifampicin pure sample had 95.5% degradation. Formulations exhibited MIC range of 0.781 to 1.562, 31.25 to 62.5 and 6.25 to 12.5 μg/ml against Salmonella typhi, Escherichia coli, and Bacillus subtilis respectively and had higher in vivo absorption than the reference rifampicin (p < 0.05).. Rifampicin-loaded SLMs could be used once daily for the treatment tuberculosis.

    Topics: Animals; Antibiotics, Antitubercular; Delayed-Action Preparations; Lipids; Male; Moringa oleifera; Particle Size; Plant Oils; Rats, Wistar; Rifampin; Tuberculosis

2015
Molecular epidemiology of tuberculosis in Cambodian children.
    Epidemiology and infection, 2015, Volume: 143, Issue:5

    SUMMARY We analysed Mycobacterium tuberculosis strains from children, hospitalized from January 2004 to July 2008 in the largest paediatric hospital complex in Cambodia. Specimens were tested for drug susceptibility and genotypes. From the 260 children, 161 strains were available. The East African-Indian genotype family was the most common (59.0%), increasing in frequency with distance from the Phnom Penh area, while the frequency of the Beijing genotype family strains decreased. The drug resistance pattern showed a similar geographical gradient: lowest in the northwest (4.6%), intermediate in the central (17.1%), and highest in the southeastern (30.8%) parts of the country. Three children (1.9%) had multidrug-resistant tuberculosis. The Beijing genotype and streptomycin resistance were significantly associated (P < 0.001). As tuberculosis in children reflects recent transmission patterns in the community, multidrug resistance levels inform about the current quality of the tuberculosis programme.

    Topics: Adolescent; Antitubercular Agents; Cambodia; Child; Child, Preschool; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Female; Genotype; Humans; Infant; Infant, Newborn; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2015
Population pharmacokinetics of rifampin in the treatment of Mycobacterium tuberculosis in Asian elephants.
    Journal of veterinary pharmacology and therapeutics, 2015, Volume: 38, Issue:2

    The objective of this study was to develop a population pharmacokinetic model for rifampin in elephants. Rifampin concentration data from three sources were pooled to provide a total of 233 oral concentrations from 37 Asian elephants. The population pharmacokinetic models were created using Monolix (version 4.2). Simulations were conducted using ModelRisk. We examined the influence of age, food, sex, and weight as model covariates. We further optimized the dosing of rifampin based upon simulations using the population pharmacokinetic model. Rifampin pharmacokinetics were best described by a one-compartment open model including first-order absorption with a lag time and first-order elimination. Body weight was a significant covariate for volume of distribution, and food intake was a significant covariate for lag time. The median Cmax of 6.07 μg/mL was below the target range of 8-24 μg/mL. Monte Carlo simulations predicted the highest treatable MIC of 0.25 μg/mL with the current initial dosing recommendation of 10 mg/kg, based upon a previously published target AUC0-24/MIC > 271 (fAUC > 41). Simulations from the population model indicate that the current dose of 10 mg/kg may be adequate for MICs up to 0.25 μg/mL. While the targeted AUC/MIC may be adequate for most MICs, the median Cmax for all elephants is below the human and elephant targeted ranges.

    Topics: Animals; Antitubercular Agents; Area Under Curve; Elephants; Female; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2015
Anti-tuberculosis treatments and risk of hepatocellular carcinoma in tuberculosis patients with liver cirrhosis: a population-based case-control study.
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2015, Volume: 34, Issue:3

    The objective of this study was to evaluate the association between the use of anti-tuberculosis (anti-TB) agents, isoniazid (INH), rifampicin (RIF), and their combination (INH + RIF), and the risk of hepatocellular carcinoma (HCC) in cirrhotic patients. This population-based case-control study was conducted using a research database of Taiwan's National Health Insurance program. Cirrhotic patients first diagnosed with HCC between 1996 and 2011 (n = 50,351), among whom 4,738 were anti-TB medication users, were evaluated. Cirrhotic patients who did not develop HCC within the same period, frequency-matched according to age, sex, and index year, were evaluated as the control group (n = 47,488). The adjusted odds ratio (OR) of HCC was 1.34 [95 % confidence interval (CI), 1.20-1.50] in INH + RIF users compared with non-INH + RIF users. Long-term (>12 months) use of INH, RIF, and INH + RIF was significantly associated with increased risk of HCC, with an adjusted OR of 3.51 (95 % CI, 2.11-5.84), 4.17 (95 % CI, 2.76-4.31), and 7.17 (95 % CI, 4.08-12.6), respectively, after adjusting for age, sex, and comorbidities. An average dose of INH + RIF >16,050 mg/year was associated with increased risk of HCC in cirrhotic patients, with an adjusted OR of 1.48 (95 % CI, 1.27-1.73). Our results indicate that cirrhotic patients with long-term or high-dose INH and RIF treatment, particularly their combination, are associated with increased risk of HCC development.

    Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Carcinoma, Hepatocellular; Case-Control Studies; Drug Therapy, Combination; Female; Humans; Isoniazid; Liver Cirrhosis; Male; Middle Aged; Rifampin; Risk; Risk Assessment; Taiwan; Tuberculosis; Young Adult

2015
Investigating gender disparities in the profile and treatment outcomes of tuberculosis in Ebonyi state, Nigeria.
    Epidemiology and infection, 2015, Volume: 143, Issue:5

    SUMMARY Globally, twice as many men as women are being diagnosed with tuberculosis (TB) annually. Little is known about gender differentials in TB in Africa. A retrospective cohort analysis of routine data was conducted on adult TB patients treated between 2011 and 2012 in two large healthcare facilities in Nigeria. Gender differences in their demographic characteristics and treatment outcomes were analysed accordingly. Of 1668 TB patients enrolled, the male:female ratio was 1.4:1. The mean ages of males and females were 40.2 ± 14.7 and 36.1 ± 14.6 years, respectively (t test 6.62, P < 0.001). Male gender was associated with a higher failure to smear convert after 2 months (21.8% vs. 17.5%, P = 0.06) and 5 months (4.3% vs. 1.5%, P = 0.02) of treatment for smear-positive TB patients. Moreover, men were more likely than women to fail treatment (2.2% vs. 0.7%, P = 0.01). No significant differences exist in the treatment success rates between women and men (78.2% vs. 74.5%, P = 0.08). Adjusted analyses showed significant association between being an urban male and a HIV-infected female with unsuccessful outcome adjusted by socio-demographic and clinical factors. We found that gender disparities exist in TB profile and treatment outcomes in Nigeria and gender-specific strategies are needed to optimize TB management.

    Topics: Adult; Antitubercular Agents; Cohort Studies; Coinfection; Ethambutol; Female; Health Status Disparities; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Nigeria; Pyrazinamide; Retrospective Studies; Rifampin; Rural Population; Sex Factors; Streptomycin; Time Factors; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary; Urban Population; Young Adult

2015
Comprehensive phenotypic characterization of rifampicin resistance mutations in Salmonella provides insight into the evolution of resistance in Mycobacterium tuberculosis.
    The Journal of antimicrobial chemotherapy, 2015, Volume: 70, Issue:3

    Mutations in the β-subunit of RNA polymerase (RNAP), encoded by rpoB, are responsible for rifampicin resistance (Rif(R)). Although many mutations in rpoB can reduce susceptibility, only a few are frequent amongst Rif(R) clinical Mycobacterium tuberculosis (MTB) isolates. It has been suggested that there is a negative correlation between the fitness costs of Rif(R) mutations and their respective clinical frequency, but so far comparable fitness cost measurements have only been conducted for a very limited number of Rif(R) mutations. We tested this hypothesis using Salmonella and Mycobacterium smegmatis as model organisms.. We constructed 122 different Rif(R) mutations in Salmonella. MICs and relative fitness costs in the presence and absence of rifampicin were determined for each mutant, including for a smaller number of Rif(R) M. smegmatis strains. Results were compared with available mutation frequency data from clinical MTB isolates.. (i) Rif(R) mutations frequently found in MTB isolates have a fitness cost in Salmonella Typhimurium and M. smegmatis. (ii) Clinically frequent Rif(R) mutations have a high rifampicin MIC. (iii) There is a strong correlation between the magnitude of the fitness cost of a Rif(R) mutation in Salmonella Typhimurium or M. smegmatis and the frequency with which that mutation is associated with secondary (putative compensatory) mutations in RNAP of clinical MTB isolates.. This suggests that the success of Rif(R) mutations in clinical MTB isolates may be dependent not only on a low initial fitness cost, but rather the results of three factors: (i) a high rifampicin MIC; (ii) a relatively low initial fitness cost; and (iii) the ability to additionally acquire compensatory mutations selected to further reduce fitness cost.

    Topics: Anti-Bacterial Agents; DNA Mutational Analysis; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Evolution, Molecular; Humans; Microbial Sensitivity Tests; Mutation; Mutation Rate; Mycobacterium smegmatis; Mycobacterium tuberculosis; Rifampin; Salmonella typhimurium; Tuberculosis

2015
Ursolic Acid Activates Intracellular Killing Effect of Macrophages During Mycobacterium tuberculosis Infection.
    Journal of microbiology and biotechnology, 2015, Volume: 25, Issue:5

    Tuberculosis is one of the most threatening infectious diseases to public health all over the world, for which Mycobacterium tuberculosis (MTB) is the etiological agent of pathogenesis. Ursolic acid (UA) has immunomodulatory function and exhibits antimycobacterial activity. However, the intracellular killing effect of UA has yet to be elucidated. The aim of this study was to evaluate the intracellular killing effect of UA during mycobacterial infection. The intracellular killing activity of UA was evaluated in the macrophage cell line THP-1 by the MGIT 960 system as well as by CFU count. The production of reactive oxygen species (ROS) and the level of nitric oxide (NO) were measured using DCF-DA and Griess reagent, respectively. Phagocytosis was observed by a fluorescence-based staining method, and the colony forming units were enumerated on 7H11 agar medium following infection. In addition, MRP8 mRNA expression was measured by qRT-PCR. UA significantly decreased the number of intracellular Mycobacterium through generation of ROS and NO. In addition, it profoundly activated the phagocytosis process of THP-1 cells during MTB-infection. Furthermore, our data demonstrated that UA activated the phagocytosis process in human monocyte cells through MRP8 induction. These data suggest that UA firmly contributes to the intracellular killing effect of macrophages during mycobacterial infection.

    Topics: Antitubercular Agents; ATP-Binding Cassette Transporters; Cell Line; Cell Survival; Host-Pathogen Interactions; Humans; Intracellular Space; Isoniazid; Macrophages; Mycobacterium tuberculosis; Reactive Oxygen Species; Rifampin; Triterpenes; Tuberculosis; Ursolic Acid

2015
A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment.
    Journal of theoretical biology, 2015, Feb-21, Volume: 367

    While active tuberculosis (TB) is a treatable disease, many complex factors prevent its global elimination. Part of the difficulty in developing optimal therapies is the large design space of antibiotic doses, regimens and combinations. Computational models that capture the spatial and temporal dynamics of antibiotics at the site of infection can aid in reducing the design space of costly and time-consuming animal pre-clinical and human clinical trials. The site of infection in TB is the granuloma, a collection of immune cells and bacteria that form in the lung, and new data suggest that penetration of drugs throughout granulomas is problematic. Here we integrate our computational model of granuloma formation and function with models for plasma pharmacokinetics, lung tissue pharmacokinetics and pharmacodynamics for two first line anti-TB antibiotics. The integrated model is calibrated to animal data. We make four predictions. First, antibiotics are frequently below effective concentrations inside granulomas, leading to bacterial growth between doses and contributing to the long treatment periods required for TB. Second, antibiotic concentration gradients form within granulomas, with lower concentrations toward their centers. Third, during antibiotic treatment, bacterial subpopulations are similar for INH and RIF treatment: mostly intracellular with extracellular bacteria located in areas non-permissive for replication (hypoxic areas), presenting a slowly increasing target population over time. Finally, we find that on an individual granuloma basis, pre-treatment infection severity (including bacterial burden, host cell activation and host cell death) is predictive of treatment outcome.

    Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Calibration; Computer Simulation; Disease Models, Animal; Dose-Response Relationship, Drug; Granuloma; Humans; Immunity; Isoniazid; Mice; Models, Biological; Mycobacterium tuberculosis; Primates; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

2015
Molecular analysis of codon 548 in the rpoB gene involved in Mycobacterium tuberculosis resistance to rifampin.
    Antimicrobial agents and chemotherapy, 2015, Volume: 59, Issue:3

    Most Mycobacterium tuberculosis rifampin-resistant strains have been associated with mutations in an 81-bp rifampin resistance-determining region (RRDR) in the gene rpoB. However, if this region alone were targeted, rifampin-resistant strains with mutations outside the RRDR would not be detected. In this study, among 51 rifampin-resistant clinical isolates analyzed by sequencing 1,681-bp-long DNA fragments containing the RRDR, 47 isolates contained mutations within the RRDR, three isolates contained mutations both within and outside the RRDR, and only one isolate had a single missense mutation (Arg548His) located outside the RRDR. A drug susceptibility test of recombinant Mycobacterium smegmatis and M. tuberculosis isolates carrying mutated rpoB (Arg548His) showed an increased MIC for rifampin compared to that of the control strains. Modeling of the Arg548His mutant RpoB-DNA complex revealed that the His548 side chain formed a more stable hydrogen bond structure than did Arg548, reducing the flexibility of the rifampin-resistant cluster II region of RpoB, suggesting that the RpoB Arg548His mutant does not effectively interact with rifampin and results in bacterial resistance to the drug. This is the first report on the relationship between the mutation in codon 548 of RpoB and rifampin resistance in tuberculosis. The novel mutational profile of the rpoB gene described here will contribute to the comprehensive understanding of rifampin resistance patterns and to the development of a useful tool for simple and rapid drug susceptibility tests.

    Topics: Amino Acid Sequence; Antibiotics, Antitubercular; Bacterial Proteins; Codon; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Molecular Sequence Data; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2015
Outcomes from treating tuberculosis with rifampicin or rifabutin in HIV-infected persons also receiving antiretroviral therapy.
    Journal of acquired immune deficiency syndromes (1999), 2015, Apr-15, Volume: 68, Issue:5

    Topics: Adult; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Female; HIV Infections; Humans; Male; Retrospective Studies; Rifabutin; Rifampin; Treatment Outcome; Tuberculosis; United Kingdom

2015
Disputed rpoB mutations can frequently cause important rifampicin resistance among new tuberculosis patients.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:2

    Greater Mymensingh area, Bangladesh.. To document among new tuberculosis (TB) patients the proportions and treatment outcomes of silent, non-disputed and disputed (generally missed by rapid drug susceptibility testing [DST]) rpoB mutations, and their detection by commercial molecular assays.. Retrospective analysis of rpoB sequences from randomly selected ethanol-preserved diagnostic sputum samples; comparison of sequencing with conventional DST results and standard first-line treatment outcome; retesting of samples with mutations using the Xpert MTB/RIF and GenoType MTBDRplus assays.. Of 1091 samples, 5.8% failed amplification, and six contained other mycobacteria. In 2005 and 2010, respectively 2/500 (0.4%) and 11/522 (2.1%) amplicons showed non-silent mutations. At least 7/13 of these belonged to the disputed group, with 5/7 patients suffering adverse treatment outcome. One silent mutation went undetected by commercial assays. Following routine DST indications, only three cases with a non-silent mutation were eventually detected.. Disputed rpoB mutations may be responsible for the majority of rifampicin (RMP) resistance among new cases, and lead to adverse outcomes of first-line treatment. Silent mutations do not necessarily cause Xpert or line-probe assay false RMP-resistant results. Molecular RMP DST could greatly simplify resistance surveillance, in addition to offering the best prospects for early and accurate individual diagnosis.

    Topics: Antitubercular Agents; Bacterial Proteins; Bangladesh; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Retrospective Studies; Rifampin; Sputum; Tuberculosis

2015
Serum drug concentrations of INH and RMP predict 2-month sputum culture results in tuberculosis patients.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:2

    In Alberta provincial tuberculosis (TB) clinics, serum drug concentrations (SDCs) are measured in patients with human immunodeficiency virus, diabetes mellitus or at extremes of weight, or showing slow clinical response to treatment, to guide treatment.. A retrospective review was performed of TB cases in Northern Alberta with SDCs measured from 1998 to 2013. Adequacy of SDC was based on the maximum concentration (Cmax) achieved in serum, with rifampicin (RMP) values <8 μg/ml and isoniazid (INH) values <3 μg/ml for daily dosing and <9 μg/ml for intermittent dosing considered inadequate. Clinical variables and microbiological outcomes were then compared between the adequate and inadequate groups.. Of 134 pulmonary TB cases with SDCs for INH and/or RMP, we found a significant increase in 2-month sputum culture positivity in the cohort with inadequate concentrations of INH compared to those with adequate INH concentrations (42.5% vs. 18.3%, P = 0.0084). A similar trend was seen in the cohort with inadequate concentrations of RMP (39% vs. 21%, P = 0.0725).. Among our study population, low SDCs of INH and, to a lesser extent, RMP, appear to be associated with reduced sputum culture conversion after 2 months of treatment.

    Topics: Adult; Aged; Alberta; Antitubercular Agents; Female; Humans; Isoniazid; Male; Middle Aged; Retrospective Studies; Rifampin; Sputum; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary

2015
Label-free DNA-based detection of Mycobacterium tuberculosis and rifampicin resistance through hydration induced stress in microcantilevers.
    Analytical chemistry, 2015, Feb-03, Volume: 87, Issue:3

    We have developed a label-free assay for the genomic detection of Mycobacterium tuberculosis and rifampicin resistance. The method relies on the quantification of the hydration induced stress on microcantilever biosensors functionalized with oligonucleotide probes, before and after hybridization with specific targets. We have found a limit of detection of 10 fg/mL for PCR amplified products of 122 bp. Furthermore, the technique can successfully target genomic DNA (gDNA) fragments of length >500 bp, and it can successfully discriminate single mismatches. We have used both loci IS6110 and rpoB as targets to detect the mycobacteria and the rifampicin resistance from gDNA directly extracted from bacterial culture and without PCR amplification. We have been able to detect 2 pg/mL target concentration in samples with an excess of interfering DNA and in a total analysis time of 1 h and 30 min. The detection limit found demonstrates the capability to develop direct assays without the need for long culture steps or PCR amplification. The methodology can be easily translated to different microbial targets, and it is suitable for further development of miniaturized devices and multiplexed detection.

    Topics: Antibiotics, Antitubercular; Biosensing Techniques; DNA, Bacterial; Equipment Design; Humans; Limit of Detection; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Oligonucleotide Probes; Rifampin; Tuberculosis

2015
In reply to 'False-positive Xpert® MTB/RIF assays in previously treated patients'.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:3

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Respiratory Tract Infections; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2015
Synergy of chemotherapy and immunotherapy revealed by a genome-scale analysis of murine tuberculosis.
    The Journal of antimicrobial chemotherapy, 2015, Volume: 70, Issue:6

    Although TB immunotherapy improves the results of conventional drug treatment, the effects of combining chemotherapy and immunotherapy have never been systematically evaluated. We used a comprehensive lung transcriptome analysis to directly compare the activity of combined chemotherapy and immunotherapy with that of single treatments in a mouse model of TB.. Mycobacterium tuberculosis-infected mice in the chronic phase of the disease (day 30) received: (i) isoniazid and rifampicin (drugs) daily for 30 days; (ii) DNA immunotherapy (DNA), consisting of four 100 μg injections at 10 day intervals; (iii) both therapies (DNA + drugs); or (iv) saline. The effects were evaluated 10 days after the end of treatment (day 70 post-infection).. In all groups a systemic reduction in the load of bacilli was observed, bacilli became undetectable in the drugs and DNA + drugs groups, but the whole lung transcriptome analysis showed 867 genes exclusively modulated by the DNA + drugs combination. Gene enrichment analysis indicated that DNA + drugs treatment provided synergistic effects, including the down-regulation of proinflammatory cytokines and mediators of fibrosis, as confirmed by real-time PCR, ELISA, histopathology and hydroxyproline assay.. Our results provide a molecular basis for the advantages of TB treatment using combined chemotherapy and DNA immunotherapy and demonstrate the synergistic effects obtained with this strategy.

    Topics: Animals; Antitubercular Agents; Combined Modality Therapy; Disease Models, Animal; Drug Therapy; Gene Expression Profiling; Immunotherapy; Isoniazid; Lung; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis; Vaccines, DNA

2015
Cavitary tuberculosis and tracheal stenosis simulating granulomatosis with polyangiitis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:3

    Topics: Adult; Antitubercular Agents; Dose-Response Relationship, Drug; Female; Granulomatosis with Polyangiitis; Humans; Isoniazid; Methotrexate; Mycobacterium tuberculosis; Prednisone; Rifampin; Tomography, X-Ray Computed; Tracheal Stenosis; Tuberculosis

2015
Limb deformity in a newborn. Is rifampicin just an innocent bystander?
    European review for medical and pharmacological sciences, 2015, Volume: 19, Issue:3

    The first-line antituberculous agents for use during pregnancy have minimal teratogenic effects. The possibility of limb deformity during rifampin use, however, was reported by some researchers.. A male newborn was born with a hypoplastic right forearm to a mother with tuberculosis who used isoniazid and rifampicin in the first two months of her pregnancy.. The limb anomaly in our case might be attributed to rifampicin usage during the first 2 months of pregnancy. Caution should be given with regard to possible congenital malformations which could be associated with the treatment of pregnant women with antituberculous drugs.

    Topics: Antitubercular Agents; Female; Humans; Infant, Newborn; Male; Pregnancy; Pregnancy Complications, Infectious; Rifampin; Tuberculosis; Upper Extremity Deformities, Congenital; Young Adult

2015
Combined effect of CYP2B6 and NAT2 genotype on plasma efavirenz exposure during rifampin-based antituberculosis therapy in the STRIDE study.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015, Jun-15, Volume: 60, Issue:12

    In STRIDE, slow metabolizer CYP2B6 and NAT2 genotypes were each associated with increased plasma efavirenz concentrations during antituberculosis therapy. Concentrations were greater on therapy than off therapy in 58% with CYP2B6 and 93% with NAT2 slow metabolizer genotypes. Individuals with slow metabolizer genotypes in both genes had markedly elevated concentrations.

    Topics: Alkynes; Antitubercular Agents; Arylamine N-Acetyltransferase; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Female; Genotype; HIV Infections; Humans; Male; Peru; Pharmacogenetics; Rifampin; South Africa; Tuberculosis; Uganda

2015
Triage tests: a new priority for tuberculosis diagnostics.
    The Lancet. Respiratory medicine, 2015, Volume: 3, Issue:3

    Topics: Biomarkers; Early Diagnosis; Humans; Point-of-Care Testing; Rifampin; Sensitivity and Specificity; Sputum; Triage; Tuberculosis

2015
Reply to Daskapan et al.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015, Jul-01, Volume: 61, Issue:1

    Topics: Antitubercular Agents; Female; HIV Infections; Humans; Male; Rifampin; Tuberculosis

2015
The Never Ending Struggle Against Development of Drug Resistance.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015, Jul-01, Volume: 61, Issue:1

    Topics: Antitubercular Agents; Female; HIV Infections; Humans; Male; Rifampin; Tuberculosis

2015
Safe and effective treatment for patients with isoniazid drug resistance.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:4

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Ethambutol; Female; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Tuberculosis

2015
False-positive Xpert(®) MTB/RIF assays and previous treatment.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:4

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Respiratory Tract Infections; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2015
In reply.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:4

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Ethambutol; Female; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Tuberculosis

2015
Use of Mycobacterium smegmatis deficient in ADP-ribosyltransferase as surrogate for Mycobacterium tuberculosis in drug testing and mutation analysis.
    PloS one, 2015, Volume: 10, Issue:4

    Rifampicin (Rif) is a first line drug used for tuberculosis treatment. However, the emergence of drug resistant strains has necessitated synthesis and testing of newer analogs of Rif. Mycobacterium smegmatis is often used as a surrogate for M. tuberculosis. However, the presence of an ADP ribosyltransferase (Arr) in M. smegmatis inactivates Rif, rendering it impractical for screening of Rif analogs or other compounds when used in conjunction with them (Rif/Rif analogs). Rifampicin is also used in studying the role of various DNA repair enzymes by analyzing mutations in RpoB (a subunit of RNA polymerase) causing Rif resistance. These analyses use high concentrations of Rif when M. smegmatis is used as model. Here, we have generated M. smegmatis strains by deleting arr (Δarr). The M. smegmatis Δarr strains show minimum inhibitory concentration (MIC) for Rif which is similar to that for M. tuberculosis. The MICs for isoniazid, pyrazinamide, ethambutol, ciprofloxacin and streptomycin were essentially unaltered for M. smegmatis Δarr. The growth profiles and mutation spectrum of Δarr and, Δarr combined with ΔudgB (udgB encodes a DNA repair enzyme that excises uracil) strains were similar to their counterparts wild-type for arr. However, the mutation spectrum of ΔfpgΔarr strain differed somewhat from that of the Δfpg strain (fpg encodes a DNA repair enzyme that excises 8-oxo-G). Our studies suggest M. smegmatis Δarr strain as an ideal model system in drug testing and mutation spectrum determination in DNA repair studies.

    Topics: ADP Ribose Transferases; Amino Acid Sequence; DNA Mutational Analysis; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium smegmatis; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2015
An interlaboratory quality control programme for the measurement of tuberculosis drugs.
    The European respiratory journal, 2015, Volume: 46, Issue:1

    Topics: Antitubercular Agents; Drug Administration Schedule; Drug Monitoring; Humans; Immunoassay; Isoniazid; Laboratories; Pyrazinamide; Quality Control; Reference Standards; Reproducibility of Results; Rifampin; Tuberculosis

2015
CYP2B6*6, CYP2B6*18, Body weight and sex are predictors of efavirenz pharmacokinetics and treatment response: population pharmacokinetic modeling in an HIV/AIDS and TB cohort in Zimbabwe.
    BMC pharmacology & toxicology, 2015, Mar-27, Volume: 16

    Efavirenz (EFV) therapeutic response and toxicity are associated with high inter-individual variability attributed to variation in its pharmacokinetics. Plasma concentrations below 1 μg/ml may result in virologic failure and above 4 μg/ml, may result in central nervous system adverse effects. This study used population pharmacokinetics modeling to explore the influence of demographic and pharmacogenetic factors including efavirenz-rifampicin interaction on EFV pharmacokinetics, towards safer dosing of EFV.. Patients receiving an EFV-based regimen for their antiretroviral therapy and a rifampicin-containing anti-TB regimen were recruited. EFV plasma concentrations were measured by HPLC and genomic DNA genotyped for variants in the CYP2B6, CYP2A6 and ABCB1 genes. All patients were evaluated for central nervous system adverse effects characterised as sleep disorders, hallucinations and headaches using the WHO ADR grading system. A pharmacokinetic model was built in a forward and reverse procedure using nonlinear mixed effect modeling in NONMEM VI followed by model-based simulations for optimal doses.. CYP2B6*6 and *18 variant alleles, weight and sex were the most significant covariates explaining 55% of inter-individual variability in EFV clearance. Patients with the CYP2B6*6TT genotype had a 63% decrease in EFV clearance despite their CYP2B6*18 genotypes with females having 22% higher clearance compared to males. There was a 21% increase in clearance for every 10 kg increase in weight. The effect of TB/HIV co-treatment versus HIV treatment only was not statistically significant. No clinically relevant association between CYP2B6 genotypes and CNS adverse effects was seen, but patients with CNS adverse effects had a 27% lower clearance compared to those without. Model- based simulations indicated that all carriers of CYP2B6*6 TT genotype would be recommended a dose reduction to 200 mg/day, while the majority of extensive metabolisers may be given 400 mg/day and still maintain therapeutic levels.. This study showed that screening for CYP2B6 functional variants has a high predictability for efavirenz plasma levels and could be used in prescribing optimal and safe EFV doses.

    Topics: Acquired Immunodeficiency Syndrome; Adult; Alkynes; Alleles; Anti-HIV Agents; ATP Binding Cassette Transporter, Subfamily B; Benzoxazines; Body Weight; Case-Control Studies; Cyclopropanes; Cytochrome P-450 CYP2A6; Cytochrome P-450 CYP2B6; Drug Interactions; Female; Hallucinations; Headache; Humans; Male; Models, Biological; Rifampin; Sex Characteristics; Sleep Wake Disorders; Tuberculosis; Zimbabwe

2015
Mixed Infections and Rifampin Heteroresistance among Mycobacterium tuberculosis Clinical Isolates.
    Journal of clinical microbiology, 2015, Volume: 53, Issue:7

    Mixed infections and heteroresistance of Mycobacterium tuberculosis contribute to the difficulty of diagnosis, treatment, and control of tuberculosis. However, there is still no proper solution for these issues. This study aimed to investigate the potential relationship between mixed infections and heteroresistance and to determine the high-risk groups related to these factors. A total of 499 resistant and susceptible isolates were subjected to spoligotyping and 24-locus variable-number tandem repeat methods to analyze their genotypic lineages and the occurrence of mixed infections. Two hundred ninety-two randomly selected isolates were sequenced on their rpoB gene to examine mutations and heteroresistance. The results showed that 12 patients had mixed infections, and the corresponding isolates belonged to Manu2 (n = 8), Beijing (n = 2), T (n = 1), and unknown (n = 1) lineages. Manu2 was found to be significantly associated with mixed infections (odds ratio, 47.72; confidence interval, 9.68 to 235.23; P < 0.01). Four isolates (1.37%) were confirmed to be heteroresistant, which was caused by mixed infections in three (75%) isolates; these belonged to Manu2. Additionally, 3.8% of the rifampin-resistant isolates showing no mutation in the rpoB gene were significantly associated with mixed infections (χ(2), 56.78; P < 0.01). This study revealed for the first time that Manu2 was the predominant group in the cases of mixed infections, and this might be the main reason for heteroresistance and a possible mechanism for isolates without any mutation in the rpoB gene to become rifampin resistant. Further studies should focus on this lineage to clarify its relevance to mixed infections.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Child; Child, Preschool; Coinfection; Cross-Sectional Studies; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Female; Genotype; Humans; Male; Middle Aged; Molecular Typing; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sequence Analysis, DNA; Tuberculosis; Young Adult

2015
A Novel Reporter Phage To Detect Tuberculosis and Rifampin Resistance in a High-HIV-Burden Population.
    Journal of clinical microbiology, 2015, Volume: 53, Issue:7

    Improved diagnostics and drug susceptibility testing for Mycobacterium tuberculosis are urgently needed. We developed a more powerful mycobacteriophage (Φ(2)GFP10) with a fluorescent reporter. Fluorescence-activated cell sorting (FACS) allows for rapid enumeration of metabolically active bacilli after phage infection. We compared the reporter phage assay to GeneXpert MTB/RIF for detection of M. tuberculosis and rifampin (RIF) resistance in sputum. Patients suspected to have tuberculosis were prospectively enrolled in Durban, South Africa. Sputum was incubated with Φ(2)GFP10, in the presence and absence of RIF, and bacilli were enumerated using FACS. Sensitivity and specificity were compared to those of GeneXpert MTB/RIF with an M. tuberculosis culture as the reference standard. A total of 158 patients were prospectively enrolled. Overall sensitivity for M. tuberculosis was 95.90% (95% confidence interval (CI), 90.69% to 98.64%), and specificity was 83.33% (95% CI, 67.18% to 93.59%). In acid-fast bacillus (AFB)-negative sputum, sensitivity was 88.89% (95% CI, 73.92% to 96.82%), and specificity was 83.33% (95% CI, 67.18% to 93.59%). Sensitivity for RIF-resistant M. tuberculosis in AFB-negative sputum was 90.00% (95% CI, 55.46% to 98.34%), and specificity was 91.94% (95% CI, 82.16% to 97.30%). Compared to GeneXpert, the reporter phage was more sensitive in AFB smear-negative sputum, but specificity was lower. The Φ(2)GFP10 reporter phage showed high sensitivity for detection of M. tuberculosis and RIF resistance, including in AFB-negative sputum, and has the potential to improve phenotypic testing for complex drug resistance, paucibacillary sputum, response to treatment, and detection of mixed infection in clinical specimens.

    Topics: Adolescent; Adult; Antitubercular Agents; Bacteriological Techniques; Drug Resistance, Bacterial; Female; Flow Cytometry; Fluorescence; Fluorometry; Genes, Reporter; Green Fluorescent Proteins; Humans; Male; Middle Aged; Mycobacteriophages; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; South Africa; Sputum; Staining and Labeling; Tuberculosis; Young Adult

2015
High mortality associated with retreatment of tuberculosis in a clinic in Kampala, Uganda: a retrospective study.
    The American journal of tropical medicine and hygiene, 2015, Volume: 93, Issue:1

    The World Health Organization recommends for tuberculosis retreatment a regimen of isoniazid (H), rifampicin (R), ethambutol (E), pyrazinamide (Z), and streptomycin (S) for 2 months, followed by H, R, E, and Z for 1 month and H, R, and E for 5 months. Using data from the National Tuberculosis and Leprosy Program registry, this study determined the long-term outcome under programmatic conditions of patients who were prescribed the retreatment regimen in Kampala, Uganda, between 1997 and 2003. Patients were traced to determine their vital status; 62% (234/377) patients were found dead. Having ≤ 2 treatment courses and not completing retreatment were associated with mortality in adjusted analyses.

    Topics: Adult; Antitubercular Agents; Coinfection; Ethambutol; Female; Follow-Up Studies; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Proportional Hazards Models; Pyrazinamide; Recurrence; Retreatment; Retrospective Studies; Rifampin; Streptomycin; Survival Rate; Treatment Failure; Treatment Outcome; Tuberculosis; Uganda

2015
Pharmacokinetics of Inhaled Rifampicin Porous Particles for Tuberculosis Treatment: Insight into Rifampicin Absorption from the Lungs of Guinea Pigs.
    Molecular pharmaceutics, 2015, Aug-03, Volume: 12, Issue:8

    Tuberculosis (TB) is a life-threatening infection that requires a lengthy treatment process that is often associated with adverse effects. Pulmonary delivery of anti-TB drugs has the potential to increase efficacy of treatment by increasing drug concentrations at the lungs, the primary site of infection. The aim of the present study is to evaluate the disposition of rifampicin (RIF) after its pulmonary administration as porous particles (PPs) to guinea pigs and contrast it to that after oral administration. RIF microparticles were prepared by spray drying a solution of RIF and L-leucine (9:1), and the resulting particles were characterized for their physicochemical properties. Animals received RIF either as intravenous solution (iv), as oral suspension of micronized RIF (ORS) and RIF-PPs (ORPP), or by insufflation of the PPs (IRPP). Plasma samples were collected at preselected time points, and bronchoalveolar lavage (BAL) was performed at the end of the study. RIF concentrations in biological samples were analyzed by HPLC. Plasma concentration versus time data was analyzed by compartmental and noncompartmental methods. RIF PPs were thin walled porous particles with mass median aerodynamic diameter (MMAD) of 4.8±0.1 μm, GSD=1.29±0.03, and fine particle fraction below 5.8 μm of 52.9±2.0%. RIF content in the resulting particles was 91.8±0.1%. Plasma concentration vs time profiles revealed that the terminal slope of the iv group was different from that of the oral or pulmonary groups, indicating the possibility of flip-flop kinetics. RIF from IRPP appeared to be absorbed faster than that of ORPP or ORS as evidenced by higher RIF plasma concentrations up until 2 h. Notably, similar AUC (when corrected by dose), similar CL, λ, and half-life were obtained after oral administration of RIF at 40 mg/kg and pulmonary administration of RIF at 20 mg/kg. However, RIF in the IRPP group had a shorter Tmax and higher bioavailability than orally dosed groups. In addition, RIF concentrations in the BAL of animals in the IRPP group were 3-4-fold larger than those in the orally dosed groups. The disposition in ORS and ORPP were best described by a model with two sequential compartments, whereas the disposition of IRPP was best described by a two parallel compartment model. The advantages of delivering RIF by the pulmonary route are demonstrated in the present study. These include achieving higher RIF concentrations in the lungs and similar systemic levels after pulmonary deli

    Topics: Administration, Inhalation; Administration, Oral; Animals; Antibiotics, Antitubercular; Dry Powder Inhalers; Guinea Pigs; Lung; Male; Microspheres; Oral Sprays; Porosity; Respiratory Tract Absorption; Rifampin; Tuberculosis

2015
SILA-421 activity in vitro against rifampicin-susceptible and rifampicin-resistant Mycobacterium tuberculosis, and in vivo in a murine tuberculosis model.
    International journal of antimicrobial agents, 2015, Volume: 46, Issue:1

    Due to the emergence of multidrug-resistant and extensively drug-resistant tuberculosis (TB), there is an urgent need for new TB drugs or for compounds that improve the efficacy of currently used drugs. In this study, time-kill kinetics of SILA-421 as a single drug and in combination with isoniazid (INH), rifampicin (RIF), moxifloxacin (MXF) or amikacin (AMK) against Mycobacterium tuberculosis were assessed. Therapeutic efficacy in vivo in a mouse TB model was also studied. Further in vitro analysis was performed with a RIF-susceptible and RIF-resistant strains of M. tuberculosis. When used as a single drug, SILA-421 in vitro showed concentration-dependent and time-dependent bactericidal activity. SILA-421 also enhanced the activity of INH and RIF, resulting in synergy in the case of INH. Emergence of INH resistance following exposure to INH can be prevented by the addition SILA-421. SILA-421 had no additional value in combination with MXF or AMK. Furthermore, SILA-421 enhanced the activity of RIF towards a RIF-resistant strain and resulted in complete elimination of RIF-resistant mycobacteria. Unfortunately, in mice with TB induced by a Beijing genotype strain, addition of SILA-421 to an isoniazid-rifampicin-pyrazinamide regimen for 13 weeks did not result in enhanced therapeutic efficacy.

    Topics: Animals; Antitubercular Agents; Disease Models, Animal; Drug Resistance, Bacterial; Drug Synergism; Drug Therapy, Combination; Female; Mice, Inbred BALB C; Microbial Viability; Mycobacterium tuberculosis; Piperazines; Rifampin; Siloxanes; Treatment Outcome; Tuberculosis

2015
Is Europe ready to reach tuberculosis elimination? An outbreak report from Southern Italy.
    The European respiratory journal, 2015, Volume: 46, Issue:1

    Topics: Adult; Child, Preschool; Communicable Disease Control; Contact Tracing; Disease Outbreaks; Ethambutol; Europe; Female; Humans; Incidence; Interferon-gamma Release Tests; Isoniazid; Italy; Male; Pyrazinamide; Rifampin; Tomography, X-Ray Computed; Tuberculosis

2015
Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis.
    Antimicrobial agents and chemotherapy, 2015, Volume: 59, Issue:8

    Rifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0-24 values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n = 1,000). The geometric mean AUC0-24 value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with an r(2) value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of -0.4%. This study showed that the rifampin AUC0-24 in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

    Topics: Adult; Area Under Curve; Bayes Theorem; Drug Monitoring; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis; Young Adult

2015
Comparison of Three Commercial Molecular Assays for Detection of Rifampin and Isoniazid Resistance among Mycobacterium tuberculosis Isolates in a High-HIV-Prevalence Setting.
    Journal of clinical microbiology, 2015, Volume: 53, Issue:9

    In a head-to-head comparison of the MTBDRplus version 2.0 (Hain Lifescience), the Xpert MTB/RIF (Cepheid), and the Anyplex MTB/NTM (Seegene) assays, we demonstrated equal sensitivity (59/61; 96.7%) and specificity (53/54; 98.1%) for detecting rifampin resistance with further analysis of discordances. The Xpert assay does not detect isoniazid resistance while the Anyplex assay showed high false positivity.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Genotyping Techniques; HIV Infections; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2015
In silico-based high-throughput screen for discovery of novel combinations for tuberculosis treatment.
    Antimicrobial agents and chemotherapy, 2015, Volume: 59, Issue:9

    There are currently 18 drug classes for the treatment of tuberculosis, including those in the development pipeline. An in silico simulation enabled combing the innumerably large search space to derive multidrug combinations. Through the use of ordinary differential equations (ODE), we constructed an in silico kinetic platform in which the major metabolic pathways in Mycobacterium tuberculosis and the mechanisms of the antituberculosis drugs were integrated into a virtual proteome. The optimized model was used to evaluate 816 triplets from the set of 18 drugs. The experimentally derived cumulative fractional inhibitory concentration (∑FIC) value was within twofold of the model prediction. Bacterial enumeration revealed that a significant number of combinations that were synergistic for growth inhibition were also synergistic for bactericidal effect. The in silico-based screen provided new starting points for testing in a mouse model of tuberculosis, in which two novel triplets and five novel quartets were significantly superior to the reference drug triplet of isoniazid, rifampin, and ethambutol (HRE) or the quartet of HRE plus pyrazinamide (HREZ).

    Topics: Animals; Antitubercular Agents; Ethambutol; Isoniazid; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Rifampin; Tuberculosis

2015
[Rifampicin-resistant Mycobacterium bovis BCG strain isolated from an infant with NEMO mutation].
    Mikrobiyoloji bulteni, 2015, Volume: 49, Issue:2

    It is well known that disseminated Mycobacterium bovis BCG infection is developed after BCG vaccination in infants with congenital cellular immune deficiencies such as mutations in genes along the interleukin (IL)-12/interferon (IFN)-γ pathway and mutations in nuclear factor-kB essential modulator (NEMO). In this report, a rifampicin-resistant M.bovis BCG strain isolated from an infant with NEMO defect was presented. An 8-month-old male infant with NEMO defect admitted to the pediatric outpatient clinic of our hospital with fever, generalized lymphadenopathy and hepatosplenomegaly. Microscopic examination of the smears prepared from lymph node and liver biopsy specimens revealed abundant amount (3+) of acid-fast bacilli (AFB). Rifampicin-susceptible Mycobacterium tuberculosis complex (MTC) was detected by real-time PCR (GeneXpert MTB/RIF; Cepheid, USA) in the samples. The growth of mycobacteria was determined on the 20th day of culture performed in MGIT960 system (Becton Dickinson, USA). The isolate was identified as M.bovis BCG by GenoType MTBC kit (Hain Lifescience, Germany) and defined as M.bovis BCG [SIT 482 (BOV_1)] by spoligotyping. In the primary anti-tuberculosis drug susceptibility test performed by MGIT960 system, the isolate was found susceptible to rifampicin (RIF), isoniazid (INH), streptomycin (STM) and ethambutol (EMB). Then anti-tuberculosis treatment was started to the patient. However, the patient at the age of 2 years, re-admitted to the hospital with the complaint of hepatosplenomegaly. Smear of spontaneously draining abscess material obtained from subcutaneous nodules revealed intensive AFB positivity (3+) once again. In the present instance RIF-resistant MTC was detected with GeneXpert system in the specimen. The growth of mycobacteria was determined on the 13th day of culture and isolate was identified as M.bovis BCG. The present isolate was found susceptible to INH, STM and EMB but resistant to RIF. A mutation in the rpoB gene (codon 531, S531L) associated with RIF resistance was detected by using the partial sequencing of the rpoB gene. Patient died due to disseminated bovis BCG infection and multiple organ failure. To our knowledge, there are only six RIF-resistant M.bovis BCG strains isolated from patients in the literature. However, this is the first RIF-resistant M.bovis BCG strain isolated from a NEMO-deficient patient.

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Ectodermal Dysplasia; Fatal Outcome; Genetic Diseases, X-Linked; Humans; Immunologic Deficiency Syndromes; Infant; Liver; Lymph Nodes; Male; Multiple Organ Failure; Mutation; Mycobacterium bovis; Primary Immunodeficiency Diseases; Rifampin; Tuberculosis

2015
Determination of [11C]rifampin pharmacokinetics within Mycobacterium tuberculosis-infected mice by using dynamic positron emission tomography bioimaging.
    Antimicrobial agents and chemotherapy, 2015, Volume: 59, Issue:9

    Information about intralesional pharmacokinetics (PK) and spatial distribution of tuberculosis (TB) drugs is limited and has not been used to optimize dosing recommendations for new or existing drugs. While new techniques can detect drugs and their metabolites within TB granulomas, they are invasive, rely on accurate resection of tissues, and do not capture dynamic drug distribution in the tissues of interest. In this study, we assessed the in situ distribution of (11)C-labeled rifampin in live, Mycobacterium tuberculosis-infected mice that develop necrotic lesions akin to human disease. Dynamic positron emission tomography (PET) imaging was performed over 60 min after injection of [(11)C]rifampin as a microdose, standardized uptake values (SUV) were calculated, and noncompartmental analysis was used to estimate PK parameters in compartments of interest. [(11)C]rifampin was rapidly distributed to all parts of the body and quickly localized to the liver. Areas under the concentration-time curve for the first 60 min (AUC0-60) in infected and uninfected mice were similar for liver, blood, and brain compartments (P > 0.53) and were uniformly low in brain (10 to 20% of blood values). However, lower concentrations were noted in necrotic lung tissues of infected mice than in healthy lungs (P = 0.03). Ex vivo two-dimensional matrix-assisted laser desorption ionization (MALDI) imaging confirmed restricted penetration of rifampin into necrotic lung lesions. Noninvasive bioimaging can be used to assess the distribution of drugs into compartments of interest, with potential applications for TB drug regimen development.

    Topics: Animals; Antitubercular Agents; Female; Mice; Mycobacterium tuberculosis; Positron-Emission Tomography; Rifampin; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tuberculosis

2015
Immigrants and tuberculosis in Hong Kong.
    Hong Kong medical journal = Xianggang yi xue za zhi, 2015, Volume: 21, Issue:4

    To examine the impact of immigrant populations on the epidemiology of tuberculosis in Hong Kong.. Longitudinal cohort study.. Hong Kong.. Socio-demographic and disease characteristics of all tuberculosis notifications in 2006 were captured from the statutory tuberculosis registry and central tuberculosis reference laboratory. Using 2006 By-census population data, indirect sex- and age-standardised incidence ratios by place of birth were calculated. Treatment outcome at 12 months was ascertained from government tuberculosis programme record forms, and tuberculosis relapse was tracked through the notification registry and death registry up to 30 June 2013.. Moderately higher sex- and age-standardised incidence ratios were observed among various immigrant groups: 1.06 (Mainland China), 2.02 (India, Pakistan, Bangladesh), 1.59 (Philippines, Thailand, Indonesia, Nepal), and 3.11 (Vietnam). Recent Mainland migrants had a lower sex- and age-standardised incidence ratio (0.51 vs 1.09) than those who immigrated 7 years ago or earlier. Age younger than 65 years, birth in the Mainland or the above Asian countries, and previous treatment were independently associated with resistance to isoniazid and/or rifampicin. Older age, birth in the above Asian countries, non-permanent residents, previous history of treatment, and resistance to isoniazid and/or rifampicin were independently associated with poor treatment outcome (other than cure/treatment completion) at 1 year. Birth outside Hong Kong was an independent predictor of relapse following successful completion of treatment (adjusted hazard ratio=1.76; 95% confidence interval, 1.07-2.89; P=0.025).. Immigrants carry with them a higher tuberculosis incidence and/or drug resistance rate from their place of origin. The higher drug resistance rate, poorer treatment outcome, and excess relapse risk raise concern over secondary transmission of drug-resistant tuberculosis within the local community.

    Topics: Adolescent; Adult; Age Distribution; Aged; Antitubercular Agents; Asia, Southeastern; Asia, Western; Child; Child, Preschool; China; Emigrants and Immigrants; Female; Hong Kong; Humans; Incidence; Infant; Infant, Newborn; Isoniazid; Longitudinal Studies; Male; Middle Aged; Population Surveillance; Recurrence; Registries; Rifampin; Sex Distribution; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2015
Correlations Between the Hollow Fiber Model of Tuberculosis and Therapeutic Events in Tuberculosis Patients: Learn and Confirm.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015, Aug-15, Volume: 61 Suppl 1

    The hollow fiber system model of tuberculosis (HFS-TB) is designed to perform pharmacokinetics/pharmacodynamics (PK/PD) experiments, and hence the design of optimal doses and dose schedules for the treatment of tuberculosis. To determine if this model is useful for deriving PK/PD data relevant to clinical outcomes, we compared its quantitative output to that from clinical trials.. We performed a PubMed search to identify clinical studies performed with antituberculosis therapy in which PK/PD data and/or parameters were documented or a dose-scheduling study design was employed. The search period was from January 1943 to December 2012. All clinical studies were published prior to HFS-TB experiments. Bias minimization was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Clinical publications were scored for quality of evidence, with 1 as the highest score (randomized controlled trials or meta-analyses of such studies), and 4 as the lowest score.. We identified 17 studies that examined the same parameters as in 8 HFS-TB studies. Fifteen of 17 studies had a quality-of-evidence score of 1. The sterilizing and bactericidal effect rates for isoniazid, rifampin, pyrazinamide, and ethambutol were the same in the HFS-TB as in patients. Time to emergence of resistance for monotherapy was the same as in patients. The PK/PD indices associated with efficacy were the same in HFS-TB as in patients for all drugs examined.. The HFS-TB model is highly accurate at identifying optimal drug exposures, doses, and dosing schedules for use in the clinic.

    Topics: Antitubercular Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Models, Biological; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

2015
Dielectrophoretic characterization of antibiotic-treated Mycobacterium tuberculosis complex cells.
    Analytical and bioanalytical chemistry, 2015, Volume: 407, Issue:25

    Multi-drug resistant tuberculosis (MDR-TB) has become a serious concern for proper treatment of patients. As a phenotypic method, dielectrophoresis can be useful but is yet to be attempted to evaluate Mycobacterium tuberculosis complex cells. This paper investigates the dielectrophoretic behavior of Mycobacterium bovis (Bacillus Calmette-Guérin, BCG) cells that are treated with heat or antibiotics rifampin (RIF) or isoniazid (INH). The experimental parameters are designed on the basis of our sensitivity analysis. The medium conductivity (σ(m)) and the frequency (f) for a crossover frequency (f(xo1)) test are decided to detect the change of σ(m)-f(xo1) in conjunction with the drug mechanism. Statistical modeling is conducted to estimate the distributions of viable and nonviable cells from the discrete measurement of f (xo1). Finally, the parameters of the electrophysiology of BCG cells, C(envelope) and σ(cyto), are extracted through a sampling algorithm. This is the first evaluation of the dielectrophoresis (DEP) approach as a means to assess the effects of antimicrobial drugs on M. tuberculosis complex cells.

    Topics: Animals; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Electrophoresis; Equipment Design; Hot Temperature; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium bovis; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2015
Molecular epidemiology study of Mycobacterium tuberculosis and its susceptibility to anti-tuberculosis drugs in Indonesia.
    BMC infectious diseases, 2015, Aug-22, Volume: 15

    Genotyping of Mycobacterium tuberculosis helps to understand the molecular epidemiology of tuberculosis and to address evolutionary questions about the disease spread. Certain genotypes also have implications for the spread of infection and treatment. Indonesia is a very diverse country with a population with multiple ethnicities and cultures and a history of many trade and tourism routes. This study describes the first attempt to map the molecular epidemiology of TB in the Indonesian archipelago.. From 2008 to 2011, 404 clinical specimens from sputum-smear (SS+) TB patients, age ≥15 years, were collected from 16 TB referral primary health centers (PHC) in 16 provincial capitals in Indonesia. Susceptibility testing to first line drugs was conducted for 262 samples using the agar proportion method as per WHO guidelines. Spoligotyping was done on all samples.. Ninety-three of the 404 samples (23 %) were from the Beijing family, making it the predominant family in the country. However, the geographic distribution of the family varied by region with 86/294 (29.3 %) in the western region, 6/72 (8.3 %) in the central region, and 2/72 (2.8 %) in the eastern region (p < 0.001). The predominant genotype in the central and eastern regions was from the East-African-Indian (EAI) family, comprising 15.3 % (11/72), and 26.3 % (10/38) of the isolates, respectively. Drug susceptibility to first-line anti-TB drugs was tested in 262 isolates. 162 (61.8 %) isolates were susceptible to all TB drugs, 70 (26.7 %) were mono-resistant 16 (6.1 %) were poly-resistant, and 14 (5.4 %) were multi-drug resistant (MDR). The proportion of Beijing family isolates in the susceptible, mono-resistant, poly-resistant, and MDR groups was 33/162 (20.4 %), 28/70 (40.0 %), 6/16 (37.5 %), and 3/14 (21.4 %), respectively. Overall, resistance of the Beijing family isolates to any of the first line TB drugs was significantly higher than non-Beijing families [37/71 (52.1 %) vs. 63/191 (33.0 %) (p-value = 0.003)].. The distribution of Mycobacterium tuberculosis genotypes in Indonesia showed high genetic diversity and tended to vary by geographic regions. Drug susceptibility testing confirmed that the Beijing family of M.tb in Indonesia exhibited greater resistance to first line anti-TB drugs than did other families.

    Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Antitubercular Agents; Ethambutol; Female; Genetic Variation; Genotype; Humans; Indonesia; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Epidemiology; Mycobacterium tuberculosis; Rifampin; Sputum; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

2015
The association between sterilizing activity and drug distribution into tuberculosis lesions.
    Nature medicine, 2015, Volume: 21, Issue:10

    Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside. In contrast, moxifloxacin, which is active in vitro against a subpopulation of Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achieved treatment shortening in mice, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug-resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration may contribute to treatment outcome has wide implications for TB.

    Topics: Antitubercular Agents; Humans; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

2015
Predictors of mortality and treatment success during treatment for rifampicin-resistant tuberculosis within the South African National TB Programme, 2009 to 2011: a cohort analysis of the national case register.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2015, Volume: 39

    The South African Electronic Drug-Resistant Tuberculosis Register (EDRweb) is the national database of registered drug-resistant tuberculosis (DR-TB) cases.. This study was a retrospective, de-identified secondary analysis of EDRweb patients initiating treatment for rifampicin-resistant TB (January 2009 to September 2011). The relative risks of death and treatment success were estimated using modified Poisson regression with robust error estimation.. Seventeen thousand six hundred and ninety-seven cases of DR-TB were registered and met the inclusion criteria; 52.0% (n=9207) were male and the median age was 35 years (interquartile range 27-43 years). Of the 9419 cases with HIV infection (53.2%), 7157 (76.0%) were on antiretroviral therapy. Most had undergone previous TB treatment (76.5%, n=13531). Multidrug-resistant TB was the most common diagnosis, at 80.6% (n=14272). No treatment outcome was available for 6934 patients (39.2%). For patients with outcomes, 4227 (39.4%) were successfully treated, 2987 (27.8%) died, 2533 (23.7%) were lost to follow-up, and 996 (9.3%) failed. Second-line drug resistance was the strongest predictor of death during DR-TB treatment; extensively drug-resistant TB patients were more likely to have died during treatment (adjusted relative risk 2.63, 95% confidence interval 2.45-2.84).. Testing for second-line drug resistance at initiation of DR-TB treatment can identify patients most at risk of treatment failure and death and most in need of individualized treatment.

    Topics: Adolescent; Adult; Antitubercular Agents; Cohort Studies; Female; HIV Infections; Humans; Male; Middle Aged; Registries; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2015
MTB-DR-RIF 9G test: Detection and discrimination of tuberculosis and multi-drug resistant tuberculosis strains.
    Tuberculosis (Edinburgh, Scotland), 2015, Volume: 95, Issue:6

    This report describes the evaluation of the novel MTB-DR-RIF 9G test for the accurate detection and discrimination of Mycobacterium tuberculosis (MTB) and rifampicin-resistant M. tuberculosis (MTB-DR-RIF) in the clinical samples. The procedure included the amplification of a nucleotide fragment of the rpoB gene of the MTB and MTB-DR-RIF strains and their hybridization with the immobilized probes. The MTB-DR-RIF 9G test was evaluated for its ability to detect and discriminate MTB and MTB-DR-RIF strains in 113 known clinical samples. The accuracy of the MTB-DR-RIF 9G test was determined by comparing its results with sequencing analysis and drug susceptibility testing. The sensitivity and specificity of the MTB-DR-RIF 9G test at 95% confidence interval were found to be 95.4% (89.5-98.5) and 100% (69.2-100), respectively. The positive predictive value and negative predictive value of the MTB-DR-RIF 9G test at 95% confidence interval were found to be 100% (85.0-95.9) and 66.7% (38.4-88.18), respectively. Sequencing analysis of all samples indicated that the mutations present in the regions identified with the MTB-DR-RIF 9G assay can be detected accurately.

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; Bacteriological Techniques; Diagnosis, Differential; Discriminant Analysis; DNA Mutational Analysis; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Humans; Molecular Diagnostic Techniques; Mutation; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Predictive Value of Tests; Reproducibility of Results; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2015
False-positive Xpert(®) MTB/RIF more than seven years after cure.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:10

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Respiratory Tract Infections; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2015
[The effect of renal replacement therapy on the plasma concentration of antituberculosis drugs].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2015, Volume: 38, Issue:5

    To explore the effect of renal replacement therapy (RRT) on the plasma drug concentration of first-line antituberculosis drugs.. Thirty patients treated with continuous RRT and who were complicated with pulmonary tuberculosis from 2009 September to 2013 September were enrolled in the study. There were 19 males and 11 females, aged 18-75 years. They received RRT 3 times a week, 4 h each. The patients took isoniazid 300 mg and rifampin 450 mg one time every day, and pyrazinamide 40 mg · kg(-1) · d (-1) one time 24 h before RRT, 3 times every week. The plasma concentration of the drugs were monitored before and after each RRT for 4 weeks.. Taken before RRT, the plasma concentration of isoniazid before RRP was (1.62 ± 0.44), (1.67 ± 0.38), (1.63 ± 0.41), (1.48 ± 0.38) mg/L respectively for 1-4 weeks; while that after RRT was (0.57 ± 0.22), (0.60 ± 0.24), (0.56 ± 0.20), (0.56 ± 0.15) mg/L (all P < 0.05). Taken before RRT, the plasma concentration of pyrazinamide before RRT was (16.08 ± 4.95), (16.32 ± 5.73), (14.89 ± 4.53), (13.81 ± 5.83) mg/L respectively for 1-4 weeks, while that after RRT was (3.73 ± 1.57), (3.57 ± 1.53), (3.22 ± 1.00), (2.81 ± 1.34) mg/L (all P < 0.05). Taken after RRT at once, the plasma concentration of pyrazinamide before RRT was (15.57 ± 3.47), (14.10 ± 2.27), (14.73 ± 2.36), (15.9 ± 3.02) mg/L respectively for 1-4 weeks, while that after RRT was (2.45 ± 1.14), (2.19 ± 1.07), (1.87 ± 1.52), (2.33 ± 1.30)mg/L. Taken before RRT, the plasma concentration of rifampin was (3.44 ± 1.17), (3.72 ± 1.24), (3.68 ± 1.16), (3.44 ± 1.22) mg/L respectively for 1-4 weeks (all P < 0.05), while that after RRT was (2.96 ± 1.10), (3.28 ± 1.04), (3.17 ± 1.02), (2.96 ± 1.05) mg/L (all P > 0.05).. Continuous RRT has different effects on the plasma drug concentration of isoniazid and pyrazinamide. It almost has no effect on rifampin. To achieve the best plasma concentration and better anti-tuberculosis results, isoniazid and pyrazinamide should be taken after RRT, but rifampin before RRT.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Female; Humans; Isoniazid; Kidney Diseases; Male; Middle Aged; Pyrazinamide; Renal Replacement Therapy; Rifampin; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

2015
The impact of nutritional state on the duration of sputum positivity of Mycobacterium tuberculosis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19, Issue:11

    The outcome of anti-tuberculosis treatment varies according to patient factors.. To retrospectively identify risks related to the extension of time to negative sputum culture (Tn) and to determine their clinical significance.. Patients with bacilli susceptible to isoniazid and rifampicin who received initial standard treatment without cessation were recruited into the study. A total of 630 consecutive in-patients were included in the risk development analysis (development cohort) and another 611 consecutive in-patients in the risk validation analysis (validation cohort).. Univariate analysis showed that Tn was related to sex, body mass index (BMI), white blood cell count (WBC), serum albumin, fasting blood sugar, haemoglobin A1c, C-reactive protein and total cholesterol levels and sputum smear positivity (SSP). Multivariate analysis showed that BMI, WBC and SSP were significant risk factors related to extended Tn. Optimal cut-offs of BMI and WBC for predicting good (Tn < 46 days) and poor responders (Tn ⩾ 46 days) according to each risk were determined by receiver operating characteristics analysis. Risks were verified with the validation cohort. Tn increased according to the number of risks; the median Tn for patients with three risks was 21 days longer than that of patients with none.. The nutritional state of a TB patient can be used to predict Tn.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Biomarkers; Body Mass Index; C-Reactive Protein; Female; Glucose Intolerance; Humans; Isoniazid; Japan; Leukocytes; Male; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Nutritional Status; Retrospective Studies; Rifampin; Risk Factors; Sputum; Tuberculosis; Young Adult

2015
Rifampin resistance and diabetes mellitus in a cross-sectional study of adult patients in rural South India.
    BMC infectious diseases, 2015, Oct-26, Volume: 15

    Despite increasing reports of the linkage between diabetes and tuberculosis (TB), there is limited information regarding diabetes and TB drug resistance.. In this cross-sectional study, sputum and blood samples were collected from 304 adult patients in rural Andhra Pradesh. Rifampin resistance was assessed by Xpert MTB/RIF (Xpert), and diabetes status was based on self-report. Additionally, samples were assayed by acid-fast bacilli sputum smear microscopy (AFB) and QuantiFERON-TB Gold In-Tube (QFT-G), in order to compare relative diagnostic performances.. Among patients with confirmed TB (n = 194), diabetes was associated with 3.0-fold higher risk of rifampin resistance (95 % CI 1.3-6.7). Considering Xpert MTB/RIF the gold standard, AFB had lower sensitivity (72.2 vs. 82.5 %) and higher specificity (96.4 vs. 37.0 %) compared to QFT-G for diagnosing TB.. The increased risk of rifampin resistance in patients with diabetes highlights the need for integrated diabetes surveillance in TB programs, particularly in settings undergoing the epidemiological transition.

    Topics: Adult; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; India; Male; Mycobacterium tuberculosis; Rifampin; Rural Population; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

2015
Clinical, molecular and drug sensitivity pattern of mycobacterial isolates from extra-pulmonary tuberculosis cases in Addis Ababa, Ethiopia.
    BMC infectious diseases, 2015, Oct-26, Volume: 15

    In conjunction with the spread of HIV infection, tuberculosis (TB) remains a major cause of illness and death worldwide. The Ethiopian national report reveals that extra pulmonary tuberculosis is on the rise and that case detection rate is exceeding that of smear positive or negative cases in many parts of the country. Different studies indicated that host and/or pathogen related factors are associated with the rise of extra pulmonary cases. However, the reason for this is not clearly known in our setting.. Specimens were taken from clinically suspected extra pulmonary patients and confirmed by cytology, histopathology and culture. Deletion typing and Spoligotyping was utilized to identify the strains. The isolates were then assigned to lineage using conformal Bayesian network (rules model) algorithm and dendrograms were drawn using UPGMA methods. In addition, drug sensitivity test was done using the indirect proportion and 24 well plate methods.. Out of the 200 clinically suspected extra pulmonary tuberculosis patients, 106 (53 %) were between 15 and 35 years of age and 167 (83.5 %) were new while 33 (16.5 %) were retreatment cases. The culture yield was 29.5 % (59). Of these only one was M. bovis and 58 were M. tuberculosis strains with 31 different spoligotype patterns grouped into seven clusters. The largest cluster (ST53) comprised 12 (20.3 %) isolates. There was higher clustering of CAS isolates in TBLN than in any other form of extra pulmonary tuberculosis cases. Resistance to rifampicin was higher (22 %) than that for INH, STM and EMB (8.1 %, 5 % and 3 % respectively). Out of the 37 isolates tested for resistance, only 2 isolates were resistant for both STM and INH and no MDR strain was found.. There is an ongoing active recent transmission among extra pulmonary tuberculosis in the study areas as shown by the presence of clusters. Although no MDR case was observed, there is a risk of emergence of MDR as noted from the high proportion of resistance to rifampicin. Detailed study at population level is recommended to monitor its trend.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Child, Preschool; Coinfection; Drug Resistance, Bacterial; Ethiopia; Female; HIV Infections; Humans; Infant; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Retreatment; Rifampin; Substance-Related Disorders; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

2015
The background and rationale for a new fixed-dose combination for first-line treatment of tuberculosis in children.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19 Suppl 1

    In 2010, the World Health Organization revised the recommendations for the treatment of tuberculosis (TB) in children. The major revision was to increase isoniazid, rifampicin and pyrazinamide dosages according to body weight in children. The recommendations for higher dosages are based on consistent evidence from 1) pharmacokinetic studies suggesting that young children require higher dosages than adolescents and adults to achieve desired serum concentrations; and 2) observational studies reporting that the higher dosages would not be associated with increased risk of toxicity in children. However, national tuberculosis programmes faced unforeseen challenges in implementing the revised recommendations. The main difficulty was to adapt the revised dosages for the treatment of children with drug-susceptible TB using available fixed-dose combinations (FDCs). A more suitable FDC for the intensive and continuation phases of treatment has now been developed for planned implementation in 2015. This paper explains the background and rationale for the development of a new FDC tablet for children with drug-susceptible TB.

    Topics: Antitubercular Agents; Body Weight; Child; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis; World Health Organization

2015
Childhood tuberculosis in the United States: shifting the focus to prevention.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2015, Volume: 19 Suppl 1

    In the last century, the United States has transitioned from a high to a low tuberculosis (TB) incidence country. A major factor in this decline has been the emphasis on identification and treatment of patients with tuberculous infection. While identification, testing, and preventive therapy pose challenges, recent developments in childhood TB offer more options for effective strategies that are acceptable to both children and their families. These include screening and testing in non-traditional settings, use of more specific assays (interferon-gamma release assays) for testing, and implementation of shorter-course preventive regimens.

    Topics: Antibiotics, Antitubercular; Child; Humans; Incidence; Interferon-gamma Release Tests; Isoniazid; Mass Screening; Rifampin; Tuberculosis; United States

2015
In silico evaluation and exploration of antibiotic tuberculosis treatment regimens.
    BMC systems biology, 2015, Nov-14, Volume: 9

    Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes.. We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data from non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment.. Our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.

    Topics: Animals; Antitubercular Agents; Computer Simulation; Drug Resistance, Bacterial; Granuloma; Isoniazid; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis

2015
Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa.
    Antimicrobial agents and chemotherapy, 2015, Dec-07, Volume: 60, Issue:3

    Effective treatment of tuberculosis during pregnancy is essential for preventing maternal and fetal mortality, but little is known about the effects of pregnancy on the disposition of antituberculosis drugs. We explored the effects of pregnancy on the pharmacokinetics of rifampin, the key sterilizing drug in tuberculosis treatment, in Tshepiso, a prospective cohort study involving pregnant HIV-infected women with or without tuberculosis in Soweto, South Africa. Participants receiving standard first-line tuberculosis treatment underwent sparse sampling for rifampin at 37 weeks' gestation or delivery and then postpartum. Cord blood was collected when possible. A population pharmacokinetic model was developed to investigate the effects of pregnancy on rifampin pharmacokinetics. Among the 48 participants, median age and weight were 28 years and 67 kg, respectively. A one-compartment model with first-order elimination, transit compartment absorption, and allometric scaling described the data well. Pregnancy reduced rifampin clearance by 14%. The median (interquartile range) model-estimated rifampin area under the concentration-time curve over 24 h (AUC0-24) during pregnancy or intrapartum was 40.8 h · mg/liter (27.1 to 54.2 h · mg/liter) compared to 37.4 h · mg/liter (26.8 to 50.3 h · mg/liter) postpartum. The maximum concentrations were similar during pregnancy and postpartum. Rifampin was detectable in 36% (8/22) of cord blood samples, and 88% (42/48) of the women had successful treatment outcomes. There was one case of perinatal tuberculosis. In conclusion, rifampin clearance is modestly reduced during the last trimester of pregnancy. Exposures are only slightly increased, so dose adjustment during pregnancy is not needed. Rifampin was detected in cord blood samples when delivery occurred soon after dosing. The consequences of exposure to this potent inducer of metabolizing enzymes among HIV-exposed infants are unclear.

    Topics: Adult; Antibiotics, Antitubercular; Area Under Curve; Cohort Studies; Coinfection; Female; Fetal Blood; HIV Infections; Humans; Infant, Newborn; Postpartum Period; Pregnancy; Pregnancy Complications, Infectious; Prospective Studies; Rifampin; South Africa; Treatment Outcome; Tuberculosis

2015
Implementing the Xpert® MTB/RIF Diagnostic Test for Tuberculosis and Rifampicin Resistance: Outcomes and Lessons Learned in 18 Countries.
    PloS one, 2015, Volume: 10, Issue:12

    The Xpert® MTB/RIF (Xpert) is an automated molecular test for simultaneous detection of tuberculosis (TB) and rifampicin resistance, recommended by the World Health Organization as the preferred diagnostic method for individuals presumed to have multi-drug resistant TB (MDR-TB) or HIV-associated TB. We describe the performance of Xpert and key lessons learned during two years of implementation under routine conditions in 33 projects located in 18 countries supported by Médecins Sans Frontières across varied geographic, epidemiological and clinical settings.. Xpert was used following three strategies: the first being as the initial test, with microscopy in parallel, for all presumptive TB cases; the second being only for patients at risk of MDR-TB, or with HIV- associated TB, or presumptive paediatric TB; and the third being as the initial test for these high-risk patients plus as an add-on test to microscopy in others. Routine laboratory data were collected, using laboratory registers. Qualitative data such as logistic aspects, human resources, and tool acceptance were collected using a questionnaire.. In total, 52,863 samples underwent Xpert testing from April 2011 to December 2012. The average MTB detection rate was 18.5%, 22.3%, and 11.6% for the three different strategies respectively. Analysis of the results on samples tested in parallel showed that using Xpert as add-on test to microscopy would have increased laboratory TB confirmation by 49.7%, versus 42.3% for Xpert replacing microscopy. The main limitation of the test was the high rate of inconclusive results, which correlated with factors such as defective modules, cartridge version (G3 vs. G4) and staff experience. Operational and logistical hurdles included infrastructure renovation, basic computer training, regular instrument troubleshooting and maintenance, all of which required substantial and continuous support.. The implementation of Xpert was feasible and significantly increased TB detection compared to microscopy, despite the high rate of inconclusive results. Xpert implementation was accompanied by considerable operational and logistical challenges. To further decentralize diagnosis, simpler, low-cost TB technologies well-suited to low-resource settings are still urgently needed.

    Topics: Adult; Child; Diagnostic Tests, Routine; Drug Resistance, Bacterial; Humans; Reagent Kits, Diagnostic; Rifampin; Risk Factors; Sputum; Surveys and Questionnaires; Treatment Outcome; Tuberculosis

2015
Cure of tuberculosis despite serum concentrations of antituberculosis drugs below published reference ranges.
    Swiss medical weekly, 2015, Volume: 145

    Therapeutic target serum concentrations of first-line antituberculosis drugs have not been well defined in clinical studies in tuberculosis (TB) patients.. We retrospectively investigated the estimated maximum serum concentrations (eC max) of antituberculosis drugs and clinical outcome of TB patients with therapeutic drug monitoring performed between 2010-2012 at our institution, and follow-up until March 2014. The eC max was defined as the highest serum concentration during a sampling period (2, 4 and 6 hours after drug ingestion). We compared the results with published eC max values, and categorised them as either "within reference range", "low eC max", or "very low eC max".Low/very low eC max-levels were defined as follows: isoniazid 2-3/<2 mg/l, rifampicin 4-8/<4 mg/l, rifabutin 0.2-0.3/<0.2 mg/l, ethambutol 1-2/<0.1 mg/l and pyrazinamide <20 mg/l.. Concentrations of antituberculosis drugs in 175 serum samples of 17 patients with TB were analysed. In 12 (71%) patients, multiple therapeutic drug monitoring samples were collected over time, in 5 (29%) patients only one sample was available for therapeutic drug monitoring. Overall, 94% of all patients had at least one low antituberculosis drug concentration. Overall, 64% of all eC max levels were classified as "low" or "very low". The eC max was below the relevant reference range in 80% of isoniazid, 95% of rifampicin, 30% of pyrazinamide, and 30% of ethambutol measurements. All but one patient were cured of tuberculosis.. Although many antituberculosis drug serum concentrations were below the widely used reference ranges, 16 of 17 patients were cured of tuberculosis. These results challenge the use of the published reference ranges for therapeutic drug monitoring.

    Topics: Adult; Aged; Antitubercular Agents; Drug Monitoring; Female; HIV Infections; Humans; Isoniazid; Linear Models; Male; Middle Aged; Pyrazinamide; Reference Values; Retrospective Studies; Rifampin; Switzerland; Tuberculosis; Young Adult

2015
[A study of the value of three molecular diagnostic techniques in the diagnosis of tuberculosis].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2015, Volume: 38, Issue:9

    To evaluate the diagnostic value of real-time fluorescent RNA isothermal amplification detection technology (simultaneous amplification and testing, SAT), Mycobacterium nucleic acid detection (PCR-fluorescence probe)method (TB-NTM-PCR) and Xpert MTB/RIF detection in the diagnosis of tuberculosis.. A total of 378 sputum specimens from pulmonary tuberculosis patients were collected between April to July 2014 in Xi'an Thoracic Tumor and Tuberculosis Hospital. The specimens were detected by 5 methods at the same time including acid-fast stain, SAT method, TB-NTM-PCR method, TB 960 rapid liquid culture and Xpert MTB/RIF. The sensitivity and specificity of SAT method, TB-NTM-PCR method and Xpert MTB/RIF were calculated according to the results of TB 960 rapid liquid culture and staining. The difference among all the 3 methods was analyzed by Chi-squared test.. The positive rate of SAT-TB,TB-NTM-PCR and Xpert MTB/RIF were 37.6% (142/378), 37.8% (143/378) and 53.4% (202/378), respectively. In specimens both positive for acid-fast stain and culture, the positive rate of SAT method was 84.6% (77/91), that of TB-NTM-PCR was 91.2% (83/91), and that of Xpert MTB/RIF was 96.7% (88/91), the difference being significant (P=0.018 2). In specimens negative for acid-fast stain but positive for culture, the positive rate of SAT method was 61.9% (60 /97), that of TB-NTM-PCR was 44.3% (43/97), and that of Xpert MTB/RIF was 80.4% (78/97), the difference being significant (P<0.000 1). In specimens both negative for acid-fast stain and culture, the positive rate of SAT method was 1.6% (3/185), that of TB-NTM-PCR was 6.5% (12/185), and that of Xpert MTB/RIF was 16.8% (31/185), the difference being significant (P=0.018). In specimens positive for acid-fast stain but negative for culture, the number of positive samples of SAT,TB-NTM-PCR and Xpert MTB/RIF were 3 (3/5), 5 (5/5),and 5 (5/5), respectively. With the result of TB 960 rapid liquid culture and staining as the reference, Xpert MTB/RIF showed the highest sensitivity of 87.6% (163/186), the minimum rate of missed diagnosis of 12.4% (24/193), and the highest negative predictive value of 88.5% (185/209); SAT-TB showed the highest specificity of 98.2% (214/218), the minimum rate of misdiagnosis of 1.8%(4/218), the highest positive predictive value of 97.2% (138/142). With the result of TB 960 rapid liquid culture as the reference, the sensitivity and the specificity of Xpert MTB/RIF were 95.52% (128/134) and 95.24% (20/21). The accordance rate of Xpert MTB/RIF and TB 960 rapid liquid culture was 95.48%(148/155).. The 3 molecular detection methods showed good results for the auxiliary diagnosis of tuberculosis. Xpert MTB/RIF had the best performance both in smear positive and negative specimens and it can detect rifampicin related rpoB gene mutations at the same time.

    Topics: Diagnostic Errors; Humans; Molecular Diagnostic Techniques; Mutation; Polymerase Chain Reaction; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

2015
[CLINICAL EFFECTS OF TREATMENT FOR MYCOBACTERIUM TUBERCULOSIS INFECTION IN PATIENTS AT A SPECIALIZED HOSPITAL IN 2011].
    Kekkaku : [Tuberculosis], 2015, Volume: 90, Issue:10

    We analyzed the clinical effects of treatment for Mycobacterium tuberculosis infection for 1 year in our specialized hospital in 2011. Two hundred and ninety-six (296) patients were admitted and received treatment.. Two hundred and fifty-six patients (86.5%) were started on the standard treatment with 3 drugs (isoniazid [INH, rifampicin [RFP], and ethambutol [EB] or streptomycin [SM]) or 4 drugs (INH, RFP, EB or SM, and pyrazinamide [PZA]). One hundred and seventy-one patients (66.8%) continued receiving the standard treatment during the admission period. Of 160 cases who could continue 4 drugs, under 80 year-old patients were 127 cases (76.0%), but over 80 year-old patients were 33 cases (49.3%). The mean duration for negative conversion of sputum culture was 40.6 days. Liver dysfunction due to 4 drugs (INH, RFP, EB, and PZA) was noted in 8.5% of patients. Eighteen of the 296 patients had multi-drug resistant tuberculosis (MDR-TB). Each MDR-TB patient received individualized treatment. Moreover, 7 of the MDR-TB cases were treated surgically.. Treatment of TB had taken long time, and some patients could not continue the treatment owing to the adverse effects of drugs. Hence, it is important to monitor adverse effects of drugs in each patient.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Child; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Ethambutol; Female; Hospitals, Special; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Retrospective Studies; Rifampin; Streptomycin; Time Factors; Treatment Outcome; Tuberculosis; Young Adult

2015
Rational design and synthesis of novel dibenzo[b,d]furan-1,2,3-triazole conjugates as potent inhibitors of Mycobacterium tuberculosis.
    European journal of medicinal chemistry, 2014, Volume: 71

    A series of novel dibenzo[b,d]furan-1,2,3-triazole conjugates, rationally designed by reorientation of dibenzo[b,d]furan pharmacophore and alkyl/aryl groups appended on 1,2,3-triazole core, were synthesized using click chemistry. The required key intermediate, 2-ethynyl dibenzo[b,d]furan 3 was prepared from dibenzofuran-2-carboxaldehyde using Corey-Fuchs reaction. Further reaction of 3 with various alkyl/aryl azides in the presence of copper catalyst produced 1,2,3-triazole conjugates in excellent yields. Evaluation of all the new compounds for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294), resulted 5a (MIC: 1.56 μg/mL), 5d (MIC: 0.78 μg/mL) and 5f (MIC: 0.78 μg/mL) as promising lead analogues. Among these three compounds, 1-(4-bromobenzyl)-4-(dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazole (5f) emerged as the most promising antitubercular agent with lowest cytotoxicity (selectivity index: ≫25) against the HEK-293T cell line.

    Topics: Antitubercular Agents; Benzofurans; Click Chemistry; HEK293 Cells; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Structure-Activity Relationship; Triazoles; Tuberculosis

2014
Synthesis and evaluation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-(2-(4-substitutedpiperazin-1-yl)acetyl)piperazin-1-yl)quinoline-3-carboxylic acid derivatives as anti-tubercular and antibacterial agents.
    European journal of medicinal chemistry, 2014, Volume: 71

    A series of twenty two novel 1-cyclopropyl-6-fluoro-4-oxo-7-(4-substitutedpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid analogues were synthesized, characterized ((1)H NMR, (13)C NMR and LCMS) and screened for their in vitro anti-tubercular and antibacterial activity. Many of these compounds exhibited MIC values in the range 7.32-136.10 μM against Mycobacterium tuberculosis H37Rv. Eight compounds were further subjected to cytotoxic studies. Furthermore, the title compounds were screened for antibacterial activity against Staphylococcus aureus ATCC 29213 (gram positive) and Escherichia coli ATCC 25922 (gram negative) bacteria. Many of these compounds exhibited MIC values in the range 0.44-34.02 μM. Compound 3f was found to be the most active with an MIC of 0.44 and 0.8 μM respectively against both the strains. In general, the antibacterial activity of title compounds was more prominent.

    Topics: Anti-Bacterial Agents; Carboxylic Acids; Escherichia coli; Escherichia coli Infections; Halogenation; Humans; Mycobacterium tuberculosis; Quinolines; Staphylococcal Infections; Staphylococcus aureus; Structure-Activity Relationship; Tuberculosis

2014
Design, synthesis and investigation on the structure-activity relationships of N-substituted 2-aminothiazole derivatives as antitubercular agents.
    European journal of medicinal chemistry, 2014, Jan-24, Volume: 72

    Tuberculosis (TB) is one of the deadliest infectious diseases of all times, and its recent resurgence is a supreme matter of concern. Co-infection with HIV and, in particular, the continuous isolation of new resistant strains, makes the discovery of novel anti-TB agents a strategic priority. The research of novel agents should be driven by the accessibility of the synthetic procedure and, in particular, by the lack of cross-resistance with the drugs already marketed. Moreover, in order to shorten the duration of the therapy, and therefore decrease the rate of resistance, these molecules should be active also against the nonreplicating persistent form (NRP-TB) of the infection. The availability of an in-house small library of compounds prompted us to investigate their anti-TB activity. Two compounds, embodying a 2-aminothiazole scaffold, were found to possess a certain inhibitory activity toward Mycobacterium tuberculosis H37Rv, and therefore a medicinal chemistry campaign was initiated in order to increase the activity of the hit compounds and, especially, construct a plausible body of structure-activity relationships. The potency of the hit compound was successfully improved, and, much more importantly, some of the molecules synthesized were found to be active toward the persistent phenotype, and, also, toward a panel of resistant strains. These findings encourage further investigations around this interesting antitubercular chemotype.

    Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Dose-Response Relationship, Drug; Drug Design; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Thiazoles; Tuberculosis; Vero Cells

2014
1,2,3,4,8,9,10,11-octahydrobenzo[j]phenanthridine-7,12-diones as new leads against Mycobacterium tuberculosis.
    Journal of medicinal chemistry, 2014, Apr-10, Volume: 57, Issue:7

    Tuberculosis (TB) continues to be a worldwide health problem with over 1.4 million deaths each year. Despite efforts to develop more effective vaccines, more reliable diagnostics, and chemotherapeutics, tuberculosis remains a threat to global health, fueled by the HIV pandemic and the rapid generation of drug resistance. The exploration of novel drugs to serve as a companion drug for existing drugs is of paramount importance. As part of our program to design new 2-aza-anthraquinones with antimycobacterial activity, various tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized. These compounds showed high in vitro potency against Mycobacterium tuberculosis, the etiological agent of TB and against other clinically relevant mycobacterial species at submicromolar concentrations. The susceptibility of a multidrug resistant strain toward these compounds and their ability to target intracellular replicating Mycobacterium tuberculosis was demonstrated. Next to the acute toxicity, the genotoxicity of these compounds was investigated. Often overlooked in studies, genotoxicity could be dismissed for the investigated compounds, making them a promising scaffold in TB drug research.

    Topics: Animals; Antitubercular Agents; Cell Proliferation; Comet Assay; DNA Damage; Drug Design; Drug Resistance, Multiple; Macrophages; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Phenanthridines; Structure-Activity Relationship; Tuberculosis

2014
Development of 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives as novel enoyl-acyl carrier protein reductase (InhA) inhibitors for the treatment of tuberculosis.
    European journal of medicinal chemistry, 2014, Oct-30, Volume: 86

    InhA, the enoyl acyl carrier protein reductase of Mycobacterium tuberculosis (MTB) is an attractive target for developing novel anti-tubercular agents. Twenty eight 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives were synthesized and evaluated for their in vitro MTB InhA inhibition. Compounds were further evaluated for their in vitro activity against drug sensitive and resistant MTB strains and cytotoxicity against RAW 264.7 cell line. Compounds were docked at the active site of InhA to understand their binding mode and differential scanning fluorimetry was performed to ascertain their protein interaction and stability.

    Topics: Acetamides; Animals; Bacterial Proteins; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Enzyme Inhibitors; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Mycobacterium tuberculosis; Oxidoreductases; Quinazolines; Structure-Activity Relationship; Tuberculosis

2014
Design, synthesis and antimycobacterial activity of various 3-(4-(substitutedsulfonyl)piperazin-1-yl)benzo[d]isoxazole derivatives.
    European journal of medicinal chemistry, 2014, Nov-24, Volume: 87

    In this communication, we synthesized a series of twenty four novel 3-(4-(substitutedsulfonyl)piperazin-1-yl)benzo[d]isoxazole analogues, characterized using various spectroscopic techniques and evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) H37Rv strain. The titled compounds exhibited Minimum inhibitory concentration (MIC) between 3.125 and >50 μg/mL. Among the tested compounds, 5c, 6a, 6j and 6p exhibited moderate activity (MIC = 12.5 μg/mL), while 5a and 6i exhibited good activity (MIC = 6.25 μg/mL) and 6b (MIC = 3.125 μg/mL) exhibited very good anti-tubercular activity. In addition, the analogues 5a, 5c, 6a, 6b, 6i, 6j and 6p were subjected to toxicity studies against mouse macrophage (RAW 264.7) cell lines to analyse the selectivity profile of the newly synthesized compounds and selectivity index of the most active compound was found to be >130 indicating suitability of the compound for further drug development. Structure of 6b was further substantiated through single crystal XRD.

    Topics: Animals; Antitubercular Agents; Cell Proliferation; Cells, Cultured; Crystallography, X-Ray; Drug Design; Isoxazoles; Macrophages; Mice; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Piperazines; Structure-Activity Relationship; Tuberculosis

2014
Development of benzo[d]oxazol-2(3H)-ones derivatives as novel inhibitors of Mycobacterium tuberculosis InhA.
    Bioorganic & medicinal chemistry, 2014, Nov-01, Volume: 22, Issue:21

    A series of twenty seven substituted 2-(2-oxobenzo[d]oxazol-3(2H)-yl)acetamide derivatives were designed based on our earlier reported Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein reductase (InhA) lead. Compounds were evaluated for MTB InhA inhibition study, in vitro activity against drug-sensitive and -resistant MTB strains, and cytotoxicity against RAW 264.7 cell line. Among the compounds tested, 2-(6-nitro-2-oxobenzo[d]oxazol-3(2H)-yl)-N-(5-nitrothiazol-2-yl)acetamide (30) was found to be the most promising compound with IC50 of 5.12 ± 0.44 μM against MTB InhA, inhibited drug sensitive MTB with MIC 17.11 μM and was non-cytotoxic at 100 μM. The interaction with protein and enhancement of protein stability in complex with compound 30 was further confirmed biophysically by differential scanning fluorimetry.

    Topics: Animals; Antitubercular Agents; Bacterial Proteins; Benzoxazoles; Cell Line; Humans; Mice; Microbial Sensitivity Tests; Molecular Docking Simulation; Mycobacterium tuberculosis; Oxidoreductases; Structure-Activity Relationship; Tuberculosis

2014
Antitubercular activity of quinolizidinyl/pyrrolizidinylalkyliminophenazines.
    Bioorganic & medicinal chemistry, 2014, Dec-15, Volume: 22, Issue:24

    Novel riminophenazine derivatives, characterized by the presence of the basic and cumbersome quinolizidinylalkyl and pyrrolizidinylethyl moieties, have been synthesized and tested (Rema test) against Mycobacterium tuberculosis H37Rv and H37Ra, and six clinical isolates of Mycobacterium avium and Mycobacterium tuberculosis. Most compounds exhibited potent activity against the tested strains, resulting more active than clofazimine, isoniazid and ethambutol. The best compounds (4, 5, 12 and 13) exhibited a MIC in the range 0.82-0.86μM against all strains of Mycobacterium tuberculosis and, with the exception of 4 a MIC around 3.3μM versus M. avium. The corresponding values for clofazimine (CFM) were 1.06 and 4.23μM, respectively. Cytotoxicity was evaluated against three cell lines and compound 4 displayed a selectivity index (SI) versus the human cell line MT-4 comparable with that of CFM (SI=5.23 vs 6.4). Toxicity against mammalian Vero 76 cell line was quite lower with SI=79.

    Topics: Animals; Antitubercular Agents; Cell Line; Cell Survival; Chlorocebus aethiops; Humans; Microbial Sensitivity Tests; Mycobacterium avium; Mycobacterium tuberculosis; Phenazines; Pyrrolidines; Quinolizidines; Structure-Activity Relationship; Tuberculosis; Vero Cells

2014
Microparticles of rifampicin: comparison of pulmonary route with oral route for drug uptake by alveolar macrophages, phagocytosis activity and toxicity study in albino rats.
    Drug delivery, 2014, Volume: 21, Issue:6

    Tuberculosis (TB) is a chronic infectious disease with increasing incidence of drug resistance. Oral treatment for TB and multidrug resistance (MDR)-TB can have serious side effects. The causative agent of TB, Mycobacterium tuberculosis, resides in alveolar macrophages (AM). Pulmonary administration of anti-TB drugs can help in delivery of high concentration to AM. The ability of AM to phagocytose can also be utilized to generate mycobactericidal nitric oxide (NO) to improve efficacy of anti-TB drugs.. To compare the uptake of rifampicin (RIF) by AM post oral and pulmonary administration of RIF microparticles (RM) and to compare hepatotoxicity and phagocytosis activity.. RM were produced by spray drying process. RM were administered to rats through oral as well as intratracheal route. The uptake of RIF by AM and liver was measured. NO was measured in bronchoalveolar lavage (BAL) fluid. SGOT and SGPT levels were measured in serum.. Significantly higher (p < 0.05) concentration of RIF was found in AM post intratracheal administration. NO production was also significantly higher but less than toxic level. SGOT and SGPT levels as well as uptake of RIF by liver were indicative of no hepatotoxicity post intratracheal administration.. Phagocytosis of RM post intratracheal administration leads to significantly higher drug level in AM as well as production of significantly higher levels of NO.. The administration of RM as dry powder inhalation (DPI) formulation may reduce treatment time of TB and chances of drug resistance TB.

    Topics: Administration, Inhalation; Administration, Oral; Animals; Chemistry, Pharmaceutical; Lung; Macrophages, Alveolar; Mycobacterium tuberculosis; Nitric Oxide; Phagocytosis; Rats; Rats, Wistar; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2014
A rifapentine-containing inhaled triple antibiotic formulation for rapid treatment of tubercular infection.
    Pharmaceutical research, 2014, Volume: 31, Issue:5

    The potential for rifapentine-containing oral therapeutic regimens to significantly shorten the current six-month anti-tubercular treatment regimen is confounded by high plasma protein binding of rifapentine. Inhaled aerosol delivery of rifapentine, a more potent anti-tubercular antibiotic drug, in combination with other first-line antibiotics may overcome this limitation to deliver a high drug dose at the pulmonary site of infection.. A formulation consisting of rifapentine, moxifloxacin and pyrazinamide, with and without leucine, was prepared by spray-drying. This formulation was assessed for its physico-chemical properties, in vitro aerosol performance and antimicrobial activity.. The antibiotic powders, with and without leucine, had similar median aerodynamic diameters of 2.58 ± 0.08 μm and 2.51 ± 0.06 μm, with a relatively high fine particle fraction of 55.5 ± 1.9% and 63.6 ± 2.0%, respectively. Although the powders were mostly amorphous, some crystalline peaks associated with the δ polymorph for the spray-dried crystalline pyrazinamide were identified.. Stabilisation of the powder with 10% w/w leucine and protection from moisture ingress was found to be necessary to prevent overt crystallisation of pyrazinamide after long-term storage. In vitro biological assays indicated antimicrobial activity was retained after spray-drying. Murine pharmacokinetic studies are currently underway.

    Topics: Administration, Inhalation; Aerosols; Animals; Antibiotics, Antitubercular; Humans; Mice; Microbial Sensitivity Tests; Microscopy, Electron, Scanning; Particle Size; Powder Diffraction; Powders; Rifampin; Tuberculosis

2014
Safety of rifabutin replacing rifampicin in the treatment of tuberculosis: a single-centre retrospective cohort study.
    The Journal of antimicrobial chemotherapy, 2014, Volume: 69, Issue:3

    The safety of rifabutin replacing rifampicin among adults having rifampicin-related adverse reactions (ARs) during the treatment of tuberculosis remains unknown.. From June 2006 to June 2010, a total of 2868 newly treated tuberculosis patients without HIV infection in a referral hospital were screened in this retrospective cohort study.. Among the screened patients, a total of 221 (8%) patients who received rifabutin replacing rifampicin were included. Of these patients, 158 (72%) tolerated rifabutin during treatment, but 47 (21%) and 16 (7%) experienced mild and severe rifabutin-related ARs (including neutropenia, severe hepatitis and uveitis), respectively, and needed to discontinue rifabutin. Those having previous rifampicin-related arthralgia, dermatological events and cholestasis had a higher AR recurrence rate (60%, 23% and 9%, respectively) than others (5% for hepatitis and gastrointestinal intolerance and 0% for flu-like syndrome, neutropenia and others; P < 0.01). Multivariate logistic regression analysis showed that females (OR 3.35; 95% CI 1.06-10.56; P = 0.04) and patients with hepatitis virus B (HBV) or hepatitis C virus (HCV) coinfection (OR 3.72; 95% CI 1.19-11.67; P = 0.02) were at a higher risk of rifabutin-related severe ARs. No development of new drug resistance and no relapse of tuberculosis were found during 2 years of follow-up.. Rifabutin replacing rifampicin was well tolerated in most adults who had rifampicin-related ARs. Females and those with HCV or HBV coinfection were more prone to rifabutin-related severe ARs and required more cautious monitoring.

    Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Female; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Male; Middle Aged; Retrospective Studies; Rifabutin; Rifampin; Tuberculosis

2014
GeneXpert MTB/RIF on bronchoalveolar lavage samples in children with suspected complicated intrathoracic tuberculosis: a pilot study.
    Pediatric pulmonology, 2014, Volume: 49, Issue:11

    Children with complicated intrathoracic tuberculosis (TB) require rapid confirmation of TB diagnosis and of drug susceptibility to institute appropriate therapy. In a pilot study, we evaluated the feasibility and potential utility of GeneXpert (Xpert) on bronchoalveolar lavage (BAL) samples in children undergoing routine diagnostic bronchoscopy.. We included children <13 years of age undergoing bronchoscopy for suspected complicated intrathoracic TB at Tygerberg Children's Hospital, October 1, 2012-May 15, 2013. A minimum of two respiratory specimens in addition to BAL were obtained from each child. In addition to fluorescent smear microscopy and automated liquid culture performed on all samples, BAL samples were analyzed by Xpert. Drug susceptibility was confirmed by GenoType(®) MTBDRplus.. Fourteen children (2 HIV positive, median age 16 months) were included. The Mantoux tuberculin skin test was positive in 11. On chest radiograph, six children had expansile pneumonia and nine had airway compression (one had both). The median duration of TB treatment before bronchoscopy was 8 days. TB was confirmed by either culture or Xpert from any sample in 11 (78%) children. Among 9/14 (64%) cases confirmed by culture, BAL Xpert was positive in 7 (78% sensitivity); in addition, Xpert confirmed 2 cases who had negative culture (14% additional diagnostic yield). Two drug resistant cases were identified: one by BAL Xpert and one from genotypic testing of a culture from gastric aspirate. All children were initiated on anti-TB treatment and responded well to therapy.. BAL Xpert resulted in additional diagnostic yield and also in the rapid detection of drug resistance in children with complicated intrathoracic TB. The clinical impact of this modality should be further evaluated in children.

    Topics: Adolescent; Antitubercular Agents; Bronchoalveolar Lavage Fluid; Bronchoscopy; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Humans; Infant; Male; Mycobacterium tuberculosis; Pilot Projects; Radiography; Rifampin; Tuberculin Test; Tuberculosis

2014
Inhaled Solid Lipid Microparticles to target alveolar macrophages for tuberculosis.
    International journal of pharmaceutics, 2014, Feb-28, Volume: 462, Issue:1-2

    The goal of the work was to evaluate an anti-tubercular strategy based on breathable Solid Lipid Microparticles (SLM) to target alveolar macrophages and to increase the effectiveness of the conventional tuberculosis (TB) therapy. Rifampicin loaded SLM composed of stearic acid and sodium taurocholate were characterized for aerodynamic diameter, surface charge, physical state of the components, drug loading and release as well as drug biological activity on Bacillus subtilis strain. Moreover, SLM cytotoxicity and cell internalization ability were evaluated on murine macrophages J774 cell lines by MTT test, cytofluorimetry and confocal laser microscopy. SLM exhibited aerodynamic diameter proper to be transported up to the alveolar epithelium, negative charged surface able to promote uptake by the macrophages and preserved drug antimicrobial activity. The negligible in vitro release of rifampicin indicated the capacity of the microparticle matrix to entrap the drug preventing its spreading over the lung fluid. In vitro studies on J774 cell lines demonstrated SLM non-cytotoxicity and ability to be taken up by cell cytoplasm. The microparticulate carrier, showing features suitable for the inhaled therapy and for inducing endocytosis by alveolar macrophages, could be considered promising in a perspective of an efficacious TB inhaled therapy by means of a Dry Powder Inhaler device.

    Topics: Administration, Inhalation; Animals; Antitubercular Agents; Bacillus subtilis; Cell Line; Drug Carriers; Drug Delivery Systems; Dry Powder Inhalers; Flow Cytometry; Lipids; Macrophages, Alveolar; Mice; Microscopy, Confocal; Microspheres; Particle Size; Rifampin; Stearic Acids; Taurocholic Acid; Tuberculosis

2014
Rifampicin-loaded 'flower-like' polymeric micelles for enhanced oral bioavailability in an extemporaneous liquid fixed-dose combination with isoniazid.
    Nanomedicine (London, England), 2014, Volume: 9, Issue:11

    Coadministration of rifampicin (RIF)/isoniazid (INH) is clinically recommended to improve the treatment of tuberculosis. Under gastric conditions, RIF undergoes fast hydrolysis (a pathway hastened by INH) and oral bioavailability loss.. We aimed to assess the chemical stabilization and the oral pharmacokinetics of RIF nanoencapsulated within poly(ε-caprolactone)-b-PEG-b-poly(ε-caprolactone) 'flower-like' polymeric micelles.. The chemical stability of RIF was evaluated in vitro under acid conditions with and without INH, and the oral pharmacokinetics of RIF-loaded micelles in rats was compared with those of a suspension coded by the US Pharmacopeia.. Nanoencapsulation decreased the degradation rate of RIF with respect to the free drug. Moreover, in vivo data showed a statistically significant increase of RIF oral bioavailability (up to 3.3-times) with respect to the free drug in the presence of INH.. Overall results highlight the potential of this nanotechnology platform to develop an extemporaneous liquid RIF/INH fixed-dose combination suitable for pediatric administration.

    Topics: Administration, Oral; Animals; Antitubercular Agents; Area Under Curve; Biological Availability; Chromatography, High Pressure Liquid; Drug Carriers; Ethylene Glycols; Hydrochloric Acid; Isoniazid; Male; Micelles; Nanomedicine; Particle Size; Polyesters; Polymers; Rats; Rats, Wistar; Rifampin; Solubility; Tuberculosis

2014
Rifampicin mono-resistant tuberculosis in France: a 2005-2010 retrospective cohort analysis.
    BMC infectious diseases, 2014, Jan-10, Volume: 14

    Rifampicin resistance is a risk factor for poor outcome in tuberculosis. Therefore, we sought to describe the characteristics and management of Rifampicin monoresistant (RMR) tuberculosis (TB) in France.. We conducted a retrospective cohort analysis in 2012 on RMR TB patients diagnosed in France between 2005 and 2010 by using a national laboratory network. A standardized questionnaire was used to collect basic demographic data, region of birth, history of TB, HIV-coinfection, alcohol use, and antituberculosis treatment. Outcome was assessed after at least 18 months of follow-up.. A total of 39 patients with RMR TB were reported (0.12% of all TB cases). Overall, 19 (49%) had a previous history of treatment, 9 (23%) were HIV-coinfected, and 24 (62%) were smear-positive. Patient with secondary RMR were more likely to have alcohol abuse (P = 0.04) and HIV-coinfection (p = 0.04). Treatment outcome could be assessed for 30 patients, the nine others being dead or lost to follow-up. A total of 20 (67%) of the 30 assessed were cured, 3 (10%) died, 3 (10%) relapsed, and 4 (13%) were lost to follow up. Four (13%) received less than 6 months of treatment, 3 did not have any modification of the standardized regimen, 13 (43%) received fluoroquinolones, 4 (13%) aminoglycosides, and 8 (26%) a combination of both.. RMR TB is a rare disease in France, and its management was heterogeneous. The lack of treatment standardization may be a consequence of low expertise and may lead to the unsatisfactory low success rate.

    Topics: Adult; Antitubercular Agents; Cohort Studies; Coinfection; Drug Resistance, Bacterial; Female; France; HIV Infections; HIV Seropositivity; Humans; Lost to Follow-Up; Male; Middle Aged; Retrospective Studies; Rifampin; Risk Factors; Treatment Outcome; Tuberculosis

2014
Correlation of plasma anti-tuberculosis drug levels with subsequent development of hepatotoxicity.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2014, Volume: 18, Issue:2

    To compare the free and total plasma drug concentrations of rifampicin (RMP), isoniazid and pyrazinamide in subjects with or without anti-tuberculosis drug-induced hepatotoxicity (DIH).. A total of 110 tuberculosis (TB) patients were administered daily anti-tuberculosis treatment and were prospectively followed for the development of DIH. Plasma drug levels were measured at 0, 1, 2 and 4 h on days 1, 7 and 14 of treatment. Plasma drug levels in 15 patients who developed DIH (cases) were compared with 95 patients who did not (controls).. Female sex, body mass index < 17 kg/m(2) and baseline serum albumin < 4 g/dl predicted risk of DIH on univariate analyses. Free and total plasma RMP levels (Cmax and AUC0-4) on days 1, 7 and 14 were significantly higher in cases compared to controls and predicted development of DIH. Day 7 total RMP Cmax and AUC0-4 were higher in cases (mean 26.73, standard deviation [SD] 5.72 and 47.58, SD 33.10) than in controls (7.87, SD 10.95 and 14.01, SD 10.69, respectively).. Plasma RMP levels were higher in cases than in controls and independently predicted subsequent development of DIH. The Cmax of Day 7 total RMP level (cut-off 12.50 mg/l) predicted subsequent development of DIH in 93.3% of the patients.

    Topics: Adult; Antitubercular Agents; Area Under Curve; Case-Control Studies; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Metabolic Clearance Rate; Prospective Studies; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis

2014
Do high rates of empirical treatment undermine the potential effect of new diagnostic tests for tuberculosis in high-burden settings?
    The Lancet. Infectious diseases, 2014, Volume: 14, Issue:6

    In tuberculosis-endemic settings, patients are often treated empirically, meaning that they are placed on treatment based on clinical symptoms or tests that do not provide a microbiological diagnosis (eg, chest radiography). New tests for tuberculosis, such as the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA), are being implemented at substantial cost. To inform policy and rationally drive implementation, data are needed for how these tests affect morbidity, mortality, transmission, and population-level tuberculosis burden. If people diagnosed by use of new diagnostics would have received empirical treatment a few days later anyway, then the incremental benefit might be small. Will new diagnostics substantially improve outcomes and disease burden, or simply displace empirical treatment? Will the extent and accuracy of empirical treatment change with the introduction of a new test? In this Personal View, we review emerging data for how empirical treatment is frequently same-day, and might still be the predominant form of treatment in high-burden settings, even after Xpert implementation; and how Xpert might displace so-called true-positive, rather than false-positive, empirical treatment. We suggest types of studies needed to accurately assess the effect of new tuberculosis tests and the role of empirical treatment in real-world settings. Until such questions can be addressed, and empirical treatment is appropriately characterised, we postulate that the estimated population-level effect of new tests such as Xpert might be substantially overestimated.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Point-of-Care Systems; Real-Time Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Species Specificity; Time Factors; Tuberculosis

2014
Intensified tuberculosis case-finding in HIV-positive adults managed at Ethiopian health centers: diagnostic yield of Xpert MTB/RIF compared with smear microscopy and liquid culture.
    PloS one, 2014, Volume: 9, Issue:1

    Detection of active tuberculosis (TB) before antiretroviral therapy (ART) initiation is important, but optimal diagnostic methods for use in resource-limited settings are lacking. We assessed the prevalence of TB, evaluated the diagnostic yield of Xpert MTB/RIF in comparison with smear microscopy and culture, and the impact of Xpert results on clinical management in HIV-positive adults eligible for ART at health centers in a region of Ethiopia.. Participants were prospectively recruited and followed up at 5 health centers. Trained nurses collected data on socio-demographic characteristics, medical history and symptoms, and performed physical examination. Two paired morning sputum samples were obtained, and lymph node aspirates in case of lymphadenopathy. Diagnostic yield of Xpert MTB/RIF in sputum was compared with smear microscopy and liquid culture.. TB was diagnosed in 145/812 participants (17.9%), with bacteriological confirmation in 137 (16.9%). Among bacteriologically confirmed cases, 31 were smear-positive (22.6%), 96 were Xpert-positive (70.1%), and 123 were culture-positive (89.8%). Xpert MTB/RIF increased the TB detection rate by 64 cases (47.4%) compared with smear microscopy. The overall sensitivity of Xpert MTB/RIF was 66.4%, and was not significantly lower when testing one compared with two samples. While Xpert MTB/RIF was 46.7% sensitive among patients with CD4 cell counts >200 cells/mm(3), this increased to 82.9% in those with CD4 cell counts ≤100 cells/mm(3). Compared with Xpert-positive TB patients, Xpert-negative cases had less advanced HIV and TB disease characteristics.. Previously undiagnosed TB is common among HIV-positive individuals managed in Ethiopian health centers. Xpert MTB/RIF increased TB case detection, especially in patients with advanced immunosuppression. An algorithm based on the use of a single morning sputum sample for individuals with negative sputum smear microscopy could be considered for intensified case finding in patients eligible for ART. However, technical and cost-effectiveness issues relevant for low-income countries warrant further study.

    Topics: Adult; Antibiotics, Antitubercular; Bacteriological Techniques; Drug Resistance, Bacterial; Ethiopia; Female; HIV Infections; Humans; Male; Mass Screening; Microscopy; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Prevalence; Prospective Studies; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2014
Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses.
    The Journal of antimicrobial chemotherapy, 2014, Volume: 69, Issue:5

    To describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children and evaluate the adequacy of steady-state exposures.. We used previously published data for 76 South African children with tuberculosis to describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid. Monte Carlo simulations were used to predict steady-state exposures in children following doses in fixed-dose combination tablets in accordance with the revised guidelines. Reference exposures were derived from an ethnically similar adult population with tuberculosis taking currently recommended doses.. The final models included allometric scaling of clearance and volume of distribution using body weight. Maturation was included for clearance of isoniazid and clearance and absorption transit time of rifampicin. For a 2-year-old child weighing 12.5 kg, the estimated typical oral clearances of rifampicin and pyrazinamide were 8.15 and 1.08 L/h, respectively. Isoniazid typical oral clearance (adjusted for bioavailability) was predicted to be 4.44, 11.6 and 14.6 L/h for slow, intermediate and fast acetylators, respectively. Higher oral clearance values in intermediate and fast acetylators also resulted from 23% lower bioavailability compared with slow acetylators.. Simulations based on our models suggest that with the new WHO dosing guidelines and utilizing available paediatric fixed-dose combinations, children will receive adequate rifampicin exposures when compared with adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. Further studies are needed to confirm these findings in children administered the revised dosages and to optimize pragmatic approaches to dosing.

    Topics: Antitubercular Agents; Child; Child, Preschool; Electronic Data Processing; Female; Humans; Infant; Isoniazid; Male; Models, Statistical; Pyrazinamide; Rifampin; South Africa; Tuberculosis

2014
Pharmacokinetics of etravirine in HIV-infected patients concomitantly treated with rifampin for tuberculosis.
    Infection, 2014, Volume: 42, Issue:4

    Etravirine is metabolized by three cytochrome P450 enzymes that are in turn induced by rifampin. Consequently, co-administration of etravirine and rifampin is not recommended. To date, however, no clinical studies exploring the drug-drug interaction of this combination have been conducted. Here we report two cases of off-label etravirine use concurrently with antitubercular treatment, dictated by the unavailability of other treatments. Plasma drug concentrations were monitored by regular measurements. Our results appear to confirm the increased metabolism of etravirine through the induction of cytochrome P450 enzymes, but the adequacy of drug levels in all of the measurements and subsequent virological suppression suggest that this drug interaction may not be clinically relevant.

    Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Drug Interactions; Female; HIV Infections; Humans; Nitriles; Plasma; Pyridazines; Pyrimidines; Rifampin; Tuberculosis

2014
Therapeutic drug monitoring and pharmacogenetic study of HIV-infected ethnic Chinese receiving efavirenz-containing antiretroviral therapy with or without rifampicin-based anti-tuberculous therapy.
    PloS one, 2014, Volume: 9, Issue:2

    Plasma efavirenz concentrations in HIV-infected patients with tuberculosis (TB) may be affected by cytochrome P450 (CYP) 2B6 single-nucleotide polymorphisms and concurrent rifampicin use. We aimed to investigate the effects of CYP2B6 G516T polymorphisms and concomitant rifampicin use on the plasma efavirenz concentrations in HIV-infected Taiwanese.. HIV-infected patients with or without TB who had received combination antiretroviral therapy containing efavirenz (600 mg daily) for two weeks or greater were enrolled for determinations of CYP2B6 G516T polymorphism and plasma efavirenz concentrations with the use of polymerase-chain-reaction restriction fragment-length polymorphism and high-performance liquid chromatography, respectively.. From October 2009 to August 2012, 171 HIV-infected patients, including 18 with TB, were enrolled 113 (66.1%) with CYP2B6 G516G, 55 (32.2%) GT, and 3 (1.8%) TT genotype. Patients receiving rifampicin had a significantly lower median plasma efavirenz concentration than the control group (2.16 vs 2.92 mg/L, P = 0.003); however, all patients achieved target plasma concentration (>1 mg/L). Patients with GT or TT genotype had a significantly higher plasma concentration than those with GG genotype (2.50 vs 3.47 mg/L for GT genotype and 8.78 mg/L for TT genotype, P<0.001). Plasma efavirenz concentration >4 mg/L was noted in 38 (22.2%) patients, which was associated with a lower weight (per 10-kg increase, odds ratio, 0.52; 95% confidence interval, 0.33-0.83) and GT or TT genotype (odds ratio, 4.35; 95% confidence interval, 1.97-9.59) in multivariate analysis.. Despite combination with rifampicin, sufficient plasma efavirenz concentrations can be achieved in HIV-infected Taiwanese with TB who receive efavirenz 600 mg daily. Carriage of CYP2B6 516 GT and TT genotypes and a lower weight are associated with higher plasma efavirenz concentrations.

    Topics: Adult; Aged; Aged, 80 and over; Alkynes; Anti-HIV Agents; Antitubercular Agents; Aryl Hydrocarbon Hydroxylases; Asian People; Benzoxazines; Body Weight; China; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Monitoring; Drug Therapy, Combination; Ethnicity; Female; HIV Infections; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis; Young Adult

2014
TB incidence and characteristics in the remote gulf province of Papua New Guinea: a prospective study.
    BMC infectious diseases, 2014, Feb-20, Volume: 14

    The incidence and characteristics of tuberculosis (TB) in remote areas of Papua New Guinea (PNG) are largely unknown. The purpose of our study was to determine the incidence of TB in the Gulf Province of PNG and describe disease characteristics, co-morbidities and drug resistance profiles that could impact on disease outcomes and transmission.. Between March 2012 and June 2012, we prospectively collected data on 274 patients presenting to Kikori Hospital with a presumptive diagnosis of TB, and on hospital inpatients receiving TB treatment during the study period. Sputum was collected for microscopy, GeneXpert analysis, culture and genotyping of isolates.. We estimate the incidence of TB in Kikori to be 1290 per 100,000 people (95% CI 1140 to 1460) in 2012. The proportion of TB patients co-infected with HIV was 1.9%. Three of 32 TB cases tested were rifampicin resistant. Typing of nine isolates demonstrated allelic diversity and most were related to Beijing strains.. The incidence of TB in Kikori is one of the highest in the world and it is not driven by HIV co-infection. The high incidence and the presence of rifampicin resistant warrant urgent attention to mitigate substantial morbidity in the region.

    Topics: Adolescent; Adult; Alleles; Antitubercular Agents; Child; Child, Preschool; Coinfection; Female; Genotype; HIV Infections; Humans; Incidence; Male; Middle Aged; Papua New Guinea; Prospective Studies; Rifampin; Risk Factors; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2014
Tuberculosis in solid-organ transplant recipients: disease characteristics and outcomes in the current era.
    Progress in transplantation (Aliso Viejo, Calif.), 2014, Volume: 24, Issue:1

    We determined the characteristics of posttransplant tuberculosis and the impact of rifampin-based antituberculosis regimens on outcomes in the current era. Patients comprised 64 transplant recipients with tuberculosis, divided into 2 consecutive cohorts: an earlier cohort (cases occurring from 2003 to 2007) and a later cohort (cases from 2008 to 2011). Patients from the later versus earlier era had tuberculosis develop later after transplant (odds ratio, 1.01; 95% CI, 1.00-1.02; P= .05), were more likely to be liver transplant recipients (odds ratio, 4.52; 95% CI, 1.32-15.53; P= .02), and were more likely to receive tacrolimus-based immunosuppression (odds ratio, 3.24; 95% CI, 1.14-9.19; P= .03). Mortality rate was 10% in the later cohort and 21% in the earlier cohort (P= .20). Rifampin-based treatment was less likely to be used in patients with prior rejection (P= .04). However, neither rejection rate (P= .71) nor mortality (P= .93) after tuberculosis differed between recipients who received rifampin and recipients who did not. Thus, notable changes have occurred in the epidemiological characteristics of tuberculosis in transplant recipients. Overall mortality rate has improved, with about 90% of the patients now surviving after tuberculosis.

    Topics: Adult; Aged; Antitubercular Agents; Female; Graft Rejection; Humans; Immunosuppressive Agents; Male; Middle Aged; Opportunistic Infections; Organ Transplantation; Rifampin; Treatment Outcome; Tuberculosis

2014
Diagnostic accuracy of Xpert MTB/RIF for extrapulmonary tuberculosis specimens: establishing a laboratory testing algorithm for South Africa.
    Journal of clinical microbiology, 2014, Volume: 52, Issue:6

    South Africa implemented Xpert MTB/RIF as the initial diagnostic test for pulmonary tuberculosis (TB). Xpert MTB/RIF's accuracy for diagnosing extrapulmonary tuberculosis (EPTB) was investigated. EPTB specimens (n = 7,916) from hospitalized patients received over a 6-month period at a high-throughput TB referral laboratory in Johannesburg were investigated. Large-volume specimens were centrifuged, tissue biopsy specimens homogenized, and all specimens checked for growth of contaminating bacteria on blood agar. Contaminated samples received NALC-NaOH (N-acetyl-l-cysteine-sodium hydroxide) decontamination prior to liquid culture. Residual specimens (volumes > 1 ml) after inoculation of culture (n = 1,175) were tested using the Xpert MTB/RIF sputum protocol. Using culture as the reference, Xpert MTB/RIF's overall sensitivity was 59% (95% confidence interval [95% CI], 53% to 65%) and specificity was 92% (CI, 90% to 94%), with the highest sensitivities of 91% (95% CI, 78% to 97%) for pus, 80% (95% CI, 56% to 94%) for lymph node aspirates, and 51% (95% CI, 44% to 58%) for fluids (ascitic, 59%; pleural, 47%). A difference in sensitivities was noticed between specimens classified as having a thick (87% [95% CI, 76% to 94%]) versus clear (watery) (48% [95% CI, 36% to 61%]) appearance. This was unchanged with traces of blood (52% [95% CI, 44% to 60%]) or precentrifugation (57% [95% CI, 28% to 82%]) among clear specimens. Xpert MTB/RIF generated an additional 124 specimen results that were contaminated by Mycobacterial Growth Indicator Tubes (MGIT; 10.5%) and diagnosed rifampin (RIF) resistance earlier (9.6% [25/260]). Xpert MTB/RIF's performance on EPTB specimens provides very promising results and should be considered for incorporation into national TB guidelines. Xpert MTB/RIF is less affected by contaminating bacteria and reduces laboratory labor and diagnostic delay compared to traditional methods.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Antitubercular Agents; Bacteriological Techniques; Body Fluids; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Humans; Infant; Infant, Newborn; Lymph Nodes; Male; Middle Aged; Molecular Diagnostic Techniques; Rifampin; Sensitivity and Specificity; South Africa; Tuberculosis; Young Adult

2014
GeneXpert(®) MTB/RIF in low prevalence settings: a UK laboratory perspective.
    The Journal of infection, 2014, Volume: 69, Issue:2

    Topics: Antibiotics, Antitubercular; Drug Resistance, Multiple, Bacterial; Humans; Mycobacterium tuberculosis; Prevalence; Rifampin; Tuberculosis; United Kingdom

2014
Concordance between molecular and phenotypic testing of Mycobacterium tuberculosis complex isolates for resistance to rifampin and isoniazid in the United States.
    Journal of clinical microbiology, 2014, Volume: 52, Issue:6

    Multidrug-resistant (MDR) isolates of Mycobacterium tuberculosis complex (MTBC) are defined by resistance to at least rifampin (RMP) and isoniazid (INH). Rapid and accurate detection of multidrug resistance is essential for effective treatment and interruption of disease transmission of tuberculosis (TB). Overdiagnosis of MDR TB may result in treatment with second-line drugs that are more costly, less effective, and more poorly tolerated than first-line drugs. CDC offers rapid confirmation of MDR TB by the molecular detection of drug resistance (MDDR) for mutations associated with resistance to RMP and INH along with analysis for resistance to other first-line and second-line drugs. Simultaneously, CDC does growth-based phenotypic drug susceptibility testing (DST) by the indirect agar proportion method for a panel of first-line and second-line antituberculosis drugs. We reviewed discordance between molecular and phenotypic DST for INH and RMP for 285 isolates submitted as MTBC to CDC from September 2009 to February 2011. We compared CDC's results with those from the submitting public health laboratories (PHL). Concordances between molecular and phenotypic testing at CDC were 97.4% for RMP and 92.5% for INH resistance. Concordances between CDC's molecular testing and PHL DST results were 93.9% for RMP and 90.0% for INH. Overall concordance between CDC molecular and PHL DST results was 91.7% for RMP and INH collectively. Discordance was primarily attributable to the absence of known INH resistance mutations in isolates found to be INH resistant by DST and detection of mutations associated with low-level RMP resistance in isolates that were RMP susceptible by phenotypic DST. Both molecular and phenotypic test results should be considered for the diagnosis of MDR TB.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Genotyping Techniques; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis; United States

2014
Profiling of rpoB mutations and MICs for rifampin and rifabutin in Mycobacterium tuberculosis.
    Journal of clinical microbiology, 2014, Volume: 52, Issue:6

    Resistance to rifampin (RIF) and rifabutin (RFB) in Mycobacterium tuberculosis is associated with mutations within an 81-bp region of the rpoB gene (RIF resistance-determining region [RRDR]). Previous studies have shown that certain mutations in this region are more likely to confer high levels of RIF resistance, while others may be found in phenotypically susceptible isolates. In this study, we sought to determine the relationship between the MICs of RIF and RFB and rpoB RRDR mutations in 32 multidrug-resistant (MDR), 4 RIF-monoresistant, and 5 susceptible M. tuberculosis clinical isolates. The MICs were determined using the MGIT 960 system. Mutations in the rpoB RRDR were determined by Sanger sequencing. RpoB proteins with mutations S531L (a change of S to L at position 531), S531W, H526Y, and H526D and the double mutation D516A-R529Q were associated with high MICs for RIF and RFB. Five isolates carrying the mutations L511P, H526L, H526N, and D516G-S522L were found to be susceptible to RIF. Several mutations were associated with resistance to RIF and susceptibility to RFB (F514FF, D516V, and S522L). Whole-genome sequencing of two MDR isolates without rpoB RRDR mutations revealed a mutation outside the RRDR (V146F; RIF MIC of 50 μg/ml). The implications of the polymorphisms identified in the second of these isolates in RIF resistance need to be further explored. Our study further establishes a correlation between the mutations and the MICs of RIF and, also, RFB in M. tuberculosis. Several rpoB mutations were identified in RIF- and RFB-susceptible isolates. The clinical significance of these findings requires further exploration. Until then, a combination of phenotypic and molecular testing is advisable for drug susceptibility testing.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Genome, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifabutin; Rifampin; Sequence Analysis, DNA; Tuberculosis

2014
In vitro-in vivo activity relationship of substituted benzimidazole cell division inhibitors with activity against Mycobacterium tuberculosis.
    Tuberculosis (Edinburgh, Scotland), 2014, Volume: 94, Issue:3

    Structure based drug design was used to develop a compound library of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles. Three structural analogs, SB-P1G10, SB-P8B2 and SB-P3G2 were selected from this library for advanced study. In vitro studies revealed that SB-P8B2 and SB-P3G2 had sigmoidal kill-curves while in contrast SB-P1G10 showed a narrow zonal susceptibility. The in vitro studies also demonstrated that exposure to SB-P8B2 or SB-P3G2 was bactericidal, while SB-P1G10 treatment never resulted in complete killing. The dose curves for the three compounds against clinical isolates were comparable to their respective dose curves in the laboratory strain of Mycobacterium tuberculosis. SB-P8B2 and SB-P3G2 exhibited antibacterial activity against non-replicating bacilli under low oxygen conditions. SB-P3G2 and SB-P1G10 were assessed in acute short-term animal models of tuberculosis, which showed that SB-P3G2 demonstrated activity against M. tuberculosis. Together, these studies reveal an in vitro-in vivo relationship of the 2,5,6-trisubstituted benzimidazoles that serves as a criterion for advancing this class of cell division inhibitors into more resource intensive in vivo efficacy models such as the long-term murine model of tuberculosis and Pre-IND PK/PD studies. Specifically, these studies are the first demonstration of efficacy and an in vitro-in vivo activity relationship for 2,5,6-trisubstituted benzimidazoles. The in vivo activity presented in this manuscript substantiates this class of cell division inhibitors as having potency and efficacy against M. tuberculosis.

    Topics: Animals; Antitubercular Agents; Benzimidazoles; Cell Division; Disease Models, Animal; Drug Combinations; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxygen; Rifampin; Tuberculosis

2014
Why did the FDA approve efavirenz 800 mg when co-administered with rifampin?
    International journal of clinical pharmacology and therapeutics, 2014, Volume: 52, Issue:6

    Literature reports regarding the efficacy of efavirenz (EFV) 600 mg with rifampin (RIF) are not consistent. Evaluation of a drug-drug interaction (DDI) study and supportive semi-mechanistic population pharmacokinetic (PK) analyses were undertaken to help delineate this issue.. DDI study and supportive semi-mechanistic population PK analyses were provided by BMS. Population PK analysis was based on six studies with intensive EFV PK sampling. An ACTG study with sparse PK sampling was used for model evaluation. Simulations compared EFV exposure at various doses in combination with RIF to EFV exposures at 600 mg once daily (QD). Effects of CYP2B6 genotypes on the magnitude of EFV-RIF interaction were also explored.. In DDI study, co-administering EFV 600 mg QD and RIF reduced mean EFV exposure by ~ 30%. Population PK model provided acceptable predictive performance of central tendency and variability for EFV C0, Cmax, and AUC. Simulations predicted that increasing EFV to 800 mg QD with RIF would result in EFV AUC and Cmax similar to EFV 600 mg QD alone. EFV AUC and Cmax were ~ 2 times higher in subjects with reduced function CYP2B6 genotypes. However, the RIF effect was consistent across all genotypes. EFV dose adjustment to 800 mg QD did not increase the risk of overexposure compared to 600 mg EFV QD within each genotype.. Dose adjustment based on matching systemic exposure was recommended to mitigate the potential for sub-therapeutic EFV exposures. Our review did not reveal any safety concerns in subjects receiving EFV 800 mg QD with RIF.

    Topics: Alkynes; Antibiotics, Antitubercular; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Coinfection; Computer Simulation; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Administration Schedule; Drug Approval; Drug Dosage Calculations; Drug Interactions; Genotype; HIV Infections; Humans; Models, Biological; Phenotype; Polypharmacy; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis; United States; United States Food and Drug Administration

2014
An unusual cause of breast lump: isolated tuberculosis of the breast.
    The American journal of tropical medicine and hygiene, 2014, Volume: 90, Issue:5

    A 60-year-old woman presented with a painful lump of 4 months duration in her right breast. She denied any history of breast trauma or family history of breast cancer. Physical examination detected a firm, tender mass in the upper inner quadrant of her right breast without an associated sinus tract. Cytology from fine-needle aspiration of the swelling showed epithelioid cells, lymphohistocytic aggregates, and necrosis. Diagnosis was confirmed by the identification of acid-fast bacilli in tissue sections using Ziehl-Neelsen staining.

    Topics: Antitubercular Agents; Biopsy, Fine-Needle; Breast Diseases; Ethambutol; Female; Humans; Isoniazid; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

2014
[Evaluation of the Xpert MTB/RIF assay for the diagnosis of pulmonary and extrapulmonary tuberculosis in an intermediate-prevalence setting].
    Mikrobiyoloji bulteni, 2014, Volume: 48, Issue:2

    Early and accurate detection of tuberculosis (TB) is a global priority for TB control. In order to obtain results in a short period of time, nucleic acid amplification tests are increasingly used worldwide for the rapid diagnosis of tuberculosis. The Xpert MTB/RIF® (Cepheid, USA) is a commercially available, real-time PCR-based assay, which can detect both TB and resistance to rifampicin directly in clinical samples. The aim of this study was to evaluate the performance of Xpert MTB/RIF assay for M.tuberculosis detection in pulmonary and extrapulmonary clinical samples in routine laboratory practice in Turkey, an intermediate-prevalence setting. A total of 2639 clinical specimens, 1611 of which were pulmonary and 1028 were extrapulmonary, were included in the study. The results of Xpert MTB/RIF assay were evaluated by comparing the results with those obtained by culture [BACTEC MGIT 960 (Becton Dickinson, USA) and Löwenstein Jensen medium]. Overall sensitivity, specificity, positive and negative predictive values of Xpert MTB/RIF assay were determined as 73.9%, 98.6%, 79.6% and 98.1%, respectively. These values were calculated as 80.8%, 98.8%, 84.9% and 98.4% for pulmonary specimens, and 58.2%, 98.4%, 66.7% and 97.7% for extrapulmonary specimens. The sensitivity and specificity were 100% and 58.1%, respectively, for acid-fast bacilli (AFB) smear-positive specimens, 39.7% and 99.1%, respectively for smear-negative specimens. The sensitivity and specificity were 100% and 76.2% for smear-positive pulmonary specimens; 100% and 20% for smear-positive extrapulmonary specimens; 47.8% and 99.1% for smear-negative pulmonary specimens; and 28.2% and 99.2% for smear-negative extrapulmonary specimens, respectively. The sensitivity and specificity of microscopic examination were found to be 56.7% and 98.7% for all specimens; 63.2% and 98.6% for pulmonary specimens; and 41.8% and 99% for extrapulmonary specimens, respectively. Rifampicin resistance was detected by Xpert MTB/RIF assay in only two specimens, however, rifampicin resistance was failed to be detected by BACTEC MGIT 960 TB method in one of these samples. Xpert MTB/RIF assay appeared to be a reliable method for the diagnosis of TB for AFB smear-positive samples, but less sensitive for smear-negative samples, particularly for extrapulmonary samples which include low numbers of bacilli. However, we concluded that the MTB/RIF is a useful assay for rapid diagnosis of tuberculosis, considering that the results can

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Predictive Value of Tests; Prevalence; Real-Time Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Pulmonary; Turkey

2014
Manufacturer stands by Xpert tuberculosis test after India study questions its reliability.
    BMJ (Clinical research ed.), 2014, May-16, Volume: 348

    Topics: Drug Resistance, Bacterial; Humans; India; Mycobacterium tuberculosis; Reproducibility of Results; Rifampin; Tuberculosis

2014
Cervical lymphadenopathy--pitfalls of blind antitubercular treatment.
    Journal of health, population, and nutrition, 2014, Volume: 32, Issue:1

    Tuberculosis (TB) is the most common cause of cervical lymphadenopathy in the TB-endemic zone, like India but it can also mimic other diseases. Four cases of cervical lymphadenopathy presented to us as initial treatment failure after completion of six months of antitubercular drugs (ATD), including rifampicin, isoniazid, pyrazinamide, and ethambutol. All were diagnosed as having tuberculosis either by fine needle aspiration cytology or clinically from outside our institution. In one case, tuberculosis was the final diagnosis but, unfortunately, it was multidrug-resistant. In other three cases, Hodgkin disease, Non-Hodgkin lymphoma, and Kikuchi's disease were the diagnoses. In resource-poor countries, like India, which is also a TB-endemic zone, TB should be the first diagnosis in all cases of chronic cervical lymphadenopathy, based on clinical and/or cytological evidences. So, they were correctly advised antitubercular therapy (ATT) initially. Sometimes, TB mimics other aetiologies where apparent initial improvement with ATT finally results in treatment failure. Hence, investigations for microbiological and histopathological diagnosis are warranted, depending on the resources and feasibility. If these tests are not routinely available, the patients should be under close monitoring so that lymphoma, drug-resistant TB, or other aetiologies of cervical lymphadenopathy are not missed. Patients with cervical lymphadenopathy rarely presents acutely; so, a physician can take the opportunity of histopathological study of lymphnode tissue.

    Topics: Adolescent; Adult; Antitubercular Agents; Biopsy; Diagnostic Errors; Ethambutol; Female; Histiocytic Necrotizing Lymphadenitis; Hodgkin Disease; Humans; India; Isoniazid; Lymphoma, Non-Hodgkin; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2014
Simvastatin increases the in vivo activity of the first-line tuberculosis regimen.
    The Journal of antimicrobial chemotherapy, 2014, Volume: 69, Issue:9

    The need to develop new, improved treatments for tuberculosis (TB) remains urgent, and the repurposing of existing drugs represents a possible shortcut to market. Recently, there has been significant interest in host-directed adjuvant therapy to enhance bacillary killing. HMG-CoA reductase inhibitors (statins), which are among the most commonly prescribed drugs, have immunomodulatory properties and improve the clinical outcomes of bacterial infections.. We studied the tuberculocidal activity of simvastatin alone and in combination with first-line anti-TB drugs in J774 macrophages and during chronic TB infection.. Exposure to 5 μM simvastatin significantly increased the tuberculocidal activity of isoniazid in J774 macrophages at Day 3 after infection versus isoniazid alone (P=0.02). Similarly, relative to the standard oral regimen of rifampicin (10 mg/kg), isoniazid (10 mg/kg) and pyrazinamide (150 mg/kg) given five times weekly, the addition of 25 mg/kg simvastatin enhanced bacillary killing, reducing the number of lung cfu by an additional 1 log10 at Day 28 (P<0.01) and by a further 1.25 log10 at Day 56 (P<0.01).. The potential additive activity of simvastatin to first-line TB treatment holds promise. However, further studies to identify the optimal statin and dosing are required. In addition the ability of combination treatment with statins to accelerate the time required to achieve a stable cure remains to be explored.

    Topics: Animals; Antitubercular Agents; Bacterial Load; Cell Line; Colony Count, Microbial; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Isoniazid; Lung; Macrophages; Mice, Inbred BALB C; Pyrazinamide; Rifampin; Simvastatin; Treatment Outcome; Tuberculosis

2014
Protective efficacy of piperine against Mycobacterium tuberculosis.
    Tuberculosis (Edinburgh, Scotland), 2014, Volume: 94, Issue:4

    Piperine a trans-trans isomer of 1-piperoyl-piperidine was evaluated for its immunomodulatory activity to enhance the efficacy of rifampicin in a murine model of Mycobacterium tuberculosis infection. In-vitro immunomodulation of piperine was tested on mouse splenocytes for lymphocyte proliferation, cytokine production and macrophage activation. Protective efficacy of piperine was tested in a mice infection model of M. tuberculosis for the activation of Th-1 response and synergistic combination efficacy with rifampicin. Murine splenocytes exposed to piperine exhibited proliferation of T and B cell, increased Th-1 cytokines and enhanced macrophage activation. Piperine (1 mg/kg) in mice infected with M. tuberculosis activated the differentiation of T cells into Th-1 sub-population (CD4+ / CD8+ subsets). There was an increase in secretion of Th-1 cytokines (IFN-γ and IL-2) by these cells. The qRT-PCR studies revealed corresponding increases in the mRNA transcripts of IFN-γ and IL-2 in the infected lung tissues. Combination of piperine and rifampicin (1 mg/kg) exhibited better efficacy of and resulted in additional 1.4 to 0.8 log reduction in lung cfu as compared to rifampicin alone. The up-regulation of Th1 immunity by piperine can be synergistically combined with rifampicin to improve its therapeutic efficacy in immune-compromised TB patients.

    Topics: Alkaloids; Animals; Antitubercular Agents; Benzodioxoles; Cell Proliferation; Cells, Cultured; Colony Count, Microbial; Drug Combinations; Drug Evaluation, Preclinical; Immunophenotyping; Interferon-gamma; Interleukin-2; Lung; Lymphocyte Activation; Macrophage Activation; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nitric Oxide; Piperidines; Polyunsaturated Alkamides; Rifampin; RNA, Messenger; Spleen; Th1 Cells; Tuberculosis

2014
Evaluation of Mycobacterium tuberculosis cross-resistance to isoniazid, rifampicin and levofloxacin with their respective structural analogs.
    The Journal of antibiotics, 2014, Volume: 67, Issue:11

    The emergence of drug-resistant, multidrug-resistant and extensively drug-resistant tuberculosis (TB) is of major public health concern in several countries. In this study, the pharmacodynamic relationships among the structural analogs of antibiotics belonging to the same family were taken into consideration. The aim of this study was to compare the susceptibility of Mycobacterium tuberculosis to isoniazid (INH), rifampicin and levofloxacin (LX) to their respective structural analogs, which are frequently used as second-line agents. The microplate colorimetric method was used to determine the MIC to INH, ethionamide (ETH), rifampicin, rifabutin, LX and moxifloxacin (MOX) in clinical isolates previously shown to be drug resistant. Mutations conferring drug resistance were detected by GenoType MTBDR plus and DNA sequencing. INH and ETH cross-resistance was found in 95.12% (39/41) of the INH-resistant isolates harboring a mutation in inhAP or inhA open reading frame, but rifabutin cross-resistance was observed in 90.0% (63/70) of the clinical isolates originally shown to be resistant to rifampicin. Isolates with high LX-resistance levels also showed high MIC to MOX. Fluoroquinolone cross-resistance was verified in isolates containing the gyrA94 and the gyrA90 mutation. In general, isolates with high INH, rifampicin and LX-resistance levels also displayed high MIC values for their structural analogs. These findings suggest the need to test in vitro the second-line drugs before their incorporation in the therapeutic schemes.

    Topics: Antitubercular Agents; Base Sequence; Colorimetry; Drug Resistance, Bacterial; Ethionamide; Fluoroquinolones; Humans; Isoniazid; Levofloxacin; Microbial Sensitivity Tests; Moxifloxacin; Mutation; Mycobacterium tuberculosis; Open Reading Frames; Rifabutin; Rifampin; Sequence Analysis, DNA; Tuberculosis

2014
Double-dose lopinavir-ritonavir in combination with rifampicin-based anti-tuberculosis treatment in South Africa.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2014, Volume: 18, Issue:6

    The optimal treatment for tuberculosis (TB) in human immunodeficiency virus (HIV) infected patients in resource-poor settings receiving lopinavir-ritonavir (LPV/r) based second-line antiretroviral therapy (ART) has yet to be determined. In South Africa, clinicians are advised to use 'double-dose' LPV/r dosed at 800 mg/200 mg twice daily during anti-tuberculosis treatment.. We conducted a retrospective study of HIV-infected patients who received ≥2 months of double-dose LPV/r-based ART during concomitant rifampicin-containing anti-tuberculosis treatment. We used standard definitions for TB and HIV outcomes; virological failure was defined as a viral load >1000 copies/ml. During co-administration, gastro-intestinal toxicity occurred in 9/25 (36%) patients, a symptomatic rise in aspartate aminotransferase or alanine aminotransferase of any grade was noted in 3 (12%), with two Grade 3 events, and 3 (12%) patients required treatment discontinuation. Outcomes were favourable, with 20/25 (80%) patients achieving TB treatment success and virological failure observed among 3 (12%) patients during co-administration.. We found the use of double-dose LPV/r during simultaneous standard anti-tuberculosis treatment to be an effective and reasonably well tolerated interim strategy.

    Topics: Adult; Antibiotics, Antitubercular; Coinfection; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Middle Aged; Retrospective Studies; Rifampin; Ritonavir; South Africa; Treatment Outcome; Tuberculosis; Viral Load; Young Adult

2014
Nanoparticles as drug delivery system against tuberculosis in zebrafish embryos: direct visualization and treatment.
    ACS nano, 2014, Jul-22, Volume: 8, Issue:7

    Nanoparticles (NPs) enclosing antibiotics have provided promising therapy against Mycobacterium tuberculosis (Mtb) in different mammalian models. However, the NPs were not visualized in any of these animal studies. Here, we introduce the transparent zebrafish embryo as a system for noninvasive, simultaneous imaging of fluorescent NPs and the fish tuberculosis (TB) agent Mycobacterium marinum (Mm). The study was facilitated by the use of transgenic lines of macrophages, neutrophils, and endothelial cells expressing fluorescent markers readily visible in the live vertebrate. Intravenous injection of Mm led to phagocytosis by blood macrophages. These remained within the vasculature until 3 days postinfection where they started to extravasate and form aggregates of infected cells. Correlative light/electron microscopy revealed that these granuloma-like structures had significant access to the vasculature. Injection of NPs induced rapid uptake by both infected and uninfected macrophages, the latter being actively recruited to the site of infection, thereby providing an efficient targeting into granulomas. Rifampicin-loaded NPs significantly improved embryo survival and lowered bacterial load, as shown by quantitative fluorescence analysis. Our results argue that zebrafish embryos offer a powerful system for monitoring NPs in vivo and rationalize why NP therapy was so effective against Mtb in earlier studies; bacteria and NPs share the same cellular niche.

    Topics: Animals; Anti-Bacterial Agents; Biological Transport; Coumarins; Drug Carriers; Embryo, Nonmammalian; Granuloma; Lactic Acid; Macrophages; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Nanoparticles; Optical Imaging; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rhodamines; Rifampin; Thiazoles; Tuberculosis; Zebrafish

2014
[Surveillance of antituberculosis-drug resistance in Cuba, 2010-2011].
    Biomedica : revista del Instituto Nacional de Salud, 2014, Volume: 34 Suppl 1

    Antituberculosis-drug resistance surveillance is very important to identify multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis isolates.. To determine the prevalence of resistance in M. tuberculosis strains isolated between 2010 and 2011, and to demonstrate the laboratory performance in the external quality control of drug susceptibility testing.. A prospective longitudinal study was carried out to determine antituberculosis-drug resistance in 657 M. tuberculosis isolates obtained throughout the country. The nitrate reductase assay was used to detect resistance to isoniazid and rifampin. The proportion method was performed to confirm resistance to these drugs and to further investigate in multidrug-resistant isolates their susceptibility to streptomycin, ethambutol, ofloxacin, kanamycin and capreomycin. Additionally, as part of external quality control, susceptibility was evaluated in two M. tuberculosis strain panels.. In 95.69% of the isolates recovered from new tuberculosis cases, and in 72.64 % of isolates from previously treated patients we found susceptibility to isoniazid and rifampicin; multidrug resistance was 1,03 and 10.38%, respectively. We found two extensively resistant isolates. Except for ethambutol and capreomycin, the efficiency of all other drugs was 100% in the external quality control.. The study confirmed the low prevalence of M. tuberculosis multidrug-resistant isolates in Cuba. This result was confirmed by the external quality control of drug susceptibility testing.

    Topics: Antitubercular Agents; Clone Cells; Cuba; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Laboratories; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Population Surveillance; Prevalence; Prospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2014
Pros and cons of the tuberculosis drugome approach--an empirical analysis.
    PloS one, 2014, Volume: 9, Issue:6

    Drug-resistant Mycobacterium tuberculosis (MTB), the causative pathogen of tuberculosis (TB), has become a serious threat to global public health. Yet the development of novel drugs against MTB has been lagging. One potentially powerful approach to drug development is computation-aided repositioning of current drugs. However, the effectiveness of this approach has rarely been examined. Here we select the "TB drugome" approach--a protein structure-based method for drug repositioning for tuberculosis treatment--to (1) experimentally validate the efficacy of the identified drug candidates for inhibiting MTB growth, and (2) computationally examine how consistently drug candidates are prioritized, considering changes in input data. Twenty three drugs in the TB drugome were tested. Of them, only two drugs (tamoxifen and 4-hydroxytamoxifen) effectively suppressed MTB growth at relatively high concentrations. Both drugs significantly enhanced the inhibitory effects of three first-line anti-TB drugs (rifampin, isoniazid, and ethambutol). However, tamoxifen is not a top-listed drug in the TB drugome, and 4-hydroxytamoxifen is not approved for use in humans. Computational re-examination of the TB drugome indicated that the rankings were subject to technical and data-related biases. Thus, although our results support the effectiveness of the TB drugome approach for identifying drugs that can potentially be repositioned for stand-alone applications or for combination treatments for TB, the approach requires further refinements via incorporation of additional biological information. Our findings can also be extended to other structure-based drug repositioning methods.

    Topics: Antitubercular Agents; Bacterial Proteins; Drug Combinations; Drug Resistance, Bacterial; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tamoxifen; Tuberculosis

2014
Analysis of combination drug therapy to develop regimens with shortened duration of treatment for tuberculosis.
    PloS one, 2014, Volume: 9, Issue:7

    Tuberculosis remains a worldwide problem, particularly with the advent of multi-drug resistance. Shortening therapy duration for Mycobacterium tuberculosis is a major goal, requiring generation of optimal kill rate and resistance-suppression. Combination therapy is required to attain the goal of shorter therapy.. Our objective was to identify a method for identifying optimal combination chemotherapy. We developed a mathematical model for attaining this end. This is accomplished by identifying drug effect interaction (synergy, additivity, antagonism) for susceptible organisms and subpopulations resistant to each drug in the combination.. We studied the combination of linezolid plus rifampin in our hollow fiber infection model. We generated a fully parametric drug effect interaction mathematical model. The results were subjected to Monte Carlo simulation to extend the findings to a population of patients by accounting for between-patient variability in drug pharmacokinetics.. All monotherapy allowed emergence of resistance over the first two weeks of the experiment. In combination, the interaction was additive for each population (susceptible and resistant). For a 600 mg/600 mg daily regimen of linezolid plus rifampin, we demonstrated that >50% of simulated subjects had eradicated the susceptible population by day 27 with the remaining organisms resistant to one or the other drug. Only 4% of patients had complete organism eradication by experiment end.. These data strongly suggest that in order to achieve the goal of shortening therapy, the original regimen may need to be changed at one month to a regimen of two completely new agents with resistance mechanisms independent of the initial regimen. This hypothesis which arose from the analysis is immediately testable in a clinical trial.

    Topics: Antitubercular Agents; Computer Simulation; Drug Interactions; Drug Therapy, Combination; Linezolid; Models, Theoretical; Monte Carlo Method; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

2014
Evaluation of Xpert MTB/RIF assay performance in diagnosing extrapulmonary tuberculosis among adults in a tertiary care centre in India.
    The European respiratory journal, 2014, Volume: 44, Issue:4

    Topics: Adult; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; India; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Tertiary Care Centers; Tuberculosis

2014
Pharmacokinetic and pharmacogenomic modelling of the CYP3A activity marker 4β-hydroxycholesterol during efavirenz treatment and efavirenz/rifampicin co-treatment.
    The Journal of antimicrobial chemotherapy, 2014, Volume: 69, Issue:12

    To assess the effect of the major efavirenz metabolizing enzyme (CYP2B6) genotype and the effects of rifampicin co-treatment on induction of CYP3A by efavirenz.. Two study arms (arm 1, n = 41 and arm 2, n = 21) were recruited into this study. In arm 1, cholesterol and 4β-hydroxycholesterol were measured in HIV treatment-naive patients at baseline and then at 4 and 16 weeks after initiation of efavirenz-based antiretroviral therapy. In arm 2, cholesterol and 4β-hydroxycholesterol were measured among patients taking efavirenz during rifampicin-based tuberculosis (TB) treatment (efavirenz/rifampicin) just before completion of TB treatment and then serially following completion of TB treatment (efavirenz alone). Non-linear mixed-effect modelling was performed.. A one-compartment, enzyme turnover model described 4β-hydroxycholesterol kinetics adequately. Efavirenz treatment in arm 1 resulted in 1.74 (relative standard error = 15%), 3.3 (relative standard error = 33.1%) and 4.0 (relative standard error = 37.1%) average fold induction of CYP3A for extensive (CYP2B6*1/*1), intermediate (CYP2B6*1/*6) and slow (CYP2B6*6/*6) efavirenz metabolizers, respectively. The rate constant of 4β-hydroxycholesterol formation [mean (95% CI)] just before completion of TB treatment [efavirenz/rifampicin co-treatment, 7.40 × 10(-7) h(-1) (5.5 × 10(-7)-1.0 × 10(-6))] was significantly higher than that calculated 8 weeks after completion [efavirenz alone, 4.50 × 10(-7) h(-1) (4.40 × 10(-7)-4.52 × 10(-7))]. The CYP3A induction dropped to 62% of its maximum by week 8 of completion.. Our results indicate that efavirenz induction of CYP3A is influenced by CYP2B6 genetic polymorphisms and that efavirenz/rifampicin co-treatment results in higher induction than efavirenz alone.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Female; Genotype; HIV Infections; Humans; Hydroxycholesterols; Male; Middle Aged; Rifampin; Tuberculosis

2014
A study of Mycobacterium tuberculosis genotypic diversity & drug resistance mutations in Varanasi, north India.
    The Indian journal of medical research, 2014, Volume: 139, Issue:6

    One-fifth of the world's new tuberculosis (TB) cases and two-thirds of cases in the South East Asian region occur in India. Molecular typing of Mycobacterium tuberculosis isolates has greatly facilitated to understand the transmission of TB. This study was aimed to investigate the molecular epidemiology of M. tuberculosis genotypes in Varanasi, north India, and their association with clinical presentation among patients with pulmonary TB.. M. tuberculosis isolates from 104 TB patients attending a tertiary referral hospital of north India were screened for susceptibility to isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STR) by proportion method and multiplex-allele-specific-polymerase chain reaction (MAS-PCR). These were genotyped by spoligotyping. The spoligotype patterns were compared with those in the international SITVIT2 spoligotyping database.. Eighty three of 104 isolates were distributed in 38 SITs, of which SIT3366 was newly created within the present study. The mass of ongoing transmission with MDR-TB isolates in Varanasi, northern India, was linked to Beijing genotype followed by the CAS1_Delhi lineage. HIV-seropositive patients had a significantly higher proportion of clustered isolates than HIV-seronegative patients and compared with the wild type(wt) isolates, the isolates with katG315Thr mutation were considerably more likely to be clustered.. This study gives an insight into the M. tuberculosis genetic biodiversity in Varanasi, north India, the predominant spoligotypes and their impact on disease transmission. In this region of north India, TB is caused by a wide diversity of spoligotypes with predominance of four genotype lineages: Beijing, CAS, EAI and T. The Beijing genotype was the most frequent single spoligotype and strongly associated with multi drug resistant (MDR)-TB isolates. These findings may have important implications for control and prevention of TB in north India.

    Topics: DNA, Intergenic; Drug Resistance, Bacterial; Ethambutol; Genetic Variation; Genotype; Humans; India; Isoniazid; Molecular Epidemiology; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Streptomycin; Tuberculosis

2014
Low rifampicin concentrations in tuberculosis patients with HIV infection.
    Journal of infection in developing countries, 2014, Aug-13, Volume: 8, Issue:8

    The efficacy of tuberculosis (TB) treatment in Human Immunodeficiency Syndrome (HIV) co-infected patients may be compromised by genetic and pharmacokinetic variation in drug disposition. Rifampicin is a critical component of TB treatment. We investigated the influence of drug transporter gene polymorphisms on rifampicin concentrations in TB-HIV co-infected patients in Durban, South Africa.. Rifampicin concentrations were measured 2.5 hours post-dose (approximated peak, C2.5 hr) in patients receiving either 450mg or 600mg rifampicin, randomized to either integrated or sequential antiretroviral treatment. Patients were genotyped for SLCO1B1 (rs4149032) polymorphisms. A mixed effects regression model was fitted to assess the influence of various factors on rifampicin concentrations. TB recurrence rates were also estimated.. In 57 patients, median (IQR) C2.5 hr was 3.6 (2.8-5.0) µg/mL. Polymorphism frequency in the SLCO1B1 (rs4149032) drug transporter gene was high (0.76) and was associated with low median rifampicin C2.5 hr, 3.7 (2.8-5.0) µg/mL in the heterozygous and 3.4 (2.7-4.7) µg/mL in the homozygous variant carriers. Concentrations were also low in males (p < 0.0001) and those with low haemoglobin (p = 0.02). Although reinfection could not be distinguished from reactivation for the 43 patients followed post trial, the incidence of TB recurrence was 7.1 per 100 person-years. Of the eight patients in whom TB recurred, seven had the polymorphism.. Approximated peak rifampicin concentrations were well below the recommended target range of 8 to 24 µg/mL in this patient population with its high frequency of the SLCO1B1 (rs4149032) polymorphism. Increased rifampicin dosage may be warranted in African, HIV- TB co-infected patients.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Cohort Studies; Female; HIV Infections; Humans; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Organic Anion Transporters; Plasma; Polymorphism, Genetic; Recurrence; Rifampin; South Africa; Time Factors; Tuberculosis; Young Adult

2014
Characterization of extensively drug-resistant Mycobacterium tuberculosis isolates circulating in Siberia.
    BMC infectious diseases, 2014, Sep-03, Volume: 14

    The spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis compromises effective control of tuberculosis (TB) in Siberia. Early identification of drug-resistant isolates is, therefore, crucial for effective treatment of this disease. The aim of this study was to conduct drug susceptibility testing and identify mutations in drug resistance genes in clinical isolates of M. tuberculosis from some TB patients presenting for treatment in Siberia.. Thirty randomly selected clinical isolates of M. tuberculosis were obtained from the Novosibirsk Research Institute of Tuberculosis, Russia. Isolates were screened for drug resistance and characterized by variable number of tandem repeats (VNTR)-typing using 15 standard and four additional loci. Deligotyping on multiple large sequences was performed using 10 loci.. Twenty-nine of the isolates were assigned XDR status. Twenty-eight isolates belonged to the M. tuberculosis Beijing family, from which 11 isolates were considered the M11 type (39%), two the M2 type (7%), and one the M33 type (3%). Seventeen isolates (60.7%) from this family exhibited unique genetic patterns. The remaining two isolates belonged to the Latino-American Mediterranean family. Gene sequences (rpoB, katG, rrs, rpsL, tlyA, gidB, gyrA, gyrB) were analyzed to identify mutations that confer resistance to rifampicin, isoniazid, amikacin, kanamycin, capreomycin, and ofloxacin. The most common mutations among the XDR isolates were S531L in RpoB, S315T in KatG, various codon 94 mutations in gyrA, A90V in GyrA, K43R in RpsL, and 1401 A → G in rrs; these confer resistance to rifampicin, isoniazid, ofloxacin, streptomycin and kanamycin/capreomycin, respectively. There was high congruence between the two typing methods (VNTR typing and deligotyping) and RD105, RD149, RD152, RD181, and RD207 regions of difference were absent from the 28 Beijing family isolates.. Deligotyping can be used for rapid and reliable screening of M. tuberculosis isolates, followed by more in-depth genotyping. Identification of Beijing family isolates with extensive drug resistance confirms that such strains have epidemiological importance in Siberia. Rapid detection of mutations that lead to drug resistance should facilitate selection of effective drug therapies, and the development of early prevention strategies to combat this infection.

    Topics: Adult; Amikacin; Antitubercular Agents; Capreomycin; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Extensively Drug-Resistant Tuberculosis; Female; Genotype; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Minisatellite Repeats; Mutation; Mycobacterium tuberculosis; Ofloxacin; Rifampin; Siberia; Tuberculosis; Young Adult

2014
Xpert(®) MTB/RIF assay for tuberculosis diagnosis: evaluation in an Indian setting.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2014, Volume: 18, Issue:8

    The present study was conducted to evaluate the performance of the Xpert(®) MTB/RIF assay and compare Xpert results with solid and MGIT 960 liquid culture system. A total of 134 patients who had failed the Category I or II regimen were recruited for evaluation. Xpert correctly identified all Mycobacterium tuberculosis isolates. The sensitivity and specificity of the Xpert assay for the detection of rifampicin resistance was respectively 98.2% and 97.0% when compared with MGIT 960 results.

    Topics: Antibiotics, Antitubercular; Bacteriological Techniques; Drug Resistance, Bacterial; Humans; India; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2014
Cost-effectiveness of the Three I's for HIV/TB and ART to prevent TB among people living with HIV.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2014, Volume: 18, Issue:10

    To evaluate the cost-effectiveness of the Three I's for HIV/TB (human immunodeficiency virus/tuberculosis): antiretroviral therapy (ART), intensified TB case finding (ICF), isoniazid preventive treatment (IPT), and TB infection control (IC).. Using a 3-year decision-analytic model, we estimated the cost-effectiveness of a base scenario (55% ART coverage at CD4 count ⩿350 cells/mm(3)) and 19 strategies that included one or more of the following: 1) 90% ART coverage, 2) IC and 3) ICF using four-symptom screening and 6- or 36-month IPT. The TB diagnostic algorithm included 1) sputum smear microscopy with chest X-ray, and 2) Xpert® MTB/RIF.. In resource-constrained settings with a high burden of HIV and TB, the most cost-effective strategies under both diagnostic algorithms included 1) 55% ART coverage and IC, 2) 55% ART coverage, IC and 36-month IPT, and 3) expanded ART at 90% coverage with IC and 36-month IPT. The latter averted more TB cases than other scenarios with increased ART coverage, IC, 6-month IPT and/or IPT for tuberculin skin test positive individuals. The cost-effectiveness results did not change significantly under the sensitivity analyses.. Expanded ART to 90% coverage, IC and a 36-month IPT strategy averted most TB cases and is among the cost-effective strategies.

    Topics: Algorithms; Antitubercular Agents; CD4 Lymphocyte Count; Cost-Benefit Analysis; Drug Resistance, Bacterial; HIV Infections; Humans; Isoniazid; Models, Economic; Mycobacterium tuberculosis; Radiography; Rifampin; Sensitivity and Specificity; Tuberculosis

2014
A field evaluation of the Hardy TB MODS Kit™ for the rapid phenotypic diagnosis of tuberculosis and multi-drug resistant tuberculosis.
    PloS one, 2014, Volume: 9, Issue:9

    Even though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST) at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA) with PATH (Seattle, WA, USA) to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory.. 2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ), conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct) DST and proportion method (indirect) DST. 778 samples (31.8%) were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals) of the MODS Kit were 99.3% (98.3-99.8%), 98.3% (97.5-98.8%), 95.8% (94.0-97.1%), and 99.7% (99.3-99.9%). Median (interquartile ranges) time to culture-positivity (and rifampicin and isoniazid DST) was 10 (9-13) days for conventional MODS and 8.5 (7-11) for MODS Kit (p<0.01). Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples) and reference indirect DST (97.9% agreement, 687/702 evaluable samples).. MODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked), readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of access to TB diagnosis and first and second-line DST in settings where the need is greatest.

    Topics: Antitubercular Agents; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Peru; Reagent Kits, Diagnostic; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

2014
Of drug susceptibility test results, gold standards, and test operating characteristics.
    The Indian journal of tuberculosis, 2014, Volume: 61, Issue:3

    Topics: Antibiotics, Antitubercular; Humans; Immunoassay; Microbial Sensitivity Tests; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Tuberculosis

2014
In memory of Piero Sensi (1920-2013).
    The Journal of antibiotics, 2014, Volume: 67, Issue:9

    Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Drug Discovery; History, 20th Century; History, 21st Century; Humans; Rifampin; Tuberculosis

2014
Evaluation of the modified colorimetric resazurin microtiter plate-based antibacterial assay for rapid and reliable tuberculosis drug susceptibility testing.
    BMC microbiology, 2014, Oct-07, Volume: 14

    The resazurin microtiter assay (classic REMA), a colorimetric liquid culture-based drug susceptibility assay for Mycobacterium tuberculosis (MTB), has been endorsed by the World Health Organization. The assay requires 8-16 days to obtain results, delaying management of drug resistant tuberculosis patients. A modified REMA which allows results in as little as 24 hours for bacterial strains, has been developed and validated using Staphylococcus aureus, but has not yet been evaluated for MTB. Therefore we assessed the performance of the modified REMA for rifampicin (RIF) and isoniazid (INH) susceptibility, using the classic REMA as the reference standard. We also compared simplicity (from the technicians' point of view), time taken to obtain results (rank-sum testing), specificity and Kappa statistics of the two methods.. The modified REMA, which is a one-step procedure, was found to be simpler to perform and results were obtained in a significantly shorter time (5 versus 9 days, p < 0.0001) compared to the classic REMA due to addition of indicator and strain at the same time. The specificity of the modified REMA was low {46.8% (35.5% - 58.4%) for RIF and 13.9% (7.2% - 23.5%) for INH}. Kappa statistics were 16.0% for RIF and 2.0% for INH. Low specificity and kappa statistics are due to indicator reduction by the strains before complete drug activity.. Although modified REMA is faster and simpler compared to classic REMA, it is not reliable for MTB drug susceptibility testing.

    Topics: Antitubercular Agents; Colorimetry; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazines; Rifampin; Tuberculosis; Xanthenes

2014
Thioridazine for treatment of tuberculosis: promises and pitfalls.
    Tuberculosis (Edinburgh, Scotland), 2014, Volume: 94, Issue:6

    The articles by De Knegt et al. and Singh et al. in a recent issue of this Journal address one of the current debates regarding the potential role of thioridazine in the treatment of tuberculosis. This commentary presents a summary of the available evidence, and, emphasizing the need for further research, asks the question: "How far can we go in repurposing thioridazine?"

    Topics: Animals; Antitubercular Agents; Female; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Thioridazine; Tuberculosis

2014
CYP2B6 genotype, but not rifampicin-based anti-TB cotreatments, explains variability in long-term efavirenz plasma exposure.
    Pharmacogenomics, 2014, Volume: 15, Issue:11

    We investigated the effects of rifampicin-based anti-TB treatment on plasma efavirenz exposure and the implications of CYP2B6 genotype.. Antiretroviral therapy-naive Ugandan HIV patients without (n = 157) or with TB coinfection (n = 106) were enrolled and treated with efavirenz-based highly active antiretroviral therapy alone or with rifampicin-based anti-TB therapy, respectively. Efavirenz plasma concentration was determined on day 3 and weeks 1, 2, 8, 12, 16, 20, 24, 28 and 32.. Rifampicin-based anti-TB cotreatment reduced plasma efavirenz exposure during the first 2 weeks (p < 0.05), but no significant effect was observed afterwards. Although not significant, rifampicin-based anti-TB cotreatment inconsistently increased efavirenz exposure over time, which was reduced immediately after completing anti-TB therapy. CYP2B6*6, *11 and ABCB1 c.4036A>G genotypes were significant predictors of efavirenz plasma exposure.. Plasma efavirenz exposure is mainly influenced by CYP2B6 genotype, but not by rifampicin cotreatment. Therefore, no efavirenz dosage adjustment during rifampicin cotreatment is required in Ugandans.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Benzoxazines; Coinfection; Cyclopropanes; Cytochrome P-450 CYP2B6; Female; Genetic Variation; Genotype; HIV Infections; Humans; Male; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

2014
Assessment of the patient, health system, and population effects of Xpert MTB/RIF and alternative diagnostics for tuberculosis in Tanzania: an integrated modelling approach.
    The Lancet. Global health, 2014, Volume: 2, Issue:10

    Several promising new diagnostic methods and algorithms for tuberculosis have been endorsed by WHO. National tuberculosis programmes now face the decision on which methods to implement and where to place them in the diagnostic algorithm.. We used an integrated model to assess the effects of different algorithms of Xpert MTB/RIF and light-emitting diode (LED) fluorescence microscopy in Tanzania. To understand the effects of new diagnostics from the patient, health system, and population perspective, the model incorporated and linked a detailed operational component and a transmission component. The model was designed to represent the operational and epidemiological context of Tanzania and was used to compare the effects and cost-effectiveness of different diagnostic options.. Among the diagnostic options considered, we identified three strategies as cost effective in Tanzania. Full scale-up of Xpert would have the greatest population-level effect with the highest incremental cost: 346 000 disability-adjusted life-years (DALYs) averted with an additional cost of US$36·9 million over 10 years. The incremental cost-effectiveness ratio (ICER) of Xpert scale-up ($169 per DALY averted, 95% credible interval [CrI] 104-265) is below the willingness-to-pay threshold ($599) for Tanzania. Same-day LED fluorescence microscopy is the next most effective strategy with an ICER of $45 (95% CrI 25-74), followed by LED fluorescence microscopy with an ICER of $29 (6-59). Compared with same-day LED fluorescence microscopy and Xpert full rollout, targeted use of Xpert in presumptive tuberculosis cases with HIV infection, either as an initial diagnostic test or as a follow-on test to microscopy, would produce DALY gains at a higher incremental cost and therefore is dominated in the context of Tanzania.. For Tanzania, this integrated modelling approach predicts that full rollout of Xpert is a cost-effective option for tuberculosis diagnosis and has the potential to substantially reduce the national tuberculosis burden. It also estimates the substantial level of funding that will need to be mobilised to translate this into clinical practice. This approach could be adapted and replicated in other developing countries to inform rational health policy formulation.

    Topics: Algorithms; Antitubercular Agents; Cost-Benefit Analysis; Drug Resistance, Bacterial; Government Programs; Humans; Microscopy, Fluorescence; Models, Econometric; Rifampin; Sputum; Tanzania; Time Factors; Tuberculosis

2014
Evaluation of the Xpert MTB/RIF assay for diagnosis of tuberculosis and rifampin resistance in county-level laboratories in Hunan province, China.
    Chinese medical journal, 2014, Volume: 127, Issue:21

    The Xpert MTB/RIF showed high sensitivity and specificity in previous studies carried out in different epidemiological and geographical settings and patient populations in high-burden tuberculosis (TB) countries. However, there were little data obtained by validation or demonstration study of the assay in China. In this study, the performance of Xpert MTB/RIF was investigated in two county-level laboratories in Hunan Province, China.. Consecutive patients with suspected pulmonary tuberculosis (PTB) and suspicion for multidrug-resistant tuberculosis (MDR-TB) were enrolled. For each patient suspected to have PTB, three sputum specimens (one spot sputum, one night sputum, and one morning sputum) were collected and each sputum was tested with smear microscopy, Löwenstein-Jensen (LJ) culture, and Xpert MTB/RIF test. For comparison across subgroups and testing methods, 95% confidence intervals were calculated. All analyses were done with SPSS 16.0, and P < 0.05 was regarded as significant.. For case detection, the sensitivity of Xpert MTB/RIF was 100% for smear- and culture-positive TB and 88.6% for smear-negative and culture-positive TB; the overall sensitivity was 94.5% for all culture-positive patients. The specificity was 99.8%. The sensitivity of Xpert MTB/RIF assay was 22.0% in clinical TB patients and the specificity reached 100.0% in the group of patients who are infected with nontuberculous mycobacteria. For the detection of rifampin resistance, the sensitivity of MTB/RIF RIF-resistance detection was 92.9%, and the specificity was 98.7%. Of the 26 Xpert MTB/RIF-positive and RIF-resistant patients confirmed by LJ proportion tests, 20 (76.9%) patients were infected by MDR-TB.. The Xpert MTB/RIF assay is a highly sensitive and specific method for diagnosis of TB and RIF resistance, which will enable it to have the potential to be used in county-level laboratories and lead to the reduction of the infectious pool and improvements in TB control in China. Further evaluations in county-level laboratories for implementing the assay are still required.

    Topics: Adult; Antibiotics, Antitubercular; China; Female; Humans; Male; Middle Aged; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

2014
Performance evaluation of the Xpert MTB/RIF assay according to its clinical application.
    BMC infectious diseases, 2014, Nov-14, Volume: 14

    The Xpert MTB/RIF assay (Xpert assay; Cepheid, Sunnyvale, CA) is becoming the test of choice for the rapid diagnosis of tuberculosis and rifampin (RIF) resistance. The aim of this study was to evaluate the performance of the Xpert assay with respect to its clinical application at a tertiary care hospital in Korea, a country with an intermediate tuberculosis burden and high-resource.. A total of 303 Xpert assay results from 109 smear-positive and 194 smear-negative respiratory specimens were retrospectively reviewed. Based on patients' medical records, four categories of clinical applications of the Xpert assay were identified: (1) the diagnosis of pulmonary tuberculosis in patients with a high probability of pulmonary tuberculosis according to their clinical and radiological features; (2) the exclusion of tuberculosis in clinically indeterminate patients for pulmonary tuberculosis; (3) the differentiation of Mycobacterium tuberculsosis (MTB) from nontuberculous mycobacteria in a smear-positive specimen; and (4) the diagnosis of RIF resistance. Standard culture and drug susceptibility tests were used as reference methods.. The sensitivity of the Xpert assay for MTB detection in category 1 was 89.8% (95% confidence interval [CI], 78.5-95.8%), but 66.7% (95% CI, 12.5-98.2%) in category 2. The positive predictive values ranged from 33.3% (95% CI, 6.0-75.9%) in category 2 to 91.3% and 91.7% in categories 1 and 3, respectively. The negative predictive values were over 90% in all categories. The Xpert assay correctly detected RIF resistance in six of the seven (85.7%) isolates tested.. The Xpert assay exhibited variable performance according to its clinical application; this finding cautions that careful interpretation for the results of this assay would be needed according to its intended purpose.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Body Fluids; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Predictive Value of Tests; Reagent Kits, Diagnostic; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Pulmonary; Young Adult

2014
Molecular epidemiology of tuberculosis in Sicily, Italy: what has changed after a decade?
    BMC infectious diseases, 2014, Nov-19, Volume: 14

    We aimed to investigate the molecular epidemiology of Mycobacterium tuberculosis complex (MTBC) isolates in the province of Palermo, Sicily, Italy, by characterizing 183 isolates identified in the years 2004-2012. A comparison with 104 MTBC strains identified in the same geographic area in the years 1994-2000 was also carried out.. One hundred eighty-three MTBC isolates identified in Palermo, Italy, in the years 2004-2012 were analyzed by spoligotyping and the 24 mycobacterial interspersed repetitive unit (MIRU)-variable-number tandem-repeat (VNTR) method typing. Susceptibility testing to streptomycin, isoniazid, rifampin and ethambutol was also performed. Furthermore, the spoligotyping dataset obtained from 104 MTBC isolates identified from 1994 to 2000 was reanalyzed. Distribution into lineages and clustering of isolates in the two periods was compared.. One hundred seventy-seven out of the 183 isolates of MTBC submitted to molecular typing were fully characterized. Of these, 108 were from Italian-born and 69 from foreign-born individuals. Eleven different lineages and 35 families-subfamilies were identified with the most represented lineages being Haarlem (26.5%), T (19.2%), LAM (13.6%) and S (8.5%). Except for the Haarlem lineage, where isolates from foreign-born patients were overrepresented, the distribution of isolates in the families belonging to the Euro-American clone reflected the proportions of the two subpopulations. A total of 27 (15.2%) strains were clustered and three clusters were mixed. Approximately 25% of the 183 MTBC isolates under study proved to be resistant to at least one antiTB drug, with only three isolates categorized as multidrug resistant (MDR). When MTBC isolates identified in the years 1994-2000 were reanalyzed, lineages T (30.8%), LAM (29.8%), Haarlem (16.3%) and S (13.5%) proved to be predominant. No MTBC isolates belonging to CAM, U, CAS, Turkish and Ural lineages were identified.. A wide heterogeneity was detected among the MTBC strains isolated in the years 2004-2012. Six lineages were not present among the isolates of the period 1994-2000. Comparison between distribution of lineages in the two consecutive periods depicts rapid and deep changes in the TB epidemiology in Palermo, Italy. An universal and continued laboratory-based surveillance of TB in Sicily is required.

    Topics: Adult; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Ethambutol; Female; Genotype; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Minisatellite Repeats; Molecular Epidemiology; Molecular Typing; Mycobacterium tuberculosis; Rifampin; Sicily; Tuberculosis

2014
Bone marrow mesenchymal stem cells provide an antibiotic-protective niche for persistent viable Mycobacterium tuberculosis that survive antibiotic treatment.
    The American journal of pathology, 2014, Volume: 184, Issue:12

    During tuberculosis (TB), some Mycobacterium tuberculosis bacilli persist in the presence of an active immunity and antibiotics that are used to treat the disease. Herein, by using the Cornell model of TB persistence, we further explored our recent finding that suggested that M. tuberculosis can escape therapy by residing in the bone marrow (BM) mesenchymal stem cells. We initially showed that M. tuberculosis rapidly disseminates to the mouse BM after aerosol exposure and maintained a stable burden for at least 220 days. In contrast, in the lungs, the M. tuberculosis burden peaked at 28 days and subsequently declined approximately 10-fold. More important, treatment of the mice with the antibiotics rifampicin and isoniazid, as expected, resulted in effective clearance of M. tuberculosis from the lungs and spleen. In contrast, M. tuberculosis persisted, albeit at low numbers, in the BM of antibiotic-treated mice. Moreover, most viable M. tuberculosis was recovered from the bone marrow CD271(+)CD45(-)-enriched cell fraction, and only few viable bacteria could be isolated from the CD271(-)CD45(+) cell fraction. These results clearly show that BM mesenchymal stem cells provide an antibiotic-protective niche for M. tuberculosis and suggest that unraveling the mechanisms underlying this phenomenon will enhance our understanding of M. tuberculosis persistence in treated TB patients.

    Topics: Adapalene; Animals; Anti-Bacterial Agents; Antitubercular Agents; Bone Marrow; Bone Marrow Cells; Disease Models, Animal; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Leukocyte Common Antigens; Lung; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Naphthalenes; Rifampin; Spleen; Tuberculosis

2014
Enhancement of in vitro activity of tuberculosis drugs by addition of thioridazine is not reflected by improved in vivo therapeutic efficacy.
    Tuberculosis (Edinburgh, Scotland), 2014, Volume: 94, Issue:6

    Assessment of the activity of thioridazine towards Mycobacterium tuberculosis (Mtb), in vitro and in vivo as a single drug and in combination with tuberculosis (TB) drugs.. The in vitro activity of thioridazine as single drug or in combination with TB drugs was assessed in terms of MIC and by use of the time-kill kinetics assay. Various Mtb strains among which the Beijing genotype strain BE-1585 were included. In vivo, mice with TB induced by BE-1585 were treated with a TB drug regimen with thioridazine during 13 weeks. Therapeutic efficacy was assessed by the change in mycobacterial load in the lung, spleen and liver during treatment and 13 weeks post-treatment.. In vitro, thioridazine showed a concentration-dependent and time-dependent bactericidal activity towards both actively-replicating and slowly-replicating Mtb. Thioridazine at high concentrations could enhance the activity of isoniazid and rifampicin, and in case of isoniazid resulted in elimination of mycobacteria and prevention of isoniazid-resistant mutants. Thioridazine had no added value in combination with moxifloxacin or amikacin. In mice with TB, thioridazine was poorly tolerated, limiting the maximum tolerated dose (MTD). The addition of thioridazine at the MTD to an isoniazid-rifampicin-pyrazinamide regimen for 13 weeks did not result in enhanced therapeutic efficacy.. Thioridazine is bactericidal towards Mtb in vitro, irrespective the mycobacterial growth rate and results in enhanced activity of the standard regimen. The in vitro activity of thioridazine in potentiating isoniazid and rifampicin is not reflected by improved therapeutic efficacy in a murine TB-model.

    Topics: Animals; Antitubercular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy, Combination; Female; Isoniazid; Mice, Inbred BALB C; Microbial Sensitivity Tests; Microbial Viability; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Stem Cells; Thioridazine; Tuberculosis

2014
Design, synthesis, and structure-activity relationship studies of tryptanthrins as antitubercular agents.
    Journal of natural products, 2013, Mar-22, Volume: 76, Issue:3

    The natural product tryptanthrin (1a) represents a potential lead for new tuberculosis (TB) drugs since tryptanthrin and its synthetic analogues possess potent in vitro activity against Mycobacterium tuberculosis (Mtb). However, in spite of their in vitro activity, none of these agents have been shown to be efficacious in vivo against animal models of TB. Described herein are syntheses of new tryptanthrin analogues together with a systematic investigation of their in vitro antitubercular activity and ADME properties followed by pharmacokinetic characterization in rodents for the most promising compounds. Those with the best potency and oral bioavailability were progressed to evaluations of efficacy against acute murine TB. The work aimed to prove the concept that this compound class can limit growth of Mtb during infection as well as to establish the SAR for in vitro activity against Mtb and the range of in vitro ADME parameters for this class of natural products. Novel C-11-deoxy (5b) and A-ring-saturated (6) tryptanthrin analogues were discovered that maintained activity against Mtb and showed improved solubility compared to tryptanthrin as well as evidence of oral bioavailability in rodents. However, neither 5b nor 6 demonstrated efficacy against acute murine TB following administration at doses up to 400 mg/kg daily for 4 weeks. Although 5b and 6 failed to inhibit replication or kill Mtb in vivo, they illuminate a path to new structural variations of the tryptanthrin scaffold that may maximize the potential of this class of compounds against TB.

    Topics: Animals; Antitubercular Agents; Cytochrome P-450 Enzyme System; Drug Design; Humans; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Quinazolines; Rats; Structure-Activity Relationship; Tuberculosis

2013
Design and synthesis of biquinolone-isoniazid hybrids as a new class of antitubercular and antimicrobial agents.
    European journal of medicinal chemistry, 2013, Volume: 65

    Twenty four biquinolone-isoniazid hybrids were designed based on molecular hybridization technique and synthesized via multicomponent cyclocondensation (MCC) approach. All the newly synthesized compounds were screened for their antimicrobial and antitubercular activities. The brine shrimp bioassay was carried out to study the cytotoxicity of the synthesized compounds. Hybrids 7f (MIC = 25 μg/mL); 7a, 7e and 7m (MIC = 50 μg/mL); 7g, 7h and 7k (MIC = 62.5 μg/mL) exhibited excellent antimicrobial activity as compared with standard drugs. Hybrids 7l and 7j displayed 99% inhibition against Mycobacterium tuberculosis bacteria with better LC50 values 35.39 and 34.59 μg/mL, respectively. These results indicate that the synthesized compounds can act as leads for the development of newer antimicrobial and antitubercular compounds.

    Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Antitubercular Agents; Artemia; Bacteria; Dose-Response Relationship, Drug; Drug Design; Fungi; Isoniazid; Microbial Sensitivity Tests; Molecular Structure; Motor Activity; Quinolones; Structure-Activity Relationship; Tuberculosis

2013
Studies on substituted benzo[h]quinazolines, benzo[g]indazoles, pyrazoles, 2,6-diarylpyridines as anti-tubercular agents.
    Bioorganic & medicinal chemistry letters, 2013, Nov-01, Volume: 23, Issue:21

    Various substituted 5,6-dihydro-8-methoxybenzo[h]quinazolin-2-amine, 1-(3-(4-alkoxyphenyl)-7-methoxy-3,3a,4,5-tetrahydro-2H benzo[g]indazol-2-yl)ethanone, pyrazole and 2,6-diarylpyridine derivatives have been synthesized in good yields by an efficient methodology. The synthesized compounds (4-23) were evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. Compounds 6a, 6c, 8a, 19a and 19e exhibited significant anti-tubercular activity at MIC values 50, 100, 50, 25 and 100μM concentration. In vitro cytotoxicity data using THP-1 cells indicated that most active compound 19a is safe as its MIC value is much lower than the cytotoxic value.

    Topics: Antitubercular Agents; Cell Line; Humans; Indazoles; Mycobacterium tuberculosis; Pyrazoles; Pyridines; Quinazolines; Tuberculosis

2013
Thiazolopyridine ureas as novel antitubercular agents acting through inhibition of DNA Gyrase B.
    Journal of medicinal chemistry, 2013, Nov-14, Volume: 56, Issue:21

    A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains at the thiazolopyridine ring C-5 position to access the ribose/solvent pocket. Potent compounds with GyrB IC50 ≤ 1 nM and Mtb MIC ≤ 0.1 μM were obtained with certain combinations of side chains at the C-5 position and heterocycles at the C-6 position of the thiazolopyridine core. Substitutions at C-5 also enabled optimization of the physicochemical properties. Representative compounds were cocrystallized with Streptococcus pneumoniae (Spn) ParE; these confirmed the binding modes predicted by the homology model. The target link to GyrB was confirmed by genetic mapping of the mutations conferring resistance to thiazolopyridine ureas. The compounds are bactericidal in vitro and efficacious in vivo in an acute murine model of tuberculosis.

    Topics: Animals; Antitubercular Agents; Disease Models, Animal; DNA Gyrase; Dose-Response Relationship, Drug; Mice; Mice, Inbred BALB C; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Pyridines; Structure-Activity Relationship; Topoisomerase II Inhibitors; Tuberculosis; Urea

2013
Emergence of Clostridium difficile infection in tuberculosis patients due to a highly rifampicin-resistant PCR ribotype 046 clone in Poland.
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2013, Volume: 32, Issue:8

    Clostridium difficile infection (CDI) is a major cause of nosocomial diarrhea. CDI is known to develop after antibiotic administration, but anti-tuberculosis agents have rarely been implicated. We documented an outbreak caused by a highly rifampicin-resistant C. difficile strain of polymerase chain reaction (PCR) ribotype 046 in patients with active tuberculosis.

    Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Antibiotics, Antitubercular; Clostridioides difficile; Clostridium Infections; Cohort Studies; Cross Infection; Disease Outbreaks; Drug Resistance, Bacterial; Female; Hospitalization; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Poland; Rifampin; Tuberculosis

2013
New diagnostic test changes tuberculosis landscape.
    Bulletin of the World Health Organization, 2013, Mar-01, Volume: 91, Issue:3

    A new diagnostic test for tuberculosis - including its most common resistant form - is being rolled out at record pace, with South Africa its biggest implementer. The challenge now is to treat the new cases. Claire Keeton reports.

    Topics: Antibiotics, Antitubercular; Comorbidity; HIV Infections; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant

2013
[Primary sinonasal tuberculosis: apropos of a case].
    The Pan African medical journal, 2013, Volume: 14

    Topics: Aged; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Maxillary Sinusitis; Mycobacterium tuberculosis; Nasal Obstruction; Nasal Polyps; Pyrazinamide; Rifampin; Tuberculosis

2013
Isoniazid could be used for antibiotic-loaded bone cement for musculoskeletal tuberculosis: an in vitro study.
    Clinical orthopaedics and related research, 2013, Volume: 471, Issue:7

    Antibiotic-loaded bone cement (ALBC) has been used in serious cases of musculoskeletal tuberculosis, but the type and amount of antibiotic that should be used in ALBC have not been determined.. We therefore determined the (1) elution characteristics and (2) antimycobacterial activity of isoniazid- and rifampicin-loaded bone cement.. A total of 240 elution samples of each of three discs from 40 g bone cement mixed with one of eight dosages: 1 g, 2 g, and 4 g isoniazid, 1 g, 2 g, and 4 g rifampicin, and a combination of 1 + 1 g or 2 + 2 g of isoniazid and rifampicin. The polymerization of rifampicin-loaded bone cement was delayed to mean 122.5 ± 31.1 minutes. We measured the quantity of isoniazid and rifampicin and the antimycobacterial activity on Days 1, 3, 7, 14, and 30.. Isoniazid eluted in almost all the samples while rifampicin was detected only on Day 1 with 2 g (0.7 ± 0.4 ug/mL/day), and until Day 14 with 4 g (0.1 ± 0.0 ug/mL/day). Most of the samples containing isoniazid showed antimycobacterial activity while the samples containing rifampicin showed antimycobacterial activity only on Day 1 with 1 g (0.52 ± 0.18 ug/mL), until Day 14 with 2 g (0.03 ± 0.00 ug/mL), and until Day 30 with 4 g (1.84 ± 1.90 ug/mL).. Rifampicin was unsuitable for ALBC because of its delayed polymerization. Isoniazid eluted and showed antimycobacterial activity for 30 days.. The data suggest isoniazid could be considered for use in ALBC for musculoskeletal tuberculosis if used with systemic treatment. For preventing resistance and systemic toxicity, a combination with a second-line drug and an in vivo study would be needed.

    Topics: Antibiotics, Antitubercular; Bone Cements; Chemistry, Pharmaceutical; Drug Carriers; Isoniazid; Microbial Sensitivity Tests; Musculoskeletal Diseases; Mycobacterium tuberculosis; Polymerization; Rifampin; Solubility; Time Factors; Tuberculosis; Tuberculosis, Osteoarticular

2013
Optimization of the rifampin dosage to improve the therapeutic efficacy in tuberculosis treatment using a murine model.
    American journal of respiratory and critical care medicine, 2013, May-15, Volume: 187, Issue:10

    The dosage of 10 mg/kg/d rifampin, as currently used in the treatment of tuberculosis (TB), is not an optimal dose. Shortening of treatment duration might be achievable using an increased rifampin dose.. Determination of optimal rifampin dosage in mice, resulting in maximum therapeutic effect and without adverse effects. Assessment of associated pharmacokinetic parameters and pharmacokinetic/pharmacodynamic indices.. A murine TB infection using a Beijing genotype Mycobacterium tuberculosis strain was established by intratracheal bacterial instillation followed by proper inhalation, while keeping mice in a vertical position. We assessed dose-dependent activity of rifampin in single-drug treatment during 3 weeks. The maximum tolerated dosage, pharmacokinetic parameters, and pharmacokinetic/pharmacodynamic index were determined. Therapeutic efficacy of a range of rifampin (R) dosages added to a regimen of isoniazid (H) and pyrazinamide (Z) was assessed.. Maximum tolerated dosage of rifampin in the murine TB was 160 mg/kg/d. Pharmacokinetic measurement in HR(10)Z and HR(160)Z therapy regimens showed for rifampin a C(max) of 16.2 and 157.3 mg/L, an AUC(0-24h) of 132 and 1,782 h·mg/L, and AUC(0-24h)/minimum inhibitory concentration ratios of 528 and 7129, respectively. A clear dose-effect correlation was observed for rifampin after 3-week single-drug treatment. Administration of HR(80)Z allowed 9-week treatment duration to be effective without relapse of infection.. Our findings indicate that the currently used rifampin dosage in the therapy of TB is too low. In our murine TB model a rifampin dosage of 80 mg/kg/d enabled a significant reduction in therapy duration without adverse effects.

    Topics: Animals; Antibiotics, Antitubercular; Area Under Curve; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Rifampin; Treatment Outcome; Tuberculosis

2013
Zero deaths from tuberculosis: progress, reality, and hope.
    The Lancet. Infectious diseases, 2013, Volume: 13, Issue:4

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Communicable Diseases; Health Policy; Humans; Mycobacterium tuberculosis; Point-of-Care Systems; Rifampin; Tuberculosis; Tuberculosis Vaccines; Tuberculosis, Multidrug-Resistant

2013
Progress and challenges in childhood tuberculosis.
    The Lancet. Infectious diseases, 2013, Volume: 13, Issue:4

    Topics: Adolescent; AIDS-Related Opportunistic Infections; Antitubercular Agents; BCG Vaccine; Child; Child, Preschool; Disease Susceptibility; Humans; Immunity, Innate; Isoniazid; Mycobacterium tuberculosis; Rifampin; Risk Factors; Tuberculosis; Tuberculosis Vaccines; Tuberculosis, Multidrug-Resistant

2013
Factors associated with the rapid implementation process of the fixed-dose combination RHZE tuberculosis regimen in Brazil: an ecological study.
    BMC public health, 2013, Apr-09, Volume: 13

    The Brazilian National Tuberculosis Control Program (NTCP) recommended the fixed-dose four-drug combination (FDC-RHZE) regimen to treat new tuberculosis cases in December 2009, expecting to increase adherence and avoid resistance. We evaluated factors associated with the speed of the new regimen implementation process in this continent-sized country.. We conducted an ecological study based on the Brazilian Case Notification Database (SINAN) having the Brazilian municipalities as the analytical unit. Municipalities with at least one case reported from December 2009 to March 2011 were considered eligible. The association of rapid (≤ 3 months) implementation of the new regimen with demographic, epidemiological and operational health service characteristics, such as compliance with NTCP recommendations (supervised treatment, bacteriological confirmation of the diagnosis and monthly bacteriological monitoring), was analyzed. We used the adjusted odds ratios (OR) and their 95% confidence interval (CI) to assess the association of independent variables with the outcome in a multiple logistic regression model.. Rapid implementation of the new regimen in municipalities was associated with small populations (OR=25.5, 95% CI= 19.1-34.1), low population density (OR=2.3, 95% CI= 1.9-2.9), low tuberculosis incidence rates (OR=8.8, 95% CI= 6.7-11.4) and good compliance with other NTCP recommendations.. We showed that SINAN secondary data analysis is feasible and useful to learn lessons from. Municipalities with high tuberculosis burden and large populations need special attention for implementing new recommendations. This is particularly important considering the Global Alliance pipeline for new tuberculosis treatment regimens.

    Topics: Antitubercular Agents; Brazil; Drug Combinations; Ethambutol; Health Plan Implementation; Humans; Incidence; Isoniazid; Population Density; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Time Factors; Tuberculosis

2013
Primary gastric tuberculosis mimicking gastric cancer: a case report.
    Journal of infection in developing countries, 2013, Apr-17, Volume: 7, Issue:4

    Gastric tuberculosis is an uncommon manifestation of extra-pulmonary tuberculosis infection. The clinical signs of this type of infection are nonspecific and misleading. Clinically gastric tuberculosis resembles peptic ulcer disease or malignancy. We report a case of gastric tuberculosis, which was treated as acid peptic disease, in an Iranian immunocompetent adult with no pulmonary tuberculosis, who received surgery for gastric cancer. Diagnosis was based on PCR despite the detection of negative acid-fast bacilli in the histopathologic specimen. We recommend PCR for Mycobacterium tuberculosis to be done when granuloma or caseation is detected on biopsy in patients who are suspected of having gastric malignancy or acid peptic diseases.

    Topics: Adult; Antitubercular Agents; Diagnostic Errors; Gastrectomy; Gastric Mucosa; Granuloma; Humans; Male; Mycobacterium tuberculosis; Rifampin; Stomach Neoplasms; Tuberculosis

2013
Relationship between weight, efavirenz exposure, and virologic suppression in HIV-infected patients on rifampin-based tuberculosis treatment in the AIDS Clinical Trials Group A5221 STRIDE Study.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2013, Volume: 57, Issue:4

    Rifampin (RIF) upregulates CYP 450 isoenzymes, potentially lowering efavirenz (EFV) exposure. The US EFV package insert recommends an EFV dose increase for patients on RIF weighing ≥50 kg. We conducted a pharmacokinetic study to evaluate EFV trough concentrations (Cmin) and human immunodeficiency virus (HIV) virologic suppression in patients on EFV (600 mg) and RIF-based tuberculosis treatment in the multicenter randomized trial (ACTG A5221).. EFV Cmin was measured 20-28 hours post-EFV dose at weeks 4, 8, 16, 24 on-RIF and weeks 4, 8 off-RIF. Results were evaluated with 2-sided Wilcoxon rank-sum, χ(2), Fisher exact tests and logistic regression (5% type I error rate).. Seven hundred eighty patients received EFV; 543 provided ≥1 EFV Cmin. Median weight was 52.8 kg (interquartile range [IQR], 48.0-59.5), body mass index 19.4 kg/m(2) (IQR, 17.5-21.6), and age 34 years (IQR, 29-41); 63% were male, 74% black. Median Cmin was 1.96 µg/mL on-RIF versus 1.80 off-RIF (P = .067). Cmin were significantly higher on-RIF versus off-RIF in blacks (2.08 vs 1.75, P = .005). Weight ≥60 kg on-RIF, compared to <60 kg, was associated with lower EFV Cmin (1.68 vs 2.02, P = .021). However, weight ≥60 kg was associated with more frequent HIV RNA < 400 copies/mL at week 48, compared to weight <60 kg (81.9% vs 73.8%, P = .023).. EFV and RIF-based tuberculosis therapy coadministration was associated with a trend toward higher, not lower, EFV Cmin compared to EFV alone. Patients weighing ≥60 kg had lower median EFV Cmin versus those <60 kg, but there was no association of higher weight with reduced virologic suppression. These data do not support weight-based dosing of EFV with RIF.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Body Weight; Cyclopropanes; Drug Interactions; Female; HIV Infections; Humans; Male; Rifampin; Treatment Outcome; Tuberculosis; Viral Load

2013
A mycobacteriophage-derived trehalose-6,6'-dimycolate-binding peptide containing both antimycobacterial and anti-inflammatory abilities.
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2013, Volume: 27, Issue:8

    Bacteriophages, the viruses of eubacteria, have developed unique mechanisms to interact with their host bacteria. They have been viewed as potential antibacterial therapeutics. Mycobacteriophage-derived compounds may interact with Mycobacterium tuberculosis (MTB) and/or its components, such as the cord factor, trehalose-6,6'-dimycolate (TDM), which is the most abundant glycolipid produced on the surface of MTB. TDM emulsion injected intravenously into mice induces lung immunopathology that mimics many aspects of MTB infection. Thus, TDM is an important target for anti-MTB agent development. On the basis of genomics information of mycobacteriophages, 200 peptides were synthesized. Their effects on MTB, their interactions with TDM, and anti-inflammatory activities were tested. One of them (PK34) showed MTB-killing activity with a minimal inhibitory concentration of 50 μg/ml and TDM-binding ability. In a mouse model, PK34 showed comparable ability to clear MTB as rifampin did in vivo. It also exerted strong activity to inhibit MTB or TDM-induced inflammation in vivo. PK34 significantly inhibited inflammatory cytokines secretions by inactivating MAPK and PKB signals while it maintained certain proinflammatory cytokine production. It is possible to prospect for TDM-binding and/or anti-MTB peptides by mining the mycobacteriophages genome. In addition to its direct MTB-killing ability, PK34 might be a useful adjunct in the treatment of granulomatous inflammation occurring during mycobacterial infection or a template for developing antituberculosis (TB) agents because of its immunoregulative effects. As a TDM-binding peptide, PK34 may be a promising tool to study TDM's interactions with corresponding receptors and signal pathways.

    Topics: Adjuvants, Immunologic; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Blotting, Western; Cell Line; Cord Factors; Cytokines; Female; Lung; Macrophages; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mitogen-Activated Protein Kinases; Mycobacteriophages; Mycobacterium tuberculosis; Peptides; Protein Binding; Proto-Oncogene Proteins c-akt; Rifampin; Tuberculosis

2013
Is chewed raltegravir an option to care for HIV-infected patients with active tuberculosis?
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2013, Volume: 57, Issue:3

    Topics: Administration, Oral; Anti-HIV Agents; Antitubercular Agents; Coinfection; Drug Interactions; HIV Infections; Humans; Pyrrolidinones; Raltegravir Potassium; Rifampin; Tuberculosis

2013
Evaluation of a pro-active strategy for managing tuberculosis-HIV co-infection in a UK tertiary care setting.
    International journal of STD & AIDS, 2013, Volume: 24, Issue:4

    Management of tuberculosis (TB)-HIV co-infection is complicated by interactions between the diseases and their therapies. We developed and evaluated a strategy to (i) treat co-infected patients in a single co-infection clinic, (ii) maximize use of first-line drugs, (iii) delay antiretroviral therapy (ART) until two months post-TB treatment except in severe immunosuppression, (iv) commence efavirenz at 600 mg daily with therapeutic drug monitoring (TDM) and (v) target treatment completion. We conducted a prospective cohort review over 5.5 years in a UK tertiary referral center where 56 HIV-positive patients treated for TB were followed-up for a median 30 months. Main outcome measures were treatment completion, adverse events, immune reconstitution inflammatory syndrome, immunological and virological parameters, and TDM for efavirenz. Treatment completion rates were 88% (49/56); four patients were lost to local follow-up and three (5.4%) died during treatment; no deaths were TB-related. Adverse events were common (55%), but caused no treatment interruptions. Standard doses (600 mg daily) of efavirenz with rifampicin achieved or exceeded therapeutic levels in 25/28 (89%). This study supports combined management for TB-HIV co-infected patients. Delaying ART to two months post-TB treatment did not seem to result in poor clinical outcomes in this well-resourced context. Although efavirenz 600 mg daily usually achieved satisfactory levels, TDM is recommended.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Coinfection; Cyclopropanes; Drug Monitoring; HIV Infections; Humans; Middle Aged; Mycobacterium; Prospective Studies; Rifampin; Time Factors; Treatment Outcome; Tuberculosis; United Kingdom; Viral Load

2013
Adjuvant host-directed therapy with types 3 and 5 but not type 4 phosphodiesterase inhibitors shortens the duration of tuberculosis treatment.
    The Journal of infectious diseases, 2013, Aug-01, Volume: 208, Issue:3

    Shortening tuberculosis treatment could significantly improve patient adherence and decrease the development of drug resistance. Phosphodiesterase inhibitors (PDE-Is) have been shown to be beneficial in animal models of tuberculosis. We assessed the impact of PDE-Is on the duration of treatment in tuberculous mice.. We analyzed the time to death in Mycobacterium tuberculosis-infected mice receiving type 4 PDE-Is (rolipram and cilomilast) and the impact on bacterial burden, time to clearance, and relapse when types 3 and 5 PDE-Is (cilostazol and sildenafil, respectively) and rolipram were added to the standard treatment. We investigated pharmacokinetic interactions between PDE-Is (cilostazol and sildenafil) and rifampin.. The type 4 PDE-Is rolipram and cilomilast accelerated the time to death in tuberculous mice. The addition of rolipram to standard tuberculosis treatment increased bacterial burden and did not decrease the time to bacterial clearance in the lung, while the addition of the cilostazol and sildenafil reduced the time to clearance by 1 month. Cilostazol and sildenafil did not have negative pharmacokinetic interactions with rifampin.. Type 4 PDE-Is may increase the severity of tuberculosis and should be carefully investigated for use in patients with latent or active tuberculosis. Cilostazol and sildenafil may benefit tuberculosis patients by shortening the duration of therapy.

    Topics: Animals; Antitubercular Agents; Bacterial Load; Cilostazol; Disease Models, Animal; Drug Interactions; Humans; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Phosphodiesterase Inhibitors; Piperazines; Purines; Rifampin; Rolipram; Sildenafil Citrate; Sulfones; Survival Analysis; Tetrazoles; Treatment Outcome; Tuberculosis

2013
Age, nutritional status and INH acetylator status affect pharmacokinetics of anti-tuberculosis drugs in children.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2013, Volume: 17, Issue:6

    The currently recommended dosages of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol in children are extrapolated from adult pharmacokinetic studies, and have not been adequately evaluated in children.. To describe the pharmacokinetics of RMP, INH and PZA given thrice weekly in children with tuberculosis (TB), and to relate pharmacokinetics to treatment outcomes.. Eighty-four human immunodeficiency virus negative children with TB aged 1-12 years in Chennai and Madurai, India, were recruited. Phenotypic INH acetylator status was determined. Nutritional status was assessed using Z scores. During the intensive phase of anti-tuberculosis treatment, a complete pharmacokinetic study was performed after directly observed administration of drugs. At 2 and 6 months, drug levels were measured 2 h post-dose. Drug concentrations were measured using high performance liquid chromatography and pharmacokinetic variables were calculated. Multivariable regression analysis was performed to explore factors impacting drug levels and treatment outcomes.. Children aged <3 years had significantly lower RMP, INH and PZA concentrations than older children, and 90% of all children had sub-therapeutic RMP Cmax (<8 μg/ml). Age, nutritional status and INH acetylator status influenced drug levels. Peak RMP and INH concentrations were important determinants of treatment outcome. Recommendations for anti-tuberculosis treatment in children should take these factors into consideration.

    Topics: Acetylation; Age Factors; Antitubercular Agents; Child; Child, Preschool; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; India; Infant; Isoniazid; Male; Multivariate Analysis; Nutritional Status; Phenotype; Pyrazinamide; Regression Analysis; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

2013
Detection of and treatment protocol for rifampicin-monoresistant tuberculosis: what is the role of isoniazid?
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2013, Volume: 17, Issue:6

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Humans; Iran; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2013
Epidemiology of isoniazid resistance mutations and their effect on tuberculosis treatment outcomes.
    Antimicrobial agents and chemotherapy, 2013, Volume: 57, Issue:8

    Isoniazid resistance is highly prevalent in Vietnam. We investigated the molecular and epidemiological characteristics and the association with first-line treatment outcomes of the main isoniazid resistance mutations in Mycobacterium tuberculosis in codon 315 of the katG and in the promoter region of the inhA gene. Mycobacterium tuberculosis strains with phenotypic resistance to isoniazid from consecutively diagnosed smear-positive tuberculosis patients in rural Vietnam were subjected to Genotype MTBDRplus testing to identify katG and inhA mutations. Treatment failure and relapse were determined by sputum culture. In total, 227 of 251 isoniazid-resistant strains (90.4%) had detectable mutations: 75.3% in katG codon 315 (katG315) and 28.2% in the inhA promoter region. katG315 mutations were significantly associated with pretreatment resistance to streptomycin, rifampin, and ethambutol but not with the Beijing genotype and predicted both unfavorable treatment outcome (treatment failure or death) and relapse; inhA promoter region mutations were only associated with resistance to streptomycin and relapse. In tuberculosis patients, M. tuberculosis katG315 mutations but not inhA mutations are associated with unfavorable treatment outcome. inhA mutations do, however, increase the risk of relapse, at least with treatment regimens that contain only isoniazid and ethambutol in the continuation phase.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Bacterial Proteins; Catalase; Codon; Drug Resistance, Multiple, Bacterial; Ethambutol; Female; Follow-Up Studies; Genotype; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Promoter Regions, Genetic; Recurrence; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Vietnam; Young Adult

2013
Lower artemether, dihydroartemisinin and lumefantrine concentrations during rifampicin-based tuberculosis treatment.
    AIDS (London, England), 2013, Mar-27, Volume: 27, Issue:6

    To investigate the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine during rifampicin intake and after stopping rifampicin.. An open-label, two-phase, longitudinal drug interaction study with patients serving as their own controls.. We recruited HIV-1-seropositive Ugandan adults who were receiving rifampicin-based tuberculosis treatment and who did not have malaria. Pharmacokinetic sampling after six doses of artemether-lumefantrine was performed during rifampicin-based tuberculosis treatment (phase 1) and repeated at least 3 weeks after stopping rifampicin-based tuberculosis treatment (phase 2).. Six and five patients completed phases 1 and 2, respectively. Median age and weight were 30 years and 64 kg. Artemether and dihydroartemisinin area under the concentration-time curve (AUC(0-12h)) were significantly lower by 89% [geometric mean ratio (GMR) 90% confidence interval (CI) 0.11, 0.05-0.26] and 85% (0.15, 0.10-0.23), respectively, during rifampicin-based treatment when compared to AUC(0-12h) after stopping rifampicin intake. Similarly, artemether and dihydroartemisinin C(max) were 83% (0.17, 0.08-0.39) and 78% (0.22, 0.15-0.33) lower, respectively, during rifampicin treatment. For artemether, mean (±SD) C(12) was 0.5(±1.0) and 5.9(±2.5) ng/ml in phases 1 and 2, respectively. Corresponding values for dihydroartemisinin (DHA) were 0.3(±0.4) and 4.7(±2.0) ng/ml, respectively. Day 8 lumefantrine concentration was significantly lower by 84% (GMR 90% CI 0.16, 0.09-0.27), and AUC(Day3-Day25) was significantly lower by 68% (GMR 90% CI 0.32, 0.21-0.49) during rifampicin-based treatment when compared to exposure values after stopping rifampicin.. Pharmacokinetic parameters for artemether-lumefantrine were markedly lower during rifampicin-based tuberculosis treatment. Artemether-lumefantrine should not be co-administered with rifampicin.

    Topics: Adult; Antimalarials; Antitubercular Agents; Artemether; Artemisinins; Drug Antagonism; Ethanolamines; Female; Fluorenes; HIV Infections; Humans; Longitudinal Studies; Lumefantrine; Male; Rifampin; Tuberculosis; Uganda

2013
Development and validation of a hydrophilic interaction liquid chromatography-tandem mass spectrometry method for the simultaneous determination of five first-line antituberculosis drugs in plasma.
    Analytical and bioanalytical chemistry, 2013, Volume: 405, Issue:19

    A new, sensitive and fast method for the simultaneous determination of pyrazinamide, isoniazid, streptomycin, ethambutol, and rifampicin in human plasma was developed and validated. The method required only 100 μL of plasma and one step for sample preparation by protein precipitation. The drugs were separated by using a hydrophilic interaction liquid chromatography (HILIC) column. The mobile phase was methanol and water (0.1% formic acid and 5 mM ammonium acetate, pH 3.0 ± 0.1) in a ratio of 65:35 (v/v), which was eluted at an isocratic flow rate of 0.5 mL/min. Tandem mass spectrometry was performed with a triple-quadrupole tandem mass spectrometer. By use of the HILIC column, the detection was free of ion-pair reagents in the mobile phase, with no significant matrix effects. The total run time was less than 2 min for each sample. The method was validated by evaluating its selectivity, sensitivity, linearity, accuracy, and precision according to US Food and Drug Administration guidelines. The lower limit of quantification was 4.0 ng/mL for pyrazinamide, isoniazid, and rifampicin, 0.5 ng/mL for ethambutol, and 10.0 ng/mL for streptomycin. The intraday precision and interday precision were less than 9%, with the accuracy ranging between -9.3 and 7.3%. The method was successfully applied to therapeutic drug monitoring of 33 patients with tuberculosis after administration of standard antituberculosis drugs. The method has been proved to meet the high-throughput requirements in therapeutic drug monitoring.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Child; Chromatography, Liquid; Drug Monitoring; Ethambutol; Female; Humans; Hydrophobic and Hydrophilic Interactions; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tandem Mass Spectrometry; Tuberculosis; Young Adult

2013
Influence of efavirenz pharmacokinetics and pharmacogenetics on neuropsychological disorders in Ugandan HIV-positive patients with or without tuberculosis: a prospective cohort study.
    BMC infectious diseases, 2013, Jun-04, Volume: 13

    HIV infection, anti-tuberculosis and efavirenz therapy are associated with neuropsychological effects. We evaluated the influence of rifampicin cotreatment, efavirenz pharmacokinetics and pharmacogenetics on neuropsychiatric disorders in Ugandan HIV patients with or without tuberculosis coinfection.. 197 treatment naïve Ugandan HIV patients, of whom 138 were TB co-infected, enrolled prospectively and received efavirenz based HAART. TB-HIV confected patients received concomitant rifampicin based anti-TB therapy. Genotypes for CYP2B6 (*6, *11), CYP3A5 (*3, *6, *7), ABCB1 (c.3435C>T and c.4036 A/G rs3842), CYP2A6 (*9, *17) and NR1I3 rs3003596 T/C were determined. Efavirenz plasma concentrations were serially quantified at 3rd day, 1st, 2nd, 4th, 6th, 8th and 12th weeks during therapy. Efavirenz neuropsychiatric symptoms were evaluated in terms of sleep disorders, hallucinations and cognitive effects at baseline, at two and twelve weeks of efavirenz treatment using a modified Mini Mental State Examination (MMSE) score.. During the first twelve weeks of ART, 73.6% of the patients experienced at least one efavirenz related neuropsychiatric symptom. Commonest symptoms experienced were sleep disorders 60.5% (n=124) and hallucination 30.7% (n=63). Neuropsychiatric symptoms during HAART were significantly predicted by efavirenz plasma concentrations consistently. Rifampicin cotreatment reduced plasma efavirenz concentrations significantly only during the first week but not afterwards. There was no significant difference in the incidence of neuropsychiatric symptoms between patients receiving efavirenz with or without rifampicin cotreatment. CYP2B6*6 and ABCB1 c.4036 A/G genotype significantly predicted efavirenz concentrations. The tendency of CYP2B6*6 genotype association with higher incidence of having vivid dream (p=0.05), insomnia (p=0.19) and tactile hallucination (p=0.09) was observed mainly at week-2.. Efavirenz related neuropsychiatric symptoms are common among Ugandan HIV patients receiving ART and is mainly predicted by higher efavirenz plasma concentrations and CYP2B6 genotype but not by rifampicin based anti-TB co-treatment.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Cognitive Dysfunction; Constitutive Androstane Receptor; Cyclopropanes; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Female; Gene Frequency; Hallucinations; HIV Infections; Humans; Kaplan-Meier Estimate; Male; Memory Disorders; Mental Disorders; Prospective Studies; Rifampin; Sleep Arousal Disorders; Tuberculosis; Uganda

2013
Rifampin drug resistance tests for tuberculosis: challenging the gold standard.
    Journal of clinical microbiology, 2013, Volume: 51, Issue:8

    The rapid diagnosis of rifampin resistance is hampered by a reported insufficient specificity of molecular techniques for detection of rpoB mutations. Our objective for this study was to document the prevalence and prognostic value of rpoB mutations with unclear phenotypic resistance. The study design entailed sequencing directly from sputum of first failure or relapse patients without phenotypic selection and comparison of the standard retreatment regimen outcome, according to the mutation present. We found that among all rpoB mutations, the best-documented "disputed" rifampin resistance mutations (511Pro, 516Tyr, 526Asn, 526Leu, 533Pro, and 572Phe) made up 13.1% and 10.6% of all mutations in strains from Bangladesh and Kinshasa, respectively. Except for the 511Pro and 526Asn mutations, most of these strains with disputed mutations tested rifampin resistant in routine Löwenstein-Jensen medium proportion method drug susceptibility testing (DST; 78.7%), but significantly less than those with common, undisputed mutations (96.3%). With 63% of patients experiencing failure or relapse in both groups, there was no difference in outcome of first-line retreatment between patients carrying a strain with disputed versus common mutations. We conclude that rifampin resistance that is difficult to detect by the gold standard, phenotypic DST, is clinically and epidemiologically highly relevant. Sensitivity rather than specificity is imperfect with any rifampin DST method. Even at a low prevalence of rifampin resistance, a rifampin-resistant result issued by a competent laboratory may not warrant confirmation, although the absence of a necessity for confirmation needs to be confirmed for molecular results among new cases. However, a result of rifampin susceptibility should be questioned when suspicion is very high, and further DST using a different system (i.e., genotypic after phenotypic testing) would be fully justified.

    Topics: Antitubercular Agents; Bangladesh; Democratic Republic of the Congo; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mutation, Missense; Mycobacterium; Rifampin; Sputum; Tuberculosis

2013
Antituberculosis therapy-associated cutaneous leukocytoclastic vasculitis.
    Journal of tropical pediatrics, 2013, Volume: 59, Issue:6

    Antituberculosis therapy-associated cutaneous leukocytoclastic vasculitis (CLV) has been rarely reported. We describe a case of CLV induced by rifampicin and pyrazinamide. A 14-year-old male diagnosed with disseminated tuberculosis developed purpuric lesions after 1.5 months of treatment. Histopathology was consistent with leukocytoclastic vasculitis. Skin lesion improved after cessation of the two drugs and treatment with corticosteroids.

    Topics: Adolescent; Antitubercular Agents; Humans; Male; Prednisolone; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis; Vasculitis, Leukocytoclastic, Cutaneous

2013
[Impact of introducing rifampicin for the treatment of tuberculosis during the 1970's in Japan].
    Kekkaku : [Tuberculosis], 2013, Volume: 88, Issue:4

    The average duration of tuberculosis chemotherapy in Japan increased year by year throughout the 1960's and reached 49 months by 1973. It then began decreasing slowly in the 1970's and more rapidly after the 1980's.. To clarify the significant factors contributing to the prefectural variation of changes in the average duration of chemotherapy that occurred from 1973 to 1979.. Multiple regression analysis was conducted with the slopes of the average duration of chemotherapy of tuberculosis in prefectures throughout Japan from 1973 through 1979 as the dependent variable and with parameters related to treatment and patient characteristics of the prefectures as independent variables.. The variables, including uses of rifampicin, proportion of bacteriologically confirmed patients among newly registered cases, and average duration of chemotherapy as of 1973, contributed significantly to the slope of change in chemotherapy duration of the prefectures; the duration decreased faster in prefectures where there were more bacteriologically confirmed patients, and where the duration had been shorter at the beginning of the study period.. Short-course chemotherapy had not been established in the study period, but confidence in the potency of antibacterial activity of the new drug seems to have facilitated the departure from unnecessarily long treatment. The recognition of the importance of bacteriology in the clinical practice of tuberculosis worked in the same way against dependence on X-ray findings causing long-term treatment. Also, the prefectures that had been less affected by the long-term treatment could depart faster from it.

    Topics: Antibiotics, Antitubercular; Drug Monitoring; Drug Utilization; Japan; Registries; Regression Analysis; Rifampin; Time Factors; Tuberculosis

2013
[Tuberculosis annual report 2010--(9) Treatment of tuberculosis-2].
    Kekkaku : [Tuberculosis], 2013, Volume: 88, Issue:4

    The standard treatment for tuberculosis (TB) is the key to its control. Here we report statistics relating to treatment status and the duration of hospitalization and treatment in Japan. Among the newly noted TB patients in 2010, sputum-smear positive pulmonary TB patients were the most likely to receive hospital treatment (91.4%); 2.5% of these patients were primarily hospitalized for other diseases. The median duration of hospitalization in newly notified TB cases in 2009 was 73 days for new sputum-smear positive pulmonary TB cases, 75 days for sputum-smear positive pulmonary TB cases undergoing further treatment, 42 days for other bacillary positive pulmonary TB cases, 40.5 days for bacillary negative pulmonary TB cases, and 44 days for extra-pulmonary TB cases. The duration of TB treatment among newly notified cases in 2009 was assessed at the end of 2010. The median treatment duration for all forms of TB was 270 days. The longest median treatment duration was 285 days for retreatment of sputum-smear positive pulmonary TB cases, and the shortest duration was 196 days for bacillary-negative pulmonary TB cases.

    Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Hospitalization; Humans; Infant; Isoniazid; Japan; Length of Stay; Male; Middle Aged; Registries; Rifampin; Time Factors; Tuberculosis; Young Adult

2013
Genetic diversity of Mycobacterium tuberculosis in Peru and exploration of phylogenetic associations with drug resistance.
    PloS one, 2013, Volume: 8, Issue:6

    There is limited available data on the strain diversity of M tuberculosis in Peru, though there may be interesting lessons to learn from a setting where multidrug resistant TB has emerged as a major problem despite an apparently well-functioning DOTS control programme.. Spoligotyping was undertaken on 794 strains of M tuberculosis collected between 1999 and 2005 from 553 community-based patients and 241 hospital-based HIV co-infected patients with pulmonary tuberculosis in Lima, Peru. Phylogenetic and epidemiologic analyses permitted identification of clusters and exploration of spoligotype associations with drug resistance.. Mean patient age was 31.9 years, 63% were male and 30.4% were known to be HIV+. Rifampicin mono-resistance, isoniazid mono-resistance and multidrug resistance (MDR) were identified in 4.7%, 8.7% and 17.3% of strains respectively. Of 794 strains from 794 patients there were 149 different spoligotypes. Of these there were 27 strains (3.4%) with novel, unique orphan spoligotypes. 498 strains (62.7%) were clustered in the nine most common spoligotypes: 16.4% SIT 50 (clade H3), 12.3% SIT 53 (clade T1), 8.3% SIT 33 (LAM3), 7.4% SIT 42 (LAM9), 5.5% SIT 1 (Beijing), 3.9% SIT 47 (H1), 3.0% SIT 222 (clade unknown), 3.0% SIT1355 (LAM), and 2.8% SIT 92 (X3). Amongst HIV-negative community-based TB patients no associations were seen between drug resistance and specific spoligotypes; in contrast HIV-associated MDRTB, but not isoniazid or rifampicin mono-resistance, was associated with SIT42 and SIT53 strains.. Two spoligotypes were associated with MDR particularly amongst patients with HIV. The MDR-HIV association was significantly reduced after controlling for SIT42 and SIT53 status; residual confounding may explain the remaining apparent association. These data are suggestive of a prolonged, clonal, hospital-based outbreak of MDR disease amongst HIV patients but do not support a hypothesis of strain-specific propensity for the acquisition of resistance-conferring mutations.

    Topics: Adult; Antitubercular Agents; Directly Observed Therapy; Drug Resistance, Multiple, Bacterial; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Peru; Phylogeny; Rifampin; Tuberculosis

2013
Multidrug- and isoniazid-resistant tuberculosis in three high HIV burden African regions.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2013, Volume: 17, Issue:8

    Despite major progress in the surveillance of drug-resistant tuberculosis (TB), data are lacking for many low-resource countries. World Health Organization estimates of multidrug-resistant TB (MDR-TB) rates in Africa are low, and based on very limited data from the African continent.. To measure MDR-TB prevalence in sub-Saharan African regions with a high prevalence of human immunodeficiency virus (HIV).. We conducted three anti-tuberculosis drug resistance surveys in sub-Saharan African regions with high HIV-TB coinfection prevalence: Homa Bay (Kenya), Chiradzulu (Malawi) and West Nile region (Uganda).. The prevalence of MDR-TB in new patients was found to be low in the three regions: 1.4% (95%CI 0.2-2.6) in Homa Bay, 2.0% (95%CI 0.4-3.6) in Chiradzulu and 0.6% (95%CI 0.0-1.5) in the West Nile region. We found no significant association between MDR-TB and HIV infection. Nonetheless, ≥ 10% of the new cases surveyed were resistant to isoniazid (INH).. The relatively high rate of resistance to INH highlights the need for rapid detection of INH resistance in addition to rifampicin (RMP) resistance, to allow rapid modification of treatment to avoid the acquisition of RMP resistance. Drug resistance should be monitored periodically.

    Topics: Adolescent; Adult; Africa South of the Sahara; Antitubercular Agents; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Prevalence; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2013
Molecular and phenotypic characterisation of Mycobacterium tuberculosis resistant to anti-tuberculosis drugs.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2013, Volume: 17, Issue:8

    Dr Cetrángolo Hospital, Buenos Aires, Argentina.. To characterise drug-resistant (DR), multidrug-resistant (MDR-) and extensively drug-resistant (XDR-) Mycobacterium tuberculosis isolates, and identify their genetic profiles, drug resistance levels and resistance-conferring mutations.. Phenotypic drug susceptibility testing methods were used to determine drug resistance profiles. Minimal inhibitory concentrations (MICs) of isoniazid (INH), rifampicin (RMP) and levofloxacin (LVX) from 169 DR tuberculosis (TB) isolates, 78 of them monoresistant to INH, 13 to RMP, 7 to LVX, and 71 MDR-TB, were determined. Multiplex allele-specific polymerase chain reaction and DNA sequencing were used to detect mutations in katG, rpoB and gyrA/B genes. Genotyping was performed using spoligotyping and insertion sequence 6110 restriction fragment length polymorphism.. In total, 38.9% of the INH-resistant (INH(R)) isolates had an MIC ≥ 32 g/ml; 61.3% of RMP-resistant (RMP(R)) isolates had an MIC ≥ 64 g/ml and 55.6% of the LVX-resistant (LVX(R)) isolates had an MIC 4 ≥ 16 g/ml. The main mutations found in INH(R) isolates were katG315 (53.7%) and inhAP-15 (25.5%), whereas in RMP(R) isolates the main mutations were rpoB531 (61.9%), followed by rpoB526 (16.7%). LVX(R) isolates showed mutations in gyrA94/90. Haarlem, LAM and T were the main spoligotyping families found. katG315 was mainly associated with Haarlem and LAM, whereas inhAP-15 was associated with T.. Several isolates showed an association between high INH(R) levels and katG mutation; others from the Haarlem family were prone to becoming MDR-TB and continue to circulate in the community.

    Topics: Antitubercular Agents; Argentina; Bacterial Typing Techniques; DNA, Bacterial; Drug Resistance, Bacterial; Extensively Drug-Resistant Tuberculosis; Genotype; Humans; Isoniazid; Levofloxacin; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Rifampin; Sequence Analysis, DNA; Tuberculosis; Tuberculosis, Multidrug-Resistant

2013
Treatment response and adverse reactions in older tuberculosis patients with immunocompromising comorbidities.
    Yonsei medical journal, 2013, Volume: 54, Issue:5

    The aim of this study was to elucidate the effects of immunocompromising comorbidities on treatment response and adverse reactions in older tuberculosis (TB) patients.. The medical records of 182 patients older than 65 years with proven TB by positive culture of Mycobacterium tuberculosis and with available drug susceptibility tests were reviewed retrospectively. These patients were subsequently assigned to either the comorbidity group (n=78) or non-comorbidity group (n=104) depending on whether they had immunocompromising comorbidities.. The mean durations of treatment were 9.9 ± 3.3 months in the comorbidity group and 9.3 ± 3.2 months in the non-comorbidity group (p=0.21). M. tuberculosis culture results converted to negative in most patients with available follow-up cultures at two months after treatment. The successful treatment rates were 94.9% and 98.9% in the comorbidity and non-comorbidity groups, respectively (p=0.30). The most common side effects of anti-TB treatment were skin rash/pruritus (13% in the comorbidity group vs. 11% in the non-comorbidity group, p=0.79), gastro-intestinal problems (14% vs. 9%, p=0.25) and hepatotoxicity (14% vs. 7%, p=0.09).. The present study shows that the successful treatment rate for TB is high and that immunocompromising comorbidities have no effect on the response to treatment and adverse effects in older TB patients.

    Topics: Age Factors; Aged; Aged, 80 and over; Antitubercular Agents; Comorbidity; Female; Humans; Immunocompromised Host; Isoniazid; Male; Retrospective Studies; Rifampin; Risk Factors; Treatment Outcome; Tuberculosis

2013
Isoniazid-gelatin conjugate microparticles containing rifampicin for the treatment of tuberculosis.
    The Journal of pharmacy and pharmacology, 2013, Volume: 65, Issue:9

    In this work, a new polymeric microparticle system based on gelatin covalently bound to isoniazid (ISN) and containing rifampicin (RFP) was prepared by spray-drying technique. Microparticle aptitude to nebulisation and their capability of interacting with A549, alveolar basal epithelial cells, were evaluated in vitro.. Microparticles were obtained by spray drying, and their morphology, size, zeta potential, thermotropic behaviour and nebulisation ability were evaluated.. Microparticles were positively charged with a mean size of 4.88 ± 0.3 μm. Microspheres were able to incorporate both RFP and ISN: encapsulation efficiency was 51 ± 6% and 22 ± 1%, respectively. X-ray diffraction study showed a new extensive and flattened diffraction peak providing evidence that the drugs were dispersed into the microparticles. Differential scanning calorimetry analysis confirmed effective interactions between gelatin and drug molecules by the presence of new transition peaks. Fifty-nine per cent of used microparticles were aerosolised. In-vitro toxicity studies on A549 alveolar basal epithelial cells showed that microparticles decreased cytotoxicity in comparison with the RFP solution. Laser scanning confocal microscopy observation confirmed that fluorescent probes delivered by microparticles are efficiently internalised in A549 cells.. Overall, microparticles based on gelatin covalently bound to ISN and containing RFP showed a promising behaviour for pulmonary drug delivery.

    Topics: Administration, Inhalation; Aerosols; Antitubercular Agents; Cell Line; Desiccation; Drug Carriers; Drug Compounding; Drug Delivery Systems; Gelatin; Humans; Isoniazid; Lung; Microspheres; Particle Size; Respiratory Mucosa; Rifampin; Tuberculosis

2013
Estimation of content of anti-TB drugs supplied at centres of the Revised National TB Control Programme in Tamil Nadu, India.
    Tropical medicine & international health : TM & IH, 2013, Volume: 18, Issue:9

    To determine the content of certain antituberculosis (TB) drugs supplied at TB treatment centres of the Revised National TB Control Programme (RNTCP) in the state of Tamil Nadu, India.. Eight districts across the state were selected, and the following drugs were collected from five settings (District TB centre, TB unit, designated microscopy centres, DOT providers) in each district: rifampicin (150 and 450 mg), isoniazid (300 mg), pyrazinamide (500 and 750 mg), ethambutol (400 and 600 mg), ethionamide (250 mg), levofloxacin (500 mg) and cycloserine (250 mg). A maximum of 10 tablets/capsules were collected from each setting. The drugs were coded prior to analysis. All drugs were assayed by validated spectrophotometric methods. The acceptable limits for drug content were taken as 90-110% of the stated content.. More than 90% of tablets of rifampicin 450 mg, isoniazid 300 mg, pyrazinamide 500 and 750 mg, ethambutol 400 and 600 mg and ethionamide 250 mg were within acceptable limits. Eighty per cent of rifampicin 150 mg, 21% of cycloserine 250 mg and 87% of levofloxacin 500 mg were within acceptable limits. The mean cycloserine content was below the acceptable limit in all districts, the mean drug content being 200 mg (range: 108-245 mg).. This systematic study showed that the stated drug content of cycloserine was not reached in all districts. Deterioration of cycloserine could be minimised by storing the drug in refrigerators. The geographical location of the districts had no influence on the drug content.

    Topics: Antitubercular Agents; Cycloserine; Drug Stability; Drug Storage; Drug Therapy, Combination; Ethambutol; Ethionamide; Humans; India; Isoniazid; Levofloxacin; Ofloxacin; Pyrazinamide; Rifampin; Spectrophotometry; Tuberculosis

2013
[Proposal of anti-tuberculosis regimens based on susceptibility to isoniazid and rifampicin].
    Revista peruana de medicina experimental y salud publica, 2013, Volume: 30, Issue:2

    To elaborate optimal anti-tuberculosis regimens following drug susceptibility testing (DST) to isoniazid (H) and rifampicin (R).. 12 311 M. tuberculosis strains (National Health Institute of Peru 2007-2009) were classified in four groups according H and R resistance. In each group the sensitivity to ethambutol (E), pirazinamide (Z), streptomycin (S), kanamycin (Km), capreomycin (Cm), ciprofloxacin (Cfx), ethionamide (Eto), cicloserine (Cs) and p-amino salicilic acid (PAS) was determined. Based on resistance profiles, domestic costs, and following WHO guidelines, we elaborated and selected optimal putative regimens for each group. The potential efficacy (PE) variable was defined as the proportion of strains sensitive to at least three or four drugs for each regimen evaluated.. Selected regimes with the lowest cost, and highest PE of containing 3 and 4 effective drugs for TB sensitive to H and R were: HRZ (99,5%) and HREZ (99,1%), respectively; RZECfx (PE=98,9%) and RZECfxKm (PE=97,7%) for TB resistant to H; HZECfx (96,8%) and HZECfxKm (95,4%) for TB resistant to R; and EZCfxKmEtoCs (82.9%) for MDR-TB.. Based on resistance to H and R it was possible to select anti-tuberculosis regimens with high probability of success. This proposal is a feasible alternative to tackle tuberculosis in Peru where the access to rapid DST to H and R is improving progressively.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Child; Child, Preschool; Clinical Protocols; Cross-Sectional Studies; Female; Humans; Infant; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Young Adult

2013
Describing the profile of patients on concurrent rifampin and warfarin therapy in western Kenya: a case series.
    Drugs in R&D, 2013, Volume: 13, Issue:3

    Rifampicin's ability to induce hepatic enzymes is responsible for causing a clinically significant drug interaction with warfarin. Little data exists to guide clinicians on managing this interaction, especially in Sub-Saharan Africa where many patients are exposed to this combination due to a higher burden of tuberculosis.. The objective of the case series is to provide insight to practicing clinicians of the unique dynamics of this drug interaction in resource-constrained settings. The case series will provide details on commonly encountered scenarios and the dosage adjustments required to maintain a therapeutic INR.. A retrospective chart review was conducted of patients attending the Moi Teaching and Referral Hospital anticoagulation clinic in Eldoret, Kenya. Patients were included if they had a history of concurrent rifampicin and warfarin therapy and a minimum follow up of 2 months. Descriptive statistics were used to explain the demographic characteristics, time to therapeutic INR and average weekly warfarin dose. The inference on proportions test was conducted to compare the time in the therapeutic range (TTR) for patients on concurrent rifampicin to the rest of the patients not receiving rifampicin in the clinic.. Of the 350 patient charts evaluated, 10 met the inclusion criteria. The median percentage increase of the weekly warfarin dose from baseline was 15.7%. For the patients in this analysis, the median TTR was 47%.. Patients on concurrent therapy should be rigorously monitored with regular INR checks and warfarin dosage adjustments. Empiric dosage adjustments of warfarin should be avoided but patient characteristics can aid in understanding the alterations seen in INR.

    Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Anticoagulants; Blood Coagulation; Child; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; International Normalized Ratio; Kenya; Male; Medical Records; Middle Aged; Practice Guidelines as Topic; Retrospective Studies; Rifampin; Rural Population; Tuberculosis; Warfarin; Young Adult

2013
[Clinical experience using rifabutin for treating infection with Mycobacterium tuberculosis in elderly Japanese patients].
    Kekkaku : [Tuberculosis], 2013, Volume: 88, Issue:8

    To clarify whether rifabutin (RBT) can be used for treating tuberculosis in elderly Japanese patients in the clinical setting.. We performed a clinical chart review from Oct 2008 to Dec 2011, for patients who were diagnosed with tuberculosis and were prescribed rifabutin, at the Fukujuji Hospital (180 beds for respiratory medicine, including 60 for TB). Primarily, we focused on characteristics of patients, the cause for RBT indication, and success rate of treatment.. During the study period, 1129 patients were diagnosed with tuberculosis, and among these, 42 (3.7%) patients were prescribed RBT. Of these, 39 patients were included in this study (3 were excluded because their prescription was terminated within 2 weeks because of reasons other than adverse effects). In all, 69% patients were male. Mean age was 69 years, and mean body mass index was 19.1 +/- 3.4 kg/m2. RFP-related adverse effects were observed in 28 patients (72%; age, 73 years); these included gastrointestinal complications in 16, liver dysfunction in 7, skin rashes in 6, and renal dysfunction and thrombocytopenia in 1 each). Additional medication was required in 6 patients, and RBT-resistant TB was noted in 5 patients (28%; age, 60 years). A success rate of 71.4% was observed in cases of RFP-related adverse effects, and that of 81.8% was observed in cases of other reasons. Except for the patient who experienced renal dysfunction, RBT could be used in all patients who experienced RFP-related adverse effects.. RBT showed a relatively good success rate, even in patients who experienced RFP-related adverse effects. Thus, RBT could be an alternative in cases of RFP-related adverse effects, even in elderly patients.

    Topics: Aged; Antibiotics, Antitubercular; Female; Humans; Male; Rifabutin; Rifampin; Tuberculosis

2013
Transmission of Mycobacterium tuberculosis in a High School and School-Based Supervision of an Isoniazid-Rifapentine Regimen for Preventing Tuberculosis - Colorado, 2011-2012.
    MMWR. Morbidity and mortality weekly report, 2013, Oct-04, Volume: 62, Issue:39

    Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is spread from person to person by the airborne route. It can be transmitted extensively in congregate settings, making investigating exposures and treating infected contacts challenging. In December 2011, a student at a Colorado high school with 1,381 students and school personnel received a diagnosis of pulmonary TB disease. One of five household contacts had TB disease, and the other four had latent M. tuberculosis infection (LTBI). Screening of 1,249 school contacts (90%) found one person with pulmonary TB disease, who was fully treated, and 162 with LTBI, of whom 159 started an LTBI treatment regimen for preventing progression to TB disease and 153 completed a regimen. Only the index patient required inpatient care for TB, and TB caused no deaths. Use of short-course treatment regimens, either 12-dose weekly isoniazid and rifapentine directly observed at school or 4 months of self-supervised rifampin daily, facilitated treatment completion. State and county incident command structures led by county TB control authorities guided a response team from multiple jurisdictions. News media reports brought public scrutiny, but meetings with the community addressed the concerns and enhanced public participation. Two contacts of the index patient outside of the school had TB disease diagnosed after the school investigation. As of July 2013, no additional TB disease associated with in-school exposure had been found. An emergency plan for focusing widespread resources, an integral public communications strategy, and new, efficient interventions should be considered in other large TB contact investigations.

    Topics: Antitubercular Agents; Capacity Building; Colorado; Communication; Community-Institutional Relations; Contact Tracing; Drug Therapy, Combination; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; School Health Services; Tuberculosis

2013
Effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by CYP2B6 genotype.
    AIDS (London, England), 2013, Jul-31, Volume: 27, Issue:12

    An efavirenz-based antiretroviral therapy (ART) regimen is preferred for children more than 3 years of age with tuberculosis. However, rifampin, a key component of antituberculosis therapy, induces CYP2B6. An increased dose of efavirenz is recommended in adults weighing more than 50 kg who require rifampin, but there is scant information in children being treated for tuberculosis.. Plasma efavirenz concentrations were compared in 40 children during concomitant treatment for tuberculosis and HIV-1, after stopping rifampicin, and in a control group of children without tuberculosis. Associations with antituberculosis treatment, metabolizer genotype (based on CYP2B6 516G→T, 983T→C, and 15582C→T), weight, and time after dose were evaluated.. Compared to children with extensive metabolizer genotypes, efavirenz concentrations were increased 1.42-fold (95% confidence interval, CI 0.94–2.15) and 2.85-fold (95% CI 1.80–4.52) in children with intermediate and slow metabolizer genotypes, respectively. Concomitant antituberculosis treatment increased efavirenz concentrations 1.49-fold (95% CI 1.10–2.01) in children with slow metabolizer genotypes, but did not affect efavirenz concentrations in extensive or intermediate metabolizer genotypes. After adjustment for dose/kg, each kilogram of weight was associated with a 2.8% (95% CI 0.9–4.7) decrease in efavirenz concentrations. Despite higher milligram per kilogram doses, a higher proportion of children in the lowest weight band (10–13.9 kg) had efavirenz concentrations less than 1.0 mg/l than larger children.. Antituberculosis treatment was not associated with reduced efavirenz concentrations in children, which does not support increased efavirenz doses. Children with slow metabolizer genotype have increased efavirenz concentrations during antituberculosis treatment, likely due to isoniazid inhibiting enzymes involved in accessory metabolic pathways for efavirenz.

    Topics: Alkynes; Anti-HIV Agents; Antitubercular Agents; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Child; Child, Preschool; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Interactions; Female; Genotype; HIV Infections; Humans; Male; Plasma; Rifampin; Tuberculosis

2013
Unfinished battle with childhood tuberculosis: is it curable with less drugs and shorter duration?
    Tuberkuloz ve toraks, 2013, Volume: 61, Issue:4

    Tuberculosis is still a global health problem all over the world despite its mortality has been decreased with effective treatment regimens. Poor treatment adherence, acquired drug resistance, treatment failure and relapse are the major problems during the course of the tuberculosis treatment. Intermittent regimens have the advantages of reducing the side effects and the cost of the therapy and increasing the adherence, especially in resource-limited areas; and have been documented to be as effective as daily regimen in the paediatric population. In this study, we compared the results of 6-month and 9-month intermittent-therapy regimens with two drugs, given to the children with pulmonary and extrapulmonary tuberculosis at our hospital.. One hundred and fifteen patients with pulmonary and extrapulmonary tuberculosis other than meningitis, who had been given intermittent anti-tuberculosis therapy between 1986 and 2001, were evaluated retrospectively. Fifty one patients were given isoniazid and rifampin daily for 15 days, followed by the same drugs and doses twice weekly for a total of 9-months. Also, 64 patients were treated with the same regimen for a total of 6-months.. Clinical recovery was observed in 75% and 79% of pulmonary tuberculosis patients at the first month of therapy in group 1 (9-month group) and group 2 (6-month group), respectively. Radiological recovery was noted between 0-6 months in 81% of the patients in group 1 and 86% of the patients in group 2. According to the clinical and radiological recovery times, no significant difference was detected between the two groups (p> 0.05). Similar results had been observed in extrapulmonary tuberculosis (p> 0.05). Follow-up periods ranged from 7 months to 15 years. There was no case of early relapse. Late relapse was noted in 4 patients, who had been received 9-month therapy (group 1).. Six-month intermittent therapy with two drugs is as efficacious as 9-month intermittent-therapy in childhood pulmonary and extrapulmonary tuberculosis, other than meningitis.

    Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Recurrence; Retrospective Studies; Rifampin; Time Factors; Treatment Failure; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2013
Lack of association between plasma levels of non-nucleoside reverse transcriptase inhibitors & virological outcomes during rifampicin co-administration in HIV-infected TB patients.
    The Indian journal of medical research, 2013, Volume: 138, Issue:6

    Among patients with HIV-associated tuberculosis (TB), reduced plasma non-nucleoside reverse transcriptase inhibitors (NNRTI) concentrations during rifampicin (RMP) co-administration could lead to HIV treatment failure. This study was undertaken to examine the association between plasma nevirapine (NVP) and efavirenz (EFV) concentrations and virological outcomes in patients infected with HIV-1 and TB.. This was a nested study undertaken in a clinical trial of patients with HIV-1 and TB, randomized to two different once-daily antiretroviral treatment (ART) regimens along with anti-TB treatment (ATT). Trough concentrations of plasma NVP and EFV were estimated at months 1 (during ATT and ART) and 6 months (ART only) by HPLC. Plasma HIV-1 RNA level >400 copies/ml or death within 6 months of ART were considered as unfavourable outcomes. Genotyping of CYP2B6 516G>T polymorphism was performed.. Twenty nine per cent of patients in NVP arm had an unfavourable outcome at 6 months compared to 9 per cent in EFV arm (P<0.08). The mean NVP and EFV levels estimated at 1 and 6 months did not significantly differ between favourable and unfavourable responders. Logistic regression analysis showed CYP2B6 516G>T polymorphism significantly associated with virologic outcome in patients receiving EFV-based regimen.. Trough plasma concentrations of NVP and EFV did not show any association with response to ART in patients on ATT and once-daily ART. CYP2B6 516G>T polymorphism was associated with virologic outcome among patients on EFV.

    Topics: Adult; Alkynes; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Female; Genetic Association Studies; HIV Infections; HIV-1; Humans; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

2013
Putative compensatory mutations in the rpoC gene of rifampin-resistant Mycobacterium tuberculosis are associated with ongoing transmission.
    Antimicrobial agents and chemotherapy, 2013, Volume: 57, Issue:2

    Rifampin resistance in clinical isolates of Mycobacterium tuberculosis arises primarily through the selection of bacterial variants harboring mutations in the 81-bp rifampin resistance-determining region of the rpoB gene. While these mutations were shown to infer a fitness cost in the absence of antibiotic pressure, compensatory mutations in rpoA and rpoC were identified which restore the fitness of rifampin-resistant bacteria carrying mutations in rpoB. To investigate the epidemiological relevance of these compensatory mutations, we analyzed 286 drug-resistant and 54 drug-susceptible clinical M. tuberculosis isolates from the Western Cape, South Africa, a high-incidence setting of multidrug-resistant tuberculosis. Sequencing of a portion of the RpoA-RpoC interaction region of the rpoC gene revealed that 23.5% of all rifampin-resistant isolates tested carried a nonsynonymous mutation in this region. These putative compensatory mutations in rpoC were associated with transmission, as 30.8% of all rifampin-resistant isolates with an IS6110 restriction fragment length polymorphism (RFLP) pattern belonging to a recognized RFLP cluster harbored putative rpoC mutations. Such mutations were present in only 9.4% of rifampin-resistant isolates with unique RFLP patterns (P < 0.01). Moreover, these putative compensatory mutations were associated with specific strain genotypes and the rpoB S531L rifampin resistance mutation. Among isolates harboring this rpoB mutation, 44.1% also harbored rpoC mutations, while only 4.1% of the isolates with other rpoB mutations exhibited mutations in rpoC (P < 0.001). Our study supports a role for rpoC mutations in the transmission of multidrug-resistant tuberculosis and illustrates how epistatic interactions between drug resistance-conferring mutations, compensatory mutations, and different strain genetic backgrounds might influence compensatory evolution in drug-resistant M. tuberculosis.

    Topics: Anti-Bacterial Agents; Bacterial Proteins; Base Sequence; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Genotype; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Rifampin; Sequence Analysis, DNA; Tuberculosis; Tuberculosis, Multidrug-Resistant

2013
Study of the rifampin monoresistance mechanism in Mycobacterium tuberculosis.
    Antimicrobial agents and chemotherapy, 2013, Volume: 57, Issue:2

    Rifampin (RIF) susceptibility is a key factor in determining the treatment effectiveness of the standardized treatment regimens. In Mycobacterium tuberculosis, both target gene mutation and the efflux pump play major roles in the resistance to antituberculosis drugs. By eliminating RIF-resistant strains with rpoB mutation, the choice of RIF-monoresistant strains may allow us to identify the RIF-specific efflux pump genes. This study explored the RIF monoresistance mechanism in M. tuberculosis. Data from DNA sequencing and MIC measurements revealed that specific mutations, including Ser531Leu and His526Asp in RpoB, show high-level drug resistance. Three-dimensional structure modeling provided further evidence that the affinity between RIF and RpoB mutants was in accordance with the drug resistance level of the corresponding isolates. Furthermore, transcription-level analysis among the nonmutated isolates indicated that three efflux pumps (Rv0783, Rv2936, and Rv0933) might be involved in exporting RIF from the cell. Compared to 8 μg/ml for wild-type Escherichia coli, the MICs for the transgenic E. coli strains with either Rv0783 or Rv2936 were 32 and 16 μg/ml, respectively. In conclusion, our study indicated that several RpoB mutant types, including Ser531Leu and His526Asp, show high-level RIF resistance attributed to low affinity between RpoB mutant proteins and RIF. In addition, this work demonstrates that Rv2936 and Rv0783 may be responsible for low-level resistance to RIF by exporting RIF from cells. The predicted structure of RpoB and the newly identified efflux pumps in this study will provide a novel approach to design new drugs and develop novel diagnosis technologies.

    Topics: Antitubercular Agents; Bacterial Proteins; Base Sequence; Biological Transport; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Escherichia coli; Ethambutol; Genotype; Isoniazid; Kanamycin; Membrane Transport Proteins; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Ofloxacin; Protein Structure, Secondary; Protein Structure, Tertiary; Rifampin; Sequence Analysis, DNA; Streptomycin; Tuberculosis

2013
Cost-effectiveness of rifampin for 4 months and isoniazid for 9 months in the treatment of tuberculosis infection.
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2013, Volume: 32, Issue:5

    The purpose of this study was to evaluate the cost-effectiveness of the strategy of controlling the contacts of tuberculosis patients with latent tuberculosis infection by means of treatment with rifampin for 4 months or isoniazid for 9 months. The cost was the sum of the cost of treating latent tuberculosis infection in all contacts plus the cost of treating tuberculosis in whom the disease was not avoided. The effectiveness was expressed as cases avoided. The efficacy adopted was 90 % for rifampin for 4 months and 93 % for isoniazid for 9 months. We carried out a sensitivity analysis for efficacies of rifampin for 4 months of 80 %, 75 %, 69 % and 65 %. Of the 1,002 patients studied, 139 were treated with rifampin for 4 months and 863 were treated with isoniazid for 9 months. The cost-effectiveness was 436,842.83/50 cases avoided with rifampin for 4 months and 692,164.42/40 cases avoided with isoniazid for 9 months. Rifampin for 4 months was dominant. In the sensitivity analysis, rifampin for 4 months was dominant for efficacies of 75 % or greater. The cost-effectiveness analysis favoured the use of rifampin for 4 months when its efficacy was 75 % or greater.

    Topics: Adult; Antitubercular Agents; Contact Tracing; Cost-Benefit Analysis; Female; Humans; Isoniazid; Latent Tuberculosis; Male; Retrospective Studies; Rifampin; Spain; Tuberculosis

2013
Impact of pharmacogenetic markers of CYP2B6, clinical factors, and drug-drug interaction on efavirenz concentrations in HIV/tuberculosis-coinfected patients.
    Antimicrobial agents and chemotherapy, 2013, Volume: 57, Issue:2

    Comprehensive information on the effects of cytochrome P450 2B6 (CYP2B6) polymorphisms, clinical factors, and drug-drug interactions on efavirenz concentrations in HIV/tuberculosis-coinfected (HIV/TB) patients is unavailable. A total of 139 HIV/TB adults, 101 of whom received a rifampin-containing anti-TB regimen, were prospectively enrolled to receive efavirenz (600 mg)/tenofovir/lamivudine. Nine single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Plasma efavirenz concentrations were measured at 12 weeks. The median (interquartile range [IQR]) efavirenz concentration was 2.3 (1.4 to 3.9) mg/liter. The SNPs (frequencies of heterozygous and homozygous mutants) were 64C>T (10% and 1%), 499C>G (0% and 0%), 516G>T (47% and 8%), 785A>G (54% and 10%), 1375A>G (0% and 0%), 1459C>T (3% and 0%), 3003C>T (44% and 27%), 18492T>C (39% and 6%), and 21563C>T (57% and 5%). The four most frequent CYP2B6 haplotypes identified were *1/*6 (41%), *1/*1 (35%), *1/*2 (7%), and *6/*6 (7%). The heterozygous/homozygous mutation associated with low efavirenz concentrations was 18492T>C (P < 0.001), and those associated with high efavirenz concentrations were 516G>T, 785A>G, and 21563C>T (all P < 0.05). Haplotype *1/*1 was associated with low efavirenz concentrations, and *6/*6, *1/*6, and *5/6 were associated with high efavirenz concentrations. As shown by multivariate analysis, low efavirenz concentrations were significantly associated with the *1/*1 haplotype (beta = -1.084, P = 0.027) and high body weight (beta = -0.076, P = 0.002). In conclusion, pharmacogenetic markers of CYP2B6 have the greatest impact with respect to inducing low plasma efavirenz concentrations in HIV/TB Thai patients.

    Topics: Adenine; Adolescent; Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Interactions; Ethambutol; Female; Genotype; HIV Infections; Humans; Isoniazid; Lamivudine; Male; Middle Aged; Organophosphonates; Oxidoreductases, N-Demethylating; Pharmacogenetics; Polymorphism, Single Nucleotide; Pyrazinamide; Reverse Transcriptase Inhibitors; Rifampin; Tenofovir; Tuberculosis; Young Adult

2013
Rapid genotypic detection of rpoB and katG gene mutations in Mycobacterium tuberculosis clinical isolates from Northern India as determined by MAS-PCR.
    Journal of clinical laboratory analysis, 2013, Volume: 27, Issue:1

    There is a growing need to develop rapid laboratory research methods to counter the menace of drug resistant tuberculosis (MDR-TB) cases worldwide especially in developing countries. The present study was undertaken to investigate the type and frequency of rpoB and katG mutations in rifampicin (RIF) and isoniazid (INH) resistant strains respectively of Mycobacterium tuberculosis (MTB) circulating in Northern India and to explore the utility of multiplex-allele-specific (MAS)-PCR assay for detection of drug-resistant MTB isolates in low resource set up.. Phenotypic and genotypic drug susceptibility testing (DST) was performed on 354 MTB isolates.. Mutation in rpoB gene was found most frequently at codons 531, 526 and 516 (59.83%, 45.29% and 22.22%, respectively). Further, combinations of 2-3 point mutations were also observed in 19.66% of RIF-resistant MTB strains. The frequency of mutations in katG gene was found at codon 315 among 82.95% of the INH-resistant MTB isolates. MAS-PCR detected rpoB and katG mutations in phenotypically resistant isolates with sensitivities of 93% and 83% respectively.. MAS-PCR assays can be used for rapid detection of drug-resistant TB strains in routine diagnostic practice, enabling early administration of appropriate treatment regimens to the affected patients.

    Topics: Adult; Antitubercular Agents; Bacterial Proteins; Catalase; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Female; Humans; India; Isoniazid; Male; Molecular Typing; Multiplex Polymerase Chain Reaction; Mycobacterium tuberculosis; Phenotype; Point Mutation; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2013
Evaluation of Xpert MTB/RIF and MODS assay for the diagnosis of pediatric tuberculosis.
    BMC infectious diseases, 2013, Jan-23, Volume: 13

    Tuberculosis (TB) in children is rarely confirmed due to the lack of effective diagnostic tools; only 10 to 15% of pediatric TB is smear positive due to paucibacillary samples and the difficulty of obtaining high-quality specimens from children. We evaluate here the accuracy of Xpert MTB/RIF in comparison with the Micoroscopic observation drug susceptibility (MODS) assay for diagnosis of TB in children using samples stored during a previously reported evaluation of the MODS assay.. Ninety-six eligible children presenting with suspected TB were recruited consecutively at Pham Ngoc Thach Hospital in Ho Chi Minh City Viet Nam between May to December 2008 and tested by Ziehl-Neelsen smear, MODS and Mycobacterial growth Indicator (MGIT, Becton Dickinson) culture. All samples sent by the treating clinician for testing were included in the analysis. An aliquot of processed sample deposit was stored at -20°C and tested in the present study by Xpert MTB/RIF test. 183 samples from 73 children were available for analysis by Xpert. Accuracy measures of MODS and Xpert were summarized.. The sensitivity (%) in detecting children with a clinical diagnosis of TB for smear, MODS and Xpert were 37.9 [95% CI 25.5; 51.6], 51.7 [38.2; 65.0] and 50.0 [36.6; 63.4], respectively (per patient analysis). Xpert was significantly more sensitive than smear (P=0.046). Testing of additional samples did not increase case detection for MODS while testing of a second sputum sample by Xpert detected only two additional cases. The positive and negative predictive values (%) of Xpert were 100.0 [88.0; 100.0] and 34.1 [20.5; 49.9], respectively, while those of MODS were 96.8 [83.3; 99.9] and 33.3 [19.6; 49.5].. MODS culture and Xpert MTB/RIF test have similar sensitivities for the detection of pediatric TB. Xpert MTB RIF is able to detect tuberculosis and rifampicin resistance within two hours. MODS allows isolation of cultures for further drug susceptibility testing but requires approximately one week to become positive. Testing of multiple samples by xpert detected only two additional cases and the benefits must be considered against costs in each setting. Further research is required to evaluate the optimal integration of Xpert into pediatric testing algorithms.

    Topics: Adolescent; Bacteriological Techniques; Child; Child, Preschool; Drug Resistance, Bacterial; Humans; Infant; Infant, Newborn; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Tuberculosis

2013
A physiologically based pharmacokinetic model of rifampin in mice.
    Antimicrobial agents and chemotherapy, 2013, Volume: 57, Issue:4

    One problem associated with regimen-based development of antituberculosis (anti-TB) drugs is the difficulty of a systematic and thorough in vivo evaluation of the large number of possible regimens that arise from consideration of multiple drugs tested together. A mathematical model capable of simulating the pharmacokinetics and pharmacodynamics of experimental combination chemotherapy of TB offers a way to mitigate this problem by extending the use of available data to investigate regimens that are not initially tested. In order to increase the available mathematical tools needed to support such a model for preclinical anti-TB drug development, we constructed a preliminary whole-body physiologically based pharmacokinetic (PBPK) model of rifampin in mice, using data from the literature. Interindividual variability was approximated using Monte Carlo (MC) simulation with assigned probability distributions for the model parameters. An MC sensitivity analysis was also performed to determine correlations between model parameters and plasma concentration to inform future model development. Model predictions for rifampin concentrations in plasma, liver, kidneys, and lungs, following oral administration, were generally in agreement with published experimental data from multiple studies. Sensitive model parameters included those descriptive of oral absorption, total clearance, and partitioning of rifampin between blood and muscle. This PBPK model can serve as a starting point for the integration of rifampin pharmacokinetics in mice into a larger mathematical framework, including the immune response to Mycobacterium tuberculosis infection, and pharmacokinetic models for other anti-TB drugs.

    Topics: Animals; Antitubercular Agents; Computer Simulation; Mice; Monte Carlo Method; Rifampin; Tuberculosis

2013
Design, synthesis of some new (2-aminothiazol-4-yl)methylester derivatives as possible antimicrobial and antitubercular agents.
    European journal of medicinal chemistry, 2012, Volume: 49

    A series of (2-aminothiazol-4-yl)methylester (5a-t) derivatives were synthesized in good yields and characterized by (1)H NMR, (13)C NMR, mass spectral and elemental analyses. The crystal structure of 5a was evidenced by X-ray diffraction study. The compounds were evaluated for their preliminary in vitro antibacterial, antifungal activity and were screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain. The synthesized compounds displayed interesting antimicrobial activity.

    Topics: Anti-Infective Agents; Antitubercular Agents; Bacteria; Bacterial Infections; Crystallography, X-Ray; Fungi; Humans; Microbial Sensitivity Tests; Models, Molecular; Mycobacterium tuberculosis; Mycoses; Thiazoles; Tuberculosis

2012
Novel imidazo[2,1-b][1,3,4]thiadiazole carrying rhodanine-3-acetic acid as potential antitubercular agents.
    Bioorganic & medicinal chemistry letters, 2012, Mar-01, Volume: 22, Issue:5

    The increase in the prevalence of multi drug-resistant and extensively drug-resistant strains of Mycobacteriumtuberculosis case demonstrates the urgent need of discovering new promising compounds with antimycobacterial activity. As part of our research program and with a aim of identifying new antitubercular drug candidates, a new class of 2-(trifluoromethyl)-6-arylimidazo[2,1-b][1,3,4]thiadiazole derivatives has been synthesized by both conventional as well as microwave assisted method and evaluated for their in vitro antitubercular activity against M. tuberculosis H(37)Rv. Moreover, various drug-likeness properties of new compounds were predicted. Seven compounds from the series exhibited good activity with MIC in range 3.12-1.56μg/ml. The present study suggests that compounds 6b, 6c, 6d, 6e and 6f may serve as promising lead scaffolds for further generation of new anti-TB agents.

    Topics: Acetates; Antitubercular Agents; Humans; Imidazoles; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rhodanine; Thiadiazoles; Tuberculosis

2012
Anti-mycobacterial activities of some cationic and anionic calix[4]arene derivatives.
    Bioorganic & medicinal chemistry, 2012, Mar-15, Volume: 20, Issue:6

    Various polycharged calix[4]arenes were assayed as anti-mycobacterial agents against Mycobacterium tuberculosis, H(37)Rv strain. The sulfonate, carboxylate and phosphonate anionic species displayed no activity. Cationic derivatives integrating four aminoethyl groups at the upper rim and two 6,6'-dimethyl-2,2'-bipyridyl- or 4,4'-dimethyl-2,2'-bithiazolyl subunits at the lower rim were also found inactive against M. tuberculosis, while the unsubstituded and the 5,5'-dimethyl-2,2'-bipyridyl-analogues exhibited MIC values of 3.2 and 0.8μM respectively. Introduction of guanidinoethyl groups at the upper rim resulted, except for the 6,6'-dimethyl-2,2'-bipyridyl-derivative, in high anti-mycobacterial activities for the unsubstituted, the 5,5'-dimethyl-2,2'-bipyridyl- and the 4,4'-dimethyl-2,2'-bithiazolyl analogues, with MIC values of 0.8, 0.8 and 1.6μM, respectively, similar to those of current commercial anti-tuberculosis agents. The five more active substances were also evaluated against the isoniazid-resistant strain MYC5165, resulting in highly interesting micromolar or sub-micromolar MIC and IC(50), ca. 4-125 times more active than isoniazid. These preliminary results are attractive for the development of new anti-TB agents.

    Topics: 2,2'-Dipyridyl; Anions; Antitubercular Agents; Calixarenes; Guanidine; Humans; Inhibitory Concentration 50; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenols; Quaternary Ammonium Compounds; Tuberculosis

2012
Discovery and optimization of benzotriazine di-N-oxides targeting replicating and nonreplicating Mycobacterium tuberculosis.
    Journal of medicinal chemistry, 2012, Jul-12, Volume: 55, Issue:13

    Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.31 μg/mL against H37Rv and a cytotoxicity (CC(50)) against Vero cells of 25 μg/mL. 20q also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of other pathogenic bacterial strains. 20q was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs.

    Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Drug Discovery; Female; Isomerism; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Nitrofurans; Nitroimidazoles; Oxides; Quinoxalines; Rats; Tirapazamine; Triazines; Tuberculosis; Vero Cells

2012
Structural requirements for the antitubercular quaternized triflupromazine pharmacophore.
    Bioorganic & medicinal chemistry letters, 2012, Sep-01, Volume: 22, Issue:17

    Quaternized triflupromazine derivatives (QTDs) must possess benzyl groups attached to the quaternary nitrogen in order to have significant antitubercular potency. Replacing the quaternary amine with a triazole abolishes antitubercular activity. A modest halogen substitution effect exists, with the 4-bromophenyl QTD 3 having the best selectivity index (>21). All N-benzyl QTDs 1-4 similarly inhibit non-replicating, persistent Mycobacterium tuberculosis with MIC<8 μM, and compounds 1-3 were all nontoxic to mammalian cells in vitro (IC(50)>128 μM).

    Topics: Animals; Antitubercular Agents; Cell Survival; Chlorocebus aethiops; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Structure-Activity Relationship; Triflupromazine; Tuberculosis; Vero Cells

2012
Cryoprotection-lyophilization and physical stabilization of rifampicin-loaded flower-like polymeric micelles.
    Journal of the Royal Society, Interface, 2012, Mar-07, Volume: 9, Issue:68

    Rifampicin-loaded poly(ε-caprolactone)-b-poly(ethylene glycol)-poly(ε-caprolactone) flower-like polymeric micelles display low aqueous physical stability over time and undergo substantial secondary aggregation. To improve their physical stability, the lyoprotection-lyophilization process was thoroughly characterized. The preliminary cryoprotectant performance of mono- and disaccharides (e.g. maltose, glucose), hydroxypropyl-β-cyclodextrin (HPβCD) and poly(ethylene glycol) (PEG) of different molecular weights was assessed in freeze-thawing assays at -20°C, -80°C and -196°C. The size and size distribution of the micelles at the different stages were measured by dynamic light scattering (DLS). A cryoprotectant factor (f(c)) was determined by taking the ratio between the size immediately after the addition of the cryoprotectant and the size after the preliminary freeze-thawing assay. The benefit of a synergistic cryoprotection by means of saccharide/PEG mixtures was also assessed. Glucose (1 : 20), maltose (1 : 20), HPβCD (1 : 5) and glucose or maltose mixtures with PEG3350 (1 : 20) (copolymer:cryoprotectant weight ratio) were the most effective systems to protect 1 per cent micellar systems. Conversely, only HPβCD (1 : 5) cryoprotected more concentrated drug-loaded micelles (4% and 6%). Then, those micelle/cryoprotectant systems that displayed f(c) values smaller than 2 were freeze-dried. The morphology of freeze-dried powders was characterized by scanning electron microscopy and atomic force microscopy and the residual water content analysed by the Karl Fisher method. The HPβCD-added lyophilisates were brittle porous cakes (residual water was between 0.8% and 3%), easily redispersable in water to form transparent systems with a minimal increase in the micellar size, as determined by DLS.

    Topics: Chromatography, High Pressure Liquid; Cryoprotective Agents; Disaccharides; Drug Delivery Systems; Freeze Drying; Micelles; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Molecular Structure; Monosaccharides; Nanotechnology; Polyesters; Polyethylene Glycols; Rifampin; Solubility; Tuberculosis

2012
Systemic exposure to rifampicin in patients with tuberculosis and advanced HIV disease during highly active antiretroviral therapy in Burkina Faso.
    The Journal of antimicrobial chemotherapy, 2012, Volume: 67, Issue:2

    Low plasma concentrations of rifampicin, an essential antituberculosis drug, have been reported particularly among HIV co-infected persons. In a prospective, longitudinal study we measured rifampicin systemic exposure at different timepoints during highly active antiretroviral therapy (HAART).. From May 2006 to April 2007, 16 tuberculosis (TB)/HIV co-infected patients were enrolled in Ouagadougou, Burkina Faso. All patients received fixed dose combinations of rifampicin, isoniazid, pyrazinamide and ethambutol under direct observation and HAART, consisting of a fixed dose combination of stavudine, lamivudine and nevirapine. Rifampicin concentrations during the dosing interval were determined by HPLC at three different timepoints: (i) after 2 weeks of TB therapy and before starting HIV therapy (T0); (ii) after 4 weeks of combined therapy (T1); and (iii) after 10 weeks of combined therapy (T2).. The median values of the area under the curve (AUC(0-24)) of rifampicin increased by 39% at T1 (15.69 μg · h/mL; P = 0.01) and by 83% at T2 (20.65 μg · h/mL; P = 0.001) compared with T0 (11.28 μg · h/mL). Similar variations were observed for the median C(max) at T0 (2.24 μg/mL) compared with T2 (2.83 μg/mL; P = 0.003). However, none of the subjects had C(max) levels >8 μg/mL at either T0 or T2.. Rifampicin systemic exposure increased during combined TB and HIV therapy, possibly due to increased drug absorption or decreased oral clearance, but remained invariably low in this population. Studies to define the C(max) rifampicin concentrations, which are associated with a significantly increased risk of treatment failure, are urgently warranted.

    Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Burkina Faso; Chromatography, High Pressure Liquid; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Plasma; Pyrazinamide; Rifampin; Tuberculosis

2012
Do adjunct tuberculosis tests, when combined with Xpert MTB/RIF, improve accuracy and the cost of diagnosis in a resource-poor setting?
    The European respiratory journal, 2012, Volume: 40, Issue:1

    Information regarding the utility of adjunct diagnostic tests in combination with Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is limited. We hypothesised adjunct tests could enhance accuracy and/or reduce the cost of tuberculosis (TB) diagnosis prior to MTB/RIF testing, and rule-in or rule-out TB in MTB/RIF-negative individuals. We assessed the accuracy and/or laboratory-associated cost of diagnosis of smear microscopy, chest radiography (CXR) and interferon-γ release assays (IGRAs; T-SPOT-TB (Oxford Immunotec, Oxford, UK) and QuantiFERON-TB Gold In-Tube (Cellestis, Chadstone, Australia)) combined with MTB/RIF for TB in 480 patients in South Africa. When conducted prior to MTB/RIF: 1) smear microscopy followed by MTB/RIF (if smear negative) had the lowest cost of diagnosis of any strategy investigated; 2) a combination of smear microscopy, CXR (if smear negative) and MTB/RIF (if imaging compatible with active TB) did not further reduce the cost per TB case diagnosed; and 3) a normal CXR ruled out TB in 18% of patients (57 out of 324; negative predictive value (NPV) 100%). When downstream adjunct tests were applied to MTB/RIF-negative individuals, radiology ruled out TB in 24% (56 out of 234; NPV 100%), smear microscopy ruled in TB in 21% (seven out of 24) of culture-positive individuals and IGRAs were not useful in either context. In resource-poor settings, smear microscopy combined with MTB/RIF had the highest accuracy and lowest cost of diagnosis compared to either technique alone. In MTB/RIF-negative individuals, CXR has poor rule-in value but can reliably rule out TB in approximately one in four cases. These data inform upon the programmatic utility of MTB/RIF in high-burden settings.

    Topics: Costs and Cost Analysis; Health Resources; HIV Infections; Humans; Interferon-gamma Release Tests; Mycobacterium tuberculosis; Predictive Value of Tests; Radiography; Rifampin; Sensitivity and Specificity; South Africa; Sputum; Tuberculin Test; Tuberculosis

2012
Uncontrolled blood pressure in tubercular patients on hemodialysis: think rifampicin.
    Hemodialysis international. International Symposium on Home Hemodialysis, 2012, Volume: 16, Issue:2

    Topics: Antibiotics, Antitubercular; Blood Pressure; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Rifampin; Tuberculosis

2012
Pharmacokinetics of nevirapine in HIV and tuberculosis-coinfected children receiving antiretroviral fixed-dose combination tablets while receiving rifampicin-containing tuberculosis treatment and after rifampicin discontinuation.
    The Pediatric infectious disease journal, 2012, Volume: 31, Issue:4

    We assessed the pharmacokinetics of nevirapine in HIV and tuberculosis-coinfected children while they were receiving nevirapine-containing fixed-dose combination tablets with rifampicin-based tuberculosis treatment and after discontinuation. The median age (range) was 9.7 (4.4-11.7) years. The nevirapine area under the concentration versus time curve from 0 to 12 hours and trough concentration with rifampicin were 85.3 (40.5-170.7) mg.h/mL and 6.4 (3.00-13.27) mg/mL, respectively, providing adequate exposure.

    Topics: Administration, Oral; Anti-HIV Agents; Antitubercular Agents; Area Under Curve; Child; Child, Preschool; Female; HIV Infections; Humans; Infant; Male; Nevirapine; Plasma; Rifampin; Tuberculosis

2012
Mycolic acids as diagnostic markers for tuberculosis case detection in humans and drug efficacy in mice.
    EMBO molecular medicine, 2012, Volume: 4, Issue:1

    Mycolic acids are attractive diagnostic markers for tuberculosis (TB) infection because they are bacteria-derived, contain information about bacterial species, modulate host-pathogen interactions and are chemically inert. Here, we present a novel approach based on mass spectrometry. Quantification of specific precursor → fragment transitions of approximately 2000 individual mycolic acids (MAs) resulted in high analytical sensitivity and specificity. We next used this tool in a retrospective case-control study of patients with pulmonary TB with varying disease burdens from South Korea, Vietnam, Uganda and South Africa. MAs were extracted from small volume sputum (200 µl) and analysed without the requirement for derivatization. Infected patients (70, 19 of whom were HIV+) could be separated from controls (40, 20 of whom were HIV+) with a sensitivity and specificity of 94 and 93%, respectively. Furthermore, we quantified MA species in lung tissue of TB-infected mice and demonstrated effective clearance of MA levels following curative rifampicin treatment. Thus, our results demonstrate for the first time the feasibility and clinical relevance of direct detection of mycobacterial lipids as biomarkers of TB infection.

    Topics: Animals; Antibiotics, Antitubercular; Biomarkers; Case-Control Studies; Chromatography, High Pressure Liquid; Female; HIV Infections; Humans; Mice; Mice, Inbred BALB C; Mycolic Acids; Retrospective Studies; Rifampin; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Sputum; Tuberculosis

2012
Respirable rifampicin-based microspheres containing isoniazid for tuberculosis treatment.
    Journal of biomedical materials research. Part A, 2012, Volume: 100, Issue:2

    The purpose of this investigation was to develop small microspheres for delivering antimycobacterial drugs to infected host macrophages. Rifampicin-based microparticles were prepared. The drug was covalently linked to acrylic moieties to obtain a polymerizable derivative for the preparation of materials useful as drug delivery systems that then were loaded with isoniazid acting in synergy with rifampicin. Their antitubercular activity was determined in vitro. Fourier transform infrared spectroscopy confirmed hydrogel structure. Morphological analysis showed microparticles with spherical shape and homogeneous surface. In vitro release studies were performed in media simulating physiologic pH (7.4) and endosomal of alveolar macrophages pH (5.2). A similar amount of isoniazid was delivered within the first 6 h at both pHs, while a smaller amount of the drug was delivered at pH 7.4 in the last phase of the study. In vitro antitubercular activity showed a behavior comparable to that of rifampicin and isoniazid free. Bioactive swelling matrices, showing a high swelling degree into a medium miming intra alveolar environment, were obtained. They could be applied for their antitubercular activity.

    Topics: Animals; Antitubercular Agents; Humans; Hydrogel, Polyethylene Glycol Dimethacrylate; Hydrogen-Ion Concentration; Isoniazid; Microbial Sensitivity Tests; Microspheres; Mycobacterium tuberculosis; Rifampin; Spectrophotometry, Infrared; Tuberculosis

2012
Therapeutic drug monitoring in the treatment of tuberculosis patients.
    Pulmonary pharmacology & therapeutics, 2012, Volume: 25, Issue:1

    At the University Centre for Chronic Diseases Dekkerswald, a tertiary tuberculosis (TB) referral hospital in The Netherlands, therapeutic drug monitoring (TDM) is used in patients in case of relapse TB, when there is delayed response to TB treatment, and when abnormal TB drug concentrations are suspected for other reasons. In this article, a case series is presented to illustrate the value of individualized TB drug dosing in four patients with low TB drug concentrations. Increased doses of the TB drugs, especially of rifampicin, resulted in adequate peak plasma concentrations and improved clinical response to treatment in these patients, while no adverse events occurred.

    Topics: Adult; Aged; Alcoholism; Antibiotics, Antitubercular; Antitubercular Agents; Chromatography, High Pressure Liquid; Diabetes Complications; Diabetes Mellitus, Type 2; Drug Monitoring; Ethambutol; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Precision Medicine; Pyrazinamide; Recurrence; Rifampin; Schizophrenia; Sputum; Treatment Failure; Tuberculosis; Tuberculosis, Multidrug-Resistant

2012
Interferon-gamma release assay and Rifampicin therapy for household contacts of tuberculosis.
    The Journal of infection, 2012, Volume: 64, Issue:3

    Longitudinal studies in household contacts to identify subgroups at risk of active tuberculosis are lacking.. Household contacts of pulmonary tuberculosis patients were prospectively enrolled to receive chest radiography, sputum studies, and T-SPOT.TB assay at initial visit. Repeat examinations every 6 months for 3 years, and 4-month rifampin preventive therapy for T-SPOT.TB-positive contacts were provided. We investigated factors predicting T-SPOT.TB-positivity and active pulmonary tuberculosis.. 583 contacts were enrolled with a follow-up duration of 20.7 ± 9.4 months. 176 (30.2%) were T-SPOT.TB-positive initially and 32 (18.2%) of them received preventive therapy. Old age, living in the same room/house with the index case, the index case having a high smear grade (3+ ∼ 4+) and pulmonary cavitation were associated with T-SPOT.TB-positivity. Active tuberculosis developed in 9 T-SPOT.TB-positive contacts; risk factors included T-SPOT.TB-positivity without preventive therapy, living in the same room, and the index case being ≤50 years or female. 108 (61.4%) T-SPOT.TB-positive contacts had repeat examinations. Forty-five had T-SPOT.TB reversion and none of them developed active tuberculosis.. Household contacts who are T-SPOT.TB-positive and live in the same room as the index case are at risk of active tuberculosis and require preventive therapy and close follow-up.

    Topics: Adult; Aged; Antibiotics, Antitubercular; Contact Tracing; Family; Female; Follow-Up Studies; Humans; Interferon-gamma Release Tests; Male; Middle Aged; Prognosis; Rifampin; Risk Factors; Tuberculosis

2012
Human Mycobacterium bovis infection in Buenos Aires: epidemiology, microbiology and clinical presentation.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2012, Volume: 16, Issue:3

    We performed a retrospective study of clinical, epidemiological and microbiological characteristics of patients with confirmed Mycobacterium bovis infection treated at Francisco Muñiz Hospital, Buenos Aires, Argentina, between 1996 and 2008. A total of 39 patients were included, accounting for 0.4% of tuberculosis cases in our hospital. Of these, 93% had at least one risk factor for M. bovis; the most frequent was occupational exposure (65%), followed by history of living in a rural area (31%) and consumption of unpasteurised milk (4%). Pulmonary disease was the most frequent clinical presentation. Rifampicin resistance and multidrug resistance were seen in two patients, both of whom had human immunodeficiency virus infection.

    Topics: Adult; Animals; Antitubercular Agents; Argentina; Female; HIV Infections; Humans; Male; Middle Aged; Milk; Mycobacterium bovis; Occupational Diseases; Retrospective Studies; Rifampin; Risk Factors; Rural Population; Tuberculosis; Tuberculosis, Multidrug-Resistant

2012
Rise in rifampicin-monoresistant tuberculosis in Western Cape, South Africa.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2012, Volume: 16, Issue:2

    Brewelskloof Hospital, Western Cape, South Africa.. To verify the perceived increase in rifampicin monoresistant tuberculosis (RMR-TB) in the Cape Winelands-Overberg region and to identify potential risk factors.. A retrospective descriptive study of trends in RMR-TB over a 5-year period (2004-2008), followed by a case-control study of RMR and isoniazid (INH) monoresistant TB cases, diagnosed from April 2007 to March 2009, to assess for risk factors.. The total number of RMR-TB cases more than tripled, from 31 in 2004 to 98 in 2008. The calculated doubling time was 1.63 years (95%CI 1.18-2.66). For the assessment of risk factors, 95 RMR-TB cases were objectively verified on genotypic and phenotypic analysis. Of 108 specimens genotypically identified as RMR cases, 13 (12%) were misidentified, multidrug-resistant TB. On multivariate analysis, previous use of antiretroviral therapy (OR 6.4, 95%CI 1.3-31.8), alcohol use (OR 4.8, 95%CI 2.0-11.3) and age ≥ 40 years (OR 5.8, 95%CI 2.4-13.6) were significantly associated with RMR-TB.. RMR-TB is rapidly increasing in the study setting, particularly among patients with advanced human immunodeficiency virus (HIV) disease. Routine drug susceptibility testing should be considered in all TB-HIV co-infected patients, and absence of INH resistance should be confirmed phenotypically if genotypic RMR-TB is detected.

    Topics: Adult; Antibiotics, Antitubercular; Diagnosis, Differential; DNA, Bacterial; Drug Resistance, Bacterial; Female; Follow-Up Studies; Humans; Incidence; Male; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Risk Factors; South Africa; Tuberculosis; Tuberculosis, Multidrug-Resistant

2012
Cost-effectiveness of tuberculosis diagnostic strategies to reduce early mortality among persons with advanced HIV infection initiating antiretroviral therapy.
    Journal of acquired immune deficiency syndromes (1999), 2012, May-01, Volume: 60, Issue:1

    In sub-Saharan Africa, patients with advanced HIV experience high mortality during the first few months of antiretroviral therapy (ART), largely attributable to tuberculosis (TB). We evaluated the cost-effectiveness of TB diagnostic strategies to reduce this early mortality.. We developed a decision analytic model to estimate the incremental cost, deaths averted, and cost-effectiveness of 3 TB diagnostic algorithms. The model base case represents current practice (symptoms screening, sputum smear, and chest radiography) in many resource-limited countries in sub-Saharan Africa. We compared the current practice with World Health Organization (WHO)-recommended practice with culture and WHO-recommended practice with the Xpert mycobacterium tuberculosis and resistance to rifampicin test and considered relevant medical costs from a health system perspective using the timeframe of the first 6 months of ART. We conducted univariate and probabilistic sensitivity analyses on all parameters in the model.. When considering TB diagnosis and treatment and ART costs, the cost per patient was $850 for current practice, $809 for the algorithm with Xpert test, and $879 for the algorithm with culture. Our results showed that both WHO-recommended algorithms avert more deaths among TB cases than does the current practice. The algorithm with Xpert test was least costly at reducing early mortality compared with the current practice. Sensitivity analyses indicated that cost-effectiveness findings were stable.. Our analysis showed that culture or Xpert were cost-effective at reducing early mortality during the first 6 months of ART compared with the current practice. Thus, our findings provide support for ongoing efforts to expand TB diagnostic capacity.

    Topics: Africa South of the Sahara; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Clinical Laboratory Techniques; Cost-Benefit Analysis; HIV Infections; Humans; Microbial Sensitivity Tests; Models, Statistical; Mycobacterium tuberculosis; Rifampin; Survival Analysis; Tuberculosis

2012
Drug treatment combined with BCG vaccination reduces disease reactivation in guinea pigs infected with Mycobacterium tuberculosis.
    Vaccine, 2012, Feb-21, Volume: 30, Issue:9

    Bacillus-Calmette-Guerin (BCG), the only human tuberculosis vaccine, primes a partially protective immune response against Mycobacterium tuberculosis infection in humans and animals. In guinea pigs, BCG vaccination slows the progression of disease and reduces the severity of necrotic granulomas, which harbor a population of drug-tolerant bacilli. The objective of this study was to determine if reducing disease severity by BCG vaccination of guinea pigs prior to M. tuberculosis challenge enhanced the efficacy of combination drug therapy. At 20 days of infection, treatment of vaccinated and non-vaccinated animals with rifampin, isoniazid, and pyrizinamide (RHZ) was initiated for 4 or 8 weeks. On days 50, 80 and 190 of infection (10 weeks after drug were withdrawn), treatment efficacy was evaluated by quantifying clinical condition, bacterial loads, lesion severity, and dynamic changes in peripheral blood and lung leukocyte numbers by flow cytometry. In a separate, long-term survival study, treatment efficacy was evaluated by determining disease reactivation frequency post-mortem. BCG vaccination alone delayed pulmonary and extra-pulmonary disease progression, but failed to prevent dissemination of bacilli and the formation of necrotic granulomas. Drug therapy either alone or in combination with BCG, was more effective at lessening clinical disease and lesion severity compared to control animals or those receiving BCG alone. Fewer residual lesions in BCG vaccinated and drug treated animals, equated to a reduced frequency of reactivation disease and improvement in survival even out to 500 days of infection. The combining of BCG vaccination and drug therapy was more effective at resolving granulomas such that fewer animals had evidence of residual infection and thus less reactivation disease.

    Topics: Animals; BCG Vaccine; Combined Modality Therapy; Female; Granuloma; Guinea Pigs; Isoniazid; Lung; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

2012
Pharmacokinetics and 48 week efficacy of adjusted dose indinavir/ritonavir in rifampicin-treated HIV/tuberculosis-coinfected patients: a pilot study.
    AIDS research and human retroviruses, 2012, Volume: 28, Issue:10

    HIV/tuberculosis (HIV/TB)-coinfected patients intolerant/resistant to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have limited treatment options. We evaluated the pharmacokinetics (PK)/safety/efficacy of an adjusted dose of indinavir/ritonavir (IDV/r) 600/100 mg plus two NRTIs in HIV/TB-coinfected Thais receiving rifampicin-based anti-TB treatment. This was a prospective, open-label study. Eighteen Thai, HIV/TB-coinfected patients between 18 and 60 years were recruited. IDV/r 600 mg/100 mg plus lamivudine and stavudine were administered every 12 h (bid). When rifampicin was stopped, IDV/r was reduced to 400/100 mg BID. Clinical outcomes, adverse events, and concomitant drugs were intensively collected. Intensive 12-h PK was performed after 2 weeks of IDV/r while on rifampicin. Samples were collected: predosing and 1, 2, 3, 4, 6, 8, 10, and 12 h after drug intake. The median body weight was 55 kg. The median CD4 was 26 cells/μl. The median HIV RNA was 5.05 log(10) copies/ml. Then 15/18 underwent intensive PK at week 2. The median time between initiating rifampicin and IDV/r was 4.5 months. The median duration of rifampicin during study (rifampicin/IDV/r together) was 15.6 weeks. All received a total of 9 months of antituberculous drugs. The geometric means (GM) of indinavir AUC(0-12) and C(12) were 8.11 mg*h/liter and 0.03 mg/liter, respectively. After stopping rifampicin and reducing IDV/r to 400/100 bid, the GM indinavir C(12) increased to 0.68 mg/liter (p=0.004). In all, 8/18 (44%) had asymptomatic ALT elevation and 2/18 (11%) had symptomatic hepatotoxicity requiring IDV/r discontinuation. All 13 patients who remained on IDV/r treatment had HIV RNA <50 copies/ml at 48 weeks. Concomitant use of rifampicin and IDV/r resulted in subtherapeutic indinavir concentrations. Although 44% of them developed asymptomatic Grade 3/4 transaminitis, the rate of study drug discontinuation due to hepatotoxicity was low. Despite good virological outcome in our cohort, prolonged exposure to subtherapeutic indinavir concentrations may lead to treatment failure.

    Topics: Acquired Immunodeficiency Syndrome; Adult; Antibiotics, Antitubercular; CD4 Lymphocyte Count; Coinfection; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Indinavir; Male; Pilot Projects; Prospective Studies; Rifampin; Ritonavir; RNA, Viral; Thailand; Treatment Failure; Tuberculosis; Viral Load

2012
Two-drug antimicrobial chemotherapy: a mathematical model and experiments with Mycobacterium marinum.
    PLoS pathogens, 2012, Volume: 8, Issue:1

    Multi-drug therapy is the standard-of-care treatment for tuberculosis. Despite this, virtually all studies of the pharmacodynamics (PD) of mycobacterial drugs employed for the design of treatment protocols are restricted to single agents. In this report, mathematical models and in vitro experiments with Mycobacterium marinum and five antimycobacterial drugs are used to quantitatively evaluate the pharmaco-, population and evolutionary dynamics of two-drug antimicrobial chemotherapy regimes. Time kill experiments with single and pairs of antibiotics are used to estimate the parameters and evaluate the fit of Hill-function-based PD models. While Hill functions provide excellent fits for the PD of each single antibiotic studied, rifampin, amikacin, clarithromycin, streptomycin and moxifloxacin, two-drug Hill functions with a unique interaction parameter cannot account for the PD of any of the 10 pairs of these drugs. If we assume two antibiotic-concentration dependent functions for the interaction parameter, one for sub-MIC and one for supra-MIC drug concentrations, the modified biphasic Hill function provides a reasonably good fit for the PD of all 10 pairs of antibiotics studied. Monte Carlo simulations of antibiotic treatment based on the experimentally-determined PD functions are used to evaluate the potential microbiological efficacy (rate of clearance) and evolutionary consequences (likelihood of generating multi-drug resistance) of these different drug combinations as well as their sensitivity to different forms of non-adherence to therapy. These two-drug treatment simulations predict varying outcomes for the different pairs of antibiotics with respect to the aforementioned measures of efficacy. In summary, Hill functions with biphasic drug-drug interaction terms provide accurate analogs for the PD of pairs of antibiotics and M. marinum. The models, experimental protocols and computer simulations used in this study can be applied to evaluate the potential microbiological and evolutionary efficacy of two-drug therapy for any bactericidal antibiotics and bacteria that can be cultured in vitro.

    Topics: Amikacin; Anti-Infective Agents; Clarithromycin; Computer Simulation; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Drug Resistance, Multiple; Humans; Microbial Sensitivity Tests; Models, Biological; Models, Theoretical; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Rifampin; Tuberculosis

2012
Analysis of gene mutations associated with isoniazid, rifampicin and ethambutol resistance among Mycobacterium tuberculosis isolates from Ethiopia.
    BMC infectious diseases, 2012, Feb-10, Volume: 12

    The emergence of drug resistance is one of the most important threats to tuberculosis control programs. This study was aimed to analyze the frequency of gene mutations associated with resistance to isoniazid (INH), rifampicin (RMP) and ethambutol (EMB) among Mycobacterium tuberculosis isolates from Northwest Ethiopia, and to assess the performance of the GenoType® MTBDRplus and GenoType® MTBDRsl assays as compared to the BacT/ALERT 3D system.. Two hundred sixty Mycobacterium tuberculosis isolates from smear positive tuberculosis patients diagnosed between March 2009 and July 2009 were included in this study. Drug susceptibility tests were performed in the Institute of Medical Microbiology and Epidemiology of Infectious Diseases, University Hospital of Leipzig, Germany.. Of 260 isolates, mutations conferring resistance to INH, RMP, or EMB were detected in 35, 15, and 8 isolates, respectively, while multidrug resistance (MDR) was present in 13 of the isolates. Of 35 INH resistant strains, 33 had mutations in the katG gene at Ser315Thr 1 and two strains had mutation in the inhA gene at C15T. Among 15 RMP resistant isolates, 11 had rpoB gene mutation at Ser531Leu, one at His526Asp, and three strains had mutations only at the wild type probes. Of 8 EMB resistant strains, two had mutations in the embB gene at Met306Ile, one at Met306Val, and five strains had mutations only at the wild type probes. The GenoType® MTBDRplus assay had a sensitivity of 92% and specificity of 99% for INH resistance, and 100% sensitivity and specificity to detect RMP resistance and MDR. The GenoType® MTBDRsl assay had a sensitivity of 42% and specificity of 100% for EMB resistance.. The dominance of single gene mutations associated with the resistance to INH and RMP was observed in the codon 315 of the katG gene and codon 531 of the rpoB gene, respectively. The GenoType® MTBDRplus assay is a sensitive and specific tool for diagnosis of resistance to INH, RMP and MDR. However, the GenoType® MTBDRsl assay shows limitations in detecting resistance to EMB.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Bacterial Proteins; Catalase; Child; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Ethambutol; Ethiopia; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Diagnostic Techniques; Mutation, Missense; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Tuberculosis; Young Adult

2012
New insight into the molecular characterization of isoniazid and rifampicin resistant Mycobacterium tuberculosis strains from Saudi Arabia.
    Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2012, Volume: 12, Issue:3

    Data on the genetic variation of isolates of Mycobacterium tuberculosis and spectrum of mutations determining resistance to principal anti-tuberculosis drugs isoniazid (INH) and rifampicin (RIF) have not yet been studied in Saudi Arabia. One hundred and fifty-one clinical isolates of M. tuberculosis from different regions in the country showing resistance to RIF and INH were subjected to drug susceptibility testing, characterization of mutations conferring drug resistance and genotyping. Phenotypically 17 (11.3%) isolates were resistance to RIF, 75 (49.6%) were resistant to INH and 59 (39.1%) were resistant to both RIF and INH, respectively. Sixteen (10.6%), 74 (49%) and 56 (37.1%) were determined as resistant to RIF, INH and to both by line probe assay. High frequency of rpoB 531 mutations (67.1%) in RIF resistant strains and katG 315 mutations (65.2%) in INH resistant strains were found. Mutations responsible for INH resistance, katG 315 (P value<0.001, odds ratio: 1.81, 95% CI [1.51, 2.18]) and inhA-15 (P value - 0.004, odds ratio: 1.48, 95% CI [1.22, 1.8]) were predominant among the newly diagnosed cases. Beijing strains were significantly associated with multi drug resistance and mutations in combination of rpoB531 and katG315 (P value - <0.001, odds ratio: 6.83, 95% CI [2.65, 17.58]). In addition multi drug resistance was significantly associated with treatment history (P value<0.001, odds ratio: 3.16, 95% CI [2.14, 4.67]). Furthermore, a higher rate (39.3%) of clustering among the multidrug resistant strains particularly with Beijing family (52.9%) was observed. Saudi Arabia harbors highly diverse drug resistant M. tuberculosis population with an ongoing transmission which needs to be immediately managed.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bacterial Proteins; Catalase; Cluster Analysis; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Female; Genetic Variation; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Odds Ratio; Rifampin; Saudi Arabia; Tuberculosis; Young Adult

2012
Assessing the utility of three TaqMan probes for the diagnosis of tuberculosis and resistance to rifampin and isoniazid in Veracruz, México.
    Canadian journal of microbiology, 2012, Volume: 58, Issue:3

    Mutations at codons 526 and 531 in the rpoB gene and at 315 in the katG gene are considered diagnostic markers for resistance to rifampin and isoniazid in tuberculosis. The aim of this study was to design and evaluate three TaqMan probes for the identification of these mutations in 138 respiratory samples positive for acid-fast bacilli, and 32 clinical isolates from a region with considerable levels of drug resistance. The specificities of the probes for the diagnosis of resistance to both drugs were 100%; however, the sensitivities were calculated to be 50% for isoniazid and 56% for rifampin. DNA sequencing of rpoB and katG; and the spoligotyping assay of the clinical isolates, confirmed the diversity of the mutations and the presence of 11 spoligotypes with a shared international type and eight unique spoligotypes. Analysis of the respiratory samples identified 22 (16%) as drug-resistant and 4 (3%) as multidrug-resistant tuberculosis. The diagnostic value of the TaqMan probes was compromised by the diversity of mutations found in the clinical isolates. This highlights the need for better understanding of the molecular mechanisms responsible for drug resistance prior to the use of molecular probes, especially in regions with significant levels of drug-resistant tuberculosis.

    Topics: Antitubercular Agents; Bacterial Proteins; Catalase; DNA-Directed RNA Polymerases; Genetic Variation; Humans; Isoniazid; Mexico; Molecular Diagnostic Techniques; Mutation; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Tuberculosis; Tuberculosis, Multidrug-Resistant

2012
Tacrolimus as a risk factor for tuberculosis and outcome of treatment with rifampicin in solid organ transplant recipients.
    Transplant infectious disease : an official journal of the Transplantation Society, 2012, Volume: 14, Issue:6

    The purpose of this study was to investigate the incidence, risk factors, and treatment outcome of tuberculosis (TB) in solid organ transplant (SOT) recipients treated with rifampicin.. The incidence density of TB was calculated by a retrospective cohort study. Risk factors for TB were analyzed by a nested case-control study. Treatment outcome and effects of anti-TB drugs on immunosuppressants and allograft were compared between patients whose initial 2-month intensive regimen included rifampicin and those whose intensive regimen did not.. Among the 2144 SOT recipients over 16 years, 40 cases of TB were found (1.7%). The incidence density was 372 cases per 10(5) patient years (95% confidence interval [CI], 270-503), which was 4 times higher than for the general Korean population (90 cases per 10(5) person years). The median time to the development of TB was 234 days (range, 33-3940 days). The use of tacrolimus (odds ratio [OR] 4.90; 95% CI, 1.74-13.80; P = 0.003) and cytomegalovirus (CMV) infection within the prior 3 months (OR 4.62; 95% CI, 1.44-14.87; P = 0.01) were found to be risk factors for TB. Patients whose intensive regimen included rifampicin were more likely to have an increased dose of calcineurin inhibitors than patients whose intensive regimen did not include rifampicin (13/15 [86.7%] vs. 3/14 [21.4%], P = 0.001). Graft rejection and mortality did not differ between the 2 groups.. Use of tacrolimus and CMV infection were major risk factors for TB in SOT recipients. The graft outcome and mortality did not differ whether rifampicin was used or not during the first 2-month intensive phase.

    Topics: Adult; Aged; Antitubercular Agents; Case-Control Studies; Drug Interactions; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Rifampin; Risk Factors; Tacrolimus; Treatment Outcome; Tuberculosis; Young Adult

2012
Discordance in Mycobacterium tuberculosis rifampin susceptibility.
    Emerging infectious diseases, 2012, Volume: 18, Issue:3

    Topics: Acquired Immunodeficiency Syndrome; Antibiotics, Antitubercular; Bacterial Proteins; Drug Resistance, Bacterial; Female; Genotype; Humans; Ill-Housed Persons; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Rifampin; Tuberculosis

2012
Clinical outcomes of pyrazinamide-monoresistant Mycobacterium tuberculosis in Quebec.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2012, Volume: 16, Issue:5

    In Quebec, 6.2% of all tuberculosis (TB) isolates from Canadian-born patients are resistant to pyrazinamide (PZA) alone. The clinical significance of PZA-monoresistant (PZA(MR)) TB is unknown.. Canadian-born patients with PZA(MR) TB diagnosed between 1 January 1990 and 31 December 2000 and reported in a prior study were compared to randomly selected Canadian-born patients with fully susceptible isolates diagnosed within the same time period.. A total of 318 patients were eligible, of whom 40 (12.6%) had missing outcome information. Mean total duration of treatment was respectively 9.0 and 8.9 months for those with PZA(MR) and pan-susceptible strains. Respectively 91% and 89% of PZA(MR) and pan-susceptible patients received at least 6 months of rifampin-containing treatment. Among 67 patients with PZA(MR) TB, 51 (76%) were cured, 3 (4%) relapsed, none failed treatment, and 16 (24%) died within 6 months of diagnosis. Of 211 subjects with fully susceptible isolates, 181 (86%) were cured, 2 (1%) relapsed, 2 (1%) failed treatment, and 30 (14%) died within 6 months of diagnosis. PZA monoresistance was associated with decreased odds of successful clinical outcomes compared with pan-susceptible TB (OR 0.4, 95%CI 0.2-0.8).. Patients with PZA(MR) TB had significantly worse clinical outcomes than patients with fully susceptible strains.

    Topics: Aged; Aged, 80 and over; Antitubercular Agents; Cohort Studies; Drug Resistance, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Quebec; Recurrence; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis

2012
Active case finding and prevention of tuberculosis among a cohort of contacts exposed to infectious tuberculosis cases in New York City.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2012, Volume: 54, Issue:9

    Tuberculosis contact investigation identifies individuals who may be recently infected with tuberculosis and are thus at increased risk for disease. Contacts with latent tuberculosis infection (LTBI) are offered chemoprophylaxis to prevent active disease; however, the effectiveness of this intervention is unclear as treatment completion is generally low.. A retrospective cohort study of 30 561 contacts identified during investigation of 5182 cases of tuberculosis diagnosed in New York City, 1997-2003, was performed. We searched the NYC tuberculosis registry to identify contacts developing active tuberculosis within 4 years of follow-up. We estimated the following: number of contacts undergoing evaluation (ie, tuberculin skin test and/or chest radiograph) per prevalent case diagnosed; number of contacts with LTBI that need to be treated with standard chemoprophylaxis to prevent 1 active case.. Of 30 561 contacts, 27 293 (89%) were evaluated and 268 prevalent cases were diagnosed (102 contacts evaluated per prevalent case diagnosed, 95% confidence interval [CI], 90-115). LTBI was diagnosed in 7597 contacts, including 6001 (79%) who initiated chemoprophylaxis, 3642 (61%) who later completed treatment, and 2359 (39%) who did not complete treatment. During 4 years of follow-up, active tuberculosis was diagnosed in 46 contacts with LTBI, including 22 of 6001 (0.4%) who initiated chemoprophylaxis and 24 of 1596 (1.5%) who did not initiate treatment. The absolute risk reduction afforded by chemoprophylaxis initiation was 1.1% (95% CI, .6%-1.9%), leading to an estimated 88 contacts treated to prevent 1 tuberculosis case (95% CI, 53-164).. Contact investigation facilitates active case finding and tuberculosis prevention, even when completion rates of chemoprophylaxis are suboptimal.

    Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Child; Child, Preschool; Cohort Studies; Contact Tracing; Female; Follow-Up Studies; Humans; Infant; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Mycobacterium tuberculosis; New York City; Numbers Needed To Treat; Prevalence; Retrospective Studies; Rifampin; Tuberculin Test; Tuberculosis; Young Adult

2012
The safety, effectiveness and concentrations of adjusted lopinavir/ritonavir in HIV-infected adults on rifampicin-based antitubercular therapy.
    PloS one, 2012, Volume: 7, Issue:3

    Rifampicin co-administration dramatically reduces plasma lopinavir concentrations. Studies in healthy volunteers and HIV-infected patients showed that doubling the dose of lopinavir/ritonavir (LPV/r) or adding additional ritonavir offsets this interaction. However, high rates of hepatotoxicity were observed in healthy volunteers. We evaluated the safety, effectiveness and pre-dose concentrations of adjusted doses of LPV/r in HIV infected adults treated with rifampicin-based tuberculosis treatment.. Adult patients on a LPV/r-based antiretroviral regimen and rifampicin-based tuberculosis therapy were enrolled. Doubled doses of LPV/r or an additional 300 mg of ritonavir were used to overcome the inducing effect of rifampicin. Steady-state lopinavir pre-dose concentrations were evaluated every second month.. 18 patients were enrolled with a total of 79 patient months of observation. 11/18 patients were followed up until tuberculosis treatment completion. During tuberculosis treatment, the median (IQR) pre-dose lopinavir concentration was 6.8 (1.1-9.2) mg/L and 36/47 (77%) were above the recommended trough concentration of 1 mg/L. Treatment was generally well tolerated with no grade 3 or 4 toxicity: 8 patients developed grade 1 or 2 transaminase elevation, 1 patient defaulted additional ritonavir due to nausea and 1 patient developed diarrhea requiring dose reduction. Viral loads after tuberculosis treatment were available for 11 patients and 10 were undetectable.. Once established on treatment, adjusted doses of LPV/r co-administered with rifampicin-based tuberculosis treatment were tolerated and LPV pre-dose concentrations were adequate.

    Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Coinfection; Drug Interactions; Female; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Rifampin; Ritonavir; Tuberculosis

2012
A screen for non-coding RNA in Mycobacterium tuberculosis reveals a cAMP-responsive RNA that is expressed during infection.
    Gene, 2012, May-25, Volume: 500, Issue:1

    A key to the success of Mycobacterium tuberculosis (Mtb) is the bacteria's ability to survive and thrive in the presence of numerous stresses mounted by the host. Small, non-coding RNAs (sRNAs) have been shown to modulate numerous stress responses in bacteria, yet to date only two studies have screened the Mtb transcriptome to identify sRNA. Their association with oxidative and acid stress has been demonstrated but the cellular function and role of these sRNAs in the pathogenesis of tuberculosis (TB) remain unknown. Here, we have identified an sRNA, ncrMT1302, in a locus involved in cAMP metabolism and demonstrate that expression of ncrMT1302 responds to changes in pH and cAMP concentration. The differential expression of ncrMT1302 observed in wild-type Mtb during growth is abolished in a strain lacking MT1302, an adenylyl cyclase encoding gene. We report that ncrMT1302 is expressed in Mtb residing in the lungs of mice during an active infection.

    Topics: Animals; Cloning, Molecular; Cyclic AMP; Disease Models, Animal; Female; Gene Expression; Humans; Hydrogen-Ion Concentration; Mice; Mycobacterium tuberculosis; Rifampin; RNA, Bacterial; RNA, Small Untranslated; Tuberculosis

2012
Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis.
    Antimicrobial agents and chemotherapy, 2012, Volume: 56, Issue:6

    Novel oral regimens composed of new drugs with potent activity against Mycobacterium tuberculosis and no cross-resistance with existing agents are needed to shorten and simplify treatment for both drug-susceptible and drug-resistant tuberculosis. As part of a continuing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, several 3- and 4-drug combinations containing new agents currently in phase 2/3 trials (TMC207 [bedaquiline], PA-824 and PNU-100480 [sutezolid], and/or clofazimine) proved superior to the first-line regimen of rifampin, pyrazinamide, and isoniazid. TMC207 plus PNU-100480 was the most effective drug pair. In the second experiment, in which 3- and 4-drug combinations composed of TMC207 and pyrazinamide plus rifapentine, clofazimine, PNU-100480, or both rifapentine and clofazimine were evaluated, the rank order of drugs improving the sterilizing activity of TMC207 and pyrazinamide was as follows: rifapentine plus clofazimine ≥ clofazimine ≥ rifapentine > PNU-100480. The results revealed potential new building blocks for universally active short-course regimens for drug-resistant tuberculosis. The inclusion of pyrazinamide against susceptible isolates may shorten the duration of treatment further.

    Topics: Animals; Antitubercular Agents; Drug Therapy, Combination; Female; Isoniazid; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nitroimidazoles; Oxazolidinones; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2012
Rifapentine and isoniazid for latent tuberculosis.
    The New England journal of medicine, 2012, 04-12, Volume: 366, Issue:15

    Topics: Antitubercular Agents; Humans; Isoniazid; Male; Rifampin; Tuberculosis

2012
Rifapentine and isoniazid for latent tuberculosis.
    The New England journal of medicine, 2012, 04-12, Volume: 366, Issue:15

    Topics: Antitubercular Agents; Humans; Isoniazid; Male; Rifampin; Tuberculosis

2012
Outcomes among tuberculosis patients with isoniazid resistance in Georgia, 2007-2009.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2012, Volume: 16, Issue:6

    The optimal management strategy for patients with isoniazid (INH) monoresistant forms of tuberculosis (TB) has been widely debated. The current daily 9-month regimen of rifampin, pyrazinamide and ethambutol was established based largely on trials in settings with low TB rates and low rates of drug resistance.. To explore the outcomes of patients with INH-monoresistant TB in the country of Georgia, a setting with both high TB rates and drug-resistant forms of the disease.. Retrospective record review of all patients diagnosed with smear-positive pulmonary TB resistant to either INH or INH+SM (streptomycin) in Georgia between 2007 and 2009.. Of 8752 patients with pulmonary TB registered in Georgia, 909 were found to have INH or INH+SM resistance. Treatment outcomes were relatively poor in this group, with only 71% treatment success. Outcomes were significantly worse among patients with older age and a history of previous treatment.. INH or INH+SM resistance in pulmonary TB patients in Georgia is common. The low rates of treatment success suggest the need for an improved treatment regimen for patients with resistance to these first-line drugs; this need is particularly pronounced among the subset of patients with a history of previous treatment.

    Topics: Adult; Antitubercular Agents; Chi-Square Distribution; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Female; Georgia (Republic); Humans; Isoniazid; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Predictive Value of Tests; Pyrazinamide; Retrospective Studies; Rifampin; Risk Assessment; Risk Factors; Sputum; Time Factors; Treatment Outcome; Tuberculosis

2012
Should Xpert® MTB/RIF be rolled out in low-income countries?
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2012, Volume: 16, Issue:5

    Topics: Antitubercular Agents; Humans; Nucleic Acid Amplification Techniques; Rifampin; Tuberculosis

2012
Location of Xpert® MTB/RIF in centralised laboratories in South Africa undermines potential impact.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2012, Volume: 16, Issue:5

    Topics: Antitubercular Agents; Humans; Nucleic Acid Amplification Techniques; Rifampin; Tuberculosis

2012
Rapid, high-throughput detection of rifampin resistance and heteroresistance in Mycobacterium tuberculosis by use of sloppy molecular beacon melting temperature coding.
    Journal of clinical microbiology, 2012, Volume: 50, Issue:7

    Rifampin resistance in Mycobacterium tuberculosis is largely determined by mutations in an 80-bp rifampin resistance determining region (RRDR) of the rpoB gene. We developed a rapid single-well PCR assay to identify RRDR mutations. The assay uses sloppy molecular beacons to probe an asymmetric PCR of the M. tuberculosis RRDR by melting temperature (T(m)) analysis. A three-point T(m) code is generated which distinguishes wild-type from mutant RRDR DNA sequences in approximately 2 h. The assay was validated on synthetic oligonucleotide targets containing the 44 most common RRDR mutations. It was then tested on a panel of DNA extracted from 589 geographically diverse clinical M. tuberculosis cultures, including isolates with wild-type RRDR sequences and 25 different RRDR mutations. The assay detected 236/236 RRDR mutant sequences as mutant (sensitivity, 100%; 95% confidence interval [CI], 98 to 100%) and 353/353 RRDR wild-type sequences as wild type (specificity, 100%; 95% CI, 98.7 to 100%). The assay identified 222/225 rifampin-resistant isolates as rifampin resistant (sensitivity, 98.7%; 95% CI, 95.8 to 99.6%) and 335/336 rifampin-susceptible isolates as rifampin susceptible (specificity, 99.7%; 95% CI, 95.8 to 99.6%). All mutations were either individually identified or clustered into small mutation groups using the triple T(m) code. The assay accurately identified mixed (heteroresistant) samples and was shown analytically to detect RRDR mutations when present in at least 40% of the total M. tuberculosis DNA. This was at least as accurate as Sanger DNA sequencing. The assay was easy to use and well suited for high-throughput applications. This new sloppy molecular beacon assay should greatly simplify rifampin resistance testing in clinical laboratories.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Oligonucleotide Probes; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Time Factors; Transition Temperature; Tuberculosis

2012
Rifapentine is not more active than rifampin against chronic tuberculosis in guinea pigs.
    Antimicrobial agents and chemotherapy, 2012, Volume: 56, Issue:7

    Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with ~200 bacilli of Mycobacterium tuberculosis H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and P at 100 mg/kg were given orally alone or in combination with isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human-equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening.

    Topics: Animals; Antitubercular Agents; Female; Guinea Pigs; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

2012
Serial interferon-gamma release assays after chemoprophylaxis in a tuberculosis outbreak cohort.
    Infection, 2012, Volume: 40, Issue:4

    Interferon-gamma release assay (IGRA) results have been suggested as a surrogate marker of treatment response in latent tuberculosis infection (LTBI). However, data have not been consistent, and most previous studies focused on participants taking isoniazid prophylaxis. The aim of this study was to elucidate the changes in the IGRA results in patients who underwent chemoprophylaxis with isoniazid and rifampicin daily for 3 months.. In a TB outbreak cohort, 26 asymptomatic close contacts with normal chest radiographs and positive QuantiFERON-TB Gold In-Tube assay (QFT-GIT) results were recruited. These patients were treated with isoniazid and rifampicin daily for 3 months. The QFT-GIT was repeated at 3 and 6 months following treatment initiation.. Compared with the initial QFT-GIT results (3.59 ± 3.39 IU/mL), the interferon-gamma (IFN-γ) levels had decreased significantly at 6 months (0.84 ± 1.14 IU/mL; P = 0.005), but not at 3 months (3.58 ± 3.64 IU/mL; P = 0.98). Reversions occurred in seven (26.9 %) patients at 3 months and in an additional two participants at 6 months; a total of nine participants (34.6 %) had reversions. Recent conversion was associated with reversion of the test results (odds ratio 26.3, 95 % confidence interval 3.04-226.6).. Chemoprophylaxis with isoniazid and rifampicin generally decreased IFN-γ levels among tuberculosis contacts. However, only a small portion of participants achieved reversion.

    Topics: Adult; Antitubercular Agents; Cohort Studies; Disease Outbreaks; Humans; Interferon-gamma Release Tests; Isoniazid; Male; Rifampin; Tuberculosis; Young Adult

2012
Rifampicin-resistant Mycobacterium tuberculosis: susceptibility to isoniazid and other anti-tuberculosis drugs.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2012, Volume: 16, Issue:3

    Based on data from 14 Supranational Tuberculosis (TB) Reference Laboratories worldwide, the proportion of rifampicin (RMP) resistant isolates that were isoniazid (INH) susceptible by phenotypic drug susceptibility testing varied widely (0.5-11.6%). RMP-resistant isolates that were INH-susceptible had significantly lower rates of resistance to other first- and second-line anti-tuberculosis drugs (except rifabutin) compared to multidrug-resistant isolates. RMP resistance is not always a good proxy for a presumptive diagnosis of multidrug-resistant TB, which has implications for use of molecular assays that identify only RMP resistance-associated DNA mutations.

    Topics: Antitubercular Agents; DNA Mutational Analysis; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2012
Rifampicin for continuation phase tuberculosis treatment in Uganda: a cost-effectiveness analysis.
    PloS one, 2012, Volume: 7, Issue:6

    In Uganda, isoniazid plus ethambutol is used for 6 months (6HE) during the continuation treatment phase of new tuberculosis (TB) cases. However, the World Health Organization (WHO) recommends using isoniazid plus rifampicin for 4 months (4HR) instead of 6HE. We compared the impact of a continuation phase using 6HE or 4HR on total cost and expected mortality from the perspective of the Ugandan national health system.. Treatment costs and outcomes were determined by decision analysis. Median daily drug price was US$0.115 for HR and US$0.069 for HE. TB treatment failure or relapse and mortality rates associated with 6HE vs. 4HR were obtained from randomized trials and systematic reviews for HIV-negative (46% of TB cases; failure/relapse -6HE: 10.4% vs. 4HR: 5.2%; mortality -6HE: 5.6% vs. 4HR: 3.5%) and HIV-positive patients (54% of TB cases; failure or relapse -6HE: 13.7% vs. 4HR: 12.4%; mortality -6HE: 16.6% vs. 4HR: 10.5%). When the initial treatment is not successful, retreatment involves an additional 8-month drug-regimen at a cost of $110.70. The model predicted a mortality rate of 13.3% for patients treated with 6HE and 8.8% for 4HR; average treatment cost per patient was predicted at $26.07 for 6HE and $23.64 for 4HR. These results were robust to the inclusion of MDR-TB as an additional outcome after treatment failure or relapse.. Combination therapy with 4HR in the continuation phase dominates 6HE as it is associated with both lower expected costs and lower expected mortality. These data support the WHO recommendation to transition to a continuation phase comprising 4HR.

    Topics: Antitubercular Agents; Cost-Benefit Analysis; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Uganda

2012
Primary isoniazid resistance in Mycobacterium bovis disease: a prospect of concern.
    American journal of respiratory and critical care medicine, 2012, Jul-01, Volume: 186, Issue:1

    Topics: Abattoirs; Adult; Agriculture; Antitubercular Agents; Drug Resistance, Bacterial; Female; Humans; Incidence; Ireland; Isoniazid; Male; Middle Aged; Mycobacterium bovis; Rifampin; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Osteoarticular; Tuberculosis, Pulmonary

2012
Rapid diagnosis of tuberculosis and multidrug resistance using a MGIT 960 system.
    Annals of laboratory medicine, 2012, Volume: 32, Issue:4

    The purpose of this study was to compare the turnaround time for liquid culturing and primary anti-tuberculous drug susceptibility testing (DST) performed using the mycobacteria growth indicator tube (MGIT) 960 system (Becton Dickinson, USA) with that for conventional culturing and DST (by the absolute concentration method) performed using solid culture medium and to determine the concordance rates of DST results obtained using these 2 methods.. In this retrospective study, we compared the turnaround times from receiving the request for mycobacterial culture to reporting the DST results before and after the introduction of the MGIT 960 system. Further, we determined the concordance between DST results for isoniazid and rifampin for Mycobacterium tuberculosis isolates obtained using the MGIT 960 system and the absolute concentration method, which was conducted at the Korean Institute of Tuberculosis.. The overall turnaround time for mycobacterial culturing and DST was 27 days for liquid culturing and DST using the MGIT 960 system versus approximately 70 days for culturing on solid medium and DST with the absolute concentration method (P<0.001). There was a good concordance between findings of DST obtained with the 2 methods (97.2%, kappa coefficient=0.855 for rifampin; and 95.6%, kappa coefficient=0.864 for isoniazid), for 1,083 clinical isolates.. The automated MGIT 960 system for culturing and DST of M. tuberculosis was successfully introduced in a hospital laboratory setting in Korea with significant shortening of the turnaround time.

    Topics: Antitubercular Agents; Automation; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Time Factors; Tuberculosis

2012
[Resistant tuberculosis: chinese anxieties].
    Revue medicale suisse, 2012, Jun-20, Volume: 8, Issue:346

    Topics: Antitubercular Agents; Anxiety; Asian People; China; Drug Resistance, Multiple, Bacterial; France; Humans; Isoniazid; Microbial Sensitivity Tests; Rifampin; Tuberculosis

2012
[Bilateral tuberculous mastitis nulliparous patient, initially treated as idiopathic granulomatous mastitis].
    Ginecologia y obstetricia de Mexico, 2012, Volume: 80, Issue:3

    The breast infection by M tuberculosis is rare, when it occurs, clinical and histologically confused with other forms of granulomatous inflammation, making it essential to use other diagnostic methods also may be negative. We report a patient with fimica mastitis that originally was treated as idiopathic granulomatous mastitis with apparent satisfactory clinical response. However, frequent relapses forced to look for other etiologies. Fortunately, the PCR showed the cause and was managed with specific treatment with disappearance of the disease. Clinical suspicion should be in mind when faced with a case like ours.

    Topics: Adult; Antitubercular Agents; Diagnostic Errors; Drug Therapy, Combination; Ethambutol; Female; Granulomatous Mastitis; Humans; Isoniazid; Mastitis; Methotrexate; Mycobacterium tuberculosis; Polymerase Chain Reaction; Prednisone; Pyrazinamide; Recurrence; Rifampin; Tuberculosis

2012
Molecular detection and drug resistance of Mycobacterium tuberculosis complex from cattle at a dairy farm in the Nkonkobe region of South Africa: a pilot study.
    International journal of environmental research and public health, 2012, Volume: 9, Issue:6

    Mycobacterium tuberculosis complex (MTBC) causes tuberculosis (TB) in humans and animals. We investigated the presence of MTBC in cattle milk and its drug resistance using polymerase chain reaction (PCR). Two hundred samples (100 mL each) were obtained from a dairy farm in the Nkonkobe region of South Africa. The samples were processed using the modified Petroff method. DNA was isolated using a Zymo Bacterial DNA kit and amplified using Seeplex(®) MTB Nested ACE assay. The Genotype(®) Mycobacterium tuberculosis-multidrug resistantplus (MTBDRplus) assay was used to perform drug susceptibility and detection of mutations conferring resistance to isoniazid (INH) and rifampicin (RIF). Eleven samples tested positive for MTBC DNA using the Seeplex(®) MTB Nested ACE assay. The Genotype(®) MTBDRplus assay showed that 10/11 samples were resistant to both INH and RIF i.e., multi-drug resistant (MDR). The most and least frequent rpoB mutations detected in RIF resistant samples were H526Y (9/10) and D516V (2/10) respectively. None of the INH resistant samples harbored mutations in the katG gene. However, all of them harbored the T8A mutation in the inhA gene. These results have clinical and epidemiological significance and calls for further studies and necessary actions to delineate the situation.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Cattle; Cattle Diseases; Dairying; Drug Resistance, Multiple, Bacterial; Female; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Pilot Projects; Prevalence; Rifampin; South Africa; Tuberculosis

2012
Characterization of Mycobacterium tuberculosis isolated from cancer patients with suspected tuberculosis infection in Egypt: identification, prevalence, risk factors and resistance pattern.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2012, Volume: 18, Issue:11

    Data are sparse on Mycobacterium tuberculosis infection among patients with cancer in Egypt. We sought to detect the presence of tuberculosis (TB) disease among patients with malignant conditions and suspected TB and to study the main risk factors. Also, we compared different diagnostic procedures and detected the antimicrobial susceptibility of M. tuberculosis isolates against rifampin and isoniazid. One hundred patients were included in this study, all of them had malignant conditions and were suspected by the clinicians of having TB. Identification of M. tuberculosis in different specimens was performed by smear microscopy, followed by Lowenstein-Jensen medium and Mycobacterium growth indicator tube (MGIT) cultures and artus(®) real-time PCR. In addition, an indirect MGIT anti-TB susceptibility test was carried out against rifampin and isoniazid. A total of 76% of studied cases were found to be TB positive. The frequencies of TB-positive cases in the bronchogenic, haematological and solid tumour malignancy groups were 21%, 25% and 30%, respectively. Significant differences between pulmonary and extrapulmonary TB in different malignancy groups were recorded. Real-time PCR showed the highest overall diagnostic efficiency. Multidrug-resistance of M. tuberculosis to both rifampin and isoniazid was detected in 28.6% of examined isolates. Infection in cancer patients with TB was significantly more often recorded among elderly patients and those suffering from poverty. Pulmonary TB is more common than extrapulmonary TB in patients with malignancy. Real-time PCR is the most accurate and rapid method for TB diagnosis. MGIT-rifampin resistance may be used as a reliable marker for detection of multidrug-resistant TB. Diagnosis and instituting treatment course for active or latent TB infection are crucial before starting anticancer therapy.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Bacteriological Techniques; Child; Drug Resistance, Bacterial; Egypt; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Neoplasms; Prevalence; Real-Time Polymerase Chain Reaction; Rifampin; Risk Factors; Sensitivity and Specificity; Tuberculosis; Young Adult

2012
Rapid implementation of new TB diagnostic tests: is it too soon for a global roll-out of Xpert MTB/RIF?
    The American journal of tropical medicine and hygiene, 2012, Volume: 87, Issue:2

    In 2011 the World Health Organization approved Xpert MTB/RIF for tuberculosis diagnosis and recommended its rapid implementation. Xpert MTB/RIF is accurate: sensitivity is 72.5 -98.2% (smear-negative and -positive cases, respectively) and specificity 99.2%. Benefits include same-day diagnosis and simultaneous detection of rifampicin resistance. However, the test has some shortcomings and has not had time for thorough evaluation. Cost-effectiveness studies are difficult to perform and few have been completed. Existing data suggest cost-effectiveness in some, but not all, settings. The urgent need for better diagnostics is evident. Yet, serial implementation of new technologies causes ineffective spending and fragmentation of services. How new tests are incorporated into existing diagnostic algorithms affects both outcomes and costs. More detailed data on performance, effect on patient-important outcomes, and costs when used with adjunct tests are needed for each setting before implementation. While awaiting further clarification it seems prudent to slow its implementation among resource-constrained tuberculosis control programs.

    Topics: Cost-Benefit Analysis; Diagnostic Tests, Routine; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; World Health Organization

2012
The impact of HIV and ART on recurrent tuberculosis in a sub-Saharan setting.
    AIDS (London, England), 2012, Nov-13, Volume: 26, Issue:17

    To estimate the impact of antiretroviral therapy (ART) on the incidence of recurrent tuberculosis (TB) in an African population.. A long-term population cohort in Karonga District, northern Malawi.. Patients who had completed treatment for laboratory-confirmed TB diagnosed since 1996 were visited annually to record vital status, ART use and screen for TB. Survival analysis estimated the effect of HIV/ART status at completion of treatment on mortality and recurrence. Analyses were stratified by time since treatment completion to estimate the effects on relapse (predominates during first year) and reinfection disease (predominates later).. Among 1133 index TB cases contributing 4353 person-years of follow-up, there were 307 deaths and 103 laboratory-confirmed recurrences (recurrence rate 4.6 per 100 person-years). Half the recurrences occurred in the first year since completing treatment. HIV infection increased the recurrence rate [rate ratio adjusted for age, sex, period and TB type 2.69, 95% confidence interval (CI) 1.69-4.26], but with less effect in the first year (adjusted rate ratio 1.71, 95% CI 0.87-3.35) than subsequently (adjusted rate ratio 4.2, 95% CI 2.16-8.15). Recurrence rates on ART were intermediate between those of HIV-negative individuals and HIV-positive individuals without ART. Compared with HIV-positive individuals without ART, the adjusted rate ratio was 0.74 (95% CI 0.27-2.06) in the first year, and 0.43 (95% CI 0.11-1.73) later.. The increased incidence of TB recurrence observed in HIV-positive patients appeared to be reduced by ART. The effects are mostly on later (likely reinfection) disease so the impact of ART on reducing recurrence will be highest in high TB incidence settings.

    Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; CD4 Lymphocyte Count; Cohort Studies; Drug Administration Schedule; Female; Follow-Up Studies; HIV Seropositivity; Humans; Incidence; Isoniazid; Malawi; Male; Middle Aged; Population Surveillance; Recurrence; Rifampin; Risk Factors; Streptomycin; Survival Analysis; Treatment Outcome; Tuberculosis; Young Adult

2012
Improved consistency in dosing anti-tuberculosis drugs in Taipei, Taiwan.
    PloS one, 2012, Volume: 7, Issue:8

    It was reported that 35.5% of tuberculosis (TB) cases reported in 2003 in Taipei City had no recorded pre-treatment body weight and that among those who had, inconsistent dosing of anti-TB drugs was frequent. Taiwan Centers for Disease Control (CDC) have taken actions to strengthen dosing of anti-TB drugs among general practitioners. Prescribing practices of anti-TB drugs in Taipei City in 2007-2010 were investigated to assess whether interventions on dosing were effective.. Lists of all notified culture positive TB cases in 2007-2010 were obtained from National TB Registry at Taiwan CDC. A medical audit of TB case management files was performed to collect pretreatment body weight and regimens prescribed at commencement of treatment. Dosages prescribed were compared with dosages recommended. The proportion of patients with recorded pre-treatment body weight was 64.5% in 2003, which increased to 96.5% in 2007-2010 (p<0.001). The proportion of patients treated with consistent dosing of a 3-drug fixed-dose combination (FDC) increased from 73.9% in 2003 to 87.7% in 2007-2010 (p<0.001), and that for 2-drug FDC from 76.0% to 86.1% (p = 0.024), for rifampicin (RMP) from 62.8% to 85.5% (p<0.001), and for isoniazid from 87.8% to 95.3% (p<0.001). In 2007-2010, among 2917 patients treated with either FDCs or RMP in single-drug preparation, the dosage of RMP was adequate (8-12 mg/kg) in 2571(88.1%) patients, too high in 282(9.7%), too low in 64(2.2%). In multinomial logistic regression models, factors significantly associated with adequate dosage of RMP were body weight and preparations of RMP. Patients weighting <40 kg (relative risk ratio (rrr) 6010.5, 95% CI 781.1-46249.7) and patients weighting 40-49 kg (rrr 1495.3, 95% CI 200.6-11144.6) were more likely to receive higher-than-recommended dose of RMP.. Prescribing practice in the treatment of TB in Taipei City has remarkably improved after health authorities implemented a series of interventions.

    Topics: Adult; Aged; Antitubercular Agents; Body Weight; Dose-Response Relationship, Drug; Drug Combinations; Drug Prescriptions; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Practice Guidelines as Topic; Practice Patterns, Physicians'; Pyrazinamide; Rifampin; Taiwan; Tuberculosis; Young Adult

2012
The Xpert® MTB/RIF assay evaluation in South Korea, a country with an intermediate tuberculosis burden.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2012, Volume: 16, Issue:11

    A central hospital laboratory in South Korea.. To evaluate the usefulness of the Xpert® MTB/RIF assay in a country with an intermediate tuberculosis burden.. A total of 71 real-time polymerase chain reaction-positive sputum sediments were tested within 24 h by the Xpert MTB/RIF assay. Mycobacterium tuberculosis detection was compared with smear microscopy and culture. Rifampicin (RMP) resistance was compared with a culture-based method and rpoB gene sequencing. We also assessed the limit of detection for mutant proportions and time savings in diagnosis.. The Xpert MTB/RIF assay detected M. tuberculosis in 71 (100%) specimens (32 smear-positive, 39 smear-negative). This assay showed 100% (62/62) concordance with drug resistance confirmed by culture and 98.4% (61/62) concordance with sequencing. A specimen containing approximately 50% of mutant p.His526Tyr was falsely interpreted as wild-type bacilli by this assay. The minimal detection ratio was 5:1 of mutant vs. wild-type cells. The median time saved was 18.5 days (range 9-30) for the diagnosis of M. tuberculosis and 81.5 days (65-136) for RMP susceptibility in smear-negative, culture-positive patients.. The Xpert MTB/RIF assay showed high sensitivity in detecting M. tuberculosis with information on RMP resistance, and had a more rapid time to diagnosis compared to conventional tests; however, the location and amount of mutation may affect test sensitivity.

    Topics: Antitubercular Agents; Bacterial Proteins; Base Sequence; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Limit of Detection; Microbial Sensitivity Tests; Microscopy; Molecular Sequence Data; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Real-Time Polymerase Chain Reaction; Republic of Korea; Rifampin; Sensitivity and Specificity; Sputum; Time Factors; Tuberculosis

2012
Upregulation of the phthiocerol dimycocerosate biosynthetic pathway by rifampin-resistant, rpoB mutant Mycobacterium tuberculosis.
    Journal of bacteriology, 2012, Volume: 194, Issue:23

    Multidrug-resistant tuberculosis has emerged as a major threat to tuberculosis control. Phylogenetically related rifampin-resistant actinomycetes with mutations mapping to clinically dominant Mycobacterium tuberculosis mutations in the rpoB gene show upregulation of gene networks encoding secondary metabolites. We compared the expressed proteomes and metabolomes of two fully drug-susceptible clinical strains of M. tuberculosis (wild type) to those of their respective rifampin-resistant, rpoB mutant progeny strains with confirmed rifampin monoresistance following antitubercular therapy. Each of these strains was also used to infect gamma interferon- and lipopolysaccharide-activated murine J774A.1 macrophages to analyze transcriptional responses in a physiologically relevant model. Both rpoB mutants showed significant upregulation of the polyketide synthase genes ppsA-ppsE and drrA, which constitute an operon encoding multifunctional enzymes involved in the biosynthesis of phthiocerol dimycocerosate and other lipids in M. tuberculosis, but also of various secondary metabolites in related organisms, including antibiotics, such as erythromycin and rifamycins. ppsA (Rv2931), ppsB (Rv2932), and ppsC (Rv2933) were also found to be upregulated more than 10-fold in the Beijing rpoB mutant strain relative to its wild-type parent strain during infection of activated murine macrophages. In addition, metabolomics identified precursors of phthiocerol dimycocerosate, but not the intact molecule itself, in greater abundance in both rpoB mutant isolates. These data suggest that rpoB mutation in M. tuberculosis may trigger compensatory transcriptional changes in secondary metabolism genes analogous to those observed in related actinobacteria. These findings may assist in developing novel methods to diagnose and treat drug-resistant M. tuberculosis infections.

    Topics: Animals; Antitubercular Agents; Bacterial Proteins; Biosynthetic Pathways; Cell Line; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Gene Expression Profiling; Gene Expression Regulation, Bacterial; Humans; Lipids; Macrophages; Metabolome; Mice; Microbial Sensitivity Tests; Mutant Proteins; Mycobacterium tuberculosis; Proteome; Rifampin; Tuberculosis

2012
Coadministration of lopinavir/ritonavir and rifampicin in HIV and tuberculosis co-infected adults in South Africa.
    PloS one, 2012, Volume: 7, Issue:9

    In HIV-infected patients receiving rifampicin-based treatment for tuberculosis (TB), the dosage of lopinavir/ritonavir (LPV/r) is adjusted to prevent sub-therapeutic lopinavir concentrations. In this setting, South African clinicians were advised to administer super-boosted LPV/r (400 mg/400 mg) twice daily, instead of standard dosed LPV/r (400 mg/100 mg) twice daily. We sought to determine--in routine practice--the tolerability and HIV treatment outcomes associated with super-boosted LPV/r compared to unadjusted LPV/r in combination with rifampicin-based TB treatment.. We conducted a retrospective review of HIV-infected patients who receiving second-line ART with a LPV/r-containing regimen who required concomitant TB treatment. We identified 29 patients; the median age was 36 years (IQR 29-40), 22 (76%) were female, the median CD4 cell count and viral load at first-line ART failure was 86 cells/mm³ (IQR 21-159) and 39,457 copies/mL (IQR 6,025-157,500), respectively. According to physician preference, 15 (52%) of 29 patients received super-boosted LPV/r (400 mg/400 mg) every 12 hours during TB treatment and 14 (48%) of 29 patients received standard dose LPV/r (400 mg/100 mg) twice daily during TB treatment. Among patients who received super-boosted LPV/r there was a trend towards a higher rate of symptomatic transaminitis (27% vs. 7%; p = 0.3), gastrointestinal toxicity (20% vs. 0%; p = 0.2) and a significantly increased need for treatment discontinuation (47% vs. 7%; p = 0.035. The durability of coadministered treatment was significantly shorter in patients who received super-boosted lopinavir/ritonavir with TB treatment compared to patients who received standard lopinavir/ritonavir dosing (log rank, P = 0.036). The rate of virologic failure was not higher in patients with unadjusted LPV/r dosing.. We observed a high rate of toxicity and need for treatment discontinuation among patients on standard rifampicin-based TB treatment who received super-boosted LPV/r.

    Topics: Adolescent; Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Child; Coinfection; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Kaplan-Meier Estimate; Lopinavir; Male; Middle Aged; Retrospective Studies; Rifampin; Ritonavir; South Africa; Time Factors; Tuberculosis; Young Adult

2012
Managing tuberculosis in patients with diabetes mellitus: why we care and what we know.
    Expert review of anti-infective therapy, 2012, Volume: 10, Issue:8

    As the global prevalence of diabetes mellitus (DM) increases, especially in low-to-middle income countries where tuberculosis (TB) remains endemic, we will encounter a growing number of TB patients with DM. This is a major concern for TB control programs, clinicians and patients alike because DM patients are at an increased risk of TB and are more likely to face poor TB treatment outcomes, including treatment failure, relapse and even death. Priority should be placed on early detection of both diseases through active screening, monitoring of adherence to medications for both diseases, and integration of TB and DM management strategies that would facilitate the provision of more comprehensive services that TB patients with DM require.

    Topics: Antitubercular Agents; Diabetes Complications; Diabetes Mellitus; Disease Management; Humans; Mycobacterium tuberculosis; Patient Compliance; Recurrence; Rifampin; Risk Factors; Treatment Failure; Tuberculosis

2012
Outcomes of Category III DOTS treatment in immunocompetent patients with tuberculosis pleural effusion.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2012, Volume: 16, Issue:11

    To study the efficacy and safety of Category III DOTS treatment (intermittent thrice-weekly rifampicin [RMP], isoniazid [INH] and pyrazinamide for 2 months, followed by RMP and INH for 4 months) under India's Revised National Tuberculosis Control Programme in patients with uncomplicated small unilateral pleural effusion (<1500 ml).. This prospective, multicentre, observational study recruited 351 patients between 2006 and 2010. Patients were regularly followed up clinically as well as with ultrasound examination of the chest.. Successful outcome (clinical response with complete resolution on ultrasound examination at 6 months) was seen in 274 patients (78.1%). Efficacy was 88.9% (excluding defaulters), and 94% among those completing follow-up as per protocol. None of the patients received corticosteroids. Other outcomes included treatment extension (n = 26, 7.4%), default (n = 43, 12.2%), treatment failure (n = 3, 0.9%) and death (n = 3, 0.9%). Seventy-nine mild/moderate adverse events and one treatment-related serious adverse event were noted; one patient developed recurrent drug-induced hepatotoxicity. Two patients (0.7%) had relapse/re-infection at 24 months follow-up.. Intermittent thrice-weekly treatment for 6 months with three drugs in the intensive phase is effective and safe for unilateral small pleural effusion in immunocompetent patients. Although Category III no longer exists in the programme, the results are reassuring for intermittent treatment in extra-pulmonary TB under programme conditions.

    Topics: Adolescent; Adult; Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunocompetence; India; Isoniazid; Male; Pleural Effusion; Prospective Studies; Pyrazinamide; Recurrence; Rifampin; Treatment Outcome; Tuberculosis; Ultrasonography; Young Adult

2012
Tuberculosis diagnosis after bleach processing for early stage tuberculosis laboratory capacity building.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2012, Volume: 16, Issue:11

    The diagnosis of tuberculosis is seriously hampered in the absence of standard biosafety laboratory facilities for specimen concentration and Mycobacterium tuberculosis culture. Within a laboratory twinning arrangement, heat-fixed direct smear and sediment from 74 bleach-processed and 20 non-processed specimens from Cumura Hospital, Guinea-Bissau, were sent to Lisbon for molecular evaluation of rifampicin resistance. Sequence analysis of a 369 base-pair rpoB locus detected 3.2% (3/94) resistant specimens. To our knowledge, this represents the first report on the molecular analysis of M. tuberculosis from bleach-processed sputum, an alternative to current diagnostic practice in low-resource settings.

    Topics: Antitubercular Agents; Bacterial Proteins; Base Sequence; Capacity Building; Clinical Laboratory Techniques; DNA-Directed RNA Polymerases; Guinea-Bissau; Humans; Laboratories; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Portugal; Rifampin; Sequence Analysis; Sodium Hypochlorite; Specimen Handling; Sputum; Tuberculosis

2012
Rifampin-zotepine interaction reduces effectiveness of antipsychotic drugs in a stable schizophrenia patient.
    Psychiatry and clinical neurosciences, 2012, Volume: 66, Issue:6

    Topics: Antipsychotic Agents; Antitubercular Agents; Dibenzothiepins; Drug Interactions; Female; Humans; Middle Aged; Rifampin; Schizophrenia; Schizophrenic Psychology; Tuberculosis

2012
Persister eradication: lessons from the world of natural products.
    Methods in enzymology, 2012, Volume: 517

    Persisters are specialized survivor cells that protect bacterial populations from killing by antibiotics. Persisters are dormant phenotypic variants of regular cells rather than mutants. Bactericidal antibiotics kill by corrupting their targets into producing toxic products; tolerance to antibiotics follows when targets are inactive. Transcriptome analysis of isolated persisters points to toxin/antitoxin modules as a principle component of persister formation. Mechanisms of persister formation are redundant, making it difficult to eradicate these cells. In Escherichia coli, toxins RelE and MazF cause dormancy by degrading mRNA; HipA inhibits translation by phosphorylating Ef-Tu; and TisB forms an anion channel in the membrane, leading to a decrease in pmf and ATP levels. Prolonged treatment of chronic infections with antibiotics selects for hip mutants that produce more persister cells. Eradication of tolerant persisters is a serious challenge. Some of the existing antibiotics are capable of killing persisters, pointing to ways of developing therapeutics to treat chronic infections. Mitomycin is a prodrug which is converted into a reactive compound forming adducts with DNA upon entering the cell. Prolonged treatment with aminoglycosides that cause mistranslation leading to misfolded peptides can sterilize a stationary culture of Pseudomonas aeruginosa, a pathogen responsible for chronic, highly tolerant infections of cystic fibrosis patients. Finally, one of the best bactericidal agents is rifampin, an inhibitor of RNA polymerase, and we suggest that it "kills" by preventing persister resuscitation.

    Topics: Anti-Bacterial Agents; Biofilms; Biological Products; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Microbial Viability; Mycobacterium tuberculosis; Ofloxacin; Pseudomonas aeruginosa; Pseudomonas Infections; Rifampin; Species Specificity; Time Factors; Tuberculosis

2012
Twelve doses for tuberculosis prevention--review of a new evidenced based regimen.
    Journal of the Mississippi State Medical Association, 2012, Volume: 53, Issue:8

    Topics: Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis; Virus Latency

2012
Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations.
    Tropical medicine & international health : TM & IH, 2012, Volume: 17, Issue:12

    The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela.. Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined.. 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01).. We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs.

    Topics: Acetyltransferases; Adolescent; Age Factors; Antitubercular Agents; Area Under Curve; Biological Availability; Child; Child, Preschool; Dose-Response Relationship, Drug; Ethambutol; Female; Humans; Infant; Isoniazid; Least-Squares Analysis; Male; Malnutrition; Polymorphism, Genetic; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis; Venezuela; World Health Organization

2012
Prevalence of anti-tuberculosis drug resistance in foreign-born tuberculosis cases in the U.S. and in their countries of origin.
    PloS one, 2012, Volume: 7, Issue:11

    Foreign-born individuals comprise >50% of tuberculosis (TB) cases in the U.S. Since anti-TB drug resistance is more common in most other countries, when evaluating a foreign-born individual for TB, one must consider the risk of drug resistance. Naturally, clinicians query The Global Project on Anti-tuberculosis Drug Resistance Surveillance (Global DRS) which provides population-based data on the prevalence of anti-TB drug resistance in 127 countries starting in 1994. However, foreign-born persons in the U.S. are a biased sample of the population of their countries of origin, and Global DRS data may not accurately predict their risk of drug resistance. Since implementing drug resistance surveillance in 1993, the U.S. National TB Surveillance System (NTSS) has accumulated systematic data on over 130,000 foreign-born TB cases from more than 200 countries and territories. Our objective was to determine whether the prevalence of drug resistance among foreign-born TB cases correlates better with data from the Global DRS or with data on foreign-born TB cases in the NTSS.. We compared the prevalence of resistance to isoniazid and rifampin among foreign-born TB cases in the U.S., 2007-2009, with US NTSS data from 1993 to 2006 and with Global DRS data from 1994-2007 visually with scatterplots and statistically with correlation and linear regression analyses. Among foreign-born TB cases in the U.S., 2007-2009, the prevalence of isoniazid resistance and multidrug resistance (MDR, i.e. resistance to isoniazid and rifampin), correlated much better with 1993-2006 US surveillance data (isoniazid: r = 0.95, P<.001, MDR: r = 0.75, P<.001) than with Global DRS data, 1994-2007 (isoniazid: r = 0.55, P = .001; MDR: r = 0.50, P<.001).. Since 1993, the US NTSS has accumulated sufficient data on foreign-born TB cases to estimate the risk of drug resistance among such individuals better than data from the Global DRS.

    Topics: Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Drug Resistance, Bacterial; Emigrants and Immigrants; Epidemiological Monitoring; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prevalence; Rifampin; Tuberculosis; United States

2012
Postoperative spondylodiscitis caused by Mycobacterium bovis BCG: a case study.
    The spine journal : official journal of the North American Spine Society, 2012, Volume: 12, Issue:12

    Postoperative spondylodiscitis (PSD) is a known complication of lumbar disc surgery. The etiology of the disease is usually bacterial, but several uncommon infectious agents have also been described; however, there are no reports about postoperative colonization with Mycobacterium bovis bacille Calmette-Guérin after lumbar discectomy.. To describe the case of PSD caused by M. bovis BCG, and to discuss diagnostic and therapeutic interventions as well as possible pathogenic mechanisms of the disease.. Case report and review of the literature.. A 31-year-old man was operated on because of L4-L5 lumbar disc herniation. Two months later, the patient presented with gradual increase of back pain, and magnetic resonance imaging confirmed PSD. He started to receive antibacterial treatment and was reoperated on because of progressive neurological deficits due to epidural abscess. Neurological status improved, but a fistula developed with intermittent pus drainage from the operative scar.. Microbiological cultures were repeatedly obtained from the pus, but all the initial stains and cultures were negative. Four months after the reoperation, the culture for M. bovis BCG from the pus appeared to be positive. The patient received antituberculosis regimen, including isoniazid, rifampin, ethambutol, and ofloxacin. The clinical symptoms resolved, and antituberculosis treatment was discontinued after 14 months.. Mycobacterium bovis BCG must be considered in the differential diagnosis of PSD. Microbiological analysis and radiological studies are vital components in diagnosis; if there is any suspicion of BCG osteomyelitis, proper diagnostic and therapeutic management must be instituted without delay to avoid an unfavorable outcome.

    Topics: Antitubercular Agents; Discitis; Diskectomy; Epidural Abscess; Humans; Intervertebral Disc Displacement; Isoniazid; Lumbar Vertebrae; Male; Mycobacterium bovis; Postoperative Period; Rifampin; Treatment Outcome; Tuberculosis

2012
Evaluation of tuberculosis underreporting in Greece through comparison with anti-tuberculosis drug consumption.
    PloS one, 2012, Volume: 7, Issue:11

    Surveillance is an integral part of tuberculosis (TB) control. Greece has a low TB notification rate, but there are doubts about underreporting. Examining anti-TB drug consumption is a way to validate the results of surveillance and estimate TB burden in the country. We used surveillance data from 2004 to 2008 to calculate the average prescribed treatment duration with the first-line anti-TB drugs isoniazid, rifampicin, ethambutol and pyrazinamide. We then obtained the best available data on consumption of these drugs, and calculated the number of treated cases to which these quantities correspond. We thus estimated underreporting at around 80% (77-81%), and annual TB incidence at about 30 cases per 100,000 population, five times over the notification rate. Underreporting was found to be constant over the study period, while incidence followed a decreasing trend. In addition we estimated that one person receives chemoprophylaxis for latent tuberculosis infection (LTBI) for every three TB cases. These results indicate the need for a comprehensive plan to improve TB surveillance and TB contact tracing in Greece, especially in light of the economic crisis affecting the country since 2009.

    Topics: Antitubercular Agents; Epidemiological Monitoring; Ethambutol; Greece; Humans; Isoniazid; Latent Tuberculosis; Prescription Drugs; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2012
Screening and rapid molecular diagnosis of tuberculosis in prisons in Russia and Eastern Europe: a cost-effectiveness analysis.
    PLoS medicine, 2012, Volume: 9, Issue:11

    Prisons of the former Soviet Union (FSU) have high rates of multidrug-resistant tuberculosis (MDR-TB) and are thought to drive general population tuberculosis (TB) epidemics. Effective prison case detection, though employing more expensive technologies, may reduce long-term treatment costs and slow MDR-TB transmission.. We developed a dynamic transmission model of TB and drug resistance matched to the epidemiology and costs in FSU prisons. We evaluated eight strategies for TB screening and diagnosis involving, alone or in combination, self-referral, symptom screening, mass miniature radiography (MMR), and sputum PCR with probes for rifampin resistance (Xpert MTB/RIF). Over a 10-y horizon, we projected costs, quality-adjusted life years (QALYs), and TB and MDR-TB prevalence. Using sputum PCR as an annual primary screening tool among the general prison population most effectively reduced overall TB prevalence (from 2.78% to 2.31%) and MDR-TB prevalence (from 0.74% to 0.63%), and cost US$543/QALY for additional QALYs gained compared to MMR screening with sputum PCR reserved for rapid detection of MDR-TB. Adding sputum PCR to the currently used strategy of annual MMR screening was cost-saving over 10 y compared to MMR screening alone, but produced only a modest reduction in MDR-TB prevalence (from 0.74% to 0.69%) and had minimal effect on overall TB prevalence (from 2.78% to 2.74%). Strategies based on symptom screening alone were less effective and more expensive than MMR-based strategies. Study limitations included scarce primary TB time-series data in FSU prisons and uncertainties regarding screening test characteristics.. In prisons of the FSU, annual screening of the general inmate population with sputum PCR most effectively reduces TB and MDR-TB prevalence, doing so cost-effectively. If this approach is not feasible, the current strategy of annual MMR is both more effective and less expensive than strategies using self-referral or symptom screening alone, and the addition of sputum PCR for rapid MDR-TB detection may be cost-saving over time.

    Topics: Antibiotics, Antitubercular; Baltic States; Clinical Laboratory Techniques; Commonwealth of Independent States; Cost-Benefit Analysis; Drug Resistance, Bacterial; Epidemics; Humans; Latvia; Mass Screening; Models, Theoretical; Mycobacterium tuberculosis; Prevalence; Prisons; Quality-Adjusted Life Years; Real-Time Polymerase Chain Reaction; Rifampin; Russia; Tajikistan; Time Factors; Tuberculosis; Tuberculosis, Multidrug-Resistant

2012
Effect of rifampicin & isoniazid on the steady state pharmacokinetics of moxifloxacin.
    The Indian journal of medical research, 2012, Volume: 136, Issue:6

    Moxifloxacin (MFX) is reported to have promising antimycobacterial activity, and has a potential to shorten tuberculosis (TB) treatment. We undertook this study to examine the influence of rifampicin (RMP) and isoniazid (INH) on the steady state pharmacokinetics of MFX individually in healthy individuals.. A baseline pharmacokinetic study of MFX (400 mg once daily) was conducted in 36 healthy adults and repeated after one week of daily MFX with either RMP (450/600 mg) (n = 18) or INH (300 mg) (n = 18). Plasma MFX concentrations were determined by a validated HPLC method.. Plasma peak concentration and exposure of MFX was significantly lower and plasma clearance significantly higher when combined with RMP (P<0.001). The C max to MIC and AUC 0-12 to MIC ratios of MFX were significantly lower during concomitant RMP (P<0.001). INH had no significant effect on the pharmacokinetics of MFX.. Concomitant RMP administration caused a significant decrease in C max and AUC 0-12 of MFX, the mean decreases being 26 and 29 per cent, respectively. It is uncertain whether this decrease would affect the treatment efficacy of MFX. Prospective studies in TB patients are needed to correlate MFX pharmacokinetics with treatment outcomes.

    Topics: Adult; Area Under Curve; Aza Compounds; Chromatography, High Pressure Liquid; Fluoroquinolones; Humans; Isoniazid; Microbial Sensitivity Tests; Moxifloxacin; Quinolines; Rifampin; Tuberculosis

2012
Novel isatinyl thiosemicarbazones derivatives as potential molecule to combat HIV-TB co-infection.
    European journal of medicinal chemistry, 2011, Volume: 46, Issue:1

    A series of novel 5-substituted-1-(arylmethyl/alkylmethyl)-1H-indole-2,3-dione-3-(N-hydroxy/methoxy thiosemicarbazone) analogues were synthesized and evaluated for their anti-HIV activity and anti-tubercular activity in both log phase and starved cultures. The compound 2-(1-{[4-(4-chlorophenyl)tetrahydropyrazin-1(2H)-yl]methyl}-5-methyl-2-oxo-1,2-dihydro-3H-indol-3-yliden)-N-(methyloxy)hydrazine-1-carbothioamide (B21) displayed promising activity against the replication of HIV-1 cells (EC(50) 1.69 μM). In anti-mycobacterial screening B21 proved effective in inhibiting the growth of both log phase (MIC 3.30 μM) and starved (MIC 12.11 μM) MTB cultures. Isocitrate lyase enzyme having momentous implication in persistent TB was shown to be inhibited by 1-cyclopropyl-6-fluoro-7-[4-{[5-methyl-3-((Z)-2-{[(methyloxy)amino]carbothioyl}hydrazono)-2-oxo-1H-indol-1(2H)-yl]methyl}tetrahydropyrazin-1(2H)-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (B30) with 63.44% inhibition at 10 mM.

    Topics: Anti-Bacterial Agents; Anti-HIV Agents; Cell Line; HIV; HIV Infections; HIV Reverse Transcriptase; Isocitrate Lyase; Models, Molecular; Molecular Conformation; Mycobacterium tuberculosis; Thiosemicarbazones; Tuberculosis

2011
Anti-tubercular agents. Part 6: synthesis and antimycobacterial activity of novel arylsulfonamido conjugated oxazolidinones.
    European journal of medicinal chemistry, 2011, Volume: 46, Issue:3

    As a part of investigation of new anti-tubercular agents in this laboratory, herein we describe the synthesis of a new class of arylsulfonamido conjugated oxazolidinones. The in vitro activity of these conjugated (6a-f, 7a-d, 9a-c and 11a-c) molecules against Mycobacterium tuberculosis H(37)Rv by using rifampicin and linezolide as positive controls is discussed, compounds 7c and 9a-c are found to be the most active members in this series. Further, cytotoxicity of the potent conjugates of the series (7c, and 9a-c) was evaluated on human foreskin fibroblast (HFF) cells by using MTT assay. Finally, these studies suggest that compounds 7c and 9a may serve as promising lead scaffolds for further generation of new as anti-TB agents.

    Topics: Antitubercular Agents; Cell Line; Cell Survival; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazolidinones; Sulfonamides; Tuberculosis

2011
Synthesis and antitubercular evaluation of novel dibenzo[b,d]furan and 9-methyl-9H-carbazole derived hexahydro-2H-pyrano[3,2-c]quinolines via Povarov reaction.
    European journal of medicinal chemistry, 2011, Volume: 46, Issue:10

    A series of novel hexahydro-2H-pyrano[3,2-c]quinoline analogues derived from dibenzo[b,d]furan and 9-methyl-9H-carbazole has been synthesized in very good yields through SnCl(2)·2H(2)O catalyzed one-pot Povarov reaction (imino-Diels-Alder reaction). The imines generated in situ from dibenzo[b,d]furan-2-carbaldehyde or 9-methyl-9H-carbazole-3-carbaldehyde and aromatic amines, were reacted with 3,4-dihydro-2H-pyran in a diasteroselective manner in acetonitrile at RT. These synthesized isomeric pyranoquinoline analogues have been evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) by agar dilution method. Among the 23 compounds screened, 5-(dibenzo[b,d]furan-2-yl)-9-fluoro-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline 4f, 5-(dibenzo[b,d]furan-2-yl)-9-fluoro-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline 5f and 9-fluoro-5-(9-methyl-9H-carbazol-3-yl)-3,4,4a,5,6,10b-hexa hydro-2H-pyrano[3,2-c]quinoline 7f (MIC 3.13 μg/mL) were resulted as most active antitubercular agents.

    Topics: Antitubercular Agents; Carbazoles; Humans; Imines; Models, Molecular; Mycobacterium tuberculosis; Pyrans; Quinolines; Structure-Activity Relationship; Tuberculosis

2011
Synthesis of 3-heteroarylthioquinoline derivatives and their in vitro antituberculosis and cytotoxicity studies.
    European journal of medicinal chemistry, 2011, Volume: 46, Issue:10

    A series of 3-heteroarylthioquinoline derivatives has been synthesized by the Friedlander annulation of 2-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]-1-aryl-1-ethanone/2-(1,3-benzothiazol-2-ylsulfanyl)-1-aryl-1-ethanone/1-aryl-2-[(2-phenyl-2H-1,2,3,4-tetraazol-5-yl)sulfanyl]-1-ethanone with 2-aminobenzophenone in good yields using YbCl(3) as the catalyst. These compounds have been screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and among the 21 compounds screened, 2-[2-(4-bromophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-methyl-1,3,4-thiadiazole (5d) and 2-[2-(4-chlorophenyl)-4-phenyl-3-quinolyl]sulfanyl-5-methyl-1,3,4-thiadiazole (5c) were found to be the most active compounds with MIC of 3.2 and 3.5 μM respectively against MTB. The cytotoxic effects against mouse fibroblasts (NIH 3T3) in vitro were evaluated for 5c and 5d, which displayed no toxic effects (IC(50) > 1000 μM) against the mouse fibroblast cell line NIH 3T3.

    Topics: Animals; Antitubercular Agents; Humans; Mice; Microbial Sensitivity Tests; Models, Molecular; Mycobacterium tuberculosis; NIH 3T3 Cells; Quinolines; Structure-Activity Relationship; Thiadiazoles; Tuberculosis

2011
Design, synthesis and docking studies of quinoline-oxazolidinone hybrid molecules and their antitubercular properties.
    European journal of medicinal chemistry, 2011, Volume: 46, Issue:10

    New series of quinoline-oxazolidinone hybrid molecules were synthesized based on the preliminary docking studies. All the newly synthesized compounds were characterized by spectral analyses. The newly synthesized compounds were screened for their antimycobacterial properties based on the promising preliminary antibacterial screening results. Amongst tested compounds, compounds 8a, 8j and 13a were active at 0.65 μg/mL against Mycobacterium tuberculosis H(37)Rv strain. The mode of action of these active compounds was carried out by docking of receptor enoyl-ACP reductase with newly synthesized candidate ligands 8a, 8j and 13a. These compounds exhibited well established bonds with one or more amino acids in the receptor active pocket. From the docking studies, compound 8j was considered to be the best inhibitor.

    Topics: Anti-Bacterial Agents; Antitubercular Agents; Bacteria; Catalytic Domain; Drug Design; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); Humans; Models, Molecular; Mycobacterium tuberculosis; Oxazolidinones; Protein Binding; Quinolines; Tuberculosis

2011
Synthesis and structure-activity relationships of novel substituted 8-amino, 8-thio, and 1,8-pyrazole congeners of antitubercular rifamycin S and rifampin.
    Bioorganic & medicinal chemistry letters, 2011, Oct-15, Volume: 21, Issue:20

    A series of rifamycin S and rifampin analogues incorporating substituted 8-amino, 8-thio, and 1,8-pyrazole substituents has been synthesized. The compounds were made by activation of the C-8 phenol as a sulfonate ester, followed by displacement with selected nitrogen and sulfur nucleophiles. The analogues were screened in assays to quantify their antitubercular activity under both aerobic and anaerobic conditions, and for inhibition of wild-type Mycobacterium tuberculosis (MTB) RNAP and rifamycin-resistant MTB RNAP (S450L) via an in vitro rolling circle transcription assay. Additionally, the MIC(90) values were determined for these analogues against Escherichia coli strains. Although none of the analogues displayed superior enzymatic or microbiological activity to their parent scaffolds, the results are consistent with the Rif C-8 hydroxyl acting as a hydrogen bond acceptor with S450 and that Rif resistance in the S450L mutant is due to loss of this hydrogen bond. Representative analogues were also evaluated in the human pregnane X receptor (PXR) activation assay.

    Topics: Antitubercular Agents; Escherichia coli; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazoles; Rifampin; Rifamycins; Tuberculosis

2011
Synthesis and in vitro antitubercular evaluation of novel sansanmycin derivatives.
    Bioorganic & medicinal chemistry letters, 2011, Nov-15, Volume: 21, Issue:22

    Tuberculosis (TB) is a major health problem worldwide. A series of novel sansanmycin derivatives were designed, semi-synthesized and evaluated for their activity against drug-susceptible Mycobacterium tuberculosis strain H(37)Rv with sansanmycin A (SSA) as the lead. Among these analogs tested, compound 1d possessing an isopropyl group at the amino terminal afforded an increased antimycobacterial activity with a MIC value of 8 μg/mL in comparison with SSA. Importantly, it was active for rifampicin- and isoniazid-resistant M. tuberculosis strain isolated from patients in China. These promising results offer an opportunity for further exploration of this novel class of analogs as antitubercular agents.

    Topics: Antitubercular Agents; China; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oligopeptides; Streptomyces; Tuberculosis; Tuberculosis, Multidrug-Resistant; Uridine

2011
Incision infection with Mycobacterium tuberculosis after total hip arthroplasty without any primary tuberculosis focus.
    The Journal of arthroplasty, 2011, Volume: 26, Issue:3

    We describe a case of a tuberculous abscess unassociated with other clinical features of tuberculosis in a 46-year-old woman with a history of 4 hip surgeries plus total hip arthroplasty (THA) due to developmental hip dislocation. Four months after THA, she developed a collection at the incision site for which specimens produced positive culture findings for Mycobacterium tuberculosis. We could not detect any primary focus of tuberculosis anywhere in the patient's body. We performed soft-tissue debridement and drainage completely above the fascia lata to remove pus. The infection recurred twice despite chemotherapy and the earlier treatment. At a 6-year follow-up examination, there was no sign of either tuberculosis or prosthetic loosening. To our knowledge, this is the first report of localized tuberculous abscess within a THA incision.

    Topics: Arthroplasty, Replacement, Hip; Drug Therapy, Combination; Ethambutol; Female; Hip Dislocation, Congenital; Hip Prosthesis; Humans; Isoniazid; Middle Aged; Mycobacterium tuberculosis; Prosthesis-Related Infections; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2011
Reactivation of tuberculosis during temsirolimus therapy.
    Investigational new drugs, 2011, Volume: 29, Issue:6

    Reactivation of tuberculosis is rare in patients receiving chemotherapy for solid tumours, and poorly documented in patients receiving molecular targeted therapy. We report on a patient with metastatic renal-cell carcinoma treated with temsirolimus, who developed respiratory symptoms and mild fever after 6 weeks of treatment. CT-scan and laboratory tests were consistent with reactivation of tuberculosis. The patient received anti-tuberculosis therapy including rifampicin, a potent CYP3A4/5 inducer. After introduction of rifampicin-based treatment, the patient experienced tumour progression, leaving questionable the potential pharmacokinetic interaction between rifampicin and temsirolimus, a substrate for CYP3A4.

    Topics: Aged, 80 and over; Antibiotics, Antitubercular; Antineoplastic Agents; Carcinoma, Renal Cell; Cytochrome P-450 CYP3A; Drug Interactions; Enzyme Induction; Humans; Kidney Neoplasms; Male; Neoplasm Metastasis; Rifampin; Sirolimus; Tuberculosis

2011
Anterior segment optical coherence tomography findings of presumed intraocular tuberculosis.
    Cutaneous and ocular toxicology, 2011, Volume: 30, Issue:1

    To report a case of anterior segment findings of presumed ocular tuberculosis using anterior-segment optical coherence tomography (AS-OCT; Visante, Carl Zeiss Meditec, Inc., Dublin, CA, USA).. A 78-year-old woman with persistent right ocular injection and pain of 2 weeks' duration was referred to our clinic. Unilateral stromal keratitis affecting the corneal periphery and angle granuloma with synechiae, scleritis, and anterior uveitis were noticed. Because of the patient's intensely positive tuberculin skin test, she was diagnosed with presumed intraocular tuberculosis. The anatomic structures of the anterior segment were monitored by AS-OCT before and after the treatment.. AS-OCT imaging showed a poorly demarcated amorphous lesion in the iridocorneal angle, corneal edema, narrowing and synechiae of the iridocorneal angle, and anterior chamber exudates and cells. Improvement of the corneal edema and a decrease of corneal thickness and exudates were observed after implementation of a daily regimen of antituberculous treatment. AS-OCT was useful for investigating the extent of the anterior synechiae and angle lesions.. AS-OCT allows noninvasive and noncontact analysis of the treatment response and is also useful to evaluate disease activity.

    Topics: Aged; Anterior Eye Segment; Antitubercular Agents; Cataract Extraction; Corneal Edema; Drug Therapy, Combination; Eye Diseases; Female; Humans; Isoniazid; Pyrazinamide; Rifampin; Tomography, Optical Coherence; Treatment Outcome; Tuberculosis

2011
Activities of TMC207, rifampin, and pyrazinamide against Mycobacterium tuberculosis infection in guinea pigs.
    Antimicrobial agents and chemotherapy, 2011, Volume: 55, Issue:1

    The experimental compound TMC207 is showing promise against infections caused by Mycobacterium tuberculosis both in a variety of animal studies and in the field. In this study, we used the guinea pig model, a species that shows several similarities to human tuberculosis, including the hallmark of primary granuloma necrosis, to determine the efficacy of a combination regimen combining TMC207 with rifampin and pyrazinamide. This drug regimen rapidly reduced the bacterial load in the lungs to undetectable levels by 8 weeks of treatment. This reduction was associated with a substantial improvement in lung pathology, but despite this effect areas of residual necrosis still remained. In the draining lymph nodes, however, tissue damage was rapid and not significantly reversed by the drug treatment. Approximately 10 to 11 months after the treatment had ended, the animals began to trigger a Karnovsky scale indicating bacterial regrowth and potential relapse, an event confirmed by the new development of both pulmonary and extrapulmonary granulomatous lesions. Interestingly, a similar rate of relapse was also seen in animals receiving 24 weeks of rifampin, pyrazinamide, and isoniazid standard chemotherapy. These data indicate that TMC207 could be a useful addition to current treatment regimens for tuberculosis.

    Topics: Animals; Antitubercular Agents; Diarylquinolines; Female; Flow Cytometry; Guinea Pigs; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Tuberculosis

2011
Disseminated Mycobacterium avium subspecies infection in a cat.
    Journal of feline medicine and surgery, 2011, Volume: 13, Issue:2

    An 18-month-old neutered male domestic shorthair cat, domiciled in the southwest of France, was first presented having suffered for a few days from dysorexia and vomiting. Abdominal palpation revealed lymph node enlargement. Cytological examinations of a fine needle aspirate demonstrated granulomatous inflammation with many non-staining elements consistent with mycobacteria. Diagnosis was confirmed by culture and polymerase chain reaction and Mycobacterium avium subspecies was isolated. Treatment was initiated with marbofloxacin, rifampicin and cefoxitin. There was a rapid clinical improvement. The cat suddenly died 2 months later. The main hypothesis is the administration of an inappropriate combination therapy that leads to the development of mycobacterial resistance. A volvulus and acute peritonitis secondary to the significant enlargement of a mesenteric lymph node were present at necropsy. Histopathological analysis of mesenteric lymph node, liver and spleen revealed multicentric granulomatous and severely necrotic lesions with numerous Ziehl-Neelsen positive intracytoplasmic elements.

    Topics: Animals; Anti-Bacterial Agents; Cat Diseases; Cats; Cefoxitin; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Fatal Outcome; Fluoroquinolones; Male; Mycobacterium avium; Rifampin; Tuberculosis

2011
[Performances of the assay MTBDRplus(®) in the surveillance of rifampicin resistance in Mycobacterium tuberculosis].
    Pathologie-biologie, 2011, Volume: 59, Issue:2

    The purpose of the survey was the routine assessment of the MTBDRplus(®) kit performance in the determination and characterization of Mycobacterium tuberculosis resistance to rifampicin. The survey was carried out on a collection of 144 strains (126 of which were resistant to rifampicin) isolated on patients from 15 countries. Sensitivity to antituberculosis drugs was determined by a liquid culture system and the reference method was the amplification and sequencing of a target region of the rpoB gene whose mutations are responsible for rifampicin resistance (codons 507 to 533). The assessed kit was based on a reverse hybridization technique using eight overlapping probes covering the target region and four probes representing the most-frequently observed mutations. The assay performance was found excellent, specificity: 100%, sensitivity: 99.2%; 17 mutations affecting 10 codons were reported, two of which were newly identified.

    Topics: Antitubercular Agents; Bacterial Proteins; Codon; Data Collection; Djibouti; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Microbial; Drug Resistance, Multiple, Bacterial; France; Genotype; Isoniazid; Mutation, Missense; Mycobacterium tuberculosis; Oxidoreductases; Point Mutation; Polymerase Chain Reaction; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Thailand; Tuberculosis; Tuberculosis, Multidrug-Resistant

2011
Comparative studies evaluating mouse models used for efficacy testing of experimental drugs against Mycobacterium tuberculosis.
    Antimicrobial agents and chemotherapy, 2011, Volume: 55, Issue:3

    Methodologies for preclinical animal model testing of drugs against Mycobacterium tuberculosis vary from laboratory to laboratory; however, it is unknown if these variations result in different outcomes. Thus, a series of head-to-head comparisons of drug regimens in three commonly used mouse models (intravenous, a low-dose aerosol, and a high-dose aerosol infection model) and in two strains of mice are reported here. Treatment with standard tuberculosis (TB) drugs resulted in similar efficacies in two mouse species after a low-dose aerosol infection. When comparing the three different infection models, the efficacies in mice of rifampin and pyrazinamide were similar when administered with either isoniazid or moxifloxacin. Relapse studies revealed that the standard drug regimen showed a significantly higher relapse rate than the moxifloxacin-containing regimen. In fact, 4 months of the moxifloxacin-containing combination regimen showed similar relapse rates as 6 months of the standard regimen. The intravenous model showed slower bactericidal killing kinetics with the combination regimens tested and a higher relapse of infection than either aerosol infection models. All three models showed similar outcomes for in vivo efficacy and relapse of infection for the drug combinations tested, regardless of the mouse infection model used. Efficacy data for the drug combinations used also showed similar results, regardless of the formulation used for rifampin or timing of the drugs administered in combination. In all three infection models, the dual combination of rifampin and pyrazinamide was less sterilizing than the standard three-drug regimen, and therefore the results do not support the previously reported antagonism between standard TB agents.

    Topics: Animals; Antitubercular Agents; Drug Therapy, Combination; Female; Isoniazid; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

2011
Paradoxically elevated efavirenz concentrations in HIV/tuberculosis-coinfected patients with CYP2B6 516TT genotype on rifampin-containing antituberculous therapy.
    AIDS (London, England), 2011, Jan-28, Volume: 25, Issue:3

    Some individuals have higher efavirenz plasma concentrations during rifampin-containing tuberculosis (TB) therapy, contrary to the expected induction effect of rifampin. Among HIV-infected patients without (n = 38) and with TB on rifampin-containing therapy (n = 18), we tested the hypothesis that drug-gene interaction may explain the highly variable drug interactions. Two-way analysis of variance revealed a significant interaction between CYP2B6 516G→T polymorphism and rifampin-containing therapy, suggesting that efavirenz dose adjustment may need to be individualized on the basis of the patient's genotype.

    Topics: Anti-HIV Agents; Antibiotics, Antitubercular; HIV Infections; HIV-1; Humans; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis

2011
Comment on: isoniazid and rifampicin resistance-associated mutations in Mycobacterium tuberculosis isolates from Yangon, Myanmar: implications for rapid molecular testing.
    The Journal of antimicrobial chemotherapy, 2011, Volume: 66, Issue:3

    Topics: Antitubercular Agents; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mutation, Missense; Myanmar; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2011
Mycobacteria infection in incomplete transverse myelitis is refractory to steroids: a pilot study.
    Clinical & developmental immunology, 2011, Volume: 2011

    Incomplete transverse myelitis (ITM) of unknown origin is associated with high rates of morbidity and mortality. This prospective, open-label study was undertaken to determine whether antituberculous treatment (ATT) might help patients with ITM whose condition continues to deteriorate despite receiving IV methylprednisolone treatment. The study consisted of 67 patients with steroid-refractory ITM in whom Mycobacterium tuberculosis (MTB) was suspected clinically and in whom other known causes of myelopathy were excluded. The study occurred from January 2003 to June 2010. Patients underwent trial chemotherapy with ATT. Efficacy was assessed by the American Spinal Injury Association (ASIA) scoring system, the Barthel Index (BI) and the Hauser Ambulation Index (AI) at baseline, 12 months, and 24 months, using magnetic resonance imaging (MRI). Of the 67 patients enrolled, 51 were assessed and 16 withdrew. At 24 months, 49 patients experienced benefits as indicated by significantly increased ASIA and BI scores. The Hauser AI index also improved with markedly decreased abnormal signals in spinal cord MRI over time. The results from this prospective study provide beneficial clinical and MRI data on the efficacy of ATT in ITM patients and suggests mycobacteria may be an important and neglected cause of myelitis.

    Topics: Adult; Aged; Antitubercular Agents; Female; Humans; Isoniazid; Magnetic Resonance Imaging; Male; Methylprednisolone; Middle Aged; Myelitis, Transverse; Pilot Projects; Prospective Studies; Pyrazinamide; Rifampin; Spinal Cord; Tuberculosis

2011
[Resistance rates of Mycobacterium tuberculosis complex strains isolated from clinical specimens].
    Mikrobiyoloji bulteni, 2011, Volume: 45, Issue:1

    The aim of this study was to investigate isoniazid, rifampicin, streptomycin and ethambutol resistance rates of Mycobacterium tuberculosis complex strains isolated from clinical specimens in the Mycobacteriology Laboratories of Karadeniz Technical University Hospital between January 2005-March 2010. A total of 212 M.tuberculosis complex strains, 152 (71.7%) of which were isolated from respiratory specimens and 60 (28.3%) from non-respiratory system specimens, were included to the study. M.tuberculosis complex strains were determined by polymerase chain reaction using primers specific for the IS6110 gene region. Single isolate of each patient were enrolled in the study. Antituberculosis drug susceptibility testing was performed by BACTEC MGIT 960 (Becton Dickinson, USA). Of the 212 isolates, 157 (74.05%) were susceptible to all of the four antimycobacterial agents while 55 (25.9%) were found resistant to one or more of the drugs. The monodrug resistance rates were found as 6.1% for isoniazid, 0.5% for rifampicin, 5.2% for streptomycin, and 2.4% for ethambutol. The number of multidrug resistant isolates characterized with resistance to isoniazid and rifampicin were 10 (4.8%). Our findings indicated that the rates of mono and multidrug resistant M.tuberculosis complex strains were significantly lower than the rates previously reported from our region and similar to the average country-base resistance rates reported by the Ministry of Health. Continuous monitoring of M.tuberculosis antimicrobial resistance at regional level would greatly aid to the success of the tuberculosis surveillance program in Turkey.

    Topics: Adult; Aged; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Ethambutol; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Polymerase Chain Reaction; Respiratory System; Rifampin; Streptomycin; Tuberculosis; Turkey

2011
[Evaluation of Xpert MTB/RIF results for the detection of Mycobacterium tuberculosis in clinical samples].
    Mikrobiyoloji bulteni, 2011, Volume: 45, Issue:1

    Tuberculosis is still a major global health problem. Nowadays nucleic acid amplification tests which are recommended by the World Health Organization (WHO) become popular methods for the rapid detection of Mycobacterium tuberculosis complex (MTC). Recently introduced commercial Xpert MTB/RIF (Cepheid, USA) system is also a molecular method based on real-time polymerase chain reaction for simultaneous detection of both MTC and rifampicin resistance in the clinical sample. The sample processing, nucleic acid extraction, amplification and detection of known mutations related to rifampicin resistance are performed in a single cartridge in this integrated system and the results are obtained in two hours. The aim of this study was to evaluate the performance of Xpert MTB/RIF system for the detection of M.tuberculosis in pre-processed clinical samples by comparing the results obtained by Bactec 460TB 12B (BD Diagnostic, USA), Löwenstein-Jensen (LJ) culture and direct microscopy of smears stained with Ziehl- Neelsen (ZN). A total of 85 clinical specimens (50 sputum, 25 bronchoalveolar lavage, five thorasynthesis fluid and five urine samples) obtained from tuberculosis-suspected patients were included to the study. All specimens were decontaminated and this decontaminated suspension was used in the diagnostic methods, except for Xpert MTB/RIF process. Twenty-five (29%) of the samples yielded positive result with Bactec 460TB, 25 (29%) were found positive with Xpert MTB/RIF, 15 (18%) were found positive with LJ and 11 (13%) were found positive with ZN staining method. High consistency was detected between the results of Bactec 460TB and Xpert MTB/RIF when Bactec 460TB was considered as the gold standard method (r= 0.943; p= 0.000). One specimen yielded false positive result with Xpert MTB/RIF when compared to the reference method. The sensitivity, specificity, positive and negative predictive values of Xpert MTB/RIF test were then estimated as 96%, 98%, 96% and 98%, respectively. No resistance were detected for the tested isolates. This study suggested that the sensitivity of Xpert MTB/RIF system in direct detection of M.tuberculosis in smear positive and smear negative samples was consistent with the reference methods. Moreover, the MTB/RIF test provided sensitive detection of tuberculosis in less than two hours.

    Topics: Antibiotics, Antitubercular; Bacteriuria; Bronchoalveolar Lavage Fluid; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Paracentesis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Thorax; Tuberculosis

2011
Mutations outside the rifampicin resistance-determining region associated with rifampicin resistance in Mycobacterium tuberculosis.
    The Journal of antimicrobial chemotherapy, 2011, Volume: 66, Issue:4

    Ninety-six percent of rifampicin resistance in Mycobacterium tuberculosis was shown to be associated with mutations inside the 81 bp rifampicin resistance-determining region (RRDR) located in the centre of the rpoB gene. The detection of rifampicin resistance by targeting the RRDR failed to match with a resistant phenotype in 4% of all cases. Our study aims to identify the mutations outside the RRDR that are associated with rifampicin resistance in M. tuberculosis.. Among 50 rifampicin-resistant and 20 rifampicin-susceptible clinical isolates of M. tuberculosis, 2 of the rifampicin-resistant isolates did not harbour any known mutations in the RRDR. Sequencing analysis of the whole rpoB gene identified two rare mutations, V146F and I572F. A molecular structure model based on Thermus thermophilus RpoB revealed that both these substituted amino acids are located in close proximity to the rifampicin-binding pocket of the β-subunit. Substitutions of simple amino acids for bulky ones are likely to affect the protein-drug interaction. Cloning and transformation of the mutated rpoB gene into wild-type Mycobacterium smegmatis and M. tuberculosis successfully elevated the MIC of rifampicin and conferred the rifampicin resistance phenotype.. Our study showed that amino acid positions 146 and 572 are associated with rifampicin resistance in M. tuberculosis in addition to the RRDR. Molecular assays for identifying rifampicin-resistant M. tuberculosis might be improved in terms of accuracy by including these two positions.

    Topics: Amino Acid Substitution; Antitubercular Agents; Binding Sites; Cloning, Molecular; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Mutation, Missense; Mycobacterium smegmatis; Mycobacterium tuberculosis; Rifampin; Thermus thermophilus; Tuberculosis

2011
Clinical experience of raltegravir-containing regimens in HIV-infected patients during rifampicin-containing treatment of tuberculosis.
    The Journal of antimicrobial chemotherapy, 2011, Volume: 66, Issue:4

    Topics: Adult; Anti-Bacterial Agents; Anti-HIV Agents; Drug Interactions; Female; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Rifampin; Tuberculosis

2011
In silico prediction of efavirenz and rifampicin drug-drug interaction considering weight and CYP2B6 phenotype.
    British journal of clinical pharmacology, 2011, Volume: 71, Issue:4

    This study aimed to test whether a pharmacokinetic simulation model could extrapolate nonclinical drug data to predict human efavirenz exposure after single and continuous dosing as well as the effects of concomitant rifampicin and further to evaluate the weight-based dosage recommendations used to counteract the rifampicin-efavirenz interaction.. Efavirenz pharmacokinetics were simulated using a physiologically based pharmacokinetic model implemented in the Simcyp™ population-based simulator. Physicochemical and metabolism data obtained from the literature were used as input for prediction of pharmacokinetic parameters. The model was used to simulate the effects of rifampicin on efavirenz pharmacokinetics in 400 virtual patients, taking into account bodyweight and CYP2B6 phenotype.. Apart from the absorption phase, the simulation model predicted efavirenz concentration-time profiles reasonably well, with close agreement with clinical data. The simulated effects of rifampicin co-administration on efavirenz treatment showed only a minor decrease of 16% (95% confidence interval 13-19) in efavirenz area under the concentration-time curve, of the same magnitude as what has been clinically observed (22%). Efavirenz exposure depended on CYP2B6 phenotype and bodyweight. Increasing the efavirenz dose during concomitant rifampicin was predicted to be most successful in patients over 50 kg regardless of CYP2B6 status.. Our findings, although based on a simulation approach using limited in vitro data, support the current recommendations for using a 50 kg bodyweight cut-off for efavirenz dose increment when co-treating with rifampicin.

    Topics: Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Body Weight; Computer Simulation; Cyclopropanes; Cytochrome P-450 CYP2B6; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Forecasting; HIV Infections; Humans; Models, Theoretical; Oxidoreductases, N-Demethylating; Phenotype; Rifampin; Tuberculosis

2011
Comparison of the Xpert MTB/RIF test with an IS6110-TaqMan real-time PCR assay for direct detection of Mycobacterium tuberculosis in respiratory and nonrespiratory specimens.
    Journal of clinical microbiology, 2011, Volume: 49, Issue:5

    The sensitivities of the Xpert MTB/RIF test and an in-house IS6110-based real-time PCR using TaqMan probes (IS6110-TaqMan assay) for the detection of Mycobacterium tuberculosis complex (MTBC) DNA were compared by use of 117 clinical specimens (97 culture positive and 20 culture negative for MTBC) that were frozen in sediment. The 97 clinical specimens included 60 respiratory and 37 nonrespiratory specimens distributed into 36 smear-positive and 61 smear-negative specimens. Among the 97 culture-positive specimens, 4 had rifampin-resistant isolates. Both methods were highly specific and exhibited excellent sensitivity (100%) with smear-positive specimens. The sensitivity of the Xpert MTB/RIF test with the whole smear-negative specimens was more reduced than that of the IS6110-TaqMan assay (48 versus 69%, P = 0.005). Both methods exhibited similar sensitivities with smear-negative respiratory specimens, but the Xpert MTB/RIF test had lower sensitivity with smear-negative nonrespiratory specimens than the IS6110-TaqMan assay (37 versus 71%, P = 0.013). Finally, the sensitivities of the Xpert MTB/RIF test and the IS6110-TaqMan assay were 79% and 84%, respectively, with respiratory specimens and 53% and 78%, respectively (P = 0.013), with nonrespiratory specimens. The Xpert MTB/RIF test correctly detected the rifampin resistance in smear-positive specimens but not in the one smear-negative specimen. The Xpert MTB/RIF test is a simple rapid method well adapted to a routine laboratory that appeared to be as sensitive as the IS6110-TaqMan assay with respiratory specimens but less sensitive with paucibacillary specimens, such as smear-negative nonrespiratory specimens.

    Topics: Antitubercular Agents; Bacteriological Techniques; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2011
Genetic variation of Mycobacterium tuberculosis circulating in Kharkiv Oblast, Ukraine.
    BMC infectious diseases, 2011, Mar-28, Volume: 11

    A persistent increase of tuberculosis cases has recently been noted in the Ukraine. The reported incidence of drug-resistant isolates of M. tuberculosis is growing steadily; however, data on the genetic variation of isolates of M. tuberculosis circulating in northern Ukraine and on the spectrum and frequency of occurrence of mutations determining resistance to the principal anti-tuberculosis drugs isoniazid and rifampicin have not yet been reported.. Isolates of M. tuberculosis from 98 tuberculosis patients living in Kharkiv Oblast (Ukraine) were analyzed using VNTR- and RFLP-IS6110-typing methods. Mutations associated with resistance to rifampicin and isoniazid were detected by RFLP-PCR methods, and also confirmed by sequencing.. We identified 75 different genetic profiles. Thirty four (34%) isolates belonged to the Beijing genotype and 23 (23%) isolates belonged to the LAM family. A cluster of isolates belonging to the LAM family had significant genetic heterogeneity, indicating that this family had an ancient distribution and circulation in this geographical region. Moreover, we found a significant percentage of the isolates (36%) belonged to as yet unidentified families of M. tuberculosis or had individual non-clustering genotypes. Mutations conferring rifampicin and isoniazid resistance were detected in 49% and 54% isolates, respectively. Mutations in codon 531 of the rpoB gene and codon 315 of the katG gene were predominant among drug-resistant isolates. An association was found for belonging to the LAM strain family and having multiple drug resistance (R = 0.27, p = 0.0059) and also for the presence of a mutation in codon 531 of the rpoB gene and belonging to the Beijing strain family (R = 0.2, p = 0.04).. Transmission of drug-resistant isolates seems to contribute to the spread of resistant TB in this oblast. The Beijing genotype and LAM genotype should be seen as a major cause of drug resistant TB in this region.

    Topics: Adult; Antitubercular Agents; Bacterial Typing Techniques; DNA, Bacterial; Drug Resistance, Bacterial; Female; Genetic Variation; Genotype; Humans; Isoniazid; Male; Middle Aged; Minisatellite Repeats; Mutation; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Rifampin; Tuberculosis; Ukraine; Young Adult

2011
Torticollis in mice intravenously infected with Mycobacterium tuberculosis.
    Journal of the American Association for Laboratory Animal Science : JAALAS, 2011, Volume: 50, Issue:2

    Female BALB/cAnNCrl (n = 170; age, 6 to 9 wk) mice were infected by intravenous inoculation of 5 × 10(6) cfu Mycobacterium tuberculosis strain Erdman (ATCC 35801). Between day 52 and 5 mo after infection, 10 of the 170 mice infected according to this protocol developed torticollis, including mice in treatment groups that received combination antibiotic therapy of rifampin-pyrazinamide or moxifloxacin-rifampin-pyrazinamide. Torticollis did not develop in mice receiving isoniazid- rifampin-pyrazinamide therapy, nor was it present in the cohort of aerogenically infected mice. Affected mice were euthanized, and complete necropsy evaluation was performed on 4 mice. Gross necropsy evaluation revealed typical tuberculosis lesions in lungs of infected mice. Histologic evaluation of tissues revealed granulomatous otitis media with intralesional acid-fast bacilli consistent with Mycobacterium tuberculosis. These cases represent an unusual finding specific to the intravenous mouse model of Mycobacterium tuberculosis and may represent a model of a similar condition in humans that is known as tuberculous otitis media.

    Topics: Animals; Antitubercular Agents; Autopsy; Aza Compounds; Disease Models, Animal; Drug Therapy, Combination; Ear, Middle; Female; Fluoroquinolones; Injections, Intravenous; Isoniazid; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Otitis Media; Pyrazinamide; Quinolines; Rifampin; Torticollis; Tuberculosis

2011
Mycobacterium tuberculosis spoligotypes and drug susceptibility pattern of isolates from tuberculosis patients in South-Western Uganda.
    BMC infectious diseases, 2011, Mar-31, Volume: 11

    Determination of the prevalence and drug susceptibility of the M. tuberculosis strains is important in tuberculosis control. We determined the genetic diversity and susceptibility profiles of mycobacteria isolated from tuberculosis patients in Mbarara, South Western Uganda.. We enrolled, consecutively; all newly diagnosed and previously treated smear-positive TB patients aged≥18 years. The isolates were characterized using regions of difference (RD) analysis and spoligotyping. Drug resistance against rifampicin and isoniazid were tested using the Genotype® MDRTBplus assay and the indirect proportion method on Lowenstein-Jensen media. HIV-1 testing was performed using two rapid HIV tests.. A total of 125 isolates from 167 TB suspects (60% males) with a mean age 33.7 years and HIV prevalence of 67.9% (55/81) were analyzed. Majority (92.8%) were new cases while only 7.2% were retreatment cases. All the 125 isolates were identified as M. tuberculosis strict sense with the majority (92.8%) of the isolates being modern strains while seven (7.2%) isolates were ancestral strains. Spoligotyping revealed 79 spoligotype patterns, with an overall diversity of 63.2%. Sixty two (49.6%) of the isolates formed 16 clusters consisting of 2-15 isolates each. A majority (59.2%) of the isolates belong to the Uganda genotype group of strains. The major shared spoligotypes in our sample were SIT 135 (T2-Uganda) with 15 isolates and SIT 128 (T2) with 3 isolates. Sixty nine (87%) of the 79 patterns had not yet been defined in the SpolDB4.0.database. Resistance mutations to either RIF or INH were detected in 6.4% of the isolates. Multidrug resistance, INH and RIF resistance was 1.6%, 3.2% and 4.8%, respectively. The rpoβ gene mutations seen in the sample were D516V, S531L, H526Y H526D and D516V, while one strain had a Δ1 mutation in the wild type probes. There were three strains with katG (codon 315) gene mutations only while one strain showed the inhA promoter gene mutation.. The present study shows that the TB epidemic in Mbarara is caused by modern M. tuberculosis strains mainly belonging to the Uganda genotype and anti-TB drug resistance rate in the region is low.

    Topics: Adult; Antitubercular Agents; Female; Genetic Variation; Genotype; HIV Infections; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Molecular Typing; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Uganda

2011
Increased rifampicin resistance in blood isolates of meticillin-resistant Staphylococcus aureus (MRSA) amongst patients exposed to rifampicin-containing antituberculous treatment.
    International journal of antimicrobial agents, 2011, Volume: 37, Issue:6

    The aim of this study was to determine the rifampicin (RIF) resistance rate of meticillin-resistant Staphylococcus aureus (MRSA) amongst patients with MRSA bacteraemia who have or have not been exposed to RIF-containing antituberculous (anti-TB) treatment. From 2000 to 2008, patients with MRSA bacteraemia and previous exposure to RIF-containing anti-TB therapy were selected. Patients matched for sex, age and time of culture of MRSA bacteraemia but without exposure to anti-TB therapy were selected as a control group. A total of 139 patients, comprising 49 with RIF exposure and 90 without RIF exposure, were analysed. The RIF resistance rate was higher in patients with previous RIF exposure (61.2% vs. 20.0%; P<0.001). The minimum inhibitory concentration of RIF that inhibited 50% of MRSA isolates (MIC(50)) for the study group was also higher (128 mg/L vs. 0.015 mg/L; P<0.001). The mortality rate was higher in the study group (59.2% vs. 41.1%; P=0.041). MRSA isolates recovered from patients with current usage of a RIF-containing anti-TB regimen were more likely to be resistant to RIF (87.5% vs. 36%; P=0.001), with higher MIC(50) values (256 mg/L vs. 1mg/L; P=0.002), and resulted in a higher mortality rate than isolates from patients with remote usage of an anti-TB regimen (79.2% vs. 40%; P=0.005). Multivariate analysis showed that current anti-TB drug usage was the only risk factor for RIF resistance [odds ratio (OR)=7.457, 95% confidence interval (CI) 1.581-35.167] and mortality (OR=7.201, 95% CI 1.583-32.766). Given the high rate of RIF resistance in patients with prior anti-TB treatment, RIF susceptibility testing should be performed before considering combination treatment of RIF in MRSA infection.

    Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteremia; Blood; Drug Resistance, Bacterial; Female; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Middle Aged; Rifampin; Staphylococcal Infections; Tuberculosis

2011
Synthesis of biodegradable polymeric nanoparticles and their controlled drug delivery for tuberculosis.
    Journal of biomedical nanotechnology, 2011, Volume: 7, Issue:1

    Tuberculosis (TB) is the leading cause of infectious diseases affecting the 2 billion people worldwide. To improve the current method of treatment a synthetic polymeric anti-TB nanodrug delivery system was attempted. A series of PLGA polymers with different molar feed ratios i.e., 90/10, 75/25, 50/50 were synthesized by direct melt polycondensation method. The PLGA nanoparticles and the drug (Rifampicin (RIF)) encapsulation were prepared by double emulsion-solvent evaporation technique. The in vitro release profile of the RIF loaded PLGA NPs showed an initial burst followed by sustained release. The nanoparticles were remarkably advantageous in terms of high drug encapsulation efficiency, low polymer consumption and better sustained release profile.

    Topics: Absorbable Implants; Antitubercular Agents; Delayed-Action Preparations; Diffusion; Drug Compounding; Humans; Lactic Acid; Nanocapsules; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin; Tuberculosis

2011
The variable clinical presentation of tuberculosis otitis media and the importance of early detection.
    Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 2011, Volume: 32, Issue:4

    Tuberculosis (TB) is a rare cause of otitis media. This study aims to increase awareness on the clinical presentation of TB otitis media and illustrate how early detection affects treatment outcome.. Chart review of 12 patients (13 ears) from a tertiary hospital in Manila, Philippines, seen from 2004 to 2009. Clinical predictors of the disease were summarized. Clinical, radiologic, and audiometric outcomes after treatment were compared between treatment groups.. The 5 otoscopic presentations were multiple perforations, single perforation with refractory otorrhea and exuberant granulation tissue formation, single perforation with minimal otorrhea and no granulation tissue formation, intact tympanic membrane with middle ear effusion, and intact tympanic membrane with tumorlike tissue in the middle ear. Clinical predictors of the disease were history of pulmonary TB, work-related contamination of the infection, positive purified protein derivative test, positive chest radiographic finding and intraoperative granulation tissue with cheesy material, and temporal bone computed tomographic scan findings. Patients who had no middle ear surgery showed significantly better clinical, radiologic, and audiometric outcomes than those who were diagnosed late and had more complicated surgical procedure.. The clinical presentation of TB otitis media is variable. Early detection of the early forms entail less surgical intervention and favors better treatment results.

    Topics: Adolescent; Adult; Audiometry, Pure-Tone; Early Diagnosis; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Otitis Media, Suppurative; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2011
Lopinavir exposure is insufficient in children given double doses of lopinavir/ritonavir during rifampicin-based treatment for tuberculosis.
    Antiviral therapy, 2011, Volume: 16, Issue:3

    Coadministration of rifampicin dramatically reduces the concentrations of protease inhibitors. A pharmacokinetic study in healthy adults showed that doubling the dose of coformulated lopinavir/ritonavir was able to overcome the inducing effect of rifampicin. We evaluated this strategy in children treated with rifampicin-based antituberculosis therapy attending antiretroviral clinics in South Africa.. Plasma concentrations of lopinavir were measured in children (aged 0.64-2.43 years) established on antituberculosis treatment who commenced antiretroviral therapy comprising double the usual recommended dose of lopinavir/ritonavir oral solution (460/115 mg/m(2) twice daily) plus two nucleoside reverse transcriptase inhibitors. Control children (0.57-4.23 years old) without tuberculosis received standard doses of lopinavir/ritonavir (230/57.5 mg/m(2) twice daily).. Pre-dose lopinavir concentrations were reduced by >80% in children with tuberculosis (median 0.7 mg/l, IQR 0.1-2.0) compared with controls (4.2 mg/l, IQR 3.4-8.1; P<0.001) and were below the minimum recommended concentration of 1 mg/l in 12 of 20 (60%) children with tuberculosis versus 2 of 24 (8%) controls (P<0.001).. Double doses of coformulated lopinavir/ritonavir results in inadequate lopinavir concentrations in young children treated concurrently with rifampicin. Suitable regimens are urgently needed for treating young children with HIV-associated tuberculosis.

    Topics: Anti-HIV Agents; Antitubercular Agents; Child, Preschool; Drug Interactions; Drug Therapy, Combination; Female; HIV; HIV Infections; Humans; Infant; Lopinavir; Male; Pyrimidinones; Rifampin; Ritonavir; South Africa; Treatment Outcome; Tuberculosis

2011
Drug susceptibility pattern of Mycobacterium tuberculosis isolates against conventional anti-tuberculosis drugs in Dhaka, Bangladesh.
    Saudi medical journal, 2011, Volume: 32, Issue:5

    To investigate the drug susceptibility pattern of isolated Mycobacterium tuberculosis (M. tuberculosis) against conventional anti-tuberculosis drugs in Dhaka, Bangladesh.. Sputum samples from 101 suspected new and previously treated patients were collected and M. tuberculosis was identified by microscopic observation and Ziehl-Neelsen staining. Drug susceptibility was performed against 4 anti-tuberculosis drugs, and the obtained data was analyzed. This study was performed in the Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders Hospital, Dhaka, Bangladesh between October 2008 and November 2009.. Among 101 suspected, 59 (58.4%) cases were identified as M. tuberculosis and the drug susceptibility pattern of 50 positives isolates was studied against 4 anti-tuberculosis drugs. Out of these 50 isolates of M. tuberculosis, 25 (50%) were sensitive to all drugs, and 25 (50%) were resistant to one or more drugs. Among 50 positive patients, 37 (74%) were new cases, and 13 (26%) were previously treated cases. Among 37 new cases, 14 (37.8%) cases were resistant to one or more drugs, whereas 11 out of 13( 84.6%) treated cases were resistant to one or more drugs. Among the 50 positive isolates, 26% demonstrated resistance to isoniazid, 12% to rifampicin, 22% to streptomycin, 20% to ethambutol, and 8% to multi drug resistance.. The emergence of drug resistant M. tuberculosis isolates in Dhaka is alarming, which is currently 5-fold higher than last decade. Strict measures should be taken to control and prevent drug-resistant tuberculosis.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Bangladesh; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sputum; Streptomycin; Tuberculosis; Young Adult

2011
Genotyping and drug resistance patterns of Mycobacterium tuberculosis strains in five provinces of China.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2011, Volume: 15, Issue:6

    To evaluate the distribution of the Mycobacterium tuberculosis Beijing genotype and the association of the genotype with drug-resistant M. tuberculosis strains in five provinces in China.. M. tuberculosis strains (n = 158) isolated from five provinces of China were subjected to insertion sequence 6110 restriction fragment length polymorphism (RFLP), spoligotyping and mycobacterial interspersed repetitive units (MIRU) analyses. The prevalence of the Beijing genotype strains in each province was determined and compared. The proportion method was used to test the drug susceptibility of all strains.. Of the 158 strains, 123 (77.8%) were identified as the Beijing genotype by RFLP and spoligotyping. Nearly all the strains (n = 152, 96.2%) were grouped into 14 shared spoligotypes. Six other spoligotypes were unique to China. The prevalence of the Beijing genotype was significantly higher in the interior than in coastal areas (P < 0.001, OR 5.4, 95%CI 2.3-12.7). Resistance to rifampicin (RMP) was associated with the Beijing strain (P = 0.05, OR 3.7, 95%CI 1.2-11.1).. The M. tuberculosis Beijing genotype varies in prevalence in different regions of China and is solely associated with RMP resistance.

    Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; China; DNA Fingerprinting; Drug Resistance, Multiple, Bacterial; Female; Genotype; Geography; Humans; Interspersed Repetitive Sequences; Male; Middle Aged; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Rifampin; Tuberculosis; Young Adult

2011
Decline in tuberculosis with 19 years of universal directly observed therapy in a comprehensive statewide program.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2011, Volume: 15, Issue:6

    The Mississippi State Department of Health tuberculosis program serves a rural southeastern US state of 2.9 million people in an area of 121,489 km(2) (46,907 square miles). Statewide, directly observed therapy (DOT) began in 1986. To evaluate the program's effectiveness, trends in Centers for Disease Prevention and Control program indicators for 1981-2005 were compared and found to be significant (P < 0.0001). Inclusion of rifampin and pyrazinamide in the regimens was reviewed. An annual decline in cases and case rates began in 1990, falling by 65% by 2005. Successful DOT is feasible over a large geographic area.

    Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Child; Child, Preschool; Databases, Factual; Directly Observed Therapy; Female; Health Policy; Humans; Infant; Infant, Newborn; Logistic Models; Male; Middle Aged; Mississippi; Pyrazinamide; Rifampin; Rural Population; Tuberculosis; United States; Young Adult

2011
[Cystic echinococcosis mimicking tuberculosis in childhood].
    Turkiye parazitolojii dergisi, 2011, Volume: 35, Issue:1

    Both cystic echinococcosis (CE) and tuberculosis (Tbc) are important health problems in developing countries. Pulmonary CE and Tbc have to be differentiated from other diseases as they have increased the risk of morbidity and mortality. Besides, these two diseases can mimic each other. Here, we discuss a 7 year-old patient admitted with fever, cough who was unresponsive to nonspecific antibiotic treatment given for pneumonia, had Tbc treatment due to a positive tuberculin skin test and radiologic appearance consistent with Tbc and on follow-up. He was eventually diagnosed as CE based on a cystic lesion consistent with CE in the liver and echinococcosis specific IgE positivity and was succesfully treated with anti-parasitic therapy.

    Topics: Albendazole; Anthelmintics; Antitubercular Agents; Bronchoalveolar Lavage; Bronchoscopy; Child; Diagnosis, Differential; Echinococcosis; Female; Humans; Radiography; Rifampin; Tuberculin Test; Tuberculosis; Ultrasonography

2011
T cell monitoring of chemotherapy in experimental rat tuberculosis.
    Antimicrobial agents and chemotherapy, 2011, Volume: 55, Issue:8

    Mycobacterium tuberculosis is the causative agent of a pulmonary epidemic that is estimated to infect one-third of the world's population and that has an increased incidence of multidrug resistance. The evaluation of new chemical entities against M. tuberculosis is hampered by the lack of biological tools to help predict efficacy, from early drug development to clinical trials. As the rat is the animal species of choice in the pharmaceutical industry, we have developed a rat model of acute and chronic phases of M. tuberculosis infection for drug efficacy testing. In this model, we have evaluated the impact of tuberculosis drugs on T cell response using the enzyme-linked immunospot assay methodology. Infected rats treated with isoniazid (INH) or rifampin (RIF) responded to therapy, the potency of which was comparable to that seen in the mouse. Peripheral blood mononuclear cells from infected rats produced gamma interferon (IFN-γ) in response to RD-1 antigens, such as the 6-kDa early secretory antigen target (ESAT-6) and the 10-kDa culture filtrate protein (CFP-10). A decrease in IFN-γ spot-forming cells (SFCs) was consistently observed in response to drug treatment. In both the acute- and chronic-phase models, the T cell response was more sensitive to ESAT-6 than to CFP-10. The SFC count in response to ESAT-6 appears to be an indicator of bacterial killing in the rat. Collectively, our data suggest that the ESAT-6 response could be used as a potential surrogate of drug efficacy in the rat and that such a readout could help shorten drug testing during preclinical development.

    Topics: Animals; Antibiotics, Antitubercular; Antigens, Bacterial; Antitubercular Agents; Bacterial Proteins; Disease Models, Animal; Drug Discovery; Drug Evaluation, Preclinical; Drug Resistance, Multiple, Bacterial; Enzyme-Linked Immunospot Assay; Female; Interferon-gamma; Isoniazid; Mycobacterium tuberculosis; Rats; Rats, Wistar; Rifampin; T-Lymphocytes; Tuberculosis

2011
Tuberculosis-associated chronic kidney disease.
    The American journal of tropical medicine and hygiene, 2011, Volume: 84, Issue:6

    Extrapulmonary tuberculosis (TB) account for approximately 15-20% of TB cases in immunocompetent patients. The genitourinary system is the third most commonly affected site. We report the case of a 20-year-old man admitted with fever, chills, dry cough, right flank pain, and oliguria who developed renal function loss. The pyelogram evidenced silence of the right kidney, and the abdominal and pelvic magnetic resonance showed significant dilation of the right pyelocaliceal system and proximal ureter. Biopsies of renal cortex and retroperitoneal lymph nodes showed caseous granuloma consistent with TB. Treatment was started with rifampicin, isoniazid, pyrazinamide, and ethambutol, and the patient presented a favorable outcome but with non-dialytic chronic kidney disease. This case illustrates a case of chronic kidney disease secondary to TB in a young, otherwise healthy man.

    Topics: Antitubercular Agents; Ethambutol; Fever; Humans; Isoniazid; Kidney Failure, Chronic; Male; Pyrazinamide; Renal Dialysis; Rifampin; Tuberculosis; Young Adult

2011
Polymeric emulsion and crosslink-mediated synthesis of super-stable nanoparticles as sustained-release anti-tuberculosis drug carriers.
    Colloids and surfaces. B, Biointerfaces, 2011, Oct-15, Volume: 87, Issue:2

    This study focused on evaluating four emulsion-based processing strategies for polymeric nanoparticle synthesis to explicate the mechanisms of nanoparticle formation and the influence on achieving sustained-release of two anti-tuberculosis drugs, isoniazid and rifampicin. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were formulated with and without sorbitan mono-oleate as a stabilizer using emulsion-solvent-surfactant-evaporation (ESSE) and emulsion-solvent-evaporation (ESE) approaches. An alginate solution gelled by ionic crosslinking with calcium chloride was employed to prepare alginate hydrogel nanoparticles via reverse-emulsion-cationic-gelification (RECG) and reverse-emulsion-surfactant-cationic-gelification (RESCG) approaches. In vitro drug release analysis was performed. The size, zeta potential and morphology of the nanoparticles were analyzed. Molecular mechanics energy relationships (MMER) were employed to explore the spatial disposition of alginate and PLGA with respect to the emulsifying profile of sorbitan monooleate and to corroborate the experimental findings. Results revealed that particle size of the PLGA nanoparticles was influenced by the stabilizer concentration. Nanoparticles synthesized by the ESSE approach had smaller sizes of 240±8.7 nm and 195.5±5.4 nm for rifampicin- and isoniazid-loaded nanoparticles, respectively. This was a substantial size reduction from nanoparticles generated by the ESE approach (>1000 nm). The RESCG approach produced stable and higher nanoparticle yields with desirable size (277±1.0 nm; 289±1.2 nm), a low polydispersity index (27.1±0.3 mV; 28.5±0.5 mV) and drug entrapment efficiency of 73% and 75% for isoniazid and rifampicin, respectively. Drug release from the ESSE and RESCG synthesized nanoparticles displayed desirable release of the two anti-TB drugs with sustained zero-order kinetics over a period of 8h. MMER supported the mechanisms of nanoparticle formation with a sphericalized interlaced network configuration.

    Topics: Alginates; Calcium Chloride; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Emulsions; Glucuronic Acid; Hexoses; Hexuronic Acids; Humans; Hydrogels; Isoniazid; Lactic Acid; Microscopy, Electron, Scanning; Models, Molecular; Nanoparticles; Organic Chemistry Phenomena; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin; Spectrum Analysis; Thermodynamics; Tuberculosis

2011
Cepheid GeneXpert MTB/RIF assay for Mycobacterium tuberculosis detection and rifampin resistance identification in patients with substantial clinical indications of tuberculosis and smear-negative microscopy results.
    Journal of clinical microbiology, 2011, Volume: 49, Issue:8

    The GeneXpert MTB/RIF assay was evaluated with microscopically negative and positive pulmonary and extrapulmonary specimens from patients with substantial clinical indications for tuberculosis. For the pulmonary samples, the sensitivity, specificity, and positive and negative predictive values were 90.6%, 94.3%, 93.5%, and 91.7%, and for the extrapulmonary samples, they were 100%, 91.6%, 50%, and 100%, respectively. For microscopically negative specimens, the respective values were 86.3%, 93%, 79%, and 95.6%. The assay correctly detected rifampin resistance in all but one specimen, which harbored a mixed population. The GeneXpert assay was highly effective for tuberculosis diagnosis and identification of rifampin-resistant strains in smear-negative samples.

    Topics: Antitubercular Agents; Bacteriological Techniques; Drug Resistance; Humans; Microscopy; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2011
Evaluation of the Genotype® MTBDRplus assay as a tool for drug resistance surveys.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2011, Volume: 15, Issue:7

    A national tuberculosis (TB) drug resistance survey in Tanzania.. To compare the performance of the Genotype® MTBDRplus line-probe assay (LPA) on smear-positive sputum specimens with conventional culture and isoniazid (INH) plus rifampicin (RMP) drug susceptibility testing (DST).. Mycobacterium tuberculosis isolates tested at the Tanzanian Central TB Reference Laboratory (CTRL) were submitted for quality assurance of phenotypic DST to its supranational reference laboratory (SRL), together with ethanol-preserved sputum specimens for LPA DST.. Only 321 samples could be tested using LPA; of these, three were identified as being non-tuberculous mycobacteria using CTRL DST. Both tests had 269 sets with interpretable results. CTRL DST yielded almost the same number of interpretable results as LPA, with 90% concordance (κ = 0.612, P < 0.001). Five (1.9%) multidrug-resistant (MDR) strains, 46 (17.1%) resistant to INH only and 0 RMP only, were found by CTRL DST. For the LPA, these results were respectively 5 (1.9%), 26 (9.7%) and 2 (0.7%). With SRL DST as the gold standard, LPA was more accurate than CTRL DST for RMP, but missed almost half the INH-resistant samples.. LPA applied directly on ethanol-preserved sputum specimens was similar to phenotypic DST in terms of yield of interpretable results. Although probably more accurate for RMP and MDR-TB, it appears to seriously underestimate INH resistance. Considering speed, easy and safe specimen transportation and low infrastructure requirements, LPA DST from sputum can be recommended for surveys in resource-poor settings.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sputum; Tanzania; Tuberculosis; Tuberculosis, Multidrug-Resistant

2011
Xpert MTB/RIF®, a novel automated polymerase chain reaction-based tool for the diagnosis of tuberculosis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2011, Volume: 15, Issue:7

    There is an urgent need for new point of care tests for tuberculosis (TB). Xpert MTB/RIF® is a real-time polymerase chain reaction-based system that detects Mycobacterium tuberculosis DNA and rifampicin (RMP) resistance modulating mutations directly from clinical samples in 2 h. The sensitivity for detecting M. tuberculosis in culture-positive samples was 93.8% (60/64) and exceeded smear microscopy (40/64, 62.5%). The specificity for detecting M. tuberculosis was 92.0% (23/25) and for RMP resistance it was 100% (8/8). The test is simple to conduct and requires basic sputum handling facilities only. These characteristics render it a promising close-to-patient test for TB in various settings.

    Topics: Antibiotics, Antitubercular; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Specimen Handling; Sputum; Tuberculosis

2011
Phagostimulatory effect of uptake of PLGA microspheres loaded with rifampicin on alveolar macrophages.
    Colloids and surfaces. B, Biointerfaces, 2011, Oct-15, Volume: 87, Issue:2

    Our previous results on the phagocytic activity of alveolar macrophages (Mϕs) toward poly(lactic-co-glycolic) acid microspheres (PLGA MS) loaded with the anti-tuberculosis agent rifampicin (R-PLGA MS) suggest that the phagocytosis of R-PLGA MS enhances the phagocytic activity of Mϕ cells. To confirm this possibility, we examined the effect of phagocytosis of R-PLGA MS and polystyrene latex (PSL) MS on the phagocytic uptake of fluorescent PSL (F-PSL) MS by cells of the rat alveolar macrophage cell line NR8383 at 37°C. Phagocytic activity was examined in terms of the population of Mϕ cells that had phagocytosed MS (N(total)) and the total number of MS phagocytosed (n(total)) by counting the phagocytic Mϕ cells and the MS ingested in optical microscopic fields. Phagocytosis of R-PLGA MS enhanced about 1.5 times the values of N(total) and n(total) of the phagocytosis of F-PSL MS under the conditions where the phagocytosis of F-PSL MS did not attain the saturated level. In contrast, the phagocytosis of PSL MS did not enhance the phagocytic activity of Mϕ cells toward F-PSL MS. In conclusion, R-PLGA MS are favorable for drug delivery of anti-tuberculosis agents into alveolar Mϕs due to their ability to up-regulate the phagocytosis of MS.

    Topics: Animals; Antitubercular Agents; Cell Line; Drug Delivery Systems; Fluorescent Dyes; Lactic Acid; Macrophages, Alveolar; Microspheres; Particle Size; Phagocytosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polystyrenes; Rats; Rifampin; Tuberculosis

2011
What is thwarting tuberculosis prevention in high-burden settings?
    The New England journal of medicine, 2011, Jul-07, Volume: 365, Issue:1

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Infant; Infant, Newborn; Isoniazid; Rifampin; Tuberculosis

2011
Global survey of national tuberculosis drug policies.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2011, Volume: 15, Issue:5

    National tuberculosis (TB) programmes (NTPs) in 100 countries.. To evaluate the relationship between the estimated prevalence of multidrug resistance in previously untreated TB cases and policies regarding sales and distribution of TB drugs, particularly rifampicin (RMP).. Questionnaire survey of national TB drug control policies, completed by NTP managers. Results were correlated with recent World Health Organization estimates of prevalence of drug resistance in new cases of TB.. Questionnaires were received from 100 countries, including 88 low- and middle-income countries (LMICs) and 17 of the 22 high-burden countries. Current policies were considered adequate in only 40 of the 88 LMICs (45%). A higher prevalence of multidrug resistance was associated with fewer years of free availability of TB drugs from the NTP (P = 0.02) and more years of availability of RMP from providers or pharmacies outside the NTP (P = 0.02). Eleven of the 20 countries with the highest prevalence of multidrug resistance had inadequate policies governing sales and distribution of TB drugs.. These findings suggest that policies regarding sales and distribution of TB drugs should receive more emphasis as part of the global strategy to control drug resistance.

    Topics: Antitubercular Agents; Commerce; Health Policy; Humans; National Health Programs; Prevalence; Rifampin; Surveys and Questionnaires; Tuberculosis; Tuberculosis, Multidrug-Resistant

2011
Pharmacokinetics of ethionamide in children.
    Antimicrobial agents and chemotherapy, 2011, Volume: 55, Issue:10

    Ethionamide (ETH), a second-line antituberculosis drug, is frequently used in treating childhood tuberculosis. Data supporting ETH dose recommendations in children are limited. The aim of this study was to determine the pharmacokinetic parameters for ETH in children on antituberculosis treatment including ETH. ETH serum levels were prospectively assessed in 31 children in 3 age groups (0 to 2 years, 2 to 6 years, and 6 to 12 years). Within each age group, half received rifampin (RMP). Following an oral dose of ETH (15 to 20 mg/kg of body weight), blood samples were collected at 0, 1, 2, 3, 4, and 6 h following 1 and 4 months of ETH therapy. The maximum serum concentration (C(max)), time to C(max) (T(max)), and area under the time-concentration curve from 0 to 6 h (AUC(0-6)) were calculated. Younger children were exposed to lower ETH concentrations than older children at the same mg/kg body weight dose. Age correlated significantly with the AUC after both 1 month (r = 0.50, P = 0.001) and 4 months (r = 0.63, P = 0.001) of therapy. There was no difference in the AUC or C(max) between children receiving concomitant treatment with RMP and those who did not. Time on treatment did not influence the pharmacokinetic parameters of ETH following 1 and 4 months of therapy. HIV infection was associated with lower ETH exposure. In conclusion, ETH at an oral dose of 15 to 20 mg/kg results in sufficient serum concentrations compared to current adult recommended levels in the majority of children across all age groups. ETH levels were influenced by young age and HIV status but were not affected by concomitant RMP treatment and duration of therapy.

    Topics: Anti-HIV Agents; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Ethionamide; Female; HIV Infections; Humans; Infant; Male; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2011
Primary nasal tuberculosis-a rare clinical entity.
    Ear, nose, & throat journal, 2011, Volume: 90, Issue:7

    Primary tuberculosis of the nose is very rare. We report a case of a 35-year-old woman who presented with bilateral nasal obstruction and epistaxis of 3 months' duration but who was otherwise healthy. She was diagnosed with primary nasal septal tuberculosis and was treated with antituberculosis DOTS (directly observed treatment, short course) therapy for 6 months with complete recovery. Given the resurgence of tuberculosis in recent times, it is important that clinicians remain aware of this rare and treatable clinical entity.

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Epistaxis; Female; Humans; Isoniazid; Nasal Obstruction; Pyrazinamide; Rhinitis; Rifampin; Sinusitis; Tuberculosis

2011
GeneXpert--a game-changer for tuberculosis control?
    PLoS medicine, 2011, Volume: 8, Issue:7

    Topics: Antibiotics, Antitubercular; Diagnostic Tests, Routine; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Point-of-Care Systems; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2011
[Anti-tuberculosis chemotherapy and management of adverse reactions].
    Nihon rinsho. Japanese journal of clinical medicine, 2011, Volume: 69, Issue:8

    Six-month regimen consisting of two-month initial intensive phase of isoniazid (INH), rifampicin (RFP), pyrazinamide (PZA) and ethambutol, (or streptomycin) and four-month maintenance phase of INH and RFP has been established as the global standard. Alternatively, 9-month regimen without PZA is acceptable for patients like elderly persons. Standard regimen is well tolerated in most patients. However some patients have adverse reactions. The frequent and serious reaction is hepatic toxicity caused by INH and PZA. Close monitoring of serum aminotransferase at every two weeks of initial treatment phase is recommended. Hypersensitivity to INH and RFP is common reaction seen in 4-5 percent of the general population. About 60-80% patients who had hypersensitivity can continue the standard regimen by desensitization therapy.

    Topics: Aged, 80 and over; Antitubercular Agents; Child; Drug Administration Schedule; Drug Hypersensitivity; Ethambutol; Female; Humans; Isoniazid; Liver; Pregnancy; Pyrazinamide; Rifampin; Tuberculosis

2011
Simultaneous determination of efavirenz, rifampicin and its metabolite desacetyl rifampicin levels in human plasma.
    Journal of pharmaceutical and biomedical analysis, 2011, Dec-05, Volume: 56, Issue:4

    A simple and rapid isocratic, high performance liquid chromatography (HPLC) assay employing solid phase extraction (SPE) for the simultaneous determination of the anti HIV drug, efavirenz, the anti-tuberculosis drug, rifampicin and the desacetyl metabolite of rifampicin in plasma from HIV/tuberculosis infected patients has been developed. Using a Zorbax SB-Phenyl reverse-phase analytical column with UV detection, good separation and detection of the drugs was attained within a 10min run time. Intra- and inter-assay precision RSD values were found to be less than 15% at the concentrations examined (0.1-20μg/mL). The LOQ was found to be 0.1μg/mL for each agent and the assay was found to generate a linear response up to 20μg/mL. This low cost assay can accurately detect efavirenz and rifampicin concentrations within a clinically relevant concentration range using standard chromatography equipment, making it particularly applicable to resource-limited settings.

    Topics: Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; Drug Monitoring; Drug Stability; HIV Infections; Humans; Reference Standards; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Tuberculosis

2011
Anti-tuberculosis drugs and human polymorphonuclear leukocyte functions.
    Chemotherapy, 2011, Volume: 57, Issue:4

    The polymorphonuclear leukocyte (PMN) is considered to be of importance in the early stages of human tuberculosis (TB). We examined the four drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) commonly used in the DOTS (directly observed treatment, short-course) strategy against TB for their effects on the functions of the human PMN, separately and combined.. PMNs were incubated with subtherapeutic, therapeutic and supratherapeutic concentrations of the drugs before being tested for phagocytosis and oxidative burst capacity with Staphylococcus aureus opsonized with pooled human serum as stimuli. Flow cytometric techniques were used to compare PMN phagocytosis and oxidative burst with and without incubation in different concentrations of the drugs.. None of the drugs influenced PMN phagocytosis as measured by flow cytometry. Oxidative burst was attenuated only with the highest (and supratherapeutic) concentrations of isoniazid and of the combined drugs as compared to lower concentrations.. This suggests that any deterioration in PMN function observed in TB is probably associated with the disease per se and not with the anti-TB treatment.

    Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethambutol; Flow Cytometry; Humans; Isoniazid; Neutrophils; Phagocytosis; Pyrazinamide; Respiratory Burst; Rifampin; Staphylococcus aureus; Tuberculosis

2011
Evaluation of the GeneXpert MTB/RIF assay for rapid diagnosis of tuberculosis and detection of rifampin resistance in pulmonary and extrapulmonary specimens.
    Journal of clinical microbiology, 2011, Volume: 49, Issue:12

    Mycobacterium tuberculosis remains one of the most significant causes of death from an infectious agent. The rapid diagnosis of tuberculosis and detection of rifampin (RIF) resistance are essential for early disease management. The GeneXpert MTB/RIF assay is a novel integrated diagnostic device for the diagnosis of tuberculosis and rapid detection of RIF resistance in clinical specimens. We determined the performance of the MTB/RIF assay for rapid diagnosis of tuberculosis and detection of rifampin resistance in smear-positive and smear-negative pulmonary and extrapulmonary specimens obtained from possible tuberculosis patients. Two hundred fifty-three pulmonary and 176 extrapulmonary specimens obtained from 429 patients were included in the study. One hundred ten (89 culture positive and 21 culture negative for M. tuberculosis) of the 429 patients were considered to have tuberculosis. In pulmonary specimens, sensitivities were 100% (27/27) and 68.6% (24/35) for smear-positive and smear-negative specimens, respectively. It had a lower sensitivity with extrapulmonary specimens: 100% for smear-positive specimens (4/4) and 47.7% for smear-negative specimens (21/44). The test accurately detected the absence of tuberculosis in all 319 patients without tuberculosis studied. The MTB/RIF assay also detected 1 RIF-resistant specimen and 88 RIF-susceptible specimens, and the results were confirmed by drug susceptibility testing. We concluded that the MTB/RIF test is a simple method, and routine staff with minimal training can use the system. The test appeared to be as sensitive as culture with smear-positive specimens but less sensitive with smear-negative pulmonary and extrapulmonary specimens that include low numbers of bacilli.

    Topics: Adult; Aged; Antitubercular Agents; Bacteriological Techniques; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2011
Plasma drug activity assay for treatment optimization in tuberculosis patients.
    Antimicrobial agents and chemotherapy, 2011, Volume: 55, Issue:12

    Low antituberculosis (TB) drug levels are common, but their clinical significance remains unclear, and methods of measurement are resource intensive. Subjects initiating treatment for sputum smear-positive pulmonary TB were enrolled from Kibong'oto National TB Hospital, Tanzania, and levels of isoniazid, rifampin, ethambutol, and pyrazinamide were measured at the time of typical peak plasma concentration (C(2 h)). To evaluate the significance of the effect of observed drug levels on Mycobacterium tuberculosis growth, a plasma TB drug activity (TDA) assay was developed using the Bactec MGIT system. Time to detection of plasma-cocultured M. tuberculosis versus time to detection of control growth was defined as a TDA ratio. TDA assays were later performed using the subject's own M. tuberculosis isolate and C(2 h) plasma from the Tanzanian cohort and compared to drug levels and clinical outcomes. Sixteen subjects with a mean age of 37.8 years ± 10.7 were enrolled. Fourteen (88%) had C(2 h) rifampin levels and 11 (69%) had isoniazid levels below 90% of the lower limit of the expected range. Plasma spiked with various concentrations of antituberculosis medications found TDA assay results to be unaffected by ethambutol or pyrazinamide. Yet with a range of isoniazid and rifampin concentrations, TDA exhibited a statistically significant correlation with drug level and drug MIC, and a TDA of ~1.0 indicated the presence of multidrug-resistant TB. In Tanzania, low (≤ 2.0) TDA was significantly associated with both lower isoniazid and rifampin C(2 h) levels, and very low (≤ 1.5) TDA corresponded to a trend toward lack of cure. Study of TDA compared to additional clinical outcomes and as a therapeutic management tool is warranted.

    Topics: Adult; Antitubercular Agents; Cohort Studies; Drug Monitoring; Humans; Isoniazid; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Tanzania; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2011
Xpert® MTB/RIF for national tuberculosis programmes in low-income countries: when, where and how?
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2011, Volume: 15, Issue:12

    Xpert ® MTB/RIF offers new and important possibilities for the diagnosis of sputum smear-negative tuberculosis (TB) and/or rifampicin (RMP) resistance, and many are encouraging rapid and widespread implementation. This simple test can be implemented almost everywhere, and it provides results within a few hours. In low-income countries (LICs), however, its cost, environmental limitations (stable and regular electricity, adequate room temperature) and difficulties involved in supply and maintenance are major obstacles. While it may be suitable for major reference hospitals, operational research is needed to evaluate the test and its additional yield above high-quality smear microscopy and clinical algorithms before its use at the peripheral level. In the meantime, direct microscopy should remain the initial diagnostic test for TB suspects. In most LICs, the prevalence of RMP resistance among new TB patients is very low; an Xpert MTB/RIF result indicating RMP resistance will thus always need confirmation by another test. In a population at high risk of RMP resistance (> 15%), however, the positive predictive value for RMP resistance by Xpert MTB/RIF is high, and identification of RMP resistance is an excellent proxy for multidrug-resistant TB (MDR-TB). The assay should be widely used for this purpose if, and only if, excellent MDR-TB management is available, both for ethical reasons and to reduce the risk of extensively drug-resistant TB.

    Topics: Algorithms; Antitubercular Agents; Developing Countries; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; National Health Programs; Nucleic Acid Amplification Techniques; Rifampin; Sputum; Tuberculosis

2011
Experience with rifabutin replacing rifampin in the treatment of tuberculosis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2011, Volume: 15, Issue:11

    The use of a rifamycin in anti-tuberculosis treatment regimens is crucial for shortening treatment and achieving favorable outcomes. Rifampin (RMP) is the recommended rifamycin, although adverse effects (AEs) may require its discontinuation. The use of rifabutin (RFB), a rifamycin with activity against Mycobacterium tuberculosis, in patients with an RMP-related AE has not been well studied.. To review our experience with RFB in tuberculosis (TB) treatment.. We included TB patients who received RFB in their treatment regimens from 2003 to 2009. We evaluated the indications for RFB and, if applicable, the likelihood that RMP caused an AE. We identified RMPrelated AEs associated with RFB intolerance.. One hundred subjects were included. The indications for RFB use were RMP-related AE (57%), con- current antiretroviral therapy (21%), potential/actual interaction with other medications (14%), and as part of an alternative regimen in liver disease (8%). Nineteen patients experienced an AE while taking RFB. Among patients with a prior RMP-related AE, 80% of whom were successfully treated with RFB, only a dermatologic AE was associated with subsequent RFB intolerance.. Our study suggests that RFB is well tolerated by patients who develop RMP-related AEs. There may be an increased risk for RFB-related AE in patients who experienced RMP-related dermatologic events.

    Topics: Adult; Aged; Antibiotics, Antitubercular; Chi-Square Distribution; Drug Substitution; Drug Therapy, Combination; Female; Humans; Logistic Models; Male; Middle Aged; Mycobacterium tuberculosis; Rifabutin; Rifampin; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Tuberculosis; Washington

2011
The ethics of national tuberculosis programmes in low-income countries not rolling out Xpert ® MTB/RIF.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2011, Volume: 15, Issue:12

    Topics: Antitubercular Agents; Humans; Nucleic Acid Amplification Techniques; Rifampin; Tuberculosis

2011
Practical preventive therapy for tuberculosis?
    The New England journal of medicine, 2011, Dec-08, Volume: 365, Issue:23

    Topics: Antitubercular Agents; Humans; Isoniazid; Male; Rifampin; Tuberculosis

2011
Pharmacogenetic & pharmacokinetic biomarker for efavirenz based ARV and rifampicin based anti-TB drug induced liver injury in TB-HIV infected patients.
    PloS one, 2011, Volume: 6, Issue:12

    Implication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients.. Newly diagnosed treatment naïve TB-HIV co-infected patients (n = 353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p = 0.001), higher plasma efavirenz level (p = 0.009), efavirenz/8-hydroxyefavirenz ratio (p = 0.036), baseline AST (p = 0.022), ALT (p = 0.014), lower hemoglobin (p = 0.008), and serum albumin (p = 0.007), NAT2 slow-acetylator genotype (p = 0.039) and ABCB1 3435TT genotype (p = 0.001).. We report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI.

    Topics: Adolescent; Adult; Aged; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Biomarkers, Tumor; Case-Control Studies; Comorbidity; Cyclopropanes; Female; Genotype; HIV Infections; Humans; Liver; Male; Middle Aged; Pharmacogenetics; Prospective Studies; Rifampin; Time Factors; Tuberculosis

2011
A case of isolated pancreatic tuberculosis mimicking pancreatic carcinoma.
    The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology, 2011, Volume: 22, Issue:5

    Topics: Aged; Antitubercular Agents; Biopsy, Fine-Needle; Diagnosis, Differential; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Pancreatic Diseases; Pancreatic Neoplasms; Pyrazinamide; Rifampin; Tomography, X-Ray Computed; Tuberculosis

2011
N-acetyltransferase 2 polymorphisms and risk of anti-tuberculosis drug-induced hepatotoxicity in Caucasians.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2011, Volume: 15, Issue:10

    To analyse slow-acetylation N-acetyltransferase 2 (NAT2) polymorphisms for their association with the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH).. A case-control study including Caucasian patients with tuberculosis (TB) treated with isoniazid, rifampicin and pyrazinamide. NAT2 genotype results were compared between ATDH cases and controls and with a healthy Spanish control population of Caucasian origin.. Fifty cases and 67 controls were included in the study. Slow, intermediate and rapid NAT2 genotypes were found in respectively 72%, 18% and 10% of cases compared with 65.7%, 25.4% and 9% of controls (P> 0.05). On comparing NAT2 genotypes among cases with those among healthy controls (n = 1312), we found more slow NAT2 genotypes and fewer intermediate genotypes among cases (respectively 72% and 18% in cases vs. 54.8% and 38.1% in controls; OR 2.07, 95%CI 1.12-2.79, P = 0.016 and OR 0.37, 95%CI 0.18-0.75, P = 0.003).. We could not demonstrate an increased risk of ATDH related to the presence of slow NAT2 polymorphisms among this Caucasian TB cohort. However, we found a significantly greater frequency of slow and a significantly lower frequency of intermediate NAT2 genotypes among the ATDH cases compared with the healthy control population.

    Topics: Adult; Antitubercular Agents; Arylamine N-Acetyltransferase; Case-Control Studies; Chemical and Drug Induced Liver Injury; Chi-Square Distribution; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Isoniazid; Logistic Models; Male; Middle Aged; Odds Ratio; Phenotype; Polymorphism, Genetic; Pyrazinamide; Rifampin; Risk Assessment; Risk Factors; Tuberculosis; White People

2011
[Study on the genotypes of 260 Mycobacterium tuberculosis isolates by Spoligotyping method in Jiangsu province, China].
    Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi, 2011, Volume: 32, Issue:12

    To study the genotypes of Mycobacterium tuberculosis (M. tuberculosis) strains isolated from Jiangsu province and to explore the relationship between the 'Beijing family' and the drug resistance of M. tuberculosis.. Two hundred and sixty M. tuberculosis strains were isolated from 30 drug surveillance sites in Jiangsu province. Susceptibility of the isolates to the first-line antituberculosis drugs (isoniazid, streptomycin, rifampicin and ethambutol) was tested by using the proportion method. Molecular typing of M. tuberculosis strains was determined by Spoligotyping and analyzed with BioNumerics software.. Based on Spoligotyping fingerprint, 260 strains showed 34 different genotypes, including 27 exclusive genotypes and 7 shared genotypes. These strains could be clustered into two groups: the Beijing family (80.4%, 209/260) and the Non-Beijing family (19.6%, 51/260). Data from logistic regression analysis revealed that infection by the Beijing family was related to an increased risk of multi-drug resistant M. tuberculosis, with the OR (95%CI) of 11.07 (1.45 - 84.50). Non-Beijing families including T1, T2, H3, H4, CAS, LAM, U and MANU2 families were also found. Among them, the CAS, LAM and MANU2 families were first reported in Jiangsu province.. It was revealed that the marked gene polymorphisms did exist in M. tuberculosis strains. The Beijing family had been the predominant strain circulating in Jiangsu province, which might be related to multi-drug resistant M. tuberculosis strains.

    Topics: Antitubercular Agents; Bacterial Typing Techniques; China; Drug Resistance, Bacterial; Genotype; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Polymorphism, Genetic; Rifampin; Tuberculosis

2011
The efficacy of the crude root bark extracts of Erythrina abyssinica on rifampicin resistant Mycobacterium tuberculosis.
    African health sciences, 2011, Volume: 11, Issue:4

    Tuberculosis (TB) is one of the leading causes of morbidity and mortality with a global mortality rate at two million deaths per year while one third of the world's population is infected with the TB bacillus.. To determine the efficacy of the crude extracts of Erythrina abyssinica root bark on rifampicin-resistant TB.. Crude extracts of root bark of Erythrina abyssinica, were screened against three strains of Mycobacterium tuberculosis including rifampicin-resistant TMC-331. Susceptibility tests used the disc diffusion method and were done on solid Middle brook 7H10, while the Minimum Inhibitory concentration (MICs) and minimum bactericidal concentration (MBCs) were determined by the Microtitre plate method using Middle brook 7H9 broth.. The total crude methanol extract showed activity against all the three strains of mycobacterium used, at 50mg/ml and diameters of zones of inhibition of up to 26 mm. Erythrina abyssinica total crude methanol extract showed the highest activity on the pan sensitive strain H37Rv (0.39±0.0 mg/ml) and the rifampicin resistant strain (TMC-331) (2.35±1.11 mg/ ml) and was also active on Mycobacterium avium (0.39±0.mg/ml. The values for isoniazid were 0.25µg/ml and 9.38µg/ml for H37Rv and TMC-331 respectively, while for rifampicin the MIC value was 0.25µg/ml for H37Rv but it was not active on TMC-331. Acute toxicity test gave an LD50 of 776.2mg/kg body weight while the phytochemical analysis showed the presence of alkaloids, tannins and flavones.. The conclusion from the study was that Erythrina abbyssinica has antimycobacterial activity and reasonable safety that merits further research.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Drug Resistance, Bacterial; Fabaceae; Humans; Mice; Microbial Sensitivity Tests; Mycobacterium avium; Mycobacterium tuberculosis; Phytotherapy; Plant Extracts; Plant Roots; Plants, Medicinal; Rifampin; Toxicity Tests, Acute; Tuberculosis

2011
Structure-activity relationship of new anti-tuberculosis agents derived from oxazoline and oxazole benzyl esters.
    European journal of medicinal chemistry, 2010, Volume: 45, Issue:5

    During the syntheses and studies of natural iron chelators (mycobactins), we serendipitously discovered that a simple, small molecule, oxazoline-containing intermediate 3 displayed surprising anti-tuberculosis activity (MIC of 7.7 microM, average). Herein we report elaboration of SAR around this hit as well as the syntheses and evaluation of a hundred oxazoline- and oxazole-containing compounds derived from an efficient three step process: 1) formation of beta-hydroxy amides with serine or threonine; 2) cyclization to afford oxazolines; and 3) dehydration to give the corresponding oxazoles. A number of compounds prepared by this method were shown to possess impressive activity against Mycobacterium tuberculosis, extremely low toxicity and therefore high therapeutic indexes, as well as activity against even the more recalcitrant non-replicating form of M. tuberculosis. The uniqueness of their structures and their simplicity should allow them to be further optimized to meet ADME (absorption, distribution, metabolism, excretion) requirements. The syntheses of eight of the most potent in vitro compounds were scaled up and the compounds were tested in an in vivo mouse infection model to evaluate their efficacy before engaging upon more elaborate compound design and optimization.

    Topics: Animals; Antitubercular Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Esters; Mice; Mice, Inbred BALB C; Molecular Conformation; Mycobacterium tuberculosis; Oxazoles; Stereoisomerism; Structure-Activity Relationship; Tuberculosis

2010
New 3-methylquinoxaline-2-carboxamide 1,4-di-N-oxide derivatives as anti-Mycobacterium tuberculosis agents.
    Bioorganic & medicinal chemistry, 2010, Apr-01, Volume: 18, Issue:7

    Mycobacterium tuberculosis (M.Tb) is a bacillus capable of causing a chronic and fatal condition in humans known as tuberculosis (TB). It is estimated that there are 8 million new cases of TB per year and 3.1 million infected people die annually. Thirty-six new amide quinoxaline 1,4-di-N-oxide derivatives have been synthesized and evaluated as potential anti-tubercular agents, obtaining biological values similar to the reference compound, Rifampin (RIF).

    Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Chromatography, Thin Layer; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Quinoxalines; Spectrophotometry, Infrared; Spectrophotometry, Ultraviolet; Structure-Activity Relationship; Tuberculosis; Vero Cells

2010
In vitro antituberculosis activities of ACH-702, a novel isothiazoloquinolone, against quinolone-susceptible and quinolone-resistant isolates.
    Antimicrobial agents and chemotherapy, 2010, Volume: 54, Issue:8

    ACH-702 is a new isothiazoloquinolone with potent in vitro and in vivo activities against important bacterial pathogens, including Staphylococcus aureus. In this study, ACH-702 was found to have promising in vitro antibacterial activity against Mycobacterium tuberculosis, with MICs of

    Topics: Antitubercular Agents; DNA Gyrase; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Quinolones; Thiazoles; Topoisomerase II Inhibitors; Tuberculosis

2010
Synthesis and antimycobacterial activity of new quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives.
    European journal of medicinal chemistry, 2010, Volume: 45, Issue:10

    As a continuation of our research and with the aim of obtaining new anti-tuberculosis agents which can improve the current chemotherapeutic anti-tuberculosis treatments, forty-three new quinoxaline-2-carboxamide 1,4-di-N-oxide derivatives were synthesized and evaluated for in vitro anti-tuberculosis activity against Mycobacterium tuberculosis strain H(37)Rv. Active compounds were also screened to assess toxicity to a VERO cell line. Results indicate that compounds with a methyl moiety substituted in position 3 and unsubstituted benzyl substituted on the carboxamide group provide an efficient approach for further development of anti-tuberculosis agents.

    Topics: Amides; Animals; Antitubercular Agents; Cell Survival; Chlorocebus aethiops; Humans; Mycobacterium tuberculosis; Oxides; Quinoxalines; Tuberculosis; Vero Cells

2010
Isoxazole analogs of curcuminoids with highly potent multidrug-resistant antimycobacterial activity.
    European journal of medicinal chemistry, 2010, Volume: 45, Issue:10

    Curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3), the curcuminoid constituents of the medicinal plant Curcuma longa L., have been structurally modified to 55 analogs and antimycobacterial activity against Mycobacterium tuberculosis has been evaluated. Among the highly active curcuminoids, the isoxazole analogs are the most active group, with mono-O-methylcurcumin isoxazole (53) being the most active compound (MIC 0.09 microg/mL). It was 1131-fold more active than curcumin (1), the parent compound, and was approximately 18 and 2-fold more active than the standard drugs kanamycin and isoniazid, respectively. Compound 53 also exhibited high activity against the multidrug-resistant M. tuberculosis clinical isolates, with the MICs of 0.195-3.125 microg/mL. The structural requirements for a curcuminoid analog to exhibit antimycobacterial activity are the presence of an isoxazole ring and two unsaturated bonds on the heptyl chain. The presence of a suitable para-alkoxyl group on the aromatic ring which is attached in close proximity to the nitrogen function of the isoxazole ring and a free para-hydroxyl group on another aromatic ring enhances the biological activity.

    Topics: Antitubercular Agents; Curcuma; Curcumin; Humans; Isoxazoles; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis

2010
Anti-tubercular agents. Part 5: synthesis and biological evaluation of benzothiadiazine 1,1-dioxide based congeners.
    European journal of medicinal chemistry, 2010, Volume: 45, Issue:10

    In an effort to discover new and effective chemotherapeutic agents from this laboratory for the treatment of tuberculosis, here in we describe the synthesis and biological evaluation of a series of novel benzothiadiazine 1,1-dioxide (BTD) based congeners by using rifampicin, streptomycin; ciprofloxacin and amphotericin as positive controls. Further, to understand structural requirements for exploring the structure activity relationship of BTDs, cytotoxicity and in vivo study of recently reported potent molecule 4 (MIC = 1 microg/mL) is also discussed.

    Topics: Animals; Antitubercular Agents; Bacteria; Benzothiadiazines; Cell Line; Cell Survival; Female; Fungi; Humans; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Tuberculosis

2010
Inhibition of mycobacterial replication by pyrimidines possessing various C-5 functionalities and related 2'-deoxynucleoside analogues using in vitro and in vivo models.
    Journal of medicinal chemistry, 2010, Aug-26, Volume: 53, Issue:16

    Tuberculosis (TB) has become an increasing problem since the emergence of human immunodeficiency virus and increasing appearance of drug-resistant strains. There is an urgent need to advance our knowledge and discover a new class of agents that are distinct than current therapies. Antimycobacterial activities of several 5-alkyl, 5-alkynyl, furanopyrimidines and related 2'-deoxynucleosides were investigated against Mycobacterium tuberculosis. Compounds with 5-arylalkynyl substituents (23-26, 33, 35) displayed potent in vitro antitubercular activity against Mycobacterium bovis and Mycobacterium tuberculosis. The in vivo activity of 5-(2-pyridylethynyl)-uracil (26) and its 2'-deoxycytidine analogue, 5-(2-pyridylethynyl)-2'-deoxycytidine (35), was assessed in BALB/c mice infected with M. tuberculosis (H37Ra). Both compounds 26 and 35 given at a dose of 50 mg/kg for 5 weeks showed promising in vivo efficacy in a mouse model, with the 2'-deoxycytidine derivative being more effective than the uracil analogue and a reference drug d-cycloserine. These data indicated that there is a significant potential in this class of compounds.

    Topics: Alkynes; Animals; Antitubercular Agents; Cell Line, Tumor; Deoxycytidine; Deoxyribonucleosides; Humans; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium bovis; Mycobacterium tuberculosis; Pyridines; Pyrimidines; Structure-Activity Relationship; Tuberculosis; Uracil

2010
A pyrosequencing method for molecular monitoring of regions in the inhA, ahpC and rpoB genes of Mycobacterium tuberculosis.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2010, Volume: 16, Issue:6

    In this study, a pyrosequencing method for monitoring two genes related to isoniazid (INH)-resistance and a region of the rpoB gene linked to rifampin (RMP)-resistance in Mycobacterium tuberculosis was developed and evaluated. Specifically, a 20-base pair (bp) region of inhA (from -24 to -4), a 35-bp region of ahpC (from -39 to -4), and a 57-bp region of rpoB (from codon 515 to 533) were analysed by pyrosequencing. For the development of the method, selected non-consecutive clinical isolates of M. tuberculosis were analysed, including: 25 isolates susceptible to both INH and RMP, 18 RMP-monoresistant isolates, 17 INH-monoresistant isolates, and 15 multidrug-resistant strains. Our pyrosequencing methodology was further evaluated using 96 M. tuberculosis isolates. Mutations in ahpC were found to be associated with INH resistance (p <0.05). By setting any mutation in ahpC as a marker of resistance, the specificity and the positive predictive value (PPV) were 100%. Similarly, any mutation in the rpoB gene was associated with a RMP resistance phenotype (p <0.01). Using any mutation in rpoB as a marker of RMP resistance, the sensitivity of this assay was 73% and the specificity and PPV were 100%. The use of this pyrosequencing method to analyse the ahpC and rpoB genes allowed us to detect INH- and/or RMP-resistant isolates. Furthermore, this method represents an opportunity to expedite the description of novel mutations related to drug resistance.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxidoreductases; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Tuberculosis

2010
Evaluation of direct method of drug susceptibility testing of Mycobacterium tuberculosis to rifampicin and isoniazid by nitrate reductase assay in a national reference laboratory.
    Diagnostic microbiology and infectious disease, 2010, Volume: 66, Issue:2

    The aim of this study was to evaluate a simple, rapid, and inexpensive colorimetric nitrate reductase assay (NRA) for direct drug susceptibility testing (DST) of Mycobacterium tuberculosis against rifampicin (RIF) and isoniazid (INH). A total of 118 smear-positive specimens were processed from patients on antituberculosis treatment. A comparison was made between the direct NRA of DST with the direct proportion method and with the internationally accepted indirect 1% proportion method as the "gold standard". The sensitivity and specificity of the direct NRA and indirect proportion method were 94% and 98%, and 100% and 98% for RIF and INH, respectively. Excellent agreement was found between the 2 tests with kappa values of 0.92 and 0.98, and P value was less than 0.001 for RIF and INH. The results in most cases were available in 14 days (turnaround time). The direct NRA is a rapid, accurate, simple, and inexpensive method to determine multidrug resistance from sputum. Direct NRA may become an appropriate alternative method, especially for the resource poor settings.

    Topics: Antitubercular Agents; Colorimetry; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitrate Reductase; Rifampin; Sensitivity and Specificity; Time Factors; Tuberculosis

2010
Rapid detection of Mycobacterium tuberculosis and rifampin resistance by use of on-demand, near-patient technology.
    Journal of clinical microbiology, 2010, Volume: 48, Issue:1

    Current nucleic acid amplification methods to detect Mycobacterium tuberculosis are complex, labor-intensive, and technically challenging. We developed and performed the first analysis of the Cepheid Gene Xpert System's MTB/RIF assay, an integrated hands-free sputum-processing and real-time PCR system with rapid on-demand, near-patient technology, to simultaneously detect M. tuberculosis and rifampin resistance. Analytic tests of M. tuberculosis DNA demonstrated a limit of detection (LOD) of 4.5 genomes per reaction. Studies using sputum spiked with known numbers of M. tuberculosis CFU predicted a clinical LOD of 131 CFU/ml. Killing studies showed that the assay's buffer decreased M. tuberculosis viability by at least 8 logs, substantially reducing biohazards. Tests of 23 different commonly occurring rifampin resistance mutations demonstrated that all 23 (100%) would be identified as rifampin resistant. An analysis of 20 nontuberculosis mycobacteria species confirmed high assay specificity. A small clinical validation study of 107 clinical sputum samples from suspected tuberculosis cases in Vietnam detected 29/29 (100%) smear-positive culture-positive cases and 33/39 (84.6%) or 38/53 (71.7%) smear-negative culture-positive cases, as determined by growth on solid medium or on both solid and liquid media, respectively. M. tuberculosis was not detected in 25/25 (100%) of the culture-negative samples. A study of 64 smear-positive culture-positive sputa from retreatment tuberculosis cases in Uganda detected 63/64 (98.4%) culture-positive cases and 9/9 (100%) cases of rifampin resistance. Rifampin resistance was excluded in 54/55 (98.2%) susceptible cases. Specificity rose to 100% after correcting for a conventional susceptibility test error. In conclusion, this highly sensitive and simple-to-use system can detect M. tuberculosis directly from sputum in less than 2 h.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Bacteriological Techniques; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Point-of-Care Systems; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Uganda; Vietnam; Young Adult

2010
Delivery of rifampicin-PLGA microspheres into alveolar macrophages is promising for treatment of tuberculosis.
    Journal of controlled release : official journal of the Controlled Release Society, 2010, Mar-19, Volume: 142, Issue:3

    Inhalation delivery of poly(lactic-co-glycolic) acid (PLGA) microspheres (MS) loaded with the anti-tuberculosis agent rifampicin (RFP-PLGA MS) to alveolar macrophage (M phi) cells could be an effective drug delivery system for the treatment of tuberculosis. To examine this possibility, we studied (1) the bactericidal effect of RFP-PLGA MS on Mycobacterium bovis Bacillus Calmette-Guérin (BCG)-infected rat alveolar M phi NR8383 cells, and (2) changes in the biochemical events induced in these cells by the uptake of RFP-PLGA MS. The amount of intracellular RFP imported into the M phi s by RFP-PLGA MS containing 0.25 and 2.50 microg RFP/mL was more than twice and ten times, respectively, than that attained with 5.00 microg/mL of RFP solution; and the MS exerted more potent bactericidal effect on BCG inside M phi cells than 5.00 microg RFP/mL solution after incubation for 7 days. RFP-PLGA MS little affected the viability of M phi cells, whereas the polystyrene latex (PSL) MS used as a reference decreased it significantly. RFP-PLGA MS did not stimulate the production of tumor necrosis factor-alpha (TNF-alpha), nitric oxide, interleukin-10 (IL-10), and transforming growth factor-beta1 (TGF-beta1) by the M phi cells, whereas PSL MS stimulated all of these mediators except IL-10. We conclude that RFP-PLGA MS are bio-safe microspheres due to their "silent" nature when taken into M phi cells and that they are promising for the treatment of tuberculosis by pulmonary inhalation.

    Topics: Animals; Antibiotics, Antitubercular; Cell Line; Cell Survival; Drug Carriers; Interleukin-10; Lactic Acid; Macrophages, Alveolar; Microspheres; Mycobacterium bovis; Nitric Oxide; Phagocytosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Rifampin; Tissue Distribution; Tuberculosis; Tumor Necrosis Factor-alpha

2010
Rifampicin determination in plasma by stir bar-sorptive extraction and liquid chromatography.
    Journal of pharmaceutical and biomedical analysis, 2010, Apr-06, Volume: 51, Issue:5

    A sensitive and reproducible stir bar-sorptive extraction and high performance liquid chromatography-UV detection (SBSE/HPLC-UV) method for therapeutic drug monitoring of rifampicin in plasma samples is described and compared with a liquid:liquid extraction (LLE/HPLC-UV) method. This miniaturized method can result in faster analysis, higher sample throughput, lower solvent consumption and less workload per sample while maintaining or even improving sensitivity. Important factors in the optimization of SBSE efficiency such as pH, temperature, extraction time and desorption conditions (solvents, mode magnetic stir, mode ultrasonic stir, time and number of steps) were optimized recoveries ranging from 75 to 80%. Separation was obtained using a reverse phase C(8) column with UV detection (254nm). The mobile phase consisted of methanol:0.25N sodium acetate buffer, pH 5.0 (58:42, v/v). The SBSE/HPLC-UV method was linear over a working range of 0.125-50.0microgmL(-1). The intra-assay and inter-assay precision and accuracy were studied at three concentrations (1.25, 6.25 and 25.0microgmL(-1)). The intra-assay coefficients of variation (CVs) for all compounds were less than 10% and all inter-CVs were less than 10%. Limits of quantification were 0.125microgmL(-1). Stability studies showed rifampicin was stable in plasma for 12h after thawing; the samples were also stable for 24h after preparation. Based on the figures of merit results, the SBSE/HPLC-UV proved to be adequate to the rifampicin analyses from therapeutic to toxic levels. This method was successfully applied to the analysis of real samples and was as effective as the LLE/HPLC-UV method.

    Topics: Antibiotics, Antitubercular; Chemical Fractionation; Chromatography, High Pressure Liquid; Drug Monitoring; Drug Stability; Humans; Hydrogen-Ion Concentration; Miniaturization; Predictive Value of Tests; Reproducibility of Results; Rifampin; Spectrophotometry, Ultraviolet; Temperature; Time Factors; Tuberculosis

2010
Pharmacokinetics of double-dose raltegravir in two patients with HIV infection and tuberculosis.
    AIDS (London, England), 2010, Jan-16, Volume: 24, Issue:2

    Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antibiotics, Antitubercular; HIV-2; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Rifampin; Tuberculosis

2010
The three RelE homologs of Mycobacterium tuberculosis have individual, drug-specific effects on bacterial antibiotic tolerance.
    Journal of bacteriology, 2010, Volume: 192, Issue:5

    In Escherichia coli, expression of the RelE and HipA toxins in the absence of their cognate antitoxins has been associated with generating multidrug-tolerant "persisters." Here we show that unlike persisters of E. coli, persisters of Mycobacterium tuberculosis selected with one drug do not acquire cross-resistance to other classes of drugs. M. tuberculosis has three homologs of RelE arranged in operons with their apparent antitoxins. Each toxin individually arrests growth of both M. tuberculosis and E. coli, an effect that is neutralized by coexpression of the cognate antitoxin. Overexpression or deletion of each of the RelE toxins had a toxin- and drug-specific effect on the proportion of bacilli surviving antibiotic killing. All three toxins were upregulated in vivo, but none of the deletions affected survival during murine infection. RelE2 overexpression increased bacterial survival rates in the presence of rifampin in vitro, while deletion significantly decreased survival rates. Strikingly, deletion of this toxin had no discernible effect on the level of persisters seen in rifampin-treated mice. Our results suggest that, in vivo, RelE-generated persisters are unlikely to play a significant role in the generation of bacilli that survive in the face of multidrug therapy or in the generation of multidrug-resistant M. tuberculosis.

    Topics: Animals; Anti-Bacterial Agents; Bacterial Proteins; Bacterial Toxins; Colony Count, Microbial; Disease Models, Animal; Drug Resistance, Bacterial; Gene Deletion; Gene Expression; Humans; Mice; Mice, Inbred C57BL; Microbial Viability; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2010
Outcomes and safety of concomitant nevirapine and rifampicin treatment under programme conditions in Malawi.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010, Volume: 14, Issue:2

    Thyolo District Hospital, rural Malawi.. To report on 1) clinical, immunological and virological outcomes and 2) safety among human immunodeficiency virus (HIV) infected patients with tuberculosis (TB) who received concurrent nevirapine (NVP) and rifampicin (RMP) based treatment.. Retrospective cohort study.. Analysis of programme data, June-December 2007.. Of a total of 156 HIV-infected TB patients who started NVP-based antiretroviral treatment, 136 (87%) completed TB treatment successfully, 16 (10%) died and 5 (4%) were transferred out. Mean body weight and CD4 gain (adults) were respectively 4.4 kg (95%CI 3.3-5.4) and 140 cells/mm(3) (95%CI 117-162). Seventy-four per cent of patients who completed TB treatment and had a viral load performed (n = 74) had undetectable levels (<50 copies/ml), while 17 (22%) had a viral load of 50-1000 copies/ml. Hepatotoxicity was present in 2 (1.3%) patients at baseline. Two patients developed Grade 2 and one developed Grade 3 alanine transaminase enzyme elevations during TB treatment (incidence rate per 10 years of follow-up 4.2, 95%CI 1.4-13.1). There were no reported deaths linked to hepatotoxicity.. In a rural district in Malawi, concomitant NVP and RMP treatment is associated with good TB treatment outcomes and appears safe. Further follow-up of patients would be useful to ascertain the longer-term effects of this concurrent treatment.

    Topics: Adolescent; Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Cohort Studies; Female; Follow-Up Studies; HIV Infections; Humans; Malawi; Male; Nevirapine; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis; Viral Load; Young Adult

2010
In vitro synergistic interactions of oleanolic acid in combination with isoniazid, rifampicin or ethambutol against Mycobacterium tuberculosis.
    Journal of medical microbiology, 2010, Volume: 59, Issue:Pt 5

    Reports have shown that oleanolic acid (OA), a triterpenoid, exists widely in food, medicinal herbs and other plants, and that it has antimycobacterial activity against the Mycobacterium tuberculosis strain H37Rv (ATCC 27294). In this study it was found that OA had antimycobacterial properties against eight clinical isolates of M. tuberculosis and that the MICs of OA against drug-sensitive and drug-resistant isolates were 50-100 and 100-200 microg ml(-1), respectively. The combination of OA with isoniazid (INH), rifampicin (RMP) or ethambutol (EMB) showed favourable synergistic antimycobacterial effects against six drug-resistant strains, with fractional inhibitory concentration indices of 0.121-0.347, 0.113-0.168 and 0.093-0.266, respectively. The combination treatments of OA/INH, OA/RMP and OA/EMB displayed either a synergistic interaction or did not show any interaction against two drug-sensitive strains. No antagonism resulting from the OA/INH, OA/RMP or OA/EMB combination was observed for any of the strains tested. OA exhibited a relatively low cytotoxicity in Vero cells. These results indicate that OA may serve as a promising lead compound for future antimycobacterial drug development.

    Topics: Antitubercular Agents; Drug Synergism; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oleanolic Acid; Rifampin; Tuberculosis

2010
New susceptibility breakpoints for first-line antituberculosis drugs based on antimicrobial pharmacokinetic/pharmacodynamic science and population pharmacokinetic variability.
    Antimicrobial agents and chemotherapy, 2010, Volume: 54, Issue:4

    Arguably, one of the most common and consequential laboratory tests performed in the world is Mycobacterium tuberculosis susceptibility testing. M. tuberculosis resistance is defined by growth of > or =1% of a bacillary inoculum on the critical concentration of an antibiotic. The critical concentration was chosen based on inhibition of > or =95% of wild-type isolates. The critical concentration of isoniazid is either 0.2 or 1.0 mg/liter, that of rifampin is 1.0 mg/liter, that of pyrazinamide is 100 mg/liter, that of ethambutol is 5.0 mg/liter, and that of fluoroquinolones is 1.0 mg/liter. However, the relevance of these concentrations to microbiologic and clinical outcomes is unclear. Critical concentrations were identified using the ability to achieve the antibiotic area under the concentration-time curve/MIC ratio associated with > or =90% of maximal kill (EC(90)) of M. tuberculosis in > or =90% of patients. Population pharmacokinetic parameters and their variability encountered in tuberculosis patients were utilized in Monte Carlo simulations to determine the probability that particular daily doses of the drugs would achieve or exceed the EC(90) in the epithelial lining fluid of 10,000 tuberculosis patients. Failure to achieve EC(90) in > or =90% of patients at a particular MIC was defined as drug resistance. The critical concentrations of moxifloxacin and ethambutol remained unchanged, but a critical concentration of 50 mg/liter was identified for pyrazinamide, 0.0312 mg/liter and 0.125 mg/liter were defined for low- and high-level isoniazid resistance, respectively, and 0.0625 mg/liter was defined for rifampin. Thus, current critical concentrations of first-line antituberculosis drugs are overoptimistic and should be set lower. With the proposed breakpoints, the rates of multidrug-resistant tuberculosis could become 4-fold higher than currently assumed.

    Topics: Antitubercular Agents; Aza Compounds; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Ethambutol; Fluoroquinolones; Humans; In Vitro Techniques; Isoniazid; Microbial Sensitivity Tests; Models, Biological; Monte Carlo Method; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2010
Combined real-time PCR and rpoB gene pyrosequencing for rapid identification of Mycobacterium tuberculosis and determination of rifampin resistance directly in clinical specimens.
    Journal of clinical microbiology, 2010, Volume: 48, Issue:4

    Our laboratory has developed a rapid, sensitive, and specific molecular approach for detection in clinical specimens, within 48 h of receipt, of both Mycobacterium tuberculosis complex (MTBC) DNA and mutations within the 81-bp core region of the rpoB gene that are associated with rifampin (RIF) resistance. This approach, which combines an initial real-time PCR with internal inhibition assessment and a pyrosequencing assay, was validated for direct use with clinical specimens. To assess the suitability of real-time PCR for use with respiratory, nonrespiratory, acid-fast bacillus (AFB)-positive and AFB-negative specimens, we evaluated specimens received in our laboratory between 11 October 2007 and 30 June 2009. With culture used as the "gold standard," the sensitivity, specificity, and positive and negative predictive values were determined for 1,316 specimens to be as follows: for respiratory specimens, 94.7%, 99.9%, 99.6%, and 98.6%, respectively; for nonrespiratory specimens, 88.5%, 100.0%, 100.0%, and 96.9%, respectively; for AFB-positive specimens, 99.6%, 100.0%, 100.0%, and 97.7%, respectively; and for AFB-negative specimens, 75.4%, 99.9%, 98.0%, and 98.4%, respectively. PCR inhibition was determined to be minimal in this assay, occurring in 0.2% of tests. The rpoB gene pyrosequencing assay was evaluated in a similar prospective study, in which 148 clinical specimens positive for MTBC DNA by real-time PCR were tested. The final results revealed that the results of direct testing of clinical specimens by the pyrosequencing assay were 98.6% concordant with the results of conventional testing for susceptibility to RIF in liquid culture and that our assay displayed adequate sensitivity for 96.6% of the clinical specimens tested. Used together, these assays provide reliable results that aid with the initial management of patients with suspected tuberculosis prior to the availability of the results for cultured material, and they also provide the ability to predict RIF resistance in Mycobacterium tuberculosis-positive specimens in as little as 48 h from the time of clinical specimen receipt.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Tuberculosis

2010
Comparison of the 'Denver regimen' against acute tuberculosis in the mouse and guinea pig.
    The Journal of antimicrobial chemotherapy, 2010, Volume: 65, Issue:4

    In this study, we sought to compare the sterilizing activity of human-equivalent doses of the 'Denver regimen' against acute tuberculosis (TB) infection in the standard mouse model and in the guinea pig.. Pharmacokinetic studies in guinea pigs were used to establish human-equivalent doses for rifampicin, isoniazid and pyrazinamide. Guinea pigs and mice were aerosol-infected with Mycobacterium tuberculosis CDC1551 and treatment was started 2 weeks later with rifampicin/isoniazid/pyrazinamide for up to 6 months. For the first 2 weeks of therapy, the dosing frequency was 5 days/week, and for the remaining period, twice weekly. Treatment was discontinued in groups of 30 mice and 10 guinea pigs at 5 months and at 6 months, and these animals were held for a further 3 months in order to assess relapse rates.. Guinea pig lungs became culture-negative after 3 months of predominantly twice-weekly treatment and relapse rates were 0% (0/10) both after 5 months and after 6 months of treatment. In contrast, all mice remained culture-positive despite 6 months of the same treatment, and 93% (28/30) and 69% (20/29) of mice relapsed after treatment for 5 and 6 months, respectively.. Treatment with rifampicin/isoniazid/pyrazinamide administered at human-equivalent doses is much more potent against acute TB infection in guinea pigs than in mice. Our findings have important implications for the use of alternative animal models in testing novel TB drug regimens and for modelling M. tuberculosis persistence.

    Topics: Animals; Antitubercular Agents; Disease Models, Animal; Female; Guinea Pigs; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2010
Effector memory T-cells dominate immune responses in tuberculosis treatment: antigen or bacteria persistence?
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010, Volume: 14, Issue:3

    To compare ex vivo immunological responses upon stimulation of lymphocytes with Mycobacterium tuberculosis-specific antigens in three groups: 1) subjects diagnosed with tuberculosis (TB) in the early 1940s and 1950s but who did not receive anti-tuberculosis chemotherapy (n = 5), 2) subjects treated with anti-tuberculosis agents prior to the rifampicin (RMP) era (n = 26) and 3) subjects who received RMP as a part of modern combination therapy (n = 7).. A total of 38 healthy subjects, mean age 70 +/- 13 years, with a history of previously treated TB were recruited. Peripheral blood mononuclear cells were collected and analysed as a batch by ELISpot. Representative samples with high reactivities were further immunophenotypically characterised.. No differences between the studied groups were detected with regard to the frequencies of reactive lymphocytes. The dominant immunophenotypic profile of the representative responders, irrespective of the treatment schemes, was CD4+CD45RO+CD45RA-CD27-CD28-CCR7-, compatible with the fast reacting effector memory T-cell lineage (T(EM)).. Specific T(EM) cells persist even in subjects treated for TB decades ago with modern anti-tuberculosis chemotherapy. Additional studies are needed to address the question of what drives the survival of T(EM) after adequate treatment: persistence of antigens or bacteria.

    Topics: Aged; Aged, 80 and over; Antigens, Bacterial; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; T-Lymphocytes; Time Factors; Tuberculosis

2010
Drug-susceptibility patterns of Mycobacterium tuberculosis in Mpumalanga province, South Africa: possible guiding design of retreatment regimen.
    Journal of health, population, and nutrition, 2010, Volume: 28, Issue:1

    Multidrug-resistant tuberculosis (MDR-TB) has been a cause of concern in both developed and developing countries. The prevalence of drug resistance in Mycobacterium tuberculosis (MTB) isolates (n=692) from Mpumalanga province was assessed. In total, 692 (64%) MTB strains from cases with pulmonary TB were tested for susceptibility against rifampicin, isoniazid, ethambutol, and streptomycin using the MGIT 960 instrument. Two hundred and nine (30.2%) strains were resistant to one or more drugs. Resistance to one drug ranged from 1.4% for ethambutol to 17.7% for rifampicin. The prevalence of MDR-TB ranged from 6.7% for three drugs to 34% for four drugs, with significant predictors being patients' age-groups of 25-54 years (p=0.0012) and >55 years (p=0.007). The result showed a high level (58.4%) of MDR-TB from cases in Mpumalanga province. To achieve a higher cure rate in this province, drug-susceptibility tests must be done for every case.

    Topics: Adolescent; Adult; Age Distribution; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Prevalence; Retreatment; Rifampin; Risk Factors; South Africa; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2010
A trial involving HIV-tuberculosis in India: the minute particulars.
    American journal of respiratory and critical care medicine, 2010, Apr-01, Volume: 181, Issue:7

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Clinical Trials as Topic; Drug Resistance, Bacterial; HIV Infections; Humans; India; Rifampin; Tuberculosis

2010
Therapeutic potential of peptide deformylase inhibitors against experimental tuberculosis.
    The Journal of infection, 2010, Volume: 60, Issue:6

    Topics: Amidohydrolases; Analysis of Variance; Animals; Antitubercular Agents; Colony Count, Microbial; Disease Models, Animal; Enzyme Inhibitors; Hydroxamic Acids; Isoniazid; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2010
Isoniazid-resistant tuberculosis in Denmark: mutations, transmission and treatment outcome.
    The Journal of infection, 2010, Volume: 60, Issue:6

    A retrospective study on isoniazid-resistant tuberculosis (TB) was conducted in the low-burden country, Denmark (DK). The aim was to describe treatment outcome and transmission and to evaluate a mutation analysis for high- and low-level isoniazid resistance detection.. In the period 2002-2007, all isoniazid-resistant TB-cases were included. Molecular genotyping was performed by standardized IS6110 restriction fragment length polymorphism (RFLP). Identical isoniazid-resistant genotypes, indicating ongoing transmission, were identified from the national RFLP database. An analysis of rifampin (rpoB) and high- or low-level (katG, inhA) isoniazid resistance mutations was performed on subcultured strains.. There were 1825 culture-confirmed cases, of which 111 (6.1%) had monoresistance or polyresistance to isoniazid. Successful short- and long-term treatment outcome was achieved in 80% and 95%, respectively. Overall, the mutation analysis predicted 94% of isoniazid resistance in 111 strains. The katG S315T1 and inhA C15T1 mutations correctly identified high- and low-level isoniazid resistance in 84% and 84% of the strains, respectively.. Isoniazid-resistant TB has a good prognosis in DK. High- and low- level isoniazid resistance does not affect treatment outcome of standard modified treatment. Rapid mutation detection identified the majority of isoniazid-resistant cases however the impact on treatment outcome remains to be determined.

    Topics: Adult; Antibiotics, Antitubercular; Denmark; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Mutation; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis

2010
rpoB gene mutation profile in rifampicin-resistant Mycobacterium tuberculosis clinical isolates from Guizhou, one of the highest incidence rate regions in China.
    The Journal of antimicrobial chemotherapy, 2010, Volume: 65, Issue:6

    Topics: Antitubercular Agents; Bacterial Proteins; China; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Gene Frequency; Humans; Incidence; Molecular Sequence Data; Mutation, Missense; Mycobacterium tuberculosis; Polymorphism, Genetic; Rifampin; Sequence Analysis, DNA; Tuberculosis

2010
PhoY2 but not PhoY1 is the PhoU homologue involved in persisters in Mycobacterium tuberculosis.
    The Journal of antimicrobial chemotherapy, 2010, Volume: 65, Issue:6

    Mycobacterial persistence is thought to be the underlying cause of the current lengthy tuberculosis therapy and latent infection. Despite some recent progress, the mechanisms of bacterial persistence are poorly understood. We have recently identified a new persister gene phoU from Escherichia coli and have shown that the phoU mutant has a defect in persisters. The objective of this study is to evaluate the role of two phoU homologues phoY1 and phoY2 from Mycobacterium tuberculosis in mycobacterial persistence.. M. tuberculosis phoY1 and phoY2 mutant strains were constructed. The persister-related phenotypes of the phoY1 and phoY2 mutants were assessed in vitro by MIC testing, drug exposure assays and also by survival in the mouse model of tuberculosis infection.. We demonstrated that M. tuberculosis PhoY2 is the equivalent of E. coli PhoU in that inactivation of phoY2 but not phoY1 caused a defect in persistence phenotype as shown by increased susceptibility to rifampicin and pyrazinamide in both MIC testing and drug exposure assays and also reduced persistence in the mouse model.. This study provides further validation that PhoU is involved in persistence not only in E. coli but also in M. tuberculosis and has implications for the development of new drugs targeting persisters for improved treatment.

    Topics: Animals; Antitubercular Agents; Bacterial Proteins; Colony Count, Microbial; Disease Models, Animal; Escherichia coli Proteins; Female; Gene Knockout Techniques; Lung; Membrane Transport Proteins; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Microbial Viability; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Spleen; Transcription Factors; Tuberculosis; Virulence Factors

2010
Anti-tuberculosis activity and drug interaction with nevirapine of inhalable lipid microspheres containing rifampicin in murine model.
    Journal of microencapsulation, 2010, Volume: 27, Issue:4

    Intranasal administration of lipid microspheres (LM) containing rifampicin (LM-RFP) exhibited the bacteriostatic effect against Mycobacterium tuberculosis H37Rv. The efficacies of intranasal LM-RFP in lung were markedly higher in immunodeficient BALB/c nude mice (p < 0.001), but not different in immunocompetent BALB/c mice (p = 1.000) compared to the results of oral rifampicin groups. When intranasal LM-RFP was given instead of oral rifampicin, the reductions of C(max) and AUC(0-3) of nevirapine were decreased from 32.2% to 11.9% and 30.5% to 12.4%, respectively. These results suggested that intranasal LM-RFP could improve the anti-tuberculosis activity in immunodeficient host and minimize drug interaction between rifampicin and nevirapine.

    Topics: Administration, Intranasal; Animals; Antibiotics, Antitubercular; Drug Interactions; Female; Lipids; Mice; Mice, Inbred BALB C; Mice, Nude; Microspheres; Models, Animal; Nevirapine; Reference Standards; Rifampin; Tuberculosis

2010
[Resistance rates to major anti-tuberculosis drugs in Mycobacterium tuberculosis strains isolated from seven different regions of Turkey in 2003-2006 period].
    Mikrobiyoloji bulteni, 2010, Volume: 44, Issue:1

    Multi-drug resistance in Mycobacterium tuberculosis (MDR-TB) is a global problem and has increased especially in areas where tuberculosis control programmes are inefficient. The aim of this study was to detect the resistance rates against isoniazide (INH), rifampisin (RMP), ethambutol (EMB) and streptomycin (SM) in M. tuberculosis strains collected from 7 different regions including 62 cities and sent to Refik Saydam Hygiene Center National Tuberculosis Reference and Research Laboratory. Of the patients included, 7.61% were children, 92.39% were adults; 76.16% were male and 23.84% were female. These strains were isolated from sputum (n = 885, 81.11%), gastric lavage (n = 49, 4.49%), pleural fluid (n = 43, 3.94%), urine (n = 30, 2.74%), bronchoalveolar lavage (n = 22, 2.01%), and other clinical samples (n = 62, 8.46%) such as cerebrospinal fluid, lymph node, abscess material, lung tissue. The susceptibilities of the 1091 M. tuberculosis strains against the major anti-tuberculosis drugs were determined by the proportion method in Lowenstein-Jensen medium. Three hundred ninety two of the isolates were from Central Anatolia, 146 from Black Sea, 419 from Aegean, 28 from Mediterranean, 20 from Marmara, 64 from Eastern Anatolia and 21 from South Eastern Anatolia regions of Turkey. The distribution of the strains according to years were as follows: 88 in 2003, 114 in 2004, 341 in 2005 and 548 in 2006. Resistance to at least one of the drugs tested was found in 264 (14.20%) strains. Overall drug resistance rates to INH, RMP, EMB and SM were 12.3%, 10.1%, 6% and 15.8%, respectively. MDR-TB rate was 10% for this 4 years study period. MDR-TB rate was detected as 13.2%, 9.7%, 10.1% and 9.6% in children, adult, male and female patients, respectively. MDR-TB rate did not exhibit a statistically significant difference in terms of sex, age and study years (p > 0.05). However, this rate showed statistically significant difference in terms of geographical regions (p < 0.05). This study emphasized that regular surveillance of M. tuberculosis resistance to the major anti-tuberculosis drugs will provide valuable data for the effective national control and treatment of tuberculosis.

    Topics: Adult; Antitubercular Agents; Child; Drug Resistance, Multiple, Bacterial; Ethambutol; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis; Turkey

2010
Detection of rpoB, katG and inhA gene mutations in Mycobacterium tuberculosis clinical isolates from Chongqing as determined by microarray.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2010, Volume: 16, Issue:11

    The emergence of multidrug-resistance Mycobacterium tuberculosis is an increasing threat to tuberculosis control programmes. Susceptibility testing of Mycobacterium tuberculosis complex isolates by traditional methods requires a minimum of 14 days. This can be reduced significantly if molecular analysis is used. DNA sequencing is a good method for detecting mutation, but cannot be used routinely because of its relatively high cost. A sensitive and specific microarray has been designed to detect mutations in the rifampin resistance determining region of rpoB and loci in katG and inhA associated with isoniazid (INH) resistance. A panel of Mycobacterium tuberculosis isolates containing 13 different rpoB genotypes, two mutation genotypes within codon 315 of katG and one mutation genotypes at inhA was used to validate the microarray. The results obtained indicate that 100% of rifampicin-resistant M. tuberculosis strains isolated in Chongqing had rpoB mutations, with 531-Ser and 526-His being the most common positions substituted. Of the total 50 INH resistant isolates, 82% had a katG315 mutation and 18% had an inhA mutation. All the mutations detected by the microarray method were also confirmed by conventional DNA sequencing. It is demonstrated that the microarray is an efficient, specialized technique and can be used as a rapid method for detecting rifampin and isoniazid resistance.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Bacterial Proteins; Catalase; China; DNA Mutational Analysis; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Oligonucleotide Array Sequence Analysis; Oxidoreductases; Polymerase Chain Reaction; Rifampin; Sequence Analysis, DNA; Tuberculosis; Tuberculosis, Multidrug-Resistant

2010
Effectiveness of 3 months of rifampicin and isoniazid chemoprophylaxis for the treatment of latent tuberculosis infection in children.
    Archives of disease in childhood, 2010, Volume: 95, Issue:8

    BACKGROUND/SETTING: Treatment for 3 months with rifampicin (R) and isoniazid (H) (3RH) for latent tuberculosis infection (LTBI), defined as an inappropriately positive tuberculin skin test with no clinical or x-ray evidence of disease, has been used locally since 1989. The efficacy of this regimen in children in the UK has only been studied indirectly. The long-term outcome of those children treated with 3RH, in the Chest Clinic of this high tuberculosis (TB) incidence district, has been studied to derive a more direct assessment of effectiveness.. All children treated with 3RH for LTBI from 1989 to 2004 inclusive were matched with the local patient administration system (PAS), GP registration and local TB notification databases. Only those persons still registered locally on PAS, or locally GP registered were then checked for subsequent TB notification.. A total of 334 patients were identified, of whom 252 remained locally, with 82 lost to follow-up; 3 cases of clinical TB developed in the 252 (1.19%), with 3113 years observation (mean 12.35 years) giving 0.964/1000 person years (95% CI 0.199 to 2.816). Sensitivity analyses showed a 'best case' scenario of 0.727/1000 person years (95% CI 0.15 to 2.12), and if 10% of those lost to follow-up developed clinical TB of 2.66/1000 person years (95% CI 1.33 to 4.77).. Follow-up of those cases treated with 3RH, for a mean of 12.35 years, and over 3100 patient years observation, shows a rate of active TB of under 1/1000 patient years. This suggests that 3RH has very high efficacy when used to treat LTBI in children in the UK and compares favourably with the expected untreated TB rate.

    Topics: Adolescent; Antitubercular Agents; Child; Drug Administration Schedule; Drug Therapy, Combination; England; Follow-Up Studies; Humans; Infant; Isoniazid; Latent Tuberculosis; Rifampin; Treatment Outcome; Tuberculosis

2010
Unequal distribution of resistance-conferring mutations among Mycobacterium tuberculosis and Mycobacterium africanum strains from Ghana.
    International journal of medical microbiology : IJMM, 2010, Volume: 300, Issue:7

    Isoniazid (INH) and rifampicin (RMP) resistance in Mycobacterium tuberculosis complex (MTC) isolates are mainly based on mutations in a limited number of genes. However, mutation frequencies vary in different mycobacterial populations. In this work, we analyzed the distribution of resistance-associated mutations in M. tuberculosis and M. africanum strains from Ghana, West Africa. The distribution of mutations in katG, fabG1-inhA, ahpC, and rpoB was determined by DNA sequencing in 217 INH-resistant (INH(r)) and 45 multidrug-resistant (MDR) MTC strains isolated in Ghana from 2001 to 2004. A total of 247 out of 262 strains investigated (94.3%) carried a mutation in katG (72.5%), fabG1-inhA (25.1%), or ahpC (6.5%), respectively. M. tuberculosis strains mainly had katG 315 mutations (80.1%), whereas this proportion was significantly lower in M. africanum West-African 1 (WA1) strains (43.1%; p<0.05). In contrast, WA1 strains showed more mutations in the fabG1-inhA region (39.2%, p<0.05) compared to M. tuberculosis strains (20.9%). In 44 of 45 MDR strains (97.8%) mutations in the 81-bp core region of the rpoB gene could be verified. Additionally, DNA sequencing revealed that 5 RMP-susceptible strains also showed mutations in the rpoB hotspot region. In conclusion, although principally the same genes were affected in INH(r)M. tuberculosis and M. africanum strains, disequilibrium in the distribution of mutations conferring resistance was verified that might influence the efficiency of molecular tests for determination of resistance.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA, Bacterial; Drug Resistance, Bacterial; Ghana; Humans; Isoniazid; Mutation; Mycobacterium; Rifampin; Sequence Analysis, DNA; Tuberculosis

2010
Previous treatment in predicting drug-resistant tuberculosis in an area bordering East London, UK.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2010, Volume: 14, Issue:8

    To determine the utility of 'risk assessment' in selecting Mycobacterium tuberculosis isolates for rifampin resistance or rpoB genotyping compared to 'non-selectively' genotyping all isolates. Secondly, we examined the association between past treatment and drug resistance.. From January 2003 to December 2006, demographic, clinical, and laboratory data were prospectively collected on patients with laboratory-confirmed tuberculosis (TB). On the basis of past treatment for active TB infection or known exposure to drug-resistant TB, selected samples were sent to a mycobacterial reference laboratory for rpoB genotyping. A multivariable logistic regression model was developed to examine the association between past treatment and drug resistance, adjusted for other factors. Sensitivity, specificity, and negative and positive predictive values of past treatment as a predictor for drug resistance were determined.. There were 392 patient episodes of culture-proven TB. Thirty-three drug-resistant isolates were cultured from 30 patients: 29 (87.9%) were isoniazid-resistant, three (9.1%) were multidrug-resistant (MDR), and one (3.0%) was rifampin mono-resistant. One patient with isoniazid resistance developed recurrent disease, and two isolates, initially isoniazid-resistant, mutated and became MDR TB. Based on risk assessment, rpoB genotyping was performed on 19 samples, and two (10.5%) had mutations that predicted multiple drug resistance. Although for MDR TB, a past history of treatment predicted two out of three patients with acquired resistance, adjusted analysis did not demonstrate a significant association between previous treatment of active TB and drug resistance (odds ratio 1.5, 95% confidence interval (CI) 0.4-5.6). The positive predictive value of past treatment as a predictor for drug resistance was 12.0% (95% CI 2.6-31.2%).. Although numbers of MDR TB were too small to draw meaningful conclusions, past treatment may be useful in selecting samples for rpoB genotyping. Overall, previous treatment had a low positive predictive value for drug resistance in an area bordering East London.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Bacterial Proteins; Child; Child, Preschool; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Female; Humans; Infant; Infant, Newborn; Logistic Models; London; Male; Microbial Sensitivity Tests; Models, Biological; Mycobacterium tuberculosis; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2010
Inconsistent dosing of anti-tuberculosis drugs in Taipei, Taiwan.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010, Volume: 14, Issue:7

    Taipei City, Taiwan.. To evaluate prescribing practices for anti-tuberculosis drugs in the treatment of tuberculosis (TB).. Medical audit of the medical charts of all patients notified and treated for TB in Taiwan in 2003 to determine the treatment regimens prescribed and to compare these with recommended dosages.. A total of 24 different anti-tuberculosis regimens were prescribed. Of 1700 patients notified, 1096 (64.5%) had their body weight recorded. Of 506 patients prescribed a three-drug fixed-dose combination (FDC), the dosage was adequate in 374 (73.9%), too low in 100 (19.8%) and too high in 32 (6.3%). Of 75 patients prescribed a two-drug FDC, the dosage was adequate in 57 (76.0%), too low in 15 (20.0%) and too high in 3 (4.0%). Of 481 patients prescribed rifampicin, the dosage was adequate in 302 (62.8%), too low in 152 (31.6%) and too high in 27 (5.6%). Of 451 patients prescribed isoniazid, the dosage was adequate in 396 (87.8%), too low in 29 (6.4%) and too high in 26 (5.8%).. The prescribing practices for anti-tuberculosis drugs were substandard and need improvement. These findings imply that the National TB Programme needs strengthening.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Isoniazid; Male; Medical Audit; Middle Aged; National Health Programs; Practice Patterns, Physicians'; Rifampin; Taiwan; Tuberculosis; Young Adult

2010
[Treatment of tuberculous infection: Where we are?].
    Medicina clinica, 2010, Sep-04, Volume: 135, Issue:7

    Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Tuberculosis

2010
The best approach to reintroducing tuberculosis treatment after hepatotoxicity is still open to debate.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2010, Aug-01, Volume: 51, Issue:3

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2010
Tuberculosis in Greece: bacteriologically confirmed cases and anti-tuberculosis drug resistance, 1995-2009.
    Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin, 2010, Jul-15, Volume: 15, Issue:28

    The Greek National Reference Laboratory for Mycobacteria is a major source of tuberculosis (TB)-related data for Greece, where the TB burden and epidemiology still need to be better defined. We present data regarding newly diagnosed TB cases and resistance to anti-TB drugs during the last 15 years in Greece. Although the total number of newly detected TB cases has declined, cases among immigrants are increasing. Resistance to first-line anti-TB drugs is widely prevalent, although stable or declining. The implementation of an efficient and effective countrywide TB surveillance system in Greece is urgently needed.

    Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Emigrants and Immigrants; Female; Greece; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; National Health Programs; Population Surveillance; Prevalence; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2010
Mediastina Tuberculosis mass in a three-month-old boy.
    La Tunisie medicale, 2010, Volume: 88, Issue:8

    Mediastinal mass of tuberculous origin is exceedingly rare in infant.. to report an exceedingly rare case of mediastinal mass of tuberculous origin.. We report a three-month-old boy who presented a one month history of wheezing and persistent pneumopathy. Radiological investigations showed a large posterior mediastinal mass which infiltrates lungs. Thoracoscopic biopsy showed caseous necrosis with granuloma suggestive of tuberculosis. The outcome was favourable with antituberculous chemotherapy.. Mediatinal mass of tuberculous origin should considered in differential diagnosis of mediastinal masses in children; be suggested in mediastinal mass in children.

    Topics: Adrenal Cortex Hormones; Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Follow-Up Studies; Humans; Infant; Isoniazid; Magnetic Resonance Imaging; Male; Mediastinal Diseases; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

2010
Bactericidal potencies of new regimens are not predictive of their sterilizing potencies in a murine model of tuberculosis.
    Antimicrobial agents and chemotherapy, 2010, Volume: 54, Issue:11

    TMC207, rifapentine, and moxifloxacin are in clinical testing for the treatment of tuberculosis. Five experimental regimens with various combinations of TMC207, rifapentine, moxifloxacin, and pyrazinamide were tested for their bactericidal and sterilizing potencies in Swiss mice intravenously inoculated with Mycobacterium tuberculosis bacilli. TMC207 had the strongest bactericidal efficacy, while rifapentine was the strongest contributor to sterilizing efficacy. The rank order of sterilizing potencies was different from the rank order of bactericidal potencies, underlining the importance of prioritizing new regimens designed to shorten the treatment duration by their sterilizing potencies rather than by their bactericidal potencies. Both 3 months of treatment with a regimen combining TMC207, pyrazinamide, and rifapentine and 5 months of treatment with a regimen combining TMC207, pyrazinamide, and moxifloxacin resulted in relapse rates similar to the rate obtained by 6 months of treatment with rifampin-isoniazid-pyrazinamide.

    Topics: Animals; Antibiotics, Antitubercular; Aza Compounds; Diarylquinolines; Disease Models, Animal; Female; Fluoroquinolones; Mice; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Tuberculosis

2010
Containment of bioaerosol infection risk by the Xpert MTB/RIF assay and its applicability to point-of-care settings.
    Journal of clinical microbiology, 2010, Volume: 48, Issue:10

    The recently introduced Xpert MTB/RIF assay (Xpert) has point-of-care potential, but its capacity for biohazard containment remained to be studied. We compared the bioaerosols generated by the Xpert assay to acid-fast bacillus (AFB) microscope slide smear preparation. The Xpert assay sample treatment reagent (SR) was also studied for its sterilizing capacity, stability, and effect on assay sensitivity after prolonged treatment. During the preparation of AFB smears, sputum samples spiked with Mycobacterium bovis BCG at 5 × 10(8) CFU/ml produced 16 and 325 CFU/m(3) air measured with an Andersen impactor or BioSampler, respectively. In contrast, neither the sample preparation steps for the Xpert assay nor its automated processing produced any culturable bioaerosols. In testing of SR sterilizing capacity, clinical sputum samples from strongly smear-positive tuberculosis patients treated with SR at a 2:1 ratio eliminated Mycobacterium tuberculosis growth in all but 1/39 or 3/45 samples cultured on solid or liquid medium, respectively. These few unsterilized samples had a mean 13.1-day delay in the time to positive culture. SR treatment at a 3:1 ratio eliminated growth in all samples. SR retained a greater than 6-log-unit killing capacity despite storage at temperatures spanning 4 to 45°C for at least 3 months. The effect of prolonged SR sample treatment was also studied. Spiked sputum samples could be incubated in SR for up to 3 days without affecting Xpert sensitivity for M. tuberculosis detection and up to 8 h without affecting specificity for rifampin resistance detection. These results suggest that benchtop use of the Xpert MTB/RIF assay limits infection risk to the user.

    Topics: Aerosols; Air Microbiology; Antitubercular Agents; Bacteriological Techniques; Containment of Biohazards; Drug Resistance, Bacterial; Humans; Mycobacterium bovis; Mycobacterium tuberculosis; Point-of-Care Systems; Rifampin; Sensitivity and Specificity; Sputum; Sterilization; Tuberculosis

2010
The combination of rifampin plus moxifloxacin is synergistic for suppression of resistance but antagonistic for cell kill of Mycobacterium tuberculosis as determined in a hollow-fiber infection model.
    mBio, 2010, Aug-10, Volume: 1, Issue:3

    Moxifloxacin is under development for expanded use against Mycobacterium tuberculosis. Rifampin is a mainstay of therapy. We examined the interaction of moxifloxacin plus rifampin for log-phase and nonreplicating persister (NRP) organisms. For this evaluation, we employed our hollow-fiber infection model, in which organisms are exposed to clinically relevant drug concentration-time profiles and the impact on bacterial cell kill and resistant subpopulation amplification is determined. In log phase, resistance emergence was observed in all monotherapy regimens and in no combination therapy regimen. No difference was seen in time to a 3-log reduction in the bacterial burden; there was a significant difference in time to resistance emergence (P = 0.0006). In the NRP experiment, no resistance emergence was seen. There was a significant difference between the monotherapy and combination therapy regimens in time to a 3-log reduction in the bacterial burden (P = 0.042). The combination is efficacious for suppressing resistant organisms but is antagonistic for cell kill.

    Topics: Antitubercular Agents; Aza Compounds; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Drug Synergism; Fluoroquinolones; Humans; Microbial Viability; Models, Biological; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Rifampin; Tuberculosis

2010
Can the drug-driven dependency and deprivation effect be used as a therapeutic tool in tuberculous patients?
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010, Volume: 14, Issue:9

    Topics: Antineoplastic Agents; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Humans; Neoplasms; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2010
High-resolution melting curve analysis for rapid detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis clinical isolates.
    Journal of clinical microbiology, 2010, Volume: 48, Issue:11

    We evaluated high-resolution melting (HRM) curve analysis as a tool for detecting rifampin (RIF) and isoniazid (INH) resistance in Mycobacterium tuberculosis in an accurate, affordable, and rapid manner. Two hundred seventeen M. tuberculosis clinical isolates of known resistance phenotype were used. Twenty-nine known rpoB mutant DNAs, including rare mutations, were also included. Four pairs of primers were designed: rpoB-F/R (for codons 516 to 539 of rpoB), rpoB-516F/R (for codons 508 to 536 of rpoB), katG-F/R (for the codon 315 region of katG), and inhA-F/R (for the nucleotide substitution of C to T at position -15 of inhA). An HRM curve was generated for each isolate after real-time PCR differentiated the mutant from the wild-type strains. DNA sequencing of the target regions was performed to confirm the results of the HRM curve analysis. All but one of the 73 RIF-resistant (RIF-R) strains and all 124 RIF-susceptible (RIF-S) isolates were correctly identified by HRM curve analysis of rpoB. Twenty-seven of 29 known rpoB mutants were detected. In HRM curve analysis of katG and inhA, 90 INH-R strains that harbored katG or inhA mutations, or both, and all INH-S strains were correctly identified. Ten phenotypically INH-R strains not harboring katG or inhA mutations were not detected. The HRM curve analysis will be a useful method for detection of RIF and INH resistance in M. tuberculosis in a rapid, accurate, simple, and cost-effective manner.

    Topics: Antitubercular Agents; Bacterial Proteins; Catalase; Codon; DNA Primers; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxidoreductases; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Transition Temperature; Tuberculosis

2010
[Exposure of a cohort of newborn infants to tuberculosis in a neonatology service].
    Archives de pediatrie : organe officiel de la Societe francaise de pediatrie, 2010, Volume: 17, Issue:10

    A nursery nurse that was working in the neonatology service had been diagnosed with tuberculosis. As a consequence, the newborn infants were in danger of a possible contamination during a 4-month period.. One hundred and thirty kids that had been in touch with the nurse were given attention. Prophylactic treatment for three months with isoniazid and rifampicin has been proposed to all families. Each of them was screened with a tuberculin sensitivity test and was given chest radiography initially and after three months.. None of the children was initially suspected for tuberculosis. Among the chest radiographies, 97.6% were normal and all the intradermal tuberculin were either negative or in the norm following a vaccination by the Bacillus Calmette-Guerin. In most cases, the treatment tolerance was high.. A 4-year-long surveillance ensured that no infant was infected. This procedure has established that the risk of transmission by a nurse is low, should it be for newborn babies, as long as guidelines are strictly adhered to.

    Topics: Antitubercular Agents; Humans; Infant, Newborn; Infant, Newborn, Diseases; Isoniazid; Nursing Staff, Hospital; Practice Guidelines as Topic; Rifampin; Risk Assessment; Tuberculosis

2010
Acute liver failure due to antitubercular therapy: Strategy for antitubercular treatment before and after liver transplantation.
    Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 2010, Volume: 16, Issue:10

    The standard antitubercular treatment (ATT), which consists of isoniazid (INH), rifampicin (RIF), ethambutol, and pyrazinamide (PZA), is the best available treatment for tuberculosis (TB). However, the hepatotoxicity of INH and PZA can be severe, and even after drug withdrawal, patients may require liver transplantation (LT). In these cases, the strategy for the treatment of TB is poorly defined. Between 1986 and 2008, 14 patients presented at our department with severe hepatitis secondary to INH and PZA treatment. Four of these patients were immunosuppressed: 2 after renal transplantation and 2 because of human immunodeficiency virus infection. In seven of the 14 patients an alternative ATT was begun on admission, which was well tolerated. Hepatitis improved spontaneously in 5 patients, and alternative ATT was continued for 9.3 ± 4.2 months; 1 patient deteriorated and underwent LT, and 1 patient died. ATT was stopped definitively in 2 patients. Six patients required urgent LT, and alternative ATT was started after transplantation and was successful. Five patients receiving RIF had an episode of acute rejection. In conclusion, hepatitis secondary to ATT can be successfully treated with alternative anti-TB regimens. The use of RIF in LT patients may lead to acute rejection. RIF should therefore be avoided in these patients.

    Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Disease Progression; Drug Therapy, Combination; Female; France; Graft Rejection; Humans; Isoniazid; Liver Failure, Acute; Liver Transplantation; Male; Middle Aged; Remission, Spontaneous; Rifampin; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Tuberculosis; Young Adult

2010
Treatment outcomes of patients co-infected with HIV and tuberculosis who received a nevirapine-based antiretroviral regimen: a four-year prospective study.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2010, Volume: 14, Issue:11

    The concurrent use of nevirapine-based antiretroviral therapy (ART) and rifampin-containing anti-tuberculosis regimens for the treatment of HIV and tuberculosis (TB) is common in resource-limited countries. Long-term outcomes of this concurrent treatment are unknown.. Seventy HIV-infected patients receiving rifampin for active TB (TB group) and 70 HIV-mono-infected patients (control group) were enrolled to receive nevirapine 400mg/day-based ART. All were followed through 4 years of ART. Plasma HIV-1 RNA and CD4 cell counts were monitored every 12 weeks until 96 weeks, and every 24 weeks thereafter.. Of the 140 patients, the median (interquartile range (IQR)) CD4 count was 31 (14-79) cells/mm(3) and median (IQR) plasma HIV-1 RNA was 5.6 (5.2-5.9) log copies/ml at baseline . Thirty-nine (55.7%) patients in the TB group were diagnosed with extrapulmonary/disseminated TB. The median duration of concurrent administration of nevirapine and rifampin was 5.4 (4.6-6.1) months. By intention-to-treat analysis, the percentage of patients who achieved HIV-1 RNA <50 copies/ml was 52.9% in the TB group and 50% in control group (p=0.866; odds ratio 1.121, 95% confidence interval 0.578-2.176); median (IQR) CD4 counts were 352 (271-580) cells/mm(3) and 425 (308-615) cells/mm(3) in the corresponding groups (p=0.238). The proportion of ART discontinuation due to any reason at 1, 2, 3, and 4 years was 21%, 34%, 37%, and 46% in the TB group and 21%, 36%, 43%, and 49% in the control group, respectively (p=0.651). The 4-year mortality rate was 6.4% in both groups.. Nevirapine-based ART is an option for HIV-infected patients who receive rifampin in resource-limited countries or those who cannot tolerate efavirenz.

    Topics: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Antitubercular Agents; CD4 Lymphocyte Count; Confidence Intervals; Female; Follow-Up Studies; HIV; HIV Infections; Humans; Male; Nevirapine; Prospective Studies; Rifampin; RNA, Viral; Thailand; Treatment Outcome; Tuberculosis; Viral Load

2010
[Epidemiology of the resistance of Mycobacterium tuberculosis to antituberculosis drugs at the main hospital in Dakar, Senegal. A 4-year retrospective study (2000-2003)].
    Revue de pneumologie clinique, 2010, Volume: 66, Issue:4

    A retrospective study was carried out from January 2000 to December 2003 to assess the resistance of Mycobacterium tuberculosis to antituberculosis drugs and the impact of this on the treatment result. Two hundred and two patients' files were studied (average age: 36 years; sex-ratio: 1.7). Pulmonary localisation (85.7%) or extrapulmonary localisation (14.3%). HIV status is negative (71.3%), positive (10.8%) or unknown (17.9%). The overall recovery rate is 60.7% (61.4% in HIV-; 46.1% in HIV+), the rate of treatment failure is 2.7% (1.1% in HIV-; 15.4% in HIV+), the death rate due to tuberculosis is 6.3% (2.3% in HIV-; 23.1% in HIV+), and the rate of patients who disappeared from the system is 30.3% (35.2% in HIV-; 14.2% in HIV+). Hepatotoxicity that occurred during treatment is observed in 14.3% of cases (recovery: 56.2%; failure: 6.2%; lost from the system: 18.8%). Eighty-four percent of patients never received antituberculosis treatment (group A) versus 15.8% of patients who had already received one or more antituberculosis drugs (group B). The rates of resistance to isoniazid are 6.4% (A) and 12.5% (B), to rifampicin 1.7% (A) and 12.5% (B), to ethambutol 0.5% (A) and 0% (B), to streptomycin 24.1% (A) and 46.8% (B). The percentage of multiresistant strains is 1% in patients not treated previously and 11% in those who had already received antituberculosis treatment. When the patients are carriers of a strain that is responsive to the treatment administered, the recovery rate is 64.2% versus 46.7% in patients whose strain is resistant to at least one of the treatments administered.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; HIV Infections; Hospitals, University; Humans; Immunocompromised Host; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Senegal; Streptomycin; Treatment Failure; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2010
Interferon-γ release assay for tuberculosis screening of healthcare workers at a Korean tertiary hospital.
    Scandinavian journal of infectious diseases, 2010, Volume: 42, Issue:11-12

    The aim of this study was to evaluate the annual incidence of tuberculosis infection among newly employed doctors and nurses in Korea. The annual incidence of tuberculosis infection ranged from 3.3% to 5.7%, based on the definition of conversion of an interferon-γ release assay, which suggests that stricter preventive strategies against nosocomial TB infection should be employed. Follow-up interferon-γ levels measured after 3 months of isoniazid and rifampicin treatment showed considerable variation. Therefore, serial testing with interferon-γ release assays after treatment of latent TB infection may be insufficient for evaluating the effects of treatment due to the variable responses.

    Topics: Adult; Antitubercular Agents; Female; Health Personnel; Hospitals; Humans; Immunoassay; Incidence; Interferons; Isoniazid; Male; Mass Screening; Republic of Korea; Rifampin; Treatment Outcome; Tuberculosis

2010
Risk of relapse and failure after retreatment with the Category II regimen in Nepal.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010, Volume: 14, Issue:11

    Kathmandu Valley urban area, Nepal.. To study the probabilities of failure and relapse and of amplifying drug resistance to isoniazid (INH) and rifampicin (RMP) after the Category II retreatment regimen.. Cohort study of smear-positive tuberculosis (TB) retreatment cases.. Of 250 cases started on Category II retreatment, 209 were relapse cases; of these, 18 were INH-resistant RMP-susceptible, 18 were INH+RMP-resistant and nine were culture-negative. Of 19 return after interruption cases, two were INH-resistant RMP-susceptible and one was INH+RMP-resistant. Among 22 failures, no case was INH-resistant RMP-susceptible, six were INH+RMP-resistant and 14 were culture-negative. No INH-susceptible RMP-resistant cases were observed. Among 182 INH+RMP-susceptible cases, one failed and four relapsed during follow-up. Two of the five cases became INH+RMP-resistant and the remaining three remained susceptible. Among 20 INH-resistant RMP-susceptible cases, two failed and none relapsed. One of the two became INH+RMP-resistant and the other case remained INH-resistant RMP-susceptible.. The proportion of resistance among retreatment cases in Kathmandu Valley was not high. The risk of relapse with amplification of RMP resistance among INH-resistant RMP-susceptible cases on the Category II retreatment regimen was 5% (1/20), and that among INH+RMP-susceptible cases was 1% (2/182).

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Cohort Studies; Drug Resistance, Bacterial; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Nepal; Recurrence; Retreatment; Rifampin; Treatment Failure; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant; Young Adult

2010
MODS accreditation process for regional reference laboratories in Peru: validation by GenoType® MTBDRplus.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2010, Volume: 14, Issue:11

    Although considerable effort has been put into the development and evaluation of new diagnostics for tuberculosis (TB) and multidrug-resistant TB (MDR-TB), little attention has thus far been paid to the technical aspects of initiating quality-assured routine service use. For implementation of the microscopic-observation drug susceptibility (MODS) methodology in the Peruvian reference laboratory network, a laboratory accreditation process was devised; MODS results from an expert reference laboratory (Universidad Peruana Cayetano Heredia [UPCH]) were used as the standard against which implementing laboratory MODS results were judged to ensure that, prior to use for patient care, implementing laboratories achieved the same high performance with MODS as previously demonstrated in the research laboratory.. To evaluate the validity of MODS-based accreditation and the concordance of MODS drug susceptibility testing (DST) with molecular testing.. Head-to-head comparison of MODS DST results from implementing Peruvian regional reference laboratories and the accrediting expert MODS laboratory (UPCH) with GenoType® MTBDRplus DST.. The concordance of phenotypic MODS rifampicin (RMP) DST with GenoType MTBDRplus was respectively 97.4%, 97.9% and 97.1% for the two implementing regional laboratories and UPCH, and respectively 94.7%, 95.7% and 94.6% for isoniazid (INH) DST.. High and consistent levels of MODS/MTBDRplus concordance for INH and RMP DST confirm the validity of the use of rapid methods as reference standards for accreditation.

    Topics: Accreditation; Antitubercular Agents; Bacteriological Techniques; Humans; Isoniazid; Laboratories; Microbial Sensitivity Tests; Mycobacterium; Peru; Quality Assurance, Health Care; Reference Standards; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2010
[Susceptibility of M. tuberculosis to antituberculosis drugs as determined by two methods, in Sucre state, Venezuela].
    Investigacion clinica, 2010, Volume: 51, Issue:4

    The objective of this study was to evaluate the resistance to isoniazid (INH), rifampicin (RIF), streptomycin (STR) and ethambutol (EMB), with the Canetti's proportions method (PM) and the nitrate reductase assay (NRA) of 59 clinical strains of Mycobacterium tuberculosis, isolated in the period of august 2005 to december 2006, in Sucre state, Venezuela. Primary and acquired drug resistance was 6.3% and 14.3%, respectively. Only one strain was found to be multidrug resistant (MDR). The overall agreement between the NRA and PM was 100% for INH, RIF and EMB, and 96% for STR. The time to obtain results was 10 to 14 days for the NRA, compared to 42 days for the PM. The NRA was easy to perform and therefore represents a useful tool for rapid and accurate determination of drug-resistant M. tuberculosis. The sequence of the rpoB gene of the RIF resistant strain demonstrated a never described mutation (change in the codon 456; TCG > CAG) in the hypervariable region of 81 base pairs where most of the mutations of the RIF resistant strains have been reported. Comparison of our results with those of the last resistance prevalence study carried out in the years 1998-1999, shows a decrease in the studied area.

    Topics: Antitubercular Agents; Bacterial Proteins; Base Sequence; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Drug Resistance, Multiple, Bacterial; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Molecular Sequence Data; Morbidity; Mutation, Missense; Mycobacterium tuberculosis; Nitrate Reductase; Point Mutation; Prevalence; Rifampin; Sequence Alignment; Sequence Homology, Nucleic Acid; Sputum; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Venezuela

2010
Synthesis and evaluation of rifabutin analogs against Mycobacterium avium and H(37)Rv, MDR and NRP Mycobacterium tuberculosis.
    Bioorganic & medicinal chemistry, 2009, Jan-15, Volume: 17, Issue:2

    Clinical utility of rifabutin 1 (RBT), a potent antibiotic used in multidrug regimens for tuberculosis (TB) as well as for infections caused by Mycobacterium avium complex (MAC), has been hampered due to dose-limiting toxicity. RBT analogs 2-11 were synthesized and evaluated against M. avium 1581 and Mycobacterium tuberculosis susceptible and resistant strains in vitro. A selection of candidates were also assayed against non-replicating persistent (NRP) M. tuberculosis. Subsequent in vivo studies with the best preclinical candidate drugs 5 and 8, in a model of progressive pulmonary tuberculosis of Balb/C mice infected either with H(37)Rv drug-sensible strain or with multidrug resistant (MDR) clinical isolates, resistant to all primary antibiotics including rifampicin, were performed. The results disclosed here suggest that 5 and 8 have potential for clinical application.

    Topics: Animals; Antitubercular Agents; Drug Resistance, Bacterial; Mice; Mice, Inbred BALB C; Mycobacterium avium; Mycobacterium tuberculosis; Rifabutin; Structure-Activity Relationship; Tuberculosis

2009
5-Nitrofuran-2-yl derivatives: synthesis and inhibitory activities against growing and dormant mycobacterium species.
    Bioorganic & medicinal chemistry letters, 2009, Feb-15, Volume: 19, Issue:4

    Eighteen 5-nitrofuran-2-yl derivatives were prepared by reacting 5-nitro-2-furfural with various (sub)phenyl/pyridyl thiosemicarbazide using microwave irradiation. The compounds were tested for their in vitro activity against tubercular and various non-tubercular mycobacterium species in log-phase and 6-week-starved cultures. Compound N-(3,5-dibromopyridin-2-yl)-2-((5-nitrofuran-2-yl)methylene)hydrazinecarbothioamide (4r) was found to be the most potent compound (MIC: 0.22 microM) and was 3 times more active than standard isoniazid (INH) and equally active as rifampicin (RIF) in log-phase culture of Mycobacterium tuberculosis H37Rv. In starved M. tuberculosis H37Rv, 4r inhibited with MIC of 13.9 microM and was found to be 50 times more active than INH and slightly more active than RIF.

    Topics: Antitubercular Agents; Combinatorial Chemistry Techniques; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitrofurans; Structure-Activity Relationship; Thiosemicarbazones; Tuberculosis

2009
Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations.
    Bioorganic & medicinal chemistry, 2009, Jul-01, Volume: 17, Issue:13

    3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H(37)Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14alpha-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values.

    Topics: Antitubercular Agents; Bacterial Proteins; Computer Simulation; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Oxadiazoles; Protein Binding; Sterol 14-Demethylase; Thermodynamics; Tuberculosis

2009
1,5-Diaryl-2-ethyl pyrrole derivatives as antimycobacterial agents: design, synthesis, and microbiological evaluation.
    European journal of medicinal chemistry, 2009, Volume: 44, Issue:11

    During the search of novel antitubercular drugs related to BM 212, new diarylpyrroles were designed and synthesized on the basis of a structure-activity relationship analysis of many pyrroles previously described by us. Among them, 1-(4-fluorophenyl)-2-ethyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole (2b) proved to be particularly active, with a minimum inhibitory concentration (MIC, expressed as microg/mL) and a protection index (PI) better than or comparable to those of reference compounds. Also the remaining compounds were very active, although their MIC and PI were in general lower than those of their parent 2-methyl analogues.

    Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Models, Molecular; Mycobacterium tuberculosis; Pyrroles; Quantitative Structure-Activity Relationship; Tuberculosis; Vero Cells

2009
Rapid speciation of 15 clinically relevant mycobacteria with simultaneous detection of resistance to rifampin, isoniazid, and streptomycin in Mycobacterium tuberculosis complex.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2009, Volume: 13, Issue:1

    To design and standardize an in-house reverse line blot hybridization (RLBH) assay for the accurate identification of 15 clinically relevant species of mycobacteria and for the detection of drug resistance to rifampin (RIF), isoniazid (INH), and streptomycin (STR) in Mycobacterium tuberculosis complex (MTB).. Oligonucleotides specific for 15 different species of mycobacteria and wild type and mutant alleles of selected codons in the rpobeta, inhA, katG, rpsL, and rrs genes were designed and immobilized on a membrane. A multiplex PCR was standardized to amplify all target genes. The assay was optimized using ATCC and known mutant strains. Three hundred MTB isolates, 85 non-tuberculous mycobacteria (NTM) isolates, and 48 smear-positive specimens were analyzed. Results were confirmed by PCR restriction enzyme assay and sequencing.. Upon RLBH analysis, among the NTM, 14% were identified as Mycobacterium fortuitum, 16% were identified as Mycobacterium abscessus, 20% showed 99% homology with Mycobacterium intracellulare, and 31% showed 98% homology with Mycobacterium simiae. Of the 300 MTB isolates analyzed, 75% RIF-resistant isolates had Ser531Leu mutation in the rpobeta gene. Of the INH-resistant isolates, 89% showed Ser315Thr mutation in the katG gene, whereas 16% showed -15 C-->T mutation in the promoter region of the inhA gene. Among STR-resistant isolates, 75% had A-->G mutation in the rpsL gene at codon 43. RLBH results showed 96-99% concordance with phenotypic culture results.. This is a first attempt at combining speciation with detection of drug resistance to RIF, INH, and STR in MTB for accurate and rapid management of mycobacterial infections as well as for compiling genotypic epidemiological data.

    Topics: Antitubercular Agents; Bacterial Proteins; Bacterial Typing Techniques; DNA Probes; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Polymerase Chain Reaction; Reproducibility of Results; Rifampin; Streptomycin; Time Factors; Tuberculosis; Tuberculosis, Multidrug-Resistant

2009
Identification of rifampin-resistant genotypes in Mycobacterium tuberculosis by PCR-reverse dot blot hybridization.
    Molecular biotechnology, 2009, Volume: 41, Issue:1

    A PCR-reverse dot blot hybridization (RDBH) assay was developed for rapid identification of rifampin (RFP)-resistant genotypes in Mycobacterium tuberculosis clinical isolates. The assay used the rpoB gene as target and was used to evaluate 148 clinical isolates (97 RFP-resistant isolates and 51 RFP-susceptible isolates). At the same time, the isolates were subjected to DNA sequencing and conventional drug susceptibility test. One hundred and forty one (95.3%) and 136 (91.9%) of the 148 strains were correctly identified by DNA sequencing and RDBH assay, respectively. None of the 51 RFP-susceptible isolates examined had alterations in rpoB. The sensitivity and specificity of the DNA sequencing were 92.8% and 100%, and the positive predictive value (PPV) and negative predictive value (NPV) were 100% and 87.9%, respectively. The sensitivity and specificity of the RDBH assay were 87.6% and 100%, and the PPV and NPV were 100% and 81.0%, respectively. Codons 531 and 526 of the rpoB were found to be the most common sites of nucleotide substitutions. Mutations at codons 511, 513, 515, 516, 517, 518, and 533 were also found. There were two-codon mutations in four isolates. No deletion and insertion was found in the rpoB gene. These results indicate that the RDBH assay is a rapid, simple, and reliable method for routine identification of RFP resistance in M. tuberculosis.

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Point Mutation; Polymerase Chain Reaction; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Tuberculosis

2009
Gelatin microspheres of rifampicin cross-linked with sucrose using thermal gelation method for the treatment of tuberculosis.
    Journal of microencapsulation, 2009, Volume: 26, Issue:1

    Oral controlled release microspheres of rifampicin (RIF) were prepared in order to circumvent the required regular high dose of the conventional dosage forms for the treatment of tuberculosis. Rifampicin containing microspheres were designed by using a biodegradable and biocompatible polymer, gelatin B, using a thermal gelation method. The microspheres were cross-linked with natural cross-linker, sucrose, to avoid the toxicities due to the synthetic di- and poly-aldehydes. This formulation was found to be controlled release for drug in the gastro-intestinal tract. Drug encapsulation efficiency was found to be in the range of 52-83%. These microspheres were characterized for; particle size analysis by optical microscopy and scanning electron microscopy; in vitro release study by USP paddle apparatus and drug polymer interaction study using DSC and FT-IR. The results suggested that microspheres prepared by the above method were smaller in size, i.e. less than 60 microm and sucrose could be used as an interesting means to cross-link gelatin B microspheres, allowing the use of this formulation for controlled release of rifampicin. Microspheres could be observed in the intestinal lumen at 4 h and were detectable in the intestine 24 h post-oral administration, although the percentage of radioactivity had significantly decreased (t(1/2) of (99m)Tc = 4-5 h). Dissolution and scintigraphy studies have shown promising results, proving the utility of the formulation for the whole intestine.

    Topics: Administration, Oral; Animals; Antibiotics, Antitubercular; Cross-Linking Reagents; Delayed-Action Preparations; Drug Compounding; Gastrointestinal Tract; Gelatin; Gels; Hot Temperature; Microspheres; Rifampin; Sucrose; Technetium; Tuberculosis

2009
Mechanisms of heteroresistance to isoniazid and rifampin of Mycobacterium tuberculosis in Tashkent, Uzbekistan.
    The European respiratory journal, 2009, Volume: 33, Issue:2

    Heteroresistance of Mycobacterium tuberculosis (MTB) is defined as the coexistence of susceptible and resistant organisms to anti-tuberculosis (TB) drugs in the same patient. Heteroresistance of MTB is considered a preliminary stage to full resistance. To date, no mechanism causing heteroresistance of MTB has been proven. Clinical specimens and cultures from 35 TB patients from Tashkent, Uzbekistan, were analysed using the Genotype MTBDR assay (Hain Lifescience, Nehren, Germany), which is designed to detect genetic mutations associated with resistance to rifampin and isoniazid. Cases of heteroresistance were further subjected to genotyping using mycobacterial interspersed repetitive unit-variable-number tandem repeat typing, spoligotyping and IS6110 fingerprinting. Heteroresistance to rifampin and/or isoniazid was found in seven cases (20%). In five of them, heteroresistance was caused by two different strains and in two by a single strain of the Beijing genotype. The latter cases had a history of relapse of their TB. For the first time, two different mechanisms of heteroresistance in tuberculosis have been proven using a stepwise molecular-biological approach: 1) superinfection with two different strains, which is of interest for clinical infection control practitioners; and 2) splitting of a single strain into susceptible and resistant organisms. The latter mechanism is most likely to be related to poor treatment quality and could serve as a quality marker for tuberculosis therapy programmes in the future.

    Topics: Antitubercular Agents; Bacterial Typing Techniques; Codon; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Phenotype; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Uzbekistan

2009
A once-weekly R207910-containing regimen exceeds activity of the standard daily regimen in murine tuberculosis.
    American journal of respiratory and critical care medicine, 2009, Jan-01, Volume: 179, Issue:1

    R207910 (TMC207 or J) is a member of the diarylquinolines, a new family of antituberculous drugs with high bactericidal activity when given daily in the murine model of tuberculosis. R207910 exhibits a long half-life and thus is a good candidate for once-weekly therapy of tuberculosis.. To study the activity of once-weekly R207910 monotherapy and combinations of R207910 with other antituberculous agents (isoniazid, rifapentine, moxifloxacin, and pyrazinamide).. The established infection model of murine tuberculosis was used. Colony counts were determined in the lungs.. Eight weeks of monotherapy reduced the bacillary load by 3 to 4 log(10) for rifapentine and by 5 to 6 log(10) for R207910 (P < 0.05). The addition of rifapentine and isoniazid or moxifloxacin did not improve the bactericidal activity of R207910 monotherapy. In contrast, the triple combination of R207910 plus rifapentine plus pyrazinamide given once weekly for 2 months (i.e., a total of only eight administrations), was significantly (P < 0.05) more active than R207910 monotherapy or other R207910 combinations, and led to lung culture negativity in 9 of 10 mice, whereas all lungs were culture positive in the groups treated with other drug combinations. Moreover, R207910 plus rifapentine plus pyrazinamide given once weekly was more active than the current standard regimen of rifampin plus isoniazid plus pyrazinamide given five times per week.. The unprecedented activity of the triple combination of R207910 plus rifapentine plus pyrazinamide suggests that it may be feasible to develop a fully intermittent once-weekly regimen.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Lung; Mice; Pyrazinamide; Quinolines; Rifampin; Tuberculosis

2009
Application of denaturing HPLC to rapidly identify rifampicin-resistant Mycobacterium tuberculosis in low- and high-prevalence areas.
    The Journal of antimicrobial chemotherapy, 2009, Volume: 63, Issue:2

    Since the emergence of multidrug-resistant and extensively drug-resistant tuberculosis, there has been a call for a rapid assay to detect rifampicin-resistant strains that can be implemented into a routine service to analyse all strains in a specific geographical location. Denaturing HPLC (dHPLC) is a rapid screening test that can detect mutations in PCR amplicons. The aim of this study was to evaluate the dHPLC analysis of rifampicin-resistant Mycobacterium tuberculosis isolates using an extensive strain collection from Hong Kong and the UK and a collection of 84 consecutive clinical isolates.. DNA from 51 rifampicin-resistant M. tuberculosis strains from the UK and Hong Kong identified from 1996 to 2005 was extracted and each mutation was defined by capillary electrophoresis. A 400 bp PCR product was amplified from each strain, heteroduplexed with a known susceptible control (H37Rv) and analysed by dHPLC at 67.0 degrees C.. Forty-five out of 51 (88.2%) rifampicin-resistant strains with known DNA mutations were detected by dHPLC. Two out of 84 clinical isolates were phenotypically rifampicin-resistant and dHPLC detected a mutation in the rpoB amplicon for both these isolates. dHPLC detected a mutation in 1 out of 82 phenotypically rifampicin-susceptible isolates (M482T, a non-cluster I/II mutation). In a combined analysis of all strains and isolates, mutation detection by dHPLC analysis exhibited 88.2% sensitivity and 98.8% specificity.. This study shows that dHPLC analysis is sensitive and specific and could be implemented in a routine clinical service.

    Topics: Antitubercular Agents; Bacterial Proteins; Chromatography, High Pressure Liquid; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Electrophoresis, Capillary; Hong Kong; Humans; Microbial Sensitivity Tests; Mutation, Missense; Mycobacterium tuberculosis; Nucleic Acid Denaturation; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis; United Kingdom

2009
CYP2B6 G516T polymorphism but not rifampin coadministration influences steady-state pharmacokinetics of efavirenz in human immunodeficiency virus-infected patients in South India.
    Antimicrobial agents and chemotherapy, 2009, Volume: 53, Issue:3

    The dose of efavirenz during concomitant rifampin (RMP) administration is a matter of debate. We studied the influence of RMP coadministration on the steady-state pharmacokinetics of efavirenz in human immunodeficiency virus type 1 (HIV-1)-infected patients in South India. Fifty-seven HIV-tuberculosis (TB)-coinfected and 15 HIV-1-infected patients receiving combination antiretroviral therapy (CART) with an efavirenz (600 mg once daily)-containing regimen were recruited. HIV-TB-coinfected patients were receiving treatment with RMP-containing regimens. A complete pharmacokinetic study was conducted with 19 HIV-TB patients on two occasions (with and without RMP). Trough concentrations of efavirenz were measured in the remaining 38 patients during RMP coadministration. The 15 HIV-infected patients underwent complete pharmacokinetic sampling on one occasion. Plasma efavirenz was estimated by high-performance liquid chromatography, and genotyping of CYP2B6 G516T polymorphism was performed by sequencing. Peak and trough concentrations and exposure to efavirenz were significantly higher in TT than in GT and GG genotype patients (P < 0.001). Although RMP coadministration decreased the peak and trough concentrations and exposure to efavirenz by 17.8, 20.4, and 18.6%, respectively, the differences were not statistically significant. The trough concentration of efavirenz was subtherapeutic (less than 1.0 microg/ml) in 6 (8%) of 72 patients. In this South Indian population of HIV-infected patients, CYP2B6 G516T polymorphism but not RMP coadministration significantly influenced the pharmacokinetics of efavirenz; patients with the TT genotype had very high blood levels of efavirenz. While a small proportion of patients had subtherapeutic efavirenz levels, the clinical implications are uncertain, as all had good immunological responses to CART.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Aryl Hydrocarbon Hydroxylases; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Therapy, Combination; Female; Geography; HIV Infections; HIV-1; Humans; India; Male; Middle Aged; Oxidoreductases, N-Demethylating; Polymorphism, Genetic; Rifampin; Tuberculosis

2009
Genotypic detection of rifampicin and isoniazid resistant Mycobacterium tuberculosis strains by DNA sequencing: a randomized trial.
    Annals of clinical microbiology and antimicrobials, 2009, Jan-30, Volume: 8

    Tuberculosis is a growing international health concern. It is the biggest killer among the infectious diseases in the world today. Early detection of drug resistance allows starting of an appropriate treatment. Resistance to drugs is due to particular genomic mutations in specific genes of Mycobacterium tuberculosis(MTB). The aim of this study was to identify the presence of Isoniazid (INH) and Rifampicin(RIF) drug resistance in new and previously treated tuberculosis (TB) cases using DNA sequencing.. This study was carried out on 153 tuberculous patients with positive Bactec 460 culture for acid fast bacilli.. Of the 153 patients, 105 (68.6%) were new cases and 48 (31.4%) were previously treated cases. Drug susceptibility testing on Bactec revealed 50 resistant cases for one or more of the first line antituberculous. Genotypic analysis was done only for rifampicin resistant specimens (23 cases) and INH resistant specimens (26 cases) to detect mutations responsible for drug resistance by PCR amplification of rpoB gene for rifampicin resistant cases and KatG gene for isoniazid resistant cases. Finally, DNA sequencing was done for detection of mutation within rpoB and KatG genes. Genotypic analysis of RIF resistant cases revealed that 20/23 cases (86.9%) of RIF resistance were having rpoB gene mutation versus 3 cases (13.1%) having no mutation with a high statistical significant difference between them (P < 0.001). Direct sequencing of Kat G gene revealed point mutation in 24/26 (92.3%) and the remaining 2/26 (7.7%) had wild type KatG i.e. no evidence of mutation with a high statistical significant difference between them (P < 0.001).. We can conclude that rifampicin resistance could be used as a useful surrogate marker for estimation of multidrug resistance. In addition, Genotypic method was superior to that of the traditional phenotypic method which is time-consuming taking several weeks or longer.

    Topics: Adult; Antitubercular Agents; Bacterial Proteins; Catalase; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Point Mutation; Random Allocation; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Tuberculosis; Young Adult

2009
MenA is a promising drug target for developing novel lead molecules to combat Mycobacterium tuberculosis.
    Medicinal chemistry (Shariqah (United Arab Emirates)), 2009, Volume: 5, Issue:2

    Potent inhibitors of MenA (1,4-dihydroxy-2-naphtoate prenyltrasferase) in Mycobacterium tuberculosis are identified, and are also effective in inhibiting growth of Mycobacterium tuberculosis at low concentrations. The MenA inhibitors possess common chemical structural features of (alkylamino)oalkoxyphenyl)(phenyl)methanones. Significantly, the MenA inhibitors can be synthesized in a few steps with high overall yields. The representative MenA inhibitors are highly effective in killing nonreplicating Mycobacterium tuberculosis that is evaluated by using the Wayne low oxygen model. In addition, a series of drug resistant Mycobacterium spp. are sensitive to the MenA inhibitors. The results are expected to be of significance in terms of discovering new lead compounds that can be developed into new drugs to combat unmet diseases caused by Mycobacterium tuberculosis.

    Topics: Alkyl and Aryl Transferases; Bacterial Proteins; Benzophenones; Catalysis; Cell Proliferation; Dimethylallyltranstransferase; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Enzyme Inhibitors; Humans; Isoniazid; Microbial Viability; Molecular Structure; Mycobacterium; Mycobacterium tuberculosis; Rifampin; Structure-Activity Relationship; Tuberculosis; Vitamin K 2

2009
Efavirenz dose reduction to 200 mg once daily in a patient treated with rifampicin.
    AIDS (London, England), 2009, Mar-27, Volume: 23, Issue:6

    Topics: AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Cyclopropanes; Drug Interactions; Humans; Male; Middle Aged; Rifampin; Tuberculosis

2009
First-line anti-tuberculosis drug resistance patterns and trends at the national TB referral center in Iran--eight years of surveillance.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2009, Volume: 13, Issue:5

    Resistance to anti-tuberculosis (anti-TB) drugs is becoming a major and alarming threat in most regions worldwide.. This was a descriptive cross-sectional study at a tertiary hospital in Iran, using patient medical records for 2000-2003. The findings were analyzed following the same framework as that used for previous reports from this center.. Among 1556 TB patients, drug susceptibility testing (DST) was performed for 548 culture-positive cases. Anti-TB drug resistance to both isoniazid and rifampin was identified in 10 (2.8%) of the new TB cases (multidrug-resistant TB; MDR-TB). Any resistance was detected in 228 (41.6%), showing an increasing trend in both new and retreatment cases. The data analysis revealed that drug-resistant TB had a statistically significant association with Afghan ethnicity, age>65 years, and the type of disease (retreatment vs. new TB case) (p<0.05). Also, assessment of the drug resistance trends showed a significant increase in resistance to any anti-TB agent, to isoniazid, and to streptomycin in new cases, and to all of the first-line anti-TB drugs in retreatment patients.. There has been an increasing trend in drug resistance in recent years, particularly in retreatment cases. Hence, revision of the national TB control program, reevaluation of the role of the World Health Organization category II (CAT II) regimen, as well as the conducting of a nationwide drug resistance survey, are recommended.

    Topics: Adolescent; Aged; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Female; Humans; Iran; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; National Health Programs; Population Surveillance; Referral and Consultation; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

2009
Rifampin hepatotoxicity associated with treatment of latent tuberculosis infection.
    The American journal of the medical sciences, 2009, Volume: 337, Issue:5

    To determine the occurrence of hepatotoxicity associated with rifampin treatment of latent tuberculosis infection in patients from a public health tuberculosis clinic.. Evaluation of rifampin hepatotoxicity in adults aged >or=18 years from a database maintained from June 2001 to May 2007 in a public health department clinic. Rifampin 600 mg daily for 4 months was prescribed. Hepatotoxicity was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels more than 3 times the upper limit of normal (ULN) with symptoms or more than 5 times the ULN without symptoms.. Rifampin therapy was initiated in 348 patients. Among 205 patients with evaluable data, 4 (1.95%, 95% confidence interval: 0%-4.33%) had AST or ALT levels >5 times the ULN (2 patients at 1 month and 2 patients at 3 months). Three of these patients had elevated AST/ALT at baseline; 1 had hepatitis C and 1 had an unconfirmed history of hepatitis. Adherence to clinic visits and prescribed treatment was poor.. Rifampin hepatotoxicity associated with treatment of latent tuberculosis infection is rare. Our report suggests that hepatotoxicity is more likely in patients with baseline hepatic dysfunction and the need for increased vigilance in monitoring transaminases in these patients.

    Topics: Adult; Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Female; Humans; Liver; Male; Middle Aged; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

2009
Costs and cost-effectiveness of four treatment regimens for latent tuberculosis infection.
    American journal of respiratory and critical care medicine, 2009, Jun-01, Volume: 179, Issue:11

    Isoniazid given daily for 9 months is the standard treatment for latent tuberculosis infection (LTBI), but its effectiveness is limited by poor completion rates. Shorter course regimens and regimens using directly observed therapy result in improved adherence but have higher upfront costs.. To evaluate the costs and cost-effectiveness of regimens for the treatment of LTBI.. We used a computerized Markov model to estimate total societal costs and benefits associated with four regimens for the treatment of LTBI: self-administered isoniazid daily for 9 months, directly observed isoniazid twice-weekly for 9 months, directly observed isoniazid plus rifapentine once weekly for 3 months, and self-administered rifampin daily for 4 months. In the base-case analysis, subjects were assumed to have newly positive tuberculin skin tests after recent exposure to infectious tuberculosis.. We determined the costs of treatment, quality-adjusted life-years gained, and cases of active tuberculosis prevented. In the base-case analysis, rifampin dominated (less costly with increased benefits) all other regimens except isoniazid plus rifapentine, which was more effective at a cost $48,997 per quality-adjusted life year gained. Isoniazid plus rifapentine dominated all regimens at a relative risk of disease 5.2 times the baseline estimate, or with completion rates less than 34% for isoniazid or 37% for rifampin. Rifampin could be 17% less efficacious than self-administered isoniazid and still be cost-saving compared with this regimen.. In our model, rifampin is cost-saving compared with the standard therapy of self-administered isoniazid. Isoniazid plus rifapentine is cost-saving for extremely high-risk patients and is cost-effective for lower-risk patients.

    Topics: Antitubercular Agents; Cost-Benefit Analysis; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Markov Chains; Rifampin; Tuberculosis

2009
Tuberculosis in solid-organ transplant recipients: consensus statement of the group for the study of infection in transplant recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2009, May-01, Volume: 48, Issue:9

    Tuberculosis is a particularly important condition in solid-organ transplant recipients because of the delay in treatment caused by the difficulties involved in its diagnosis and because of the pharmacological toxicity associated with this treatment. Both treatment delay and toxicity are responsible for the many clinical complications of and high mortality associated with tuberculosis in this population. The Consensus Statement from the Spanish Group for the Study of Infectious Diseases in Transplant Recipients defines the indications for treatment of latent tuberculosis infection in solid-organ transplant recipients, especially in patients with a high risk of pharmacological toxicity, as is the case with liver recipients. We established a series of recommendations regarding the types of drugs and the duration of treatment of tuberculosis in solid-organ recipients, giving special attention to pharmacological interactions between rifampin and immunosuppressive drugs (cyclosporine, tacrolimus, rapamycin, and corticosteroids).

    Topics: Antitubercular Agents; Drug Interactions; Humans; Immunosuppressive Agents; Organ Transplantation; Rifampin; Spain; Transplantation; Tuberculosis

2009
Genotypic rpoB and gyrA profiles for detection of rifampicin and fluoroquinolone susceptibilities of Mycobacterium tuberculosis isolates directly from clinical sputum specimens.
    International journal of antimicrobial agents, 2009, Volume: 34, Issue:2

    Topics: Anti-Bacterial Agents; Bacterial Proteins; DNA Gyrase; DNA-Directed RNA Polymerases; DNA, Bacterial; Fluoroquinolones; Genotype; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis

2009
Therapeutic drug monitoring of antimycobacterial drugs in patients with both tuberculosis and advanced human immunodeficiency virus infection.
    Pharmacotherapy, 2009, Volume: 29, Issue:5

    To determine the feasibility of therapeutic drug monitoring for adjusting low serum antimycobacterial concentrations in patients with both tuberculosis and advanced human immunodeficiency virus (HIV).. Retrospective cohort study.. De-identified dataset from a tuberculosis clinic.. Twenty-one patients (median age 38 yrs, range 25-68 yrs) with advanced HIV infection (CD4(+) cell count < 100 cells/mm(3)) who received treatment for active tuberculosis between March 2002 and September 2007.. We evaluated data based on the practices performed at the tuberculosis clinic. After the daily doses of isoniazid and rifamycins (rifampin or rifabutin) were ingested, serum concentrations were obtained at 2 hours for isoniazid and rifampin, at 3 hours for rifabutin, and, when possible, at 6 hours for all three drugs to detect delayed absorption. Antimycobacterial drug concentrations were compared with published reference levels, and dosages were adjusted to achieve desired concentrations. Costs of monitoring were recorded for all patients. Of the 21 patients, 18 (86%) had low serum concentrations of at least one drug 2 hours after ingestion: 2 (10%) had low isoniazid concentrations, 5 (24%) had low rifamycin concentrations, and 11 (52%) had low serum concentrations of both drugs. The median number of dosage adjustments to attain normal concentrations was 1 (range 0-4 adjustments). The median cost/patient for therapeutic drug monitoring was $619 (range $230-1948). The median final doses to achieve normal concentrations were isoniazid 600 mg/day (range 300-1500 mg/day), rifampin 1050 mg/day (range 600-1200 mg/day), and rifabutin 300 mg (range 150-450 mg) 3 times/week. No patient demonstrated any adverse effects attributed to these higher doses.. Low serum concentrations of antituberculous drugs, which suggest malabsorption, are common among patients with advanced HIV who also have tuberculosis but can be overcome with higher doses. Therapeutic drug monitoring may be an effective tool to optimize therapy, but needs further study.

    Topics: Adult; Aged; Anti-Bacterial Agents; Anti-Retroviral Agents; Cohort Studies; Drug Monitoring; Drug Therapy, Combination; Feasibility Studies; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Retrospective Studies; Rifabutin; Rifampin; Tuberculosis

2009
Efavirenz and nevirapine interactions with rifampicin: resolving the dilemmas?
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2009, Jun-15, Volume: 48, Issue:12

    Topics: Alkynes; Anti-Bacterial Agents; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Interactions; HIV Infections; Humans; Nevirapine; Rifampin; Tuberculosis

2009
[Primary tuberculosis of the tongue].
    Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale, 2009, Volume: 38, Issue:2

    Topics: Adult; Antitubercular Agents; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Tongue Diseases; Tuberculosis

2009
In vitro and ex vivo activity of peptide deformylase inhibitors against Mycobacterium tuberculosis H37Rv.
    International journal of antimicrobial agents, 2009, Volume: 34, Issue:3

    Bacterial peptide deformylase (PDF) catalyses removal of the N-terminal formyl group of proteins and is essential for protein maturation, growth and survival of bacteria. Thus, PDF appears to be a good antimycobacterial drug target. In the present study, various well-known PDF inhibitors, such as BB-3497, actinonin, 1,10-phenanthroline, hydroxylamine hydrochloride and galardin, were selected to evaluate their inhibitory activity against Mycobacterium tuberculosis. All compounds were found to be active against M. tuberculosis, with MIC(90) values (lowest drug concentration at which 90% of growth was inhibited on the basis of CFU enumeration) ranging from 0.2 mg/L to 74 mg/L. BB-3497 and 1,10-phenanthroline exhibited potent in vitro antimycobacterial activity, and also showed synergism with isoniazid and rifampicin. All compounds showed a bacteriostatic mode of inhibition. Under ex vivo conditions and short-course chemotherapy, BB-3497 and actinonin were found to be significantly active, with BB-3497 exhibiting comparable efficacy to that of isoniazid. Collectively, promising activities of PDF inhibitors such as BB-3497 and actinonin suggest their potential use against M. tuberculosis.

    Topics: Amidohydrolases; Animals; Antibiotics, Antitubercular; Dipeptides; Drug Synergism; Drug Therapy, Combination; Hydroxamic Acids; Hydroxylamine; Isoniazid; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Phenanthrolines; Protease Inhibitors; Rifampin; Tuberculosis

2009
Comparison of two commercial assays for the characterization of rpoB mutations in Mycobacterium tuberculosis and description of new mutations conferring weak resistance to rifampicin.
    The Journal of antimicrobial chemotherapy, 2009, Volume: 64, Issue:2

    The aim of this study was to compare the efficiency of two commercial assays, INNO-LiPA Rif.TB and MTBDRplus, for the identification of mutations in the rpoB hot-spot region and to assess the efficiency of these mutations in conferring resistance to rifampicin.. A collection of 126 rifampicin-resistant Mycobacterium tuberculosis and Mycobacterium africanum isolates and 18 rifampicin-susceptible isolates from different countries were analysed using the two hybridization assays.. For 60 strains the hot-spot region of the rpoB gene was sequenced, confirming the results of the hybridization assays and allowing the identification of new mutations. In total, 17 mutations involving 10 codons were observed, two of which are newly described (D516Y and E562G/P564L). Mutations L533P, H526L, D516Y and L511P and the double mutation E562G/P564L conferred a low level of resistance.. The assays INNO-LiPA Rif.TB and MTBDRplus identified rpoB mutations in 98.4% of cases. MTBDRplus provided additional information due to the overlapping hybridization probes and in addition allowed the investigation of katG mutations for isoniazid resistance.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Genotype; Humans; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mutation, Missense; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Tuberculosis

2009
A retrospective evaluation of completion rates, total cost, and adverse effects for treatment of latent tuberculosis infection in a public health clinic in central massachusetts.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2009, Aug-01, Volume: 49, Issue:3

    Completion rates, total cost, and adverse effects were compared for patients in central Massachusetts treated for latent tuberculosis infection with 9 months of isoniazid or 4 months of rifampin. Although the adverse effects were similar between the 2 groups, 4 months of rifampin was associated with significantly better completion rates and less hepatotoxicity yet higher total cost.

    Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Female; Humans; Isoniazid; Liver; Male; Massachusetts; Middle Aged; Patient Compliance; Rifampin; Treatment Outcome; Tuberculosis; Young Adult

2009
Mutations in the rpoB gene of rifampin-resistant Mycobacterium tuberculosis isolates from Eastern Poland.
    The new microbiologica, 2009, Volume: 32, Issue:2

    This study investigated mutations in the rpoB gene of rifampin-resistant isolates obtained from patients living in Eastern Poland. A total of 37 phenotypically and/or genotypically confirmed M. tuberculosis rifampin-resistant clinical isolates were included in this study. The strains were selected from symptomatic patients with a diagnosis of pulmonary and extrapulmonary tuberculosis. A line probe assay kit (INNO-LiPA rif Tb) was used for any specific mutational pattern of rpoB gene. Our data support the common notion that rifampin resistance genotypes with mutation at a critical codon, i.e. the one encoding Ser-531, is frequent in M. tuberculosis populations regardless of geographic origin. Our findings also suggest that in a geographic area such as Eastern Poland less common mutations of the rpoB gene occur more frequently. The frequency of substitution at codon 526 (His-Asp) was found to be high in Lublin. This study indicates that mutations associated with nucleotide replacements in codons 526 (His-Asp) and 531 (Ser-Leu) were associated with a high percentage of RMP resistance, whereas mutations in codons 516 (Asp-Val) and 526 (His-Tyr) were observed in a low percentage of RMP-resistance.

    Topics: Amino Acid Substitution; Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Genetic Variation; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Poland; Reagent Kits, Diagnostic; Rifampin; Tuberculosis

2009
Sterilizing activity of R207910 (TMC207)-containing regimens in the murine model of tuberculosis.
    American journal of respiratory and critical care medicine, 2009, Sep-15, Volume: 180, Issue:6

    The diarylquinoline R207910 (TMC207) has potent bactericidal activity in a murine model of tuberculosis (TB), but its sterilizing activity has not been determined.. To evaluate the sterilizing activity of R207910-containing combinations in the murine model of TB.. Swiss mice were intravenously inoculated with 6 log(10) of Mycobacterium tuberculosis strain H37Rv, treated with R207910-containing regimens, and followed for 3 months to determine relapse rates (modified Cornell model).. Quantitative lung and spleen colony-forming unit counts and bacteriological relapse rates 3 months after the end of therapy were compared for the following regimens: 2, 3, or 4 months of R207910 (J) and pyrazinamide (Z) combined with rifampin (R) or isoniazid (H) or both and 3 or 4 months of a moxifloxacin (M)-containing regimen and 6 months of the standard WHO regimen RHZ. All J-treated mice were culture negative after 4 months of therapy. The relapse rate in the group treated with 4 months of JHRZ was similar to that of mice treated for 6 months with the RHZ regimen (6 vs. 17%; P = 0.54) and lower than that of RMZ (6 vs. 42%; P = 0,03), a moxifloxacin-containing regimen that was the most active in mice on once-daily basis.. Four months of treatment with some J-containing regimens was as effective as the 6-month standard regimen and more effective than 4 months of treatment with M-containing regimens. Supplementation of standard regimen (RHZ) with J or substitution of J for H may shorten the treatment duration needed to cure TB in patients.

    Topics: Animals; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Hydrolases; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Splenic

2009
[Evaluation of the genotype MTBDR assay for rapid detection of rifampin and isoniazid resistance in clinical Mycobacterium tuberculosis complex clinical isolates].
    Mikrobiyoloji bulteni, 2009, Volume: 43, Issue:2

    Rapid identification of resistant Mycobacterium tuberculosis complex isolates is quite important for the establishment of early and appropriate therapy. The Genotype MTBDR (Hain Lifescience, Nehren, Germany) is a commercially available DNA strip assay designed for the rapid detection of rpoB and katG gene mutations in clinical isolates. This study was conducted to determine the mutation types of phenotypically drug resistant 26 M. tuberculosis complex clinical isolates [15 isoniazid (INH), 1 rifampin (RMP) and 10 INH and RMP resistant] by Genotype MTBDR (G-MTBDR) DNA strip assay and to compare the diagnostic performance of this test. Sixteen of 25 (64%) INH-resistant and 9 of 11 (81.8%) RMP-resistant clinical isolates were correctly identified with the presence of hybridization in mutation probe or lack of hybridization at least by one of the wild type probes, by G-MTBDR assay. Hybridization with mutation probes was detected in only 5 of the RMP resistant isolates. We observed rpoB MUT3 (S531L, Ser-->4Leu) mutation in 4 and rpoB MUT1 (D516V) in one of these isolates. In 56% (14/25) of the INH-resistant isolates, katG T1 (S315T1) hybridization pattern was observed at katG mutation probe. G-MTBDR assay couldn't identify two of the 11 (18.2%) RMP-resistant isolates and one of these iSolates was shown to have a mutation at codon 531 (TCG-GCG) and the other at codon 545 (CTG-->ATG), possibly not associated with resistance, by sequence analysis. In four of the eight (8/25; 32%) INH-resistant isolates not identified by G-MTBDR assay, DNA cycle sequencing revealed different nucleotide changes outside the most common mutation zone. One of these were at codon 293 (GCT-->ACT) in katG, one with dual mutation at 279 (GGC-->ACC) in katG and at 15th C-->T in inhA gene, one at 15th C-->T in inhA gene and one at 279 (GGC-->ACC) in katG gene region. DNA membrane strip assay can be a use ful tool for the rapid detection of resistant M. tuberculosis complex isolates and therefore accelerate th initiation of the appropriate treatment. However, due to its restrictions in the determination of relatively rare mutations, this rapid screening test should be used together with conventional susceptibility tests in routine laboratory practices.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Bacterial Proteins; Catalase; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

2009
Relapse associated with active disease caused by Beijing strain of Mycobacterium tuberculosis.
    Emerging infectious diseases, 2009, Volume: 15, Issue:7

    The role of microbial factors in outcomes of tuberculosis treatment has not been well studied. We performed a case-control study to evaluate the association between a Beijing strain and tuberculosis treatment outcomes. Isolates from patients with culture-positive treatment failure (n = 8) or relapse (n = 54) were compared with isolates from randomly selected controls (n = 296) by using spoligotyping. Patients with Beijing strains had a higher risk for relapse (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.0-4.0, p = 0.04) but not for treatment failure. Adjustment for factors previously associated with relapse had little effect on the association between Beijing strains and relapse. Beijing strains were strongly associated with relapse among Asian-Pacific Islanders (OR 11, 95% CI 1.1-108, p = 0.04). Active disease caused by a Beijing strain was associated with increased risk for relapse, particularly among Asian-Pacific Islanders.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Asian People; Case-Control Studies; China; HIV Infections; Humans; Mycobacterium tuberculosis; Recurrence; Rifampin; Risk Factors; Treatment Failure; Treatment Outcome; Tuberculosis; Tuberculosis, Pulmonary

2009
Evaluation of wild-type MIC distributions as a tool for determination of clinical breakpoints for Mycobacterium tuberculosis.
    The Journal of antimicrobial chemotherapy, 2009, Volume: 64, Issue:4

    The aim of this study was to establish wild-type MIC distributions of first-line drugs for Mycobacterium tuberculosis, as well as to explore the usefulness of such distributions when setting clinical breakpoints.. We determined the MICs of rifampicin, isoniazid and ethambutol for M. tuberculosis using a Middlebrook 7H10 dilution method for 90 consecutive clinical isolates, 8 resistant strains and 16 isolates from the WHO proficiency test panel. M. tuberculosis H37Rv was used for quality control and susceptibility results using 7H10 were compared with the results obtained with BACTEC460.. The agreement with BACTEC460 was very high for isoniazid (99.1%) and rifampicin (99.1%) but lower for ethambutol (94.7%). Intra- and inter-assay variation was below one MIC dilution. The MIC distributions for isoniazid and rifampicin provided a clear separation between susceptible and resistant strains. Regarding ethambutol, the current breakpoint for 7H10 (5 mg/L) is close to the wild-type and all strains (n = 6) showing a disagreement between BACTEC460 and 7H10 were distributed very close to the breakpoint (MIC 4-8 mg/L). This problematic relation was confirmed by investigating isolates from the WHO panel with an agreement <95% (64%-88% among 26 laboratories, n = 4) for which the MICs were 4-8 mg/L.. Utilizing the wild-type MIC distribution was found to be as useful in M. tuberculosis as in other bacteria when setting clinical breakpoints. We suggest that the present clinical breakpoints should be re-evaluated, taking into account wild-type MIC distributions and available pharmacokinetic data.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2009
Body weight cutoff for daily dosage of efavirenz and 60-week efficacy of efavirenz-based regimen in human immunodeficiency virus and tuberculosis coinfected patients receiving rifampin.
    Antimicrobial agents and chemotherapy, 2009, Volume: 53, Issue:10

    Seventy-one human immunodeficiency virus-infected patients with tuberculosis who were receiving a rifampin (rifampicin)-containing regimen were initiated on treatment with efavirenz at 600 mg/day plus stavudine-lamivudine. Fasting efavirenz concentrations at 12 h after dosing (C12) were monitored. The mean +/- standard deviation efavirenz C12 at weeks 6 and 12 and after rifampin discontinuation were 4.5 +/- 4.3, 3.8 +/- 3.5, and 3.5 +/- 2.7 mg/liter, respectively. High body weight was associated with a low efavirenz C12 at weeks 6 and 12 (P = 0.003, r = -0.255). The efavirenz C12 regression prediction line at 1 mg/liter intercepted a mean body weight of 57.5 kg.

    Topics: Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Body Weight; Cyclopropanes; Drug Administration Schedule; Female; HIV Infections; Humans; Male; Multivariate Analysis; Rifampin; Tuberculosis

2009
Incomplete immunological recovery following anti-tuberculosis treatment in HIV-infected individuals with active tuberculosis.
    The Indian journal of medical research, 2009, Volume: 129, Issue:5

    Mycobacterium tuberculosis infection has been shown to result in increased HIV replication and disease progression in HIV-infected individuals through increased immune activation. The objective of this study was to correlate plasma levels of immune activation markers with the presence of tuberculosis (TB) in HIV-infected and uninfected individuals, and to study the changes following anti-tuberculosis treatment.. Plasma markers of immune activation - neopterin, beta-2-microglobulin (beta2M) and soluble tumour necrosis factor alpha receptor type I (sTNFalpha-RI) were measured by ELISA in 42 HIV positive TB patients (HIV+TB+) undergoing a six-month course of TB chemotherapy. Thirty seven HIV+ persons without active TB, 38 TB patients without HIV infection, and 62 healthy volunteers served as controls.. Plasma levels of all three markers were elevated in HIV+ individuals, more so in those with active TB. When HIV+ individuals were further categorized based on CD4+ T cell counts, HIV+TB+ patients with CD4+ T cells counts

    Topics: Acquired Immunodeficiency Syndrome; Analysis of Variance; beta 2-Microglobulin; Biomarkers; CD4-Positive T-Lymphocytes; Cell Count; Enzyme-Linked Immunosorbent Assay; Ethambutol; Humans; India; Isoniazid; Neopterin; Pyrazinamide; Receptors, Tumor Necrosis Factor, Type I; Rifampin; Tuberculosis

2009
Use of non-invasive bioluminescent imaging to assess mycobacterial dissemination in mice, treatment with bactericidal drugs and protective immunity.
    Microbes and infection, 2009, Volume: 11, Issue:14-15

    Monitoring the spread of mycobacterium in vivo using biophotonic imaging provides a fast, reliable and sensitive method to evaluate the distribution of the infection. Moreover, this technique allows for a significant reduction in the number of animals required in comparison to conventional anatomopathological studies. Here, we describe for the first time and validate the use of a luciferase-tagged recombinant Mycobacterium bovis BCG for non-invasive bioluminescent imaging of 1) bacterial dissemination in tissues, 2) the efficacy of treatment with anti-mycobacterial drugs and 3) the role of adaptive immune responses in controlling mycobacterial infection in vivo.

    Topics: Animals; Antitubercular Agents; Diagnostic Imaging; Disease Models, Animal; Humans; Isoniazid; Luciferases; Luminescent Measurements; Mice; Mycobacterium bovis; Rifampin; Treatment Outcome; Tuberculosis

2009
Isoniazid and rifampicin resistance-associated mutations in Mycobacterium tuberculosis isolates from Yangon, Myanmar: implications for rapid molecular testing.
    The Journal of antimicrobial chemotherapy, 2009, Volume: 64, Issue:4

    To evaluate the frequency and nature of mutations in genes associated with resistance to rifampicin and isoniazid in Mycobacterium tuberculosis isolates collected from Yangon, Myanmar.. Ninety-six isoniazid-resistant M. tuberculosis isolates, including 29 multidrug-resistant isolates, were analysed for mutations in the rpoB, katG, inhA, oxyR and ahpC genes.. Mutations in the rpoB gene were detected in 25 (86.2%) of the 29 rifampicin-resistant isolates. Of the 96 isoniazid-resistant isolates, 61 (63.5%) had mutations in codon 315 of the catalase-peroxidase-encoding gene (katG). Mutations in codon 315 were observed at a higher frequency in the multidrug-resistant isolates than in the isoniazid-resistant isolates (86.2% versus 53.7%, respectively, P = 0.003). Mutations in the oxyR-ahpC promoter region and in the inhA gene were observed in 14.6% and 2.1% of the isolates, respectively. Genotyping performed on the 96 M. tuberculosis isolates revealed a total of 94 different genotyping patterns. A distinct genotypic pattern was found in 92 isolates, whereas 4 isolates belonged to two clusters with identical genotypes, suggesting that the majority of the isolates were not from an outbreak of a single drug-resistant clone.. This study provides the first molecular characterization of isoniazid- and rifampicin-resistant M. tuberculosis isolates from Myanmar and gives information on the molecular basis for rifampicin and isoniazid drug resistance in M. tuberculosis. The study generates useful information for the development of potential rapid molecular drug susceptibility tests.

    Topics: Antitubercular Agents; Bacterial Proteins; Bacterial Typing Techniques; Catalase; Cluster Analysis; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation, Missense; Myanmar; Mycobacterium tuberculosis; Oxidoreductases; Point Mutation; Polymorphism, Restriction Fragment Length; Promoter Regions, Genetic; Rifampin; Sequence Analysis, DNA; Tuberculosis

2009
Short-course therapy with daily rifapentine in a murine model of latent tuberculosis infection.
    American journal of respiratory and critical care medicine, 2009, Dec-01, Volume: 180, Issue:11

    Regimens recommended to treat latent tuberculosis infection (LTBI) are 3 to 9 months long. A 2-month rifampin+pyrazinamide regimen is no longer recommended. Shorter regimens are highly desirable. Because substituting rifapentine for rifampin in the standard regimen for active tuberculosis halves the treatment duration needed to prevent relapse in mice, we hypothesized daily rifapentine-based regimens could shorten LTBI treatment to 2 months or less.. To improve an existing model of LTBI chemotherapy and evaluate the efficacy of daily rifapentine-based regimens.. Mice were immunized with a more immunogenic recombinant Bacille Calmette-Guérin strain (rBCG30) and received very low-dose aerosol infection with Mycobacterium tuberculosis to establish a stable lung bacterial burden below 10(4) CFU without drug treatment. Mice received a control (isoniazid alone, rifampin alone, rifampin+isoniazid, rifampin+pyrazinamide) or test (rifapentine alone, rifapentine+isoniazid, rifapentine+pyrazinamide, rifapentine+isoniazid+pyrazinamide) regimen for 8 weeks. Rifamycin doses were 10 mg/kg/d, analogous to the same human doses. Outcomes were biweekly lung CFU counts and relapse after 4 to 8 weeks of treatment.. M. tuberculosis CFU counts remained stable around 3.65 log(10) in immunized, untreated mice. Isoniazid or rifampin left all or most mice culture-positive at week 8. Rifampin+isoniazid cured 0 and 53% of mice and rifampin+pyrazinamide cured 47 and 100% of mice in 4 and 8 weeks, respectively. Rifapentine-based regimens were more active than rifampin+isoniazid and indistinguishable from rifampin+pyrazinamide.. In this improved murine model of LTBI chemotherapy with very low lung burden, existing regimens were well represented. Daily rifapentine-based regimens were at least as active as rifampin+pyrazinamide, suggesting they could effectively treat LTBI in 6 to 8 weeks.

    Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Drug Administration Schedule; Female; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis

2009
Reversible reduction of nevirapine plasma concentrations during rifampicin treatment in patients coinfected with HIV-1 and tuberculosis.
    Journal of acquired immune deficiency syndromes (1999), 2009, Sep-01, Volume: 52, Issue:1

    Nevirapine (NVP) plasma levels are reduced in patients receiving rifampicin (RFM) for tuberculosis (TB) treatment. We determined variations over time of the pharmacokinetic parameters of NVP in patients who receive RFM.. HIV-1-infected patients with CD4+ T-lymphocyte count

    Topics: Adult; Anti-HIV Agents; Antibiotics, Antitubercular; CD4 Lymphocyte Count; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Lamivudine; Longitudinal Studies; Male; Middle Aged; Nevirapine; Prospective Studies; Rifampin; Stavudine; Tuberculosis

2009
[Relationship between Beijing genotypes of Mycobacterium tuberculosis and drug-resistant phenotypes].
    Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae, 2009, Volume: 31, Issue:4

    To investigate the distribution of the Beijing genotypes of Mycobacterium tuberculosis (M. tuberculosis) and the relationships between Beijing genotype strains and drug-resistant phenotypes in China.. Clinical isolates were collected during a 9-month research period from April to December in 2008 in six geographic regions of China. One isolate that had been biochemically confirmed to be a member of the M. tuberculosis complex was collected from each patient. The demographic data of the patients (eg. sex, age, and history of tuberculosis) as well as the drug resistance patterns and sources of the clinical isolates were collected. Drug susceptibility testing was performed using proportion method. Beijing genotypes of M. tuberculosis were identified by spacer oligonucleotide typing or insertion of IS6110 in the genomic dnaA-dnaN locus.. Among the 410 M. tuberculosis clinical isolates, 67.1% (275/410) isolates were Beijing genotypes of M. tuberculosis. Significantly larger proportions of tuberculosis patients were infected with Beijing genotypes in the northeastern regions of China than that of in the central-western regions (chi2 = 20.50, P = 0.000). No significant associations were found either between Beijing genotype strains and patients' age, sex, or treatment history. Multidrug-resistant isolates and rifampin-resistant isolates were more common among Beijing genotype strains than among non-Beijing strains (P = 0.002, P = 0.005).. About two third of the clinical isolates of M. tuberculosis in China are Beijing genotypes. Beijing genotype strains are not correlated with patients' age, sex, treatment history. People living in the northeastern regions of China are more susceptible to Beijing genotypes than those living in the central-western of China. Beijing genotype strains tend to be rifampin-resistant or multidrug-resistant.

    Topics: Antitubercular Agents; China; Genotype; Humans; Mycobacterium tuberculosis; Phenotype; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2009
An integrated approach to rapid diagnosis of tuberculosis and multidrug resistance using liquid culture and molecular methods in Russia.
    PloS one, 2009, Sep-23, Volume: 4, Issue:9

    To analyse the feasibility, cost and performance of rapid tuberculosis (TB) molecular and culture systems, in a high multidrug-resistant TB (MDR TB) middle-income region (Samara, Russia) and provide evidence for WHO policy change.. Performance and cost evaluation was conducted to compare the BACTEC MGIT 960 system for culture and drug susceptibility testing (DST) and molecular systems for TB diagnosis, resistance to isoniazid and rifampin, and MDR TB identification compared to conventional Lowenstein-Jensen culture assays.. 698 consecutive patients (2487 sputum samples) with risk factors for drug-resistant tuberculosis were recruited. Overall M. tuberculosis complex culture positivity rates were 31.6% (787/2487) in MGIT and 27.1% (675/2487) in LJ (90.5% and 83.2% for smear-positive specimens). In total, 809 cultures of M. tuberculosis complex were isolated by any method. Median time to detection was 14 days for MGIT and 36 days for LJ (10 and 33 days for smear positive specimens) and indirect DST in MGIT took 9 days compared to 21 days on LJ. There was good concordance between DST on LJ and MGIT (96.8% for rifampin and 95.6% for isoniazid). Both molecular hybridization assay results correlated well with MGIT DST results, although molecular assays generally yielded higher rates of resistance (by approximately 3% for both isoniazid and rifampin).. With effective planning and logistics, the MGIT 960 and molecular based methodologies can be successfully introduced into a reference laboratory setting in a middle incidence country. High rates of MDR TB in the Russian Federation make the introduction of such assays particularly useful.

    Topics: Bacterial Typing Techniques; Bacteriological Techniques; Communicable Disease Control; Cost-Benefit Analysis; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenotype; Rifampin; Risk Factors; Russia; Tuberculosis; Tuberculosis, Multidrug-Resistant

2009
Synthesis and antitubercular activity of 7-chloro-4-quinolinylhydrazones derivatives.
    Bioorganic & medicinal chemistry letters, 2009, Nov-15, Volume: 19, Issue:22

    A series of twenty-one 7-chloro-4-quinolinylhydrazones (3a-u) have been synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H(37)Rv. The compounds 3f, 3i and 3o were non-cytotoxic and exhibited an important minimum inhibitory concentration (MIC) activity (2.5 microg/mL), which can be compared with that of the first line drugs, ethambutol (3.12 microg/mL) and rifampicin (2.0 microg/mL). These results can be considered an important start point for the rational design of new leads for anti-TB compounds.

    Topics: Anti-Bacterial Agents; Antitubercular Agents; Ethambutol; Humans; Microbial Sensitivity Tests; Microbial Viability; Mycobacterium tuberculosis; Quantitative Structure-Activity Relationship; Rifampin; Structure-Activity Relationship; Tuberculosis

2009
Do we still need lead-in dosing of nevirapine in HIV-infected patients who are receiving rifampicin-containing antituberculous therapy?
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2009, Nov-01, Volume: 49, Issue:9

    Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Interactions; Female; HIV Infections; Humans; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Treatment Outcome; Tuberculosis

2009
Serious adverse reactions in a tuberculosis programme setting in Kyrgyzstan.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2009, Volume: 13, Issue:12

    Serious adverse reactions among new smear-positive patients were studied in a programme setting in Kyrgyzstan. Two per cent of patients on tuberculosis (TB) treatment had to interrupt treatment for > or =1 week, and more than 80% of the reactions occurred during the first month of treatment. Pyrazinamide was the most common causative agent, followed by rifampicin.

    Topics: Adult; Antitubercular Agents; Communicable Disease Control; Humans; Kyrgyzstan; Pyrazinamide; Rifampin; Sputum; Tuberculosis

2009
[Diagnostic image. A man with a swelling under his jaw].
    Nederlands tijdschrift voor geneeskunde, 2009, Volume: 153

    A 79-year-old man had a tumour under his jaw, due to tuberculosis in a lymph node following BCG treatment for carcinoma of the bladder.

    Topics: Aged; BCG Vaccine; Carcinoma; Humans; Isoniazid; Lymph Nodes; Male; Rifampin; Treatment Outcome; Tuberculosis; Urinary Bladder Neoplasms

2009
Effectiveness of highly active antiretroviral therapy (HAART) used concomitantly with rifampicin in patients with tuberculosis and AIDS.
    The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases, 2009, Volume: 13, Issue:5

    This study evaluated the effectiveness of two HAART regimens concomitant to rifampicin based tuberculosis (TB) treatment. Patients with TB/HIV diagnosis followed at the TB program between June 2000 and March 2005 were prospectively evaluated. The different HAART regimens in antiretrovirals (ARV) treatment naïve and ARV experienced patients were compared. The effectiveness of HAART was defined as a VL <80 copies/mL from month 4 to month 10 after TB treatment. One hundred and forty-two patients were included. Among these, 68 (47%) were treatment naïve and 76 (53%) previously exposed. Odds ratio (OR) in naïve patients treated with efavirenz (EFV) based regimen (n=42) compared to ritonavir/saquinavir (RTV/SQV) based regimen (n=26) was 8.0 (CI=1.67-38.35, p=0.008). OR from ARV experienced patients treated with RTV/SQV based regimen compared to EFV was 3.08 (CI=0.65-14.6, p=0.15), although with no statistical significance. Better effectiveness and tolerability were observed in antiretrovirals treatment naïve patients using EFV based regimens. Although not statistically significant, a favorable virologic response and a better tolerability were observed in the ARV experienced patients group who received a RTV/SQV based regimen.

    Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; CD4 Lymphocyte Count; Female; Follow-Up Studies; HIV Infections; Humans; Male; Middle Aged; Rifampin; Treatment Outcome; Tuberculosis; Viral Load; Young Adult

2009
Tetrahdroxysqualene from Rhus taitensis shows antimycobacterial activity against Mycobacterium tuberculosis.
    Journal of natural products, 2008, Volume: 71, Issue:9

    Tuberculosis has become a major health problem, in particular with the emergence of extremely drug resistant tuberculosis (XDRTB). In our search for new therapeutic leads against TB, we isolated a new triterpene (1) from the plant Rhus taitensis collected in Papua New Guinea. Tetrahydroxysqualene (1) was isolated using bioassay-guided fractionation of the methanolic extract of R. taitensis leaves and twigs. The structure of tetrahydroxysqualene (1) was elucidated on the basis of HRESIMS and 1D and 2D NMR spectra. Tetrahydroxysqualene (1) exhibited antituberculosis activity with an MIC of 10.0 microg/mL, while showing only modest cytotoxicity.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Drug Screening Assays, Antitumor; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nuclear Magnetic Resonance, Biomolecular; Papua New Guinea; Plant Leaves; Plant Stems; Plants, Medicinal; Rhus; Squalene; T-Lymphocytes; Tuberculosis

2008
Rifampin resistance, Beijing-W clade-single nucleotide polymorphism cluster group 2 phylogeny, and the Rv2629 191-C allele in Mycobacterium tuberculosis strains.
    Journal of clinical microbiology, 2008, Volume: 46, Issue:8

    Rifampin resistance is a key prognostic marker for treatment success in tuberculosis patients. Recently, Wang et al. demonstrated that Rv2629 A191C mutations were present in 99.1% of rifampin-resistant and 0% of rifampin-susceptible clinical Mycobacterium tuberculosis isolates and that overexpression of the Rv2629 191C allele in Mycobacterium smegmatis produced an eightfold increase in rifampin resistance. These results suggested that Rv2629 could be a cause of rifampin resistance and a valuable target for rifampin resistance detection assays. We developed a molecular-beacon assay to study the association between Rv2629 191 alleles and rifampin resistance in 246 geographically and phylogenetically diverse clinical M. tuberculosis isolates. The 191C allele was present in 30/98 (30.6%) rifampin-resistant isolates and 25/148 (16.9%) rifampin-susceptible isolates and was more common in isolates from Asia. Phylogenetic analysis demonstrated complete overlap between the 191C allele and single nucleotide polymorphism cluster group 2 (SCG-2), a phylogenetic lineage that corresponds to the Beijing-W clade of M. tuberculosis. All 55 (100%) 191C isolates were SCG-2, while none of the 191 191A isolates were SCG-2 (P < 0.001). No association was found between the 191C allele and rifampin resistance in an analysis that included the SCG type (P = 1.0). Also, in contrast to the findings of Wang et al., we found that overexpression of either Rv2629 191 allele in M. smegmatis did not produce an increase in rifampin resistance. We conclude that the Rv2629 191C allele is not associated with rifampin resistance and that the allele cannot be used as a molecular target to detect rifampin resistance. The allele appears to be an excellent marker for the Beijing-W clade/SCG-2 phylogenetic group.

    Topics: Alleles; Amino Acid Substitution; Antitubercular Agents; Bacterial Proteins; DNA, Bacterial; Drug Resistance, Bacterial; Gene Dosage; Humans; Mycobacterium smegmatis; Mycobacterium tuberculosis; Phylogeny; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; Rifampin; Tuberculosis

2008
Drug lymphocyte stimulation test in the diagnosis of adverse reactions to antituberculosis drugs.
    Chest, 2008, Volume: 134, Issue:5

    Tuberculosis (TB) is a worldwide infectious disease. Recently, standard therapy has become very effective for treating patients with TB; however, as a result of this powerful regimen, serious side effects have become an important problem. The aim of this prospective study was to evaluate the usefulness of the drug lymphocyte stimulation test (DLST) to determine anti-TB drugs causing side effects.. Four hundred thirty-six patients with TB were admitted to our hospital for treatment between January 2002 and August 2007. DLST was performed in patients who had certain adverse drug reactions during TB treatment. The causative drug was identified by the drug provocation test (DPT). The tested drugs were mainly isoniazid (INH), rifampin (RIF), ethambutol (EMB) and pyrazinamide (PZA).. Of 436 patients, 69 patients (15.8%) had certain adverse drug reactions to anti-TB drugs. Of the 261 agents that underwent the DLST and DPT, 28 agents (10.7%) in 20 patients (28.9%) were positive by DLST, and 67 agents (25.7%) in 46 patients (66.6%) were identified as causative drugs by DPT. The sensitivity of DLST was only 14.9% for all drugs (INH, 14.3%; RIF, 13.6%; EMB, 14.3%; PZA, 0%).. DLST offers little contribution to the detection of causative agents in patients with adverse anti-TB drug reactions.

    Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Lymphocyte Activation; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2008
Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy.
    JAMA, 2008, Aug-06, Volume: 300, Issue:5

    Rifampicin-based antitubercular therapy reduces the plasma concentrations of nevirapine and efavirenz. The virological consequences of these interactions are not well described.. To assess the effectiveness and tolerability of concomitant efavirenz- or nevirapine-based combination antiretroviral therapy and rifampicin-based antitubercular therapy.. Cohort analysis of prospectively collected routine clinical data in a community-based South African antiretroviral treatment program. Antiretroviral treatment-naive adults enrolled between May 2001 and June 2006 were included in the analysis, and were followed up until the end of 2006.. Patients starting antiretroviral therapy with or without concurrent antitubercular therapy received either efavirenz or nevirapine at standard doses. Patients developing tuberculosis while taking antiretroviral therapy that included nevirapine were either changed to efavirenz or continued taking nevirapine.. Viral load of 400 copies/mL or more after 6, 12, and 18 months of antiretroviral therapy; time to the first viral load of 400 copies/mL or more; time to confirmed virological failure (2 consecutive values > or = 5000 copies/mL); time to death; and time to treatment-limiting toxicity were assessed.. The analysis included 2035 individuals who started antiretroviral therapy with efavirenz (1074 with concurrent tuberculosis) and 1935 with nevirapine (209 with concurrent tuberculosis). There were no differences in time to death or substitution of either antiretroviral drug for toxicity with and without concurrent tuberculosis. Patients starting nevirapine with concurrent tuberculosis were at a higher risk of elevated viral load most notably at 6 months (16.3%; 95% confidence interval [CI], 10.6%-23.5%) than those without tuberculosis (8.3%; 95% CI, 6.7%-10.0%; adjusted odds ratio [OR], 2.1; 95% CI, 1.2-3.4; and in the combined estimate, adjusted OR, 1.7; 95% CI, 1.2-2.6). In the time-to-event analysis of confirmed virological failure (2 consecutive values of > or = 5000 copies/mL), patients starting nevirapine with concurrent tuberculosis developed virological failure sooner (adjusted hazard ratio [HR] 2.2; 95% CI, 1.3-3.7). There were no differences between patients starting efavirenz with and without concurrent tuberculosis (adjusted OR, 1.1; 95% CI, 0.8-1.5 [combined estimate] and adjusted HR, 1.1; 95% CI, 0.6-2.0, respectively). There was no difference in time to virological rebound in patients free of tuberculosis and those developing tuberculosis during follow-up while taking nevirapine (adjusted HR, 1.0; 95% CI, 0.5-2.0) or efavirenz (adjusted HR, 0.8; 95% CI, 0.4-1.7).. In this cohort study, virological outcomes were inferior when nevirapine-based antiretroviral therapy was commenced while taking antitubercular treatment (vs without concurrent tuberculosis) but comparable when starting efavirenz-based antiretroviral therapy (vs without concurrent tuberculosis) or when tuberculosis developed while taking established nevirapine- or efavirenz-based therapies.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Benzoxazines; Cyclopropanes; Drug Interactions; Female; HIV Infections; Humans; Male; Nevirapine; Rifampin; South Africa; Treatment Failure; Treatment Outcome; Tuberculosis; Viral Load

2008
[Utility of gene analysis for evaluation of the current status of tuberculosis developing long after primary infection].
    [Nihon koshu eisei zasshi] Japanese journal of public health, 2008, Volume: 55, Issue:6

    The purpose of this study was to examine the utility of gene analysis of Mycobacterium tuberculosis as a means of determining the current status of tuberculosis developing in patients long after primary infection and identifying the source of infection.. We analyzed two outbreaks of tuberculosis involving chronic carriers in 2004 within Okayama prefecture. DNA was extracted from Mycobacterium tuberculosis stains isolated from the patients, and subjected to IS6110-RFLP and PGRS-RFLP analyses. The resulting IS6110-RFLP patterns were compared with a database (compiled since December 1999) of RFLP patterns of isolates from newly registered tuberculosis patients in the prefecture. Mutations in the rpoB gene for rifampicin resistance and the katG gene for isoniazid resistance ofMycobacterium tuberculosis were detected by real-time PCR followed by melting curve analysis. Bacterial isolates were tested for antimycobacterial susceptibility by the microdilution susceptibility method and the proportion method on Ogawa's medium.. In outbreak 1, an epidemiological survey suggested that two individuals contracted tuberculosis from the same patient after an interval of about 20 years. They differed from the suspected patient in the drug susceptibility patterns of bacterial isolates and mutations in the drug susceptibility-related genes, but the results of IS6110-RFLP and PGRS-RFLP analyses supported a conclusion of a common source of infection. In outbreak 2, a hospital employee developed primary multidrug-resistant tuberculosis of unknown origin. Comparison between the IS6110-RFLP patterns of the employee's bacterial isolate and the IS6110-RFLP database showed identity to a bacterial isolate from a chronic carrier who had died in the same hospital 4 years and 8 months earlier. Moreover, the two isolates were identical regarding drug susceptibility patterns and mutations in drug resistance-related genes, suggesting a nosocomial infection.. These results indicates that tuberculosis gene analysis provides useful information for comprehension of the current status of tuberculosis developing in patients long after primary infection. Genotype database construction may allow detection of the source of infection, which cannot be identified by contact examination alone.

    Topics: Contact Tracing; Drug Resistance, Bacterial; Humans; Mutation; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Reverse Transcriptase Polymerase Chain Reaction; Rifampin; Tuberculosis

2008
Evaluation of methods for rapid detection of resistance to isoniazid and rifampin in Mycobacterium tuberculosis isolates collected in the Caribbean.
    Journal of clinical microbiology, 2008, Volume: 46, Issue:10

    The rapid identification of drug-resistant strains of Mycobacterium tuberculosis is crucial for the timely initiation of appropriate antituberculosis therapy. The performance of the Genotype MTBDRplus assay was compared with that of the Bactec 460 TB system, a "gold standard" culture-based method. The Genotype MTBDRplus assay was quicker and more cost-effective for the detection of rifampin resistance, but it was not as good for the detection of isoniazid-resistant strains in our setting.

    Topics: Antitubercular Agents; Caribbean Region; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

2008
Isoniazid or moxifloxacin in rifapentine-based regimens for experimental tuberculosis?
    American journal of respiratory and critical care medicine, 2008, Nov-01, Volume: 178, Issue:9

    Recent studies have demonstrated that combined substitutions of rifapentine for rifampin and moxifloxacin for isoniazid in the standard, daily, short-course regimen of rifampin, isoniazid, and pyrazinamide produces stable cure in 12 weeks or less. This study was designed to more precisely evaluate the contribution of moxifloxacin and isoniazid to rifapentine-based regimens.. We compared bactericidal activity and treatment-shortening potential between regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide administered either thrice-weekly or daily.. Using a mouse model of tuberculosis, we assessed bactericidal activity by performing quantitative cultures of lung homogenates over the first 12 weeks of treatment. Relapse rates were assessed after completing 8, 10, and 12 weeks of treatment to determine the duration of treatment necessary for stable cure.. After 4 weeks of treatment, daily and thrice-weekly therapy with rifapentine, moxifloxacin, and pyrazinamide was significantly more active than treatment with rifapentine, isoniazid, and pyrazinamide. By 8 weeks of treatment, all mice receiving the moxifloxacin-containing regimens were lung culture negative, whereas those mice receiving the isoniazid-containing regimens continued to be lung culture positive. However, the duration of treatment necessary to achieve stable cure was 10 weeks for daily regimens and 12 weeks for thrice-weekly regimens, regardless of whether isoniazid or moxifloxacin was used. All mice receiving standard daily therapy with rifampin, isoniazid, and pyrazinamide relapsed after 12 weeks of treatment.. These results suggest that regimens consisting of isoniazid or moxifloxacin plus rifapentine and pyrazinamide may dramatically shorten the duration of treatment needed to cure human tuberculosis.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluoroquinolones; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Moxifloxacin; Pyrazinamide; Quinolines; Recurrence; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

2008
Update on the treatment of tuberculosis.
    American family physician, 2008, Aug-15, Volume: 78, Issue:4

    Approximately one third of the world's population, including more than 11 million persons in the United States, is latently infected with Mycobacterium tuberculosis. Although most cases of tuberculosis in the United States occur in foreign-born persons from endemic countries, the prevalence is generally greater in economically disadvantaged populations and in persons with immunosuppressive conditions. Delays in detection and treatment allow for greater transmission of the infection. Compared with the traditional tuberculin skin test and acid-fast bacilli smear, newer interferon-gamma release assays and nucleic acid amplification assays lead to more rapid and specific detection of M. tuberculosis infection and active disease, respectively. Nine months of isoniazid therapy is the treatment of choice for most patients with latent tuberculosis infection. When active tuberculosis is identified, combination therapy with isoniazid, rifampin, pyrazinamide, and ethambutol should be promptly initiated for a two-month "intensive phase," and in most cases, followed by isoniazid and a rifamycin product for a four- to seven-month "continuation phase." Directly observed therapy should be used. Although currently limited in the United States, multidrug-resistant and extensively drug-resistant strains of tuberculosis are increasingly recognized in many countries, reaffirming the need for prompt diagnosis and adequate treatment strategies. Similarly, care of persons coinfected with human immunodeficiency virus and tuberculosis poses additional challenges, including drug interactions and immune reconstitution inflammatory syndrome.

    Topics: Antitubercular Agents; Comorbidity; Directly Observed Therapy; Disease Progression; Drug Therapy, Combination; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Male; Mass Screening; Mycobacterium tuberculosis; Patient Compliance; Pregnancy; Pregnancy Complications, Infectious; Pyrazinamide; Rifampin; Risk Factors; Tuberculin Test; Tuberculosis

2008
GenoType MTBDRplus assay for molecular detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis strains and clinical samples.
    Journal of clinical microbiology, 2008, Volume: 46, Issue:11

    The purpose of this study was to evaluate the GenoType MTBDRplus assay (Hain Lifescience GmbH, Nehren, Germany) for its ability to detect resistance to rifampin (RIF) and isoniazid (INH) in Mycobacterium tuberculosis clinical strains and directly in clinical samples. A total of 62 clinical strains characterized with the Bactec 460TB system were included. For the INH-resistant strains, the MIC was measured and sequencing was performed. Sixty-five clinical samples from 28 patients (39 smear-positive samples and 26 smear-negative samples) were also tested directly. The corresponding isolates of the clinical specimens were studied with the Bactec 460TB system. The overall rates of concordance of the MTBDRplus assay and the Bactec 460TB system for the detection of RIF and INH susceptibility in clinical strains were 98.3% (61/62) and 79% (49/62), respectively. The rate of concordance between the Bactec 460TB system and the MTBDRplus test for the detection of INH resistance in the group of 27 strains with low-level resistance was 62.9% (17/27), and that for the detection of INH resistance in the group of 21 strains with high-level resistance was 85.71% (18/21). Valid test results were obtained for 78.45% (51/65) of the clinical samples tested. The rates of concordance between both assays for the detection of drug resistance in these samples were 98% (50/51) for RIF and 96.2% (49/51) for INH. Taking into account only one sample per patient, the overall rate of concordance between both tests was 92.85% (26/28). The GenoType MTBDRplus assay is easy to perform and is a useful tool for the management of tuberculosis, as it allows the detection of resistance to RIF and INH in M. tuberculosis strains and also in clinical samples.

    Topics: Antitubercular Agents; Bacteriological Techniques; DNA, Bacterial; Drug Resistance; Genotype; Germany; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Tuberculosis

2008
Pharmacokinetics interaction studies between rifampicin and protease inhibitors: methodological problems.
    AIDS (London, England), 2008, Oct-01, Volume: 22, Issue:15

    Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Drug Interactions; HIV Protease Inhibitors; Humans; Research Design; Rifampin; Tuberculosis

2008
Durability of stavudine, lamivudine and nevirapine among advanced HIV-1 infected patients with/without prior co-administration of rifampicin: a 144-week prospective study.
    BMC infectious diseases, 2008, Oct-14, Volume: 8

    To date, data on the durability of a regimen of stavudine, lamivudine and nevirapine are very limited, particularly from the resource-limited settings.. A prospective cohort study was conducted among 140 antiretroviral-naïve patients who were enrolled to initiate d4T, 3TC and NVP between November 2004 and March 2005. The objectives were to determine immunological and virological responses after 144 weeks of antiretroviral therapy. Seventy patients with tuberculosis also received rifampicin during the early period of antiviral treatment (TB group).. Of all, median (IQR) baseline CD4 cell count was 31 (14-79) cells/mm3; median (IQR) baseline HIV-1 RNA was 433,500 (169,000-750,000) copies/mL. The average body weight was 55 kilograms. By intention-to-treat analysis at 144 weeks, the overall percentage of patients who achieved plasma HIV-1 RNA <50 copies/mL was 59.3% (83/140). In subgroup analysis, 61.4% (43/70) patients in TB group and 57.1% (40/70) patients in control group achieved plasma HIV-1 RNA <50 copies/mL (RR = 1.194, 95%CI = 0.608-2.346, P = 0.731). Eight (5.8%) patients discontinued d4T due to neuropathy and/or symptomatic lactic acidosis.. The overall durability and efficacy of antiviral response of d4T, 3TC and NVP are satisfied and they are not different between HIV-1 infected patients with and without co-administration of rifampicin due to tuberculosis. However, stavudine-related adverse effects are concerns.. ClinicalTrials.gov Identifier NCT00703898.

    Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Male; Middle Aged; Nevirapine; Prospective Studies; Rifampin; RNA, Viral; Stavudine; Thailand; Treatment Outcome; Tuberculosis; Viral Load

2008
[Case report--tuberculosis in a health care worker during pregnancy].
    Pneumologie (Stuttgart, Germany), 2008, Volume: 62, Issue:11

    We report active tuberculosis in a pregnant physician caused by TB-transmission at the workplace. Because of increased liver enzymes, therapy with Rifampicin was temporarily interrupted. During pregnancy and the first seven month of the 12 month lactation period, the mother was treated for tuberculosis. The healthy newborn showed elevated GOT for the following two years after birth. Moderately elevated GPT was observed during the first months. A normal liver was seen in pre- and post-natal sonography. Therefore it is likely that the increased liver enzymes were caused by the chemotherapy of the mother.

    Topics: Adult; Antibiotics, Antitubercular; Female; Humans; Infectious Disease Transmission, Professional-to-Patient; Pregnancy; Pregnancy Complications, Infectious; Rifampin; Treatment Outcome; Tuberculosis

2008
Surgical site infection with methicillin-resistant Staphylococcus aureus after primary total hip replacement.
    The Journal of bone and joint surgery. British volume, 2008, Volume: 90, Issue:11

    Topics: Anti-Bacterial Agents; Arthroplasty, Replacement, Hip; Cross Infection; Humans; Methicillin; Methicillin-Resistant Staphylococcus aureus; Prosthesis-Related Infections; Rifampin; Staphylococcal Infections; Surgical Wound Infection; Tuberculosis

2008
Efavirenz-rifampicin interaction: therapeutic drug monitoring to efavirenz dosage optimization in HIV/TBC patients.
    AIDS (London, England), 2008, Nov-30, Volume: 22, Issue:18

    Topics: Adult; Alkynes; Antibiotics, Antitubercular; Benzoxazines; Cyclopropanes; Drug Interactions; Drug Monitoring; Female; HIV Infections; Humans; Male; Middle Aged; Pharmacogenetics; Reverse Transcriptase Inhibitors; Rifampin; Treatment Outcome; Tuberculosis

2008
Needed: new and better tools to combat latent tuberculosis infection.
    Annals of internal medicine, 2008, Nov-18, Volume: 149, Issue:10

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Humans; Isoniazid; Patient Compliance; Rifampin; Tuberculosis

2008
Prevalence of tuberculosis drug resistance in 10 provinces of China.
    BMC infectious diseases, 2008, Dec-11, Volume: 8

    The emergence of drug-resistant tuberculosis (TB) hampers TB control. Ten provinces in China performed drug resistance surveys among tuberculosis (TB) patients in 1996-2004 to assess levels of drug resistance.. Provincial drug resistance surveys included all isolates from newly diagnosed, smear-positive TB patients. Drug susceptibility testing (DST) against isoniazid, rifampicin, streptomycin and ethambutol was carried out in the provincial laboratories. For purposes of quality assurance, a random sample (11.6%) was re-tested by the national reference laboratory (NRL).. Of 14,059 patients tested 11,052 (79%) were new TB cases. The weighted mean prevalence of multi-drug resistant tuberculosis (MDR-TB) among all cases was 9.3% (range 2.2%-10.4%); 5.4% (range 2.1% - 10.4%) among new cases and 25.6% (range 11.7%-36.9%) among previously treated cases. Adjusting the drug resistance proportions using the re-testing results did not change the estimated national mean prevalence significantly. However, in some individual provinces the estimated resistance proportions were greatly influenced, especially among re-treatment patients.. MDR-TB levels varied greatly between provinces in China, but on average were high compared to the global estimated average of 4.8%. This study shows the importance of quality-assured laboratory performance. Programmatic management of drug-resistant TB, including high quality DST for patients at high risk of resistance and treatment with second-line drugs, should become the standard, especially in high MDR-TB settings.

    Topics: Antitubercular Agents; China; Drug Resistance, Multiple, Bacterial; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prevalence; Reproducibility of Results; Rifampin; Sputum; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant; World Health Organization

2008
Evaluation of a semi-automated reporter phage assay for susceptibility testing of Mycobacterium tuberculosis isolates in South Africa.
    Tuberculosis (Edinburgh, Scotland), 2008, Volume: 88, Issue:1

    In a prospective study conducted by laboratory technologists in a diagnostic laboratory in Cape Town, South Africa, a semi-automated phage-based antibiotic susceptibility assay was implemented and the performance of the luciferase reporter mycobacteriophage (LRP) system for susceptibility testing of clinical Mycobacterium tuberculosis complex (MTC) isolates against rifampin and isoniazid was evaluated. Two hundred consecutive clinical MGIT cultures of MTC species were included in this study. Antibiotic susceptibility assays were set up manually for the LRP and BACTEC radiometric systems (BACTEC) and read in a plate luminometer and the BACTEC 460 instrument, respectively. Discrepant susceptibility results were resolved by the conventional agar proportion method. Of the 200 secondary cultures prepared for this study, 9 (4.5%) were lost to contamination (LRP 4, BACTEC 1, both 4). All of the remaining 191 cultures underwent susceptibility testing by both methods and the overall agreement between the LRP and BACTEC was 98.4% (rifampin 100%; isoniazid 96.9%). Of the 6 discrepant cultures tested by the agar proportion method, 2 gave results in agreement with the LRP. The sensitivity of the LRP for detection of drug-resistant isolates was 100% for both rifampin (n=9) and isoniazid (n=12). The median turnaround time for susceptibility testing was 2 days with the LRP and 9 days with BACTEC. In conclusion, the semi-automated LRP-based assay offers a rapid and practical approach for accurate susceptibility testing of M. tuberculosis cultures in diagnostic laboratories with limited financial resources, but with competent technologists.

    Topics: Antitubercular Agents; Biological Assay; Genes, Reporter; Humans; Isoniazid; Luciferases; Microbial Sensitivity Tests; Mycobacteriophages; Mycobacterium tuberculosis; Prospective Studies; Rifampin; South Africa; Tuberculosis

2008
The clinical impact of nucleic acid amplification tests on the diagnosis and management of tuberculosis in a British hospital.
    Thorax, 2008, Volume: 63, Issue:4

    Nucleic acid amplification tests (NAAT) based on PCR provide rapid identification of Mycobacterium tuberculosis and the detection of rifampicin resistance. Indications for their use in clinical samples are now included in British tuberculosis guidelines.. A retrospective audit of patients with suspected mycobacterial infection in a Liverpool hospital between 2002 and 2006. Documentation of the impact of NAAT usage in acid fast bacillus (AFB) microscopy positive samples on clinical practice and the influence of a multidisciplinary group on their appropriate use, compared with British guidelines.. Mycobacteria were seen or isolated from 282 patients and identified as M tuberculosis in 181 (64%). NAAT were indicated in 87/123 AFB positive samples and performed in 51 (59%). M tuberculosis was confirmed or excluded by this method in 86% of tested samples within 2 weeks, compared with 7% identified using standard methods. The appropriate use of NAAT increased significantly over the study period. The NAAT result had a clinical impact in 20/51 (39%) tested patients. Culture results suggest the potential for a direct clinical impact in 8/36 (22%) patients in which it was indicated but not sent and 5/36 (14%) patients for whom it was not indicated. Patients managed by the multidisciplinary group had a higher rate of HIV testing and appropriate use of NAAT.. There were significant clinical benefits from the use of nucleic acid amplification tests in this low prevalence setting. Our data suggest that there would be additional benefit from their use with all AFB smear positive clinical samples.

    Topics: Antibiotics, Antitubercular; Bronchoalveolar Lavage Fluid; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

2008
Effect of rifampicin-based antitubercular therapy on nevirapine plasma concentrations in South African adults with HIV-associated tuberculosis.
    The Journal of antimicrobial chemotherapy, 2008, Volume: 61, Issue:2

    Nevirapine-containing antiretroviral therapy (ART) and rifampicin-based antitubercular therapy are commonly co-administered in Africa, where nevirapine is often the only available non-nucleoside reverse transcriptase inhibitor. Rifampicin induces the metabolism of nevirapine, but the extent of the reduction in nevirapine concentrations has varied widely in previous studies. We describe the steady-state pharmacokinetics of nevirapine during and after antitubercular therapy in South African patients.. Sixteen patients receiving ART including standard doses of nevirapine were admitted twice for intensive pharmacokinetic sampling: during and after rifampicin-based antitubercular therapy.. Geometric mean ratios for nevirapine pharmacokinetic parameters during versus after antitubercular therapy were 0.61 [90% confidence interval (CI) 0.49-0.79] for Cmax, 0.64 (90% CI 0.52-0.80) for area under the curve up to 12 h (AUC(0-12)) and 0.68 (90% CI 0.53-0.86) for Cmin. Nevirapine Cmin was subtherapeutic (<3 mg/L) in six patients during antitubercular therapy (one of whom developed virological failure) and in none afterwards. There was no correlation between rifampicin concentrations and the degree of nevirapine induction assessed by the proportional change in nevirapine concentrations between the two admissions. The ratio of nevirapine AUC(0-12) to the AUC(0-12) of its 12-hydroxy metabolite was significantly lower in the presence of antitubercular therapy, consistent with induced metabolism.. Nevirapine concentrations were significantly decreased by concomitant rifampicin-based antitubercular therapy and a high proportion of patients had subtherapeutic plasma concentrations. Further study in African patients is required to determine the implications for treatment outcomes.

    Topics: Adult; Antitubercular Agents; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine; Rifampin; South Africa; Tuberculosis

2008
Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis.
    Journal of acquired immune deficiency syndromes (1999), 2008, Apr-15, Volume: 47, Issue:5

    Rifampicin dramatically reduces plasma lopinavir concentrations (coformulated with ritonavir in a 4:1 ratio). A study in healthy adult volunteers showed that this reduction could be ameliorated if additional ritonavir is given. We evaluated the effect of additional ritonavir on plasma lopinavir concentrations in HIV-infected children receiving rifampicin-based treatment for tuberculosis.. We measured plasma lopinavir concentrations in 2 parallel groups receiving combination antiretroviral therapy that included lopinavir-ritonavir, with and without rifampicin-based antitubercular treatment. Additional ritonavir was given (lopinavir/ritonavir ratio of 1:1) during antitubercular treatment. Lopinavir concentrations were determined using liquid chromatography-tandem mass spectrometry.. There were 15 children (aged 7 months to 3.9 years) in each group. Lopinavir pharmacokinetic measures (median [interquartile range]) for children with and without rifampicin, respectively, were maximum concentration (Cmax) of 10.5 [7.1 to 14.3] versus 14.2 [11.9 to 23.5] mg/L (P = 0.018), area under the curve from 0 to 12 hours (AUC0-12) of 80.9 [50.9 to 121.7] versus 117.8 [80.4 to 176.1] mg/h/L (P = 0.036), and trough concentration (Cmin) of 3.94 [2.26 to 7.66] versus 4.64 [2.32 to 10.40] mg/L (P = 0.468). Thirteen of 15 children receiving antitubercular treatment (87%) had a lopinavir Cmin greater than the recommended minimum therapeutic concentration (1 mg/L).. The effect of rifampicin-based antitubercular treatment on lopinavir concentrations was attenuated by adding ritonavir to rifampicin. Although the median Cmax and AUC0-12 were lowered by 26% and 31%. respectively, the Cmin was greater than the minimum recommended concentration in most children.

    Topics: Antibiotics, Antitubercular; Child, Preschool; Drug Interactions; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Lopinavir; Male; Pyrimidinones; Rifampin; Ritonavir; Tuberculosis

2008
[Drug-induced hepatotoxicity caused by anti-tuberculosis drugs in tuberculosis patients complicated with chronic hepatitis].
    Kekkaku : [Tuberculosis], 2008, Volume: 83, Issue:1

    To investigate retrospectively the incidence of drug-induced hepatitis (DIH) caused by antituberculosis drugs including isoniazid (INH), rifampicin (RFP), with and without pyrazinamide (PZA), and to evaluate risk factors for DIH in tuberculosis patients complicated with chronic hepatitis (CH).. One hundred and seven tuberculosis patients with CH (M/F= 96/11, mean age +/- SE, 60.8 +/- 1.4 yr) admitted to our hospital during 1998-2006, whose laboratory data had been followed before and at least 2 months after starting antituberculosis chemotherapy, were enrolled in this study. Of these, 58 were being treated with anti-tuberculosis chemotherapy consisting of INH, RFP and PZA (HRZ group) and the remaining 49 with INH and RFP (HR group). For a case-control study, patients admitted to the hospital during the same period and without CH were selected to each CH patient (n=107) of the same gender, the same treatment regimens, and the same age. Clinical diagnosis of CH was based on laboratory data and in some cases pathological findings; etiology of CH was C-CH (CH caused by hepatitis C virus) in 68 patients, B-CH (CH caused by hepatitis B virus) in 23, and alcoholic CH in 16.. DIH was defined by elevation of serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at 1 or 2 months after starting anti-tuberculosis chemotherapy. For patients with serum levels of AST or ALT already abnormally high before starting chemotherapy, an increase of > 1.5 times from the initial serum level was defined to indicate DIH, whereas for patients with AST and ALT within the normal range, and increase of > 3X the normal upper limit was defined to indicate DIH. The incidence of DIH was calculated separately in the groups HRZ and HR for patients with and patients without CH (control). In the HRZ group, the severity of DIH was defined by the maximum serum levels of AST and ALT, and their mean values were compared between CH patients and the control. Risk factors for DIH were examined by comparing patients with and without CH. The clinical course after development of DIH was also followed. [Results] The incidence of DIH in the HRZ group was 13/ 58 (22.4%) for CH patients and 10/36 (27.8%), 2/13 (15.4%) and 1/9 (11.1%) for C-CH, B-CH and alcoholic hepatitis patients, respectively, which was significantly (p < 0.05) higher than that in the control [4/58 (6.9%)]. Confining to the C-CH patients, the incidence of DIH was 10/36 (27.8%) compared with the control 2/36 (5.6%) (p < 0.05). In contrast, the incidence of DIH in the HR group was not significantly different between CH patients and the control, [2/49 (4.1%) vs 2/49 (4.1%)], respectively. The severity of DIH in the HRZ group estimated by the maximum level of serum AST and ALT was not significantly different in CH patients and the control (176.6 +/- 28.1 vs. 311.0 +/- 154.5 IU/L for AST and 187.8 +/- 19.1 vs. 277.8 +/- 72.4 IU/L for ALT). Of the 13 CH patients suffering from DIH caused by antituberculosis chemotherapy containing INH, RFP and PZA, 3 were continued treatment without altering the regimen, and 9 were continued treatment after changing the regimen to INH and RFP, omitting PZA. The one remaining patient was re-treated using INH, RFP and ethambutol (EB), but this again resulted in development of DIH, and he was ultimately treated with INH, EB and levofloxacin, with a successful outcome. Thus, at least 12 out of the 13 CH patients who developed DIH in the HRZ group could be treated by an anti-tuberculosis chemotherapy regimen containing INH and RFP excluding PZA. In C-CH patients who were treated with INH, RFP and PZA, the incidence of DIH was significantly higher when the dail. In CH patients, anti-tuberculosis chemotherapy containing INH and RFP without PZA can be used safely. The inclusion of PZA in the regimen does substantially increase the incidence of DIH but nonetheless it can be used with caution, especially bearing in mind that daily alcohol intake of >20 g is a significant risk factor for C-CH patients.

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Hepatitis, Chronic; Humans; Isoniazid; Liver; Male; Middle Aged; Retrospective Studies; Rifampin; Tuberculosis

2008
Hepatotoxicity of pyrazinamide: cohort and case-control analyses.
    American journal of respiratory and critical care medicine, 2008, Jun-15, Volume: 177, Issue:12

    Relatively little is known about the hepatotoxicity of pyrazinamide.. We compared continuation-phase regimens incorporating pyrazinamide, isoniazid, and/or rifampin with those containing isoniazid and rifampin to evaluate the hepatotoxicity of pyrazinamide.. Cohort and nested case-control analyses were conducted on a cohort of 3,007 patients with active tuberculosis (TB) managed at government chest clinics under a TB control program with treatment started from January 1 through June 30, 2001. Cases included all patients with probable hepatotoxicity from 12 or more weeks after starting treatment. Hepatotoxicity was considered probable when serum alanine transaminase exceeded three times the upper limit of normal. Each case was matched by sex and age with three control subjects selected randomly from the rest of the cohort. Treatment regimens of cases within 4 weeks preceding hepatotoxicity were compared with those of matched control subjects in comparable periods relative to the date of commencing treatment.. Hepatotoxicity occurred in 150 (5.0%) patients at any time including 48 (1.6%) cases. From 12 or more weeks after starting treatment, the estimated risk of hepatotoxicity was 2.6% for regimens incorporating pyrazinamide, isoniazid, and/or rifampin, and 0.8% for standard regimens containing isoniazid and rifampin. Multivariable conditional logistic analysis showed a significant association between hepatotoxicity and, respectively, hepatitis B, previous hepatotoxicity, and treatment regimens. The adjusted odds ratio (95% confidence interval) of hepatotoxicity for regimens incorporating pyrazinamide, isoniazid, and/or rifampin relative to standard regimens was 2.8 (1.4-5.9).. Adding pyrazinamide to isoniazid and rifampin increases the risk of hepatotoxicity appreciably.

    Topics: Adult; Aged; Antitubercular Agents; Case-Control Studies; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Isoniazid; Logistic Models; Male; Matched-Pair Analysis; Middle Aged; Multivariate Analysis; Pyrazinamide; Rifampin; Tuberculosis

2008
An ounce of tuberculosis prevention.
    Chest, 2008, Volume: 133, Issue:4

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Humans; Isoniazid; Patient Compliance; Rifampin; Risk Factors; Tuberculosis

2008
Standard-dose efavirenz vs. standard-dose nevirapine in antiretroviral regimens among HIV-1 and tuberculosis co-infected patients who received rifampicin.
    HIV medicine, 2008, Volume: 9, Issue:5

    There is limited comparative data between efavirenz (EFV) 600 mg/day and nevirapine (NVP) 400 mg/day-based antiretroviral therapy (ART) among HIV-1 patients with tuberculosis (TB) and receiving rifampicin.. A retrospective cohort study was conducted in all ART-naïve patients who were receiving rifampicin between January 2002 and December 2005.. Of 188 patients, 77 and 111 patients were initiated on EFV-based ART (EFV group) and NVP-based ART (NVP group), respectively. Overall, median [interquartile range (IQR)] CD4 count was 36 (15-77) cells/microL and median (IQR) viral load was 5.6 (5.2-5.9) HIV-1 RNA log copies/mL. At 48 weeks, 77.9% (60/77) in the EFV group and 67.6% (75/111) in the NVP group achieved HIV-1 RNA <50 copies/mL (P=0.140, odds ratio=0.590, 95% confidence interval=0.302-1.153). At 24 and 48 weeks, respective median CD4 counts were 174 and 254 cells/muL in the EFV group and 156 and 218 cells/microL in the NVP group (P>0.05). By binary logistic regression, treatment group was not associated with HIV-1 RNA <50 copies/mL (P>0.05). No patient in the EFV group and eight (7.2%) patients in the NVP group discontinued ART because of adverse reactions (P=0.084).. For HIV-TB co-infected patients who receive rifampicin, efficacy of 600 mg EFV-based and 400 mg NVP-based ART may be similar, although adverse events tend to be higher in NVP-based ART.

    Topics: Adult; AIDS-Related Opportunistic Infections; Alkynes; Antitubercular Agents; Benzoxazines; CD4 Lymphocyte Count; Cohort Studies; Cyclopropanes; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Nevirapine; Retrospective Studies; Reverse Transcriptase Inhibitors; Rifampin; Treatment Outcome; Tuberculosis; Viral Load

2008
Older antibiotic gains new respect as potent treatment for tuberculosis. Rifapentine is already approved for use with humans.
    Home healthcare nurse, 2008, Volume: 26, Issue:4

    Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Drug Approval; Drug Evaluation, Preclinical; Drug Therapy, Combination; Humans; Mice; Rifampin; Tuberculosis; United States; United States Food and Drug Administration

2008
[Detection of rifampin resistant mycobacterium tuberculosis complex using denaturing HPLC].
    The Korean journal of laboratory medicine, 2008, Volume: 28, Issue:2

    Tuberculosis (TB) remains an important cause of morbidity and mortality throughout the world. The surge of TB has been accompanied by an increase in multi-drug-resistant tuberculosis (MDR-TB). In this study, we developed a denaturing HPLC (DHPLC) method for detecting rpoB gene mutation as a rifampin resistance based on sequence.. In this study, we used 99 mycobacterial isolates grown in Ogawa media. At first, we used a PCR method that can amplify the 235 bp and 136 bp rpoB DNAs of Mycobacterium tuberculosis complex (MTB) and Non-tuberculous mycobacteria (NTM). And then, PCR-restriction fragment length polymorphism (RFLP) of rpoB DNA (342 bp), which comprises the Rif(T) region, was used for the differential identification of Mycobacteria. Finally, we detected these amplicons by DHPLC, compared to PCR-RFLP results, and performed sequencing.. Among 99 mycobacterial isolates, 80 (81%) were MTB and 19 (19%) were NTM. NTM were identified to 7 different species by DHPLC and PCR-RFLP. rpoB mutation was detected in 9 (11%) of the MTB specimens. These results were confirmed by using sequencing.. DHPLC provided a rapid, simple, and automatable performance for detection of rifampin resistant Mycobacterium tuberculosis complex and would be helpful as a supplemental method in high-throughput clinical laboratories.

    Topics: Antibiotics, Antitubercular; Bacterial Typing Techniques; Chromatography, High Pressure Liquid; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2008
Effect of concomitantly administered rifampin on the pharmacokinetics and safety of atazanavir administered twice daily.
    Antimicrobial agents and chemotherapy, 2007, Volume: 51, Issue:9

    The potent induction of hepatic cytochrome P450 3A isoforms by rifampin complicates therapy for coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. We performed an open-label, single-arm study to assess the safety and pharmacokinetic interactions of the HIV protease inhibitor atazanavir coadministered with rifampin. Ten healthy HIV-negative subjects completed pharmacokinetic sampling at steady state while receiving 300 mg atazanavir every 12 h without rifampin (period 1), 300 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 2), and 400 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 3). During period 1, the mean concentration of drug in serum at 12 h (C(12 h)) was 811 ng/ml (range, 363 to 2,484 ng/ml) for atazanavir, similar to historic seronegative data for once-daily treatment with 300 mg atazanavir boosted with 100 mg ritonavir. During periods 2 and 3, the mean C(12 h) values for atazanavir were 44 ng/ml (range, <25 to 187 ng/ml) and 113 ng/ml (range, 39 to 260 ng/ml), respectively, well below historic seronegative data for once-daily treatment with 400 mg atazanavir without ritonavir. Although safe and generally well tolerated, 300 mg or 400 mg atazanavir administered every 12 h did not maintain adequate plasma exposure when coadministered with rifampin.

    Topics: Adolescent; Adult; Anti-HIV Agents; Antitubercular Agents; Area Under Curve; Atazanavir Sulfate; Biotransformation; Drug Interactions; Female; Half-Life; HIV Infections; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Rifampin; Tuberculosis

2007
Active community surveillance of the impact of different tuberculosis control measures, Tiruvallur, South India, 1968-2001.
    International journal of epidemiology, 2007, Volume: 36, Issue:2

    Tuberculosis is curable, but community surveys documenting epidemiological impact of the WHO-recommended DOTS strategy on tuberculosis prevalence have not been published. We used active community surveillance to compare the impact of DOTS with earlier programmes.. We conducted tuberculosis disease surveys using random cluster sampling of a rural population in South India approximately every 2.5 years from 1968 to 1986, using radiography as a screening tool for sputum examination. In 1999, DOTS was implemented in the area. Prevalence surveys using radiography and symptom screening were conducted at the start of DOTS implementation and after 2.5 years.. From 1968 to 1999, culture-positive and smear-positive tuberculosis declined by 2.3 and 2.5% per annum compared with 11.9 and 5.6% after DOTS implementation. The 2.5 year period of DOTS implementation accounted for one-fourth of the decline in prevalence of culture-positive tuberculosis over 33 years. Multivariate analysis showed that prevalence of culture-positive tuberculosis decreased substantially (10.0% per annum, 95% CI: 2.8-16.6%) owing to DOTS after only slight declines related to temporal trends (2.1% annual decline, 95% CI: 1.1-3.2%) and short-course chemotherapy (1.5% annual decline, 95% CI: -9.7% to 11.5%). Under DOTS, the proportion of total cases identified through clinical care increased from 81 to 92%.. Following DOTS implementation, prevalence of culture-positive tuberculosis decreased rapidly following a gradual decline for the previous 30 years. In the absence of a large HIV epidemic and with relatively low levels of rifampicin resistance, DOTS was associated with rapid reduction of tuberculosis prevalence.

    Topics: Adolescent; Adult; Data Collection; Directly Observed Therapy; Enzyme Inhibitors; Female; Humans; India; Male; Middle Aged; Prevalence; Rifampin; Rural Health; Sputum; Tuberculosis

2007
Nevirapine levels after discontinuation of rifampicin therapy and 60-week efficacy of nevirapine-based antiretroviral therapy in HIV-infected patients with tuberculosis.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2007, Jan-01, Volume: 44, Issue:1

    Seventy patients with human immunodeficiency virus (HIV) and tuberculosis coinfection who initiated nevirapine-based antiretroviral therapy and had trough nevirapine levels determined while receiving rifampicin were enrolled in a study. After discontinuation of rifampicin therapy, mean nevirapine levels (+/- standard deviation) increased from 5.4+/-3.5 mg/L to 6.4+/-3.4 mg/L (P=.047), but no nevirapine-related adverse events occurred. There was no statistically significant difference in 60-week antiviral efficacy between these patients and patients receiving nevirapine-based antiretroviral therapy alone (P>.05).

    Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Treatment Outcome; Tuberculosis

2007
Use of the INNO LiPA Rif.TB for detection of Mycobacterium tuberculosis DNA directly in clinical specimens and for simultaneous determination of rifampin susceptibility.
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2007, Volume: 26, Issue:1

    The INNO LiPA Rif.TB (Innogenetics, Ghent, Belgium) is a reverse hybridization test developed to detect genetic markers of resistance to rifampin in Mycobacterium tuberculosis complex. In the present study, this test was used directly on 3,763 clinical specimens by adopting a nested amplification of the target. The specificity of the system (98.4%) was optimal, but sensitivity (69.5%) was unsatisfactory. However, when use of the system was limited to smear-positive specimens, the sensitivity rose to 91.7%. As expected, the ability of the system to predict rifampin resistance was not influenced by its direct use on clinical specimens and confirmed the favorable results repeatedly reported in the literature.

    Topics: Antibiotics, Antitubercular; DNA Probes; DNA, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2007
Safety of the rifampin and pyrazinamide short-course regimen for treating latent tuberculosis infection.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2007, Feb-01, Volume: 44, Issue:3

    Topics: Antitubercular Agents; Drug Administration Schedule; Humans; Liver; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2007
Pharmacokinetics of rifampicin.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2007, Feb-15, Volume: 44, Issue:4

    Topics: Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Rifampin; Risk Factors; Sensitivity and Specificity; Treatment Outcome; Tuberculosis

2007
Differential drug susceptibility of intracellular and extracellular tuberculosis, and the impact of P-glycoprotein.
    Tuberculosis (Edinburgh, Scotland), 2007, Volume: 87, Issue:3

    If tuberculosis therapy is to be shortened it is imperative that the sterilising activity of current and future anti-tuberculosis drugs is enhanced. Intracellular Mycobacterium tuberculosis (MTB) phagocytosed by macrophages may be a key subpopulation of bacteria that are less readily eliminated by therapy. Here we investigate whether macrophages provide MTB with a pharmacological sanctuary site, making them less susceptible to chemotherapy than extracellular bacilli. Intracellular drug activity was determined by a novel colorimetric method that measures the ability of a drug to protect A-THP1 cells from infection-mediated cell death by H37Rv. Extracellular bactericidal activity was determined by the microplate alamar blue assay (MABA). Further, the effect of P-glycoprotein (P-gp) expressed on macrophages on the intracellular kill of H37Rv was assessed. To screen the anti-tuberculosis drugs for P-gp substrate specificity, their toxicity and cellular accumulation were determined in CEM and CEM(VBL100) cells. Intracellular and extracellular anti-tuberculosis drug activity following 7-day treatment with isoniazid (mean EC(50)+/-SD: 36.7+/-2.2 and 57.2+/-2.5 ng/mL, respectively) and ethambutol (243+/-95 and 263+/-12 ng/mL, respectively) were similar. However, for rifampicin a higher concentration was required to kill intracellular (148+/-32 ng/mL) versus extracellular (1.27+/-0.02 ng/mL) bacilli. The P-gp inhibitor tariquidar, significantly increased intracellular kill of H37Rv by ethambutol and rifampicin and both of these drugs were shown to be substrates for P-gp using the P-gp overexpressing CEM(VBL100) cells. We observed a large discrepancy between intracellular and extracellular activity of rifampicin (but not with isoniazid or ethambutol). Several factors could have accounted for this including inoculum size, media and cell-mediated metabolism. These factors make the comparison of intracellular and extracellular drug activity complex. However, the intracellular assay described here has potential for studying the impact of host proteins (such as drug transporters) on the intracellular activity of drugs, and has been used successfully here to demonstrate that both rifampicin and ethambutol are substrates for P-gp.

    Topics: Antitubercular Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cell Survival; Cells, Cultured; Colorimetry; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Ethambutol; Humans; Indicators and Reagents; Isoniazid; Macrophages; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazines; Phagocytosis; Quinolines; Rifampin; Spectrometry, Fluorescence; Tuberculosis; Xanthenes

2007
Minimal inhibitory concentration of isoniazid in isoniazid-resistant Mycobacterium tuberculosis isolates from children.
    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology, 2007, Volume: 26, Issue:3

    The aim of the study presented here was to determine the minimal inhibitory concentration of isoniazid for strains of isoniazid-resistant or multidrug-resistant Mycobacterium tuberculosis isolated from children in the Western Cape Province of South Africa. During the period March 2003-October 2005, 45 INH-resistant M. tuberculosis isolates (21 also rifampicin-resistant) were cultured from children less than 13 years of age. Drug susceptibility testing by the radiometric BACTEC 460 method found 11 isolates resistant at 0.1 microg/ml, 27 resistant at 0.2 microg/ml, and seven resistant at > or =5 microg/ml. Thus, the minimal inhibitory concentration of isoniazid for more than 80% of the isoniazid-resistant strains isolated from children in this study was relatively low and could be exceeded by high-dose (15-20 mg/kg) isoniazid regimens.

    Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Humans; Infant; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2007
Colorimetric phage-based assay for detection of rifampin-resistant Mycobacterium tuberculosis.
    Journal of clinical microbiology, 2007, Volume: 45, Issue:4

    Tests based on bacteriophage replication enable rapid screening of Mycobacterium tuberculosis for drug resistance. We describe a novel broth-based colorimetric method for detecting phage replication. When clinical isolates were tested by this novel method, high concordance was observed with both the traditional phage assay and gene mutation analysis for detection of resistance to rifampin.

    Topics: Antibiotics, Antitubercular; Colorimetry; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Microbial Viability; Mycobacteriophages; Mycobacterium tuberculosis; Rifampin; Statistics as Topic; Tuberculosis; Viral Plaque Assay; Virus Replication

2007
Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis.
    The Journal of antimicrobial chemotherapy, 2007, Volume: 59, Issue:4

    To assess plasma steady-state pharmacokinetics (PK) of rifampicin, isoniazid, saquinavir and ritonavir in HIV and tuberculosis (TB) co-infected patients, and investigate potential interactions between TB drugs and protease inhibitors (PIs).. Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions.. Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. Ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid.. There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. Saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.

    Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Area Under Curve; Chromatography, High Pressure Liquid; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Models, Statistical; Rifampin; Ritonavir; Saquinavir; Spectrophotometry, Ultraviolet; Tuberculosis

2007
Pharmacokinetic interaction between rifampicin and ritonavir-boosted atazanavir in HIV-infected patients.
    HIV medicine, 2007, Volume: 8, Issue:2

    Tuberculosis (TB) is a common opportunistic infection among HIV-infected people, and rifampicin is an important drug for the treatment of TB. However, administration of rifampicin in combination with antiretroviral therapy, particularly protease inhibitors, is difficult because of drug-drug interactions.. We have performed a prospective study in three HIV-infected patients with TB treated with a rifampicin-containing regimen (rifampicin 600 mg per day) and antiretroviral therapy including only nucleoside reverse transcriptase inhibitors (NRTIs) plus atazanavir 300 mg once a day (qd) and ritonavir 100 mg qd, to evaluate whether the inducing effect of rifampicin on the drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 could be overcome by the inhibitory effect of ritonavir. A complete pharmacokinetic evaluation of the steady-state concentrations of atazanavir and ritonavir was performed.. In all three cases, more than 50% of the time the atazanavir level was below the minimum recommended trough plasma level (150 ng/mL according to current pharmacokinetic guidelines) to inhibit HIV wild-type replication.. These results strongly indicate that the administration of rifampicin with a combination of atazanavir 300 mg qd plus ritonavir 100 mg qd must be avoided because subtherapeutic concentrations of atazanavir are produced.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Area Under Curve; Atazanavir Sulfate; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Drug Therapy, Combination; Female; HIV Protease Inhibitors; Humans; Male; Oligopeptides; Prospective Studies; Pyridines; Rifampin; Ritonavir; Tuberculosis

2007
[Treatment results of rifampicin (RFP) resistant isoniazid (INH) susceptible tuberculosis, a hospital based study].
    Kekkaku : [Tuberculosis], 2007, Volume: 82, Issue:2

    To evaluate treatment results of Rifampicin (R) resistant Isoniazid (H) susceptible tuberculosis cases.. Cohort analysis of twenty-three H susceptible R resistant tuberculosis cases started treatment in 1985-2004 at Fukujuji Hospital, by the retrospective review.. Three cases became Multi-drug resistant tuberculosis (MDR TB), seventeen cases were cured, two cases died, and one case transferred out. One started treatment with HR became MDR, one of the two started treatment with HR+ Ethambutol (E) became MDR and one of them was cured, eight among ten cases started treatment with HR+Pyrazinamide + (E or Streptomycine (S)) were cured, one among the ten died and one among the ten transferred out, one started treatment with RZE was cured, three among the five cases started treatment with three effective drugs without Z were cured, one among the five died, one among the five became MDR. Three cases started treatment with four effective drugs were cured. Among the nineteen cases continued treatment for more than six months, ten cases treated with four or five effective drugs for at least two months were cured, two cases of nine cases treated with three drugs or less became MDR, seven of the nine cases were cured. Among the same nineteen cases, eleven cases not treated with two or less effective drugs were cured, one case treated with two or less effective drugs for six months became MDR and one of them treated with one or two effective drug for one to three months became MDR and some were cured. The used drugs were H, E, Pyrazinamide, Streptomycin, Kanamycin, Ethionamide and New Quinolones. The duration of treatment of cured cases were eleven to twelve months in 3 cases, twelve to eighteen months in 3 cases, eighteen to twenty-four months in 8 cases and more than two years in 3 cases.. If the starting regimen is HRZE, we can cure R resistant H susceptible tuberculosis by the use of four effective drugs for more than two months and at least three effective drugs with the total duration of treatment for twelve to twenty-four months.

    Topics: Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2007
Three-fold reduction in the prevalence of tuberculosis over 25 years in Indonesia.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2007, Volume: 11, Issue:4

    Tuberculosis (TB) remains the principal cause of death from a curable infectious disease. Indonesia is estimated to have the third highest case load worldwide, but TB prevalence has not been measured for 25 years.. In 2004, 20000 households were selected in all 30 provinces. All adults (aged >/=15 years) in every household were screened for symptoms of pulmonary tuberculosis (PTB). Among those with symptoms, TB was diagnosed by sputum smear microscopy and sputum culture.. Eighty adults were positive on at least two sputum smears (104 per 100000 population, 95%CI 66-142). Prevalence was lower in Central Indonesia (Java-Bali, 59/100000) than in the Western (Sumatra, 160/100000) or Eastern regions (189/100000), but the estimated 225000 prevalent cases were distributed evenly among the three regions. The national per capita prevalence in 2004 was lower than in 1979-1982 by a factor of three (3.1, 95%CI 1.2-4.9), and the total number of cases was lower by a factor of two.. Although the 2004 national survey may have underestimated the prevalence of smear-positive TB in Indonesia, there is strong evidence that it fell markedly between 1979-1982 and 2004.

    Topics: Adult; Antitubercular Agents; Female; Health Surveys; Humans; Indonesia; Male; Middle Aged; Prevalence; Rifampin; Sputum; Tuberculosis

2007
[Case report: tuberculosis of parotid gland].
    Mikrobiyoloji bulteni, 2007, Volume: 41, Issue:1

    Primary tuberculosis of the parotid gland is an unusual clinical presentation. In this report a 32 years old male patient with parotid gland tuberculosis has been presented. The patient has been admitted to Ear, Nose & Throat outpatient clinic of our hospital with the complaint of left facial nodule. Histopathologic examination of the needle aspiration biopsy (NAB) specimen yielded benign necrotic lenfoid tissue, and in cervical ultrasonography cystic formations in left parotid gland were detected. Since the nodule size has increased in the follow-up period, cervical tomography was performed and heterogenous mass in the left side with lobular contour and hypodense appearance in posterior cervical region was detected. Histopathologic examination of the repeated NAB revealed chronic sialadenitis and benign lymphoid hyperplasia, and the patient has undergone left parotidectomy and lymph node dissection. Histopathologic examination of the excisional biopsy specimen revealed necrotising granuloma with diffuse caseification lesions concordant with tuberculosis. The patient was diagnosed as parotid gland tuberculosis, and anti-tuberculous therapy was started with isoniazid, rifampin, ethambutol and pyrazinamide. The history of the patient pointed out that he had used steroid for four months with a suspective diagnosis of rheumatoid arthritis, and his father had tuberculosis. In conclusion, since tuberculosis is a common infection in our country, it should be considered in the differential diagnosis of parotid nodules.

    Topics: Adult; Antitubercular Agents; Biopsy; Diagnosis, Differential; Ethambutol; Humans; Isoniazid; Lymph Node Excision; Male; Parotid Diseases; Parotid Gland; Pyrazinamide; Radiography; Rifampin; Tuberculosis

2007
Molecular characteristics of rifampicin- and isoniazid-resistant Mycobacterium tuberculosis isolates from the Russian Federation.
    The Journal of antimicrobial chemotherapy, 2007, Volume: 59, Issue:6

    Three Mycobacterium tuberculosis genetic loci--rpoB and katG genes and the fabG1(mabA)-inhA operon promoter region--were studied to reveal the mutations associated with rifampicin and isoniazid resistance.. Four hundred and twelve isolates of M. tuberculosis from different regions of the Russian Federation were collected during 1997-2005. A matrix-assisted laser-desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS)-based minisequencing method was used for the detection of mutations.. Thirteen different variants of single mutations in codons 533, 531, 526, 516, 513 and 511 of the rifampicin resistance-determining region of the rpoB gene as well as the TTG insertion in the 514a position were found among the rifampicin-resistant isolates. Single nucleotide substitutions in codons 531, 526 and 516 (64.8%, 10.3% and 7.7%, respectively) were the most prevalent mutations. Codon 526 was shown to be the most variable of all. No mutations were detected in rpoB genes for 29 (10.7%) of the rifampicin-resistant isolates. 76.9% of the isoniazid-resistant isolates carried single mutations in codon 315 of the katG gene. For another 12.9% of them, double mutations in the katG gene and the fabG1(mabA)-inhA promoter region were revealed. No mutations were detected in 8.2% of the isoniazid-resistant isolates.. Molecular analysis of the loci of rpoB and katG genes and the inhA promoter region of 412 M. tuberculosis clinical isolates from various parts of the Russian Federation was carried out. The new MALDI-TOF MS-based method may be used for rapid and accurate monitoring of the spread of drug resistance.

    Topics: Antitubercular Agents; Codon; DNA, Bacterial; Drug Resistance, Bacterial; Genes, Bacterial; Humans; Isoniazid; Mass Spectrometry; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Rifampin; Russia; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tuberculosis

2007
Multiple-dose pharmacokinetics of efavirenz with and without the use of rifampicin in HIV-positive patients.
    Current HIV research, 2007, Volume: 5, Issue:3

    Rifampicin (RIF) decreases serum concentrations of several antiretroviral drugs. We carried out a prospective, comparative study to define efavirenz (EFV) pharmacokinetics in 16 cases and 13 controls. Cases were HIV and tuberculosis (TB) co-infected adults assuming RIF 600 mg once daily and EFV 800 mg once daily. Patients on EFV at standard 600 mg dose without RIF were taken as controls. EFV levels in plasma were assayed by high-performance liquid chromatography (HLPC) predose (C(trough)) and at 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 16, 18, 22 and 24 hours post-dose, and pharmacokinetic parameters were determined by non-compartmental methods. Among cases, 81% were males, mean age was 37 years, 50% were Caucasians, mean weight was 64 kg, mean CD4 cell counts and log HIV RNA copies were 160/microl and 5.2 /microl, respectively. Cases had a significantly higher Cl/F/kg if compared with controls (0.269 +/- 0.12 versus 0.167 + 0.05 L/h/kg, p<0.01). Otherwise, dose-dependent pharmacokinetic parameters of EFV were similar between cases and controls. Interindividual variability was consistently higher among TB cases compared to controls for all considered parameters. All cases completed combined treatment and no increased EFV toxicity was observed. These results suggest that a dose of 800 mg of EFV in association with rifampicin may be appropriate for patients of weight > 60 kg in Europe. Therapeutic drug monitoring may be beneficial for patients on combination therapy with RIF.

    Topics: Adult; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Biological Availability; Cyclopropanes; Drug Interactions; Female; HIV Infections; Humans; Male; Prospective Studies; Rifampin; Tuberculosis

2007
Short-course regimens for latent tuberculosis: what is ready for prime time?
    Enfermedades infecciosas y microbiologia clinica, 2007, Volume: 25, Issue:5

    Topics: Antitubercular Agents; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Virus Latency

2007
Location of persisting mycobacteria in a Guinea pig model of tuberculosis revealed by r207910.
    Antimicrobial agents and chemotherapy, 2007, Volume: 51, Issue:9

    The lengthy chemotherapy of tuberculosis reflects the ability of a small subpopulation of Mycobacterium tuberculosis bacteria to persist in infected individuals. To date, the exact location of these persisting bacteria is not known. Lung lesions in guinea pigs infected with M. tuberculosis have striking similarities, such as necrosis, mineralization, and hypoxia, to natural infections in humans. Guinea pigs develop necrotic primary lesions after aerosol infection that differ in their morphology compared to secondary lesions resulting from hematogenous dissemination. In infected guinea pigs conventional therapy for tuberculosis during 6 weeks reduced the bacterial load by 1.7 logs in the lungs and, although this completely reversed lung inflammation associated with secondary lesions, the primary granulomas remained largely unaffected. Treatment of animals with the experimental drug R207910 (TMC207) for 6 weeks was highly effective with almost complete eradication of the bacteria throughout both the primary and the secondary lesions. Most importantly, the few remnants of acid-fast bacilli remaining after R207910 treatment were to be found extracellular, in a microenvironment of residual primary lesion necrosis with incomplete dystrophic calcification. This zone of the primary granuloma is hypoxic and is morphologically similar to what has been described for human lung lesions. These results show that this acellular rim may, therefore, be a primary location of persisting bacilli withstanding drug treatment.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Female; Granuloma; Guinea Pigs; Hypoxia; Isoniazid; Lung; Mycobacterium tuberculosis; Nitroimidazoles; Pyrazinamide; Quinolines; Radiation-Sensitizing Agents; Rifampin; Spleen; Tuberculosis

2007
Drug resistance in tuberculosis.
    Journal of tropical pediatrics, 2007, Volume: 53, Issue:3

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis

2007
Evaluation of the GenoType MTBDRplus assay for rifampin and isoniazid susceptibility testing of Mycobacterium tuberculosis strains and clinical specimens.
    Journal of clinical microbiology, 2007, Volume: 45, Issue:8

    The new GenoType MTBDRplus assay (Hain Lifescience GmbH, Nehren, Germany) was tested with 125 clinical isolates and directly with 72 smear-positive sputum specimens for its ability to detect rifampin (RMP) and isoniazid (INH) resistance in Mycobacterium tuberculosis complex (MTBC) strains. In total, 106 RMP(r)/INH(r), 10 RMP(s)/INH(r), and 80 RMP(s)/INH(s) MTBC strains were comparatively analyzed with the new and the old MTBDR assays. Besides the detection of mutations within the 81-bp hot spot region of rpoB and katG codon 315, the GenoType MTBDRplus assay is designed to detect mutations in the regulatory region of inhA. The applicability of the new assay directly to specimens was shown, since 71 of 72 results for smear-positive sputa and all 125 results for clinical isolates were interpretable and no discrepancies compared with the results of real-time PCR or DNA sequencing were obtained. In comparison to conventional drug susceptibility testing, both assays were able to identify RMP resistance correctly in 74 of 75 strains (98.7%) and 30 of 31 specimens (96.8%). The misidentification of RMP resistance was obtained for two strains containing rpoB P533L mutations. Compared to the old MTBDR assay, the new GenoType MTBDRplus assay enhanced the rate of detection of INH resistance from 66 (88.0%) to 69 (92.0%) among the 75 INH-resistant strains and 36 (87.8%) to 37 (90.2%) among the 41 specimens containing INH-resistant strains. Thus, the new GenoType MTBDRplus assay represents a reliable and upgraded tool for the detection of INH and RMP resistance in strains or directly from smear-positive specimens.

    Topics: Antitubercular Agents; Bacterial Proteins; Catalase; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Polymerase Chain Reaction; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Tuberculosis

2007
Gatifloxacin in combination with rifampicin in a murine tuberculosis model.
    The Journal of antimicrobial chemotherapy, 2007, Volume: 60, Issue:2

    Gatifloxacin previously demonstrated good in vitro and in vivo activities against Mycobacterium tuberculosis. Several regimens of gatifloxacin in combination with rifampicin were compared with isoniazid plus rifampicin in a mouse tuberculosis model.. C57BL/6 mice were infected intranasally with approximately 10(6) viable M. tuberculosis organisms. Treatment with various regimens of gatifloxacin plus rifampicin was started 1 week post-infection and was administered for 4-12 weeks. Mice were euthanized at the end of therapy and their right lungs were removed and cell counts were determined.. Gatifloxacin 100 mg/kg plus rifampicin 10 mg/kg has activity similar to that of isoniazid plus rifampicin in the 12 week treatment model. Gatifloxacin 300 mg/kg plus rifampicin 20 mg/kg yields a non-cultivatable state after 12 weeks of therapy and approaches but does not achieve a durable cure.. Gatifloxacin in combination with rifampicin is a promising combination for potential evaluation in human clinical trials. Gatifloxacin plus rifampicin regimens had activities similar to or better than isoniazid plus rifampicin. A quinolone plus rifampicin combination may provide the foundation for shorter course regimens than the current isoniazid plus rifampicin-based regimen.

    Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Drug Combinations; Female; Fluoroquinolones; Gatifloxacin; Isoniazid; Lung; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2007
Safety of treatment of latent tuberculosis infection in compensated cirrhotic patients during transplant candidacy period.
    Transplantation, 2007, Jun-27, Volume: 83, Issue:12

    Treatment of latent tuberculosis infection with isoniazid (INH) or rifampin (RIF) is controversial in liver transplant candidates due to potential hepatotoxicity. In this study, treatment of latent tuberculosis during transplant candidacy period is explored, and relevant literature is reviewed.. Liver transplant candidates with latent tuberculosis infection by positive tuberculin skin test (>5 mm) were prospectively enrolled and treated with 9 months of INH or 4 months of RIF, and were monitored monthly for their liver enzyme profiles, adverse effects, compliance, and completion rate.. Four of nine patients with INH had asymptomatic, mild elevations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) versus none of five patients in the RIF group. Two cases of elevations were attributed to INH. Two other cases were attributed to alcoholism or active chronic hepatitis B virus infection. Only one patient in the INH group experienced symptoms possibly attributed to INH hepatotoxicity. Compliance was 100% per patient reporting. Completion rates were 79% for INH and 100% for RIF. No fulminant hepatic failure or death was observed.. Treatment of latent tuberculosis in liver transplant patients during their candidacy with INH or RIF appears to be a safe, viable option, if carefully monitored for adverse effects and liver enzymes.

    Topics: Adolescent; Adult; Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Comorbidity; Female; Humans; Isoniazid; Liver Cirrhosis; Liver Transplantation; Male; Postoperative Complications; Preoperative Care; Rifampin; Safety; Treatment Outcome; Tuberculin Test; Tuberculosis

2007
Patient choice promotes adherence in preventive treatment for latent tuberculosis.
    The European respiratory journal, 2007, Volume: 30, Issue:4

    The aim of the present study was to compare the effect of patient choice on completion rates and adverse drug reactions for patients treated for latent tuberculosis infection (LTBI) using 3-month rifampicin and isoniazid treatment (3RH) or 6-month isoniazid treatment (6H). Data for all patients treated using 3RH or 6H for LTBI between 1998 and 2004 were analysed. In total, 675 patients attended for chemoprophylaxis. Of these, 314 received 3RH and 277 received 6H. From April 1, 2000, patients were offered a choice of regimen; 53.5% completed the regimen successfully, a further 10.3% potentially completed it successfully and 36.2% failed to complete treatment. Logistic regression analysis suggested that successful completion was more likely in patients who were younger (an association that was lost after removing all patients aged <16 yrs), were offered a choice of regimen and attended all clinic visits before commencing treatment. Treatment was discontinued due to adverse reactions in 16 (5.1%) patients who were prescribed 3RH and 16 (5.8%) who were prescribed 6H. Treatment failure was most likely during the first 4 weeks of treatment for both regimens. At 13 weeks of treatment, more patients taking 6H had stopped compared with those completing the 3RH regimen. Drug costs were greater using 6H compared with 3RH. In conclusion, offering a choice of regimen improves completion. Most patients chose the 3-month rifampicin and isoniazid treatment over the 6-month isoniazid treatment. Adverse drug reaction rates between the two regimens were similar.

    Topics: Adolescent; Adult; Age Factors; Antibiotics, Antitubercular; Antineoplastic Agents; Attitude to Health; Child; Female; Humans; Isoniazid; Male; Patient Compliance; Patient Satisfaction; Regression Analysis; Rifampin; Risk; Time Factors; Treatment Outcome; Tuberculosis

2007
Characterization of rpoB mutations by line probe assay in rifampicin-resistant mycobacterium tuberculosis clinical isolates from the aegean region in Turkey.
    Japanese journal of infectious diseases, 2007, Volume: 60, Issue:4

    The nature and frequency of mutations in the rpoB gene of rifampicin (RIF)-resistant Mycobacterium tuberculosis clinical isolates vary considerably according to the geographical location, and very little information is available regarding specific mutational patterns in our country. The main objective of this study was to determine the frequency of mutations in the hypervariable region of the rpoB gene in RIF-resistant M.tuberculosis isolates recovered from tuberculosis patients in our region by using the INNO-LiPA Rif. TB kit and to evaluate the performance of the kit for the detection of RIF-resistance. Mutations associated with RIF resistance were studied by line probe assay (LiPA) in 65 RIF-resistant and 56 RIF-susceptible M. tuberculosis strains isolated from different patients in the Aegean region of Turkey. The LiPA identified all susceptible strains (100%) as RIF-sensitive and 63 of 65 (96.9%) phenotypically documented RIF-resistant M. tuberculosis isolates as RIF-resistant, with specific detection of mutation in 44 (67.7%) isolates, whilst 2 strains were identified as RIF-susceptible. The R5-pattern (Ser-531-Leu mutation) was the most frequently observed (35 of 65, 53.8%), followed by the deltaS2-pattern (7.7%) and deltaS4-pattern (7.7%).

    Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Turkey

2007
A rapid and sensitive HPLC-MS method for the detection of plasma and cellular rifampicin.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2007, Sep-15, Volume: 857, Issue:1

    Rifampicin is active against both intracellular and extracellular Mycobacterium tuberculosis. The ability to measure rifampicin drug concentrations in both plasma and in cells may be useful in evaluating the suitability of dosage regimens for populations and individuals. Here a novel simple, precise and accurate method for the quantification of rifampicin in both cells and plasma is reported. Sample proteins were precipitated with acetonitrile containing the internal standard and then diluted with water. Aliquots of supernatant were then injected into the HPLC-MS system for chromatographic separation and detection. Rifampicin calibration curves encompassed concentrations from 100 to 12,800 ng/mL. Intra- and inter-assay precision and accuracy were determined using low, medium and high concentration quality control samples and was found to be within 10% in all cases. Rifampicin concentrations were found to be unaffected by freeze-thaw cycles, but were significantly affected by heat-inactivation (58 degrees C, 40 min). This assay was successfully utilised to determine the pharmacokinetic profile of rifampicin in plasma and peripheral blood mononuclear cells (PBMC) in 8 tuberculosis patients receiving rifampicin over an 8h period.

    Topics: Administration, Oral; Antitubercular Agents; Calibration; Chromatography, High Pressure Liquid; Drug Stability; Female; Humans; Leukocytes, Mononuclear; Male; Mass Spectrometry; Reference Standards; Reproducibility of Results; Rifampin; Rifamycins; Sensitivity and Specificity; Tuberculosis

2007
Characterization of Tunisian Mycobacterium tuberculosis rifampin-resistant clinical isolates.
    Journal of clinical microbiology, 2007, Volume: 45, Issue:9

    Analysis of the gene encoding the beta-subunit of Mycobacterium tuberculosis RNA polymerase (rpoB) has demonstrated a small region that harbors the mutations most frequently associated with rifampin resistance. In this study, we determined the occurrence of rifampin resistance in 544 Tunisian clinical M. tuberculosis strains isolated in a university hospital between 2004 and 2006 by using the standard-proportion agar method, the INNO-LiPA Rif.TB assay, and DNA sequencing.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mycobacterium tuberculosis; Rifampin; Sequence Analysis, DNA; Tuberculosis; Tunisia

2007
Nevirapine-based antiretroviral therapy started early in the course of tuberculosis treatment in adult Malawians.
    Antiviral therapy, 2007, Volume: 12, Issue:4

    The tuberculosis (TB) mortality rate of registered TB patients in Malawi is 23%, and 59% of the deaths occur in the first 2 months of treatment. HIV-related complications appear to be an important cause. Starting antiretroviral therapy early during tuberculosis treatment may improve outcome but problems often arise with drug interactions, adherence, toxicity and immune reconstitution disease (IRD).. We prospectively followed 27 HIV-infected adult Malawians after starting Triomune (a generic fixed drug combination of stavudine, lamivudine and nevirapine) in the second week of tuberculosis treatment.. At baseline, 88% had CD4+ T-cell counts <100 cells/ml, all were anaemic and 78% were malnourished. Five patients (19%) died, two withdrew consent and one stopped all drugs due to hepatitis. At 6 months, all but one of the 19 remaining patients had good virological results (16 patients: <400 copies/ml, two patients: <1,000 copies/ml) and the median CD4+ T cell increase was 170 cells/ml. Adverse events were numerous, particularly in the first 2 months. Suspected IRD episodes could be managed without treatment interruptions. During the lead-in phase, 59% of nevirapine plasma levels were sub-therapeutic despite good adherence, compared with only 14% during weeks 4 and 8.. It is feasible to start Triomune early during TB treatment with good treatment outcome. The nevirapine lead-in phase should be avoided when rifampicin-based tuberculosis treatment is started >1 week beforehand.

    Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Lamivudine; Malawi; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Stavudine; Treatment Outcome; Tuberculosis

2007
Adverse reaction to Bacille-Calmette-Guérin vaccine in a HIV positive healthcare worker.
    Irish journal of medical science, 2007, Volume: 176, Issue:3

    The Bacille-Calmette-Guérin (BCG) vaccine is used in Mycobacterium tuberculosis prophylaxis in at risk tuberculin-negative healthcare workers. Its use is contraindicated however in individuals with HIV infection.. We herein highlight the case of a healthcare worker who developed a localised reaction at a BCG vaccination site and who was subsequently found to be HIV positive.. This case emphasises the importance of eliciting risk factors for immunocompromise in individuals for whom BCG vaccination is being considered.

    Topics: Adult; Allied Health Personnel; Antibiotics, Antitubercular; BCG Vaccine; Contraindications; HIV Seropositivity; Humans; Male; Mycobacterium bovis; Rifampin; Skin Ulcer; Tuberculosis

2007
Urine levels of rifampicin & isoniazid in asymptomatic HIV-positive individuals.
    The Indian journal of medical research, 2007, Volume: 125, Issue:6

    AIDS and its associated gastrointestinal complications may impair the absorption of anti-tuberculosis (TB) drugs. Impaired absorption of anti-TB drugs could lead to low drug exposure, which might contribute to acquired drug resistance and reduced effectiveness of anti-TB treatment. The aim of this study was to obtain information on the status of absorption of rifampicin (RMP) and isoniazid (INH) in asymptomatic HIV- positive individuals, who are less immunocompromised. The D-xylose absorption test was also carried out to assess the absorptive capacity of intestive.. The absorption of RMP, INH and D-xylose was studied in 15 asymptomatic HIV-positive individuals with CD4 cell counts>350 cells/mm3 and 16 healthy volunteers, after oral administration of single doses of RMP (450 mg), INH (300 mg) and D-xylose (5 g). Urine was collected up to 8 h after drug administration. Percentage dose of the drugs and their metabolites and D-xylose excreted in urine were calculated.. A significant reduction in the urinary excretion of INH and D-xylose in HIV-positive persons compared to healthy volunteers was observed. The per cent dose of RMP and its metabolite, desacetyl RMP was also lower in HIV-positive persons compared to healthy volunteers, but this difference was not statistically significant.. Decreased urinary excretion of D-xylose and INH are suggestive of intestinal malabsorption in HIV-positive individuals. HIV infection could cause malabsorption of anti-TB drugs even at an early stage of the disease. The clinical implications of these findings need to be confirmed in larger studies.

    Topics: Adult; Antitubercular Agents; CD4-Positive T-Lymphocytes; Drug Administration Schedule; Drug Resistance; HIV Infections; HIV Seropositivity; Humans; Immunocompromised Host; Isoniazid; Middle Aged; Models, Biological; Rifampin; Tuberculosis; Xylose

2007
Adverse drug reactions associated with first-line anti-tuberculosis drug regimens.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2007, Volume: 11, Issue:8

    Standard treatment of active tuberculosis (TB) consists of isoniazid (INH), rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB). Although this regimen is effective in treating active TB, it is associated with many adverse drug reactions (ADRs) and poses a significant challenge to completion of treatment.. To examine the incidence of major ADRs and risk factors associated with first-line anti-tuberculosis medications.. This study evaluated patients receiving treatment for active TB from a population-based database (2000-2005). The nature of the ADRs, likelihood of association with the study medications and severity were evaluated.. A total of 1061 patients received treatment, of whom 318 (30%) had at least one major ADR. The overall incidence of all major ADRs was 7.3 events per 100 person-months (95%CI 7.2-7.5): 23.3 (95%CI 23.0-23.7) when on all four first-line drugs, 13.6 (95%CI 13.3-14.0) when on RMP, INH and PZA, and 2.4 (95%CI 2.3-2.6) when on INH and RMP. Adjusted hazard ratio (HR) revealed that combination regimens containing PZA, females, subjects aged 35-59 and >or=60 years, baseline aspartate aminotransferase >or=80 U/l and drug resistance were associated with any major event.. First-line anti-tuberculosis drugs are associated with significant ADRs. There are several risk factors associated with the development of ADRs, including exposure to regimens containing PZA.

    Topics: Antitubercular Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2007
What is the best strategy for treating TB-HIV co-infected patients with HAART and rifampicin without saquinavir?
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2007, Volume: 11, Issue:8

    Topics: Antiretroviral Therapy, Highly Active; Coinfection; HIV Infections; Humans; Rifampin; Saquinavir; Tuberculosis

2007
Successful treatment with intravenous immunoglobulins in a patient affected by dermatomyositis/systemic lupus erythematosus overlap syndrome and tuberculosis.
    Clinical immunology (Orlando, Fla.), 2007, Volume: 125, Issue:2

    The case of a 56-year-old woman, with a previous history of systemic lupus erythematosus (SLE), later diagnosed as also affected by active dermatomyositis (DM) associated with tuberculosis (TB) is reported. Since TB is a contra-indication to receive immunosuppressive therapy for DM/SLE, intravenous immunoglobulins (IVIG) with low-dose steroids and anti-TB therapy were administered with excellent clinical results. This report underlines the crucial role of IVIG in the treatment of critical patients suffering from connective tissue disorders associated with severe infections.

    Topics: Antitubercular Agents; Dermatomyositis; Female; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Isoniazid; Lupus Erythematosus, Systemic; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis

2007
[Use of a mini-sequencing test, followed by the MALDI-TOF mass-spectrometric analysis to evaluate rifampicin and izoniazid resistance in Mycobacterium tuberculosis circulating in the Russian Federation].
    Problemy tuberkuleza i boleznei legkikh, 2007, Issue:7

    Topics: Antitubercular Agents; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Mycobacterium tuberculosis; Oligonucleotide Array Sequence Analysis; Phenotype; Reproducibility of Results; Rifampin; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tuberculosis

2007
[Statistically mapping modeling of the spread of rifampicin-resistant M. tuberculosis strains in different regions of the Kyrghyz Republic].
    Problemy tuberkuleza i boleznei legkikh, 2007, Issue:7

    Mapping modeling of the distribution of rifampicin-resistant tuberculosis was made in different regions of the Kyrghyz Republic. The results of determination of rifampicin resistance in Mycobacterium tuberculosis (MBT) by the biochip test were used to examine 904 MBT DNA samples taken when examining the patients living in different regions of the Kyrghyz Republic: Bishkek (n = 323), the Chui (n = 185), Issyk-Kul (n = 68), Naryn (n = 75), Talas (n = 47), Osh (n = 65), Dzhalal-Abad (n = 90), and Batken (n = 51) Regions. Comparison of the distribution of drug-resistant forms of tuberculosis by different regions revealed that rifampicin-resistant MBT strains were more frequently encountered in the densely populated regions of the republic - Bishkek and the Chui Region. Rifampicin resistance in MBT was caused by mutations in codons 531, 526, 522, 516, 511, 513, 512, and 513 of the rpoB gene. At the same time, there was a predominant selection of MBT with mutations in codons 531, 526, 516, and 511 in the republic. The spectrum of mutant MBT strains occurring in some regions varied. The broadest spectrum of genetic variability was observed in Bishkek and the Chui Region. Thus, Bishkek and the Chui Region are the hot points of concentration of mutant rifampicin-resistant MBT strains.

    Topics: Adult; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; Humans; Incidence; Kyrgyzstan; Male; Middle Aged; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Tuberculosis

2007
Targeted drug delivery to enhance efficacy and shorten treatment duration in disseminated Mycobacterium avium infection in mice.
    The Journal of antimicrobial chemotherapy, 2007, Volume: 60, Issue:5

    Improvement of the efficacy of drug treatment in mycobacterial infection by the development and application of targeted drug delivery.. In disseminated Mycobacterium avium infection in mice, the relative efficacy of the antimycobacterial agents that are currently used in combination therapy was investigated. Next, the effect of the addition of targeted delivery of amikacin to the infected tissues in the initial phase of treatment was studied. Amikacin was chosen because of its unique rapid and high mycobacterial killing capacity. As drug delivery tool, long-circulating sterically stabilized liposomes were used.. Treatment with clarithromycin alone daily (6 days a week) slowly killed most of the mycobacteria in the lung, liver, spleen, inguinal and mesenterial lymph nodes. However, after 24 weeks of treatment, persistence of substantial numbers of mycobacteria in the infected organs was observed. The addition of ethambutol to the clarithromycin regimen did not significantly enhance the efficacy of treatment, neither did rifampicin as a third agent. In contrast, the addition of liposomal amikacin in the initial phase of therapy resulted in rapid and complete elimination of the mycobacteria in all infected organs within 12 weeks of treatment without relapse of infection. As a result, total treatment duration could be significantly reduced to 12 weeks.. In M. avium infection in mice, the approach of targeted drug delivery was successful. The rapid decrease in the mycobacterial load followed by complete killing, including the persistent mycobacteria considered responsible for relapse of infection, allows a significant reduction of the total treatment duration.

    Topics: Amikacin; Animals; Antitubercular Agents; Clarithromycin; Drug Administration Schedule; Drug Delivery Systems; Ethambutol; Female; Liposomes; Mice; Mice, Inbred C57BL; Mycobacterium avium; Rifampin; Specific Pathogen-Free Organisms; Tuberculosis

2007
Lack of correlation between embB mutation and ethambutol MIC in Mycobacterium tuberculosis clinical isolates from China.
    Antimicrobial agents and chemotherapy, 2007, Volume: 51, Issue:12

    Seventy-four Mycobacterium tuberculosis clinical isolates from China were subjected to drug susceptibility testing using ethambutol, isoniazid, rifampin, and ofloxacin. The results revealed that the presence of embB mutations did not correlate with ethambutol resistance but was associated with multiple-drug resistance, especially resistance to both ethambutol and rifampin.

    Topics: Antitubercular Agents; Bacterial Proteins; China; Drug Resistance, Bacterial; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Ofloxacin; Pentosyltransferases; Rifampin; Tuberculosis

2007
Development of an antimicrobial formulation for control of specimen-related contamination in phage-based diagnostic testing for tuberculosis.
    Journal of applied microbiology, 2007, Volume: 103, Issue:4

    To develop and evaluate an antimicrobial supplement for use with phage-based tests for rapid detection of drug resistance of tuberculosis (TB).. An antimicrobial formulation containing nystatin, oxacillin and aztreonam (NOA) (final concentrations of 50,000 IU l(-1), 2 mg l(-1), and 30 mg l(-1) respectively) was developed. This formulation was tested for its influence on detection of a number of Mycobacterium tuberculosis (MTB) strains using the phage amplification (FASTPlaque) assay. Addition of the supplement did not lead to significant reduction in assay sensitivity. Antimicrobial efficacy was assessed with a range of Gram-positive and -negative organisms. The NOA supplement had a broad antimicrobial effect. The supplement was tested for its effect on growth of MTB culture, and on determination of rifampicin resistance using the phage-based methodology (FASTPlaque-Response). NOA did not significantly affect the growth of a range of rifampicin susceptible and resistant MTB strains, nor did it have an adverse effect on the number of interpretable results, nor the ability to discriminate between rifampicin susceptibility and resistance.. Use of NOA antimicrobial supplement with rapid phage-based tests for TB will increase the proportion of interpretable results obtained, and enable their wider implementation in disease-endemic countries by improved control of specimen-related contamination.

    Topics: Anti-Infective Agents; Antibiotics, Antitubercular; Aztreonam; Culture Media; Drug Combinations; Drug Resistance, Bacterial; Equipment Contamination; Humans; Microbial Sensitivity Tests; Mycobacteriophages; Mycobacterium tuberculosis; Nystatin; Oxacillin; Rifampin; Tuberculosis

2007
Liver and pancreatic injury induced by antituberculous therapy.
    Digestive diseases and sciences, 2007, Volume: 52, Issue:11

    Topics: Adult; Antitubercular Agents; Biopsy; Chemical and Drug Induced Liver Injury; Cholangiopancreatography, Endoscopic Retrograde; Ethambutol; Female; Follow-Up Studies; Humans; Pancreatitis; Pyrazinamide; Rifampin; Tomography, X-Ray Computed; Tuberculosis

2007
Diagnosis and treatment of latent tuberculosis infection in arthritis patients treated with tumor necrosis factor antagonists in Korea.
    Journal of Korean medical science, 2007, Volume: 22, Issue:5

    Tumor necrosis factor (TNF) is essential for host defense against Mycobacterium tuberculosis, and the risk of reactivation of latent tuberculosis infection (LTBI) increases with anti-TNF therapy. This study estimated the prevalence of LTBI and evaluated the safety and completion rate of short-course therapy with isoniazid plus rifampin for 3 months to treat LTBI in a cohort of Korean arthritis patients before initiating anti-TNF therapy. We retrospectively studied the files of 112 consecutive patients to evaluate LTBI before starting anti-TNF drugs. Screening tests were performed, including a tuberculin skin test and chest radiography. LTBI treatment was indicated in 41 patients (37%). Of these, three patients refused the LTBI treatment. Of the 38 patients who underwent LTBI treatment, 36 (95%) took isoniazid plus rifampin for 3 months. Six patients (16%) showed transient elevations of liver enzymes during the LTBI treatment. Overall, 35 patients (92%) completed the LTBI treatment as planned. In conclusion, LTBI was diagnosed in one-third of Korean arthritis patients before initiating anti-TNF therapy. A high percentage of these patients completed 3 months of LTBI treatment with isoniazid plus rifampin without serious complications.

    Topics: Adult; Antibiotics, Antitubercular; Arthritis, Rheumatoid; Female; Humans; Korea; Male; Middle Aged; Retrospective Studies; Rifampin; Spondylitis; Spondylitis, Ankylosing; Tuberculin Test; Tuberculosis; Tumor Necrosis Factor-alpha

2007
Anti-tuberculosis drug susceptibility testing of Mycobacterium bovis BCG Tokyo strain.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2007, Volume: 11, Issue:12

    The Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine is the only vaccine against tuberculosis (TB), owing to its valuable protective effects and low virulence. However, it can occasionally cause systemic infection in immunocompromised hosts. Isoniazid (INH), rifampicin (RMP), streptomycin (SM) and ethambutol (EMB) are known to be effective anti-tuberculosis drugs and are used for the treatment of BCG infections. Unfortunately, there are few studies of the susceptibility of BCG vaccine strains to these drugs.. To measure the minimum inhibitory concentrations (MICs) of BCG Tokyo vaccine products for anti-tuberculosis drugs and assess vaccine safety in terms of drug susceptibility.. We measured the MIC for one seed and five product lots of BCG Tokyo strain for INH, RMP, SM and EMB using Middlebrook 7H11 agar plates.. The MIC results for INH were 0.06 and 0.125 mg/ml for the product and seed lots, respectively. The MIC results for RMP, SM and EMB were 0.25-0.5, 0.25 and 2-4 microg/ml, respectively.. Our results indicate that the BCG Tokyo strain was susceptible to the major anti-tuberculosis drugs and treatable even in cases of severe adverse events, including systemic infection.

    Topics: Antitubercular Agents; BCG Vaccine; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium bovis; Rifampin; Streptomycin; Tuberculosis

2007
Tuberculosis peritonitis.
    Medicine and health, Rhode Island, 2007, Volume: 90, Issue:11

    Topics: Aged; Antitubercular Agents; Dominican Republic; Ethambutol; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Peritonitis; Rhode Island; Rifampin; Tuberculosis

2007
Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model.
    PLoS medicine, 2007, Volume: 4, Issue:12

    Availability of an ultra-short-course drug regimen capable of curing patients with tuberculosis in 2 to 3 mo would significantly improve global control efforts. Because immediate prospects for novel treatment-shortening drugs remain uncertain, we examined whether better use of existing drugs could shorten the duration of treatment. Rifapentine is a long-lived rifamycin derivative currently recommended only in once-weekly continuation-phase regimens. Moxifloxacin is an 8-methoxyfluoroquinolone currently used in second-line regimens.. Using a well-established mouse model with a high bacterial burden and human-equivalent drug dosing, we compared the efficacy of rifapentine- and moxifloxacin-containing regimens with that of the standard daily short-course regimen based on rifampin, isoniazid, and pyrazinamide. Bactericidal activity was assessed by lung colony-forming unit counts, and sterilizing activity was assessed by the proportion of mice with culture-positive relapse after 2, 3, 4, and 6 mo of treatment. Here, we demonstrate that replacing rifampin with rifapentine and isoniazid with moxifloxacin dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice receiving rifapentine- and moxifloxacin-containing regimens were found to have negative lung cultures, while those given the standard regimen still harbored 3.17 log10 colony-forming units in the lungs (p < 0.01). No relapse was observed after just 3 mo of treatment with daily and thrice-weekly administered rifapentine- and moxifloxacin-containing regimens, whereas the standard daily regimen required 6 mo to prevent relapse in all mice.. Rifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. Our results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and moxifloxacin may permit shortening the current 6 mo duration of treatment to 3 mo or less. Such regimens warrant urgent clinical investigation.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Colony Count, Microbial; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Fluoroquinolones; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Secondary Prevention; Time Factors; Tuberculosis

2007
Doctors report breakthrough antibiotic treatment for TB.
    The AIDS reader, 2007, Volume: 17, Issue:11

    Topics: Animals; Antitubercular Agents; Aza Compounds; Clinical Trials as Topic; Drug Combinations; Fluoroquinolones; Humans; Mice; Moxifloxacin; Quinolines; Rifampin; Treatment Outcome; Tuberculosis

2007
OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice.
    PLoS medicine, 2006, Volume: 3, Issue:11

    Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment.. Here we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006-0.024 microg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 microg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 microg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes.. We concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment.

    Topics: Animals; Antitubercular Agents; Blood; Cell Line; Humans; In Vitro Techniques; Intracellular Membranes; Macrophages; Mammals; Mice; Microbial Sensitivity Tests; Microsomes, Liver; Mycobacterium; Mycobacterium bovis; Mycolic Acids; Nitroimidazoles; Oxazoles; Treatment Outcome; Tuberculosis

2006
Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles.
    Journal of medicinal chemistry, 2006, Dec-28, Volume: 49, Issue:26

    In an effort to develop potent new antituberculosis agents that would be effective against both drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis, we prepared a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles substituted at the 2-position with various phenoxymethyl groups and a methyl group and investigated the in vitro and in vivo activity of these compounds. Several of these derivatives showed potent in vitro and in vivo activity, and compound 19 (OPC-67683) in particular displayed excellent in vitro activity against both drug-susceptible and drug-resistant strains of M. tuberculosis H37Rv (MIC = 0.006 microg/mL) and dose-dependent and significant in vivo efficacy at lower oral doses than rifampicin in mouse models infected with M. tuberculosis Kurono. The synthesis and structure-activity relationships of these new compounds are presented.

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazoles; Rifampin; Structure-Activity Relationship; Tuberculosis

2006
Severe or fatal liver injury in 50 patients in the United States taking rifampin and pyrazinamide for latent tuberculosis infection.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2006, Feb-01, Volume: 42, Issue:3

    Severe liver injuries were attributed to the rifampin and pyrazinamide (RZ) regimen after it was recommended for treating latent tuberculosis infection. Implicating RZ as the likeliest cause required excluding alternative causes.. US health departments reported data on patients who died or were hospitalized for liver disease within 1 month after taking RZ for latent tuberculosis infection from October 1998 through March 2004. The circumstances were investigated on site for each case. Illness characteristics, reasons for RZ treatment, doses and frequency of administration of pyrazinamide, monitoring during treatment, and causes of liver injury were determined.. Liver injury was attributable to RZ use for all 50 patients reported, 12 of whom died. For 47 patients, RZ was the likeliest cause of liver injury. The median patient age was 44 years (range, 17-73 years). Thirty-two patients (64%) were male. Seven (16%) of 43 patients tested had hepatitis C virus antibodies, 1 (2%) of 45 had chronic hepatitis B, 3 (14%) of 22 had positive results of HIV serologic tests, 34 (71%) of 48 had alcohol use noted, and 33 (66%) of 50 were taking additional hepatotoxic medications. Six patients, 2 of whom died, had no predictors for liver disease. Patients who died were older (median age, 52 vs. 42 years; P=.08) and took a greater number of other medications (median number of medications, 4 vs. 2; P=.05) than did those who recovered, but these 2 factors were correlated (P<.01). Thirty-one patients (62%) were monitored according to guidelines, 9 of whom died.. RZ was the likeliest cause of most of these liver injuries, some of which were fatal in spite of monitoring. Fatality was predicted by age or use of other medications, but none of the cofactors showed promise as a reliable clinical predictor of severe liver injury.

    Topics: Adolescent; Adult; Aged; Alcohol Drinking; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Pyrazinamide; Rifampin; Risk Factors; Substance-Related Disorders; Tuberculosis; United States

2006
Evaluation of the CombiChip Mycobacteria Drug-Resistance detection DNA chip for identifying mutations associated with resistance to isoniazid and rifampin in Mycobacterium tuberculosis.
    Diagnostic microbiology and infectious disease, 2006, Volume: 54, Issue:3

    The CombiChip Mycobacteriatrade mark Drug-Resistance Detection DNA chip, recently developed by GeneIn (Pusan, South Korea), is an oligonucleotide microchip coupled with polymerase chain reaction for the detection of mutations associated with resistance to isoniazid (INH) and rifampin (RIF). This oligonucleotide chip was compared with DNA sequencing and phenotypic drug susceptibility testing with 69 INH- and/or RIF-resistant and 27 all tested drug-susceptible Mycobacterium tuberculosis isolates. Two selected codons (the katG codon 315 and inhA15) allowed identification of 84.1% of INH-resistant isolates and 100% of RIF resistance were detected by screening for 7 codons: rpoB511, rpoB513, rpoB516, rpoB522, rpoB526, rpoB531, and rpoB533. The overall specificity of this oligonucleotide chip for detecting INH and RIF resistance were 100 and 95.3%, respectively. This level of sensitivity and specificity is concordant with that from the determination of M. tuberculosis drug resistance by DNA sequencing. This oligonucleotide chip is a rapid and reliable genotypic method capable of detecting multiple mutations associated with INH and RIF resistance simultaneously in a single microchip slide.

    Topics: Antitubercular Agents; Codon; DNA Mutational Analysis; DNA, Bacterial; Drug Resistance, Bacterial; Genes, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis

2006
Diagnosing smear-negative tuberculosis using case definitions and treatment response in HIV-infected adults.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2006, Volume: 10, Issue:1

    To assess the diagnostic utility of expanded case definitions for HIV-associated smear-negative pulmonary tuberculosis (PTB) and extra-pulmonary TB (EPTB), and to derive objective criteria for response to anti-tuberculosis treatment.. A prospective cohort study of HIV-infected adults who met expanded clinical case definitions for smear-negative PTB and EPTB.. All participants were started on rifampicin-based anti-tuberculosis treatment after mycobacterial cultures from multiple sites. At weeks 2, 4 and 8, response to treatment (RTT) was assessed by measuring changes in weight, haemoglobin, C-reactive protein, Karnofsky performance score and symptom count ratio.. Of 147 participants enrolled, 105 (71%) were diagnosed with definite (culture-positive) or probable (histological features) TB and 25 (17%) with possible TB (treatment response). The positive predictive value for the most common case definitions ranged from 89% to 96%. Significant improvements in all the RTT parameters occurred in the subjects with confirmed TB (P < 0.001). Clinically relevant RTT criteria were derived, two or more of which were met at week 8 in 97.5% of subjects with confirmed TB, 91.3% of subjects with possible TB and none of the subjects without TB.. Expanded case definitions could enhance the diagnosis of PTB and EPTB in HIV-infected adults in resource-limited settings. Using objective criteria, RTT can be assessed within 8 weeks of initiating anti-tuberculosis treatment.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; C-Reactive Protein; Cohort Studies; Female; Hemoglobins; HIV Infections; Humans; Karnofsky Performance Status; Male; Mycobacterium tuberculosis; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2006
Rifampin and pyrazinamide for treatment of latent tuberculosis infection.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2006, Mar-15, Volume: 42, Issue:6

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Hospitalization; Humans; Liver Diseases; Pyrazinamide; Rifampin; Tuberculosis

2006
Emergence of rifampicin resistance in methicillin-resistant Staphylococcus aureus in tuberculosis wards.
    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy, 2006, Volume: 12, Issue:1

    To assess whether the occurrence of rifampicin (RFP) resistance in methicillin-resistant Staphylococcus aureus (MRSA) is related to treatment of tuberculosis, we determined the RFP susceptibility of MRSA isolates obtained from tuberculosis patients and screened for mutation(s) in the rpoB gene of these isolates. The MICs of RFP for 84 MRSA isolates obtained from two hospitals in Japan were determined. DNA was sequenced in the region 1318-1602 nucleotides (nt) of the rpoB gene, which includes RFP resistance-determining clusters I (1384-1464 nt, 462-488 amino acids). The majority of MRSA isolates from tuberculosis wards, i.e., 48 of 51 (94%) [33 of 34 in a Tokyo hospital (97%) and 15 of 17 in a Chubu hospital (88%)], were resistant to RFP. Meanwhile, no isolates of 33 from the other wards were resistant to RFP. All RFP-resistant MRSA isolates had a mutation(s), including novel mutation(s) such as Val453-->AEPhe, Asp471-->AEAsn, and Ile527-->AELeu, in rpoB. An emergence of RFP-resistant MRSAs in tuberculosis wards in Japan was strongly suggested.

    Topics: Amino Acid Sequence; Antibiotics, Antitubercular; Base Sequence; DNA, Bacterial; Drug Resistance, Bacterial; Genotype; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Tuberculosis

2006
Ritonavir/saquinavir safety concerns curtail antiretroviral therapy options for tuberculosis-HIV-co-infected patients in resource-constrained settings.
    AIDS (London, England), 2006, Jan-09, Volume: 20, Issue:2

    Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Developing Countries; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Rifampin; Ritonavir; Saquinavir; Tuberculosis

2006
Statistical evaluation of physiological variability of rifampicin in fixed dose combinations.
    International journal of pharmaceutics, 2006, Apr-26, Volume: 313, Issue:1-2

    Tuberculosis is one of the microbial diseases having a long history of its occurrence and yet to be eradicated from the world. Due to the development of bacterial resistance, treatment has changed from monotherapy to combotherapy to fixed dose combinations (FDCs). Rifampicin has been found one of the most important anti-tubercular drugs, however variable bioavailability of rifampicin in some FDCs as well as separate formulations has been reported in the literature, and led to the development of WHO model protocol for evaluation of FDCs for bioequivalence trials. In present investigation, role of physiological variability in rifampicin bioequivalence was studied. Influence of subject's body weight, inter/intra-individual variability of elimination rate and impact of outliers on the decision of bioequivalence were investigated. Normalization of pharmacokinetic measures for bioequivalence (AUC and C(max)) were carried out as per body weights and elimination rate constants of subjects, then different statistical tests like two-way ANOVA, hauschke analysis, normal and log-transformed confidence interval were applied to check for the change in bioequivalence decision. It was found that normalization as per body weights did not play a significant role in the outcome of bioequivalence endpoint. Similarly, elimination rate variability and outliers have been found insignificant regarding final outcome of bioequivalence study. Hence, it has been concluded that physiological variability did not play a significant role in bioequivalence of rifampicin in FDCs.

    Topics: Analysis of Variance; Antibiotics, Antitubercular; Biological Availability; Clinical Protocols; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Humans; Practice Guidelines as Topic; Rifampin; Therapeutic Equivalency; Tuberculosis; World Health Organization

2006
Mycobacterium tuberculosis in a Saudi Arabian hospital.
    Chest, 2006, Volume: 129, Issue:3

    Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Saudi Arabia; Tuberculosis; Tuberculosis, Multidrug-Resistant

2006
Rapid detection of specific gene mutations associated with isoniazid or rifampicin resistance in Mycobacterium tuberculosis clinical isolates using non-fluorescent low-density DNA microarrays.
    The Journal of antimicrobial chemotherapy, 2006, Volume: 57, Issue:5

    A new, fast 'low cost and density' DNA microarray (LCD array), designed for the detection of mutations that confer isoniazid or rifampicin resistance in Mycobacterium tuberculosis isolates, has been developed and was evaluated using 46 resistant clinical isolates from Barcelona.. LCD chips are pre-structured polymer supports using a non-fluorescent detection principle based on the precipitation of a clearly visible dark substrate. One LCD chip consists of eight identical microarrays, designed to detect mutations within the 90 bp rpoB region, codon 315 in the katG gene and the mabA-inhA regulatory region. A total of 22 strains with a katG 315 mutation, 19 strains with alterations in the mabA-inhA regulatory region and 16 strains with mutations in the rpoB region, characterized previously, were studied.. The identification of S315T and S315N mutations using the LCD was 100% concordant with the sequencing data. A strain with the S315R mutation, which is not tiled on the LCD array, was detected by the absence of hybridization using the wild-type probe. Of 19 strains with low-level isoniazid resistance related to the mabA-inhA regulatory region, 18 were identified correctly. The detection of mutations in the rpoB region was 93.8% concordant with the sequencing data. One mabA-inhA and rpoB mutated strain showed a cross-hybridization.. The LCD array protocol takes 45 min (15 min 'hands-on' time) after prior PCR amplification. Only minimal laboratory equipment is required. LCD arrays provide a rapid and economical method to characterize mutations in codon 315 of the katG gene, in the mabA-inhA regulatory region and in the rpoB gene.

    Topics: Antitubercular Agents; Bacterial Proteins; Catalase; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Genes, Bacterial; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Oligonucleotide Array Sequence Analysis; Oxidoreductases; Promoter Regions, Genetic; Regulatory Sequences, Nucleic Acid; Rifampin; Tuberculosis

2006
The Directly Observed Therapy Short-Course (DOTS) strategy in Samara Oblast, Russian Federation.
    Respiratory research, 2006, Mar-23, Volume: 7

    The World Health Organisation (WHO) defines Russia as one of the 22 highest-burden countries for tuberculosis (TB). The WHO Directly Observed Treatment Short Course (DOTS) strategy employing a standardised treatment for 6 months produces the highest cure rates for drug sensitive TB. The Russian TB service traditionally employed individualised treatment. The purpose of this study was to implement a DOTS programme in the civilian and prison sectors of Samara Region of Russia, describe the clinical features and outcomes of recruited patients, determine the proportion of individuals in the cohorts who were infected with drug resistant TB, the degree to which resistance was attributed to the Beijing TB strain family and establish risk factors for drug resistance.. Prospective study.. 2,099 patients were recruited overall. Treatment outcomes were analysed for patients recruited up to the third quarter of 2003 (n = 920). 75.3% of patients were successfully treated. Unsuccessful outcomes occurred in 7.3% of cases; 3.6% of patients died during treatment, with a significantly higher proportion of smear-positive cases dying compared to smear-negative cases. 14.0% were lost and transferred out. A high proportion of new cases (948 sequential culture-proven TB cases) had tuberculosis that was resistant to first-line drugs; (24.9% isoniazid resistant; 20.3% rifampicin resistant; 17.3% multidrug resistant tuberculosis). Molecular epidemiological analysis demonstrated that half of all isolated strains (50.7%; 375/740) belonged to the Beijing family. Drug resistance including MDR TB was strongly associated with infection with the Beijing strain (for MDR TB, 35.2% in Beijing strains versus 9.5% in non-Beijing strains, OR-5.2. Risk factors for multidrug resistant tuberculosis were: being a prisoner (OR 4.4), having a relapse of tuberculosis (OR 3.5), being infected with a Beijing family TB strain (OR 6.5) and having an unsuccessful outcome from treatment (OR 5.0).. The implementation of DOTS in Samara, Russia, was feasible and successful. Drug resistant tuberculosis rates in new cases were high and challenge successful outcomes from a conventional DOTS programme alone.

    Topics: Adult; Antitubercular Agents; Cohort Studies; Directly Observed Therapy; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Prevalence; Prisons; Prospective Studies; Recurrence; Rifampin; Risk Factors; Russia; Treatment Failure; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2006
Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients.
    Antimicrobial agents and chemotherapy, 2006, Volume: 50, Issue:4

    Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in a cohort of tuberculosis patients established on first-line treatment regimens and to evaluate the determinants of pharmacokinetic variation. Plasma concentration-time profiles were determined for each of the drugs in 142 patients with drug-sensitive pulmonary tuberculosis after 2 months of daily treatment in hospital. Pharmacokinetic measures were described by noncompartmental analysis. Multiple linear regression was used to evaluate the patient and the treatment factors associated with variation of the area under the concentration-time curve from 0 to 8 h. Several factors independently associated with variations in antituberculosis drug concentrations were identified: human immunodeficiency virus infection was associated with 39% and 27% reductions for rifampin and ethambutol, respectively; formulation factors were determinants of rifampin and isoniazid bioavailability; female patients had increased rifampin and isoniazid concentrations but reduced ethambutol concentrations; older patients had higher levels of isoniazid and ethambutol; patients with a history of previous antituberculosis treatment had lower ethambutol concentrations; and the dose per kilogram of body weight was associated with the concentrations of all four agents. Further studies are required to assess the implications of variations in antituberculosis drug concentrations for efficacy and safety before decisions are made to change the dosing strategy in patients at risk.

    Topics: Adult; Antitubercular Agents; Area Under Curve; Cohort Studies; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis

2006
Increasing nevirapine dose can overcome reduced bioavailability due to rifampicin coadministration.
    Journal of acquired immune deficiency syndromes (1999), 2006, Volume: 42, Issue:1

    We studied the effect of rifampicin on steady-state pharmacokinetics of nevirapine and the impact of increasing the dose of nevirapine on its peak (Cmax) and trough (Cmin) levels in 13 HIV-infected patients on regular antiretroviral treatment with nevirapine-containing regimens (200 mg twice daily). A baseline pharmacokinetic study was conducted and repeated after 1 week of daily rifampicin (450/600 mg). The study was repeated in 7 of 8 patients who had subtherapeutic Cmin nevirapine levels after increasing nevirapine dose to 300 mg twice daily. Liver function was monitored. Rifampicin caused significant reductions in Cmax (42%), Cmin (53%), and exposure (46%) of nevirapine (P <.01). The Cmin of nevirapine fell below the therapeutic range of 3 microg/ml in 8 of 13 patients. An increase of nevirapine to 300 mg twice daily raised Cmin to therapeutic range in all 7 patients without exceeding the toxic level of 12 microg/mL. There were no clinical or laboratory adverse events. Our findings suggest that decreased bioavailability of nevirapine because of rifampicin coadministration could be overcome by increasing the dose of nevirapine from 200 to 300 mg twice daily without short-term adverse events. Further studies to evaluate the long-term safety of higher dose of nevirapine are required.

    Topics: Administration, Oral; Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Drug Administration Schedule; Drug Interactions; Female; HIV Infections; Humans; India; Male; Middle Aged; Nevirapine; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

2006
Passive serum therapy with polyclonal antibodies against Mycobacterium tuberculosis protects against post-chemotherapy relapse of tuberculosis infection in SCID mice.
    Microbes and infection, 2006, Volume: 8, Issue:5

    We investigated the protective role of immune-sera against reactivation of Mycobacterium tuberculosis infection in SCID mice and found that passive immunization with sera obtained from mice treated with detoxified M. tuberculosis extracts (delivered in liposomes in a composition known as RUTI) exerted significant protection. Our SCID mouse model consisted of aerosol infection by M. tuberculosis, followed by 3 to 8weeks of chemotherapy with isoniazid+rifampicin (INH+RIF) (25 and 10mg/kg, respectively). After infection and antibiotic administration, two groups of mice were treated for up to 10weeks with intraperitoneal passive immunization using hyperimmune serum (HS) obtained from mice infected with M. tuberculosis, treated with chemotherapy (INH+RIF) for 8weeks and inoculated with RUTI (HS group) or with normal serum (CT group). Significant differences were found between HS and CT groups in the number of bacilli in the lungs (3.68+/-2.02 vs. 5.72+/-1.41log(10) c.f.u.), extent of pulmonary granulomatomous infiltration (10.33+/-0.67 vs. 31.2+/-1.77%), and percentage of animals without pulmonary abscesses (16.7% vs. 45.5%). These data strongly suggest a protective role of specific antibodies against lung dissemination of M. tuberculosis infection.

    Topics: Animals; Antibodies, Bacterial; Antitubercular Agents; Disease Models, Animal; Female; Humans; Immune Sera; Immunization, Passive; Isoniazid; Lung; Mice; Mice, Inbred DBA; Mice, SCID; Mycobacterium tuberculosis; Rifampin; Secondary Prevention; Specific Pathogen-Free Organisms; Tuberculosis

2006
Mycobacterium tuberculosis and rifampin resistance, United Kingdom.
    Emerging infectious diseases, 2006, Volume: 12, Issue:5

    The United Kingdom Health Protection Agency Mycobacterium Reference Unit offers a national "Fastrack" molecular service for detecting Mycobacterium tuberculosis complex (MTBC) and rifampin resistance by using the INNO-LiPA Rif.TB assay. We analyzed the service in a routine, nontrial context of 1,997 primary clinical specimens, including 658 nonrespiratory specimens. The overall adjusted concordance, sensitivity, specificity, positive predictive value, and negative predictive value for detecting MTBC were 91.2%, 85.2%, 96.2%, 95.7%, and 86.7%, respectively (unadjusted, 86.7%, 85.2%, 88.2%, 86.9%, and 86.7%), when false-positive samples from patients (n = 83) with a known microbiologic diagnosis of MTBC or patients receiving current or recent antituberculous treatment were excluded. The parameters for detecting rifampin resistance were 99.1%, 95.0%, 99.6%, 92.7%, and 99.7%, respectively. The assay enabled earlier diagnosis of MTBC and rifampin resistance (15.2 days) compared with culture-based techniques (30.7 days).

    Topics: Antibiotics, Antitubercular; Bacterial Typing Techniques; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Predictive Value of Tests; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Time Factors; Tuberculosis; United Kingdom

2006
Plasma nevirapine levels and 24-week efficacy in HIV-infected patients receiving nevirapine-based highly active antiretroviral therapy with or without rifampicin.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2006, Jul-15, Volume: 43, Issue:2

    Seventy human immunodeficiency virus (HIV)-infected patients receiving rifampicin and 70 HIV-infected patients not receiving rifampicin were enrolled to receive 400 mg of nevirapine-based highly active antiretroviral therapy per day. Mean plasma nevirapine levels at 8 and 12 weeks were lower in patients receiving rifampicin (P=.048). However, virological and immunological outcomes at 24 weeks were not different between the 2 groups (P>.05).

    Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Drug Interactions; Female; HIV Infections; Humans; Male; Nevirapine; Prospective Studies; Rifampin; Treatment Outcome; Tuberculosis

2006
Safety and completion rate of short-course therapy for treatment of latent tuberculosis infection.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2006, Aug-01, Volume: 43, Issue:3

    Nine months of isoniazid therapy is the recommended regimen for treatment of latent tuberculosis infection, but low completion rates are a serious problem. The search for shorter regimens, compared with the standard isoniazid regimen, is of vital importance. We describe our experience using short-course regimens for the treatment of latent tuberculosis infection.. We conducted a nonrandomized, observational study of 459 patients in a county health department from June 2000 to January 2006. Short-course therapy was defined as pyrazinamide and rifampin taken daily or twice weekly for 2 months or rifampin taken daily for 4-6 months. Conventional therapy consisted of a 9-month regimen of isoniazid. Liver function testing was performed for both groups in accordance with clinical guidelines. Treatment completion and hepatotoxicity (according to the World Health Organization classification) were determined for the short-course and conventional therapy groups.. Treatment was completed by 241 (77.7%) of 310 patients in the short-course group and by 98 (65.8%) of 149 patients in the isoniazid group (P = .009). Moderate to severe hepatotoxicity (grades 3 and 4) occurred in 6.1% of patients receiving short-course therapy and in 2.0% of patients receiving isoniazid (P=.09). The hepatotoxicity observed in the short-course group was confined to patients receiving pyrazinamide and rifampin daily and was self limited in all cases after the medications were discontinued.. The rate of treatment completion was significantly higher with short-course regimens, compared with the isoniazid regimen. Although the overall risk of hepatotoxicity in patients receiving pyrazinamide and rifampin daily for the treatment of latent tuberculosis infection was higher, liver functions returned to normal after the medications were discontinued.

    Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Female; Humans; Male; Patient Compliance; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

2006
In house reverse line hybridization assay for rapid detection of susceptibility to rifampicin in isolates of Mycobacterium tuberculosis.
    Journal of microbiological methods, 2006, Volume: 67, Issue:2

    We developed a Reverse Hybridization Assay (RHA) slightly modified from the Rifoligotyping assay and analyzed the presence of mutations in a specific region of rpoB gene in 157 isolates (90 rifampin-resistant and 67 rifampin sensitive) of Mycobacterium tuberculosis from patients attended in South and Southeast region of Brazil. Comparing to standardized drug susceptibility testing results, the sensitivity and specificity of the RHA was respectively 93% (95% IC: 86.6%-97.2%) and 100% respectively. Additionally, a high agreement (kappa coefficient 95%) between the RHA assay and sequencing was obtained. Among the 90 rifampicin-resistant isolates, RHA identified point mutations in the following codons: 42 isolates (46.6%) in 531; 29 isolates (32.2%) in 526, 6 isolates (6.7%) in 516, 3 isolates (3.3%) in 522, 2 isolates (2.2%) in 515, 514, 513 and 1 isolate (1.1%) in 511, 524 and 525. Mutations in different codons were simultaneously identified in 8 isolates (8.9%). The RHA used in the present study had a high accuracy and can be rapidly performed. However, more reproducible hybridization conditions should be looked for to increase reliability of mutant probe interpretation.

    Topics: Antitubercular Agents; DNA, Bacterial; Drug Resistance, Bacterial; Genotype; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Point Mutation; Polymerase Chain Reaction; Rifampin; Sequence Analysis, DNA; Tuberculosis

2006
Evaluation of the Genotype MTBDR assay for rapid detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis isolates.
    Journal of clinical microbiology, 2006, Volume: 44, Issue:7

    A novel PCR-based reverse hybridization method Genotype MTBDR assay (Hain Lifescience GmbH, Nehren, Germany) was evaluated for rapid detection of rifampin (RIF) and isoniazid (INH) resistance in Turkish Mycobacterium tuberculosis isolates. The Genotype MTBDR assay is designed to detect mutations within the 81-bp hotspot region of rpoB and mutations at katG codon 315. A total of 41 RIF-resistant M. tuberculosis isolates with rpoB mutations that were previously tested by the INNO-LiPA Rif.TB kit and also characterized by DNA sequencing were included in the study. Thirty-seven of these isolates were also resistant to INH. RIF resistance was correctly identified in 39 of 41 isolates (95.1%) with the Genotype MTBDR assay probes specific for these mutations. One isolate with a Gln-490-His mutation and another one with a CGG insertion between codons 514 and 515 were identified as RIF sensitive by the Genotype MTBDR assay. While the INNO-LiPA Rif.TB kit was able to determine the CGG insertion between codons 514 and 515, the Gln-490-His mutation outside the 81-bp hotspot region was not detected by the INNO-LiPA Rif.TB kit. These isolates had MICs of >or=32 microg/ml for RIF. The Genotype MTBDR assay also correctly identified 27 of 37 INH-resistant isolates (73%) with mutations in katG codon 315. In conclusion, the Genotype MTBDR assay may be useful for the rapid diagnosis of the most common mutations found in multidrug-resistant M. tuberculosis strains. However, the test results should always be confirmed with phenotypic methods.

    Topics: Amino Acid Substitution; Antitubercular Agents; Bacterial Proteins; Catalase; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Polymerase Chain Reaction; Recombination, Genetic; Rifampin; Sensitivity and Specificity; Tuberculosis; Turkey

2006
Mutations prevalent among rifampin- and isoniazid-resistant Mycobacterium tuberculosis isolates from a hospital in Vietnam.
    Journal of clinical microbiology, 2006, Volume: 44, Issue:7

    Vietnam is ranked 13th among the WHO list of 22 high-burden countries, based upon estimated total number of tuberculosis cases. Despite having a model national tuberculosis program, consistently achieving and exceeding WHO targets for detection and cure, drug-resistant and multidrug-resistant tuberculosis cases continue to rise. Rapid multidrug-resistant tests applicable in this setting, coupled with effective treatment regimens, would be a useful tool in reversing this trend, allowing early identification of patients with multidrug-resistant tuberculosis and avoiding resistance-amplifying regimens. Sequencing of consecutive isolates identified by the National Tuberculosis Program showed 89% of isoniazid-resistant isolates could be detected by targeting just 2 codons, katG 315 and -15C-->T in the inhA promoter, while rifampin resistance will be more complex to detect, with many different mutation and insertion events in rpoB. The most prevalent rifampin resistance-conferring mutations, as in other countries, were in rpoB codons 531 (43%), 526 (31%), and 516 (15%). However, a hybridization-based resistance test with probes targeting the 5 most common mutations would only detect 78% of rifampin-resistant isolates. Overall, these data suggest that rifampin resistance may be used as a surrogate marker for multidrug-resistant tuberculosis and that a sensitivity of between 70 to 80% may be possible for rapid molecular detection of multidrug-resistant tuberculosis in this setting.

    Topics: Amino Acid Substitution; Antitubercular Agents; Bacterial Proteins; Catalase; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Hospitals; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Promoter Regions, Genetic; Recombination, Genetic; Rifampin; Sequence Analysis, DNA; Tuberculosis; Vietnam

2006
Use of genotype MTBDR assay for molecular detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis clinical strains isolated in Italy.
    Journal of clinical microbiology, 2006, Volume: 44, Issue:7

    Mycobacterium tuberculosis is one of the leading causes of death worldwide, and multidrug-resistant tuberculosis (MDR-TB) is associated with a high case fatality rate. Rapid identification of resistant strains is crucial for the early administration of appropriate therapy, for prevention of development of further resistance, and to curtail the spread of MDR strains. The Genotype MTBDR (Hain Lifescience, Nehren, Germany) is a reverse hybridization line probe assay designed for the rapid detection of rpoB and katG gene mutations in clinical isolates. The ability of this technique to correctly identify resistant and MDR-TB strains was tested on 206 isolates from the Italian drug resistance surveillance system. This panel included the majority of MDR strains isolated in Italy in the past 3 years. The results of the test were compared to conventional drug susceptibility test performed on isolated strains and verified by sequencing the regions of interest of the bacterial genome. The rate of concordance between the results of the MTBDR and those obtained with "in vitro" sensitivity was 91.5% (130 of 142) for rifampin and 67.1% (116 of 173) for isoniazid. We also applied this test directly to a panel of 36 clinical specimens collected from patients with active TB. The MTBDR correctly identified the two cases of MDR-TB included in the panel. These results show that the MTBDR test is useful in the detection and management of tuberculosis when MDR disease is suspected.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Isoniazid; Italy; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Rifampin; Sequence Analysis, DNA; Tuberculosis

2006
Mixed infection and clonal representativeness of a single sputum sample in tuberculosis patients from a penitentiary hospital in Georgia.
    Respiratory research, 2006, Jul-17, Volume: 7

    Studies on recurrent tuberculosis (TB), TB molecular epidemiology and drug susceptibility testing rely on the analysis of one Mycobacterium tuberculosis isolate from a single sputum sample collected at different disease episodes. This scheme rests on the postulate that a culture of one sputum sample is homogeneous and representative of the total bacillary population in a patient.. We systematically analysed several pre-treatment isolates from each of 199 smear-positive male adult inmates admitted to a prison TB hospital by standard IS6110 DNA fingerprinting, followed by PCR typing based on multiple loci containing variable number of tandem repeats (VNTRs) on a subset of isolates. Drug susceptibility testing (DST) was performed on all isolates for isoniazid, rifampicin, streptomycin and ethambutol.. We found mixed infection in 26 (13.1%) cases. In contrast, analysis of a single pre-treatment isolate per patient would have led to missed mixed infections in all or 14 of these 26 cases by using only standard DNA fingerprinting or the PCR multilocus-based method, respectively. Differences in DST among isolates from the same patient were observed in 10 cases, of which 6 were from patients with mixed infection.. These results suggest that the actual heterogeneity of the bacillary population in patients, especially in high TB incidence settings, may be frequently underestimated using current analytical schemes. These findings have therefore important implications for correct interpretation and evaluation of molecular epidemiology data and in treatment evaluations.

    Topics: Adult; Antitubercular Agents; DNA Fingerprinting; Drug Resistance, Bacterial; Georgia (Republic); Hospitals; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Minisatellite Repeats; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Prisoners; Prospective Studies; Quality Control; Rifampin; Sputum; Streptomycin; Tuberculosis

2006
Molecular characterization of mutation associated with rifampicin and isoniazid resistance in Mycobacterium tuberculosis isolates.
    Indian journal of experimental biology, 2006, Volume: 44, Issue:7

    Nucleotide changes in catalase peroxidase (Kat G) gene and gene encoding the beta subunit of RNA polymerase (rpo B), responsible for isoniazid and rifampicin drug resistance were determined in the clinical isolates of Mycobacterium tuberculosis by PCR-RFLP, Line probe assay and DNA sequencing. PCR-RFLP test was performed by HapII cleavage of an amplified fragment of Kat G gene to detect the transversion 315AGC-->ACC(Ser-->Thr) which is associated with INH drug resistance. The Line probe assay kit was evaluated to detect the mutation in 81bp RMP resistance determining region of rpo B gene associated with RMP drug resistance. These results were validated by DNA sequencing and drug susceptibility test. Kat G S 315 T mutation was found in 74.19% strains of M. tuberculosis from Delhi. This mutation was not found in any of the susceptible strains tested. The line probe assay kit and DNA sequencing identified 18 isolates as RMP resistant with specific mutation, while one of the RMP resistant strain was identified as RMP susceptible, with a concordance of 94.73% with the phenotypic drug susceptibility result. Majority (8 of 19, 42.1%) of resistant isolates involved base changes at codon 531 of rpo B gene. Both PCR-RFLP and Line probe assay test can be used in many of the clinical microbiology laboratories for early detection of isoniazid and rifampicin drug resistance in clinical isolates of M. tuberculosis.

    Topics: Adolescent; Adult; Antitubercular Agents; Bacterial Proteins; Catalase; Codon; Drug Resistance, Multiple, Bacterial; Electrophoresis, Polyacrylamide Gel; Humans; Isoniazid; Middle Aged; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; RNA Polymerase II; Tuberculosis

2006
Anti-tuberculosis drug inducd hepatitis - a Sri Lankan experience.
    The Ceylon medical journal, 2006, Volume: 51, Issue:1

    To assess the incidence of anti-tuberculosis (TB) drug induced hepatitis (AIH) in Sri Lankan patients, determine risk factors of AIH, and to address management options in AIH.. A prospective study.. Chest Hospital, Welisara, Sri Lanka, from April 2001 to April 2002.. Seven hundred and eighty three patients with a confirmed diagnosis of TB and resident in the Colombo and Gampaha districts who presented to Chest Hospital, Welisara, Sri Lanka.. WHO recommended treatment was commenced in all cases. AIH was diagnosed when patients complained of decreased appetite with nausea or vomiting and elevated serum bilirubin (SB; >1.1 mg/dL) or elevated serum alanine transferase (ALT; > 3 times upper limit of normal).. Of 783 enrolled patients, 74 (9.5%) developed AIH, the majority (58%) developing AIH within the first 2 weeks of the intensive phase of treatment. AIH was more common among patients over 60 years (p = 0.018), who developed pulmonary TB (p = 0.028), and in patients weighing 33-55 kg (p = 0.004). Age, weight and rifampicin overdosage were significant predictors of AIH. Of the 74 AIH patients, standard treatment was restarted in 60, treatment modified in six, two defaulted and six died.. The incidence of AIH in Sri Lanka is 9.5% in treated patients. AIH was associated with age, low body weight and rifampicin overdosage.

    Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Female; Humans; Incidence; Isoniazid; Male; Middle Aged; Prospective Studies; Rifampin; Risk Assessment; Risk Factors; Sri Lanka; Streptomycin; Tuberculosis

2006
Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2006, Oct-01, Volume: 43, Issue:7

    Type 2 diabetes (DM) is a strong risk factor for tuberculosis (TB) and is associated with a slower response to TB treatment and a higher mortality rate. Because lower concentrations of anti-TB drugs may be a contributing factor, we compared the pharmacokinetics of rifampicin in patients with TB, with and without DM.. Seventeen adult Indonesian patients with TB and DM and 17 age- and sex-matched patients with TB and without DM were included in the study during the continuation phase of TB treatment. All patients received 450 mg of rifampicin (10 mg/kg) and 600 mg of isoniazid 3 times weekly. Steady-state plasma concentrations of rifampicin and its metabolite desacetylrifampicin were assessed at 0, 2, 4, and 6 h after drug intake.. Geometric means of rifampicin exposure (AUC(0-6 h)) were 12.3 mg x h/L (95% confidence interval [CI], 8.0-24.2) in patients with TB and DM, and 25.9 mg x h/L (95% CI, 21.4-40.2) in patients with TB only (P=.003). Similar differences were found for the maximum concentration of rifampicin. No significant differences in time to maximum concentration of rifampicin were observed. The AUC(0-6 h) of desacetylrifampicin was also much lower in patients with TB and DM versus patients with TB only (geometric mean, 0.60 vs. 3.2 mg x h/L; P=.001). Linear regression analysis revealed that higher body weight (P<.001), the presence of DM (P=.06), and plasma glucose concentration (P=.016) were correlated with exposure to rifampicin.. Exposure (AUC(0-6 h)) to rifampicin was 53% lower in Indonesian patients with TB and DM, compared with patients with TB only. Patients with TB and DM who have a higher body weight may need a higher dose of rifampicin.

    Topics: Adult; Antitubercular Agents; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2006
Combinations of R207910 with drugs used to treat multidrug-resistant tuberculosis have the potential to shorten treatment duration.
    Antimicrobial agents and chemotherapy, 2006, Volume: 50, Issue:11

    The objective of the present study was to identify the optimal R207910-containing regimen to administer to patients who cannot receive rifampin (RIF) and isoniazid (INH) because of multidrug-resistant tuberculosis (MDR-TB), concomitant use of antiretroviral drugs, or toxicity. Mice were infected intravenously with 5 x 10(6) CFU of the H37Rv strain and treated five times per week with R207910 alone or various combinations of R207910 with the second-line drugs amikacin (AMK), pyrazinamide (PZA), moxifloxacin (MXF), and ethionamide (ETH). All R207910-containing regimens were significantly more active than the non-R207910-containing regimens after 1 month of therapy. When given for 2 months, R207910 alone was more active than the WHO standard first-line regimen RIF-INH-PZA. When R207910 was combined with second-line drugs, the combinations were more active than the currently recommended regimen of MDR-TB AMK-ETH-MXF-PZA, and culture negativity of both the lungs and spleen was reached after 2 months of treatment in almost every case.

    Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Aza Compounds; Colony Count, Microbial; Diarylquinolines; Drug Combinations; Drug Resistance, Multiple, Bacterial; Ethionamide; Fluoroquinolones; Lung; Mice; Moxifloxacin; Mycobacterium tuberculosis; Organ Size; Pyrazinamide; Quinolines; Rifampin; Spleen; Survival Analysis; Tuberculosis

2006
Evaluation of dosing regimen of respirable rifampicin biodegradable microspheres in the treatment of tuberculosis in the guinea pig.
    The Journal of antimicrobial chemotherapy, 2006, Volume: 58, Issue:5

    The efficacy of rifampicin-loaded polymeric microspheres (RPLGA) delivered to guinea pigs infected with Mycobacterium tuberculosis (H37Rv) was compared with a daily dose of nebulized rifampicin suspension.. Aerosol-infected animals were subjected to multiple dose or single dose treatment with RPLGA, PLGA microspheres or micronized rifampicin suspension aerosols. For comparison with treatment with suspensions of microspheres, additional groups received daily doses of rifampicin-only suspensions for 20 (20-RIF) and 10 (10-RIF) days.. Drug and polymer treated multiple dose groups exhibited significantly lower wet lung weights than untreated animals. Spleen wet weights and viable bacterial counts (VBCs) were much lower for drug microsphere treated animals than for all other groups. In multiple dose studies with rifampicin-only suspensions, wet lung weights for 10-RIF and 20-RIF treated animals were much smaller than controls. Likewise, wet spleen weights of 10-RIF and 20-RIF treated animals were much smaller than controls, consistent with reduced inflammation. Spleen VBC of 20-RIF treated animals was much smaller than controls. No statistical differences were observed in the lung VBC among single dose groups. However, a trend similar to that of the wet weights was observed.. Aerosolized RPLGA reduced most measures of tuberculosis (TB) infection. These studies are further evidence for the potential of inhaled aerosol therapy for the treatment of TB. However, additional studies are required to elucidate underlying mechanisms of action and optimize this route of drug delivery.

    Topics: Administration, Inhalation; Animals; Antibiotics, Antitubercular; Drug Delivery Systems; Guinea Pigs; Lung; Male; Microspheres; Mycobacterium tuberculosis; Organ Size; Rifampin; Spleen; Tuberculosis

2006
Improved adherence and less toxicity with rifampin vs isoniazid for treatment of latent tuberculosis: a retrospective study.
    Archives of internal medicine, 2006, Sep-25, Volume: 166, Issue:17

    Treatment of latent tuberculosis infection (LTBI) is an important aspect of tuberculosis control in the United States, but the effectiveness of this strategy is compromised by poor adherence to the recommended 9-month isoniazid regimen. In this study, we compared treatment completion and clinically recognized adverse drug reactions in patients prescribed 9 months of isoniazid therapy or 4 months of rifampin therapy for LTBI.. Retrospective chart review of patients who received LTBI treatment at a public health clinic.. A total of 770 patients were prescribed 9 months of isoniazid therapy, and 1379 patients were prescribed 4 months of rifampin therapy. The percentages of patients who completed 80% or more of their prescribed treatment were 52.6% and 71.6% in the isoniazid and rifampin groups, respectively (P<.001). In multivariate logistic regression analysis, treatment regimen was independently associated with treatment completion (adjusted odds ratio for treatment completion, 2.88 for rifampin group vs isoniazid group; 95% confidence interval, 2.27-3.66). Clinically recognized adverse reactions resulting in permanent treatment discontinuation occurred in 4.6% and 1.9% of patients in the isoniazid and rifampin groups, respectively (P<.001). Clinically recognized hepatotoxicity was more common in the isoniazid group (1.8%) than in the rifampin group (0.08%, P<.001).. Compared with a 9-month isoniazid regimen, a 4-month rifampin regimen was associated with a higher percentage of patients completing treatment and a lower percentage of patients with clinically recognized adverse reactions. Additional studies are warranted to determine efficacy and effectiveness of rifampin therapy for LTBI.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Female; Humans; Isoniazid; Male; Patient Compliance; Retrospective Studies; Rifampin; Socioeconomic Factors; Treatment Outcome; Tuberculosis

2006
Predominance of multi-drug-resistant LAM and Beijing family strains among Mycobacterium tuberculosis isolates recovered from prison inmates in Tula Region, Russia.
    Journal of medical microbiology, 2006, Volume: 55, Issue:Pt 10

    The genotypic characteristics and drug susceptibility profiles of clinical isolates of Mycobacterium tuberculosis recovered from prison hospital patients in the Tula region (central Russia) during 2001 and 2002 are reported. The emergence of multi-drug-resistant tuberculosis (TB) poses a major health risk to the population, with economic implications for TB control. Prisons serve as a continuous source of TB transmission. The results showed that members of the LAM and Beijing families are major contributors to the epidemiological picture of TB in the population studied. The two families of strains accounted for most of the drug-resistant TB in the population. The genotypic characteristics of the M. tuberculosis predominant LAM strain that was responsible for 31 % of TB cases in this setting are presented.

    Topics: Adult; Antibiotics, Antitubercular; Bacterial Typing Techniques; DNA Transposable Elements; Drug Resistance, Multiple, Bacterial; Hospitals, Special; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Prisoners; Rifampin; Risk Factors; Russia; Species Specificity; Tuberculosis; Tuberculosis, Multidrug-Resistant

2006
Direct detection of Mycobacterium tuberculosis complex DNA and rifampin resistance in clinical specimens from tuberculosis patients by line probe assay.
    Journal of clinical microbiology, 2006, Volume: 44, Issue:12

    The INNO-LiPA.Rif TB test (LiPA) has only been applied to a limited number of clinical specimens. To assess the utility of this test for detecting Mycobacterium tuberculosis complex DNA and rifampin (RMP) resistance, 420 sputum samples comprising specimens from untreated (n=160) and previously treated (n=260) patients from 11 countries in Asia, Africa, Europe, and Latin America were tested. DNA was extracted from sputum samples by using a modification of the Boom's method, while the rpoB core region was amplified by nested PCR. The results were analyzed in conjunction with those obtained by Ziehl-Neelsen (ZN) microscopy and by culture on solid media. The LiPA test was positive for M. tuberculosis complex DNA in 389 (92.9%) specimens, including 92.0% (286 of 311) ZN-positive and 94.5% (103 of 109) ZN-negative specimens. Of these, 30.6% were RMP resistant. In contrast, 74.3% of the specimens were positive for M. tuberculosis by culture, and 30.8% of them were RMP resistant. LiPA detected M. tuberculosis complex DNA in 92.4% (110 of 119) of the culture-positive and 100.0% (41 of 41) of the culture-negative specimens from untreated patients. There was a 99.6% concordance between the RMP resistance as determined by culture and by the LiPA test. With an optimal DNA extraction method, LiPA allows rapid detection of M. tuberculosis complex DNA and RMP resistance directly from sputum specimens. LiPA can still provide useful information when culture fails for various reasons. The rapid availability of this information is necessary to adjust patient treatment and avoid the risk of amplification of drug resistance.

    Topics: Antitubercular Agents; Bacterial Proteins; Bacteriological Techniques; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Staining and Labeling; Tuberculosis; Tuberculosis, Multidrug-Resistant

2006
Use of smear-positive samples to assess the PCR-based genotype MTBDR assay for rapid, direct detection of the Mycobacterium tuberculosis complex as well as its resistance to isoniazid and rifampin.
    Journal of clinical microbiology, 2006, Volume: 44, Issue:12

    Isoniazid (INH) and rifampin (RIF) are two of the most important antituberculosis drugs, and resistance to both of these drugs can often result in treatment failure and fatal clinical outcome. Resistance to these two first-line drugs is most often attributed to mutations in the katG, inhA, and rpoB genes. Historically, the identification and testing of the susceptibility of Mycobacterium tuberculosis complex (MTBC) strains takes weeks to complete. Rapid detection of resistance using the PCR-based Genotype MTBDR assay (Hain Lifescience GmbH, Nehren, Germany) has the potential to significantly shorten the turnaround time from specimen receipt to reporting of results of susceptibility testing. Therefore, the aim of the present study was to determine (i) the sensitivity and accuracy of the Genotype MTBDR assay for the detection of MTBC strains and (ii) the ability of the assay to detect the presence of INH and RIF resistance-associated mutations in katG and rpoB from samples taken directly from smear-positive clinical specimens. The results were compared with those obtained with the reference BACTEC 460TB system combined with standard DNA sequencing analysis methods for katG, inhA, and rpoB. A total of 92 drug-resistant and 51 pansusceptible smear-positive specimens were included in the study. The Genotype MTBDR assay accurately and rapidly detected MTBC strains in 94.4% of the 143 specimens and showed a sensitivity of 94.4% for katG and 90.9% for rpoB when used directly on smear-positive specimens. The assay correctly identified INH resistance in 48 (84.2%) of the 57 specimens containing strains with resistance to high levels of INH (0.4 microg/ml) and RIF resistance in 25 (96.2%) of the 26 specimens containing RIF-resistant strains.

    Topics: Antitubercular Agents; Bacterial Proteins; Catalase; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Oxidoreductases; Polymerase Chain Reaction; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Sputum; Tuberculosis

2006
Tuberculosis in patients receiving anti-TNF agents despite chemoprophylaxis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2006, Volume: 10, Issue:10

    A major concern surrounding the use of tumor necrosis factor-alpha (TNF-alpha) inhibitors is their potential to increase the risk of opportunistic infections, particularly tuberculosis (TB).. To estimate the incidence of active TB in patients with rheumatic diseases receiving anti-TNF drug therapy and to evaluate the effectiveness of an antituberculosis chemoprophylaxis regimen.. Retrospective study of the files of 613 patients with rheumatic diseases who had received anti-TNF agent (etanercept, infliximab and adalimumab) therapy from July 2000 to June 2004 at the Aristotle University of Thessaloniki, Greece. All patients had a tuberculin skin test (TST) and a postero-anterior chest radiograph (CXR) prior to anti-TNF therapy. When indicated (TST > or =10 mm and/or fibrotic lesions on CXR), treatment for latent TB was established (6 months isoniazid [INH] or 3 months INH and rifampicin [RMP]). Anti-TNF agent therapy was started again 2 months later.. Of 45 patients who fulfilled the criteria for chemoprophylaxis, only 36 were treated correctly. Eleven patients developed active TB 2-35 months after the beginning of anti-TNF therapy. Six patients developed pulmonary and five extra-pulmonary TB. Eight of these had received infliximab and three adalimumab.. The incidence of active TB in this study population was estimated at 449 cases per 100,00 population annually. Anti-tuberculosis chemoprophylaxis was only of partial preventive success in these patients.

    Topics: Adalimumab; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Antitubercular Agents; Arthritis; Arthritis, Rheumatoid; Comorbidity; Etanercept; Female; Greece; Humans; Immunoglobulin G; Incidence; Infliximab; Isoniazid; Male; Middle Aged; Receptors, Tumor Necrosis Factor; Retrospective Studies; Rifampin; Spondylitis, Ankylosing; Tuberculosis; Tuberculosis, Pulmonary

2006
Rapid and low-cost colorimetric method using 2,3,5-triphenyltetrazolium chloride for detection of multidrug-resistant Mycobacterium tuberculosis.
    Journal of medical microbiology, 2006, Volume: 55, Issue:Pt 12

    A rapid and inexpensive method for the detection of drug resistance in Mycobacterium tuberculosis is essential for the effective control of tuberculosis. The aim of this study was to evaluate a colorimetric method using 2,3,5-triphenyltetrazolium chloride (TTC) for antibiotic susceptibility testing of M. tuberculosis isolates. Eleven multidrug-resistant (MDR) isolates of M. tuberculosis and 12 isolates which were susceptible to rifampicin (RIF) and isoniazid (INH) were used. The test was performed with a critical concentration of 0.2 microg ml(-1) for INH and 2.0 microg ml(-1) for RIF in 7H9GC broth with 0.625 microg TTC ml(-1). Each isolate was inoculated under these conditions and inspected daily for colour changes; the results were obtained after a mean of 4.9 days. The sensitivity and specificity of this method were 100 % and 92 %, respectively, for both antibiotics. Considering the speed, technical ease and cost-effectiveness of this method, the TTC assay is a good alternative method for drug susceptibility testing of M. tuberculosis isolates.

    Topics: Antibiotics, Antitubercular; Bacteriological Techniques; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tetrazolium Salts; Tuberculosis

2006
Molecular characterization of rpoB gene mutations in rifampicine-resistant Mycobacterium tuberculosis isolates from tuberculosis patients in Belarus.
    Biotechnology journal, 2006, Volume: 1, Issue:12

    The aim of this study was to investigate the frequency, location and type of rpoB mutations in Mycobacterium tuberculosis isolated from patients in Belarus. Tuberculosis cases are increasing every year in Belarus. Moreover, resistance to anti-tuberculosis drugs, especially to rifampicine, has increased. In this study, 44 rifampicine-resistance M. tuberculosis clinical isolates (including multidrug-resistant isolates) were subjected to DNA sequencing analysis of the hypervariable region (hot-spot) of the rpoB gene originating from different geographical regions in Belarus. Sixteen different types of mutations were identified. The most common point mutations were in codons 510 (47.7%), 526 (45.5%), 523 (40.86%) and 531 (29.5%). Eleven isolates (27.7%) carried one mutation and 23 (52%), 7 (16%), 3 (7%) of isolates carried 2, 3 and 4 mutations, respectively. A characteristic, prominent finding of this study was high frequency of multiple mutations in different codons of the rpoB gene (27.7%) and also the detection of unusual types of mutations in the 510 codon, comprising CAG mutations (deletion or changing, to CTG, CAC or CAT). In our study, the change TTG in codon 531 was found in 92% of isolates and the change TGC in 8% of isolates. A TAC change in codon 526 was not found, but the GAC change was found in all isolates. Isolates of M. tuberculosis isolated in Belarus were characterized by the wide spectrum of the important mutations and might belong to the epidemic widespread clones.

    Topics: Antitubercular Agents; Bacterial Proteins; DNA Mutational Analysis; DNA-Directed RNA Polymerases; Genetic Predisposition to Disease; Humans; Mutation; Mycobacterium tuberculosis; Prevalence; Republic of Belarus; Rifampin; Risk Assessment; Risk Factors; Tuberculosis; Tuberculosis, Multidrug-Resistant

2006
[The animal experimental study on rifampicin-dependent Mycobacterium tuberculosis].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2006, Volume: 29, Issue:9

    To investigate the presence of rifampicin-dependent Mycobacterium tuberculosis strains by use of a guinea pig model of tuberculosis of rifampicin-dependent Mycobacterium tuberculosis.. Guinea pigs were randomly divided into groups of infection by rifampicin-dependent Mycobacterium tuberculosis strains (1130 strain, 1219 strain, b858 strain), rifampicin-resistant Mycobacterium tuberculosis strain (1290 strain) and ATCC 35810 strain and each group was further divided into an experimental group and a control group. The guinea pigs were challenged with 1130 strain, 1219 strain, b858 strain, 1290 strain and ATCC 35810 strain to establish the tuberculosis model. The experimental groups were treated with rifampicin. The parameters including macroscopic visceral pathological change index, visceral weight index (spleen, lungs and liver), the colony-forming units (CFU) quantity of visceral Mycobacterium tuberculosis culture (spleen, lungs) and tissue pathology of guinea pigs were observed.. At the 7th week after challenged with 1130 strain, 1219 strain, 1290 strain and b858 strain, all animals were sacrificed. The macroscopic visceral pathological change indices of the experimental group were 68.7 +/- 13.8, 60.0 +/- 13.5, 70.0 +/- 5.8 and 23.8 +/- 18.9, whereas all those parameters of the control group were 76.2 +/- 18.9, 40.0 +/- 16.8, 63.8 +/- 10.3 and 22.5 +/- 15.5 respectively, and there was no significance between the experimental group and the control group (t = 0.64, 1.85, 0.35 and 0.10, all P > 0.05). The spleen weight indices of experimental group were 0.229 +/- 0.048, 0.256 +/- 0.067, 0.324 +/- 0.054 and 0.199 +/- 0.029, whereas all those parameters of control groups were 0.278 +/- 0.025, 0.216 +/- 0.076, 0.368 +/- 0.033 and 0.213 +/- 0.038 respectively, and there was no significance between the experimental group and the control group (t = 1.75, 0.79, 1.41 and 0.57, all P > 0.05). The CFU quantity of spleen Mycobacterium tuberculosis culture of the experimental group were 4.98 +/- 0.30, 4.68 +/- 1.26, 5.07 +/- 0.47 and 3.85 +/- 0.45, whereas all those parameters of control groups were 4.90 +/- 1.03, 4.79 +/- 0.45, 5.08 +/- 0.55 and 4.23 +/- 0.95 respectively, and there was no significance between the experimental group and the control group (t = 0.11, 0.15, 0.03 and 0.73, all P > 0.05); Moreover, the tissue pathology of both groups was similar.. The tuberculosis model of rifampicin-dependent Mycobacterium tuberculosis strains was similar to the model of rifampicin-resistant Mycobacterium tuberculosis in guinea pigs. Rifampicin-dependency was not evident in this guinea pig tuberculosis model.

    Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Female; Guinea Pigs; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2006
Saquinavir and rifampicin for tuberculosis and AIDS: new considerations.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2006, Volume: 10, Issue:11

    Topics: Acquired Immunodeficiency Syndrome; Antibiotics, Antitubercular; Drug Therapy, Combination; HIV Protease Inhibitors; Humans; Rifampin; Saquinavir; Treatment Outcome; Tuberculosis

2006
Optic neuritis and bitemporal hemianopsia associated with isoniazid treatment in end-stage renal failure.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2006, Volume: 10, Issue:12

    Topics: Adult; Antitubercular Agents; Combined Modality Therapy; Drug Therapy, Combination; Ethambutol; Hemianopsia; Humans; Isoniazid; Kidney Failure, Chronic; Male; Optic Neuritis; Renal Dialysis; Rifampin; Tuberculosis

2006
[Study of rifampicin resistance in L-forms of Mycobacterium tuberculosis, by analyzing rpoB gene mutations].
    Problemy tuberkuleza i boleznei legkikh, 2006, Issue:11

    Twenty-nine Mycobacterium tuberculosis (MBT) L-form strains isolated from biopsy and surgery samples taken in 27 patients with extrapulmonary tuberculosis were studied. Since a direct examination of the resistance of L-forms is impossible due to their in vitro culturing features, it is expedient to use molecular genetic methods, by studying rpoB gene mutations. The study showed a high mutation rate (89.7%) in MBT L-forms associated with rifampicin resistance. The findings correlate with the recent years' monitoring of drug resistance in MBT in extrapulmonary tuberculosis, which has indicated that the total resistance of MBT from the foci of this form of tuberculosis to antituberculous drugs is as high as 90% and multidrug resistance is 30%. Moreover, the mycobacterial population was found to be heterogeneous. The ratio of rifampicin-resistant L-forms to sensitive ones in the established heterogeneity of the mycobacterial population calls for further studies.

    Topics: Bacterial Proteins; DNA Mutational Analysis; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Point Mutation; Polymerase Chain Reaction; Rifampin; Tuberculosis

2006
Distribution of the Beijing family genotypes of Mycobacterium tuberculosis in Taiwan.
    Journal of clinical microbiology, 2005, Volume: 43, Issue:1

    To investigate the distribution of the Beijing family genotypes of Mycobacterium tuberculosis in Taiwan, we collected 421 M. tuberculosis complex clinical isolates at random from four geographic regions of Taiwan and analyzed them by spacer oligonucleotide typing (spoligotyping) in 2003. We found 113 resolved spoligotypes, among which we identified 28 (24.8%) clusters. One hundred eighty-seven (44.4%) isolates were Beijing family genotypes and consisted of 172 (40.9%) characteristic Beijing genotypes and 15 (3.6%) Beijing-like ones. We also found that substantially larger proportions of tuberculosis patients were infected with Beijing family genotypes in the northern (51.6%) and eastern (46.2%) regions of Taiwan, while 31.6 and 28.0% of the tuberculosis patients in the central and southern regions, respectively, were infected with these genotypes. The proportion of Beijing genotype isolates was the highest in patients below the age of 24 years (61.5%), the second highest in elderly patients over age 65 years (46.8%), and the lowest in middle-age patients between the ages of 45 and 54 years (34.0%). Geographic location and age were found by multivariate analysis to be associated with Beijing family genotypes. Antituberculosis drug resistance was found more often in Beijing family genotype strains (46.4%) than in non-Beijing family genotype strains (34.3%), with more Beijing family genotype strains being resistant to ethambutol and isoniazid. These findings suggest that M. tuberculosis Beijing family genotypes have been dominant for several decades and that they are the cause of a significant proportion of the recent transmissions of tuberculosis in Taiwan.

    Topics: Adolescent; Adult; Age Distribution; Aged; Antitubercular Agents; Bacterial Typing Techniques; Drug Resistance, Multiple, Bacterial; Female; Genotype; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Prevalence; Rifampin; Taiwan; Tuberculosis

2005
Immunotherapy with fragmented Mycobacterium tuberculosis cells increases the effectiveness of chemotherapy against a chronical infection in a murine model of tuberculosis.
    Vaccine, 2005, Feb-03, Volume: 23, Issue:11

    Reduction of colony forming units by rifampicin-isoniazid therapy given 9-17 weeks post-infection was made more pronounced by immunotherapy with a vaccine made of fragmented Mycobacterium tuberculosis cells detoxified and liposomed (RUTI), given on weeks 17, 19 and 21 post-infection, in the murine model of tuberculosis in C57BL/6 and DBA/2 inbred strains. RUTI triggered a Th1/Th2 response, as demonstrated by the production of IgG1, IgG2a and IgG3 antibodies against a wide range of peptides. The histological analysis did not show neither eosinophilia nor necrosis, and granulomatous infiltration was only slightly increased in C57BL/6 mice when RUTI was administered intranasally.

    Topics: Animals; Antibodies, Bacterial; Antitubercular Agents; Colony Count, Microbial; Combined Modality Therapy; Disease Models, Animal; Female; Immunoglobulin G; Immunotherapy; Interferon-gamma; Isoniazid; Lung; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mycobacterium tuberculosis; Rifampin; Spleen; Tuberculosis; Tuberculosis Vaccines; Tumor Necrosis Factor-alpha

2005
Phagosomal processing of Mycobacterium tuberculosis antigen 85B is modulated independently of mycobacterial viability and phagosome maturation.
    Infection and immunity, 2005, Volume: 73, Issue:2

    Control of Mycobacterium tuberculosis infection requires CD4 T-cell responses and major histocompatibility complex class II (MHC-II) processing of M. tuberculosis antigens (Ags). We have previously demonstrated that macrophages process heat-killed (HK) M. tuberculosis more efficiently than live M. tuberculosis. These observations suggested that live M. tuberculosis may inhibit Ag processing by inhibiting phagosome maturation or that HK M. tuberculosis may be less resistant to Ag processing. In the present study we examined the correlation between M. tuberculosis viability and phagosome maturation and efficiency of Ag processing. Since heat treatment could render M. tuberculosis Ags more accessible to proteolysis, M. tuberculosis was additionally killed by antibiotic treatment and radiation. Processing of HK, live, radiation-killed (RadK), or rifampin-killed (RifK) M. tuberculosis in activated murine bone marrow macrophages was examined by using an I-A(b)-restricted T-cell hybridoma cell line (BB7) that recognizes an epitope derived from Ag 85B. Macrophages processed HK M. tuberculosis more rapidly and efficiently than they processed live, RadK, or RifK M. tuberculosis. Live, RadK, and RifK M. tuberculosis cells were processed with similar efficiencies for presentation to BB7 T hybridoma cells. Furthermore, phagosomes containing live or RadK M. tuberculosis expressed fewer M. tuberculosis peptide-MHC-II complexes than phagosomes containing HK M. tuberculosis expressed. Since only live M. tuberculosis was able to prevent acidification of the phagosome, our results suggest that regulation of phagosome maturation does not explain the differences in processing of different forms of M. tuberculosis. These findings suggest that the mechanisms used by M. tuberculosis to inhibit phagosomal maturation differ from the mechanisms involved in modulating phagosome Ag processing.

    Topics: Acyltransferases; Animals; Antibiotics, Antitubercular; Antigens, Bacterial; Bacterial Proteins; Mice; Microscopy, Confocal; Mycobacterium tuberculosis; Phagosomes; Rifampin; Tuberculosis

2005
Rifampin-induced hypothyroidism in patients with Hashimoto's thyroiditis.
    The New England journal of medicine, 2005, Feb-03, Volume: 352, Issue:5

    Topics: Aged; Antibiotics, Antitubercular; Female; Humans; Hypothyroidism; Male; Middle Aged; Rifampin; Thyroid Hormones; Thyroiditis, Autoimmune; Tuberculosis

2005
Autoimmune hepatitis and thyroiditis associated with rifampin and pyrazinamide prophylaxis: an unusual reaction.
    Digestive diseases and sciences, 2005, Volume: 50, Issue:1

    Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Hepatitis, Autoimmune; Humans; Male; Pyrazinamide; Rifampin; Thyroiditis; Tuberculosis

2005
Completing tuberculosis prophylaxis in jail: targeting treatment and a comparison of rifampin/pyrazinamide with isoniazid regimens.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2005, Volume: 9, Issue:2

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Prisons; Pyrazinamide; Rifampin; Tuberculosis

2005
Rifampin plus pyrazinamide-induced hepatitis requiring hospitalization in a 30-y-old male with latent tuberculosis.
    Scandinavian journal of infectious diseases, 2005, Volume: 37, Issue:2

    The case of a 30-y-old male with latent tuberculosis who developed chemical hepatitis requiring hospitalization after 50 d of treatment with rifampin and pyrazinamide is reported. This case justifies the CDC guidelines that were updated on 31 August 2003 advising against the use of this brief regimen for patients with latent tuberculosis due to its risk for hepatotoxicity.

    Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Humans; Male; Pyrazinamide; Rifampin; Tuberculosis

2005
Optimal latent TB control methods.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2005, Volume: 9, Issue:3

    Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

2005
Susceptibility testing of Mycobacterium tuberculosis: comparison of the BACTEC TB-460 method and flow cytometric assay with the proportion method.
    Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases, 2005, Volume: 11, Issue:5

    Tuberculosis is a leading cause of morbidity and mortality worldwide. Susceptibility testing of the causative agent, Mycobacterium tuberculosis, is critical for control of the disease. This study compared the flow cytometric susceptibility assay with the proportion method and the BACTEC TB-460 system. There was agreement between the flow cytometric and proportion methods for 73 (94%) of 78 isoniazid tests, and complete agreement for 26 ethambutol and rifampicin tests. In contrast, the proportion and BACTEC methods failed to agree for 22%, 15% and 8% of isoniazid, ethambutol and rifampicin tests, respectively. These findings indicated that susceptibility testing by the flow cytometric assay is accurate, with results available within 24 h of initiation of the testing procedure.

    Topics: Antitubercular Agents; Ethambutol; Flow Cytometry; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Quality Control; Rifampin; Tuberculosis

2005
[Risk of acquisition of RFP resistance out of INH resistant RFP susceptible tuberculosis].
    Kekkaku : [Tuberculosis], 2005, Volume: 80, Issue:1

    To investigate the prognosis of isoniazid (H) resistant rifampicin (R) susceptible tuberculosis cases with emphasis on the risk factors of developing MDR.. Retrospective review of H resistant R susceptible tuberculosis cases that were treated at Fukujuji Hospital in Japan between 1990 and 2000.. Four cases developed drug resistance and became MDR. Seventy seven cases completed treatment with bacteriological confirmation of negativity during treatment and 2 years after treatment (cure). Other 38 cases completed treatment with confirmation of culture negativity at the end of treatment but one of them relapsed within 2 years and the remaining 37 cases were not followed up for 2 years. Fourteen cases died, 13 cases defaulted and 17 cases were transferred out. The comparison of the regimen of chemotherapy between cured cases and cases who became MDR showed that more cured cases were found among those who started treatment with 4 drugs or more than cases who started treatment with 3 drugs or less. Other factors that were related (but not significant) to cure rate were non-diabetics in comparison with diabetics and 4 drug standard regimen (HRZS, HRZE) in comparison with 3 drug standard regimen (HRS, HRE).. Prevention of MDR could be achieved by wider use of 4-drug standard regimen and changes of chemotherapy regimen promptly responding to the results of drug susceptibility tests.

    Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Prognosis; Retrospective Studies; Rifampin; Risk; Tuberculosis; Tuberculosis, Multidrug-Resistant

2005
Solid lipid particle-based inhalable sustained drug delivery system against experimental tuberculosis.
    Tuberculosis (Edinburgh, Scotland), 2005, Volume: 85, Issue:4

    The present study was planned to evaluate the chemotherapeutic potential of nebulized solid lipid particles (SLPs) incorporating rifampicin, isoniazid and pyrazinamide against experimental tuberculosis. The SLPs prepared by the "emulsion solvent diffusion" technique possessed a favourable mass median aerodynamic diameter suitable for bronchoalveolar drug delivery. Following a single nebulization to guinea pigs, therapeutic drug concentrations were maintained in the plasma for 5 days and in the organs (lungs, liver and spleen) for 7 days whereas free drugs were cleared by 1-2 days. The mean residence time and drug bioavailability were improved several-fold in the case of drug-loaded SLPs. A similar pharmacokinetic profile was observed in Mycobacterium tuberculosis-infected guinea pigs. On nebulization of drug-loaded SLPs to infected guinea pigs at every 7th day, no tubercle bacilli could be detected in the lungs/spleen after 7 doses of treatment whereas 46 daily doses of orally administered drugs were required to obtain an equivalent therapeutic benefit. Further, there was no evidence of any biochemical hepatotoxicity. Thus, nebulization of SLP-based antitubercular drugs forms a sound basis for improving drug bioavailability and reducing the dosing frequency for better management of pulmonary tuberculosis.

    Topics: Administration, Inhalation; Animals; Antitubercular Agents; Area Under Curve; Biological Availability; Drug Carriers; Drug Delivery Systems; Guinea Pigs; Isoniazid; Lipids; Nanostructures; Pyrazinamide; Rifampin; Tuberculosis

2005
Relapse and acquired rifampin resistance in HIV-infected patients with tuberculosis treated with rifampin- or rifabutin-based regimens in New York City, 1997-2000.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2005, Jul-01, Volume: 41, Issue:1

    The relationship between rifamycin use and either relapse or treatment failure with acquired rifampin resistance (ARR) among human immunodeficiency virus (HIV)-infected patients with tuberculosis (TB) is not well understood.. We conducted a retrospective cohort study of HIV-infected and HIV-uninfected persons with rifampin-susceptible TB, (1) to compare relapse rates, ARR, and treatment failure, according to HIV serostatus; and (2) to examine whether and how use of rifamycin was associated with clinical outcomes of interest among HIV-infected patients with TB.. HIV-infected patients were more likely to have ARR than were HIV-uninfected patients (0.9% vs. 0.1%; P = .007), and the association remained significant in multivariate analysis (adjusted odds ratio [OR], 5.5; 95% confidence interval [CI], 1.4-21.5). Among HIV-infected patients with TB, none of 57 patients treated with rifabutin-based regimens alone had ARR, and only 1 of 395 patients treated with rifabutin given in combination with a rifampin-based regimen had ARR, whereas 6 of 355 patients treated with a rifampin-based regimen alone had relapse and ARR. HIV-infected patients treated with rifampin-based regimens alone had a higher risk for relapse and development of rifampin resistance if intermittent dosing of rifampin was started during the intensive phase of treatment, compared with patients who did not receive intermittent dosing (hazard ratio [HR] for relapse, 6.7 [95% CI, 1.1-40.1]; HR for ARR, 6.4 [95% CI, 1.1-38.4]). This association remained when confined to patients with a CD4+ T lymphocyte count of < 100 lymphocytes/mm3. Intermittent dosing started only after the intensive phase of treatment did not increase the risks of relapse and ARR among HIV-infected patients with TB.. The risk for ARR among HIV-infected persons with TB did not depend on the rifamycin used but, rather, on the rifampin dosing schedule in the intensive phase of treatment.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Cohort Studies; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Male; Mycobacterium tuberculosis; New York City; Recurrence; Retrospective Studies; Rifabutin; Rifampin; Treatment Failure; Tuberculosis

2005
Significant increases in the levels of liver enzymes in mice treated with anti-tuberculosis drugs.
    International journal of antimicrobial agents, 2005, Volume: 26, Issue:2

    Besides the long-term effectiveness of a given compound, safety is a very important feature to consider when developing new compounds for chemotherapy against tuberculosis. Reports of fatal and severe liver injury associated with rifampicin-pyrazinamide (RIF-PZA) treatment regimens for latent tuberculosis infections prompted this study to evaluate whether a mouse model has any potential as a tool to assess liver injury following extensive exposure to tuberculosis drugs. Mice were administered high doses of existing drug regimens for latent tuberculosis over a relatively short time period. Alanine aminotransferase (ALT), aspartate aminotransferase and bilirubin levels were determined after 2 weeks and 4 weeks of treatment in serum samples collected from uninfected mice as well as mice infected with Mycobacterium tuberculosis. ALT levels increased significantly after a RIF-PZA treatment regimen for 4 weeks in uninfected mice and after 2 weeks in infected mice. Bilirubin serum levels were also significantly elevated in the M. tuberculosis-infected mice after 4 weeks of RIF-PZA treatment. The data obtained indicate that changes in serum enzyme levels in mice after extensive exposure to tuberculosis drugs could be useful as an initial indicator of drug-related hepatotoxicity.

    Topics: Alanine Transaminase; Animals; Antitubercular Agents; Disease Models, Animal; Drug Therapy, Combination; Liver; Pyrazinamide; Rifampin; Tuberculosis

2005
[Medicine and television: a diagnosis history].
    Medicina clinica, 2005, Jun-11, Volume: 125, Issue:2

    Topics: Adult; Antitubercular Agents; Cholestasis, Intrahepatic; Diagnostic Errors; Hepatitis B; Hepatitis C; HIV Infections; Humans; Isoniazid; Male; Medicine in the Arts; Mercury Poisoning; Pyrazinamide; Rifampin; Television; Tuberculosis

2005
The role of four months of rifampicin in the treatment of latent tuberculosis infection.
    American journal of respiratory and critical care medicine, 2005, Aug-15, Volume: 172, Issue:4

    Topics: Antibiotics, Antitubercular; Drug Administration Schedule; Humans; Rifampin; Time Factors; Tuberculosis

2005
Caspofungin treatment failure in a patient with invasive candidiasis and concomitant rifampicin treatment.
    International journal of antimicrobial agents, 2005, Volume: 26, Issue:3

    Topics: Antibiotics, Antitubercular; Candida; Candidiasis; Caspofungin; Echinocandins; Female; Humans; Lipopeptides; Microbial Sensitivity Tests; Middle Aged; Peptides, Cyclic; Rifampin; Treatment Failure; Tuberculosis

2005
Pharmacokinetic interactions between efavirenz and rifampicin in the treatment of HIV and tuberculosis: one size does not fit all.
    AIDS (London, England), 2005, Sep-23, Volume: 19, Issue:14

    The concomitant treatment of HIV-tuberculosis co-infection is complicated by pharmacological interactions between drugs, resulting in unpredictable drug levels. We monitored efavirenz levels in all tuberculosis-HIV-treated patients over 2 years. Using 800 mg/day of efavirenz, high levels and toxicity were detected in seven out of nine patients, necessitating reduction or discontinuation. Polymorphisms in cytochrome P450 2B6 may account for this. Therapeutic drug monitoring, dose reduction or a lower starting dose may be appropriate in some patients to abrogate toxicity.

    Topics: Adult; Aged; AIDS-Related Opportunistic Infections; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Oxazines; Rifampin; Tuberculosis

2005
Determination of in vitro synergy when three antimicrobial agents are combined against Mycobacterium tuberculosis.
    International journal of antimicrobial agents, 2005, Volume: 26, Issue:4

    We determined the in vitro antimycobacterial activity of rifampicin, isoniazid and a third agent in combination using a three-dimensional chequerboard in Middlebrook 7H9 broth microdilutions. Of 28 agents screened, ethambutol, streptomycin, clarithromycin, minocycline, ciprofloxacin, levofloxacin, sparfloxacin, gatifloxacin and sitafloxacin were potentially synergistic. A further three-dimensional chequerboard assay quantitatively looked for synergy against ten clinical isolates of Mycobacterium tuberculosis, including seven multidrug-resistant isolates. Sitafloxacin, gatifloxacin and clarithromycin showed significant synergy, with fractional inhibitory concentration indices ranging from 0.41 to 0.79, 0.39 to 0.90 and 0.48 to 0.95, respectively. It is concluded that three-dimensional chequerboard assay can quantitatively determine antimycobacterial synergy, and that fluoroquinolones and antibacterial agents such as clarithromycin are effective against multidrug-resistant isolates of M. tuberculosis when combined with rifampicin and isoniazid.

    Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Ciprofloxacin; Clarithromycin; Drug Synergism; Ethambutol; Fluoroquinolones; Humans; Isoniazid; Levofloxacin; Microbial Sensitivity Tests; Minocycline; Mycobacterium tuberculosis; Ofloxacin; Rifampin; Tuberculosis

2005
Rifapentine, moxifloxacin, or DNA vaccine improves treatment of latent tuberculosis in a mouse model.
    American journal of respiratory and critical care medicine, 2005, Dec-01, Volume: 172, Issue:11

    Priorities for developing improved regimens for treatment of latent tuberculosis (TB) infection include (1) developing shorter and/or more intermittently administered regimens that are easier to supervise and (2) developing and evaluating regimens that are active against multidrug-resistant organisms.. By using a previously validated murine model that involves immunizing mice with Mycobacterium bovis bacillus Calmette-Guérin to augment host immunity before infection with virulent Mycobacterium tuberculosis, we evaluated new treatment regimens including rifapentine and moxifloxacin, and assessed the potential of the Mycobacterium leprae heat shock protein-65 DNA vaccine to augment the activity of moxifloxacin.. Quantitative spleen colony-forming unit counts, and the proportion of mice with culture-positive relapse after treatment, were determined.. Three-month, once-weekly regimens of rifapentine combined with either isoniazid or moxifloxacin were as active as daily isoniazid for 6-9 mo. Six-month daily combinations of moxifloxacin with pyrazinamide, ethionamide, or ethambutol were more active than pyrazinamide plus ethambutol, a regimen recommended for latent TB infection after exposure to multidrug-resistant TB. The combination of moxifloxacin with the experimental nitroimidazopyran PA-824 was especially active. Finally, the heat shock protein-65 DNA vaccine had no effect on colony-forming unit counts when given alone, but augmented the bactericidal activity of moxifloxacin.. Together, these findings suggest that rifapentine, moxifloxacin, and, perhaps, therapeutic DNA vaccination have the potential to improve on the current treatment of latent TB infection.

    Topics: Animals; Antibiotics, Antitubercular; Aza Compounds; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Female; Fluoroquinolones; Follow-Up Studies; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Rifampin; Spleen; Treatment Outcome; Tuberculosis; Vaccines, DNA

2005
Inhalable alginate nanoparticles as antitubercular drug carriers against experimental tuberculosis.
    International journal of antimicrobial agents, 2005, Volume: 26, Issue:4

    Pharmacokinetic and chemotherapeutic studies have been carried out with aerosolised alginate nanoparticles encapsulating isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA). The nanoparticles were prepared by cation-induced gelification of alginate and were 235.5 +/- 0 nm in size, with drug encapsulation efficiencies of 70-90% for INH and PZA and 80-90% for RIF. The majority of particles (80.5%) were in the respirable range, with mass median aerodynamic diameter of 1.1 +/- 0.4 microm and geometric standard deviation of 1.71 +/- 0.1 microm. The relative bioavailabilities of all drugs encapsulated in alginate nanoparticles were significantly higher compared with oral free drugs. All drugs were detected in organs (lungs, liver and spleen) above the minimum inhibitory concentration until 15 days post nebulisation, whilst free drugs stayed up to day 1. The chemotherapeutic efficacy of three doses of drug-loaded alginate nanoparticles nebulised 15 days apart was comparable with 45 daily doses of oral free drugs. Thus, inhalable alginate nanoparticles can serve as an ideal carrier for the controlled release of antitubercular drugs.

    Topics: Aerosols; Alginates; Animals; Antitubercular Agents; Drug Carriers; Drug Evaluation, Preclinical; Female; Glucuronic Acid; Guinea Pigs; Hexuronic Acids; Inhalation; Isoniazid; Liver; Lung; Male; Mycobacterium tuberculosis; Nanostructures; Pyrazinamide; Rifampin; Spleen; Time Factors; Tuberculosis

2005
National survey to measure rates of liver injury, hospitalization, and death associated with rifampin and pyrazinamide for latent tuberculosis infection.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2005, Oct-15, Volume: 41, Issue:8

    Cases of severe and fatal liver injury were reported after a 2-month course of rifampin-pyrazinamide therapy was recommended in 2000 as an alternative to isoniazid for treatment of latent tuberculosis infection. We estimated rates of rifampin-pyrazinamide-associated liver injury and compared these with historical rates for isoniazid.. We conducted a survey of state and city tuberculosis programs and other health care settings in the United States where rifampin-pyrazinamide was prescribed. The number of rifampin-pyrazinamide therapy initiations was collected, as well as the number of occurrences of (1) asymptomatic aspartate aminotransferase serum concentration >5 times the upper limit of normal, (2) symptomatic hepatitis (in which the patient was not hospitalized), (3) hospitalization for liver injury, (4) death with liver injury, and (5) treatment completion. We also searched a national pharmacy claims database (Verispan). Rates of these events were calculated.. Among 139 programs, 110 (79%) responded; 87 (79%) had initiated rifampin-pyrazinamide therapy for a total of 8087 patients between January 2000 and June 2002. Rates per 1000 rifampin-pyrazinamide therapy initiations during this period were 25.6 (95% confidence interval [CI], 22.3-29.3) for asymptomatic aspartate aminotransferase level >5 times the upper limit of normal and 18.7 (95% CI, 15.9-21.9) for hepatitis. Seven fatalities and 23 hospitalizations occurred, with rates of 0.9 (95% CI, 0.4-1.9) and 2.8 (95% CI, 1.8-4.3) per 1000 rifampin-pyrazinamide therapy initiations, respectively. Of 8087 patients, 64% completed rifampin-pyrazinamide therapy. The Verispan search revealed 1 rifampin-pyrazinamide-associated hospitalization (2.9 hospitalizations per 1000 rifampin-pyrazinamide therapy initiations; 95% CI, 0.1-18.4) and no deaths. Articles on the use of isoniazid therapy for latent tuberculosis infection that were published after 1990 reported fatality rates of 0.0-0.3 deaths per 1000 persons.. Rates of liver injury, hospitalization, and death associated with rifampin-pyrazinamide therapy exceed rates reported for isoniazid therapy. Because earlier randomized trials of rifampin-pyrazinamide lacked adequate statistical power to detect fatal events, the Centers for Disease Control and Prevention recommends that rifampin-pyrazinamide generally should not be used for treatment of latent tuberculosis infection.

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Health Surveys; Hospitalization; Humans; Liver Diseases; Pyrazinamide; Rifampin; Tuberculosis; United States

2005
Incidence of cross resistance between rifampicin and rifabutin in Mycobacterium tuberculosis strains in Izmir, Turkey.
    Journal of chemotherapy (Florence, Italy), 2005, Volume: 17, Issue:4

    Rifabutin is a spiro-piperidyl-rifamycin derived from rifamycin-S. This study was planned to determine the minimal inhibitory concentrations (MICs) of rifabutin and rifampicin against Mycobacterium tuberculosis strains and to investigate cross resistance between two drugs. The agar dilution method was performed for detection of MICs of rifabutin and rifampicin for 112 M. tuberculosis strains obtained from patients with active pulmonary tuberculosis. Cross resistance between rifampicin and rifabutin was detected in 73.1%. Rifabutin MICs for rifampicin resistant strains were three- to four-fold higher than rifabutin-susceptible and/or -resistant strains' MIC values for rifampicin. Despite having 73% cross-resistance with rifampicin in M. tuberculosis isolates, it was concluded that rifabutin might be a valid component of combination therapy in rifampicin resistant tuberculosis cases when the isolate is tested and detected susceptible to rifabutin.

    Topics: Drug Resistance, Multiple, Bacterial; Hospitals, Teaching; Humans; Incidence; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Probability; Rifabutin; Rifampin; Sampling Studies; Sensitivity and Specificity; Tuberculosis; Turkey

2005
Efficient intermittent rifapentine-moxifloxacin-containing short-course regimen for treatment of tuberculosis in mice.
    Antimicrobial agents and chemotherapy, 2005, Volume: 49, Issue:10

    Long-half-life drugs raise the hope of once-a-week administration of antituberculous treatment. In a previous study with the murine model of tuberculosis, the most active intermittent regimen which contained rifapentine (RFP), isoniazid (INH), and moxifloxacin (MXF) given once a week during 5.5 months, preceded by 2 weeks of daily treatment with INH, rifampin (RIF), pyrazinamide (PZA), and MXF, was less active than the standard 6-month daily RIF-INH-PZA regimen. We evaluated with the same model similar regimens in which we increased the dosing of rifapentine from 10 to 15 mg/kg of body weight and of moxifloxacin from 100 to 400 mg/kg. Mice infected intravenously by 6.2 x10(6) CFU of Mycobacterium tuberculosis H37Rv were treated 2 weeks later when infection was established. After 6 months of treatment, all mice had negative lung culture. After 3 months of follow-up, no relapse occurred in the two groups that received moxifloxacin at 400 mg/kg, whatever the dosage of RFP, and in the group receiving the standard RIF-INH-PZA control regimen. In contrast, in the two groups receiving moxifloxacin at a lower dosage, the relapse rate was significantly higher (13% in mice receiving RFP at 15 mg/kg and 27% in those receiving RFP at 10 mg/kg). Finally, the fully intermittent once-a-week regimen (26 drug ingestions) of INH, RFP (15 mg/kg), and MXF (400 mg/kg) led to a relapse rate of 11%. In conclusion, when used at high dosage, rifapentine and moxifloxacin are very efficient when combined with isoniazid in a once-a-week treatment in mouse tuberculosis.

    Topics: Animals; Animals, Outbred Strains; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Drug Therapy, Combination; Female; Fluoroquinolones; Mice; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Random Allocation; Rifampin; Survival Rate; Time Factors; Tuberculosis

2005
[Use of rifabutin in cases of toxicity to rifampicin].
    Revista clinica espanola, 2005, Volume: 205, Issue:9

    Rifampicin is an essential drug in the present treatment of tuberculosis. On some occasions, it cannot be used due to severe adverse effects. Rifabutin is a drug of the same family, with a similar activity and difference adverse effects. This study describes the beneficial results of the substitution of rifampicin with rifabutin in patients with severe toxicity.

    Topics: Adult; Aged; Antibiotics, Antitubercular; Female; Humans; Male; Middle Aged; Rifabutin; Rifampin; Tuberculosis

2005
Selection of rifampicin-resistant Staphylococcus aureus during tuberculosis therapy: concurrent bacterial eradication and acquisition of resistance.
    The Journal of antimicrobial chemotherapy, 2005, Volume: 56, Issue:6

    Acquired antimicrobial resistance is commonly attributed to regimens that expose bacteria to subinhibitory concentrations; consequently, eradication of susceptible cells is advocated. The mutant selection window hypothesis predicts that resistance can be acquired even when inhibitory concentrations are exceeded and susceptible bacteria are eradicated. The objective was to test that prediction clinically.. Tuberculosis patients (n = 372) were sampled for nasal colonization by Staphylococcus aureus at the beginning of anti-tuberculosis therapy with rifampicin-containing regimens and again after 2 and 4 weeks. Rifampicin susceptibility of S. aureus was determined, and S. aureus isolates from patients developing acquired resistance were examined by molecular strain typing. Diabetes patients (n = 200) served as untreated controls.. Nasal colonization was 17% and 20% for the tuberculosis and diabetes patients, respectively. Four patients were initially colonized with rifampicin-resistant S. aureus and were excluded from further sampling. Initiation of anti-tuberculosis therapy eradicated S. aureus nasal colonization in 53/58 tuberculosis patients while allowing acquisition of rifampicin resistance in 5/58. Pulsed-field gel electrophoresis (PFGE) band patterns and protein A repeat sequence determination differed in S. aureus isolated from different patients but was identical in isolates obtained from the same patient before and after acquisition of resistance. No resistance was acquired in untreated control patients, which differed statistically from treated patients (P = 0.025).. Acquired resistance and eradication of susceptible bacteria can occur concurrently; restricting acquired resistance may require direct suppression of mutant growth and viability in addition to elimination of susceptible bacteria.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carrier State; DNA Fingerprinting; DNA, Bacterial; Drug Resistance, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Genotype; Humans; Male; Middle Aged; Nasal Cavity; Polymorphism, Restriction Fragment Length; Rifampin; Selection, Genetic; Staphylococcal Infections; Staphylococcal Protein A; Staphylococcus aureus; Tuberculosis

2005
Meeting notes from the 3rd IAS Conference. Treating TB and HIV concurrently.
    AIDS clinical care, 2005, Volume: 17, Issue:10

    Several IAS reports focused on strategies for overcoming reduced levels of nevirapine due to rifampin coadministration.

    Topics: Brazil; Congresses as Topic; Drug Therapy, Combination; HIV Infections; Humans; Nevirapine; Rifampin; Tuberculosis

2005
Concurrence of granular cell tumor and Mycobacterium tuberculosis.
    Southern medical journal, 2005, Volume: 98, Issue:10

    Granular cell tumors (GCT) are rare, usually benign neoplasms of Schwann cell origin. Since discovery in 1926, fewer than 80 cases of GCT involving the lung have been reported. This report presents a 45-year-old male who presented with symptoms consistent with chronic pancreatitis associated with night sweats, weight loss, and a chronic productive cough. Chest radiography revealed a 3 x 4 cm left upper lobe lung mass with an unremarkable right lung field. Bronchoscopy revealed mixed mucosal abnormalities in the left upper lobe and a 4-mm polypoidal lesion in the right lower lobe. Bronchial washings stained positive for acid-fast bacilli. The left upper lobe lesion biopsy showed granulomatous inflammation with caseous necrosis consistent with tuberculosis. The right lower lobe lesion was a GCT without evidence of tuberculosis. This report reviews the literature regarding GCT and presents this unusual case of granular cell tumor co-occurring with active tuberculosis.

    Topics: Antitubercular Agents; Bronchoscopy; Ethambutol; Granular Cell Tumor; Humans; Isoniazid; Lung; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2005
Nevirapine plasma concentrations and concomitant use of rifampin in patients coinfected with HIV-1 and tuberculosis.
    Antiviral therapy, 2005, Volume: 10, Issue:8

    In countries with high numbers of HIV/tuberculosis coinfection nevirapine and rifampin are used extensively. However, limited data are available about whether or not nevirapine and rifampin can be safely coadministered without the plasma concentration of nevirapine falling below therapeutic levels.. Blood samples for determination of nevirapine plasma concentrations were collected from patients using nevirapine 200 mg twice daily with or without concomitant rifampin. Bivariate and multivariate linear regression models were used to investigate factors possibly related to nevirapine concentrations.. We received 74 blood samples from patients using nevirapine plus rifampin, and collected blood samples from an equal number of controls using nevirapine only. Groups were similar for age, gender, weight, height and body mass index (BMI). In the rifampin group the mean nevirapine concentration was 5.47 +/- 2.66 mg/l, whereas in the control group the mean nevirapine concentration was 8.72 +/- 3.98 mg/l. In the rifampin group seven nevirapine trough concentrations were low (< 3.1 mg/l), while in the control group two patients had low nevirapine trough concentrations (P = 0.164). In the multivariate linear regression analysis, corrected for time after drug intake, the use of rifampin was significantly (P < 0.001) associated with lower nevirapine plasma concentrations, whereas higher BMI reached borderline significance (P = 0.065).. Although nevirapine plasma concentrations were 3.3 mg/l lower when co-administered with rifampin, still more than 86% of these patients had nevirapine plasma concentrations > 3.1 mg/l. Our results suggest that from a pharmacological point of view the majority of Thai coinfected patients, who have low BMIs, reach nevirapine plasma concentrations that are adequate for treatment of HIV. However this can only be undertaken if nevirapine plasma concentration monitoring is available and can be closely followed.

    Topics: Anti-Infective Agents; Antibiotics, Antitubercular; Female; HIV Infections; Humans; Male; Middle Aged; Multivariate Analysis; Nevirapine; Rifampin; Thailand; Tuberculosis

2005
In closely monitored patients, adherence in the first month predicts completion of therapy for latent tuberculosis infection.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2005, Volume: 9, Issue:12

    Current therapy for latent TB infection (LTBI) is long, and requires close follow-up. This results in sub-optimal adherence-the major reason for failure of therapy.. In an open label randomised trial comparing 4 months of rifampicin with 9 months of isoniazid, the proportion and regularity of doses taken, measured with an electronic monitoring system (MEMS), and provider estimates of adherence in the first month of therapy, were assessed as predictors of treatment completion.. Of 104 patients analysed, 86 took more than 80% of doses within the expected interval, 11 took more than 80% of doses but over a longer time interval than usually allowed, and seven did not complete treatment. Treatment completion was associated with the number of doses taken, and the variability of intervals between doses during the first month of treatment.. Adherence in the first month, based on the number of doses and variability of times when taken, could be useful to predict completion of LTBI therapy. Interventions could be targeted to patients with suboptimal adherence in the first month.

    Topics: Adult; Antitubercular Agents; Carrier State; Cohort Studies; Directly Observed Therapy; Drug Administration Schedule; Female; Humans; Isoniazid; Male; Patient Compliance; Rifampin; Tuberculosis

2005
[Development and estimation of nanosomal rifampicin].
    Antibiotiki i khimioterapiia = Antibiotics and chemoterapy [sic], 2005, Volume: 50, Issue:8-9

    A lab-scale method for preparation of rifampicin-loaded polybutylcyanoacrylate nanoparticles (nanosames) was developed. The biodistribution of the nanosome-entrapped rifampicin after its intravenous administration was studied on healthy mice. The nanoparticles provided significant liver and spleen accumulation of rifampicin. Modification of the nanoparticles surface with poloxamer 407 or poloxamine 908 led to optimization of the biodistribution: the concentrations of rifampicin in the lungs and plasma increased, whereas the liver accumulation decreased vs. the unmodified nanoparticles. The increased lung accumulation of rifampicin enhanced bacterial clearance in the lungs of the mice infected with M. tuberculosis. The results showed that the use of the nanoparticles for optimization of the drug biodistribution was effective for increasing the efficacy of antiinfective chemotherapy.

    Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Injections, Intravenous; Male; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nanostructures; Nanotechnology; Rifampin; Tuberculosis

2005
Malabsorption of rifampin and isoniazid in HIV-infected patients with and without tuberculosis.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2004, Jan-15, Volume: 38, Issue:2

    The absorption of rifampin, isoniazid, and D-xylose in patients with human immunodeficiency virus (HIV) infection and diarrhea, in patients with HIV infection and tuberculosis (TB), in patients with pulmonary TB alone, and in healthy subjects was studied. Percentage of dose of the drugs, their metabolites, and D-xylose excreted in urine were calculated. A significant reduction in the absorption of drugs and D-xylose in both the HIV infection/diarrhea and HIV infection/TB groups was observed (P<.05), and the correlation between them was significant. Our results indicate that patients with HIV infection and diarrhea and those with HIV infection and TB have malabsorption of rifampin and isoniazid.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; HIV Infections; Humans; Intestinal Absorption; Isoniazid; Malabsorption Syndromes; Male; Middle Aged; Rifampin; Tuberculosis; Xylose

2004
Evaluation of the fully automated Bactec MGIT 960 system for the susceptibility testing of Mycobacterium tuberculosis to first-line drugs: a multicenter study.
    Journal of microbiological methods, 2004, Volume: 56, Issue:2

    The accuracy of the Bactec MGIT 960 system for susceptibility testing of 177 clinical isolates of Mycobacterium tuberculosis to first line drugs (isoniazid, rifampicin, ethambutol and streptomycin) was compared with the agar reference method. The sensitivity, the ability to detect resistance, of the MGIT system was 100%, while the specificity, the ability to detect susceptibility, ranged from 98.6% to 100% for all drugs tested.

    Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Streptomycin; Tuberculosis

2004
Tuberculosis prevention in Mexican immigrants: limitations of short-course therapy.
    American journal of preventive medicine, 2004, Volume: 26, Issue:2

    Two months of rifampin and pyrazinamide (RIF/PZA) for tuberculosis prevention has been advocated as a way to improve adherence in mobile populations, such as recent immigrants. However, RIF/PZA requires intensive patient and laboratory monitoring for hepatotoxicity.. To describe the feasibility and outcomes of using RIF/PZA for TB prevention during a tuberculosis outbreak in a Mexican immigrant community, where 23 adults and 11 children were treated with RIF/PZA between August 2001 and October 2001.. Retrospective chart review and interviews with health department employees were conducted to assess completion rates, hepatotoxicity, cost, and feasibility of monitoring.. Ten (91%) children and 13 (57%) adults completed RIF/PZA. One child (9%) and four adults (17%) developed drug-induced hepatitis. Cultural barriers affected care. The adults resisted the biweekly blood draw, believing it would "drain them of energy." RIF/PZA, plus monitoring, was twice as costly as 4 months of rifampin.. RIF/PZA was associated with significant hepatotoxicity, poor completion, and cultural barriers to monitoring, and was more costly than standard therapy. Tuberculosis prevention must address potential clinical, cultural, and economic barriers to completion and monitoring of short-course therapy in immigrants.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Disease Outbreaks; Drug Therapy, Combination; Emigration and Immigration; Female; Humans; Interviews as Topic; Male; Mexican Americans; Mexico; Middle Aged; Patient Compliance; Pyrazinamide; Rifampin; Tuberculosis; United States

2004
Pancytopenia due to extensive hemophagocytosis following anti-tubercular treatment.
    American journal of hematology, 2004, Volume: 75, Issue:2

    Topics: Adult; Antitubercular Agents; Biopsy, Needle; Bone Marrow; Hepatomegaly; Histiocytosis; Humans; Isoniazid; Male; Pancytopenia; Pyrazinamide; Rifampin; Tuberculosis

2004
Direct colorimetric assay for rapid detection of rifampin-resistant Mycobacterium tuberculosis.
    Journal of clinical microbiology, 2004, Volume: 42, Issue:2

    The colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was standardized for direct detection of rifampin-resistant Mycobacterium tuberculosis in sputum samples. The sensitivity and specificity of the direct MTT assay matched those of the standard indirect susceptibility assay on 7H10 medium, and interpretable results were obtained for 98.5% of the samples within 2 weeks. Traditional methods of in vitro drug susceptibility testing are time consuming and laborious. Susceptibility tests on clinical isolates require 6 to 9 weeks, and tests conducted directly on smear-positive samples take about 3 weeks (International Union Against Tuberculosis and Lung Disease, The public health service national tuberculosis reference laboratory and the national laboratory network. Minimum requirements, role and operation in a low-income country, Paris, France, 1998, and P. T. Kent and G. P. Kubica, Public health mycobacteriology. A guide for the level III laboratory, Centers for Disease Control and Prevention, Atlanta, Ga., 1985). More-rapid methods are available but are very expensive for routine use under program conditions in countries with high levels of tuberculosis endemicity.

    Topics: Colorimetry; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Reproducibility of Results; Rifampin; Tuberculosis

2004
Development of acquired drug resistance in recurrent tuberculosis patients with various previous treatment outcomes.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2004, Volume: 8, Issue:1

    Chiang Rai province, Northern Thailand.. To study the probability of acquiring drug resistance to isoniazid (H) and rifampicin (R) on recurrence after treatment success, default and failure, among sputum smear-positive pulmonary tuberculosis (TB) patients treated with standardised short-course chemotherapy.. Retrospective analysis of registration records of TB patients from May 1996 to December 2000 in Chiang Rai, where routine drug susceptibility testing (DST) is conducted for surveillance purposes. Patients registered twice or more were examined.. Of 59 cases treated with HRZE/HR who underwent DST at the time of registration, 31 were fully susceptible to H and R at first registration, of whom four acquired drug resistance to H or R. Of 13 cases resistant to H or R at first registration, 11 became multidrug-resistant (MDR). The remaining 15 patients were original MDR cases. Among 28 MDR or H- or R-resistant cases, six reverted from resistant to susceptible.. A high proportion of patients with H- or R-resistant TB became MDR after treatment with 2HRZE/HR. Using this regimen, MDR may increase in a population with a high prevalence of H or R resistance. We are unable to explain why some drug-resistant cases became drug-susceptible. Further investigation is necessary.

    Topics: Antitubercular Agents; Developing Countries; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prevalence; Recurrence; Registries; Retrospective Studies; Rifampin; Risk Factors; Sputum; Thailand; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

2004
[Cardiac tamponade with paroxysmal atrial flutter controlled by antituberculous therapy].
    Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics, 2004, Volume: 41, Issue:1

    We report a rare and unique case of possible extrapulmonary tuberculosis in an 83-year-old man who had cardiac tamponade and paroxysmal atrial flutter. The patient was admitted to our hospital because of syncope. The cardiac tamponade and paroxysmal atrial flutter were treated by pericardiocentesis and drainage of bloody pericardial fluid. Mycobacterium tuberculosis was not detected in diagnostic specimens, nor was any evidence of malignancy found. The remarkable elevation of adenosine deaminase and the predominance of lymphocytes in the pericardial fluid, considering the past history of tuberculosis, led to a diagnosis of extrapulmonary tuberculosis. After receiving standard antituberculous therapy by ethambutol, isoniazid, and rifampicin, the patient recovered and has remained well up to the present day. Thirty-six months have passed since his recovery without the recurrence of cardiac tamponade or any other cardiac events.

    Topics: Aged; Aged, 80 and over; Antitubercular Agents; Atrial Flutter; Cardiac Tamponade; Drainage; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Male; Rifampin; Tuberculosis

2004
Rifampicin-containing regimens for the treatment of latent tuberculosis infection also prevented diarrheal illnesses in HIV-infected Ugandan adults.
    AIDS (London, England), 2004, Mar-05, Volume: 18, Issue:4

    Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotic Prophylaxis; Antitubercular Agents; Diarrhea; Humans; Rifampin; Tuberculosis

2004
Rifampicin/pyrazinamide therapy should not be used for latent tuberculosis infection.
    Journal of the American Academy of Dermatology, 2004, Volume: 50, Issue:5

    Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Liver; Pyrazinamide; Rifampin; Tuberculosis

2004
IDV concentrations plummet with rifampicin.
    IAPAC monthly, 2004, Volume: 10, Issue:2

    Topics: Antibiotics, Antitubercular; CD4 Lymphocyte Count; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Rifampin; Tuberculosis; Viral Load

2004
Subcutaneous nanoparticle-based antitubercular chemotherapy in an experimental model.
    The Journal of antimicrobial chemotherapy, 2004, Volume: 54, Issue:1

    Poly (DL-lactide-co-glycolide) (PLG) nanoparticles encapsulating three front-line antitubercular drugs, i.e. rifampicin, isoniazid and pyrazinamide, were prepared by the multiple emulsion technique and administered subcutaneously to mice for pharmacokinetic/chemotherapeutic study. A single subcutaneous dose of drug-loaded PLG nanoparticles resulted in sustained therapeutic drug levels in the plasma for 32 days and in the lungs/spleen for 36 days. The mean residence time and absolute bioavailability were increased several-fold as compared with unencapsulated drugs. Further, drug-loaded PLG nanoparticles resulted in undetectable bacterial counts in the lungs and spleen of Mycobacterium tuberculosis-infected mice, thereby demonstrating a better chemotherapeutic efficacy, as compared with daily free drug treatment. Hence, injectable PLG nanoparticles hold promise for increasing drug bioavailability and reducing dosing frequency for better management of tuberculosis.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Biological Availability; Drug Combinations; Drug Compounding; Injections, Subcutaneous; Isoniazid; Lactic Acid; Lung; Mice; Microspheres; Mycobacterium tuberculosis; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Pyrazinamide; Rifampin; Spleen; Tissue Distribution; Tuberculosis

2004
Completing tuberculosis prophylaxis in jail: targeting treatment and comparison of rifampin/pyrazinamide with isoniazid regimens.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2004, Volume: 8, Issue:3

    A county jail.. To characterize the treatment of latent tuberculosis infection and the impact on treatment completion of the 2-month rifampin and pyrazinamide regimen as compared to the traditional 6- to 12-month isoniazid regimen among persons incarcerated at a county correctional facility.. Retrospective review of tuberculosis records from January 1998 to December 2000.. Of 2127 inmates who were tuberculin skin test positive, 146 were started on treatment. This was generally limited to those expected to remain incarcerated long enough to complete the course of treatment. Completion rates were 88% (67/76) for the 2-month and 74% (51/69) for the 6- to 12-month courses (P = 0.03), and 82% overall. The two regimens were similarly tolerated, but inmates on isoniazid were more likely to be released (despite longer projected incarceration) and not complete treatment once in the community. Thirty-seven per cent of persons for whom treatment was not indicated by the previous guidelines should have had treatment by the new guidelines.. The 2-month rifampin/pyrazinamide regimen had a higher completion rate than the longer isoniazid regimen, without additional toxicity, and allowed more patients to be treated. Latent tuberculosis treatment targeted to those able to complete the regimen in jail yields high completion rates.

    Topics: Antitubercular Agents; Carrier State; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Patient Compliance; Prisons; Pyrazinamide; Retrospective Studies; Rifampin; Tuberculosis

2004
Drug resistance trends among previously treated tuberculosis patients in a national registry in Peru, 1994-2001.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2004, Volume: 8, Issue:4

    National mycobacteriology reference laboratory in Peru conducting routine testing of susceptibility to isoniazid, rifampin, ethambutol, pyrazinamide, and streptomycin, in Mycobacterium tuberculosis isolates from previously treated patients.. To determine the percentage of isolates resistant to each of five anti-tuberculosis agents and to ascertain in these data the presence of trends of clinical relevance.. Retrospective study of a national registry of M. tuberculosis isolates from patients referred for drug susceptibility testing between 1994 and 2001.. Among 14,736 isolates tested, 10,837 (73.5%, 95%CI 72.8-74.3) demonstrated anti-tuberculosis resistance, and 8455 (57.4%, 95%CI 56.6-58.2) demonstrated resistance to at least both isoniazid and rifampin, by convention defined as multidrug-resistant tuberculosis (MDR-TB). A significant increasing trend could be discerned for resistance to each of the drugs tested and in isolates classified as MDR-TB (P < 0.001 for trend). Additional clinically relevant trends were found in polyresistance and multidrug resistance percentages.. Data from a national reference laboratory can be used to inform the design of retreatment regimens.

    Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Ethambutol; Humans; Isoniazid; Peru; Pyrazinamide; Registries; Retrospective Studies; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis

2004
Antituberculosis drugs and hepatotoxicity.
    Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 2004, Volume: 4, Issue:2

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis

2004
Simultaneous identification of rifampin-resistant Mycobacterium tuberculosis and nontuberculous mycobacteria by polymerase chain reaction-single strand conformation polymorphism and sequence analysis of the RNA polymerase gene (rpoB).
    Journal of microbiological methods, 2004, Volume: 58, Issue:1

    Interspecies variations and mutations associated with rifampin resistance in rpoB of Mycobacterium allow for the simultaneous identification of rifampin-resistant Mycobacterium tuberculosis and nontuberculous mycobacteria by PCR-SSCP analysis and PCR- sequencing. One hundred and ten strains of rifampin-susceptible M. tuberculosis, 14 strains of rifampin-resistant M. tuberculosis, and four strains of the M. avium complex were easily identified by PCR-SSCP. Of another seven strains, which showed unique SSCP patterns, three were identified as rifampin-resistant M. tuberculosis and four as M. terrae complex by subsequent sequence analysis of their rpoB DNAs (306 bp). These results were concordant with those obtained by susceptibility testing, biochemical identification, and 16S rDNA sequencing.

    Topics: Antitubercular Agents; Base Sequence; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Molecular Sequence Data; Mycobacterium avium Complex; Mycobacterium tuberculosis; Phylogeny; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Rifampin; Sequence Alignment; Tuberculosis

2004
[Current aspects of laryngeal tuberculosis].
    Anales otorrinolaringologicos ibero-americanos, 2004, Volume: 31, Issue:2

    In the preantibiotic era laryngeal tuberculosis was the most frequent pathology of the larynx. In the last decades some changes in the presentation and evolution of the pathology have occurred due to the new chemiotherapy and the improvement of the nutrition. Actually it presents less incidence and infectivity and less evidence of pulmonary disease. In this article we analyse, on occasion of a clinical case and with a revision of the literature, the actual patterns of the laryngeal tuberculosis.

    Topics: Aged; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Isoniazid; Laryngeal Diseases; Mycobacterium tuberculosis; Rifampin; Tomography, X-Ray Computed; Tuberculosis

2004
Rapid alternative methods for detection of rifampicin resistance in Mycobacterium tuberculosis.
    The Journal of antimicrobial chemotherapy, 2004, Volume: 54, Issue:1

    To study the performance of three rapid low cost methods for the detection of rifampicin resistance.. A panel of 20 coded Mycobacterium tuberculosis strains was tested blindly by the low cost methods: nitrate reductase, MTT and resazurin assays, and compared with the results obtained with the gold standard methods: the proportion method on Löwenstein-Jensen medium and the BACTEC TB 460 system. We have also tested two commercial tests: MGIT and INNO LiPA Rif.TB kit.. Complete agreement was observed among all methods.. These three simple methods might become inexpensive alternative procedures for rapid detection of rifampicin resistance in low-resource countries.

    Topics: Antibiotics, Antitubercular; Colorimetry; Culture Media; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Indicators and Reagents; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitrate Reductase; Nitrate Reductases; Oxazines; Oxidation-Reduction; Peru; Reagent Kits, Diagnostic; Rifampin; Tetrazolium Salts; Thiazoles; Tuberculosis; Xanthenes

2004
Lung specific stealth liposomes as antitubercular drug carriers in guinea pigs.
    Indian journal of experimental biology, 2004, Volume: 42, Issue:6

    The problem of patient non-compliance in the management of tuberculosis (TB) can be overcome by reducing the dosing frequency of antitubercular drugs (ATD) employing drug carriers. This study reports on the intravenous (iv) administration of lung specific stealth liposomes encapsulating ATD (rifampicin and isoniazid in combination) to guinea pigs and the detailed pharmacokinetic/chemotherapeutic studies. Following a single iv administration of liposomal drugs, the latter were found to exhibit sustained therapeutic levels in plasma for 96-168 hr with half-lives of 24-70 hr, mean residence time (MRT) of 35-81 hr and organ drug levels up to day 7. The relative bioavailability (as compared to oral free drugs) was increased by 5.4-8.9 folds, whereas the absolute bioavailability (as compared to iv free drugs) was increased by 2.9-4.2 folds. Weekly therapy with liposomal ATD for 6 weeks produced equivalent clearance of Mycobacterium tuberculosis from organs as did daily therapy with oral free drugs. Hence, intravenous liposomal ATD offer the therapeutic advantage of reducing the dosing frequency and improving the patient compliance in the management of TB.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Drug Carriers; Drug Therapy, Combination; Guinea Pigs; Infusions, Intravenous; Isoniazid; Liposomes; Lung; Rifampin; Time Factors; Tuberculosis

2004
Is the recommendation not to use rifampin plus pyrazinamide for latent tuberculosis treatment always imperative?
    Chest, 2004, Volume: 126, Issue:2

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Pyrazinamide; Rifampin; Tuberculosis

2004
[Experimental evidence for Mycobacterium tuberculosis persistence in M. tuberculosis-infected H37RV mice in the treatment with 3 first-line drugs (rifampicin, isoniazid, pyrazinamide)].
    Problemy tuberkuleza i boleznei legkikh, 2004, Issue:3

    To detect Mycobacterium tuberculosis (MBT) DNA in the blood and organs of tuberculosis-infected animals treated by the standard regimen including 3 first-line drugs, to assess the cellular reactions of organs of MBT-infected mice, and to evaluate the effect of rifampicin supplemented to the Cornell treatment regimen on the occurrence of endogenous reactivation of a tuberculous process, 150 BALB/c mice were intravenously infected with the MTB H(3)7Rv strain in a dose of 2.5 x 10(4) CFU/mouse and given chemotherapy with 3 drugs: rifampicin, 12 mg/kg body weight, isoniazid, 5 mg/kg, and pyrazinamide, 35 mg/kg. On day 20 of infection 2, 4, and 6 months after treatment and 2 months after termination of 4- and 6-month courses of therapy, the authors made inoculation, impressionsmears from parenchymatous organs stained by the Romanovsky-Gimse method, and conducted polymerase chain reaction for MBT DNA in the blood and organs of mice. The results indicated that supplementation of rifampicin to the Cornell treatment regimen prevented endogenous reactivation of the process, as confirmed by negative inoculations of the organs of the mice left untreated for 2 months. However, detection of MBT DNA and the cytological picture characteristic of tuberculous inflammation in the blood and organs of mice from these groups suggested that an occult tuberculous process was preserved.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Disease Models, Animal; DNA, Bacterial; Drug Therapy, Combination; Isoniazid; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Polymerase Chain Reaction; Pyrazinamide; Rifampin; Time Factors; Tuberculosis

2004
Hepatotoxicity of rifampin-pyrazinamide and isoniazid preventive therapy and tuberculosis treatment.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2004, Aug-15, Volume: 39, Issue:4

    Severe liver injury has been attributed to preventive treatment of latent tuberculosis infection with a 2-month course of rifampin-pyrazinamide.. A retrospective cohort study in The Netherlands compared the hepatotoxicity of preventive treatment with rifampin-pyrazinamide with that of preventive treatment with isoniazid, and also with that of treatment for active tuberculosis containing at least isoniazid, rifampin, and pyrazinamide.. Preventive treatment with rifampin-pyrazinamide caused severe hepatotoxicity more often than did preventive treatment with isoniazid (odds ratio [OR], 2.61; 95% confidence interval [CI], 1.26-5.39; P=.012), especially in patients <25 years old. It also caused severe hepatotoxicity more often than triple- or quadruple-drug tuberculosis treatment (OR, 2.61; 95% CI, 1.21-5.59; P=.016), especially if the pyrazinamide dose was > or =30 mg/kg. Preventive treatment with rifampin-pyrazinamide was more hepatotoxic even when the advised pyrazinamide dose of up to 20 mg/kg for preventive treatment was compared with the pyrazinamide dose of 30 mg/kg for tuberculosis treatment.. Preventive treatment with rifampin-pyrazinamide causes severe hepatotoxicity more often than does preventive treatment with isoniazid or curative treatment for tuberculosis.

    Topics: Adolescent; Adult; Anti-Bacterial Agents; Antibiotics, Antitubercular; Chemical and Drug Induced Liver Injury; Cohort Studies; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Netherlands; Prospective Studies; Pyrazinamide; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis

2004
Hepatotoxicity of rifampin and pyrazinamide in the treatment of latent tuberculosis infection in HIV-infected persons: is it different than in HIV-uninfected persons?
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2004, Aug-15, Volume: 39, Issue:4

    In 2000, results of a multinational trial demonstrated that a 2-month course of rifampin and pyrazinamide (RZ) was as effective as isoniazid (INH) in reducing tuberculosis in human immunodeficiency virus (HIV)-infected individuals with latent tuberculosis infection (LTBI). After the release of new guidelines, the Centers for Disease Control and Prevention received reports of severe hepatotoxicity associated with the use of the RZ regimen for the treatment of LTBI in the general population. To better understand the occurrence of hepatotoxicity in an HIV-infected population, we conducted a more detailed analysis of the liver function test results obtained in the multinational trial of RZ.. At study entry, patients were required to have a bilirubin level of < or =2.5 mg/dL and both an aspartate aminotransferase (AST) level and an alkaline phosphatase level of < or =5 times the upper limit of normal. Patients with acute hepatitis were excluded. At months 1 and 2 of the study, all patients had bilirubin and AST levels measured.. There was no difference between the RZ and INH groups with regard to AST level or bilirubin level at baseline. An increase in the AST level of > or =40 U/L was associated with the use of INH and older age; and an increase in the bilirubin level of > or =0.5 mg/dL was associated with the use of RZ, male sex, and nonwhite race (P<.05). An absolute AST level of >250 U/L occurred in 12 of 745 INH recipients and in 15 of 721 RZ recipients (P=.56), and an absolute bilirubin level of >2.5 mg/dL occurred in 5 of 743 INH recipients and 13 of 718 RZ recipients (P=.06).. These data demonstrate very little liver injury associated with either INH or RZ in the HIV-infected subjects, leaving unclear the reasons for serious RZ-related liver damage in the general population.

    Topics: Adolescent; Adult; Aspartate Aminotransferases; Bilirubin; Chemical and Drug Induced Liver Injury; Drug Administration Schedule; Female; HIV Infections; Humans; Isoniazid; Liver; Male; Middle Aged; Multicenter Studies as Topic; Multivariate Analysis; Pyrazinamide; Randomized Controlled Trials as Topic; Regression Analysis; Rifampin; Tuberculosis

2004
Rifampicin sparing treatment protocols in posttransplant tuberculosis.
    International urology and nephrology, 2004, Volume: 36, Issue:2

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Humans; Kidney Transplantation; Rifampin; Tuberculosis

2004
Role of human neutrophil peptide-1 as a possible adjunct to antituberculosis chemotherapy.
    The Journal of infectious diseases, 2004, Oct-15, Volume: 190, Issue:8

    We report the role of human neutrophil peptide (HNP)-1 as an adjunct to antituberculosis (anti-TB) drugs. The combination of HNP-1, isoniazid, and rifampicin was evaluated against Mycobacterium tuberculosis H(37)Rv in vitro, ex vivo, and in vivo, and synergism was observed on the basis of reductions in minimum inhibitory concentrations (MICs) of these agents. In vitro results revealed >1-log unit reductions even when HNP-1 and anti-TB drugs were used at 1/16 MICs. This combination was also found to be bactericidal against intracellular mycobacteria even at 1/8 MICs of HNP-1 and drugs. HNP-1 used in conjunction with anti-TB drugs resulted in significant clearance of bacterial load from lungs, liver, and spleen of infected, compared with control animals. The effective therapeutic dosage of drugs could be reduced to half by supplementing HNP-1 in the therapeutic schedule. These results clearly suggest that HNP-1 can be used as adjunct chemotherapy with conventional drugs against TB.

    Topics: alpha-Defensins; Animals; Anti-Infective Agents; Antitubercular Agents; Cell Line; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Isoniazid; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2004
Direct detection of rifampin-resistant mycobacterium tuberculosis in respiratory specimens by PCR-DNA sequencing.
    Journal of clinical microbiology, 2004, Volume: 42, Issue:10

    This study evaluated the feasibility of a molecular strategy based on identification of Mycobacterium tuberculosis by IS6110 PCR or Cobas Amplicor PCR, and rpoB PCR-DNA sequencing of the 81-bp rifampin resistance determining region (RRDR) for direct detection of rifampin resistance in respiratory specimens. A collection of 2,138 respiratory specimens and 352 nonduplicate M. tuberculosis isolates (including 233 isolates from the evaluated respiratory specimens and an additional collection of 119 stored isolates) from Southern China was investigated. Using culture as the reference test, the overall diagnostic sensitivities of an acid-fast bacillus (AFB) smear, Cobas Amplicor PCR, IS6110 PCR were 54.5% (156 of 286), 86.7% (248 of 286), and 89.2% (255 of 286), respectively. The sensitivities of the rpoB PCR for the specimens with positive AFB smears and with positive PCR results in the IS6110 PCR and/or Cobas Amplicor PCR were 100% (156 of 156) and 92.3% (239 of 259), respectively. Of the 352 nonduplicate M. tuberculosis isolates, the agar proportion method for rifampin reported 39 resistant strains. Full agreement (352 of 352) was found with the agar proportion method and the genotype inferred from the rpoB DNA sequencing data for rifampin. Thirty-nine mutations of nine distinct kinds, eight point mutations, and one deletion within the RRDR were found in the 39 resistant strains. For the direct DNA sequencing performed on rpoB PCR-positive respiratory specimens, the concordance with the agar proportion method and the subsequent PCR-sequencing for the culture isolate was 100%. This strategy has potential application for direct and rapid diagnosis of rifampin-resistant M. tuberculosis in IS6110 PCR or Cobas Amplicor PCR-positive respiratory specimens.

    Topics: Antibiotics, Antitubercular; DNA Transposable Elements; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Sputum; Tuberculosis

2004
[The resistance rates of Mycobacterium tuberculosis strains to antituberculosis drugs: evaluation of two years' data in Aegean region, Turkey].
    Mikrobiyoloji bulteni, 2004, Volume: 38, Issue:3

    The aim of this study was to determine the primary, secondary and total resistance rates of Mycobacterium tuberculosis strains in the Aegean Region, Turkey, between November 1st 1999 and November 30th 2001. A total of 490 M. tuberculosis strains isolated from patients admitted to 27 different tuberculosis dispensaries, were evaluated. The isolates have been identified as Mycobacterium tuberculosis with the colony morphology, growth rate and standard biochemical tests, and their sensitivities to isoniazid, rifampicin and ethambutol were tested by using indirect proportion method. H37Rv, ATCC 35838 and ATCC 35825 were used as standard control strains. Clinical information could be obtained about 474 patients and it has been detected that 387 (81.6%) of them received no prior antituberculous therapy, while 87 of them (18.4%) received antituberculous therapy longer than one month. Primary, secondary and total resistance rates to one or more drugs was found as 18.4%, 32.2% and 20.9%, respectively. Primary, secondary and total resistance rates for isoniazid (INH) and rifampicin (R) were found as follows, respectively; 12.4%, 26.4%, 14.9% and 5.7%, 19.5%, 8.2%. Primary resistance rate against INH+R were found 4.4%, secondary resistance rate were 17.2% and total resistance rate were 6.8%, in the multi-drug resistant isolates. According to these results it could be concluded that, drug resistance which requires immediate solution, continues to be a major problem in our region.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis; Turkey

2004
Rapid direct detection of multiple rifampin and isoniazid resistance mutations in Mycobacterium tuberculosis in respiratory samples by real-time PCR.
    Antimicrobial agents and chemotherapy, 2004, Volume: 48, Issue:11

    Rapid detection of resistance in Mycobacterium tuberculosis can optimize the efficacy of antituberculous therapy and control the transmission of resistant M. tuberculosis strains. Real-time PCR has minimized the time required to obtain the susceptibility pattern of M. tuberculosis strains, but little effort has been made to adapt this rapid technique to the direct detection of resistance from clinical samples. In this study, we adapted and evaluated a real-time PCR design for direct detection of resistance mutations in clinical respiratory samples. The real-time PCR was evaluated with (i) 11 clinical respiratory samples harboring bacilli resistant to isoniazid (INH) and/or rifampin (RIF), (ii) 10 culture-negative sputa spiked with a set of strains encoding 14 different resistance mutations in 10 independent codons, and (iii) 16 sputa harboring susceptible strains. The results obtained with this real-time PCR design completely agreed with DNA sequencing data. In all sputa harboring resistant M. tuberculosis strains, the mutation encoding resistance was successfully detected. No mutation was detected in any of the susceptible sputa. The test was applied only to smear-positive specimens and succeeded in detecting a bacterial load equivalent to 10(3) CFU/ml in sputum samples (10 acid-fast bacilli/line). The analytical specificity of this method was proved with a set of 14 different non-M. tuberculosis bacteria. This real-time PCR design is an adequate method for the specific and rapid detection of RIF and INH resistance in smear-positive clinical respiratory samples.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; DNA Primers; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Isoniazid; Mycobacterium tuberculosis; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Rifampin; Sputum; Tuberculosis

2004
Clinical outcomes of tuberculosis in renal transplant recipients.
    Yonsei medical journal, 2004, Oct-31, Volume: 45, Issue:5

    Tuberculosis (TB) is an important cause of morbidity and mortality in renal transplant recipients. Rifampin has a potent sterilizing activity, but it reduces the serum concentrations of the immunosuppressive agents. Moreover, the possible contribution made by mycobacterial infection to the incidence of graft rejection or renal dysfunction remains unclear. In this study, we investigated the recurrence of TB and graft survival duration according to rifampin usage, and we evaluated the factors that could influence the duration time until the recurrence of TB. Seventy-eight TB patients diagnosed after kidney transplantation were studied. Pulmonary TB was diagnosed in 26 of the 78 patients (33.3%), pleural TB in 23 (29.5%), combined pulmonary and pleural TB in 5 (6.4%), miliary TB in 19 (24.4%), and intestinal TB in 2 patients. In the pulmonary (pulmonary TB and pleural TB) TB group, no differences in graft survival and the TB free duration period were observed between the rifampin usage subgroup and the non- rifampin usage subgroup. In the extrapulmonary TB group, no difference was found in mean graft survival time between the rifampin usage subgroup and the non-rifampin usage subgroup, but the rifampin usage subgroup showed that the TB had a tendency to recur later than for the non-rifampin usage subgroup (87 +/- 8 vs. 44 +/- 7 months, respectively, p=0.30). The factor affecting the duration period until the recurrence of TB was the treatment duration (RR=0.761, p=0.030). This study suggests that rifampin does not affect graft survival in renal transplant recipients in whom immunosuppression is carefully monitored. Also, the study results indicate that rifampin may prevent a recurrence of extrapulmonary tuberculosis. Prolonged treatment appears to be appropriate for renal transplant recipients with TB.

    Topics: Adult; Female; Graft Survival; Humans; Kidney Transplantation; Male; Middle Aged; Recurrence; Rifampin; Time Factors; Tuberculosis

2004
Rapid, simple in vivo screen for new drugs active against Mycobacterium tuberculosis.
    Antimicrobial agents and chemotherapy, 2004, Volume: 48, Issue:12

    We evaluated the use of a simple and easy-to-obtain potential marker of tuberculosis (TB) drug efficacy, body weight, and correlated weight loss or gain with the number of CFU of Mycobacterium tuberculosis in lungs and spleens of infected mice. C3H mice were infected intravenously with 10(6) CFU of virulent M. tuberculosis H37Rv, and body weight was evaluated for several weeks after infection. At day 20, infected untreated mice consistently lost more than 25% of their body weight. Chemotherapy with selected orally active anti-TB drugs was initiated 7 days following infection and continued for 13 days. Drugs that were administered daily by gavage included isoniazid (INH), ethambutol (EMB), rifampin (RIF), and moxifloxacin (MXF). At the most effective doses, each of these drugs inhibited bacterial growth and abolished infection-induced body weight loss. Chemotherapy with 1/10 the standard dose of INH determined in accepted long-term murine models of TB also prevented body weight loss, while chemotherapy with 1/10 the standard dose of RIF did not. With only 2 weeks of chemotherapy, we observed a good reverse correlation between CFU in lung or spleen and body weight of mice. The simple measurement of weight in TB-infected drug-treated mice required only a weight balance, and go/no-go drug efficacy data was available on day 20 without the necessity of prolonged drug treatment and long (3 weeks or more) in vitro culture times to obtain organ CFU values.

    Topics: Animals; Antitubercular Agents; Colony-Forming Units Assay; Drug Evaluation, Preclinical; Female; Isoniazid; Lung; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mycobacterium tuberculosis; Rifampin; Spleen; Tuberculosis; Weight Loss

2004
Treatment of latent tuberculosis infection: back to the beginning.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2004, Dec-15, Volume: 39, Issue:12

    Topics: Antitubercular Agents; Female; Humans; Male; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculin Test; Tuberculosis

2004
The use of saquinavir/ritonavir 1000/100 mg twice daily in patients with tuberculosis receiving rifampin.
    Antiviral therapy, 2004, Volume: 9, Issue:6

    Topics: Adult; CD4 Lymphocyte Count; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Rifampin; Ritonavir; RNA, Viral; Saquinavir; Treatment Outcome; Tuberculosis

2004
[The prospect of application research on Mycobacteriophages].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2004, Volume: 27, Issue:12

    Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacteriophages; Mycobacterium tuberculosis; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Tuberculosis

2004
Chemotherapy of leprosy.
    Journal of the Indian Medical Association, 2004, Volume: 102, Issue:12

    The WHO MDT regimens have proved highly successful in preventing relapse of leprosy cases. It has indirectly lad to marked reduction in prevalence of disabilities. For PB leprosy, rifampicin 600 mg monthly and 100 mg dapsone daily for a total of 6 months therapy is required. For MB leprosy clofazimine 300 mg once monthly, supervised and 50 mg daily self administered is added. For single skin lesion the current WHO recommendation is 600 mg rifampicin + 400 mg ofloxacin + 100 mg minocycline given as a single dose for adults. Dose adjustment for children and clinical information have been discussed in a nutshell. A number of trials are going on, some are yet to be completed which do offer the prospect of perhaps simplifying therapy and improving with shorter duration.

    Topics: Anti-Bacterial Agents; Clofazimine; Dapsone; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; HIV Infections; Humans; Hypersensitivity; India; Leprosy; Minocycline; Nausea; Ofloxacin; Rifampin; Secondary Prevention; Tuberculosis; World Health Organization

2004
Adverse drug reactions observed during DOTS.
    The Journal of communicable diseases, 2004, Volume: 36, Issue:4

    A total of 8.37% of the 1195 patients treated at NDTB Centre with DOTS under RNTCP between January 2002 to June 2003 presented with adverse drug reactions. Patients showing any sort of adverse reactions were studied in detail by personal interviews and a semi-structured questionnaire. The profile of patients presenting with adverse reactions showed that majority of the patients (53%) had gastrointestinal reactions, the commonest presenting complaint being nausea and vomiting. General aches and pains were complained by about 35% and giddiness was the presenting complaint in 27% irrespective of the use of streptomycin, although giddiness was observed more often in Category II patients (59%). Skin rash and itching was complained by about 17% of patients and 11% complained of arthralgia, while only 1% had hepatotoxicity during treatment. Majority of the adverse reactions (67%) were observed within the first four weeks of treatment and only 0.25% of patients treated with DOTS had interruption of treatment for short periods.

    Topics: Adolescent; Adult; Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; India; Isoniazid; Male; Middle Aged; National Health Programs; Patient Compliance; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

2004
Safety of 2 months of rifampin and pyrazinamide for treatment of latent tuberculosis.
    American journal of respiratory and critical care medicine, 2003, Mar-15, Volume: 167, Issue:6

    An alternative regimen for the treatment of latent tuberculosis infection is 2 months of rifampin and pyrazinamide, but some patients have died of hepatitis associated with this therapy. One hundred fourteen patients received rifampin/pyrazinamide in Wake County, North Carolina, between December 1999 and May 2002; 60.5% of these patients were homeless, and at least 17% drank alcohol to excess. Seventy-seven patients (67.5%) completed a full 2-month course. Nine patients had a history of viral hepatitis or chronic liver disease. Four of 114 (3.5%; 95% confidence interval, 1.0-8.7%) patients developed hepatitis on therapy, and another two had symptoms consistent with hepatitis but did not report for laboratory testing (total confirmed plus suspected hepatitis rate 5.3%; 95% confidence interval, 2.0-11.1%). No patient who developed hepatitis had a history of viral hepatitis or liver disease, and none had been previously treated with isoniazid. No patients died or were hospitalized due to drug side effects. Rifampin/pyrazinamide was associated with a significantly higher rate of hepatitis than previously described with isoniazid therapy for latent tuberculosis but resulted in a high completion rate. The rifampin/pyrazinamide regimen for latent tuberculosis infection may be useful for high-risk, traditionally nonadherent patient groups, but careful monitoring for toxicity is required.

    Topics: Adolescent; Adult; Aged; Alcoholism; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Cohort Studies; Comorbidity; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Hepatitis B; Hepatitis C; Humans; Ill-Housed Persons; Infant; Liver Diseases; Male; Middle Aged; North Carolina; Pyrazinamide; Rifampin; Safety; Treatment Outcome; Tuberculosis

2003
A regimen containing rifabutin for the treatment of tuberculosis in patients intolerant to rifampin.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2003, Jan-01, Volume: 36, Issue:1

    Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Drug Hypersensitivity; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Rifabutin; Rifampin; Tuberculosis

2003
Co-administration of rifampin and nevirapine in HIV-infected patients with tuberculosis.
    AIDS (London, England), 2003, Mar-07, Volume: 17, Issue:4

    Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Infections; Humans; Male; Middle Aged; Nevirapine; Rifampin; Treatment Outcome; Tuberculosis

2003
Characterization of rifampicin-resistant Mycobacterium tuberculosis in Taiwan.
    Journal of medical microbiology, 2003, Volume: 52, Issue:Pt 3

    Sixty-three rifampicin-resistant (Rif(r)) isolates of Mycobacterium tuberculosis from Kaohsiung, Taiwan, were analysed for mutations in the core region (69 bp, codons 511-533) of the rpoB gene. Some 84.1 % (53/63) of the resistant isolates showed mutations in this region, especially in codons 531 (41.5 %), 526 (18.9 %), 516 (15.1 %) and 533 (7.5 %). Five novel alleles of a total of 16 different types of mutations were identified in Rif(r) isolates. Ten Rif(r) isolates (15.9 %) exhibited no mutations in the core region of rpoB. Also, they did not show mutations in another 365 bp fragment (codons 99-220) of rpoB. The agar proportion method was used to determine the relationship between the degree of rifampicin resistance and alterations in the core region of rpoB. The results revealed that the mean MIC was 92.38 micro g ml(-1) for the 53 isolates with a mutation in the core region, whereas the mean MIC of the other 10 isolates without mutations was only 24.8 micro g ml(-1). This indicates that the isolates with mutations in the core region had higher levels of resistance than those without mutations in this region. IS6110 restriction fragment length polymorphism (RFLP) was used for typing of 55 Rif(r) M. tuberculosis isolates. Isolates contained two to 19 copies of IS6110, with sizes ranging from 600 to 16 000 bp. The majority (85 %) contained six to 16 copies. No strains lacking IS6110 were found. A total of 54 of 55 RFLP types were defined at the 90 % similarity level. The observation of varied IS6110-associated banding patterns indicates that an outbreak of drug-resistant tuberculosis did not occur in this area.

    Topics: Base Sequence; Drug Resistance, Multiple; Genes, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Mycobacterium tuberculosis; Phylogeny; Polymorphism, Genetic; Rifampin; Taiwan; Tuberculosis

2003
Fatal liver injury associated with rifampin-pyrazinamide treatment of latent tuberculosis infection.
    Chest, 2003, Volume: 123, Issue:3

    Topics: Adverse Drug Reaction Reporting Systems; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Drug Therapy, Combination; Humans; Liver Failure; Pyrazinamide; Rifampin; Tuberculosis; United States

2003
Management of latent tuberculosis infection in immigrants.
    The New England journal of medicine, 2003, Mar-27, Volume: 348, Issue:13

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cost-Benefit Analysis; Drug Resistance, Bacterial; Emigration and Immigration; Health Care Costs; Humans; Pyrazinamide; Rifampin; Tuberculosis

2003
Management of latent tuberculosis infection in immigrants.
    The New England journal of medicine, 2003, Mar-27, Volume: 348, Issue:13

    Topics: Antitubercular Agents; Cost-Benefit Analysis; Emigration and Immigration; Health Care Costs; Humans; Pyrazinamide; Rifampin; Tuberculosis

2003
Treatment of latent tuberculosis infection.
    The New England journal of medicine, 2003, Mar-27, Volume: 348, Issue:13

    Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Tuberculosis

2003
Anti-tuberculosis 4FDC tablets--mystery to chemistry.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2003, Volume: 7, Issue:3

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Combinations; Drug Stability; Drug Storage; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Tablets; Tuberculosis

2003
Evaluation of FASTPlaqueTB-RIF for determination of rifampicin resistance in Mycobacterium tuberculosis complex isolates.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2003, Volume: 7, Issue:3

    The Microbiology and Clinical Microbiology Department, Gulhane Military Medical Academy, Ankara, Turkey, a tertiary referral hospital in a region endemic for tuberculosis.. To evaluate rifampicin resistance of Mycobacterium tuberculosis complex strains using FASTPlaqueTB-RIF, a rapid and novel bacteriophage-based susceptibility technique.. Results of isolates tested with the BACTEC 460 TB system were compared with FASTPlaqueTB-RIF.. Susceptibility to rifampicin of M. tuberculosis complex isolates was tested for 88 isolates using FASTPlaqueTB-RIF. Sixty-seven isolates were susceptible and 21 were resistant to rifampicin using the BACTEC 460 TB system. Overall accuracy for FASTPlaqueTB-RIF was 94.3% (95%CI 87.3-97.5) for the detection of rifampicin susceptibility. The sensitivity and specificity of FASTPlaqueTB-RIF were respectively 100.0% (95%CI 84.5-100) and 92.5% (95%CI 83.6-96.7).. This study demonstrates that FASTPlaqueTB-RlFM is a rapid and inexpensive test which has a good correlation with the BACTEC 460 TB system.

    Topics: Antibiotics, Antitubercular; Cell Culture Techniques; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Tuberculosis

2003
Pharmaceutical formulation of a fixed-dose anti-tuberculosis combination.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2003, Volume: 7, Issue:3

    Department of Pharmacy and Pharmacology, University of the Witwatersrand. Despite the availability of highly effective treatment regimens for tuberculosis (TB), the cure rate still remains relatively low. This may be attributed to the high incidence of patient non-compliance, which subsequently leads to the emergence of multidrug-resistant TB (MDR-TB). To avoid the problem of further creation and propagation of MDR-TB, it may be proposed that patients should be given fixed-dose combinations of anti-tuberculosis drugs whenever self-administration is permitted.. To optimise an anti-tuberculosis extemporaneous powder formulation for suspension in order to develop a fixed combination of rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as a powder to be reconstituted with water by the patient prior to administration.. Different suspending agents were evaluated for their influence on powder flow properties, and sediment volume on the powder blends. Sodium starch glycolate was selected as the suspending agent because of its favourable powder flow properties and sediment volume produced. The dissolution characteristics of the extemporaneous powder for suspension were also compared to the dissolution profiles of commercially available anti-tuberculosis tablet dosage forms.. The powder for suspension for rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride all compared favourably to the dissolution rate from the commercially available tablet dosage forms.

    Topics: Administration, Oral; Antibiotics, Antitubercular; Antitubercular Agents; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Combinations; Drug Compounding; Ethambutol; Excipients; Feasibility Studies; Humans; Isoniazid; Powders; Pyrazinamide; Rifampin; Tuberculosis

2003
A pilot stability study on four-drug fixed-dose combination anti-tuberculosis products.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2003, Volume: 7, Issue:3

    A pilot stability study was carried out on four fixed-dose combination anti-tuberculosis products at 40 degrees C and 75% RH. The strip-packed products were stable, while the blister-packed products showed both physical and chemical changes. The products in unpacked conditions showed severe (approximately 60%) decomposition of rifampicin and extensive physical changes. The main decomposition product in the solid state was isonicotinyl hydrazone of 3-formylrifamycin and isoniazid. It is suggested that attention should be paid to the detection and quantitation of this product in the marketed formulations. The packing material used in the manufacture of FDC products should also be of the highest quality.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Biological Availability; Drug Combinations; Drug Labeling; Drug Packaging; Drug Stability; Drug Storage; Ethambutol; Humans; Isoniazid; Pilot Projects; Pyrazinamide; Rifampin; Tablets; Time Factors; Tuberculosis

2003
[Tuberculous otitis media. Report of 3 cases].
    Anales otorrinolaringologicos ibero-americanos, 2003, Volume: 30, Issue:1

    Tuberculous otitis media (TOM) is a rare cause of chronic suppurative infection of the middle ear. Due to that the symptoms and signs are often indistinguishable from those of nontuberculosis chronic otitis media and the fact that the index of suspicion is low, there is frequently a considerable delay prior to diagnosis. This can lead to irreversible complications such as facial nerve paralysis and labyrinthitis. Medical therapy with antituberculous drugs is usually effective. We report three cases with TOM diagnosticated and followed up in our Service from january 1993 to july 2001. Their charts were retrospectively reviewed for relevant historical data, physical findings, complementary studies, treatment and clinical response. We performed a review of the literature, emphasizing that TOM should be considered in the differential diagnosis of chronic otitis media.

    Topics: Adult; Aged; Amoxicillin; Antitubercular Agents; Cerebrospinal Fluid Otorrhea; Drug Combinations; Ear Diseases; Female; Humans; Isoniazid; Male; Mycobacterium Infections; Mycobacterium tuberculosis; Otitis Media; Penicillins; Proteus Infections; Proteus mirabilis; Pyrazinamide; Rifampin; Staphylococcal Infections; Staphylococcus aureus; Tuberculosis

2003
Rapid detection of resistance against rifampicin in isolates of Mycobacterium tuberculosis from Brazilian patients using a reverse-phase hybridization assay.
    Journal of microbiological methods, 2003, Volume: 53, Issue:3

    The main objective of this study was to evaluate INNO-LiPA Rif.TB and to determine the frequency of mutations in rpoB in rifampicin-resistant Mycobacterium tuberculosis isolates of Brazilian tuberculosis patients. We used the reverse hybridization assay on 113 resistant and 15 sensitive clinical isolates of M. tuberculosis and on reference strains belonging to 37 different species. All MTB complex strains and none of the other strains reacted with the MTB complex-specific probe, meaning that the assay is 100% specific and 100% sensitive for detection of strains of the MTB complex. In 80 resistant strains, mutations causing S531L (n=55), H526Y (n=9), H526D (n=12) or D516V (n=9) were detected while in 30 strains, mutations were present but their exact nature was not determined by the assay (DeltaS patterns). All sensitive strains had the sensitive genotype while among resistant isolates, a sensitive genotype was obtained in three due to the absence of mutations in the hot spot region, demonstrating an assay accuracy of 97.6% for detection of drug susceptibility. In 10 resistant cultures, two or more mutations were detected and in five, mixed sensitive and resistant genotypes were observed. The sensitivity of the assay for detection of resistant organisms in a mixture with sensitive ones were 2% and 70%, respectively, considering the appearance and disappearance of the R2 and S2 bands. The sensitivity to detect heteroresistance is similar to that of the proportion method when a specific probe for the mutation is present but the performance of the assay in the patient population will depend on the frequency of mutation distribution.

    Topics: Antibiotics, Antitubercular; Brazil; Drug Resistance, Bacterial; Genotype; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Polymerase Chain Reaction; Rifampin; Sequence Analysis, DNA; Time Factors; Tuberculosis

2003
Control of anti-tuberculosis drug resistance in Botswana.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2003, Volume: 7, Issue:1

    Botswana, where in 2000 the prevalence of human immunodeficiency virus (HIV) infection among adults was 38%, and the tuberculosis (TB) rate was 591/100,000. A 1995-1996 survey demonstrated low levels of anti-tuberculosis drug resistance.. Because TB drug resistance may increase rapidly in HIV-infected populations, a second survey was undertaken in 1999 to determine any increase in anti-tuberculosis drug resistance.. Sputum specimens positive for acid-fast bacilli from patients without prior TB treatment (new patients), and all sputum specimens from patients reporting prior TB treatment (retreatment patients) were collected nationwide. Specimens were cultured for Mycobacterium tuberculosis and tested for resistance to isoniazid, rifampicin, ethambutol, and streptomycin.. From January to May 1999, 783 patients were consecutively enrolled from all districts. Of these, 483 (61.7%) were male, the median age was 33 years, and 82% were new patients. Drug resistance occurred in 6.3% of new patients (95 % confidence interval [CI] 4.6-8.6) and 22.8% of retreatment patients (95% CI 16.5-30.1). Resistance to at least isoniazid and rifampicin was found in 0.5% of new (95% CI 0.1-1.3) and 9.0% of retreatment patients (95% CI 5.1-14.5).. Anti-tuberculosis drug resistance remains relatively low in Botswana, probably as a result of a well-functioning TB program. Periodic surveys will be essential to adequately determine any significant trend.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Botswana; Child; Child, Preschool; Drug Resistance, Microbial; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2003
Mutations in the rpoB gene of multidrug-resistant Mycobacterium tuberculosis isolates from China.
    Journal of clinical microbiology, 2003, Volume: 41, Issue:5

    Mutations in the 81-bp rifampin resistance determining region (RRDR) and mutation V176F locating at the beginning of the ropB gene were analyzed by DNA sequencing of 86 Mycobacterium tuberculosis clinical isolates (72 resistant and 14 sensitive) from different parts of China. Sixty-five mutations of 22 distinct kinds, 21 point mutations, and 1 insertion were found in 65 of 72 resistant isolates. The most common mutations were in codons 531 (41%), 526 (40%), and 516 (4%). Mutations were not found in seven (10%) of the resistant isolates. Six new alleles within the RRDR, along with five novel mutations outside the RRDR, are reported. None of isolates contained the V176 mutation.

    Topics: Alleles; Amino Acid Sequence; Antibiotics, Antitubercular; Base Sequence; China; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Genes, Bacterial; Humans; Molecular Sequence Data; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2003
Utility of an in-house mycobacteriophage-based assay for rapid detection of rifampin resistance in Mycobacterium tuberculosis clinical isolates.
    Journal of clinical microbiology, 2003, Volume: 41, Issue:6

    A rapid in-house mycobacteriophage-based assay to identify multidrug resistance by detecting the rifampin susceptibility of Mycobacterium tuberculosis in a microtiter plate format was evaluated. The sensitivity, specificity, and overall accuracy of the assay were 100%. This test is rapid to perform and suitable for widespread implementation.

    Topics: Antibiotics, Antitubercular; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacteriophages; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

2003
Severe hepatotoxicity associated with rifampin-pyrazinamide preventative therapy requiring transplantation in an individual at low risk for hepatotoxicity.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2003, Jun-15, Volume: 36, Issue:12

    We report a case of severe hepatotoxicity associated with rifampin-pyrazinamide preventative therapy that required liver transplantation in a closely monitored, human immunodeficiency virus-uninfected individual who had no risk for hepatotoxicity. Because hepatotoxicity associated with this treatment appears to be idiosyncratic, we recommend closer monitoring of liver enzyme levels than do the Centers for Disease Control and Prevention guidelines, as well as at least temporary interruption of treatment during any elevation of liver enzyme levels greater than the normal value.

    Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Chemical and Drug Induced Liver Injury; Humans; Liver Function Tests; Male; Organ Transplantation; Pyrazinamide; Rifampin; Risk; Tuberculosis; United States

2003
Use of molecular methods to identify the Mycobacterium tuberculosis complex (MTBC) and other mycobacterial species and to detect rifampin resistance in MTBC isolates following growth detection with the BACTEC MGIT 960 system.
    Journal of clinical microbiology, 2003, Volume: 41, Issue:7

    A prospective study was organized by using a total of 1,585 consecutive clinical specimens to determine whether biomass obtained from positive growth in the MGIT 960 system could be used directly in AccuProbe DNA hybridization tests, the PCR-based Inno-LiPA Rif.TB (LiPA) assay, and a PCR-based DNA sequencing of the rpoB gene for the rapid identification of the Mycobacterium tuberculosis complex (MTBC) and other mycobacterial species and for the determination of rifampin (RIF) resistance in MTBC strains. The results were compared to routine culture, identification, and susceptibility testing techniques performed on the same samples. The study results revealed that the DNA AccuProbe assay (on the day of growth positivity) readily identified 95.7%, the LiPA assay readily identified 98.6%, and rpoB sequencing readily identified 97.1% of the 70 MTBC isolates from mycobacterial growth indicator tubes (MGIT). In addition, application of the LiPA for the identification and RIF susceptibility testing of the MTBC in growth-positive MGIT resulted in a turnaround time of less than 2 weeks after specimen receipt. Although DNA sequencing of rpoB required a slightly longer (16 days) turnaround time, this method was capable of identifying several species of nontuberculous mycobacteria in addition to identifying MTBC and determining RIF susceptibility or resistance. The molecular methods were also found to rapidly identify RIF-susceptible and -resistant MTBC in two of the three mixed mycobacterial cultures weeks earlier than conventional methods. In conclusion, the biomass obtained in MGIT at the time of growth positivity in the 960 system is sufficient for use in all three molecular tests, and this approach can reduce the turnaround time for reporting results.

    Topics: Antibiotics, Antitubercular; Bacterial Typing Techniques; Culture Media; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Nucleic Acid Hybridization; Polymerase Chain Reaction; Prospective Studies; Reagent Kits, Diagnostic; Rifampin; Sequence Analysis, DNA; Tuberculosis

2003
Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection--United States, 2003.
    MMWR. Morbidity and mortality weekly report, 2003, Aug-08, Volume: 52, Issue:31

    CDC has reported previously surveillance data of severe liver injury in patients treated for latent tuberculosis infection (LTBI) with a daily and twice-weekly 2-month regimen of rifampin with pyrazinamide (RZ). On the basis of these initial reports, CDC cautioned clinicians in the use of this therapy with advised additional monitoring. To estimate the incidence of RZ-associated severe liver injury and provide more precise data to guide treatment for LTBI, CDC collected data from cohorts of patients in the United States who received RZ for the treatment of LTBI during January 2000-June 2002 and for whom data were reported to CDC through June 6, 2003. This report summarizes the analysis, which found high rates of hospitalization and death from liver injury associated with the use of RZ. On the basis of these findings, the American Thoracic Society (ATS) and CDC now recommend that this regimen should generally not be offered to persons with LTBI. The revised ATS/CDC recommendations described in this report have been endorsed by the Infectious Diseases Society of America (IDSA). Clinicians are advised to use the recommended alternative regimens for the treatment of LTBI. Rifampin and pyrazinamide (PZA) should continue to be administered in multidrug regimens for the treatment of persons with active tuberculosis (TB) disease.

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Pyrazinamide; Retrospective Studies; Rifampin; Tuberculosis; United States

2003
Rifamycin treatment of tuberculosis in a patient receiving atenolol: less interaction with rifabutin than with rifampin.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2003, Aug-15, Volume: 37, Issue:4

    Topics: Aged; Antibiotics, Antitubercular; Antihypertensive Agents; Atenolol; Drug Interactions; Humans; Male; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins; Tuberculosis

2003
USPHS-CDC news.
    The Annals of pharmacotherapy, 2003, Volume: 37, Issue:10

    Topics: Centers for Disease Control and Prevention, U.S.; Chemical and Drug Induced Liver Injury; Communication; Humans; Pyrazinamide; Rifampin; Tuberculosis; United States; United States Public Health Service

2003
Frequency and antibiotic susceptibility pattern of mycobacterial isolates from extra-pulmonary tuberculosis cases.
    JPMA. The Journal of the Pakistan Medical Association, 2003, Volume: 53, Issue:8

    To determine the frequency and antimicrobial susceptibility pattern of extra-pulmonary tuberculosis in Rawalpindi.. Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi.. Between September 2000 and August 2002, 899 pulmonary and 460 extra-pulmonary specimens from suspected cases of tuberculosis were examined. The radiometric BACTEC 460 TB system was used for culture and antimicrobial susceptibility testing.. Mycobacteria were isolated from 291 pulmonary specimens and 98 extra-pulmonary specimens. The frequency of extra-pulmonary tuberculosis was 25.2%. The commonest source of isolation was pus (44.9%, frequency 11.3%), followed by lymph nodes (13.3%, frequency 3.3%) and pleural fluid (13.3%, frequency 3.3%). We tested the anti-microbial susceptibility of the isolates to the four first line anti-tuberculous drugs, rifampicin, isoniazid, streptomycin and ethambutol. Of the extra-pulmonary isolates 13.3% were resistant to a single drug, 21.4% were multi-drug resistant and 9.2% were resistant to all the four drugs.. Increased awareness of the magnitude of the problem posed by extra-pulmonary tuberculosis is required so that appropriate control measures can be adopted.

    Topics: Antitubercular Agents; Drug Resistance, Bacterial; Drug Resistance, Multiple; Ethambutol; Humans; Isoniazid; Lymph Nodes; Mycobacterium tuberculosis; Pleural Effusion; Rifampin; Streptomycin; Suppuration; Tuberculosis

2003
Status of drug resistance in tuberculosis after the introduction of rifampicin in India.
    Journal of the Indian Medical Association, 2003, Volume: 101, Issue:3

    The current threat in tuberculosis treatment lies on the fact of emergence of strains resistant to two most antituberculous drugs, isoniazid and rifampicin. Drug resistance to TB may be classified as primary and acquired. Causes of drug resistance are inefficient administration of effective treatment, poor case handling, use of sub-standard drugs, ignorance of healthcare workers, etc. Multidrug resistant TB (MDR-TB) prevalence (median) in new case is highest (14.1%) in Estonia. Studies undertaken in different regions in India by Tuberculosis Research Centre (TRC) during 1997-2000 revealed acquired MDR-TB resistance levels of 25-100%. The key to successful prevention of the emergence of drug resistance remains adequate case finding, prompt and correct diagnosis and effective treatment of infective patients.

    Topics: Antitubercular Agents; Drug Resistance, Multiple; Humans; India; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2003
Rapid colorimetric method for testing susceptibility of Mycobacterium tuberculosis to isoniazid and rifampin in liquid cultures.
    Journal of clinical microbiology, 2003, Volume: 41, Issue:11

    We have developed a rapid colorimetric method for testing the susceptibility of M. tuberculosis to isoniazid (INH) and rifampin (RIF) based on incorporation of nitrate in broth cultures containing growth supplements. The performance of this colorimetric nitrate reductase-based antibiotic susceptibility (CONRAS) test was compared with that of the radiometric BACTEC 460TB system in determining the susceptibilities of 74 M. tuberculosis strains to INH and RIF. By using the BACTEC 460TB system as the "gold standard," the sensitivity (i.e., the ability to detect true drug resistance) and specificity (i.e., the ability to detect true drug susceptibility) of the CONRAS test were 100 and 95% for INH and 94 and 100% for RIF, respectively. The repeatability of the CONRAS test was excellent (for INH, kappa = 1 and P < 0.001; for RIF, kappa = 0.88 and P < 0.001). For the majority of strains, results were obtained within 5 days. The CONRAS test is rapid, accurate, and inexpensive and is an adequate alternative, particularly for resource-poor countries.

    Topics: Antitubercular Agents; Colorimetry; Drug Resistance, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitrites; Reproducibility of Results; Rifampin; Time Factors; Tuberculosis

2003
Poly (DL-lactide-co-glycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis.
    The Journal of antimicrobial chemotherapy, 2003, Volume: 52, Issue:6

    To improve the bioavailability of antitubercular drugs (ATDs) as well as to assess the feasibility of administering ATDs via the respiratory route, this study reports the formulation of three frontline ATDs, i.e. rifampicin, isoniazid and pyrazinamide encapsulated in poly (DL-lactide-co-glycolide) nanoparticles suitable for nebulization.. Drug-loaded nanoparticles were prepared by the multiple emulsion technique, vacuum-dried and nebulized to guinea pigs. The formulation was evaluated with respect to the pharmacokinetics of each drug and its chemotherapeutic potential in Mycobacterium tuberculosis infected guinea pigs.. The aerosolized particles exhibited a mass median aerodynamic diameter of 1.88 +/- 0.11 microm, favourable for bronchoalveolar lung delivery. A single nebulization to guinea pigs resulted in sustained therapeutic drug levels in the plasma for 6-8 days and in the lungs for up to 11 days. The elimination half-life and mean residence time of the drugs were significantly prolonged compared to when the parent drugs were administered orally, resulting in an enhanced relative bioavailability (compared to oral administration) for encapsulated drugs (12.7-, 32.8- and 14.7-fold for rifampicin, isoniazid and pyrazinamide, respectively). The absolute bioavailability [compared to intravenous (i.v.) administration] was also increased by 6.5-, 19.1- and 13.4-fold for rifampicin, isoniazid and pyrazinamide, respectively. On nebulization of nanoparticles containing drugs to M. tuberculosis infected guinea pigs at every 10th day, no tubercle bacilli could be detected in the lung after five doses of treatment whereas 46 daily doses of orally administered drug were required to obtain an equivalent therapeutic benefit.. Nebulization of nanoparticles-based ATDs forms a sound basis for improving drug bioavailability and reducing the dosing frequency for better management of pulmonary tuberculosis.

    Topics: Administration, Inhalation; Aerosols; Animals; Antibiotics, Antitubercular; Antitubercular Agents; Area Under Curve; Biological Availability; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemistry, Physical; Colony Count, Microbial; Drug Carriers; Drug Combinations; Drug Compounding; Female; Guinea Pigs; Half-Life; Injections, Intravenous; Isoniazid; Lactic Acid; Lung; Male; Microspheres; Mycobacterium tuberculosis; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Pyrazinamide; Rifampin; Tuberculosis

2003
Nanoparticle encapsulated antitubercular drugs as a potential oral drug delivery system against murine tuberculosis.
    Tuberculosis (Edinburgh, Scotland), 2003, Volume: 83, Issue:6

    Patient non-compliance is the major drawback associated with the long-duration chemotherapy of tuberculosis (TB); hence, reduction in dosing frequency forms an important therapeutic strategy. The present study reports the formulation of three frontline antitubercular drugs (ATD), i.e. rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) encapsulated in poly (DL-lactide-co-glycolide) (PLG) nanoparticles. Drug encapsulation efficiencies were 56.9+/-2.7% for RIF, 66.3+/-5.8% for INH and 68+/-5.6% for PZA. Following a single oral administration of these preparations to mice, the drugs could be detected in the circulation for 6 days (RIF) and 9 days (INH/PZA), whereas therapeutic concentrations in the tissues were maintained for 9-11 days. Further, on oral administration of drug-loaded nanoparticles to Mycobacterium tuberculosis-infected mice at every 10th day, no tubercle bacilli could be detected in the tissues after 5 oral doses of treatment. Therefore, nanoparticle-based ATD therapy forms a sound basis for reduction in dosing frequency for better management of TB.

    Topics: Administration, Oral; Animals; Antitubercular Agents; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Female; Glycolates; Isoniazid; Lactic Acid; Liver; Lung; Male; Mice; Mycobacterium tuberculosis; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrazinamide; Rifampin; Spleen; Tuberculosis

2003
Evaluation of a PCR-based universal heteroduplex generator assay as a tool for rapid detection of multidrug-resistant Mycobacterium tuberculosis in Peru.
    Journal of clinical microbiology, 2003, Volume: 41, Issue:12

    Multidrug-resistant tuberculosis is an increasing health problem worldwide, especially in developing countries. The PCR-UHG-Rif assay, which detects mutations within the rpoB gene associated with rifampin resistance, was evaluated for its ability and reliability to detect and identify drug-resistant Mycobacterium tuberculosis in a developing country where tuberculosis is highly endemic.

    Topics: Antitubercular Agents; DNA-Directed RNA Polymerases; Drug Resistance, Multiple; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Peru; Polymerase Chain Reaction; Predictive Value of Tests; Rifampin; Sensitivity and Specificity; Tuberculosis

2003
Typing of Mycobacterium tuberculosis strains resistant to rifampicin and isoniazid by molecular biological methods.
    Bulletin of experimental biology and medicine, 2003, Volume: 136, Issue:3

    Mutations in the rpoB, katG, inhA, oxyR/ahpC genes in rifampicin- and isoniazid-resistant M. tuberculosis strains isolated from residents of Moscow, Astrakhan', and Moldova Republic were studied by molecular biological methods (heteroduplex analysis, single strand conformational polymorphism, biochips). Twenty-five combinations of mutations were detected. Some differences in the type distribution of detected mutations were found. The use of biochips is the most perspective method for determining the type of mutation.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Bacterial Typing Techniques; Codon; DNA; Drug Resistance, Microbial; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Nucleic Acid Heteroduplexes; Oligonucleotide Array Sequence Analysis; Polymorphism, Single-Stranded Conformational; Rifampin; Tuberculosis

2003
Effect of drug resistance on the generation of secondary cases of tuberculosis.
    The Journal of infectious diseases, 2003, Dec-15, Volume: 188, Issue:12

    The results of animal studies suggest that isoniazid-resistant strains of Mycobacterium tuberculosis are less pathogenic than isoniazid-susceptible strains. Here, we assess the relative pathogenicity of drug-resistant and drug-susceptible strains, in a human population.. We linked IS6110 genotype patterns of M. tuberculosis strains with drug-susceptibility test results and epidemiologic information for 85% of culture-positive incident cases of tuberculosis (TB) in San Francisco during 1991-1999. We assumed that drug-susceptible and drug-resistant strains were transmitted to secondary case patients if the drug-resistance and genotype patterns were identical. We calculated the number of secondary cases for each drug-resistance pattern and determined the relative secondary-case rate ratio (SR) of drug-resistant TB to drug-susceptible TB.. There were 1800 patients with culture-positive TB, drug-susceptibility test results, and genotyping results. The overall SR of drug-resistant to drug-susceptible TB cases was 0.51 (95% confidence interval [CI], 0.37-0.69). The SR was 0.29 (95% CI, 0.15-0.57) for isoniazid-resistant strains, 0.10 (95% CI, 0.02-0.42) for strains resistant to both isoniazid and streptomycin, and 0.88 (95% CI, 0.53-1.47) for streptomycin-resistant strains. There were no secondary cases caused by multidrug-resistant (MDR) TB. The SR for rifampin-resistant cases was 2.33 (95% CI, 1.04-5.25). Seventy-eight percent (7/9) of the patients with rifampin-resistant secondary cases of TB were seropositive for human immunodeficiency virus.. In the context of an effective TB program in San Francisco, strains that were resistant to isoniazid either alone or in combination with other drugs were less likely to result in secondary cases than were drug-susceptible strains. In this setting, isoniazid-resistant and MDR TB cases were not likely to produce new, incident drug-resistant TB cases.

    Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Confidence Intervals; DNA Transposable Elements; Drug Resistance, Bacterial; Humans; Incidence; Isoniazid; Mycobacterium tuberculosis; Rifampin; San Francisco; Streptomycin; Tuberculosis

2003
Rifampin and recurrence of tuberculosis among patients infected with HIV.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2003, Dec-15, Volume: 37, Issue:12

    Topics: Antitubercular Agents; HIV; HIV Infections; Humans; Recurrence; Rifampin; Tuberculosis

2003
[Septic loosening of a Wagner revision stem provoked by Mycobacterium tuberculosis].
    Der Orthopade, 2003, Volume: 32, Issue:12

    Only a few cases of specific tuberculous infections of total hip arthroplasties have been published. We report the case of a 66-year-old male patient who received a cementless total hip arthroplasty due to osteoarthritis of the left hip in 1990. Four years later, revision arthroplasty with a Wagner revision stem was performed because of aseptic loosening. In 1995 revision of a loosened acetabular cup was necessary. In 1996 we saw the patient for the first time in our outpatient unit. He complained of increasing pain in the region of the left hip. X-rays showed loosening of the Wagner stem. Aspiration of the synovial fluid of the left hip revealed an infection with mycobacterium tuberculosis (radioimmunoassay). There were no signs of tuberculous infection in the patient's history. Treatment consisted of removal of the prosthesis followed by antituberculosis chemotherapy for 12 months with rifampicin, ethambutol, isoniazid, and pyrazinamide. In April 2001 revision of the left hip joint and implantation of a MRP titanium revision stem and reconstruction of the acetabulum with an acetabular reconstruction ring was done. Until today the patient exhibits no signs of recurrence of the tuberculous infection.

    Topics: Acetabulum; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Arthroplasty, Replacement, Hip; Ethambutol; Follow-Up Studies; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Prosthesis Failure; Prosthesis-Related Infections; Pyrazinamide; Radioimmunoassay; Reoperation; Rifampin; Synovial Fluid; Time Factors; Titanium; Tuberculosis

2003
Tuberculosis in Australia: bacteriologically confirmed cases and drug resistance, 2002: a report of the Australian Mycobacterium Reference Laboratory Network.
    Communicable diseases intelligence quarterly report, 2003, Volume: 27, Issue:4

    The Australian Mycobacterium Reference Laboratory Network collected and analysed laboratory data on new cases of disease caused by Mycobacterium tuberculosis complex in the year 2002. A total of 712 cases were identified by bacteriology, representing an annual reporting rate of 3.6 cases of laboratory-confirmed tuberculosis per 100,000 population. The most commonly encountered culture-positive specimens were sputum (n=325), lymph node (n=142) and bronchoscopy (n=100). Smears containing acid fast bacilli were present in sputum (53.2%), bronchoscopy (37.9%) and lymph node (21.2%). Eight children (male n=3, female n=5) under 10 years of age had bacteriologically-confirmed tuberculosis. A total of 55 isolates (7.7%) of M. tuberculosis were resistant to at least one of the standard anti-tuberculosis agents. Resistance to at least isoniazid and/or rifampicin was noted for 53 isolates (7.4%), with multidrug-resistance (MDRTB) observed in 12 (1.9%) isolates. Of the 12 MDRTB isolates, eight were from the respiratory tract and five were from smear positive specimens. Of the patients with drug resistant M. tuberculosis isolates, 51/55 (92.7%) were classified as having initial resistance, none had acquired resistance during treatment in Australia. The country of birth was known for 54 of 55 such patients; four were Australian-born, and 50 (90.9%) had migrated from a total of 17 countries. Nucleic acid amplification testing (NAAT) was performed on 139 (19.5%) of the 712 culture-positive specimens. Of smear positive respiratory specimens, 74/80 (92.5%) were NAAT positive. For smear negative respiratory specimens, 12/17 (70.6%) reported a NAAT positive result. Importantly, false-negative NAAT results were obtained from 1/16 and 5/64 of smear positive bronchoscopy and sputum specimens respectively.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Australia; Bronchoscopy; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; False Negative Reactions; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Predictive Value of Tests; Rifampin; Sputum; Tuberculosis

2003
Resazurin microtiter assay plate: simple and inexpensive method for detection of drug resistance in Mycobacterium tuberculosis.
    Antimicrobial agents and chemotherapy, 2002, Volume: 46, Issue:8

    A method for detecting multidrug-resistant Mycobacterium tuberculosis by using a reduction of resazurin is described. Eighty clinical isolates were evaluated against isoniazid and rifampin; results at 7 days were compared with those of the proportion method. Specificity and sensitivity were excellent. The method is simple, inexpensive, and rapid and might be used with other antituberculosis drugs.

    Topics: Antitubercular Agents; Colorimetry; Drug Resistance, Microbial; Humans; Indicators and Reagents; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazines; Peru; Rifampin; Tuberculosis; Xanthenes

2002
The resurgence of disease: social and historical perspectives on the 'new' tuberculosis.
    Social science & medicine (1982), 2002, Volume: 55, Issue:3

    The resurgence of tuberculosis is one of the most serious global public health challenges of the twenty-first century. This paper argues that the decline of tuberculosis since the nineteenth century is far better understood than its resurgence over the last twenty years. It is suggested that insights gained from the historical study of disease may provide a better analytical framework for understanding the contemporary dynamics of disease epidemiology than the current emphasis on the bio-medical and behavioural characteristics of individual patients. It is concluded that tuberculosis research requires a combination of advances in bio-medical knowledge with a broader understanding of the evolving relationship between disease and modern societies.

    Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Attitude to Health; Communicable Disease Control; Cost of Illness; Global Health; Humans; Incidence; Poverty; Public Health; Rifampin; Social Justice; Socioeconomic Factors; Tuberculosis; Tuberculosis, Multidrug-Resistant

2002
Antitubercular therapy decreases nitric oxide production in HIV/TB coinfected patients.
    BMC infectious diseases, 2002, Jul-29, Volume: 2

    Nitric oxide (NO) production is increased among patients with human immunodeficiency virus (HIV) infection and also those with tuberculosis (TB). In this study we sought to determine if there was increased NO production among patients with HIV/TB coinfection and the effect of four weeks chemotherapy on this level.. 19 patients with HIV/TB coinfection were studied. They were treated with standard four drug antitubercular therapy and sampled at baseline and four weeks. 20 patients with HIV infection but no opportunistic infections were disease controls and 20 individuals as healthy controls. Nitrite and citrulline, surrogate markers for NO, were measured it spectrophotometrically.. Mean age of HIV/TB patients was 28.4+6.8 years and CD4 count was 116+36.6/mm3. Mean nitrite level among HIV/TB coinfected was 207.6+48.8 nmol/ml. This was significantly higher than 99.7+26.5 nmol/ml, the value for HIV infected without opportunistic infections and 46.4+16.2 nmol/ml, the value for healthy controls (p value <0.01). Level of HIV/TB coinfected declined to 144.5+ 34.4 nmol/ml at four weeks of therapy (p value < 0.05). Mean citrulline among HIV/TB coinfected was 1446.8+468.8 nmol/ml. This was significantly higher than 880.8+ 434.8 nmol/ml, the value for HIV infected without opportunistic infections and 486.6+212.5 nmol/ml, the value for healthy controls (p value <0.01). Levels of HIV/TB infected declined to 1116.2+388.6 nmol/ml at four weeks of therapy (p value <0.05).. NO production is elevated among patients with HIV infection, especially so among HIV/TB coinfected, but declines significantly following 4 weeks of antitubercular therapy.

    Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Biomarkers; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Citrulline; Drug Administration Schedule; Enzyme Inhibitors; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Mycobacterium; Nitric Oxide; Nitrites; Pyrazinamide; Rifampin; T-Lymphocyte Subsets; Tuberculosis

2002
Tuberculosis and immune thrombocytopenia.
    Haematologica, 2002, Volume: 87, Issue:8

    Topics: Adrenal Cortex Hormones; Antineoplastic Combined Chemotherapy Protocols; Antitubercular Agents; Asparaginase; Comorbidity; Daunorubicin; HIV Infections; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; India; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Purpura, Thrombocytopenic, Idiopathic; Retrospective Studies; Rifampin; Thrombocytopenia; Tuberculosis; Vincristine

2002
Bacteriological conversion in twenty urinary tuberculosis patients treated with ofloxacin, rifampin and isoniazid: a 10-year follow-up study.
    International microbiology : the official journal of the Spanish Society for Microbiology, 2002, Volume: 5, Issue:3

    Twenty patients with urinary tuberculosis were treated with ofloxacin (200 mg/day, 6 months), rifampin (600 mg/day, 3 months) and isoniazid (300 mg/day, 3 months) between 1989 and 1990. All patients were new cases, diagnosed by observation and/or isolation of Mycobacterium tuberculosis in one of the three morning urine samples. Bacteriological culture conversion (negativization) was assessed as a clinical guide of efficacy, comparing it, as the only parameter, against a control group (150 patients) with urinary tuberculosis who received conventional therapy. Bacteriological follow-up studies were performed in both groups monthly for 6 months, then again 6 months later and then every year for 10 years after completion of treatment. In the 20 patients, the initial culture was positive with over 100 colonies per culture (>50%); the smear was positive in 45% of the patients (most were 2+). All strains were susceptible to rifampin, isoniazid and ofloxacin. Two patients discontinued treatment. Beginning with the first month of treatment, the bacteriological conversion was 100%, 89.5% and 100% in the remaining controls. In the control group, which received conventional treatment, the conversion was: 90%, 87%, 93% and 100% in the remaining controls. Treatment with ofloxacin resulted in a bacteriological conversion similar to that following conventional treatment ( p>0.05, Fisher's exact test). After 10 years of patient follow-up, we conclude that ofloxacin, in combination with rifampin and isoniazid (both for 3 months only is effective against M. tuberculosis, providing satisfactory bacteriological and clinical efficacy.

    Topics: Adult; Aged; Anti-Infective Agents, Urinary; Antitubercular Agents; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Ofloxacin; Rifampin; Treatment Outcome; Tuberculosis; Urinary Tract Infections

2002
Acquired rifampin resistance in AIDS-related TB.
    AIDS clinical care, 2002, Volume: 14, Issue:8

    Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Drug Resistance, Microbial; Humans; Male; Rifampin; Tuberculosis

2002
Simultaneous determination of rifampicin and efavirenz in plasma.
    Therapeutic drug monitoring, 2002, Volume: 24, Issue:5

    Complex drug interactions involving antiretroviral agents and drugs for the management of opportunistic infections demand the monitoring of plasma drug concentrations to prevent treatment failure. The high occurrence of tuberculosis in HIV-infected subjects makes the management of HIV treatment complex. Rifampicin, a potent inducer of the cytochrome P 450 metabolic pathway, is a very active antituberculosis drug that accelerates the metabolism of protease inhibitors. Regimens containing efavirenz, a non-nucleoside reverse transcription inhibitor, could be an alternative, but efavirenz plasma concentrations may be altered after the coadministration of rifampicin. Efavirenz is also a cytochrome P 450 inducer and may alter rifampicin plasma levels. Due to the increasing need to monitor plasma concentrations in HIV patients with tuberculosis, a high-performance liquid chromatographic (HPLC) method has been developed to measure rifampicin and efavirenz at the same time in a small amount of sample. This HPLC method is highly sensitive and precise, suitable for pharmacokinetic studies or routine clinical monitoring of rifampicin and efavirenz simultaneously in HIV patients with tuberculosis.

    Topics: Adult; Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Chromatography, High Pressure Liquid; Cyclopropanes; HIV Infections; Humans; Male; Middle Aged; Oxazines; Rifampin; Tuberculosis

2002
The value of urine testing for verifying adherence to anti-tuberculosis chemotherapy in children and adults in Uganda.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2002, Volume: 6, Issue:10

    Mulago Hospital, Kampala, Uganda.. To evaluate the usefulness of urine dipsticks for monitoring adherence to anti-tuberculosis chemotherapy.. In-house urine dipsticks for detection of isoniazid (INH) metabolites were compared to commercial test strips. The value of n-butanol to detect rifampicin was compared to coloration of the urine. Non-adherence was assessed through a questionnaire and reviews of the Mulago Hospital TB register.. Urine was obtained from 236 patients (127 adults and 109 children) on daily chemotherapy. Using commercial test strips as standard, the sensitivity of in-house urine dipsticks was 99.5% and specificity was 96.4%. The sensitivity and the specificity of n-butanol and of coloration of urine to detect rifampicin were low (64.0% and 54.9%, and 85.5% and 64.8%, respectively). Fifty patients (21.2%) admitted non-adherence to treatment during the previous month. An additional 15 (6.8%) were detected through urine testing. Of 911 patients in the TB register of Mulago Hospital who had started treatment in the first 3 months of 2000, 39.7% did not complete their treatment. Two-thirds of these had discontinued treatment in the first 2 months.. In-house INH test strips are as effective as commercially available strips for detecting isoniazid in the urine. They are a simple tool for monitoring adherence. Adherence to anti-tuberculosis chemotherapy as determined by the use of isoniazid test strips and review of the TB register showed poor compliance. Tests for rifampicin are less sensitive and specific.

    Topics: 1-Butanol; Adult; Antitubercular Agents; Child; False Negative Reactions; False Positive Reactions; Humans; Isoniazid; Patient Compliance; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Tuberculosis; Uganda; Urinalysis

2002
Chemotherapeutic activity against murine tuberculosis of once weekly administered drugs (isoniazid and rifampicin) encapsulated in liposomes.
    International journal of antimicrobial agents, 2002, Volume: 20, Issue:4

    Co-administration of isoniazid (INH) and rifampicin (RIF) encapsulated in lung specific stealth liposomes at one third of their recommended doses of 12 and 10 mg/kg b.wt., respectively, exhibited a sustained release of these drugs in plasma (5 days) and lungs, liver and spleen (7 days). At these concentrations, T(max) and area under curve (AUC) values of liposomal drugs were more than that observed with free drugs. The elimination constant (Kel) was higher for liposomal INH (-0.034+/-0.008) and RIF (-0.017+/-0.009) compared with free INH (-0.392) and RIF (-0.243). Chemotherapeutic efficacy of once weekly-administered liposomal drugs for 6 weeks reduced the mycobacterial load significantly in lungs, liver and spleen of infected mice compared with untreated animals.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Carriers; Drug Therapy, Combination; Female; Isoniazid; Liposomes; Lung; Male; Mice; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

2002
Rifampin- and multidrug-resistant tuberculosis in Russian civilians and prison inmates: dominance of the beijing strain family.
    Emerging infectious diseases, 2002, Volume: 8, Issue:11

    Consecutive patient cultures (140) of Mycobacteriium tuberculosis were collected from five Russian civilian and prison tuberculosis laboratories and analyzed for rifampin (rpoB) and isoniazid resistance (inhA, katG, ahpC); transmission of Beijing family isolates; and the importance of prison and previous therapy in drug resistance. Rifampin, isoniazid, and multidrug resistance occurred in 58.2%, 51.6%, and 44.7% of cultures, respectively; 80% of prison cultures were rifampin resistant. Spoligotyping and variable number tandem repeat (VNTR) fingerprinting divided the isolates into 43 groups. Spoligotyping demonstrated that a high proportion (68.1%) of patients were infected with Beijing family strains and that most (69.1%) were rifampin resistant; the highest proportion (81.6%) occurred in prison. One VNTR subgroup (42435) comprised 68 (72.3%) of the Beijing isolates with a small number of IS6110 types; 50 (73.5%) were rifampin resistant. Rifampin-resistant Beijing isolates are dominant within the patient population, especially among prisoners, and threaten treatment programs.

    Topics: Antitubercular Agents; China; Drug Resistance, Multiple, Bacterial; Female; Humans; Male; Minisatellite Repeats; Mutation; Mycobacterium tuberculosis; Prisoners; Rifampin; Russia; Tuberculosis

2002
Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide treatment for latent tuberculosis infection.
    MMWR. Morbidity and mortality weekly report, 2002, Nov-08, Volume: 51, Issue:44

    Reports of fatal and severe liver injury associated with treatment of latent tuberculosis infection (LTBI) with the drug combination rifampin and pyrazinamide (RZ) prompted CDC to issue revised guidelines for the use of this regimen on August 31, 2001. To determine if these revised guidelines were effective in reducing morbidity and mortality, CDC has continued to collect reports on adverse effects associated with this regimen. This update summarizes the results of this ongoing investigation.

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis; United States

2002
Cerebral hemorrhage associated with vitamin K deficiency in congenital tuberculosis treated with isoniazid and rifampin.
    The Pediatric infectious disease journal, 2002, Volume: 21, Issue:11

    We report a male infant with congenital tuberculosis who developed cerebral hemorrhage associated with vitamin K deficiency during treatment with isoniazid and rifampin. Despite an absence of risk factors for vitamin K deficiency, the severe hemorrhagic disorder occurred at 4 months of age. We speculate that vitamin K deficiency in the present case may have resulted from a synergic effect of antituberculosis agents and immaturity of vitamin K metabolism and/or its absorption.

    Topics: Cerebral Hemorrhage; Humans; Infant; Infectious Disease Transmission, Vertical; Isoniazid; Male; Rifampin; Streptomycin; Tuberculosis; Vitamin K; Vitamin K Deficiency

2002
Population pharmacokinetics of antituberculous drugs and treatment of Mycobacterium bovis infection in bongo antelope (Tragelaphus eurycerus isaaci).
    Journal of zoo and wildlife medicine : official publication of the American Association of Zoo Veterinarians, 2002, Volume: 33, Issue:3

    After clinical illness, treatment, and death of a captive male bongo antelope (Tragelaphus eurycerus isaaci) caused by tuberculosis involving Mycobacterium bovis, four tuberculin test reactive captive bongos were treated for 6 mo with isoniazid (INH) and rifampin (RIF) and intermittent single doses of other medications before being euthanized. In all cases, postmortem examination indicated no evidence of active disease and cultures of multiple organs were negative. We present detailed pharmacokinetic (PK) data for amikacin (AMK), ethambutol (EMB), INH, pyrazinamide (PZA), RIF, and levofloxacin in four female bongos. Adequate absorption and serum levels were obtained after parenteral administration of AMK, EMB, and INH and after oral administration of INH and PZA. Parenterally administered drugs were well described by a one-compartment PK model with first-order absorption and elimination processes. Treatment with INH and RIF over a 6-mo period did not result in demonstrable adverse effects. Starting doses of 10-15 mg/kg, i.m., or 30 mg/kg, p.o., of INH, 50 mg/kg, p.o., of EMB, and 25 mg/kg, i.m., s.i.d., of AMK are recommended. The treatment is continued with at least two drugs to which the organism is susceptible for a total treatment length of 6-12 mo. Treatment may be an option to eradicate M. bovis from suspect animals, with carefully administered and monitored drug treatment.

    Topics: Amikacin; Animals; Antelopes; Antitubercular Agents; Area Under Curve; Ethambutol; Female; Isoniazid; Levofloxacin; Male; Mycobacterium bovis; Ofloxacin; Pyrazinamide; Rifampin; Tuberculosis

2002
[Urinary tuberculosis in children. Report of a severe form with a followup of 19 years].
    Progres en urologie : journal de l'Association francaise d'urologie et de la Societe francaise d'urologie, 2002, Volume: 12, Issue:4

    The authors report the case of a 13-year-old migrant girl with urinary tuberculosis, presenting with urinary tract infection, severe frequency and unexplained fever. Intravenous urography demonstrated a non-functioning left kidney and a small fibrotic bladder. Retrograde cystography revealed stage 4 right vesicoureteric reflux. The presence of the Koch bacillus was identified on urine culture. Medical treatment by Rifampicin and Isoniazid was instituted for 18 months. Surgical management, consisting of left nephroureterectomy, subtotal cystectomy with augmentation enterocystoplasty and resection of the pelvic part of the right ureter with ureterointestinal reimplantation, was performed. With a follow-up of 19 years, this patient has normal renal function and no urinary disorders. This case recalls the reality of urinary tuberculosis in children and confirms its insidious nature. The destructive course of urinary tuberculosis may require major urinary tract reconstruction, as in our case.

    Topics: Adolescent; Antitubercular Agents; Female; Follow-Up Studies; Humans; Rifampin; Time Factors; Treatment Outcome; Tuberculosis; Urinary Tract Infections

2002
From the Centers for Disease Control and Prevention. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide treatment for latent tuberculosis infection.
    JAMA, 2002, Dec-18, Volume: 288, Issue:23

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Humans; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis; United States

2002
Tuberculosis in renal transplant recipients: rifampicin sparing treatment protocol.
    International urology and nephrology, 2002, Volume: 34, Issue:4

    The reactivation of mycobacterium infection in renal transplant recipients in developing countries is a common therapeutic dilemma, especially in those patients receiving cyclosporin immunosuppression. The inclusion of rifampicin in the antituberculosis protocol increases the risk of precipitating acute allograft rejection due to its interaction with cyclosporin and also increases the financial burden. We successfully treated 16 patients who developed mycobacterial infection post renal transplant with a rifampicin sparing antituberculosis drug regimen. Pyrexia of unknown origin was the most common manifestation observed and a therapeutic trial with antituberculosis drugs is justified. De novo diabetes mellitus appears to be an added risk factor and increases the susceptibility to mycobacterial infection.

    Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Cyclosporine; Developing Countries; Female; Fever of Unknown Origin; Humans; Immunosuppressive Agents; India; Kidney Transplantation; Male; Retrospective Studies; Rifampin; Tuberculosis

2002
Tuberculosis presenting as immune thrombocytopenic purpura.
    Haematologica, 2002, Volume: 87, Issue:2

    Topics: Anti-Bacterial Agents; Antitubercular Agents; Autoimmune Diseases; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Lymph Nodes; Middle Aged; Mycobacterium tuberculosis; Purpura, Thrombocytopenic, Idiopathic; Pyrazinamide; Pyridoxine; Rifampin; Tuberculosis

2002
Sample survey of drug-resistant tuberculosis in Henan, China, 1996.
    Respirology (Carlton, Vic.), 2002, Volume: 7, Issue:1

    There is little reliable data on the global drug resistance to tuberculosis (TB) as most of the existing data is based upon biased samples, is not standardized or was obtained using poor techniques. For this reason, the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) developed a global project on anti-TB drug resistance surveillance (DRS) in 1994. China joined this project in 1995 and the province of Henan was selected as the first site for collection of representative samples to survey the prevalence of drug-resistant TB.. Standard drug susceptibility testing by the proportion method against streptomycin (S), isoniazid (H), rifampicin (R), and ethambutol (E) was performed with Mycobacterium tuberculosis isolated from 916 new cases and 456 previously treated cases. Treatment outcome of these patients has been evaluated according to the regimens and drug susceptibility patterns.. Drug resistance among new cases to any drug was found to be 43.0% and any resistance: S, 32.5%; H, 31.0%; R, 20.7%; and E, 10.3%. Drug resistance among previously treated cases to any drug was 68.2% and any resistance: S, 52.2%; H, 49.3%; R, 48.3%; and E, 20.4%. The cure rate for new cases was 43.3% and 29.4% for previously treated cases. The poor cure rate resulted mainly from a high defaulter rate.. Drug-resistant TB was found to be highly prevalent in Henan and the cure rate remained poor. The results strongly indicated that Henan should take immediate action to improve the cure rate of patients through expansion of the introduction of the directly observed treatment short-course strategy.

    Topics: Adult; Aged; China; Data Collection; Drug Resistance, Bacterial; Ethambutol; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant; World Health Organization

2002
[Molecular genetic methods for the detection of rifampicin-resistant Mycobacterium tuberculosis strains].
    Vestnik Rossiiskoi akademii meditsinskikh nauk, 2002, Issue:2

    RCR-heteroduplex (GDA) and chip methods were used to detect rifampricin-resistant (RR) and rifampicin-sensitive (RS) Mycobacterium tuberculosis (MTB) in the samples from patients (sputum) and in the clinical isolates of MTB from these patients (MB/BacT liquid medium and Lowenstein Jensen's (LJ) solid medium. The efficiency of detecting RR and RS of MTB (from the sputum) is 100 and 92.3% in the chip and GDA tests, respectively. Correlations between GDA (sputum) and drug test (LJ) were 91.7%, that of chip (sputum) and drug test LJ, 88.5%, chip (sputum) and chip clinical isolates (LJ), 100%. The efficacy of GDA and chip in the detection of RR of MTB strains is under discussion.

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Humans; Molecular Biology; Mycobacterium Infections; Mycobacterium tuberculosis; Point Mutation; Rifampin; Tuberculosis

2002
[Latent tuberculosis infection: diagnosis and treatment].
    Harefuah, 2002, Volume: 141, Issue:3

    The essential component of tuberculosis elimination strategy is to identify and treat persons with latent tuberculosis infection (LTBI) who are at high risk for developing active tuberculosis. The tuberculin skin test is the only proven method for identifying LTBI. Although the specificity and the sensitivity are decreased by cross reaction with BCG vaccination and by non tuberculous mycobacteria, there is no better diagnostic tool. The test's positive predictive value is poor in populations with low risk for tuberculosis. Identification of persons with LTBI is focused on groups at high risk who would benefit from therapy (targeted tuberculin testing). The interpretation of the tuberculin skin test reaction is dependent on the risk factors and the immune status of the patient. For the past 30 years, Isoniazid has been the drug of choice for treating patients with LTBI, but its application has been limited by poor compliance and toxicity. Therefore, there has been interest in the development of shorter course treatments such as rifampin (4 months) or rifampin and pyrazinamide (2 months). We describe the new guidelines for targeted tuberculin testing and different treatment regimens for LTBI as recommend by the American Thoracic Society.

    Topics: Antitubercular Agents; BCG Vaccine; Humans; Isoniazid; Predictive Value of Tests; Pyrazinamide; Rifampin; Tuberculin Test; Tuberculosis

2002
Tuberculosis preventative treatment also prevented diarrhoea in HIV-infected patients in Zambia.
    AIDS (London, England), 2002, Mar-29, Volume: 16, Issue:5

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Diarrhea; Drug Therapy, Combination; Follow-Up Studies; HIV Infections; Humans; Incidence; Isoniazid; Pyrazinamide; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis; Zambia

2002
Noncompliance with tuberculosis treatment by patients at a tuberculosis and AIDS reference hospital in midwestern Brazil.
    The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases, 2002, Volume: 6, Issue:2

    In developing countries, there is little information about the risk factors that predict noncompliance with tuberculosis (TB) treatment in hospitals.. This study analyzes possible factors associated with noncompliance with TB treatment among patients treated at HAA.. A retrospective cohort study was made including all patients who initiated TB treatment at HAA, from January to December 1998. A standard form was used to review medical records and to collect data on each patient. This data was evaluated in comparison with data from the state TB control program.. Of the 341 patients included in the study, 186 (61.2%) were considered cured and 67 (22%) were non-compliant. The factors associated with noncompliance were: previous anti-TB treatment (RR = 1.95, 95% CI 1.29 to 2.93), prescription of drugs other than the standard first-line regimen proposed by the Brazilian Health Ministry (Rifampin + Isoniazide + Pyrazinamide) (RR = 0.54, 95% CI 0.35 to 0.83), the need for hospitalization (RR = 2.19, 95% CI 1.46 to 3.29) and non-inclusion in the hospital s TB Control Program for treatment follow up (RR = 0.54, 95% CI 0.35 to 0.82).. Anuar Auad Hospital (HAA) Goiânia, Goiás, Brazil.. Our results indicate the importance of establishing Tuberculosis Control Programs in hospitals, while paying special attention to patients with risk factors for noncompliance with TB treatment.

    Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Antitubercular Agents; Brazil; Child; Child, Preschool; Female; Hospitals; Humans; Infant; Infant, Newborn; Isoniazid; Male; Medical Records; Middle Aged; Patients; Pyrazinamide; Rifampin; Risk Factors; Treatment Refusal; Tuberculosis

2002
Tuberculosis of the pancreas diagnosed with needle aspiration.
    Scandinavian journal of infectious diseases, 2002, Volume: 34, Issue:4

    Tuberculosis of the pancreas is very rare and can present with many signs and symptoms, including obstructive jaundice, weight loss and a mass in the head of the pancreas. Hence the diagnosis of pancreatic tuberculosis remains a challenge and a high index of suspicion is required. If a tumour is suspected then an ultrasound- or CT-guided fine needle aspiration should be performed. Even if the initial microbiological results are negative, using conventional techniques, PCR can yield more rapid results and avoid an unnecessary laparotomy.

    Topics: Adult; Biopsy, Needle; Diagnosis, Differential; Ethambutol; Humans; Isoniazid; Male; Pancreas; Pancreatic Diseases; Rifampin; Tomography, X-Ray Computed; Tuberculosis

2002
European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.7.2. Late infections. Tuberculosis.
    Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2002, Volume: 17 Suppl 4

    A. Tuberculosis (TB) is not rare after renal transplantation, and can be life-threatening. Treatment of active TB in renal transplant recipients should be the same as in the general population, i.e. 2 months of quadruple therapy combining rifampin, isoniazid, ethambutol and pyrazinamide, followed by a 4-months double therapy with isoniazid and rifampin. The drug ethambutol should not be used initially if the rate of resistance to isoniazid is less than 4% in the community. B. As rifampin will reduce the plasma concentration of calcineurin antagonists and rapamycin, the blood levels of these agents must be monitored closely. Rifabutin may be used as an alternative to rifampin, as this drug is a less potent inducer of the microsomal P450 enzymes. C. Renal transplant candidates and renal transplant recipients should be screened for latent TB infection. Patients considered to have latent TB infection are defined as: (i) those who display a 5 mm (renal transplant recipients) or a 10 mm (dialysis patients) induration after tuberculin skin testing; (ii) those with chest X-ray images suggestive of past TB infection; (iii) those with a history of past TB infection that was not treated adequately; and (iv) those who have been in close contact with infectious patients. The preferred treatment of latent TB infection is isoniazid 300 mg/day for 9 months.

    Topics: Humans; Isoniazid; Kidney Transplantation; Liver; Rifampin; Tuberculin Test; Tuberculosis

2002
Safety and tolerability of intermittent rifampin/pyrazinamide for the treatment of latent tuberculosis infection in prisoners.
    JAMA, 2002, Jul-10, Volume: 288, Issue:2

    Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Maryland; Prisoners; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2002
Therapeutic efficacy of Poly(DL-lactide-Co-Glycolide)-encapsulated antitubercular drugs against Mycobacterium tuberculosis infection induced in mice.
    Antimicrobial agents and chemotherapy, 2001, Volume: 45, Issue:1

    Poly(DL-lactide-co-glycolide) (PLG) microparticles were developed as carriers for isoniazid and rifampin in order to improve compliance of tuberculous chemotherapy. Antitubercular drugs encapsulated in PLG polymers and injected in a single dose subcutaneously resulted in a sustained release (up to 6 weeks) of drugs in various organs of mice. Further, Mycobacterium tuberculosis H(37)Rv-infected animals given a single shot of chemotherapy in PLG microparticles exhibited a better or equivalent clearance of CFU in various organs compared to those given a daily administration of free drugs.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Biocompatible Materials; Drug Combinations; Drug Compounding; Isoniazid; Lactic Acid; Mice; Mycobacterium tuberculosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Rifampin; Tissue Distribution; Tuberculosis

2001
Frequency of rpoB mutations inside and outside the cluster I region in rifampin-resistant clinical Mycobacterium tuberculosis isolates.
    Journal of clinical microbiology, 2001, Volume: 39, Issue:1

    The prevalence of recently described mutation V176F, located in the beginning of the rpoB gene and associated with rifampin resistance and the wild-type cluster I sequence, was determined by analyzing the distribution of rpoB mutations among 80 rifampin (RIF)-resistant Mycobacterium tuberculosis strains isolated in Germany during 1997. The most frequent rpoB mutations were changes in codon 456 (52 isolates, 65%), followed by changes in codon 441 (13 isolates, 16%) and codon 451 (11 isolates, 14%). The V176F mutation was detected in one isolate of the study population and in 5 of 18 RIF-resistant strains with no cluster I mutation from six previously published studies. In three isolates, a mixture of resistant and susceptible subpopulations (heteroresistance) prohibited the detection of rpoB mutations in the initial analysis; however, in these isolates, cluster I mutations could be verified after a passage on RIF-containing medium. IS6110 DNA fingerprinting of 76 strains revealed eight clusters comprising 27 strains with identical restriction fragment length polymorphism patterns that mainly also show identical rpoB mutations and identical or similar drug resistance patterns. In conclusion, our results indicate that the V176F mutation should be included in molecular tests for prediction of RIF resistance in M. tuberculosis. We further demonstrated that heteroresistance caused by a mixture of mycobacterial subpopulations with different susceptibilities to RIF may influence the sensitivity of molecular tests for detection of resistance.

    Topics: Adult; Antitubercular Agents; DNA Transposable Elements; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Female; Humans; Male; Middle Aged; Mutation; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Prevalence; Rifampin; Tuberculosis

2001
Transmission of Mycobacterium tuberculosis to a funeral director during routine embalming.
    Chest, 2001, Volume: 119, Issue:2

    Several studies have shown that funeral directors have an increased risk of tuberculosis (TB). Although there is indirect evidence of transmission of TB from cadavers to mortuary workers, there is only one recently documented case in the literature. We report here another case of occupationally acquired TB in a funeral director, which was confirmed by conventional epidemiology and genotyping. This case illustrates the risk of TB transmission to mortuary workers from routine embalming of deceased TB patients with active disease.

    Topics: Adult; Antibiotics, Antitubercular; DNA Fingerprinting; Drug Resistance, Microbial; Embalming; Fatal Outcome; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Occupational Diseases; Rifampin; Tuberculosis

2001
Acceptability of short-course rifampin and pyrazinamide treatment of latent tuberculosis infection among jail inmates.
    Chest, 2001, Volume: 119, Issue:3

    To determine whether short-course treatment of latent tuberculosis infection (LTBI) with 2 months of rifampin and pyrazinamide (2RZ) is well tolerated and leads to increased treatment completion among jail inmates, a group who may benefit from targeted testing and treatment for LTBI but for whom completion of > or = 6 months of isoniazid treatment is difficult because of the short duration of incarceration.. Prospective cohort.. Large, urban county jail.. All inmates admitted to the Fulton County Jail who had positive tuberculin skin test results, normal findings on chest radiography, and expected duration of incarceration of at least 60 days.. Inmates were offered 2RZ via daily directly observed therapy for 60 doses as an alternative to isoniazid therapy.. We measured the completion of 2RZ treatment and toxicity due to 2RZ treatment during incarceration. From December 14, 1998, through December 13, 1999, 1,360 new inmates had positive tuberculin skin test results and normal findings on chest radiography, and 168 new inmates had an expected duration of incarceration of > or = 60 days. One hundred sixty-six inmates (> 99%) were HIV-negative. Eighty-one inmates (48%) completed 60 doses of 2RZ treatment while incarcerated. Seventy-four inmates (44%) were released before completion. Treatment was stopped in 1 inmate (< 1%) for asymptomatic elevation of asparginine aminotransferase (> or = 10 times normal) and in 12 inmates (7%) for minor complaints. Twenty-one inmates had completed isoniazid treatment in the year before the availability of 2RZ, and 9 inmates completed isoniazid treatment in the year during the availability of 2RZ.. 2RZ was acceptable to and well tolerated by inmates, and led to a marked increase in the number of inmates completing treatment of LTBI during incarceration.

    Topics: Adult; Antitubercular Agents; Cohort Studies; Drug Therapy, Combination; Female; Georgia; Humans; Male; Prisoners; Prisons; Prospective Studies; Pyrazinamide; Rifampin; Time Factors; Tuberculin Test; Tuberculosis

2001
Short-course instead of long-course chemotherapy for smear-negative patients in sub-Saharan Africa.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2001, Volume: 5, Issue:1

    The use of short-course chemotherapy (SCC) in directly-observed treatment, short-course (DOTS) programmes in sub-Saharan Africa was often restricted to patients with infectious and serious forms of tuberculosis, because of high costs of such regimens. With reduced drug prices and wide-scale substitution of thiacetazone by ethambutol in the continuation phase of treatment, various short-course regimens are now available at the same or even lower costs than long-course regimens. Several DOTS programmes are considering extending access to short-course chemotherapy to non-infectious patients, or have done so already. The authors provide an overview of the issues regarding the debate on the introduction of universal SCC in national tuberculosis control programmes in low-income countries in sub-Saharan Africa. They advise on a low-risk strategy to avoid the emergence of rifampicin resistance as a consequence of the wide availability of rifampicin associated with universal short-course, and strengthening of the health system to maintain high performance levels in diagnosis and treatment.

    Topics: Africa South of the Sahara; AIDS-Related Opportunistic Infections; Antitubercular Agents; Cost-Benefit Analysis; Drug Administration Schedule; Humans; National Health Programs; Outcome Assessment, Health Care; Rifampin; Sputum; Tuberculosis; Tuberculosis, Multidrug-Resistant

2001
HIV-1 infection and risk of tuberculosis after rifampicin treatment.
    Lancet (London, England), 2001, Mar-24, Volume: 357, Issue:9260

    Topics: Antibiotics, Antitubercular; HIV Infections; HIV-1; Humans; Recurrence; Rifampin; Tuberculosis

2001
Mutations in the rpoB gene of rifampin-resistant Mycobacterium tuberculosis isolates in Spain and their rapid detection by PCR-enzyme-linked immunosorbent assay.
    Journal of clinical microbiology, 2001, Volume: 39, Issue:5

    Genetic alterations in the rpoB gene were characterized in 50 rifampin-resistant (Rif(r)) clinical isolates of Mycobacterium tuberculosis complex from Spain. A rapid PCR-enzyme-linked immunosorbent assay (ELISA) technique for the identification of rpoB mutations was evaluated with isolates of the M. tuberculosis complex and clinical specimens from tuberculosis patients that were positive for acid-fast bacilli (AFB). Sequence analysis demonstrated 11 different rpoB mutations among the Rif(r) isolates in the study. The most frequent mutations were those associated with codon 531 (24 of 50; 48%) and codon 526 (11 of 50; 22%). Although the PCR-ELISA does not permit characterization of the specific Rif(r) allele within each strain, 10 of the 11 Rif(r) genotypes were correctly identified by this method. We used the PCR-ELISA to predict the rifampin susceptibility of M. tuberculosis complex organisms from 30 AFB-positive sputum specimens. For 28 samples, of which 9 contained Rif(r) organisms and 19 contained susceptible strains, results were concordant with those based on culture-based drug susceptibility testing and sequencing. Results from the remaining two samples could not be interpreted because of low bacillary load (microscopy score of 1+ for 1 to 9 microorganisms/100 fields). Our results suggest that the PCR-ELISA is an easy technique to implement and could be used as a rapid procedure for detecting rifampin resistance to complement conventional culture-based methods.

    Topics: Amino Acid Sequence; Antibiotics, Antitubercular; Base Sequence; Culture Media; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Enzyme-Linked Immunosorbent Assay; Humans; Molecular Sequence Data; Mutation; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Spain; Tuberculosis

2001
Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection--New York and Georgia, 2000.
    MMWR. Morbidity and mortality weekly report, 2001, Apr-20, Volume: 50, Issue:15

    One of the recommended treatments for latent tuberculosis infection (LTBI) is a 9-month regimen of isoniazid (INH); a 2-month regimen of rifampin (RIF) and pyrazinamide (PZA) is an alternative in some instances. In September 2000, a man in New York died of hepatitis after 5 weeks of RIF-PZA, and in December, a woman in Georgia was admitted to a hospital because of hepatitis after 7 weeks of this regimen. This report summarizes the findings of the investigations of these incidents, which underscore the need for clinical monitoring for adverse effects in all patients receiving treatment for LTBI.

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Fatal Outcome; Female; Humans; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis

2001
Increasing resistance of M. tuberculosis to anti-TB drugs in Saudi Arabia.
    International journal of antimicrobial agents, 2001, Volume: 17, Issue:5

    The incidence of drug resistance in Mycobacterium tuberculosis (MTB) isolated from our hospital between April 1996 and March 1998 was compared with an earlier study (1993-1995). Thirty (29.7%) of 101 MTB isolates were resistant to one or more anti-TB drugs and 21 (20%) of 101 were multi-drug resistant M. tuberculosis (MDR-TB). Resistance was most common to isoniazid (28.7%), followed by streptomycin (22.8%) and rifampicin (20.8%). Resistance to pyrazinamide and ethambutol was 7.9 and 6.9%, respectively. There was a three-fold increase in resistance compared with the earlier study.

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prevalence; Pyrazinamide; Rifampin; Saudi Arabia; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2001
Treatment of tuberculosis using a combination of sustained-release rifampin-loaded microspheres and oral dosing with isoniazid.
    Antimicrobial agents and chemotherapy, 2001, Volume: 45, Issue:6

    Previously, we reported on the use of rifampin-loaded microspheres to effectively treat Mycobacterium tuberculosis-infected macrophages and mice. Using similar biocompatible polymeric excipients of lactide and glycolide copolymers, we have increased the rifampin loading of small microsphere formulations (1 to 10 microm) by fourfold. Improved formulations were evaluated individually and in combination with oral regimens of isoniazid for the treatment of Mycobacterium tuberculosis H37Rv-infected mice. Groups (10 mice per group) consisted of mice that received (i) oral dosages of isoniazid (25 to 0.19 mg/kg of body weight/day), (ii) two intraperitoneal injections of rifampin-loaded microspheres on days 0 and 7, (iii) a combination of small rifampin-loaded microspheres on days 0 and 7 and isoniazid orally for 25 days (12.5 to 0.39 mg/kg/day), (iv) placebo injections, and (v) no treatment. Treatment with rifampin-loaded microspheres alone resulted in significant reductions in the numbers of CFU in the lungs and spleens by day 26. A bioassay revealed that plasma rifampin levels from the microspheres exceeded the MICs by more than twofold throughout the 26-day experimental period. Susceptibility testing demonstrated continued sensitivity to rifampin during the treatment period. Whereas isoniazid alone significantly reduced the numbers of CFU for dosages ranging from 12.5 to 1.56 mg/kg, combination therapy with rifampin-loaded microspheres increased the effective range to 0.39 mg/kg. In many cases, complete elimination of CFU was obtained with the combination therapy, something not achieved with most of the single therapies. These results demonstrate the ability to use small microsphere formulations alone to achieve significant results in a murine tuberculosis model and also the ability to use them safely in combination with another antimycobacterial agent.

    Topics: Administration, Oral; Animals; Antibiotics, Antitubercular; Chemistry, Pharmaceutical; Colony Count, Microbial; Delayed-Action Preparations; Drug Therapy, Combination; Female; Injections, Intraperitoneal; Isoniazid; Mice; Microspheres; Mycobacterium tuberculosis; Rifampin; Tuberculosis

2001
Chemotherapy of Mycobacterium tuberculosis infections in mice with a combination of isoniazid and rifampicin entrapped in Poly (DL-lactide-co-glycolide) microparticles.
    The Journal of antimicrobial chemotherapy, 2001, Volume: 47, Issue:6

    Strategies to improve patient compliance in tuberculosis chemotherapy include the use of sustained release drug delivery systems. In this study, Poly (DL-lactide-co-glycolide) (PLG) microparticles containing a combination of isoniazid and rifampicin were developed as sustained release carrier systems. A single dose of PLG microparticles exhibited a sustained release of isoniazid and rifampicin in vivo up to 7 and 6 weeks, respectively. Free drugs (in combination) injected in the same doses were detectable in vivo up to 24 h only. One dose of PLG microparticles cleared bacteria more effectively from lungs and liver in an experimental murine model of tuberculosis after low-dose PLG combination drug therapy and in liver after high-dose PLG combination drug therapy as compared with a daily administration of the free drugs. These results suggest that PLG microparticles offer an improvement for tuberculosis chemotherapy over the conventional treatment.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Capsules; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Drug Therapy, Combination; Female; Isoniazid; Lactic Acid; Male; Mice; Mycobacterium tuberculosis; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Rifampin; Treatment Outcome; Tuberculosis

2001
Treatment of tuberculosis in HIV-infected patients: safety and antiretroviral efficacy of the concomitant use of ritonavir and rifampin.
    AIDS (London, England), 2001, Jun-15, Volume: 15, Issue:9

    Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; CD4 Lymphocyte Count; Consumer Product Safety; Drug Therapy, Combination; HIV Protease Inhibitors; HIV-1; Humans; Pilot Projects; Pyrazinamide; Rifampin; Ritonavir; RNA, Viral; Tuberculosis; Viral Load

2001
Capillary electrophoresis-based heteroduplex analysis with a universal heteroduplex generator for detection of point mutations associated with rifampin resistance in tuberculosis.
    Clinical chemistry, 2001, Volume: 47, Issue:7

    Slab gel heteroduplex analysis (HDA), a popular scanning method for genetic mutations, uses DNA fragments typically generated by PCR to create homo- and heteroduplex molecules with conformational differences and sequence-dependent electrophoretic profiles. Use of a universal heteroduplex generator (UHG) enhances the subtle variations caused by single-base substitutions.. The HDA-UHG slab gel format was modified for an efficient capillary-based method. The effect of staining dyes TOPRO5 and YOPRO1 on the analysis of heteroduplexes was studied, as well as ultraviolet absorbance and laser-induced fluorescence (LIF) detection methods. In addition, the entangled polymers hydroxyethyl cellulose, methyl cellulose, and linear polyacrylamide were evaluated as separation matrices.. This assay was able to detect the presence of Mycobacterium tuberculosis and its rifampin susceptibility directly from clinical specimens in dramatically reduced analysis time (30 min vs 2.5 h). Optimized conditions included 0.3% methyl cellulose as the separation matrix, on-line staining using 1 micromol/L YOPRO1, and LIF detection for quantitative and reproducible analysis of single-base substitutions in the rifampin resistance-determining region of rpoB that give rise to the rifampin-resistant phenotype of M. tuberculosis. We generated 95% confidence limits using the wild-type sequence and used these limits to determine rifampin susceptibility in samples.. Capillary electrophoresis, combined with the HDA-UHG technique, may be of value for rapid and efficient clinical diagnosis of rifampin-resistant tuberculosis strains.

    Topics: Amino Acid Sequence; Antibiotics, Antitubercular; Base Sequence; Coloring Agents; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Electrophoresis, Capillary; Fluorescence; Heteroduplex Analysis; Lasers; Molecular Sequence Data; Mycobacterium tuberculosis; Point Mutation; Reproducibility of Results; Rifampin; Spectrophotometry, Ultraviolet; Tuberculosis

2001
Detection of rifampin-resistant Mycobacterium tuberculosis in sputa by nested PCR-linked single-strand conformation polymorphism and DNA sequencing.
    Journal of clinical microbiology, 2001, Volume: 39, Issue:7

    Either PCR-mediated single strand conformation polymorphism (SSCP) analysis or DNA sequencing of rpoB DNA (157 bp) can be used as a rapid screening method for the detection of mutations related to the rifampin resistance of Mycobacterium tuberculosis. However, due to the nonspecific amplification of rpoB DNA from nontuberculous mycobacteria these methods cannot be directly applied to clinical specimens such as sputa. We developed a nested PCR method that can specifically amplify the rpoB DNA of M. tuberculosis on the basis of rpoB DNA sequences of 44 mycobacteria. Nested PCR-linked SSCP analysis and the DNA sequencing method were applied directly in order to detect M. tuberculosis and determine its rifampin susceptibility in 56 sputa. The results obtained by nested PCR-SSCP and DNA sequencing were concordant with those of conventional drug susceptibility testing and DNA sequencing performed with culture isolates.

    Topics: Antibiotics, Antitubercular; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Humans; Mycobacterium tuberculosis; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Rifampin; Sequence Analysis, DNA; Sputum; Tuberculosis

2001
Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection--New York and Georgia, 2000.
    Canada communicable disease report = Releve des maladies transmissibles au Canada, 2001, Jul-01, Volume: 27, Issue:13

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Fatal Outcome; Female; Georgia; Humans; Liver Function Tests; Male; Middle Aged; New York; Pyrazinamide; Rifampin; Tuberculosis

2001
Tuberculosis and drug resistance among patients seen at an AIDS Reference Center in São Paulo, Brazil.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 2001, Volume: 5, Issue:2

    To assess the frequency of resistance of Mycobacterium tuberculosis to antituberculosis drugs and the factors associated with it among patients with tuberculosis (TB) and acquired immunodeficiency syndrome (AIDS).. The medical records of TB and AIDS cases diagnosed from 1992 to 1997 in a public service for AIDS care were reviewed.. Resistance was diagnosed in 82 (19%) of 431 cases. The mean and median values between the diagnosis of AIDS and the diagnosis of TB were 214.8 days and 70.5 days, respectively. Multidrug-resistant TB (MDR TB) occurred in 11.3% of cases. Of the 186 patients with no previous treatment, 13 (6.9%) presented primary MDR TB. Of the 90 cases with previous treatment, six (6.7%) presented monoresistance to rifampin and 27 (30%) presented MDR TB. The distribution of cases with sensitive and resistant M. tuberculosis strains was homogeneous in terms of the following variables: gender, age, category of exposure to human immunodeficiency virus (HIV), alcoholism, and homelessness. Multivariate analysis showed an association between resistance and the two following variables: previous treatment and duration of AIDS prior to TB exceeding 71 days. The rates of primary multiresistance and of monoresistance to rifampin were higher than those detected in HIV-negative patients in Brazil.. In this patient series, M. tuberculosis resistance was predominantly of the acquired type, and resistance was independently associated with previous treatment for TB and with duration of AIDS prior to TB exceeding 71 days.

    Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antitubercular Agents; Brazil; Community Health Centers; Confidence Intervals; Drug Resistance, Microbial; Drug Resistance, Multiple; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Odds Ratio; Rifampin; Time Factors; Tuberculosis

2001
Tuberculous otitis media -- a diagnostic dilemma.
    Auris, nasus, larynx, 2001, Volume: 28, Issue:3

    Tuberculous otitis media can provide a diagnostic challenge even to the most astute and experienced clinician. The rarity of the condition and its propensity to masquerade as commoner otological conditions further delays diagnosis and treatment. We present the case of a 22-year-old female who presented with chronic aural discharge, unilateral hearing loss and recurrent hemifacial paralysis. The paper highlights the difficulty in diagnosis and stresses the need for a high index of suspicion in cases resistant to the common methods of treatment.

    Topics: Adult; Antitubercular Agents; Diagnosis, Differential; Drug Therapy, Combination; Ear Diseases; Facial Paralysis; Female; Hearing Loss; Hearing Loss, Conductive; Humans; Isoniazid; Mycobacterium Infections; Otitis Media; Pyrazinamide; Rifampin; Tinnitus; Tuberculosis

2001
Airways delivery of rifampicin microparticles for the treatment of tuberculosis.
    The Journal of antimicrobial chemotherapy, 2001, Volume: 48, Issue:3

    A Mycobacterium tuberculosis (H37Rv)-infected guinea pig model was used to screen for targeted delivery to the lungs by insufflation (with lactose excipient) or nebulization, of either rifampicin alone, rifampicin within poly(lactide-co-glycolide) microspheres (R-PLGA) or polymer microparticles alone (PLGA). Animals treated with single and double doses of R-PLGA microspheres exhibited significantly reduced numbers of viable bacteria, inflammation and lung damage compared with lactose-, PLGA- or rifampicin-treated animals 28 days post-infection (P < 0.05). Two doses of R-PLGA resulted in reduced splenic enlargement. These studies support the potential of R-PLGA delivered to the lung to treat pulmonary tuberculosis.

    Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Drug Delivery Systems; Guinea Pigs; Insufflation; Male; Nebulizers and Vaporizers; Particle Size; Rifampin; Tuberculosis

2001
US guidelines for treatment of latent tuberculosis revised.
    Lancet (London, England), 2001, Sep-08, Volume: 358, Issue:9284

    Topics: Chemical and Drug Induced Liver Injury; Drug Combinations; Humans; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis; United States

2001
Efforts of the WHO/IUATLD to solve the problem of poor bioavailability of rifampicin from FDC anti-tuberculosis products: is a change required in the direction of the approach in view of recent findings?
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2001, Volume: 5, Issue:9

    Topics: Antitubercular Agents; Biological Availability; Drug Combinations; Humans; Rifampin; Tuberculosis; World Health Organization

2001
Treatment of tuberculosis in Haiti.
    American journal of public health, 2001, Volume: 91, Issue:10

    Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Haiti; Health Services Research; Humans; Isoniazid; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

2001
Adverse reaction to antimycobacterials administered as a combination tablet with no reaction to the same drugs in isolation.
    Sexually transmitted infections, 2001, Volume: 77, Issue:5

    Topics: Adult; Antitubercular Agents; Drug Combinations; Drug Therapy, Combination; HIV Seropositivity; Humans; Isoniazid; Male; Rifampin; Tablets; Tuberculosis

2001
[Molecular medicine and treatment of tuberculosis].
    Problemy tuberkuleza, 2001, Issue:5

    Topics: Adjuvants, Immunologic; Animals; Antibiotics, Antitubercular; Antitubercular Agents; BCG Vaccine; Female; Genetic Engineering; Humans; Isoniazid; Male; Mice; Mutation; Mycobacterium tuberculosis; Polymorphism, Genetic; Rifampin; Risk Factors; Tuberculosis

2001
From the Centers for Disease Control and Prevention. Update: Fatal and severe liver injuries associated with Rifampin and Pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations--United States, 2001.
    JAMA, 2001, Sep-26, Volume: 286, Issue:12

    Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis

2001
Tuberculosis: guidelines changed for latent TB treatment.
    AIDS treatment news, 2001, Sep-21, Issue:371

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Drug Therapy, Combination; Humans; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis; United States

2001
Respirable PLGA microspheres containing rifampicin for the treatment of tuberculosis: screening in an infectious disease model.
    Pharmaceutical research, 2001, Volume: 18, Issue:9

    Targeted delivery of rifampicin loaded microspheres to the alveolar macrophage, the host cell for Mycobacterium tuberculosis (MTB), may be an effective targeted approach to pulmonary tuberculosis therapy. A guinea pig infection model has been adopted as a post-treatment screening method for antimicrobial effect. Insufflation and nebulization methods of drug delivery were evaluated.. Rifampicin alone (RIF, 1.03-1.72 mg/kg), within poly(lactide-co-glycolide) microspheres (R-PLGA, equivalent to 1.03-1.72 mg/kg) or polymer microparticles alone (PLGA) were administered by insufflation or nebulization, 24 h before bacterial aerosol exposure. Animals were infected with an aerosol containing a small number (2 x 10(5) cfu/mL) of virulent H37Rv strain of MTB. Lung and spleen tissue samples were collected 28 days after infection for quantitative bacteriology and histopathological analysis.. There was a dose-effect relationship between insufflated R-PLGA and burden of bacteria in the lungs. In addition, guinea pigs treated with R-PLGA had a significantly smaller number of viable bacteria (P < 0.05), reduced inflammation and lung damage than lactose or saline control, PLGA or RIF treated animals.. These studies indicate the potential of R-PLGA, delivered by insufflation or nebulization directly to the lungs, to affect the early development of pulmonary TB.

    Topics: Administration, Inhalation; Aerosols; Animals; Antibiotics, Antitubercular; Colony Count, Microbial; Dose-Response Relationship, Drug; Drug Carriers; Drug Compounding; Drug Delivery Systems; Drug Evaluation, Preclinical; Guinea Pigs; Indicators and Reagents; Lactic Acid; Lung; Macrophages; Male; Microbial Sensitivity Tests; Microspheres; Mycobacterium tuberculosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Rifampin; Tuberculosis

2001
Effectiveness of once-weekly rifapentine and moxifloxacin regimens against Mycobacterium tuberculosis in mice.
    Antimicrobial agents and chemotherapy, 2001, Volume: 45, Issue:12

    Mice infected with 1.6 x 10(7) CFU of Mycobacterium tuberculosis were treated 14 days later for 6 months with a regimen of once-weekly 10 mg of rifapentine and 75 mg of isoniazid per kg of body weight supplemented with either 150 mg of streptomycin per kg or 100 mg of moxifloxacin per kg during either both the 2-week daily initial and once-weekly continuation phases or only in the daily 2-week initial phase. On completion of treatment, all lung cultures were negative, except for three mice, each with a single colony: two whose rifapentine-isoniazid regimen was supplemented with streptomycin during the whole course of therapy and one whose rifapentine-isoniazid regimen had no initial daily phase, but was supplemented with streptomycin and moxifloxacin during the whole course of therapy. After 3 months of follow-up, positive lung cultures were obtained from 61 and 56% of mice supplemented with streptomycin during either the full course of therapy or only the daily 2-week initial phase, respectively, and 15 and 50% of mice supplemented with moxifloxacin during either the full course of therapy or only the daily 2-week initial phase, respectively. These results suggest that moxifloxacin has sterilizing activity against M. tuberculosis.

    Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Colony Count, Microbial; Drug Resistance, Microbial; Female; Fluoroquinolones; Isoniazid; Lung; Mice; Moxifloxacin; Mycobacterium tuberculosis; Organ Size; Quinolines; Rifampin; Spleen; Streptomycin; Survival Rate; Tuberculosis

2001
Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis.
    Journal of acquired immune deficiency syndromes (1999), 2001, Dec-15, Volume: 28, Issue:5

    To determine whether rifampicin reduces serum concentrations of nevirapine and whether nevirapine modifies serum concentrations of rifampicin, levels of these agents were determined at steady state by high-performance liquid chromatography in 10 HIV-infected patients with tuberculosis. The median area under the curve (AUC) 0-12h of nevirapine before and after rifampicin was 56.2 and 32.8 microg/ml per hour, respectively ( p =.04). This represents a 31% reduction in serum nevirapine concentrations. The C(max) decreased from 5.6 to 4.5 microg/ml ( p =.04), which represented a 36% reduction. A 21% decrease in the C(min) was not statistically significant. Exposure to rifampicin did not significantly differ between those patients who were receiving and were not receiving nevirapine. However, our study shows that rifampicin reduces serum exposure to nevirapine. The clinical implications for this reduction remain to be established. Given that the lowest trough serum concentration of nevirapine exceeded by more than 40 times the protein binding adjusted median infective dose (IC(50)) of wild-type HIV in all patients, we suggest that there is no need to increase nevirapine dosage when it is given with rifampicin.

    Topics: Anti-HIV Agents; Antibiotics, Antitubercular; Chromatography, High Pressure Liquid; Drug Interactions; HIV Infections; Humans; Nevirapine; Rifampin; Tuberculosis

2001
[Rapid detection of Mycobacterium tuberculosis resistance to rifampin using DNA chip].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 2001, Volume: 24, Issue:9

    To develop a new method, DNA chip, which can be used for rapid detection of Mycobacterium tuberculosis resistance to RFP.. Designing probe according to the sequence of Mycobacterium tuberculosis rpoB gene and fabricating DNA chip. The DNA fragment which contains hot mutation sites of rpoB gene was labelled with cy5 fluorescence and amplified by PCR technique. Then it was hybridized with DNA chip. DNA sequence was used as the control.. 14 strains were detected out of 17 randomly selected Mycobacterium tuberculosis resistant to RFP using DNA chip. The efficiency was 83%. A little bit DNA in the sick sputa was sufficient for drug resistance detection without being incubated.. It showed higher specialty and sensitivity using DNA chip to detect Mycobacterium tuberculosis resistance to RFP. This method was rapid and accurate and could be used for clinical detection of RFP-resistant strains.

    Topics: Antibiotics, Antitubercular; DNA, Bacterial; Drug Resistance, Microbial; Humans; Mutation; Mycobacterium tuberculosis; Oligonucleotide Array Sequence Analysis; Rifampin; Tuberculosis

2001
Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations--United States, 2001.
    MMWR. Morbidity and mortality weekly report, 2001, Aug-31, Volume: 50, Issue:34

    During February 12-August 24, 2001, a total of 21 cases of liver injury associated with a 2-month rifampin-pyrazinamide (RIF-PZA) regimen for the treatment of latent tuberculosis infection (LTBI) was reported to CDC. These 21 cases are in addition to two previously reported RIF-PZA-associated cases. Cases of liver injury have occurred each year since 1999. CDC also received reports of 10 cases associated with other LTBI treatment regimens; however, risk for liver injury cannot be compared among treatment regimens in part because the number of patients treated for LTBI with each treatment regimen is unknown. This report provides preliminary information about the 21 cases associated with RIF-PZA and the revised recommendations on selecting appropriate LTBI therapy for patients and monitoring the use of RIF-PZA to treat LTBI. In most instances, the 9-month isoniazid (INH) regimen is preferred for the treatment of patients with LTBI. RIF-PZA may be used in selected cases and requires more intensive clinical and laboratory monitoring than previously recommended.

    Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis

2001
Management of tuberculosis.
    The New England journal of medicine, 2001, Nov-15, Volume: 345, Issue:20

    Topics: Antibiotics, Antitubercular; Drug Interactions; Drug Therapy, Combination; Humans; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

2001
Management of tuberculosis.
    The New England journal of medicine, 2001, Nov-15, Volume: 345, Issue:20

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Humans; Isoniazid; Patient Compliance; Rifampin; Sensitivity and Specificity; Time Factors; Tuberculosis; Urinalysis

2001
Acute renal failure complicating rifampicin therapy.
    The Journal of the Association of Physicians of India, 2001, Volume: 49

    Since 1971, 55 case-reports of rifampicin-induced acute renal failure (ARF) have been published. Covic et al described 60 consecutive cases of rifampicin-induced ARF during a period of eight years (1987-1995) from Iasi Dialysis Centre, Romania. The systenic data on this condition are not available, in view of the anecdotal nature of the observation from our country.. The aims of study were to analyze clinical features, course and outcome of ARF complicating rifampicin therapy at our centre.. We retrospectively studied prevalence, clinical presentations and renal histology and outcome of 11 cases (eight males, three females, aged 42-72 years) who were referred to Nephrology Unit of University Hospital, Varanasi for acute renal failure following retreatment with rifampicin between period of 1994-1999.. The gastrointestinal symptoms (abdominal pain, nausea and vomiting) and 'flu like' (fever, weakness and body ache) syndrome were the most frequent presenting features. The clinical signs of intravascular hemolysis were observed in four cases. The commonest laboratory findings included: Anaemia (7), leukocytosis (5), thrombocytopenia (3) and toxic hepatitis in (2) patients. Toxic hepatitis, hemolysis and ARF was seen in one patient in combination. The typical clinical features of allergic interstitial nephritis and acute tubular necrosis were seen in six and two patients respectively. Renal biopsy in three cases revealed; crescentic GN (1) and ATN in (2) patients. Acute renal failure complicating rifampicin accounted for 1.8% (11/607) of all ARF cases hospitalized in our centre during the study period. Renal function returned to normal in nine cases and one patient died on account of hepatic failure (toxic hepatitis). The patients with crescentic GN remained anuric and became dialysis dependent. Thus, clinical course of rifampicin induced ARF was favourable; with only one mortality, compared to a 18% mortality rate among all ARF patients.. Acute renal failure complicating rifampicin therapy is not an uncommon condition, and typically occurs after reintroduction of rifampicin. The renal prognosis is usually favourable. Intermittent or interrupted therapy appears to be a significant risk factor for the development of acute renal failure.

    Topics: Acute Kidney Injury; Adult; Age Distribution; Aged; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Incidence; India; Male; Middle Aged; Retrospective Studies; Rifampin; Risk Factors; Sex Distribution; Tuberculosis

2001
Rapid, efficient detection and drug susceptibility testing of Mycobacterium tuberculosis in sputum by microscopic observation of broth cultures. The Tuberculosis Working Group in Peru.
    Journal of clinical microbiology, 2000, Volume: 38, Issue:3

    Inexpensive, rapid, and reliable methods of detecting infection by and drug susceptibility of Mycobacterium tuberculosis (MTB) are crucial to the control of tuberculosis. The novel microscopic observation broth-drug susceptibility assay (MODS) detects early growth of MTB in liquid medium, allowing more timely diagnosis and drug susceptibility testing. Sputum samples from hospitalized patients in Peru were analyzed by using stains, culture, and PCR. Sensitivity of MODS (92%) compared favorably with the most sensitive of the other culture methods (93%). Sputum samples positive for tuberculosis were tested for susceptibility to isoniazid and rifampin with the microwell alamar blue assay (MABA) and MODS. In 89% of cases, there was concordance between MODS and MABA. Of the diagnostic and susceptibility testing methods used, MODS yielded results most rapidly (median, 9.0 and 9.5 days, respectively). MODS is a rapid, inexpensive, sensitive, and specific method for MTB detection and susceptibility testing; it is particularly appropriate for use in developing countries burdened by significant infection rates and increasing numbers of multiple-drug-resistant cases.

    Topics: Antitubercular Agents; Bacterial Typing Techniques; Costs and Cost Analysis; Drug Resistance, Microbial; Humans; Inpatients; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Peru; Polymerase Chain Reaction; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis

2000
[Molecular mechanisms of mycobacterium tuberculosis strains resistance to rifampicin and isoniazid].
    Problemy tuberkuleza, 2000, Issue:1

    The levels and spectra of the drug resistance of clinical M. tuberculosis strains were defined. There was a relationship of treatment regimens to the drug resistance of mycobacteria isolated from the strains. The fragments of genes rpoB, inhA, and katG were analyzed by polymerase chain reaction and sequencing. In addition to earlier identified substitutions, new mutations were found in rpoB: A-->T/233, G-->A/395, C-->T/232, G-->T/202, C-->T/221, C-->T/260, GA-->TT/202-203, delta 199-207 ATGGACCAG. Strain 12/7 was found to have 30 point mutations leading to substitution of only 3 amino acids and to have GGG(Gly)354 deletion as well. Most mutations in this strain are "silent". Substitutions at 944 and 463 positions were revealed in katG.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Bacterial Proteins; Colony Count, Microbial; DNA Primers; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Microbial; Humans; Isoniazid; Mycobacterium tuberculosis; Oxidoreductases; Peroxidases; Point Mutation; Polymerase Chain Reaction; Rifampin; Tuberculosis

2000
Antituberculosis activity of once-weekly rifapentine-containing regimens in mice. Long-term effectiveness with 6- and 8-month treatment regimens.
    American journal of respiratory and critical care medicine, 2000, Volume: 161, Issue:5

    The effectiveness of various once-weekly 10 mg/kg rifapentine (P)- containing regimens for treatment of tuberculosis was assessed in mice infected intravenously with 4.3 x 10(6) colony-forming units (cfu) of Mycobacterium tuberculosis H37Rv, and treated 14 d later with various combinations of rifampin (R), P, isoniazid (H), pyrazinamide (Z), ethambutol (E), or streptomycin (S). Control mice treated daily with either 2-mo HRZ + 4-mo HR or 2-mo HRZ + 6-mo HE were rendered spleen and lung culture-negative at 6 mo and 8 mo, respectively. Treatment failure with emergence of R-resistant bacilli occurred in all mice given once-weekly monotherapy with P for 6 mo. Once-weekly PH treatment was successful at 6 mo when it was preceded by a 2-mo daily phase with HRZ. When the initial daily phase was reduced to 2 wk, once-weekly PH-containing treatment was successful, at 6 mo, only if it was supplemented with S during the initial daily and the once-weekly phases, and at 8 mo if it was supplemented with daily H during the once-weekly phase. Without these supplements, once-weekly treatment failed in some mice with selection of R-resistant or H-resistant mutants.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Female; Isoniazid; Lung; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Spleen; Streptomycin; Tuberculosis

2000
Targeted tuberculin testing and treatment of latent tuberculosis infection. American Thoracic Society.
    MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports, 2000, Jun-09, Volume: 49, Issue:RR-6

    This statement provides new recommendations for targeted tuberculin testing and treatment regimens for persons with latent tuberculosis infection (LTBI) and updates previously published guidelines (1,2). This statement is issued in recognition of the importance of these activities as an essential component of the TB Elimination Strategy promoted by the U.S. Public Health Service Advisory Council on the Elimination of Tuberculosis, and reports the deliberations of expert consultants convened by the American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Isoniazid for 6-12 mo has been the mainstay of treatment for LTBI in the United States for more than 30 yr. However, the application of isoniazid for LTBI has been limited because of poor adherence, due to the relatively long duration of treatment required, and because of concerns about toxicity. Therefore, there has been interest in the development of shorter, rifampin-based regimens as alternatives to isoniazid for the treatment of LTBI. During the past decade, a series of studies of "short-course" treatment of LTBI in persons with human immunodeficiency virus (HIV) infection has been undertaken. The results of these trials have recently become available, and the in-depth analyses of these and prior studies of isoniazid form the scientific basis of the treatment guidelines presented in this report. In addition, many changes to previous recommendations regarding testing for and treatment of LTBI are presented (Table 1).

    Topics: Antitubercular Agents; Humans; Isoniazid; Rifampin; Tuberculin Test; Tuberculosis

2000
Trends in antituberculosis drug resistance in Karonga District, Malawi, 1986-1998.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2000, Volume: 4, Issue:8

    Karonga District, Malawi.. To examine long term trends in initial and acquired resistance to antituberculosis drugs in a rural area of Africa.. Monitoring of all patients with culture-confirmed tuberculosis 1986-1998.. Initial drug resistance results were available for 1121 patients. The proportion resistant to any of the first line drugs (streptomycin, isoniazid, rifampicin or ethambutol) was 9.6%, and to isoniazid 7.2%. Initial resistance to at least isoniazid and rifampicin (multidrug resistance) was seen in only six patients. No initial resistance to ethambutol was found. There was no significant change in initial drug resistance over time. Overall, 22/120 (18%) patients with previous treatment were resistant to at least one drug; only one had multidrug resistance. Acquired resistance decreased over the period of the study. There were no associations between age, sex or human immunodeficiency virus (HIV) status and initial or acquired drug resistance.. Changes in acquired resistance may reflect the recent performance of a control programme more quickly than those in initial resistance. It is encouraging that acquired resistance decreased and levels of multidrug resistance were low despite more than a decade of use of rifampicin. The lack of association between HIV and drug resistance confirms findings elsewhere in Africa.

    Topics: Adult; Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Female; HIV Seropositivity; Humans; Isoniazid; Malawi; Male; Microbial Sensitivity Tests; Middle Aged; Recurrence; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant

2000
rpoB mutations as an epidemiologic marker in rifampin-resistant Mycobacterium tuberculosis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 2000, Volume: 4, Issue:8

    Cases of rifampin-resistant Mycobacterium tuberculosis from the prison population in Madrid and from the general population in Spain.. To identify the rpoB mutations associated with resistance to rifampin and to investigate rpoB genotyping as an epidemiological marker in rifampin-resistant M. tuberculosis.. Twenty-nine rifampin-resistant clinical isolates of M. tuberculosis, 15 obtained from the prison population in Madrid and 14 from the general population in Spain, were characterized by sequence analysis of the 81-bp core region of the rpoB gene and IS6110 DNA fingerprinting.. All the isolates had mutations in rpoB, with those in codon 531 accounting for 41% of the total. Twenty-three (79%) isolates were highly resistant to rifampin (minimum inhibitory concentration > or = 64 mg/L). Nineteen different IS6110 fingerprints were observed: one was shared by seven isolates, one by three, two by two, and 15 were unique. Two IS6110 clusters could be divided into subclusters on the basis of rpoB analysis. Epidemiologic links were identified among patients whose isolates had identical IS6110 patterns and rpoB genotypes, but not between those with identical IS6110 patterns and different rpoB genotypes.. Characterization of rpoB mutations can provide information about susceptibility to rifampin and be a useful epidemiological tool for discrimination of rifampin-resistant strains of M. tuberculosis with identical IS6110 fingerprints.

    Topics: Antibiotics, Antitubercular; Biomarkers; DNA Fingerprinting; Drug Resistance, Microbial; Genotype; Mutation; Mycobacterium tuberculosis; Prisoners; Rifampin; Sequence Analysis, DNA; Spain; Tuberculosis

2000
Primary and acquired resistance of Mycobacterium tuberculosis in Western Mexico.
    Microbial drug resistance (Larchmont, N.Y.), 2000,Summer, Volume: 6, Issue:2

    Resistance of Mycobacterium tuberculosis to antimycobacterial agents is a worldwide problem. The proposite of this study was to analyze the current resistance patterns of patients with initial episodes, as well as relapses, due to M. tuberculosis in western Mexico. From January 1993 to February 1999 a total of 237 strains of M. tuberculosis (120 from initial cases and 117 from relapse cases) were analyzed. Two hundred and four (86%) strains were isolated from the lower respiratory tract, and 33 strains (14%) from extrapulmonary sites. Twenty-three percent of M. tuberculosis isolated from patients with initial episodes were resistant to both isoniazid and rifampin, and 52% of M. tuberculosis isolated from relapse cases were also resistant to both isoniazid and rifampin.

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Drug Resistance, Multiple; Humans; Isoniazid; Mexico; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Recurrence; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

2000
Evaluation of rifalazil in a combination treatment regimen as an alternative to isoniazid-rifampin therapy in a mouse tuberculosis model.
    Antimicrobial agents and chemotherapy, 2000, Volume: 44, Issue:11

    The newer rifamycin, rifalazil (RLZ) (previously known as KRM-1648), has been shown in prior experiments to be a highly potent drug against Mycobacterium tuberculosis. In this report, we studied the efficacy of RLZ in combination with pyrazinamide (PZA) and ethambutol (EMB) in a long-term in vivo experiment and compared their activity with the isoniazid (INH)-rifampin (RIF) combination which is presently used in the clinic. Combinations of RLZ with PZA alone or with both PZA and EMB were both found to have sterilizing activities comparable to that of the INH-RIF combination but significantly better activity with respect to relapse of infection. These results suggest that RLZ, or other agents with similar activity, could be combined with available agents to act as a potential alternative drug regimen to the currently used INH-RIF combination.

    Topics: Animals; Antitubercular Agents; Colony-Forming Units Assay; Disease Models, Animal; Drug Therapy, Combination; Ethambutol; Female; Isoniazid; Mice; Pyrazinamide; Rifampin; Rifamycins; Tuberculosis

2000
Second episode of tuberculosis in an HIV-infected child: relapse or reinfection?
    The Journal of infection, 2000, Volume: 41, Issue:1

    We report a case of an HIV-infected child with a second episode of tuberculosis 22 months after completing antituberculosis treatment. DNA fingerprinting of organisms from both episodes showed an identical strain of Mycobacterium tuberculosis. We believe this to be the first case of confirmed relapsed tuberculosis in an HIV-infected child, and suggest that a longer course of antituberculosis treatment be given to such children. ¿ 2000 The British Infection Society.

    Topics: AIDS-Related Opportunistic Infections; Amoxicillin-Potassium Clavulanate Combination; Antibiotics, Antitubercular; Antitubercular Agents; Child, Preschool; DNA, Bacterial; Drug Therapy, Combination; Ethionamide; HIV; HIV Infections; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Pyrazinamide; Radiography, Thoracic; Rifampin; Secondary Prevention; South Africa; Tomography, X-Ray Computed; Tuberculin Test; Tuberculosis; Tuberculosis, Meningeal

2000
Detection of mRNA transcripts and active transcription in persistent Mycobacterium tuberculosis induced by exposure to rifampin or pyrazinamide.
    Journal of bacteriology, 2000, Volume: 182, Issue:22

    Mycobacterium tuberculosis can persist in an altered physiological state for many years after initial infection, and it may reactivate to cause active disease. An analogous persistent state, possibly consisting of several different subpopulations of bacteria, may arise during chemotherapy; this state is thought to be responsible for the prolonged period required for effective chemotherapy. Using two models of drug-induced persistence, we show that both microaerophilic stationary-phase M. tuberculosis treated with a high dose of rifampin in vitro and pyrazinamide-induced persistent bacteria in mice are nonculturable yet still contain 16S rRNA and mRNA transcripts. Also, the in vitro persistent, plate culture-negative bacteria incorporate radioactive uridine into their RNA in the presence of rifampin and can rapidly up-regulate gene transcription after the replacement of the drug with fresh medium and in response to heat shock. Our results show that persistent M. tuberculosis has transcriptional activity. This finding provides a molecular basis for the rational design of drugs targeted at persistent bacteria.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Disease Models, Animal; Drug Resistance, Microbial; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; RNA, Bacterial; RNA, Messenger; RNA, Ribosomal, 16S; Time Factors; Transcription, Genetic; Tuberculosis

2000
Treatment of tuberculosis: a well-standardised protocol.
    Prescrire international, 2000, Volume: 9, Issue:48

    (1) The recommended treatment protocol for the vast majority of cases of tuberculosis is a 6-month course of isoniazid and rifampicin, plus pyrazinamide and ethambutol for the first two months. (2) This protocol is recommended for both adults and children, and for both pulmonary and extra-pulmonary disease (except for central nervous system involvement). (3) Good adherence to this protocol induces relapse-free recovery in more than 97% of patients with tuberculosis due to non resistant strains.

    Topics: Adult; Child; Clinical Protocols; Ethambutol; France; Humans; Isoniazid; Pyrazinamide; Rifampin; Time Factors; Tuberculosis; United Kingdom; United States; World Health Organization

2000
[Desensitization therapy for antituberculous drugs].
    Kekkaku : [Tuberculosis], 2000, Volume: 75, Issue:9

    We retrospectively evaluated the effectiveness of desensitization therapy for antituberculous drugs (Rifampicin and Isoniazid) in 28 cases (29 episodes) with adverse reactions to these drugs. Desensitization therapy for RFP was performed in 23 cases (24 episodes) with administration of a first dose of 1-150 mg and a final dose of 300-450 mg for 1-29 days. The success rate of this therapy was 79% (19 of 24 episodes). Desensitization therapy for INH was performed in 12 cases with administration of a first dose of 2.5-100 mg and a final dose of 200-400 mg for 3-25 days. The success rate of this therapy was 83% (10 of 12 cases). Based on a comparative study of cases between successful and unsuccessful desensitization to RFP and INH it was concluded that there were no significant differences with regard to allergic history, adverse effects and their periods of appearance, the first dose and final dose of administration and the interval of administration, starting periods of the desensitization therapy and the periods of appearance of adverse effects due to this therapy. We evaluated desensitization therapy for two antituberculous drugs (RFP and INH) for tuberculous patients for whom the use of such drugs was restricted because of adverse effects, and we found it is a useful treatment, showing a high rate of success (80%).

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Desensitization, Immunologic; Female; Humans; Isoniazid; Male; Middle Aged; Retrospective Studies; Rifampin; Tuberculosis

2000
Tuberculous abscess of the graft in a renal transplant recipient after chronic rejection: case report.
    Transplantation proceedings, 2000, Volume: 32, Issue:7

    Topics: Abscess; Adult; Antitubercular Agents; Chronic Disease; Drug Therapy, Combination; Ethambutol; Female; Graft Rejection; Humans; Isoniazid; Kidney Transplantation; Nephrectomy; Pyrazinamide; Reoperation; Rifampin; Tuberculosis

2000
Tuberculosis after renal transplantation.
    Transplantation proceedings, 2000, Volume: 32, Issue:7

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Humans; Incidence; India; Isoniazid; Kidney Transplantation; Living Donors; Male; Postoperative Complications; Pyrazinamide; Pyridoxine; Retrospective Studies; Rifampin; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

2000
Contralateral pleural effusion during chemotherapy for tuberculous pleural effusion.
    The Medical journal of Malaysia, 2000, Volume: 55, Issue:3

    A 25 year old woman developed a right pleural effusion 6 weeks after commencement of short course chemotherapy for left sided tuberculous pleural effusion. Since the patient improved following continuation of the same treatment, it is presumed to be a case of paradoxical response to anti-tuberculosis treatment.

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Isoniazid; Pleural Effusion; Pyrazinamide; Radiography, Thoracic; Rifampin; Tuberculosis

2000
Revised treatment and testing guidelines for latent tuberculosis infection.
    Report on medical guidelines & outcomes research, 2000, Apr-27, Volume: 11, Issue:9

    Topics: Adolescent; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Child; Child, Preschool; Humans; Isoniazid; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Risk Factors; Societies, Medical; Tuberculosis; United States

2000
Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors.
    MMWR. Morbidity and mortality weekly report, 2000, Mar-10, Volume: 49, Issue:9

    A previously published report provided guidelines for managing the pharmacologic interactions that can result when patients receive protease inhibitors and nonnucleoside reverse transcriptase inhibitors (NNRTIs) for treatment of human immunodeficiency virus (HIV) infection together with rifamycins for the treatment of tuberculosis (TB). Protease inhibitors and NNRTIs are antiretroviral agents that are substrates that may inhibit or induce cytochrome P-450 isoenzymes (CYP450). Rifamycins are antituberculosis agents that induce CYP450 and may decrease substantially blood levels of the antiretroviral drugs. The pharmacologic interactions are called "drug-drug" because, in addition to the effect rifamycins have on protease inhibitors and NNRTIs, the antiretroviral agents may affect the blood levels of rifamycins. This notice presents updated data pertaining to drug-drug interactions between these agents and recommendations for their use from a group of CDC scientists and outside expert consultants.

    Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antibiotics, Antitubercular; HIV Infections; Humans; Rifabutin; Rifampin; Tuberculosis

2000
Lymphocyte transformation test for the evaluation of adverse effects of antituberculous drugs.
    European journal of medical research, 1999, Feb-25, Volume: 4, Issue:2

    The usefulness of the lymphocyte transformation test (LTT) for the analysis of adverse reactions to antituberculous drugs was evaluated. - The LTT was performed with isoniazid and rifampicin in 15 tuberculosis and 2 MOTT (Mycobacteria other than tuberculosis)-infection patients who suffered drug reactions, in 23 patients without any adverse reactions, in 7 controls previously exposed to antituberculous drugs, and in 14 controls who had never been exposed. 4/15 of the hepatotoxic reactions only showed a positive LTT with rifampicin, 3/15 only with isoniazid, and in 8/15 the LTT was negative. In an anaphylactoid shock reaction the LTT was extremely exaggerated for both rifampicin and isoniazid. In patients without any side effects only one slightly increased LTT due to isoniazid was observed. Two healthy controls with previous contact to these drugs showed a positive LTT for isoniazid, one of those with both rifampicin and isoniazid. The LTT was negative in all control persons without any former contact to antituberculous medications. In most cases hepatotoxicity seems to be a pure toxic reaction without the participation of cellular immune mechanisms. LTT can be useful for identifying the drug responsible for immunological side effects.

    Topics: Adult; Anaphylaxis; Anti-Bacterial Agents; Antitubercular Agents; Bromodeoxyuridine; Cells, Cultured; Chemical and Drug Induced Liver Injury; DNA Replication; Drug Eruptions; Drug Hypersensitivity; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunity, Cellular; Isoniazid; Kidney Diseases; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Mycobacterium Infections; Mycobacterium Infections, Nontuberculous; Mycobacterium kansasii; Nervous System Diseases; Rifampin; Tuberculosis

1999
Rifapentine--a long-acting rifamycin for tuberculosis.
    The Medical letter on drugs and therapeutics, 1999, Feb-26, Volume: 41, Issue:1047

    Topics: Antitubercular Agents; Clinical Trials as Topic; Dosage Forms; Drug Administration Schedule; HIV Seronegativity; Humans; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis

1999
[A case of partial Addison's disease activated with the administration of rifampicin (RFP)].
    Kekkaku : [Tuberculosis], 1999, Volume: 74, Issue:2

    The patient was a 76 year-old female with tuberculous tendonitis, treated with anti-tuberculous drugs including rifampicin (RFP). About two weeks after the start of RFP, she noticed general malaise and started vomiting, and the laboratory data showed severe hyponatremia. Because of mild liver dysfunction, RFP was discontinued and her symptoms gradually improved. Abdominal X-ray and CT showed swellings and calcifications of adrenal glands bilaterally. Serum ACTH level was high and cortisole, 17-OHCS, and 17-KS levels were normal. Her response to rapid ACTH stimulation was blunted significantly. After another trial of RFP, she started to vomit and complain general malaise again. We diagnosed her as partial Addison's disease and administered hydrocortisone with RFP. After this treatment her improvement was rapid. It has been known that RFP causes induction of enzymes in hepatic microsomes which increase the catabolism of glucocorticoids. To avoid the risk of adrenal insufficiency, patients with insufficient adrenal hormone reserve should receive compensatory hydrocortisone while they are taking RFP.

    Topics: Addison Disease; Aged; Antibiotics, Antitubercular; Female; Humans; Hydrocortisone; Rifampin; Tendinopathy; Tuberculosis

1999
Solid-phase sequence scanning for drug resistance detection in tuberculosis.
    Molecular and cellular probes, 1999, Volume: 13, Issue:2

    DNA chip arrays hold considerable promise for diagnostic sequencing of polymerase chain reaction (PCR) products. To date, however, arrays have been relatively expensive, complex to use and difficult to interpret, preventing their adaptation to the clinical lab. A moderate density array method has been developed that enables efficient, easy-to-interpret and robust solid-phase PCR product sequencing. Here, the results of Mycobacterium tuberculosis rifampin resistance mutation detection by primer-extension-based sequence scanning of the rpo B gene of M. tuberculosis are presented. Rifampin resistant clinical isolates were identified in as little as 1 h post PCR amplification with visual results detection.

    Topics: Bacterial Proteins; Codon; DNA Mutational Analysis; DNA Primers; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Microbial; Genes, Bacterial; Genotype; Humans; Image Processing, Computer-Assisted; Mycobacterium tuberculosis; Oligonucleotide Array Sequence Analysis; Plant Proteins; Polymerase Chain Reaction; Rifampin; Sequence Analysis, DNA; Software; Time Factors; Tuberculosis

1999
Efficacy of microencapsulated rifampin in Mycobacterium tuberculosis-infected mice.
    Antimicrobial agents and chemotherapy, 1999, Volume: 43, Issue:5

    Rifampin is a first-line drug useful in the treatment of tuberculosis. By using biocompatible polymeric excipients of lactide and glycolide copolymers, two microsphere formulations were developed for targeted and sustained delivery of rifampin, with minimal dosing. A small-microsphere formulation, with demonstrated ability to inhibit intracellularly replicating Mycobacterium tuberculosis H37Rv, was tested along with a large-microsphere formulation in an infected mouse model. Results revealed that by using a single treatment of the large-microsphere formulation, it was possible to achieve a significant reduction in M. tuberculosis H37Rv CFUs in the lungs of mice by 26 days postinfection. A combination of small (given as two injections on day 0 and day 7) and large (given as one injection at day 0) rifampin-loaded microsphere formulations resulted in significant reductions in CFUs in the lungs by 26 days, achieving a 1.23 log10 reduction in CFUs. By comparison, oral treatment with 5, 10, or 20 mg of rifampin/kg of body weight, administered every day, resulted in a reduction of 0.42, 1.7, or 1.8 log10 units, respectively. Thus the microsphere formulations, administered in one or two doses, were able to achieve results in mice similar to those obtained with a daily drug regimen within the range of the highest clinically tolerated dosage in humans. These results demonstrate that microsphere formulations of antimycobacterial drugs such as rifampin can be used for therapy of tuberculosis with minimal dosing.

    Topics: Animals; Antibiotics, Antitubercular; Drug Carriers; Drug Delivery Systems; Female; Mice; Microspheres; Mycobacterium tuberculosis; Polymers; Rifampin; Tuberculosis

1999
Tuberculosis after renal transplantation.
    Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 1999, Volume: 14, Issue:5

    Topics: Antibiotics, Antitubercular; Drug Resistance, Microbial; Humans; Kidney Transplantation; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Polymerase Chain Reaction; Rifampin; Tuberculosis

1999
Twice-weekly, directly observed treatment for HIV-infected and uninfected tuberculosis patients: cohort study in rural South Africa.
    AIDS (London, England), 1999, May-07, Volume: 13, Issue:7

    To determine the effectiveness of twice-weekly directly observed therapy (DOT) for tuberculosis (TB) in HIV-infected and uninfected patients, irrespective of their previous treatment history. Also to determine the predictive value of 2-3 month smears on treatment outcome.. Four hundred and sixteen new and 113 previously treated adults with culture positive pulmonary TB (58% HIV infected, 9% combined drug resistance) in Hlabisa, South Africa. Daily isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) given in hospital (median 17 days), followed by HRZE twice a week to 2 months and HR twice a week to 6 months in the community.. Outcomes at 6 months among the 416 new patients were: transferred out 2%; interrupted treatment 17%; completed treatment 3%; failure 2%; and cured 71%. Outcomes were similar among HIV-infected and uninfected patients except for death (6 versus 2%; P = 0.03). Cure was frequent among adherent HIV-infected (97%; 95% CI 94-99%) and uninfected (96%; 95% CI 92-99%) new patients. Outcomes were similar among previously treated and new patients, except for death (11 versus 4%; P = 0.01), and cure among adherent previously treated patients 97% (95% CI 92-99%) was high. Smear results at 2 months did not predict the final outcome.. A twice-weekly rifampicin-containing drug regimen given under DOT cures most adherent patients irrespective of HIV status and previous treatment history. The 2 month smear may be safely omitted. Relapse rates need to be determined, and an improved system of keeping treatment interrupters on therapy is needed. Simplified TB treatment may aid implementation of the DOTS strategy in settings with high TB caseloads secondary to the HIV epidemic.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Cohort Studies; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Predictive Value of Tests; Prospective Studies; Pyrazinamide; Rifampin; South Africa; Sputum; Treatment Outcome; Tuberculosis

1999
Mutations in the rpoB gene of rifampin-resistant Mycobacterium tuberculosis strains isolated mostly in Asian countries and their rapid detection by line probe assay.
    Journal of clinical microbiology, 1999, Volume: 37, Issue:8

    Mutations in the rpoB gene of 90 rifampin-resistant Mycobacterium tuberculosis isolates mostly from Asian countries were analyzed. Ten distinct single-nucleotide substitutions were found among the isolates by automated sequencing. A 3-nucleotide insertion was found in two isolates, and no mutation was found in five isolates (5.6%). A reverse hybridization-based line probe assay (INNO-LiPA Rif TB) for rapid detection of the mutations was evaluated with these isolates. Concordance rates with sequencing results for five wild-type probes (S probes) and four probes for specific mutations (R probes) were 96.7 and 100%, respectively. The overall concordance rate with the in vitro susceptibility testing results was 92.2% (83 of 90 isolates). These results indicate that a commercial line probe assay kit may be useful for rapid diagnosis of rifampin-resistant tuberculosis.

    Topics: Antibiotics, Antitubercular; Asia; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Humans; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1999
Decrease in serum concentrations of Helicobacter pylori IgG antibodies during antituberculosis therapy: the possible eradication by rifampicin and streptomycin.
    The American journal of gastroenterology, 1999, Volume: 94, Issue:7

    Topics: Antibiotics, Antitubercular; Antibodies, Bacterial; Helicobacter Infections; Helicobacter pylori; Humans; Immunoglobulin G; Rifampin; Streptomycin; Tuberculosis

1999
Analysis of rifapentine for preventive therapy in the Cornell mouse model of latent tuberculosis.
    Antimicrobial agents and chemotherapy, 1999, Volume: 43, Issue:9

    Rifapentine is a long-acting rifamycin which may be useful for intermittent drug therapy against tuberculosis. In this study we measured the efficacies of rifapentine-containing intermittent drug regimens for preventive therapy using the Cornell mouse model of latent tuberculosis. We infected groups of mice intravenously with Mycobacterium tuberculosis and then treated them with isoniazid and pyrazinamide for 12 weeks according to the Cornell latency development protocol. After a 4-week interval of no treatment, experimental preventive therapy was administered by esophageal gavage for 12 or 18 weeks. After equilibration and dexamethasone amplification treatment, mouse organs were analyzed by quantitative colony counts to measure the effectiveness of therapy. Our results showed that once-weekly isoniazid plus rifapentine combination therapy for 18 weeks was an effective preventive regimen with sterilizing potency and bacillary load reduction comparable to those of daily isoniazid therapy for 18 weeks. Monotherapy with rifapentine weekly or fortnightly or with rifampin twice weekly for up to 18 weeks did not offer advantages in reducing bacillary load or in sterilizing organs compared to the effects of a placebo. These results with the Cornell mouse model indicate that once-weekly, short-course preventive therapy with isoniazid plus rifapentine is effective and may warrant investigation in humans with latent tuberculosis infection.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Female; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Stem Cells; Tuberculosis

1999
Line probe assay in the rapid detection of rifampin-resistant Mycobacterium tuberculosis directly from clinical specimens.
    Scandinavian journal of infectious diseases, 1999, Volume: 31, Issue:3

    The sensitivity of a PCR-based line probe assay (Inno-LiPA Rif. TB Assay; Innogenetics NV Zwijndrecht, Belgium) was studied by using nested-PCR technique. A total of 75 specimens, representing various body locations from 70 suspected tuberculosis patients were obtained. LiPA yielded 30 Mycobacterium tuberculosis complex positive results (sensitivity 58.8%, compared with final diagnoses) whereas culture for M. tuberculosis was positive in 18 specimens (sensitivity 35.3%). Genotypic rifampin resistance testing by LiPA showed that 7 specimens contained rpoB mutations associated with RMP resistance, and sequencing data of the rpoB gene and LiPA patterns agreed in 29 of 30 M. tuberculosis positive specimens (96.7%). This indicates reliable performance, which makes the test suitable for the rapid determination of resistance to rifampin directly in clinical samples. However, the best results are obtained if LiPA is combined with conventional staining and culture methods.

    Topics: Antibiotics, Antitubercular; DNA, Bacterial; Drug Resistance, Microbial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Polymerase Chain Reaction; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Tuberculosis

1999
Evaluation of rifapentine in long-term treatment regimens for tuberculosis in mice.
    Antimicrobial agents and chemotherapy, 1999, Volume: 43, Issue:10

    Besides direct bactericidal activity, long-term effectiveness is one of the most important features to consider when developing new drugs for chemotherapy. In this study, we evaluated the ability of rifapentine (RFP), in monotherapy and combination therapy, to completely eradicate a Mycobacterium tuberculosis infection and to prevent relapse posttreatment in a Swiss mouse model. The combination of RFP, isoniazid (INH), and pyrazinamide (PZA) administered daily resulted in an apparent clearance of M. tuberculosis organisms in the lungs and spleens of infected mice after 10 weeks of treatment. However, 3 months after the cessation of therapy, bacterial regrowth occurred in mice treated for a 12-week period, indicating a relapse of infection. In intermittent treatment regimens of RFP in combination with INH and PZA, sterilization was achieved when mice were treated two to five times per week for 9 weeks. Bacterial growth was still observed in the once-weekly treatment group. Our results show that mouse models can predict important parameters for new drugs. We stress the necessity for long-term posttreatment observation in animal models for the routine evaluation of new drugs for antituberculosis chemotherapy.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Disease Models, Animal; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Rifamycins; Tuberculosis

1999
Relapse rates after short-course (6-month) treatment of tuberculosis in HIV-infected and uninfected persons.
    AIDS (London, England), 1999, Oct-01, Volume: 13, Issue:14

    To determine the rate of tuberculosis relapse among HIV-seropositive and -seronegative persons treated for active tuberculosis with short-course (6-month) therapy.. Consecutive cohort study.. City of Baltimore tuberculosis clinic.. Tuberculosis patients treated between 1 January 1993 and 31 December 1996.. Patients received 2 months of isoniazid, rifampin, pyrazinamide and ethambutol followed by 4 months of isoniazid and rifampin.. Passive follow-up for tuberculosis relapse was performed through September 30, 1998.. There were 423 cases of tuberculosis during the study period; 280 patients completed a 6-month course of therapy. Therapy was directly-observed for 94% of patients. Of those who completed therapy, 47 (17%) were HIV-seropositive, 127 (45%) were HIV-seronegative, and 106 (38%) had unknown HIV status. HIV-infected patients required more time to complete therapy (median 225 versus 205 days; P = 0.04) but converted sputum culture to negative within the same time period (median 77 versus 72 days; P = 0.43) as HIV-seronegative or unknown patients. Relapse occurred in three out of 47 (6.4%) HIV-infected patients compared to seven out of 127 (5.5%) HIV-seronegative patients (P = 1.0). Relapse rates also did not differ when HIV-seropositive patients were compared with HIV-seronegative and patients with unknown HIV status (6.4% versus 3.0%; P = 0.38). Of the 10 patients with tuberculosis relapse, restriction fragment length polymorphism data were available for five; all five relapse isolates matched the initial isolate.. These results support current recommendations to treat tuberculosis in HIV-infected patients with short-course (6-month) therapy.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; AIDS-Related Opportunistic Infections; Antitubercular Agents; Child; Child, Preschool; Cohort Studies; Ethambutol; Female; Follow-Up Studies; Humans; Infant; Isoniazid; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Time Factors; Tuberculosis

1999
Evaluation of reverse transcription-PCR and a bacteriophage-based assay for rapid phenotypic detection of rifampin resistance in clinical isolates of Mycobacterium tuberculosis.
    Journal of clinical microbiology, 1999, Volume: 37, Issue:11

    New rapid phenotypic assays for the detection of rifampin resistance in Mycobacterium tuberculosis have recently been described, but most of these require liquid cultures, which reduces the utility of many tests in terms of turnaround times. In the United Kingdom, over 90% of rifampin-resistant isolates are also resistant to isoniazid, so rifampin resistance can be used as a sensitive marker for multidrug-resistant tuberculosis. In this study, two new rapid phenotypic assays were compared to the standard resistance ratio method on 91 clinical isolates of M. tuberculosis. One, the phage amplified biologically (PhaB) assay, has been described previously and is based on the inability of susceptible isolates of M. tuberculosis to support the replication of bacteriophage D29 in the presence of inhibitory doses of rifampin. The other employed reverse transcription (RT)-PCR to demonstrate a reduction in inducible dnaK mRNA levels in susceptible isolates treated with rifampin. After incubation for 18 h with 4 microg of rifampin per ml, the PhaB assay showed concordance with the resistance ratio method for 46 of 46 (100%) susceptible and 31 of 31 (100%) resistant isolates, while RT-PCR showed concordance for 46 of 48 (96%) susceptible and 35 of 36 (97%) resistant isolates. We believe these assays provide a reliable rapid means of susceptibility testing with a total turnaround time of only 48 h, although the PhaB assay is better in terms of its lower technical demand and cost and its applicability to tuberculosis susceptibility testing in developing countries.

    Topics: Antibiotics, Antitubercular; Base Sequence; DNA Primers; Drug Resistance, Microbial; Drug Resistance, Multiple; Escherichia coli Proteins; Evaluation Studies as Topic; HSP70 Heat-Shock Proteins; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacteriophages; Mycobacterium tuberculosis; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Rifampin; RNA, Bacterial; RNA, Messenger; Tuberculosis

1999
Tuberculosis in the inner city: impact of a continuing epidemic in the 1990s.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 1999, Volume: 29, Issue:5

    Tuberculosis cases have recently declined in the United States, renewing interest in disease elimination. We examined the epidemiology of tuberculosis from 1991 through 1997 at an inner-city public hospital and assessed population-based tuberculosis rates by ZIP code in the 8 metropolitan Atlanta counties. During the 7 years, 1378 new patients had tuberculosis diagnosed at our hospital (mean, 197 patients/year), accounting for 25% of tuberculosis cases in Georgia. Coinfection with human immunodeficiency virus (HIV) was common, but a significant decrease in the proportion of HIV-infected patients with tuberculosis was noted over time. Most patients were members of a minority group (93%) and were born in the United States (96%). Two inner-city ZIP code areas had annual tuberculosis rates >120 cases per 100,000 persons, and 8 ZIP code areas had annual rates of 47-88 cases per 100,000 persons between 1993 and 1997, compared with the annual national average of 8.7 cases per 100,000 persons. Our hospital continues to care for large numbers of tuberculosis patients, and rates of tuberculosis remain high in the inner city. These data mandate a concentration of efforts and resources in urban locations if tuberculosis control and elimination is to be achieved in the United States.

    Topics: Female; Georgia; HIV Infections; Humans; Incidence; Male; Rifampin; Time Factors; Tuberculosis

1999
Bacteriological and molecular analysis of rifampin-resistant Mycobacterium tuberculosis strains isolated in Australia.
    Journal of clinical microbiology, 1999, Volume: 37, Issue:12

    To develop a better understanding of the epidemiology and molecular biology of rifampin-resistant Mycobacterium tuberculosis strains in Australia, 50 clinical isolates (33 rifampin-resistant and 17 rifampin-sensitive strains) cultured between 1990 and 1997 were analyzed by a number of bacteriological and molecular techniques. Examination of the drug resistance profiles of the 33 rifampin-resistant isolates revealed that 91% were resistant to rifampin in combination with resistance to isoniazid, 88% were resistant to rifampin on first isolation, and 81% showed cross-resistance with rifabutin. On the basis of the demographic data provided for the patients infected with the rifampin-resistant strains, 90% of the patients were born overseas. Of these patients, 64% developed clinical symptoms within 5 years of residence in Australia. On a molecular level, analysis of the rpoB gene revealed that 97% of the rifampin-resistant isolates had missense mutations within a conserved region of the gene, and eight types of missense mutations were detected. Of the 31 rifampin-resistant isolates that were typed by restriction fragment length polymorphism (RFLP) analysis, 28 distinct patterns were obtained by RFLP analysis with IS6110, and three clusters of genetically related isolates were identified. All isolates within the clusters were from patients who were born overseas and who had the same country of origin. The results from this study provide an overview of the current situation of rifampin resistance in Australia and can serve as a basis for continued monitoring of drug-resistant M. tuberculosis strains isolated within the country.

    Topics: Adolescent; Adult; Aged; Amino Acid Sequence; Antibiotics, Antitubercular; Australia; Base Sequence; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Drug Resistance, Multiple; Emigration and Immigration; Female; HIV Infections; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Sequence Data; Mycobacterium tuberculosis; Polymorphism, Restriction Fragment Length; Rifabutin; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

1999
Tuberculosis in renal transplant recipients.
    Transplantation, 1999, Nov-15, Volume: 68, Issue:9

    Tuberculosis is an important cause of morbidity and mortality in renal transplant recipients, but there are insufficient data regarding the efficacy and complications of therapy and of INH prophylaxis.. This study is a retrospective review of the records of 880 renal transplant recipients in two centers in Turkey.. Tuberculosis developed in 36 patients (4.1%) at posttransplant 3-111 months, of which 28 were successfully treated. Eight patients (22.2%) died of tuberculosis or complications of anti-tuberculosis therapy. Use of rifampin necessitated a mean of 2-fold increase in the cyclosporine dose, but no allograft rejection occurred due to inadequate cyclosporine levels. Hepatotoxicity developed in eight patients during treatment, two of whom died due to hepatic failure. No risk factor, including age, gender, renal dysfunction, hepatitis C, or past hepatitis B infection, was found to be associated with development of hepatic toxicity. A subgroup of 36 patients with a past history of or radiographic findings suggesting inactive tuberculosis, was considered to be at high risk for developing active disease, of whom 23 were given isoniazid (INH) prophylaxis. None versus 1 of 13 (7.7%) of cases with and without INH prophylaxis, respectively, developed active disease (P>0.05). None of the patients receiving INH had hepatic toxicity or needed modification of cyclosporine dose.. These data show that tuberculosis has a high prevalence in transplant recipients, that it can effectively be treated using rifampin-containing antituberculosis drugs with a close follow-up of serum cyclosporine levels, and that INH prophylaxis is safe but more experience is needed to define the target population.

    Topics: Adult; Female; Humans; Isoniazid; Kidney Transplantation; Liver; Male; Middle Aged; Retrospective Studies; Rifampin; Tuberculosis

1999
Ritonavir enables combined therapy with rifampin and saquinavir.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 1999, Volume: 29, Issue:6

    Topics: Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Mycobacterium tuberculosis; Rifampin; Ritonavir; Saquinavir; Tuberculosis

1999
Assuring bioavailability of fixed-dose combinations of anti-tuberculosis medications. A joint statement of the International Union Against Tuberculosis and Lung Diseases and the World Health Organization.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1999, Volume: 3, Issue:11 Suppl 3

    Topics: Antitubercular Agents; Biological Availability; Drug Combinations; Humans; Rifampin; Tuberculosis

1999
Fixed-dose combination formulations for tuberculosis treatment.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1999, Volume: 3, Issue:11 Suppl 3

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Biological Availability; Drug Combinations; Humans; Quality Control; Rifampin; Tuberculosis; World Health Organization

1999
Review of the Indian market of anti-tuberculosis drugs: focus on the utilisation of rifampicin-based products.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1999, Volume: 3, Issue:11 Suppl 3

    There is a need to better understand the extent of the utilisation of rifampicin in the market, particularly in fixed-dose combinations (FDC).. To review the Indian market of antituberculosis drugs, as this is the largest single market in the world of this therapeutic class.. Review and analysis of the sales data proffered by the Indian market audit. Estimated data relating to public sector product usage were utilised in order to obtain a more complete scenario.. The use of rifampicin-based products is very important in the Indian market of anti-tuberculosis drugs. Particularly common is the use of FDCs, which represent 62% of anti-tuberculosis drugs sold in the private market.. The Indian market for anti-tuberculosis drugs is very large and well integrated. FDCs are widely used. In addition to double- and triple-drug FDCs, four-drug combinations have recently been introduced into the market. The Indian industry also exports raw materials and pharmaceutical specialities.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Combinations; Drug Industry; Drug Utilization; Humans; India; Rifampin; Tuberculosis

1999
Estimate of the global market for rifampicin-containing fixed-dose combination tablets.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1999, Volume: 3, Issue:11 Suppl 3

    Despite WHO and IUATLD recommendations to use fixed-dose combination (FDC) tablets for treatment of tuberculosis, more than 75% of all rifampicin used in the public sector globally is administered as single drug tablets.. To estimate the potential global market for rifampicin-containing FDCs in the public and private sectors.. The public sector market for FDCs was calculated from the number of tuberculosis cases notified to WHO for 1996 and from information on treatment regimens currently used in each country. The private sector market was calculated from the estimated number of treated tuberculosis cases and the treatment regimens presumed to be used in the private sector.. The potential global market for the four-drug FDC tablet (rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400 mg and ethambutol 275 mg) is 305 (90%CI 145-505) million tablets per year, 105 (90%CI 50-160) and 200 (90%CI 95-345) million of which would be distributed in the public and private sectors, respectively. The uncertainty of the estimate remains considerable, as shown by the 90% confidence intervals.. The study demonstrated a large potential global market for FDCs that should encourage pharmaceutical manufacturers to produce WHO-recommended dosages of FDCs at affordable prices.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Combinations; Drug Industry; Drug Utilization; Health Care Sector; Humans; Private Sector; Public Sector; Rifampin; Tuberculosis

1999
The evaluation of rifampicin bioavailabilities of fixed-dose combinations of anti-tuberculosis drugs: procedures for ensuring laboratory proficiency.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1999, Volume: 3, Issue:11 Suppl 3

    The perceived need to demonstrate whether or not the rifampicin bioavailability of commercially manufactured fixed-dose combinations is satisfactory.. To establish an international laboratory network to assess rifampicin bioavailability.. Convenient assay kits were devised to evaluate the ability of laboratories in China, India, Italy, South Africa, Thailand and the USA to determine plasma and urinary concentrations of rifampicin and desacetyl-rifampicin.. Five laboratories, all of whom used high pressure liquid chromatographic methods, were shown to be able to accurately and precisely determine the two compounds.. Such a procedure is simple, convenient and objective and could be further employed to enlarge the intended international laboratory network.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Biological Availability; Drug Combinations; Humans; Laboratories; Program Development; Quality Control; Rifampin; Tuberculosis; World Health Organization

1999
Proposed minimum registration requirements for fixed-dose combination anti-tuberculosis drugs.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1999, Volume: 3, Issue:11 Suppl 3

    Registration requirements for combined pharmaceutical preparations have been published before, but not specifically for fixed-dose combination (FDC) anti-tuberculosis preparations. With tuberculosis being a high priority disease world-wide and concerns being raised over substandard FDC anti-tuberculosis preparations being marketed on a wide scale, specific guidelines for industry seem to be indicated. This is predominantly necessitated by the fact that rifampicin bioavailability can be adversely affected when put in combination with isoniazid and pyrazinamide, and by the need for standardisation of the formulations to only a few essential combinations in order to better control quality. This paper proposes certain minimum requirements to be met when standardising dose in the combinations and when ensuring bioavailability of the preparations. Nine rifampicin-containing combinations are listed as essential. Furthermore, bioavailability testing of the rifampicin component only by a restricted assay protocol of six sample times over 8 hours is advocated, whilst in vitro procedures for other actives in the combination would suffice for registration purposes.

    Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Biological Availability; Chemistry, Pharmaceutical; Child; Drug and Narcotic Control; Drug Approval; Drug Combinations; Drug Industry; Guidelines as Topic; Humans; Quality Control; Rifampin; Tuberculosis; World Health Organization

1999
Unusual clinical manifestation of tuberculosis in a renal transplant recipient.
    Transplantation proceedings, 1999, Volume: 31, Issue:8

    Topics: Adult; Antitubercular Agents; Ethambutol; Fatal Outcome; Female; Humans; Isoniazid; Kidney Transplantation; Liver; Liver Function Tests; Postoperative Complications; Pyrazinamide; Rifampin; Tuberculin Test; Tuberculosis

1999
Quality assurance of fixed-dose combinations of anti-tuberculosis medications. Proceedings of an IUATLD/WHO workshop, 29th IUATLD World Conference. Bangkok, Thailand, November 1998.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1999, Volume: 3, Issue:11 Suppl 3

    Topics: Antitubercular Agents; Biological Availability; Drug Combinations; Humans; Rifampin; Tuberculosis

1999
FDA clears tuberculosis drug for marketing.
    Indian journal of medical sciences, 1999, Volume: 53, Issue:3

    Topics: Antibiotics, Antitubercular; Drug Approval; Humans; Rifampin; Tuberculosis; United States; United States Food and Drug Administration

1999
Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate Alamar Blue assay.
    Journal of clinical microbiology, 1998, Volume: 36, Issue:2

    A colorimetric, microplate-based Alamar Blue assay (MABA) method was used to determine the MICs of isoniazid (INH), rifampin, streptomycin (SM), and ethambutol (EMB) for 34 Peruvian Mycobacterium tuberculosis isolates (including both pansensitive and multidrug-resistant strains) and the H37Rv strain by using bacterial suspensions prepared directly from solid media. Results for all isolates were available within 8 days. Discordant results were observed on initial tests for 3 of 16 INH-susceptible isolates, 5 of 31 EMB-susceptible isolates, and 2 of 4 SM-resistant isolates (by the BACTEC 460 system). The overall agreements between the MICs obtained by MABA and the results obtained with the BACTEC 460 system were 87.9% for initial results and 93.6% after retesting 12 of 17 samples with discrepant results. Interpretation of MABA endpoints improved with technical experience. The MABA is a simple, rapid, low-cost, appropriate technology which does not require expensive instrumentation and which makes use of a nontoxic, temperature-stable reagent.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Bacteriological Techniques; Coloring Agents; Culture Media; Drug Resistance, Microbial; Drug Resistance, Multiple; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Oxazines; Peru; Rifampin; Sensitivity and Specificity; Streptomycin; Tuberculosis; Xanthenes

1998
The pharmacokinetics of oral rifampicin in AIDS patients.
    Journal of the Medical Association of Thailand = Chotmaihet thangphaet, 1998, Volume: 81, Issue:1

    Previous studies in AIDS patients have shown that the peak serum concentration of rifampicin at 2 hours after administration are below normal ranges. These may be due to malabsorption of the drug resulting in therapeutic failure. However, there is no published data to demonstrate the pharmacokinetics of rifampicin in these AIDS patients. Therefore, the aim of this study was to provide such data. Eight AIDS patients with tuberculosis participated in this study. All patients were scheduled to receive oral rifampicin 600 mg once daily in the morning on an empty stomach. Rifampicin pharmacokinetics were studied on day 14. The mean Cmax was 9.81 +/- 4.41 ug/ml. The mean Tmax was 2.25 +/- 0.71 h. The mean AUC0-24 was 60.25 +/- 36.88 ug.h/ml. The results of our study did not confirm the previous studies. The absorption of rifampicin in most of our AIDS patients were not reduced and delayed. Therefore, rifampicin dosage adjustment for Thai patients may not be necessary.

    Topics: Administration, Oral; Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Area Under Curve; Chromatography, High Pressure Liquid; Humans; Male; Middle Aged; Rifampin; Tuberculosis

1998
Physician compliance with national tuberculosis treatment guidelines: a university hospital study.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1998, Volume: 2, Issue:3

    The Aga Khan University Hospital, in Karachi, Pakistan, is a 650-bed university teaching hospital.. There is little data from Pakistan on the awareness and application of the World Health Organization (WHO)'s tuberculosis treatment guidelines among physicians. This study evaluates physician compliance with these guidelines.. A questionnaire to measure physician compliance was developed, pilot tested and standardised. Case records of all patients hospitalized with tuberculosis were reviewed (January-December 1995, n = 229), and were classified into WHO Category 1 (n = 191), Category 2 (n = 9) and Category 3 (n = 29).. A total of 53 (23%) patients had a diagnostic bacteriological sputum smear examination, of which 38% were smear positive and 47% culture positive. Of 25 cerebrospinal fluid cultures 12% were positive. No sputum smear tests were conducted during treatment. Of 58 patients in Category 1 who completed therapy 74% received a 2-month intensive phase consisting of HRZE (isoniazid, rifampicin, pyrazinamide, ethambutol) (n = 43), while 41% received a 6 month continuation phase with HE (n = 24). Over 70% patients were lost to follow up, more than half of these during the intensive phase.. Our study reflects poor awareness of the WHO guidelines and low compliance among physicians, and a high loss to follow-up. Efforts are needed to create physician awareness about the WHO guidelines and their use. This study can be used to assess the effectiveness of any future physician education and to identify areas of weakness in health care.

    Topics: Antitubercular Agents; Cerebrospinal Fluid; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Hospitals, University; Humans; Isoniazid; Mycobacterium tuberculosis; Pakistan; Physicians; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Sputum; Surveys and Questionnaires; Tuberculosis; World Health Organization

1998
[Therapeutic efficacy of benzoxazinorifamycin KRM-1648 against experimental murine tuberculosis: (1). A study on the efficacy of short course treatment with the intratracheal and intravenous infection model].
    Kekkaku : [Tuberculosis], 1998, Volume: 73, Issue:2

    This study aims to compare in vivo activity of benzoxazinorifamycin KRM-1648 (KRM) with those rifampicin (RFP) and rifabutin (RBT) against experimental murine tuberculosis.. Mice were infected with Mycobacterium tuberculosis or M. bovis by the intratracheal (i.t.) or intravenous (i.v.) routes, and treated for 10 days with various doses of each drug starting from the 9th or 11th day after the TB-infection.. (A) A rapid test for in vivo evaluation of three rifamycins was conducted by examining the survival days of treated mice infected with 106 cfu of M. bovis Ravenel. Mice treated with KRM exhibited 2.13.7 times longer survival times, in comparison with those treated with RFP or RBT. (B) In the i.t.-model of M. bovis Ravenel infection, three rifamycin derivatives gave "distinctive dose-response curves" in the correlation of dose sizes with the mean survival times or "log10CFU/lungs reductions". (C) In M. tuberculosis Kurono infection models, the ranking of the anti-TB activity of the three rifamycins in each organ was as follows: i.t.-and i.v.-lungs: KRM >> RFP not equal to RBT, i.v.-spleen: KRM not equal to RBT > RFP, i.v.-liver: KRM not equal to RBT > RFP. (D) Based on the results of "log10CFU reduction" in different organs in M. tuberculosis Kurono infection models, "characteristic in vivo activity patterns of each rifamycin" were obtained. (E) The therapeutic efficacy of KRM in lungs was greater than in spleen and liver with any dose. In contrast, RBT exhibited more remarkable in vivo activity in the spleen and liver than in lungs.. The prominent in vivo activity of KRM may allow small dose for effective therapy; 1/3 dose or less in comparison with those of RFP or RBT, or intermittent therapy of tuberculosis.

    Topics: Animals; Antibiotics, Antitubercular; Female; Mice; Mice, Inbred BALB C; Mycobacterium bovis; Rifabutin; Rifampin; Rifamycins; Tuberculosis

1998
Rifampicin and isoniazid prophylactic chemotherapy for tuberculosis.
    Archives of disease in childhood, 1998, Volume: 78, Issue:2

    Prophylaxis of tuberculosis in children with four month (n = 53) and three month regimens (n = 213) of rifampicin and isoniazid from 1987 to 1996 were tolerated without any toxicity. The reduction in the proportion of paediatric tuberculosis, which was seen after the introduction of chemoprophylaxis with longer regimens in 1981, was maintained with the shorter duration regimens. Altered immigration patterns and a fall in the proportion of infectious tuberculosis, as defined by sputum culture positivity, have been excluded as factors in the reduced paediatric proportion of tuberculosis. The data show such regimens have little toxicity and provide indirect evidence that three months chemoprophylaxis may be as effective as longer regimens.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Chi-Square Distribution; Child; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

1998
Once-weekly rifapentine-containing regimens for treatment of tuberculosis in mice.
    American journal of respiratory and critical care medicine, 1998, Volume: 157, Issue:5 Pt 1

    The bactericidal activities of several once-weekly rifapentine (P)-containing combination regimens against Mycobacterium tuberculosis, and their ability to prevent the selection of rifampin (R)-resistant mutants, were compared with those of the standard six-times-weekly regimen consisting of R, isoniazid (H), and pyrazinamide (Z) in a mouse experiment. Mice were infected intravenously with 1.3 x 10(7) cfu of M. tuberculosis strain H37Rv, and 8 wk of treatment began on Day 14 after infection, when mice were randomly allocated to an untreated control group and nine treatment groups of 30 mice each. At the end of 8 wk of treatment, all the tested regimens showed promising bactericidal activities. Once-weekly P alone was less bactericidal than six-times-weekly R alone; likewise, the once-weekly P-containing combined regimens were less bactericidal than the six-times-weekly standard regimen. However, the difference in killing was about 1 log10, which represented only a fraction of the overall 4 log10 to 5 log10 magnitude of killing effects. The addition of streptomycin (S) improved the bactericidal effect of once-weekly PHZ, and the effect of once-weekly PHZS was further enhanced when it was preceded by 2 wk of daily HZS. The latter regimen achieved the same level of activity as the standard six-times-weekly regimen. All of the once-weekly P-containing combined regimens were able to prevent the selection of R-resistant mutants, whereas monotherapy with R or P selected resistant mutants in approximately 50% of animals.

    Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Lung; Mice; Mutation; Mycobacterium tuberculosis; Organ Size; R Factors; Rifampin; Spleen; Streptomycin; Tuberculosis

1998
Global surveillance for antituberculosis-drug resistance, 1994-1997. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance.
    The New England journal of medicine, 1998, Jun-04, Volume: 338, Issue:23

    Drug-resistant tuberculosis threatens efforts to control the disease. This report describes the prevalence of resistance to four first-line drugs in 35 countries participating in the World Health Organization-International Union against Tuberculosis and Lung Disease Global Project on Anti-Tuberculosis Drug Resistance Surveillance between 1994 and 1997.. The data are from cross-sectional surveys and surveillance reports. Participating countries followed guidelines to ensure the use of representative samples, accurate histories of treatment, standardized laboratory methods, and common definitions. A network of reference laboratories provided quality assurance. The median number of patients studied in each country or region was 555 (range, 59 to 14,344).. Among patients with no prior treatment, a median of 9.9 percent of Mycobacterium tuberculosis strains were resistant to at least one drug (range, 2 to 41 percent); resistance to isoniazid (7.3 percent) or streptomycin (6.5 percent) was more common than resistance to rifampin (1.8 percent) or ethambutol (1.0 percent). The prevalence of primary multidrug resistance was 1.4 percent (range, 0 to 14.4 percent). Among patients with histories of treatment for one month or more [corrected], the prevalence of resistance to any of the four drugs was 36.0 percent (range, 5.3 to 100 percent), and the prevalence of multidrug resistance was 13 percent (range, 0 to 54 percent). The overall prevalences were 12.6 percent for resistance to any of the four drugs [corrected] (range, 2.3 to 42.4 percent) and 2.2 percent for multidrug resistance (range, 0 to 22.1 percent). Particularly high prevalences of multidrug resistance were found in the former Soviet Union, Asia, the Dominican Republic, and Argentina.. Resistance to antituberculosis drugs was found in all 35 countries and regions surveyed, suggesting that it is a global problem.

    Topics: Antitubercular Agents; Cross-Sectional Studies; Drug Resistance, Microbial; Ethambutol; Global Health; Humans; Isoniazid; Mycobacterium tuberculosis; Population Surveillance; Prevalence; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant

1998
Isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection.
    Lancet (London, England), 1998, Jun-13, Volume: 351, Issue:9118

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Developing Countries; Drug Therapy, Combination; HIV-1; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

1998
Rifampicin and pruritus.
    South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 1998, Volume: 88, Issue:7

    Topics: Antibiotics, Antitubercular; Child; Cholestasis; Contraindications; Drug Resistance, Microbial; Humans; Pruritus; Rifampin; Tuberculosis

1998
[The usefulness of the desensitization to rifampin in the treatment of mycobacterial disease in patients with AIDS].
    Medicina clinica, 1998, Jun-27, Volume: 111, Issue:3

    Hypersensitivity reactions to rifampin are relatively uncommon, but they may result in cessation of therapeutic medications.. We report our experience with oral desensitization protocol to rifampin in a group of 35 HIV-positive patients with mycobacterial disease who had some hypersensitivity reaction to this drug.. Adverse reactions with this protocol were few and easily treated.. Oral desensitization to rifampin is safe and effective, allowing some of these patients (60%) to reintroduce the drug and to reduce the time of treatment.

    Topics: Acquired Immunodeficiency Syndrome; Adult; Antibiotics, Antitubercular; Desensitization, Immunologic; Drug Hypersensitivity; Female; Humans; Male; Rifampin; Tuberculosis

1998
Development of rifapentine: the way ahead.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1998, Volume: 2, Issue:8

    Topics: Antitubercular Agents; Biological Availability; China; Clinical Trials as Topic; Drug Industry; Hong Kong; Humans; Recurrence; Rifampin; Tuberculosis

1998
Does AIDS impair the absorption of antituberculosis agents?
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1998, Volume: 2, Issue:8

    Case reports of low serum concentrations of antituberculosis drugs, with resultant treatment failure and emergence of drug-resistant organisms in patients with the acquired immune-deficiency syndrome (AIDS), have prompted suggestions that therapeutic drug monitoring (TDM) may be indicated in patients co-infected with the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis.. To test whether the bioavailability of antituberculosis drugs is altered in HIV-infected patients with tuberculosis.. Twenty-seven hospitalized tuberculosis patients (13 with AIDS, 14 HIV-negative) were entered into a pharmacokinetic trial. Following the supervised administration of standardized doses of isoniazid, rifampicin and pyrazinamide, the plasma concentrations of the drugs were measured repeatedly over 12 hours and the following parameters were derived for each agent: maximum measured drug concentration (Cmax), time-to-maximum measured drug concentration (Tmax) and area-under-the-concentration-time curve to 12 hours (AUC).. No significant differences emerged between the two groups in Cmax, Tmax, and AUC for isoniazid and pyrazinamide. For rifampicin the AIDS patients showed a greater AUC (P < 0.01) than the controls, but there were no significant differences in Cmax and Tmax.. There was no evidence that HIV infection reduced the plasma concentrations of antituberculosis drugs.

    Topics: Absorption; Acquired Immunodeficiency Syndrome; Adolescent; Adult; Antitubercular Agents; Biological Availability; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis

1998
Peptide-specific T cell response to Mycobacterium tuberculosis: clinical spectrum, compartmentalization, and effect of chemotherapy.
    The Journal of infectious diseases, 1998, Volume: 178, Issue:3

    The T cell repertoire of 59 patients with untreated tuberculosis was compared with that of 46 bacille Calmette-Guérin-vaccinated controls by assaying the proliferative responses to six permissively recognized peptides from the 16-, 19-, and 38-kDa molecules of Mycobacterium tuberculosis. A trend from higher to lower reactivity following this order: vaccinated controls > lymph node disease > localized extrapulmonary > pulmonary > pleural was seen for 4 of the peptides (P < .03). The decreased response of blood lymphocytes from patients with pleural tuberculosis was partially accounted for by sequestration of peptide-responsive cells within the pleural fluid. Chemotherapy "reversed" the depressed proliferative responses of patients with pulmonary and pleural tuberculosis depending on the peptide origin, being greatest for peptides of 16 kDa, transient for those of 19 kDa, and least for those of 38 kDa. These data demonstrate antigen specificity in the decreased responsiveness of patients with tuberculosis.

    Topics: Adolescent; Adult; Antigens, Bacterial; Antitubercular Agents; Bacterial Proteins; BCG Vaccine; Cell Division; Cells, Cultured; Epitopes, T-Lymphocyte; Ethambutol; Female; Humans; Interferon-gamma; Interleukin-10; Isoniazid; Leukocytes, Mononuclear; Lipoproteins; Male; Middle Aged; Mycobacterium tuberculosis; Peptides; Pleural Effusion; Pyrazinamide; Rifampin; T-Lymphocytes; Tuberculin; Tuberculosis

1998
Prevention of tuberculosis in HIV-1.
    Lancet (London, England), 1998, Aug-29, Volume: 352, Issue:9129

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Resistance, Microbial; HIV-1; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

1998
[Multi-organ tuberculosis in a child: diagnosis and therapeutic problems].
    Wiadomosci lekarskie (Warsaw, Poland : 1960), 1998, Volume: 51, Issue:7-8

    Diagnostic and therapeutic problems in the course of tuberculosis in a 4 year old boy were described. First symptoms of disease such as specific inflammation of lymph nodes were observed in THE third month of liFe. After typical antituberculous treatment the signs of disease regressed. In consequence of the contact with an individual expeCtorating tubercle bacilli superinfection and generalization of the disease took place what led to the boy's death.

    Topics: Antitubercular Agents; Child, Preschool; Fatal Outcome; Humans; Isoniazid; Male; Rifampin; Tuberculosis

1998
Short-term tuberculosis prophylaxis is effective in persons with HIV.
    American family physician, 1998, Sep-15, Volume: 58, Issue:4

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Humans; Isoniazid; Patient Compliance; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis

1998
Action of metronidazole in combination with isoniazid & rifampicin on persisting organisms in experimental murine tuberculosis.
    The Indian journal of medical research, 1998, Volume: 108

    To study the activity of metronidazole on persisting tubercle bacilli, BALB/c mice were infected with Mycobacterium tuberculosis and, after 14 days, treated with isoniazid (H) or rifampicin (R) or isoniazid + rifampicin (HR) for 2 months. An untreated group and a group treated with metronidazole (M) alone served as controls. At the end of 2 months, M was added to the H, R, and HR regimen in half the mice, and the treatment was continued for 1 more month in all mice. At the end of treatment, no viable organisms were detected in the lung or spleen of mice treated with HR or HRM regimens. In contrast, compared to the mice treated with R alone, the log10 colony forming units (cfu) of mice treated with RM were lower by 1.84 and 0.52 in the lung and spleen, respectively. Similarly, compared to the H group, the log10 cfu were lower by 0.67 in the spleen of mice treated with HM, and no additional effect due to M was seen in the lung. Three months after stopping treatment, viable organisms were isolated from both the organs of all the groups. However, the log10 cfu in the lung and spleen for the groups with metronidazole were below the log10 cfu for the respective single or 2 drug groups, except the log10 cfu in the lung for the RM group. These findings suggest that metronidazole, given with bactericidal drugs such as rifampicin and isoniazid may be of value in eliminating persisting tubercle bacilli, but further studies are warranted.

    Topics: Animals; Antitubercular Agents; Drug Therapy, Combination; Female; Isoniazid; Metronidazole; Mice; Mice, Inbred BALB C; Rifampin; Tuberculosis

1998
Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 1998, Volume: 27, Issue:5

    Tuberculosis is a serious opportunistic infection in transplant recipients. On the basis of the compilation of published reports in the literature, the incidence of Mycobacterium tuberculosis infection in organ transplant recipients worldwide ranged from 0.35% to 15%. Nonrenal transplantation (P = .004), rejection within 6 months before the onset of tuberculosis (P = .02) and type of primary immunosuppressive regimen (P = .007) were predictors of M. tuberculosis infection occurring within 12 months after transplantation. Thirty-three percent (155) of 476 transplant patients with tuberculosis had disseminated infection; receipt of OKT3 or anti-T cell antibodies (P = .005) was a significant predictor of disseminated tuberculosis. Overall, the mortality rate among 499 patients was 29%; disseminated infection (P = .0003), prior rejection (P = .006), and receipt of OKT3 or anti-T cell antibodies (P = .0013) were significant predictors of mortality in patients with tuberculosis. Clinically significant hepatotoxicity due to isoniazid occurred in 2.5%, 4.5%, and 41% of renal, heart and lung, and liver transplant recipients, respectively. The diagnosis and effective management of tuberculosis after transplantation warrant recognition of the unique epidemiological and clinical characteristics of tuberculosis in transplant recipients.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Isoniazid; Liver; Male; Middle Aged; Mycobacterium tuberculosis; Opportunistic Infections; Organ Transplantation; Retrospective Studies; Rifampin; Risk Factors; Tuberculosis

1998
Effects of rifampin on cyclosporine disposition in kidney recipients with tuberculosis.
    Transplantation proceedings, 1998, Volume: 30, Issue:7

    Topics: Adult; Antibiotics, Antitubercular; Azathioprine; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Prednisone; Rifampin; Statistics, Nonparametric; Tuberculosis

1998
Short-course prophylaxis against tuberculosis in HIV-infected persons. A decision and cost-effectiveness analysis.
    Annals of internal medicine, 1998, Nov-15, Volume: 129, Issue:10

    Isoniazid prophylaxis for 12 months effectively prevents tuberculosis in HIV-infected persons and may decrease the incidence of other HIV-related disease and mortality. Recent clinical trials have found that some short-course regimens also effectively prevent tuberculosis.. To compare the benefits, risks, and cost-effectiveness of isoniazid prophylaxis and short-course prophylaxis regimens.. Decision and cost-effectiveness analysis.. United States.. Hypothetical patients who are HIV-infected and have CD4 counts of 200 cells/mm3 or less and positive results on tuberculin skin tests.. Isoniazid prophylaxis lasting 12 months and six short-course prophylaxis regimens of isoniazid, rifampin, and pyrazinamide alone or in combination.. 5-year survival rate, life expectancy, lifetime incidence of tuberculosis, and cost per quality-adjusted life-year saved.. Compared with no prophylaxis, the 12-month isoniazid regimen increased 5-year survival rates by 9% and life expectancy by 8.7 months, decreased incidence of tuberculosis by 27%, and saved 4 medical care dollars for every 1 spent on prophylaxis. Regimens of isoniazid for 6 months, isoniazid and rifampin for 3 months, and rifampin and pyrazinamide for 2 months had similar results: 6.2- to 8.6-month increases in life expectancy, 19% to 26% reductions in incidence of tuberculosis, and 1 to 7 medical care dollars saved for every 1 spent on prophylaxis. A 3-month regimen of isoniazid, rifampin, and pyrazinamide resulted in fewer clinical benefits and was the only regimen tested that did not save medical care dollars.. Prophylaxis decreases the incidence of tuberculosis and increases life expectancy for HIV-infected patients. Some regimens save medical care dollars, and some short-course regimens have clinical and economic benefits similar to those of the 12-month isoniazid regimen. Short-course prophylaxis is a reasonable alternative to the 12-month isoniazid regimen.

    Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cost-Benefit Analysis; Decision Trees; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Quality-Adjusted Life Years; Rifampin; Survival Rate; Tuberculosis

1998
From the Centers for Disease Control and Prevention. Use of short-course tuberculosis preventive therapy regimens in HIV-seronegative persons.
    JAMA, 1998, Nov-25, Volume: 280, Issue:20

    Topics: Antitubercular Agents; Drug Administration Schedule; HIV Seronegativity; Humans; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis

1998
[Efficacy of a short 6 month therapeutic coursefor HIV infected tuberculosis patients in Abidjan, Côte d'Ivoire].
    Bulletin de la Societe de pathologie exotique (1990), 1998, Volume: 91, Issue:4

    From December 1992 to February 1993, 104 newly diagnosed pulmonary tuberculosis patients were enrolled in a prospective cohort study to assess the response to the 6 month-short-course regimen implemented in Cote d'Ivoire. This treatment encompassed the daily intake of Rifampicin and Pyrazinamide for 2 months followed by Rifampicin and Isoniazid for the remaining 4 months. All the patients were enrolled at the Treichville Tuberculosis Treatment Centre in Abidjan, and a follow-up of 6 months was observed for each patient. All in all, 41 patients were HIV-positive whereas 63 where HIV-negative. No statistical difference was noted between HIV-positive and HIV-negative patients with regard to the completion of therapy (85% versus 87%). The cure rate after an effective 6 month-therapy was similar among HIV-positive and HIV-negative patients (83% versus 84%) as well as the treatment failure rate which was 2.4% and 3% respectively. The results clearly indicate that the 6 month-short-course regimen policy implemented in Côte d'Ivoire is as effective for the treatment of HIV-associated tuberculosis as for the treatment of tuberculosis.

    Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Antitubercular Agents; Cohort Studies; Cote d'Ivoire; Female; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis

1998
Relationship between antimycobacterial activities of rifampicin, rifabutin and KRM-1648 and rpoB mutations of Mycobacterium tuberculosis.
    The Journal of antimicrobial chemotherapy, 1998, Volume: 42, Issue:5

    We compared the in-vitro antimycobacterial activities of rifabutin and KRM-1648, two rifamycin derivatives, with that of rifampicin against 163 strains of Mycobacterium tuberculosis. We also evaluated the correlation between the level of resistance to rifampicin, rifabutin and KRM-1648 and genetic alterations in the rpoB gene. All 82 strains susceptible to rifampicin or resistant to rifampicin with MICs < or = 16 mg/L were susceptible to rifabutin and KRM-1648 with MICs < or = 1 mg/L. Seventy-six of 81 strains resistant to rifampicin with MICs > or = 32 mg/L were resistant to both rifabutin and KRM-1648, but with lower MICs than those of rifampicin. KRM-1648 showed more potent antimycobacterial activity than rifabutin against organisms with low MICs (< or = 1 mg/L), while rifabutin was more active than KRM-1648 against organisms with high MICs (> or = 2 mg/L). A total of 96 genetic alterations around the 69 bp core region of the rpoB gene were detected in 92 strains. Alterations at codons 515, 521 and 533 in the rpoB gene did not influence the susceptibility to rifampicin, rifabutin and KRM-1648. Point mutations at codons 516 and 529, deletion at codon 518 and insertion at codon 514 influenced the susceptibility to rifampicin but not that to rifabutin or KRM-1648. With the exception of one strain, all alterations at codon 513 and 531 correlated with resistance to the three test drugs. The resistant phenotype of strains with an alteration at codon 526 depended on the type of amino acid substitution. Our results suggest that analysis of genetic alterations in the rpoB gene might be useful not only for predicting rifampicin susceptibility, but also for deciding when to use rifabutin for treating tuberculosis. Further studies may be required to determine the usefulness of KRM-1648.

    Topics: Amino Acid Sequence; Antibiotics, Antitubercular; Base Sequence; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Microbial; Genes, Bacterial; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins; Sequence Analysis, DNA; Tuberculosis

1998
Tuberculosis of the pyriform fossa--a rare entity.
    The Journal of laryngology and otology, 1998, Volume: 112, Issue:8

    Tuberculosis of the pharynx is less common than tuberculosis of the larynx. We present a rare case of tuberculosis of the pyriform fossa which clinically masqueraded as a malignancy. Our patient showed a prompt improvement in symptoms after commencing antitubercular treatment.

    Topics: Adult; Antitubercular Agents; Diagnosis, Differential; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Laryngoscopy; Male; Pharyngeal Diseases; Pharyngeal Neoplasms; Pyrazinamide; Radiography; Rifampin; Tuberculosis; Tuberculosis, Laryngeal; Tuberculosis, Pulmonary

1998
[Tuberculosis among hemodialysis patients in Dakar, apropos of 2 cases].
    Dakar medical, 1998, Volume: 43, Issue:1

    Hemodialysis permits a long term survival to patients with End Stage Renal Disease (E.S.R.D.). However the patients ongoing hemodialysis presented a immunodeficiency and a important modification of drugs biodisponibility. Tuberculosis is an endemic disease in our countries. Extrapulmonary tuberculosis is reported from these two cases among 13 patients treated in C.H.U.A. Le Dantec hemodialysis center. Clinical symptoms are not specific bacteria is not found. Diagnosis is obtained by a bundle of arguments. Antituberculosis treatment need to be adjusted in this field. Even if Rifampicine can be administrated at normal dose. The others drugs must be adapted on their clearance and the underlying disease. The two patients presented psychiatrical symptoms motivating a reduction of isoniazide dose witch threshold toxicity is lowered by renal failure state. These observations must increase watchfulness on nephrologist of undeveloping countries, confronted with tuberculosis renewed out break.

    Topics: Adolescent; Adult; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Hallucinations; Humans; Isoniazid; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Renal Dialysis; Rifampin; Senegal; Streptomycin; Tuberculosis

1998
[Characterization of the rpoB gene mutations in clinical isolates of rifampicin-resistant Mycobacterium tuberculosis].
    Enfermedades infecciosas y microbiologia clinica, 1998, Volume: 16, Issue:9

    Characterization and frequency of the rpoB gene mutations associated with rifampin resistance in Mycobacterium tuberculosis clinical isolates in Sevilla.. Characterization of rpoB mutations in 21 rifampicin-resistant strains of M. tuberculosis isolated during a three-year period (1994-1996) by three different molecular methods: a nonradioactive Single-strand conformation polymorphism (SSCP) analysis, DNA sequence analysis and a commercial method the line probe assay InnoLiPA.. Five distinct rpoB mutations were identified. Ser531-->Leu mutation was detected in 14 strains (66.7%), H526-->Asp in 3 strains (14.3%), Ans512-->Ser in 1 strain (4.8%), Glu513-->Leu in 1 strain (4.8%). A nine nucleotide deletion (codon 510-513) was found in one strain (4.8%) while in the remaining resistant strain (4.8%) no mutation was detected.. The frequency of the different mutations found in the rpoB gene, associated with rifampicin resistance in Mycobacterium tuberculosis clinical isolates in Seville, are similar to those previously reported. However, two new mutations has been detected: a nine nucleotide deletion (codon 510-513), and the Asn512-->Ser point mutation. The characterization of the mutations in the rpoB gene could serve as epidemiological marker for the rifampicin resistant clinical isolates of M. tuberculosis.

    Topics: Amino Acid Substitution; Bacterial Proteins; DNA Mutational Analysis; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Microbial; Genes, Bacterial; Humans; Mutation; Mutation, Missense; Mycobacterium tuberculosis; Plant Proteins; Polymorphism, Single-Stranded Conformational; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

1998
Medical advances with international impact.
    AIDS treatment news, 1998, Mar-06, Issue:No 290

    Several medical developments have great implications for treating HIV patients in developing countries, who account for about 90 percent of all cases. A simplified AZT regimen tested in Thailand may cut maternal-infant transmissions in half. The dispute on placebo trials to reduce transmission in developing countries may end. A two-drug tuberculosis regimen taken for two months has been found as effective as the current single-drug treatment taken for a year. Dried blood spots can be used to test viral loads, requiring a significantly smaller amount of blood for test accuracy; this will be especially useful in diagnosing and treating infants. Several studies testing dried blood are described.

    Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antibiotics, Antitubercular; Antitubercular Agents; Clinical Trials as Topic; Developing Countries; Drug Therapy, Combination; Female; Health Services Accessibility; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Isoniazid; Pregnancy; Pregnancy Complications, Infectious; Pyrazinamide; Reagent Kits, Diagnostic; Rifampin; RNA, Viral; Tuberculosis; Viral Load; Zidovudine

1998
A short two-drug regimen prevents active TB.
    GMHC treatment issues : the Gay Men's Health Crisis newsletter of experimental AIDS therapies, 1998, Volume: 12, Issue:4

    Study results presented at the 5th Conference on Retroviruses and Opportunistic Infections showed that a two-month regimen of rifampin with pyrazinamide proved to be as effective as a twelve-month regimen of isoniazid in the prevention of tuberculosis (TB) in HIV-positive individuals. HIV-positive individuals have a ten times greater chance of developing TB than HIV-negative individuals, and TB may contribute to greater viral loads and HIV progression. The short-term course is not recommended for patients using protease inhibitors due to drug interactions with rifampin to treat active TB. The recommendations for the prevention of TB in HIV-positive individuals will probably be changed when all the data are analyzed and confirmed.

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Pyrazinamide; Rifampin; Tuberculosis

1998
New TB therapy works for HIV-positive patients.
    AIDS alert, 1998, Volume: 13, Issue:5

    A joint, international study, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and the Centers for Disease Control and Prevention (CDC), has determined that a two-month therapy to block tuberculosis (TB) in HIV-positive individuals is as effective as the current one-year treatment. The short-term therapy consists of two drugs, rifampin and pyrazinamide. According to Dr. Anthony Fauci, director of NIAID, HIV and TB infections work cooperatively to spur each other's development. Therefore it is significant that the new shorter treatment alternative enables patients to delay or briefly discontinue use of protease inhibitors and has a higher compliance rate for patients completing therapy. Although the two-drug regimen was designed to treat HIV-positive patients, it could be effective in treating patients who have dormant TB infection.

    Topics: Antitubercular Agents; Clinical Trials as Topic; Disease Progression; HIV Infections; Humans; Isoniazid; Patient Compliance; Pyrazinamide; Rifampin; Tuberculosis

1998
Short course preventive therapy for tuberculosis is successful in HIV-infected patients.
    The Hopkins HIV report : a bimonthly newsletter for healthcare providers, 1998, Volume: 10, Issue:3

    Two independent clinical trials are showing that patients with HIV and latent tuberculosis infections may only need two months of treatment to prevent active tuberculosis development. Studies examined the use of rifampin (RIF) and pyrazinamide (PZA), or isoniazid (INH) and pyridoxine. Results show that RIF/PZA, dosed either daily or twice weekly, is as effective in preventing tuberculosis in dually-infected adults, as INH/pyridoxine given for 6-12 months. Data on drug regimens used in preventing tuberculosis in patients with HIV infection are highlighted.

    Topics: AIDS-Related Opportunistic Infections; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis

1998
New TB guidelines for persons with HIV.
    AIDS treatment news, 1998, Nov-06, Issue:No 306

    The Centers for Disease Control and Prevention issued new guidelines for preventing and treating tuberculosis (TB) in persons with HIV. The guidelines recommend that all people with HIV be tested for TB and be treated if necessary. Also, the drug Rifampin, which can be used to treat TB, should not be used with protease inhibitors or with non-nucleoside reverse transcriptase inhibitors, as it impairs the effectiveness of those drugs. However, Rifabutin can be used with antiretroviral treatments. The guidelines also mention that there is a 2-month preventive treatment, which may be an alternative to the traditional 1-year Isoniazid treatment regimen.

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Contraindications; Drug Interactions; Guidelines as Topic; HIV Protease Inhibitors; Humans; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis

1998
Tuberculosis in heart transplant recipients.
    Chest, 1997, Volume: 111, Issue:2

    To clarify the prevalence and factors associated with tuberculosis, as well as patient survival in heart transplant recipients.. A retrospective review of case records of all heart transplant recipients from March 1989 to February 1996 during a 7-year period.. During the period reviewed, 727 orthotopic heart transplantations were performed in 716 patients at the Heart Center Northrhine-Westphalia, Germany.. Tuberculosis was proved in seven (1%) patients (four men/three women; age, 33 to 71 years; two miliary lesions, three pulmonary lesions, and two urogenital lesions). None of them had primary history of tuberculosis. Tuberculin skin tests were not performed before transplantation because there were no lesions indicating primary infection of turberculosis. The immunosuppressive regimen was based on double-drug (cyclosporine + azathioprine) therapy. Immunosuppression had been intensified by methylprednisolone pulses at least three times in those seven patients, and prednisone had been used orally in six of seven patients. Tuberculosis developed from 2.5 to 41 months after transplantation. Tuberculosis was found by routine examinations in four of seven patients. Diagnoses were made with both direct microscopy and cultures in six patients, and by histologic study in one. Treatment consisted of isoniazid, rifampicin, ethambutol, and pyrazinamide. Two patients with miliary lesions were treated with four drugs, and the others were treated with three drugs. Isoniazid was used in all patients. Rifampicin, which decreases cyclosporine serum levels, was not used from the beginning in one patient and treatment with it was stopped halfway in another patient because low cyclosporine level had induced rejection. Six of the seven patients are doing well while receiving antituberculous therapy. One patient died with miliary tuberculosis as a cause of death.. The prevalence of tuberculosis in heart transplant recipients was higher than that in the general population. We recommend that a high degree of clinical suspicion is maintained for tuberculosis in heart transplant recipients with meticulous follow-up, and that the treatment of tuberculosis has to be with meticulous care, especially during the use of rifampicin.

    Topics: Adult; Aged; Antibiotics, Antitubercular; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Rifampin; Tuberculosis

1997
[Desensitization to rifampicin].
    Medicina clinica, 1997, Jan-11, Volume: 108, Issue:1

    Topics: AIDS-Related Opportunistic Infections; Desensitization, Immunologic; Drug Hypersensitivity; Humans; Rifampin; Tuberculosis

1997
A hepatic graft tuberculosis transmitted from a living-related donor.
    Transplantation, 1997, Mar-27, Volume: 63, Issue:6

    Exclusion of occult diseases in the donor organ and prevention of infectious disease transmission are minimal requirements in organ transplantation. We report here a case of hepatic graft tuberculosis, which was most likely transmitted by the graft from the living-related donor. The course of the recipient included tuberculosis, rejection, and other infections, which led to vanishing bile duct syndrome. Due to various infections and tuberculosis, as well as a strong interaction between rifampicin and tacrolimus, the patient died of pneumonia on day 273 after transplantation. This case emphasizes the importance of care in the selection of a living-related donor for liver transplantation.

    Topics: Adult; Drug Interactions; Fatal Outcome; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Function Tests; Liver Transplantation; Living Donors; Mothers; Postoperative Complications; Rifampin; Tacrolimus; Tuberculosis

1997
Lung specific stealth liposomes: stability, biodistribution and toxicity of liposomal antitubercular drugs in mice.
    Biochimica et biophysica acta, 1997, Mar-15, Volume: 1334, Issue:2-3

    Liposomes with enhanced affinity towards lung tissue were prepared for the development of more effective chemotherapy against tuberculosis. Modification of surface of stealth liposomes by tagging O-stearylamylopectin (O-SAP) resulted in the increased affinity of these liposomes towards lung tissue of mice. Liposomes containing egg phosphatidylcholine (ePC), cholesterol (CH), dicetylphosphate (DCP), O-SAP and monosialogangliosides (GM1)/distearylphosphatidylethanolamine-poly(ethylene glycol) 2000 (DSPE-PEG 2000) were found to be most stable in serum. Tissue distribution of these liposomes showed more accumulation in lungs than in reticuloendothelial systems (RES) of normal and tuberculous mice. Pre administration of PC and CH (2:1.5) liposomes before the injection of lung specific stealth liposomes further enhanced their uptake in lungs. In vivo stability of these liposomes demonstrated the slow and controlled release of their encapsulated contents. Isoniazid and rifampicin encapsulated in liposomes were less toxic to peritoneal macrophages as compared to free drugs. Further, encapsulated drugs also demonstrated reduced in vivo toxicity in comparison to free drug(s). These findings suggest liposomes to be better drug delivery vehicles for experimental tuberculosis.

    Topics: Alanine Transaminase; Alkaline Phosphatase; Amylopectin; Animals; Antitubercular Agents; Bilirubin; Cholesterol; Drug Delivery Systems; Isoniazid; Liposomes; Liver; Lung; Macrophages; Mice; Phosphatidylcholines; Rifampin; Transaminases; Tuberculosis

1997
Evaluation of a line probe assay kit for characterization of rpoB mutations in rifampin-resistant Mycobacterium tuberculosis isolates from New York City.
    Journal of clinical microbiology, 1997, Volume: 35, Issue:5

    A commercial line probe assay kit (Inno-LiPA Rif.TB) for rapid identification of mutations in the rpoB gene associated with rifampin resistance in Mycobacterium tuberculosis was evaluated with a collection of 51 rifampin-resistant strains. Nine distinct rpoB mutations were identified. Concordances with automated sequence results for five wild-type kit probes and four probes for specific mutations were 94.1 and 100%, respectively. Overall concordance of the line probe assay kit with phenotypic rifampin susceptibility testing results was 90.2%.

    Topics: Antibiotics, Antitubercular; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Humans; Molecular Probe Techniques; Mutation; Mycobacterium tuberculosis; New York City; Rifampin; Tuberculosis

1997
Laboratory diagnosis of antibiotic resistant Mycobacterium bovis within 48 h: a qualitative change in the approach to mycobacterial diseases in AIDS patients.
    AIDS (London, England), 1997, Volume: 11, Issue:6

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; DNA, Bacterial; Drug Resistance, Microbial; Female; Humans; Mycobacterium bovis; Polymerase Chain Reaction; Rifampin; Tuberculosis

1997
Rapid detection of multidrug-resistant tuberculosis.
    The European respiratory journal, 1997, Volume: 10, Issue:5

    Transmission of multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) presents a serious problem for infection control in hospitals, particularly in the context of co-infection with the human immunodeficiency virus (HIV). We report on the use of molecular genetic tools to allow rapid assessment of samples from patients potentially infected with MDR-TB. Sputum and bronchoalveolar lavage samples were obtained from two HIV-positive patients with suspected tuberculosis, who had previous contact with a known MDR-TB index case. Polymerase chain reaction (PCR) was used directly on clinical samples to amplify genetic loci associated with rifampicin resistance (rpoB), and strain-specific polymorphisms (the direct repeat (DR) region). Drug resistance was determined using a commercially available kit for detection of point mutations in the rpoB gene (Inno-Lipa RifTB; Innogenetics, Belgium), and confirmed by nucleotide sequencing. Strain variation was determined using the spoligotyping method, based on the presence or absence of variable linker sequences within the DR region. In one patient, infection with a MDR strain identical to that of a known index case was demonstrated. A second patient, although positive for M. tuberculosis, was found to be infected with a rifampicin-sensitive strain. Results were obtained within 48 h, allowing appropriate treatment to be initiated and infection control measures to be implemented. PCR-based tests for strain-typing and for identification of rifampicin resistance provide important tools for identifying patients with MDR-TB and for rapid monitoring of potential nosocomial spread of MDR-TB. Prompt confirmation or exclusion of possible transmission allows early clinical intervention to prevent future outbreaks of multidrug-resistant M. tuberculosis.

    Topics: Antibiotics, Antitubercular; Bronchoalveolar Lavage Fluid; Cross Infection; Drug Resistance, Microbial; Drug Resistance, Multiple; HIV Infections; Humans; Male; Microbial Sensitivity Tests; Molecular Biology; Mycobacterium tuberculosis; Polymerase Chain Reaction; Polymorphism, Genetic; Repetitive Sequences, Nucleic Acid; Rifampin; Sputum; Tuberculosis

1997
Therapeutic efficacies of isoniazid and rifampin encapsulated in lung-specific stealth liposomes against Mycobacterium tuberculosis infection induced in mice.
    Antimicrobial agents and chemotherapy, 1997, Volume: 41, Issue:6

    One recent promising development in the modification of drug formulations to improve chemotherapy is the use of a liposome-mediated drug delivery system. The efficacies of isoniazid and rifampin encapsulated in lung-specific stealth liposomes were evaluated by injecting liposomal drugs and free drugs into tuberculous mice twice a week for 6 weeks. Liposome-encapsulated drugs at and below therapeutic concentrations were more effective than free drugs against tuberculosis, as evaluated on the basis of CFUs detected, organomegaly, and histopathology. Furthermore, liposomal drugs had marginal hepatotoxicities as determined from the levels of total bilirubin and hepatic enzymes in serum. The elimination of mycobacteria from the liver and spleen was also higher with liposomal drugs than with free drugs. The encapsulation of antitubercular drugs in lung-specific stealth liposomes seems to be a promising therapeutic approach for the chemotherapy of tuberculosis.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Dose-Response Relationship, Drug; Isoniazid; Liposomes; Lung; Mice; Mice, Inbred Strains; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis

1997
Synergistic activities of clarithromycin and pyrazinamide against Mycobacterium tuberculosis in human macrophages.
    Antimicrobial agents and chemotherapy, 1997, Volume: 41, Issue:9

    The combination of clarithromycin and pyrazinamide was found to be synergistic against Mycobacterium tuberculosis in human macrophages. MICs were four- to eightfold lower for this combination than they were for either drug alone. Clarithromycin and rifampin, however, had only an additive effect.

    Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Cells, Cultured; Clarithromycin; Drug Synergism; Humans; Macrophages; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

1997
Administration of anti-tuberculosis drugs through patient empowerment.
    Tropical doctor, 1997, Volume: 27, Issue:4

    Topics: Adult; Antitubercular Agents; Chi-Square Distribution; Drug Therapy, Combination; Female; Hospitals, District; Humans; Isoniazid; Malawi; Male; Middle Aged; Patient Compliance; Patient Education as Topic; Patient Participation; Rifampin; Tuberculosis

1997
Evaluation of the INNO-LiPA Rif. TB assay, a reverse hybridization assay for the simultaneous detection of Mycobacterium tuberculosis complex and its resistance to rifampin.
    Antimicrobial agents and chemotherapy, 1997, Volume: 41, Issue:10

    Mycobacterium tuberculosis resistance to rifampin results from nucleotide changes in the gene encoding the beta-subunit of the RNA polymerase (rpoB). We developed a reverse hybridization-based line probe assay (LiPA; the INNO-LiPA Rif. TB) carrying one oligonucleotide probe for the detection of M. tuberculosis complex strains and nine probes designed to detect nucleotide changes in the relevant part of rpoB. This assay was evaluated with 107 M. tuberculosis isolates with known rpoB sequences, 52 non-M. tuberculosis complex strains, and 61 and 203 clinical isolates found to be sensitive and resistant, respectively, by in vitro testing. The results indicated that (i) the M. tuberculosis complex probe was 100% specific, (ii) when compared to the results of nucleotide sequencing, no discrepancies with the results of INNO-LiPA Rif. TB were observed, (iii) all strains sensitive by in vitro susceptibility testing were correctly identified, and (iv) among the strains resistant by in vitro susceptibility testing, only 4 (2%) yielded conflicting results. The INNO-LiPA Rif. TB is therefore a reliable and widely applicable assay and a valuable tool for routine diagnostic use, given its simplicity and rapid performance.

    Topics: Antibiotics, Antitubercular; Base Sequence; Drug Resistance, Microbial; Microbial Sensitivity Tests; Molecular Sequence Data; Mycobacterium; Mycobacterium tuberculosis; Nucleic Acid Hybridization; Polymerase Chain Reaction; Rifampin; RNA Probes; RNA, Bacterial; Tuberculosis; Tuberculosis, Multidrug-Resistant

1997
Detection of rifampin resistance by single-strand conformation polymorphism analysis of cerebrospinal fluid of patients with tuberculosis of the central nervous system.
    Journal of clinical microbiology, 1997, Volume: 35, Issue:11

    Mutations in a 69-bp region of the rpoB gene of Mycobacterium tuberculosis are associated with rifampin resistance (Rif[r]). These have been detected with mycobacterial DNA extracted from bacterial suspensions or respiratory specimens that were acid-fast smear positive. We experimented with a strategy for the rapid detection of Rif(r) in cerebrospinal fluid (CSF) samples. The strategy involves the amplification of the 69-bp region of rpoB by means of PCR and the identification of nucleotide mutations by single-strand conformation polymorphism (SSCP) analysis of the amplification products. Sixty-five CSF specimens collected from 29 patients (19 patients were coinfected with human immunodeficiency virus) with culture or autopsy-confirmed (22 patients) or highly probable (7 patients) tuberculosis of the central nervous system (CNS-TB) were processed. Amplified products suitable for evaluation by SSCP analysis were obtained from 37 CSF specimens from 25 subjects (86.2%). PCR-SSCP of CSF correctly identified the rifampin susceptibility phenotype of isolates from all 17 patients for whom the results of susceptibility tests carried out with strains cultured from CSF or respiratory samples were available. Moreover, this assay revealed the rifampin susceptibility genotype of isolates from the eight patients (three patients with culture-confirmed CNS-TB and five patients in whom CNS-TB was highly probable) for whom no susceptibility test results were available; the PCR-SSCP data obtained for these patients were concordant with the outcome after a standard antituberculosis treatment. The evolution of a mutation in the rpoB gene was documented in a patient during the course of treatment. PCR-SSCP analysis of CSF seems to be an efficacious method of predicting Rif(r) and would reduce the time required for susceptibility testing from approximately 4 to 8 weeks to a few days.

    Topics: Adult; Aged; AIDS-Related Opportunistic Infections; DNA-Directed RNA Polymerases; Drug Resistance, Microbial; Female; Genes, Bacterial; HIV Seropositivity; Humans; Italy; Male; Middle Aged; Mycobacterium tuberculosis; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Rifampin; Tuberculosis

1997
[A case of tuberculous abscess in the chest wall close to the thickening pleural lesion following tuberculous pleuritis].
    Nihon Kyobu Shikkan Gakkai zasshi, 1997, Volume: 35, Issue:9

    A 33-year-old woman with a history of right tuberculous pleuritis was successfully treated in December 1992 by administration of anti-tuberculous drugs, she demonstrated residual localized pleural thickening on chest computed tomography (CT) and gradually developed a subcutaneous mass in the right chest which became apparent in March 1993. In September, chest CT revealed a periocostal abscess in the right anterior chest wall close to the localized pleural thickening. The patient was diagnosed with tuberculous abscess in the right chest wall on confirmation of acid-fast bacilli in a needle aspiration material of the abscess, and was referred to our hospital. Anti-tuberculous chemotherapy was continued but the chest abscess grew, so on January 28, 1994 she underwent a resection of the abscess, the third costal cartilage and bone, and the parietal pleural lesion connected to the abscess. Histopathological examination showed that the abscess and parietal pleural lesion were compatible with tuberculosis, i.e. both lesions consisted of caseous necrosis and epitheloid cell granuloma, but acid-fast bacilli were not demonstrated in both lesions. After one year of postoperative anti-tuberculous chemotherapy, she was followed without any therapy for 3 years and there has been no recurrence to date. When a localized thickening pleural lesion remains after tuberculous pleuritis, complication of tuberculous abscess in the chest wall should be considered.

    Topics: Abscess; Adult; Antitubercular Agents; Female; Humans; Isoniazid; Rifampin; Thoracic Diseases; Tuberculosis; Tuberculosis, Pleural

1997
Acquired drug resistance in Mycobacterium tuberculosis isolates recovered from compliant patients with human immunodeficiency virus-associated tuberculosis.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 1997, Volume: 25, Issue:5

    We describe five compliant patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB) that relapsed, with acquisition of resistance by the original Mycobacterium tuberculosis strains. Both the first and second isolates from each patient had the same IS (insertion sequence) 6110-based DNA fingerprint patterns. Three of the five patients developed TB that was resistant to rifampin alone; no mutation in the region of the rpoB gene was detected by a line probe assay in two of the isolates from these patients. We discuss several factors presumably associated with acquired drug resistance in HIV-infected patients, including exogenous reinfection, drug interactions, malabsorption of drugs, and the presence of a large organism burden.

    Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Microbial; Humans; Isoniazid; Mycobacterium tuberculosis; Patient Compliance; Rifampin; Tuberculosis

1997
Outbreak of drug-resistant tuberculosis with second-generation transmission in a high school in California.
    The Journal of pediatrics, 1997, Volume: 131, Issue:6

    In spring 1993, four students in a high school were diagnosed with tuberculosis resistant to isoniazid, streptomycin, and ethionamide.. To investigate potential transmission of drug-resistant tuberculosis, a retrospective cohort study with case investigation and screening by tuberculin skin tests and symptom checks was conducted in a high school of approximately 1400 students. Current and graduated high-school students were included in the investigation. DNA fingerprinting of available isolates was performed.. Eighteen students with active tuberculosis were identified. Through epidemiologic and laboratory investigation, 13 cases were linked; 8 entered 12th grade in fall 1993; 9 of 13 had positive cultures for Mycobacterium tuberculosis with isoniazid, streptomycin, and ethionamide resistance, and all 8 available isolates had identical DNA fingerprints. No staff member had tuberculosis. One student remained infectious for 29 months, from January 1991 to June 1993, and was the source case for the outbreak. Another student was infectious for 5 months before diagnosis in May 1993 and was a treatment failure in February 1994 with development of rifampin and ethambutol resistance in addition to isoniazid, streptomycin, and ethionamide. In the fall 1993 screening, 292 of 1263 (23%) students tested had a positive tuberculin skin test. Risk of infection was highest among 12th graders and classroom contacts of the two students with prolonged infectiousness. An additional 94 of 928 (10%) students tested in spring 1994 had a positive tuberculin skin test; 22 were classroom contacts of the student with treatment failure and 21 of these had documented tuberculin skin test conversions.. Extensive transmission of drug-resistant tuberculosis was documented in this high school, along with missed opportunities for prevention and control of this outbreak. Prompt identification of tuberculosis cases and timely interventions should help reduce this public health problem.

    Topics: Adolescent; California; Cohort Studies; Disease Outbreaks; Drug Resistance, Multiple; Ethambutol; Ethionamide; Female; Humans; Infectious Disease Transmission, Vertical; Isoniazid; Male; Mass Screening; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Schools; Skin Tests; Sputum; Streptomycin; Tuberculosis

1997
Rifampin-monoresistant tuberculosis in New York City, 1993-1994.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 1997, Volume: 25, Issue:6

    All New York City patients whose cultures yielded Mycobacterium tuberculosis with isolated resistance to rifampin in 1993 and 1994 were included in this study. Of the 96 patients, 48 (50%) had primary resistance, 32 (33%) had acquired resistance, and 16 (17%) had unclassified resistance; 66% had histories of illicit drug use, and 79% were infected with human immunodeficiency virus (HIV). The median time to emergence of resistance was 40 weeks among the 32 patients with acquired resistance. Each of the HIV-infected patients with acquired resistance (cases, n = 29) was matched to two HIV-infected patients who had disease due to fully susceptible M. tuberculosis (controls, n = 58). In multivariate analysis, factors associated with the emergence of rifampin resistance were as follows: a sputum smear positive for acid-fast bacilli, advanced immunosuppression, and nonadherence to therapy.

    Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; Antibiotics, Antitubercular; Drug Resistance, Microbial; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; New York City; Rifampin; Tuberculosis

1997
Short-course chemoprophylaxis evaluated in gold miners with chronic silicosis.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1997, Volume: 1, Issue:1

    Topics: Antitubercular Agents; Gold; Humans; Isoniazid; Mining; Patient Compliance; Pyrazinamide; Rifampin; Silicosis; Treatment Outcome; Tuberculosis

1997
[Immunologic memory induced by Mycobacterium bovis in the inbred mice].
    Biulleten' eksperimental'noi biologii i meditsiny, 1997, Volume: 124, Issue:11

    Topics: Animals; Antitubercular Agents; Female; Fluorescent Antibody Technique, Direct; Immunologic Memory; Ionomycin; Isoniazid; Mice; Mice, Inbred CBA; Mycobacterium bovis; Phenotype; Rifampin; Spleen; T-Lymphocytes; Tuberculosis; Vaccination

1997
[Tuberculosis of the breast].
    Revue des maladies respiratoires, 1997, Volume: 14, Issue:5

    The authors report a case of tuberculosis of the breast in a patient aged 71. The case described is an example of a rare form of extra pulmonary tuberculosis whose diagnosis can pose problems. In view of the recent increase in the incidence of tuberculosis in certain developed countries and the growth in the proportion of cases of extra pulmonary tuberculosis especially in HIV sero-positive individuals an observation such as this is useful in that it recalls for clinicians the fact that tuberculosis may present in very unusual forms which are easily forgotten.

    Topics: Abscess; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Breast Diseases; Female; Follow-Up Studies; Humans; Isoniazid; Mammography; Prognosis; Radiography, Thoracic; Rifampin; Time Factors; Tomography, X-Ray Computed; Tuberculosis

1997
A lesson to be learned.
    The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1997, Volume: 1, Issue:6

    Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Industry; Ethics, Medical; Humans; Rifampin; Tuberculosis

1997
[Tuberculosis in hemodialysis].
    Nephrologie, 1997, Volume: 18, Issue:7

    The authors report a retrospective study in order to illustrate the particular features of tuberculosis in hemodialysis population. Thirty two patients over 203 (15.8%) in periodic hemodialysis, have presented a tuberculosis between 1983 and 1996. There were 17 men and 15 women aged from 14 to 60 years old. The features of the tuberculosis in these cases were marked by the extrapulmonary localizations (50%) notably nodes tuberculosis, and the difficulties of the diagnosis certainty. The diagnosis was suspected basing on the fever, the weigh loss, the rate sedimentation increase and the radiologic lesions in pulmonary tuberculosis and peripheric or deep lymph nodes involvement. The diagnosis confirmation was established bacteriologically in 6 cases (18.7%) and histologically in 14 cases (43.8%). The treatment consisted on the association of isoniazide, rifampicin and pyrazinamide which leads to recovery in 87.5%. This treatment was a diagnosis proof in the absence of confirmation.

    Topics: Adolescent; Adult; Antibiotics, Antitubercular; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Renal Dialysis; Retrospective Studies; Rifampin; Tuberculosis

1997
Brief report: rifampin-resistant tuberculosis in a patient receiving rifabutin prophylaxis.
    The New England journal of medicine, 1996, Jun-13, Volume: 334, Issue:24

    Topics: Adult; AIDS-Related Opportunistic Infections; Bacteriological Techniques; DNA Mutational Analysis; DNA, Bacterial; Drug Resistance, Microbial; Humans; Male; Mycobacterium tuberculosis; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Rifampin; Tuberculosis

1996
[Efficacy and tolerance of the treatment of tuberculosis in the aged].
    Archivos de bronconeumologia, 1996, Volume: 32, Issue:3

    We analyzed 55 confirmed cases of tuberculosis in patients over 65, a sample that amounted to 9% of all patients seen in our practice over a period of 5 years. Mean age was 72.4 and the male/female ratio was 4/1. The most frequently associated diseases were tobacco addiction (49%), chronic obstructive pulmonary disease (33%), alcoholism (25%) and prior diagnosis of tuberculosis (20%). Lung involvement was the most common clinical presentation (76%), followed by pleural (9%) and skeletal (7%) involvement. The clinical picture was non specific, with 13% remaining asymptomatic. Cough was the most frequent symptom (45%) and unilateral apical fibrosis with ulceration was the most frequent radiological finding. Pleural discharge and cavitation were demonstrated in 14 and 22%, respectively. Scarring was visible on X-rays in 44%. The tuberculin test was positive in 88% of the cases in which it was performed. Mean delay in diagnosis was 3.4 months; 62% were diagnosed by sputum test, 11% by culture, and 27% histology. In 4% death was directly caused by tuberculosis. Three patients withdrew from treatment, in one case treatment failed, and there was one relapse detected at follow-up. We observed adverse side effects in 33%, and found no statistically significant differences between the 2 therapeutic protocols used (2 months RHS/7 months RH and 2 months RHZS/4 months RH). The incidence of tuberculosis among the elderly is low in our practice and the entity behaves much as it does in the rest of the adult population. Both the efficacy and tolerance of treatment can be considered optimal.

    Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Drug Tolerance; Ethambutol; Evaluation Studies as Topic; Female; Follow-Up Studies; Humans; Isoniazid; Male; Rifampin; Risk Factors; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

1996
Hepatotoxic effects of tuberculosis therapy. A practical approach to a tricky management problem.
    Postgraduate medicine, 1996, Volume: 99, Issue:5

    Side effects of the most commonly used first-line antituberculosis drugs range from minor gastrointestinal symptoms to severe hepatotoxicity. If unrecognized, they can lead to increased morbidity and mortality as well as to higher healthcare costs. Side effects are most evident in patients with underlying compromise in hepatic function. Erratic treatment protocols not only promote secondary drug resistance but also offset all gains in tuberculosis control. Recognition of this problem, mandatory directly observed therapy, judicious standardized follow-up planning, and implementation of modified treatment protocols when needed may play a dominant role in treating and controlling tuberculosis and may also prevent the morbidity and mortality sometimes associated with tuberculosis treatment. In view of the changing epidemiology of tuberculosis and its global impact, the American Thoracic Society and the Centers for Disease Control and Prevention may need to look closely into the issues outlined here to develop a consensus and establish more specific guidelines.

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Humans; Isoniazid; Liver; Liver Diseases; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis

1996
[Oxidative metabolism changes in respiratory tract cells of guinea pigs during natural development of experimental tuberculosis and under specific chemotherapy].
    Problemy tuberkuleza, 1996, Issue:2

    108 guinea pigs were infected with M-tuberculosis 2 weeks later 36 of them were put on treatment with rifampicin and isoniazid, the rest served as untreated control. The comparison was made of mixed population of all the cells isolated from bronchoalveolar lavage versus pure fraction of alveolar macrophages (AM) by spontaneous and BCG killed culture-stimulated NBT-test, activity of superoxide dismutase and catalase, levels of malonic dialdehyde. Estimations were conducted 1 day, 1, 2 and 6 weeks after inoculation in untreated animals and after 1 months of treatment in treated animals. AM lost ability for stimulation to the end of 24 h period since inoculation. 1-2 weeks later metabolic depression and complete areactivity occurred. Mixed population within postinoculation week 1 mobilized its defense potential. In extensive generalized tuberculosis all the cells of the respiratory tract worked for self-defense and lost protecting abilities. Specific chemotherapy reestablished functional status of both AM and cell population on the whole.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Bronchoalveolar Lavage Fluid; Catalase; Cells, Cultured; Guinea Pigs; Isoniazid; Lung; Macrophages, Alveolar; Malondialdehyde; Oxidoreductases; Rifampin; Superoxide Dismutase; Time Factors; Tuberculosis

1996
Remission of hypercalciuria in patients with tuberculosis after treatment.
    Calcified tissue international, 1996, Volume: 59, Issue:1

    The hypercalciuria evolution and other bone metabolism parameters were evaluated in patients with tuberculosis after treatment. Twenty-two patients with tuberculosis and 54 normal subjects were studied; they consumed an average diet (calcium intake 1000 mg/day). Ten of these patients and nine normal subjects were also studied after a low calcium diet (400 mg/calcium/day) and after a load of oral calcium of 1000 mg (calcium absorption test). The study with an average diet was performed after 1 week (basal) and 3, 6, and 12 months after the antituberculosis treatment was started; the calcium absorption test was carried out 2 weeks, 3 and 12 months after the treatment was started. On an average diet, patients with tuberculosis presented, at baseline state, lower calcidiol levels than normal controls. Serum calcitriol levels at baseline were higher than at 6 and 12 months. Serum parathyroid hormone (PTH) levels in patients with tuberculosis were lower than in normal controls at baseline, but these levels were similar to controls at 3, 6, and 12 months after treatment. During the calcium absorption test and under basal conditions, patients with tuberculosis showed lower serum PTH and calcidiol levels in all the dietetic situations than in normal controls. However, serum calcitriol levels were higher than in controls after the restrictive diet. After 3 months of treatment, urinary calcium excretion was normal in patients with tuberculosis during the average and low diets, but higher than in control group after calcium load. After 12 months of treatment, all the biochemical parameters of the patients with tuberculosis were similar to the control group under all the dietetic situations. These data indicate that antituberculous treatment, although it may contribute to the production of some alteration in the calcium and vitamin D metabolism, basically favors the correction of disturbances associated with tuberculosis.

    Topics: Adult; Calcitriol; Calcium; Female; Humans; Isoniazid; Male; Parathyroid Hormone; Remission Induction; Rifampin; Tuberculosis; Vitamin D

1996
Whither the roles of rifater and rifamate?
    Pennsylvania medicine, 1996, Volume: 99, Issue:3

    Topics: Antitubercular Agents; Drug Combinations; Humans; Isoniazid; Pyrazinamide; Rifampin; Trimethoprim; Tuberculosis

1996
Chemotherapeutic activity of benzoxazinorifamycin, KRM-1648, against Mycobacterium tuberculosis in C57BL/6 mice.
    Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1996, Volume: 77, Issue:2

    To investigate the chemotherapeutic activity of benzoxazinorifamycin, KRM-1648, in comparison with rifabutin (RFB) and rifampin (RIF) against experimental tuberculosis.. C57BL/6 mice were infected with 10(5)-10(6) colony forming units (CFU) of either drug-susceptible virulent Mycobacterium tuberculosis (H37Rv) or multi-drug resistant (MDR) M. tuberculosis strain (2230) and were treated from the next day (early treatment) or after 2 weeks following infection (established infection) with 20 mg/kg dose of each drug or none (untreated control). The efficacy of chemotherapy was assessed based on prevention of mortality and on CFU levels in the lungs and spleens.. All three drugs prevented mortality for up to 28 weeks of observation, while all the untreated control mice died by 4 weeks. Analysis of CFUs revealed superior therapeutic activity of both KRM-1648 and RFB as compared to RIF against the drug-susceptible strain of M. tuberculosis under the early treatment protocol. Twelve weeks' treatment with KRM-1648 or RFB caused complete sterilization of the lungs. However, residual organisms started appearing in the spleens 6 weeks after cessation of treatment with RFB and 16 weeks after KRM-1648 treatment. In mice infected with a MDR strain of M. tuberculosis, which was susceptible in vitro to KRM-1648, the drug did not appear to have any activity. Since the MDR organisms did not multiply in vivo, and did not cause any mortality up to 28 weeks in the RIF-treated control mice, a state of semi-dormancy of the organisms which might prevail in vivo could be responsible for refractoriness to treatment with KRM-1648.. KRM-1648 showed an excellent chemotherapeutic activity, as compared to RFB and RIF, against drug-susceptible tuberculosis. However, all three analogues were ineffective against infection with multi-drug resistant strain of M. tuberculosis.

    Topics: Animals; Antibiotics, Antitubercular; Colony Count, Microbial; Female; Lung; Male; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins; Spleen; Tuberculosis; Tuberculosis, Multidrug-Resistant

1996
Mycobacterial tenosynovitis of the flexor tendons of the hand. A report of five cases.
    Journal of hand surgery (Edinburgh, Scotland), 1996, Volume: 21, Issue:3

    We present five cases of mycobacterial tenosynovitis of the flexor tendons of the fingers. These cases were observed during the last 12 years and treated by the same surgeon. This pathology is uncommon now, but it is becoming more frequent, especially in patients with diminished immunity. The diagnosis was most commonly made after synovectomy in patients presenting with carpal tunnel syndrome associated with slightly painful swelling at the wrist. Histological and bacteriological examinations are very important and revealed tuberculosis in four of our patients and mycobacterium in one, and the treatment consists of synovectomy and appropriate antibiotics. The functional result is usually good, but recurrence is not uncommon. Long-term follow-up is necessary. Local corticosteroid therapy could have a part in the causation of this condition.

    Topics: Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Carpal Tunnel Syndrome; Combined Modality Therapy; Ethambutol; Female; Hand; Humans; Isoniazid; Male; Middle Aged; Mycobacterium avium-intracellulare Infection; Rifampin; Tenosynovitis; Tuberculosis

1996
Effect of rifampin on the plasma concentration and the clinical effect of haloperidol concomitantly administered to schizophrenic patients.
    Journal of clinical psychopharmacology, 1996, Volume: 16, Issue:3

    We assessed the changes of plasma haloperidol concentrations and clinical responses repeatedly up to 4 weeks after coadministration or discontinuation of rifampin in 12 schizophrenic patients taking haloperidol alone (group I) and 5 patients taking haloperidol and antituberculotic drugs (group II). After coadministration of rifampin in group I, daily trough haloperidol concentrations rapidly decreased and reached 63% of baseline level by day 3, 41.3% by day 7, and 30% by day 28. On the other hand, after discontinuation of rifampin in group II, plasma haloperidol concentration increased to 140.7% of baseline level by day 3, 228.7% by day 7, and 329% by day 28. In this study, a 30% or greater change in the clinical rating scale was considered a positive clinical response of the drug interaction. Using this criterion, 50% of the group I subjects responded according to the Brief Psychiatric Rating Scale (BPRS) total score, and 25% responded according to the BPRS subscale for psychiatric symptoms. No positive responses were observed in group II patients. These results strongly suggest that rifampin interacts with the clinical effects as well as the plasma concentrations of coadministered haloperidol, and careful monitoring should be considered when coadministration or discontinuation of rifampin is needed in a schizophrenic patient taking haloperidol.

    Topics: Adult; Antibiotics, Antitubercular; Antipsychotic Agents; Drug Interactions; Drug Therapy, Combination; Female; Haloperidol; Humans; Male; Rifampin; Schizophrenia; Tuberculosis

1996
Activity of KRM-1648 in combination with isoniazid against Mycobacterium tuberculosis in a murine model.
    Antimicrobial agents and chemotherapy, 1996, Volume: 40, Issue:2

    The activity of KRM-1648, alone and in combination with isoniazid, was compared with those of isoniazid, rifampin, and the combination of rifampin plus isoniazid in a murine model of tuberculosis. Four-week-old female CD-1 mice were infected intravenously with approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms. Treatment was started 1 week postinfection and was given by gavage 5 days per week. The duration of the treatment phase was 12 weeks, with groups of mice sacrificed at 2, 4, 6, 8, and 12 weeks. For the observation phase, additional groups of treated mice were sacrificed at 4, 8, 16, and 24 weeks after the cessation of treatment. Viable cell counts were determined from homogenates of the spleens and the right lungs. KRM-1648 was the most active single agent evaluated and resulted in no detectable CFUs in the spleens and lungs by the end of 6 weeks of treatment. Neither rifampin nor isoniazid reduced cell counts to undetectable levels, even after 12 weeks of treatment. The combination of KRM-1648 plus isoniazid was much more active than rifampin plus isoniazid. KRM-1648 plus isoniazid resulted in the apparent sterilization of organs at 6 months following the cessation of treatment. The promising activity of KRM-1648 may allow for ultrashort-course therapy of tuberculosis, i.e., treatment regimens of 4 months or less.

    Topics: Animals; Antibiotics, Antitubercular; Colony Count, Microbial; Drug Therapy, Combination; Female; Isoniazid; Lung; Mice; Mycobacterium tuberculosis; Rifampin; Rifamycins; Spleen; Time Factors; Tuberculosis

1996
In vitro bactericidal and in vivo therapeutic activities of a new rifamycin derivative, KRM-1648, against Mycobacterium tuberculosis.
    Antimicrobial agents and chemotherapy, 1996, Volume: 40, Issue:2

    The in vitro and in vivo activities of a new rifamycin derivative, KRM-1648, against Mycobacterium tuberculosis H37Rv were compared with those of rifampin. Bactericidal activity was evaluated by using a silicone-coated slide culture method. The MBC of KRM-1648 was 0.15 to 0.3 microgram/ml for 24 h of exposure, while that of rifampin was > 160 microgram/ml under the same conditions. Against experimental murine tuberculosis, KRM-1648 exhibited significant therapeutic effects, in terms of prolonged survival times for mice compared with those with rifampin treatment, even at lower doses, such as 1 and 3 mg/kg. At a dose of 3 mg/kg, KRM-1648 was at least as effective as rifampin at 10 mg/kg. The combination of KRM-1648 (3 mg/kg) plus isoniazid (3 mg/kg) plus ethambutol (10 mg/kg) exhibited much more activity than did rifampin (10 mg/kg) plus isoniazid (3 mg/kg) plus ethambutol (10 mg/kg). These findings suggest that KRM-1648 is a promising candidate for the treatment of tuberculosis.

    Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Combinations; Ethambutol; Isoniazid; Male; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Rifamycins; Tuberculosis

1996
Activity of KRM-1648 alone or in combination with both ethambutol and kanamycin or clarithromycin against Mycobacterium intracellulare infections in beige mice.
    Antimicrobial agents and chemotherapy, 1996, Volume: 40, Issue:2

    The in vivo activities of KRM-1648 alone or in combination with both ethambutol (EB) and kanamycin (KM) or clarithromycin (CAM) were tested against Mycobacterium intracellulare infections in beige mice. KRM-1648 was more active than rifampin (RFP) when each drug was used alone, and the efficacy of KRM-1648 was similar to those of both kanamycin and clarithromycin. The combination KRM-1648-KM-EB was strongly active and rapidly reduced the numbers of bacilli both in lungs and in spleens compared with RFP-KM-EB. The combination KRM-1648-CAM had greater therapeutic effects than RFP-CAM; this difference in efficacy was more pronounced for lungs than for spleens. These findings suggest that KRM-1648 is a promising candidate for combination therapy with other potent antimycobacterial drugs.

    Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Clarithromycin; Colony Count, Microbial; Drug Combinations; Drug Therapy, Combination; Ethambutol; Female; Kanamycin; Lung; Male; Mice; Mycobacterium avium Complex; Rifampin; Rifamycins; Spleen; Tuberculosis

1996
Preventive chemotherapy of tuberculosis in Cornell model mice with combinations of rifampin, isoniazid, and pyrazinamide.
    Antimicrobial agents and chemotherapy, 1996, Volume: 40, Issue:3

    The efficacies of rifampin-containing preventive regimens were measured in Cornell model mice in which an initially severe infection with Mycobacterium tuberculosis H37Rv was first treated for 7 weeks with 25 mg of isoniazid and 1,000 mg of pyrazinamide per kg of body weight in the diet and then with one of four test regimens given by daily oral gavage for 6 weeks. These regimens were 15 mg of rifampin per kg alone (R), rifampin plus 25 mg of isoniazid per kg (RH), rifampin plus 150 mg of pyrazinamide per kg (RZ), or rifampin plus isoniazid and pyrazinamide (RHZ). The interval between the rifampin gavage and the gavage with the other drugs ranged from 10 to 45 min, so that interference with rifampin absorption did not occur. Mice were sacrificed at 11 and 20 weeks after the termination of chemotherapy, with each killing being preceded by 3 weeks of high-dose dihydrocortisone treatment. Entire spleens and lungs were cultured. The proportions of mice with positive spleens at either killing time were 74% of 43 mice treated with R, 63% of 41 mice treated with RH, 65% of 43 mice treated with RZ, and 53% of 45 mice treated with RHZ, a just significant (P = 0.04) trend for fewer positive spleens with increasing numbers of drugs in the regimen. However, no trend was found in the corresponding proportions of mice with positive spleens or lungs, which were 81, 63, 65, and 71% for mice treated with R, RH, RZ, and RHZ, respectively. Thus, in the Cornell model, R alone, RH, RZ, and RHZ all had similar efficacies.

    Topics: Animals; Antitubercular Agents; Colony Count, Microbial; Culture Media; Drug Combinations; Drug Interactions; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Pyrazinamide; Rats; Rifampin; Spleen; Tuberculosis

1996
Antituberculosis activities of clofazimine and its new analogs B4154 and B4157.
    Antimicrobial agents and chemotherapy, 1996, Volume: 40, Issue:3

    In our efforts to develop new drugs for the treatment of tuberculosis, especially that caused by multidrug-resistant strains, we investigated clofazimine (CFM) and two of its analogs, B4154 and B4157, for their antituberculosis activities. Twenty M. tuberculosis strains were tested, including 16 drug-resistant strains (strains resistant to one or more antituberculosis drugs), for their susceptibilities to these three agents. All of the strains were found to be susceptible to B4154 and B4157, and one strain showed moderate resistance to CFM. The MICs of B4154, B4157, and CFM at which 90% of strains were inhibited were 0.25, 0.12, and < or = 1.0 microgram/ml, respectively. The intracellular activities of CFM and B4157 were superior to that of B4154. The chemotherapeutic activities of the three compounds were evaluated in C57BL/6 mice. At a dose of 20 mg/kg of body weight, the activity of CFM was slightly superior to that of B4157; however, both compounds prevented mortality and caused a significant reduction in the numbers of CFU in the lungs and spleens. The animals treated with B4157 showed less pigmentation than animals treated with CFM. The chemotherapeutic activity of CFM was comparable to those of rifampin and isoniazid. Complete susceptibility of multidrug-resistant strains to CFM and B4157 and the therapeutic efficacies of these compounds against mouse tuberculosis make these drugs attractive agents for the treatment of drug-resistant tuberculosis.

    Topics: Animals; Antitubercular Agents; Cell Line; Clofazimine; Drug Resistance, Multiple; Female; Isoniazid; Macrophages; Male; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rats; Rifampin; Tuberculosis

1996
Focal tuberculosis of the liver with local hemorrhage in a patient with acquired immunodeficiency syndrome.
    Liver, 1996, Volume: 16, Issue:3

    Tuberculosis of the liver is common in patients with acquired immunodeficiency syndrome (AIDS). Tuberculous liver granulomas in such patients are usually atypical. The liver granulomas may be even totally absent, but liver tissue usually reveals numerous acid-fast bacilli. Focal tuberculosis of the liver is a less common form of liver tuberculous infection. We present a 33-year old white homosexual man infected with the human immunodeficiency virus. He had three tumour-like lesions in the left liver lobe, which were subsequently diagnosed as focal hepatic tuberculosis with local hemorrhage. This unusual presentation of liver tuberculosis indicates the necessity of an aggressive diagnostic approach for the evaluation of focal liver lesions in patients with AIDS.

    Topics: Acquired Immunodeficiency Syndrome; Adult; Ethambutol; Granuloma; Histocytochemistry; Homosexuality, Male; Humans; Isoniazid; Liver; Male; Mycobacterium; Pyrazinamide; Rifampin; Tuberculosis

1996
[Cytokine production during the development and correction of an immunodeficiency in experimental tuberculosis].
    Problemy tuberkuleza, 1996, Issue:1

    The authors investigated spontaneous and induced secretion of cytokins at different stages of generalized tuberculosis. In the development of infection there were inhibited IL-2 synthesis in response to ConA, emerging activity of PNO-alpha in response to the inductors in blood serum and culture of peritoneal macrophages, enhanced secretion of IL-6. Complete immunodeficiency was associated with cessation of IL-2 synthesis by splenocytes, elevated production of IL-6 by peritoneal macrophages, low concentrations of PNO-alpha in the serum and peritoneal macrophage cultures. In the treatment of M. bovis-infected mice with antibacterial drugs alone IL-6 secretion by peritoneal macrophages and PNO-alpha activity in the serum were increased. Immunocorrection resulted in marked activation of IL-2 production by splenocytes in response to ConA as well as enhanced synthesis of IL-6 in unstimulated cultures of peritoneal macrophages.

    Topics: Adjuvants, Immunologic; Animals; Antitubercular Agents; Concanavalin A; Drug Evaluation, Preclinical; Drug Therapy, Combination; Immunity, Cellular; Immunologic Deficiency Syndromes; Interleukin-2; Interleukin-6; Isoniazid; Mice; Mycobacterium bovis; Rifampin; Thymus Hormones; Tuberculosis; Tumor Necrosis Factor-alpha

1996
From the Centers for Disease Control and Prevention. Clinical update: impact of HIV protease inhibitors on the treatment of HIV-infected tuberculosis patients with rifampin.
    JAMA, 1996, Nov-20, Volume: 276, Issue:19

    Topics: Anti-HIV Agents; Antibiotics, Antitubercular; Contraindications; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Practice Guidelines as Topic; Rifampin; Tuberculosis

1996
Clinical update: impact of HIV protease inhibitors on the treatment of HIV-infected tuberculosis patients with rifampin.
    MMWR. Morbidity and mortality weekly report, 1996, Oct-25, Volume: 45, Issue:42

    In 1995 and 1996, the Food and Drug Administration (FDA) approved three products in the new protease inhibitor class of drugs--saquinavir (Invirase), ritonavir (Norvir), and indinavir (Crixivan). Another drug in this class of agents, nelfinavir (Viracept) (Agouron Pharmaceuticals), is expected to be available soon from the manufacturer through an expanded-access program. All four drugs, which inhibit HIV protease and thus interfere with viral maturation and replication, are the most potent antiretroviral agents available to treat patients with HIV disease. However, these protease inhibitors interact with rifamycin derivatives, such as rifampin and rifabutin, which are used to treat and prevent the mycobacterial infections commonly observed in HIV-infected patients. Rifamycins accelerate the metabolism of protease inhibitors (through induction of hepatic P450 cytochrome oxidases), resulting in subtherapeutic levels of the protease inhibitors. In addition, protease inhibitors retard the metabolism of rifamycins, resulting in increased serum levels of rifamycins and the likelihood of increased drug toxicity. This report describes approaches for managing patients who are candidates for or who are undergoing protease inhibitor therapy when tuberculosis (TB) is diagnosed and presents interim recommendations for managing these patients until additional data are available and formal guidelines are issued.

    Topics: Anti-HIV Agents; Antibiotics, Antitubercular; Contraindications; Drug Interactions; HIV Infections; HIV Protease Inhibitors; Humans; Practice Guidelines as Topic; Rifampin; Tuberculosis

1996
Four-drug initial therapy for TB is standard treatment.
    Pennsylvania medicine, 1996, Volume: 99, Issue:1

    Topics: Aminosalicylic Acid; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1996
[Influence of rifampicin on antihypertensive effects of dihydropiridine calcium-channel blockers in four elderly patients].
    Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics, 1996, Volume: 33, Issue:9

    Rifamicin, an antituberculosis agent, is one of the most potent inducers of hepatic drug-oxidation enzymes. Rifampicin can reduce the efficacy of several therapeutically important drugs (including verapamil and diltiazem) by accelerating systemic elimination or by increasing hepatic first-pass metabolism. Because dihydropyridine calcium-channel blockers are mainly metabolized by the liver, rifampicin may also increase the extraction of these drugs and thereby reduce their antihypertensive effects. Here we report four possible cases of interaction between rifampicin and dihydropiridine calcium-channel blockers. Rifampicin was given to treat tuberculosis in four elderly hypertensive patients whose blood pressure was well-controlled by one or more dihydropiridine calcium-channel blockers (nisoldipine, nifedipine, or barnidipine and manidipine), shortly after the start of antituberculosis therapy, their blood pressures rose. Either much greater doses of dihydropyridines or additional antihypertensive agents had to be given to keep blood pressure under control. After withdrawal of rifampicin, blood pressure fell in all patients and the doses of the antihypertensive agents had to be reduced. These findings indicate that rifampicin may lessen the antihypertensive effects of dihydropiridine calcium-channel blockers.

    Topics: Aged; Aged, 80 and over; Antibiotics, Antitubercular; Blood Pressure; Calcium Channel Blockers; Cytochrome P-450 CYP2E1; Dihydropyridines; Drug Interactions; Drug Therapy, Combination; Enzyme Induction; Female; Humans; Hypertension; Male; Rifampin; Tuberculosis

1996
Tuberculosis control programme guidelines--treatment regimens.
    South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 1996, Volume: 86, Issue:10

    Topics: Antitubercular Agents; Body Weight; Dose-Response Relationship, Drug; Drug Combinations; Ethambutol; Humans; Isoniazid; Optic Neuritis; Practice Guidelines as Topic; Pyrazinamide; Rifampin; South Africa; Streptomycin; Tuberculosis

1996
Experience of tacrolimus-based immunosuppression in living-related liver transplantation complicated with graft tuberculosis: interaction with rifampicin and side effects.
    Transplantation proceedings, 1996, Volume: 28, Issue:6

    Topics: Adult; Antibiotics, Antitubercular; Drug Interactions; Ethambutol; Female; Histocompatibility Testing; Humans; Immunosuppressive Agents; Infant; Isoniazid; Liver Transplantation; Living Donors; Mycobacterium tuberculosis; Postoperative Complications; Rifampin; Streptomycin; Tacrolimus; Tuberculosis

1996
Tuberculosis and renal transplantation.
    Transplantation proceedings, 1996, Volume: 28, Issue:6

    Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Follow-Up Studies; Humans; Isoniazid; Kidney Transplantation; Male; Postoperative Complications; Pyrazinamide; Retrospective Studies; Rifampin; Time Factors; Tuberculosis

1996
CDC lists options for managing rifampin, protease inhibitor therapy.
    American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 1996, Dec-15, Volume: 53, Issue:24

    Topics: Antibiotics, Antitubercular; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; HIV Infections; Humans; Protease Inhibitors; Rifampin; Tuberculosis

1996
Osteomalacia during rifampicin and isoniazid therapy is rare in Hong Kong.
    International journal of clinical pharmacology and therapeutics, 1996, Volume: 34, Issue:12

    Prolonged therapy with rifampicin and isoniazid can cause vitamin D deficiency or osteomalacia, particularly in patients with marginal vitamin D stores. In the New Territories East of Hong Kong, there were at least 1,526 new cases of tuberculosis over a 14-month period in 1994-1995. Any severe cases of osteomalacia were expected to be hospitalized in the sole general teaching hospital of the region. However, among all the general medical patients with one of their discharge ICD codes being 268 (vitamin D deficiency) or 275 (disorders of mineral metabolism), none had osteomalacia due to rifampicin and isoniazid chemotherapy. Thus, this complication appears to be rare in Hong Kong whose residents generally have a higher vitamin D status than those of the U.K.

    Topics: Antitubercular Agents; Hong Kong; Hospitals, Teaching; Humans; Isoniazid; Osteomalacia; Rifampin; Tuberculosis

1996
[Tuberculosis of the middle ear: a rare extrapulmonary manifestation].
    Deutsche medizinische Wochenschrift (1946), 1996, Dec-06, Volume: 121, Issue:49

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Diagnosis, Differential; Ear Diseases; Ear, Middle; Female; Humans; Isoniazid; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

1996
CPCRA researchers present OI studies at Vancouver.
    NIAID AIDS agenda, 1996

    The Community Programs for Clinical Research on AIDS (CPCRA) presented several recent findings from clinical trials at the International Conference on AIDS. Weekly doses of fluconazole can safely prevent persistent yeast infections in HIV-infected women who frequently develop yeast infections of the mouth, vagina and throat. Combination antibiotic therapy given intermittently is an effective initial treatment for persons with HIV-related tuberculosis. High dosages of clarithromycin should not be given to patients with Mycobacterium avium complex (MAC); doses above 500 mg are associated with higher mortality levels. Researchers have also determined the genetic sequence of the virus that causes molluscum contagiosum, a skin disease affecting up to 18 percent of AIDS patients.

    Topics: Adult; AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Antitubercular Agents; Candidiasis; Child; Clarithromycin; Clinical Trials as Topic; DNA, Viral; Drug Therapy, Combination; Ethambutol; Female; Fluconazole; Humans; Isoniazid; Molluscum Contagiosum; Molluscum contagiosum virus; Multicenter Studies as Topic; Mycobacterium avium-intracellulare Infection; Ofloxacin; Patient Compliance; Pyrazinamide; Rifampin; Sequence Analysis, DNA; Tuberculosis

1996
Treating concurrent HIV and TB. Centers for Disease Control and Prevention.
    AIDS clinical care, 1996, Volume: 8, Issue:12

    The Centers for Disease Control and Prevention's (CDC) clinical alert on how to treat concurrent HIV and TB are reprinted. Three physicians, Edward Nardell, Gerald Friedland, and Carol Braun Trapnell, comment on the HIV-TB issue and the CDC's guidelines. Dr. Nardell discusses protease inhibitor treatment and rifampin-containing TB regimens. Dr. Friedland emphasizes the individualization of therapy. Dr. Trapnell discusses the need for further clinical trials to study the interactions of protease inhibitors and the rifamycins. Dr. Trapnell also points out the need for drugs that do not interact with the cytochrome P450 system.

    Topics: Antitubercular Agents; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Rifampin; Treatment Outcome; Tuberculosis

1996
Tuberculosis of the breast.
    The European journal of surgery = Acta chirurgica, 1995, Volume: 161, Issue:7

    To present our 20 years experience of tuberculosis of the breast.. Retrospective study.. Teaching hospital, Turkey.. 9 women with tuberculous mastitis.. Cure.. All cases underwent frozen section and excision. One required a simple mastectomy because of the extent of destruction; the remainder underwent lumpectomy. All patients were given rifampicin, ethambutol, and isoniazid, and the three who had tuberculosis of other organs were also treated with streptomycin. Mean follow up was 87 months (range 6-178) and two patients were lost to follow up, at three and six years, respectively. Histological examination showed the presence of tubercle and central caseation in 8 cases and granulomatous infiltration in one.. Tuberculous mastitis is rare, and should be suspected in any woman with persistent breast abscesses and sinuses, particularly if she lives in an area from which tuberculosis has not been eradicated. Conservative surgery and antituberculous drugs are the treatment of choice.

    Topics: Adult; Aged; Antitubercular Agents; Combined Modality Therapy; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Mastectomy, Segmental; Mastitis; Middle Aged; Retrospective Studies; Rifampin; Streptomycin; Tuberculosis

1995
Use of thiacetazone.
    Lancet (London, England), 1995, Jan-07, Volume: 345, Issue:8941

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Therapy, Combination; Female; HIV Seropositivity; Humans; Male; Patient Compliance; Rifampin; Risk Factors; South Africa; Thioacetazone; Tuberculosis

1995
Rifampicin-resistant tuberculosis.
    Lancet (London, England), 1995, Oct-07, Volume: 346, Issue:8980

    Topics: Animals; Antibiotics, Antitubercular; Drug Resistance, Microbial; Humans; Mice; Mycobacterium avium-intracellulare Infection; Mycobacterium tuberculosis; Rifabutin; Rifampin; Tuberculosis

1995
An economic evaluation of alternative programme designs for tuberculosis control in rural Uganda.
    Social science & medicine (1982), 1995, Volume: 40, Issue:9

    Tuberculosis (TB) and AIDS are infections that are among the most feared of all diseases. Both have been widely discussed by the western media in recent months, for a variety of reasons, but it is the combination of the two diseases in an ever increasing number of patients that is causing concern to health planners and health economists. While AIDS is untreatable and prevention of further infection depends largely on changes in sexual behaviour, TB remains eminently treatable. Preventing the spread of TB depends on the effective treatment of active cases, taking 6-12 months, depending on the drugs used. In order to ensure completion of treatment, a programme of registering and following up patients is required. A number of different programme designs are considered and an analysis of both costs and consequences is attempted in order to find the most cost-effective alternative. Data from western Uganda for 1992 are used for the study and the implications of the findings for both Uganda and other African countries are discussed. It is concluded that a programme based on the ambulatory treatment of patients at their nearest health unit, whilst living at home, is the most cost-effective design, largely because of reduced costs to the patients themselves. Specific recommendations are made regarding the implementation of such a programme.

    Topics: Ambulatory Care; Cost of Illness; Cost-Benefit Analysis; Drug Packaging; Guidelines as Topic; Humans; Isoniazid; Patient Education as Topic; Program Development; Program Evaluation; Rifampin; Rural Health; Time Factors; Treatment Outcome; Tuberculosis; Uganda

1995
Drugs for tuberculosis.
    The Medical letter on drugs and therapeutics, 1995, Aug-04, Volume: 37, Issue:954

    Topics: Adult; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Combinations; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

1995
[BCG vaccination (present-day and future)].
    Problemy tuberkuleza, 1995, Issue:3

    Topics: Adolescent; Adult; Age Factors; BCG Vaccine; Child; Child, Preschool; Dimethyl Sulfoxide; Humans; Infant; Infant, Newborn; Rifampin; Time Factors; Tuberculosis; Vaccination

1995
Tuberculosis drug resistance in the Western Cape.
    South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 1995, Volume: 85, Issue:6

    Drug resistance is a serious problem in the treatment of tuberculosis and a threat to successful tuberculosis control programmes. Local health workers have expressed concern that the increasing tuberculosis epidemic in the Western Cape is partly attributable to drug resistance. The aim of this study was to determine the prevalence of tuberculosis drug resistance (including multidrug resistance) and to investigate possible relationships between drug resistance and patient demographic characteristics.. During a defined period, all adult (> or = 15 years) patients with pulmonary tuberculosis (confirmed by culture) from all tuberculosis clinics in the Western Cape were included. Previous tuberculosis treatment history was obtained by interviews, utilising a standardised questionnaire. Acquired drug resistance was determined on cultures from patients with a prior history of tuberculosis treatment, while initial resistance was determined from tuberculosis cases with no history of previous treatment.. Data from 7,266 patients were analysed. After adjusting for missing information by way of a random sample validation study, 32% of patients were found to have a history of previous treatment, 63% indicated no previous treatment, and in 5% the treatment history was unknown. Rates for initial resistance were found to be low at 3,9% for isoniazid, 1,1% for rifampicin and 0,2% for ethambutol. Combined resistance to isoniazid and rifampicin (multidrug resistance) was found to be 1,1% in patients not treated before. Acquired resistance rates were higher at 10,8% for isoniazid, 4,2% for rifampicin, 0,3% for ethambutol and 4,0% for multidrug resistance. Logistic regression analysis of the data indicated that drug resistance was not influenced by population group, gender or age. Patients with a history of tuberculosis treatment were found to be at an increased risk of developing drug resistance (relative risk 2,6). Some regions in the Western Cape had higher proportions of previously treated patients with consequent higher acquired resistance rates.. Results from this study indicated that drug resistance is currently not a major problem in the Western Cape, rates comparing favourably with those reported from developed countries and being much lower than those for developing countries. Every effort should therefore be made to maintain the status quo and to prevent the emergence of further resistance. The priority for tuberculosis control in the Western Cape should remain to limit transmission of the disease by reducing the infectious pool through improved cure of (especially) smear-positive cases.

    Topics: Adolescent; Adult; Aged; Drug Resistance, Multiple; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; South Africa; Tuberculosis

1995
[Tuberculous dacryocystitis].
    Archives de pediatrie : organe officiel de la Societe francaise de pediatrie, 1995, Volume: 2, Issue:2

    Acute infection and inflammation of the nasolacrimal sac may complicate congenital obstruction of the nasolacrimal duct. Acute dacryocystitis is uncommon later and tuberculosis is exceptionally responsible for it.. A 4 1/2 year-old boy was admitted because he suffered from acute left dacryocystitis with fever and cervical adenitis. Involvement of both lacrymal gland and lymph node persisted despite antibiotic and corticosteroid therapy. Needle biopsy of the lymph node showed presence of Mycobacterium tuberculosis and excision revealed caseating granulomas. The tuberculin skin test was positive while pulmonary tuberculosis was discovered in the patient's father. The patient was successfully given izoniazid, rifampin for 9 months and pyrazinamide for 2. Drainage of the sac area was necessary after 1 month of treatment followed by dacryocystorhinostomy.. This rare case of tuberculous dacryocystitis permits to delineate the difficulties of ophthalmologic therapy.

    Topics: Acute Disease; Child, Preschool; Dacryocystitis; Dacryocystorhinostomy; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

1995
Drug therapy of bacillus Calmette-Guérin sepsis.
    Urological research, 1995, Volume: 22, Issue:6

    Intravesical bacillus Calmette-Guérin (BCG) is widely used for the treatment of transitional cell carcinoma of the bladder. Although it is usually well tolerated, sepsis can occur, which has resulted in at least eight deaths [3]. The survival of Connaught BCG-infected mice treated with single and combination antibiotic and steroid therapy was evaluated. Triple-drug therapy with isoniazid, rifampin, and prednisolone resulted in 53% survival compared with 25% survival in the control group (P = 0.0209). A survival of only 10.5% was observed with treatment using prednisolone alone. This survival was worse than that of the control group (25%), and approached statistical significance (P = 0.0669). Our data suggest that BCG sepsis probably has components of both a hypersensitivity reaction and bacterial sepsis; they support the current use of combination antibiotic and steroid therapy for treatment of BCG sepsis in humans, but argue against treatment with steroids alone.

    Topics: Animals; Body Weight; Cycloserine; Drug Combinations; Isoniazid; Mice; Mice, Inbred C3H; Mycobacterium bovis; Prednisone; Rifampin; Survival Analysis; Tuberculosis

1995
Antituberculosis activity of clarithromycin.
    Antimicrobial agents and chemotherapy, 1995, Volume: 39, Issue:12

    Antituberculosis activity of clarithromycin (CLA), a macrolide antibiotic, was investigated in vitro, in macrophages, and in C57BL/6 mice, CLA showed high in vitro MICs (4 to > 16 micrograms/ml) for several strains of Mycobacterium tuberculosis and caused slight enhancement of activity of rifampin (RIF) against H37Rv but failed to increase the activity of either RIF or isoniazid (INH) against other strains. However, inside J774A.1 macrophages, CLA showed high activity and was synergistic with RIF against some strains of tubercle bacilli susceptible or resistant to INH and RIF. In the in vivo studies with a drug-susceptible strain (H37Rv), CLA protected mice from mortality due to tuberculosis for up to 8 weeks of observation. The CFU data for lungs and spleens revealed that the antituberculosis activity of CLA is inferior to those of INH and streptomycin. However, the activity of CLA when used alone or in combination was comparable to that of thiacetazone, indicating its potential usefulness as a secondary drug for the treatment of tuberculosis.

    Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Clarithromycin; Colony Count, Microbial; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Synergism; Female; Isoniazid; Macrophages; Male; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1995
Management of primary chest wall tuberculosis.
    Scandinavian journal of thoracic and cardiovascular surgery, 1995, Volume: 29, Issue:3

    Primary tuberculosis of the chest wall is rare and its clinical presentation may resemble pyogenic abscess or tumour. The diagnosis is difficult, since smears or cultures of aspirate frequently fail to show tubercle bacilli. Seven cases of primary chest-wall tuberculosis treated between 1973 and 1992 are described. All presented with a progressively enlarging mass. The diagnosis was based on bacteriologic and histologic findings, but definitive diagnosis was obtained before treatment in only two cases. Satisfactory results were obtained with surgical debridement and specific chemotherapy in six cases and with chemotherapy alone in one case. From this limited experience, we suggest that primary chest-wall tuberculosis should initially be treated with a combination regimen of antituberculous chemotherapy, which should take more than 9 months. If the lesion progressively enlarges or secondary infection occurs, however, adequate surgical debridement is also required.

    Topics: Abscess; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Combined Modality Therapy; Debridement; Diagnosis, Differential; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Suppuration; Thoracic Diseases; Thoracic Neoplasms; Treatment Outcome; Tuberculosis

1995
In vitro and in vivo activities of the benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis.
    Antimicrobial agents and chemotherapy, 1995, Volume: 39, Issue:10

    The in vitro and in vivo activities of a new benzoxazinorifamycin, KRM-1648 (KRM), against Mycobacterium tuberculosis were studied. The MIC at which 50% of the isolates are inhibited (MIC50) and the MIC90 of KRM for 30 fresh isolates of M. tuberculosis measured by the BACTEC 460 TB System were 0.016 and 2 micrograms/ml, respectively. These values were much lower than those for rifampin (RMP), which were 4 and >128 micrograms/ml, respectively, and considerably lower than those for rifabutin (RBT), which were 0.125 and 8 micrograms/ml, respectively. A correlational analysis of the MICs of these drugs for the clinical isolates revealed the presence of cross-resistance of the organisms to KRM and either RMP or RBT although the MICs of KRM were distributed over a much lower range than were those of the other two drugs. KRM and RMP at concentrations of 1 to 10 micrograms/ml almost completely inhibited the bacterial growth of RMP-sensitive strains (H37Rv, Kurono, and Fujii) of M. tuberculosis phagocytosed in macrophage-derived J774.1 cells. KRM was more active than RMP in inhibiting the growth of the RMP-resistant (MIC = 8 micrograms/ml) Kurata strain but failed to show such an effect against the RMP-resistant (MIC >128 micrograms/ml) Watanabe stain. When KRM was given to M. tuberculosis-infected mice at dosages of 5 to 20 mg/kg of body weight by gavage, one daily six times per week from day 1 after infection, it was much more efficacious than RMP against infections induced in mice by the RMP-sensitive Kurono strain, as measured by a reduction of rates of mortality, a reduction of the frequency and extent of gross lung lesions, histopathological changes in lung tissues, and a decrease in the bacterial loads in the lungs and spleens of infected mice. KRM also displayed significant therapeutic efficacy against infection induced by the RMP-resistant Kurata strain, while neither KRM nor RMP was efficacious against infection by the RMP-resistant Watanabe strain. In the case of infection with the Kurono strain, the efficacy of the drugs in prolonging the time of survival was in the order KRM, RBT, RMP. KRM was much more efficacious than RMP, when given at 1- to 4-week intervals. These findings suggest that KRM may be useful for the clinical treatment of tuberculosis contracted through RMP-sensitive strains, even when it is administered at long intervals.

    Topics: Animals; Antibiotics, Antitubercular; Drug Resistance, Microbial; Female; Lung; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Rifamycins; Tuberculosis

1995
Antimycobacterial activity of a new rifamycin derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV (T9).
    Antimicrobial agents and chemotherapy, 1995, Volume: 39, Issue:10

    The antimycobacterial activities of a new rifampin (RIF) derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV (To), against 20 susceptible and multidrug-resistant strains of Mycobacterium tuberculosis and 20 Mycobacterium avium complex (MAC) strains were investigated. The radiometric MICs of T9 for M. tuberculosis were significantly lower than those of RIF. The MICs of T9 and RIF at which 90% of the RIF-susceptible strains were inhibited were < or = 0.25 and < or = 0.5 micrograms/ml, respectively. Interestingly, T9 had lower MICs against some RIF-resistant M. tuberculosis strains. T9 had better activity against MAC strains, and the MIC at which 90% of the MAC strains were inhibited was < or = 0.125 micrograms/ml, and that of RIF was < or = 2.0 micrograms/ml. T9 also showed high in vitro bactericidal and intracellular activities which were significantly superior to those of RIF against both M. tuberculosis, and MAC strains. More importantly, T9 showed excellent in vivo activity against M. tuberculosis H37Rv compared with that of RIF in both the lungs and spleens of C57BL/6 mice, indicating the potential therapeutic value of T9 in the treatment of mycobacterial infections.

    Topics: Animals; Antibiotics, Antitubercular; Cell Line; Female; Male; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Rifampin; Rifamycins; Tuberculosis

1995
Analysis of RNA polymerase gene mutation in three isolates of rifampicin resistant Mycobacterium tuberculosis.
    The Southeast Asian journal of tropical medicine and public health, 1995, Volume: 26 Suppl 1

    Drug resistance in tuberculosis (TB) has become a major public health threat, particularly when the disease cannot be 100% controlled by BCG vaccination. In Thailand, resistance to rifampicin, a major component of multidrug regimens of treatment, is the common cause of tuberculosis recurrence. The mechanism of rifampicin resistance involves alterations of the RNA polymerase subunit beta (rpo B) gene. Mutations in rpo B gene were often found to cluster within a region of 23 amino acids starting from amino acid residue 511 to residue 533. Direct PCR sequencing was utilized to compare base changes in rpo B gene in three rifampicin resistant phenotypes of M. tuberculosis isolated from Thai patients. The sequences showed one base substitution at codon 531 resulting in an amino acid change from serine (TCG) to leucine (TTG) in a multidrug resistant isolate compared to that of a sensitive isolate, whereas a point mutation at codon 516 causing a change from aspartic acid (GAC) to tyrosine (TAC) was detected in a multidrug resistant isolate from a HIV positive patient. In an isolate resistant only to rifampicin a double mutation at codon 531 changing serine (TCG) to phenylalanine (TTT) was found. No mutations were observed in the same region in streptomycin, ethambutol or isoniazid resistant isolates. This finding reports two new types of mutation (GAC to TAC at codon 516 and TCG to TTT at codon 531) and confirms a direct correlation between rpo B gene alteration and rifampicin resistant phenotype in M. tuberculosis.

    Topics: Amino Acid Sequence; Base Sequence; DNA Primers; Drug Resistance, Microbial; Humans; Molecular Sequence Data; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; RNA Polymerase II; Thailand; Tuberculosis

1995
Alternatives to INH chemoprophylaxis.
    Indian pediatrics, 1995, Volume: 32, Issue:8

    Topics: Antibiotics, Antitubercular; Antitubercular Agents; Chemoprevention; Child; Child, Preschool; Drug Resistance, Multiple; Humans; India; Isoniazid; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

1995
Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis.
    Chest, 1994, Volume: 105, Issue:2

    We report three patients who experienced hepatotoxic reactions in association with acetaminophen ingestion while undergoing treatment for active tuberculosis with isoniazid, rifampin, and other agents. All were young adult women. One patient intentionally took a large amount of acetaminophen and had typical signs and symptoms of acetaminophen overdosage; another took acetaminophen in combination form for a minor upper respiratory illness. She experienced no symptoms. The remaining patient took acetaminophen to ameliorate the symptoms of fever and malaise that were subsequently attributed to tuberculosis. She had the rapid onset of signs and symptoms of isoniazid hepatotoxicity. The patterns of liver function abnormalities were similar: each patient experienced pronounced serum elevations of hepatocellular enzymes with at most only modest rises in those of bilirubin. All antituberculous drugs were withheld until symptoms resolved and laboratory values became normal; then treatment for tuberculosis was resumed without isoniazid and was successfully completed in all three patients. These cases plus similar reports in the literature suggest that isoniazid or rifampin, or both, may potentiate the hepatotoxicity of acetaminophen, perhaps by induction of cytochrome P450 isozymes that oxidize acetaminophen to its toxic metabolites.

    Topics: Acetaminophen; Adult; Capreomycin; Ciprofloxacin; Drug Combinations; Drug Overdose; Ethambutol; Female; Humans; Isoniazid; Liver; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

1994
Treating tuberculosis with one combination drug.
    South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 1994, Volume: 84, Issue:8 Pt 1

    Topics: Antitubercular Agents; Drug Combinations; Ethambutol; Humans; Isoniazid; Patient Compliance; Pyrazinamide; Rifampin; Tuberculosis

1994
Activity of KRM-1648, a new benzoxazinorifamycin, against Mycobacterium tuberculosis in a murine model.
    Antimicrobial agents and chemotherapy, 1994, Volume: 38, Issue:10

    The activity of KRM-1648 was evaluated in a murine model of tuberculosis. Approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms were given intravenously to 4-week-old female outbred mice. Treatment was started 1 week postinfection and given by gavage for 4 weeks. Viable-cell counts were determined from homogenates of spleen and lung tissues. The activity of KRM-1648 was compared with those of rifampin and rifabutin at 20 mg/kg of body weight. KRM-1648 was more active than either rifampin or rifabutin against organisms in spleens and lungs. KRM-1648 alone and in combination with either isoniazid, ethambutol, pyrazinamide, or levofloxacin was evaluated. Other treatment groups received isoniazid, ethambutol, pyrazinamide, or levofloxacin as single agents. KRM-1648 was the most active single agent evaluated. KRM-1648-pyrazinamide and KRM-1648-isoniazid were the most active combinations. These combinations were more active than KRM-1648 alone. The promising activity of KRM-1648 in M. tuberculosis-infected mice suggests that it is a good candidate for clinical development as a new antituberculosis agent.

    Topics: Animals; Antibiotics, Antitubercular; Drug Therapy, Combination; Female; Isoniazid; Mice; Pyrazinamide; Rifabutin; Rifampin; Rifamycins; Tuberculosis

1994
Empiric antituberculosis treatment: benefits for earlier diagnosis and treatment of tuberculosis.
    Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1994, Volume: 75, Issue:5

    Tuberculosis may be diagnosed too late, especially in HIV-infected patients, with consequences on bacillus transmission and survival. Empiric antibuberculosis treatment (EATT) may be started before diagnosis of tuberculosis is confirmed. As rifampicin is a broad spectrum antibiotic, EATT including rifampicin may be effective in infections other than tuberculosis, leading to misdiagnosis.. To define the efficiency criteria of EATT with or without rifampicin.. Between 1988 and 1991, 20 febrile patients with suspected tuberculosis (including 15 who were HIV-positive) were started on EATT in the absence of bacteriological or histological proof of tuberculosis. 10 patients (50%) received a 4-drug non-specific EATT including rifampicin, isoniazid, pyrazinamide and ethambutol, and 10 (50%), received a 3-drug specific EATT without rifampicin.. In 10 patients (50%), the diagnosis of tuberculosis was confirmed by positive cultures within a mean of 32 days (15-57 days) after the beginning of EATT (group TB 1). Of the 10 patients whose cultures remained negative, 4 (20%) became afebrile and showed improvement under EATT (group TB 2), and 6 (30%) remained febrile and did not improve (group No TB). Patients from groups TB 1 and TB 2 became afebrile within a mean of 11 days (1-54 days). This delay was not different between patients receiving specific or non-specific EATT. In patients receiving specific EATT, rifampicin was added to the initial 3-drug treatment after resolution of fever.. EATT appears to be a useful method for rapid presumptive diagnosis and treatment of tuberculosis.

    Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Body Weight; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Fever; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis

1994
Tuberculosis in human immunodeficiency virus-exposed or -infected United States children.
    The Pediatric infectious disease journal, 1994, Volume: 13, Issue:11

    This study was designed to provide a preliminary assessment of the occurrence of tuberculosis exposure, infection and disease within a national sample of infants and children with human immunodeficiency virus (HIV) exposure or infection, and to determine the prevalence of Mycobacterium tuberculosis isolates resistant both to isoniazid and rifampin in these patients or their adult source contacts. A retrospective questionnaire survey was conducted of infants and children with HIV exposure or infection evaluated by pediatric HIV referral centers in the United States comprising the pediatric units or subunits of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group (PACTG). Seventy of 72 sites during a mean period of 5 (range, 1 to 12) years participated in this study and had provided care for 14,038 patients. There were 75 cumulative total cases of tuberculosis disease seen since each site was established. Therapy for asymptomatic infection was given to another 40 children and for tuberculosis exposure to 71 children. Annualized case rates were 478/100,000 for sites established in 1990 to 1992, 117/100,000 for 1988 to 1989, 63/100,000 for 1986 to 1987 and 58/100,000 for 1981 to 1985 (P = 0.05, Spearman's p test for trend). By comparison, the 1992 age-specific tuberculosis case rate for all U.S. children < 5 years was 5.5/100,000. Twenty percent of isolates from PACTG patients and 15% of isolates from adult source contacts were resistant to isoniazid and rifampin.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Adult; Child; Child, Preschool; Drug Resistance, Multiple; HIV Infections; Humans; Infant; Isoniazid; Retrospective Studies; Rifampin; Surveys and Questionnaires; Tuberculosis; United States

1994
Isoniazid and acetylisoniazid kinetics in serum and urine in pulmonary primary complex with intermittent regimen.
    Indian pediatrics, 1994, Volume: 31, Issue:3

    Twenty patients, 1 through 13 years of age from Pediatric Tuberculosis Clinic of All India Institute of Medical Sciences, New Delhi, suffering from pulmonary primary complex (PPC) were investigated for serum and urine concentrations of isoniazid (INH) and acetylisoniazid (AcINH). Patients were put on an intermittent regimen - 2HR, 4H2R2, INH (H) was given in a dose of 10 mg/kg/day for first 2 months (the daily dose phase), followed by 20 mg/kg/dose in biweekly phase of regimen for rest of the 4 months, whereas, rifampicin (R) was given as 12 mg/kg in both daily as well as biweekly phases. In the biweekly phase of regimen, after 7 days of biweekly administration of drugs, INH and AcINH concentrations were estimated by HPLC at 0,1,3,5 and 7 hours in serum, and at 0-3, 3-6, 6-12 and 12-24 hour-intervals of drug administration in urine. Peak concentrations of INH and AcINH (Mean +/- SD) were 2.6 +/- 1.8 and 5.5 +/- 2.6 micrograms/ml in serum (Cmax), and 5.7 +/- 4.8 and 21.5 +/- 12.1 mg in urine, respectively. Time to achieve Cmax (Tmax), for INH and AcINH were 1 and 5 hours respectively while time of peak concentration in urine for INH was 3-6 hours and for AcINH 6-12 hours. The half-life (T1/2) of INH was 4.5 hours and area under serum-concentration time-curve (AUC0-7h) was 20.7 micrograms/ml/h (mean values). In biweekly phase (4H2R2) of regimen, just before administration of next dose, 0 hour (or 72 hours) concentration of INH was estimated at 0.47 +/- 0.3 micrograms/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Infant; Isoniazid; Male; Rifampin; Tuberculosis

1994
The promise and reality of fixed-dose combinations with rifampicin. A joint statement of the International Union Against Tuberculosis and Lung Disease and the Tuberculosis Programme of the World Health Organization.
    Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1994, Volume: 75, Issue:3

    Topics: Biological Availability; Drug Combinations; Humans; Rifampin; Societies, Medical; Tuberculosis; World Health Organization

1994
Preventive therapy of tuberculosis with rifapentine in immunocompetent and nude mice.
    American journal of respiratory and critical care medicine, 1994, Volume: 150, Issue:5 Pt 1

    The effectiveness of intermittent administration of rifapentine (RPT), with or without isoniazid (INH), for preventive therapy of tuberculosis was evaluated in immunocompetent (normal) and nude mice. After infection with a small inoculum of Mycobacterium tuberculosis H37Rv, normal mice developed a chronic and nonfatal infection, and the bacterial population became relatively stable after an initial period of limited multiplication. On the other hand, nude mice developed an acute and fatal infection, and all untreated mice died within 5 wk, with very high colony-forming-unit (CFU) counts in their organs. Various degrees of bactericidal activity were shown in normal mice after daily treatment with rifampin (RMP) plus pyrazinamide (PZA) for 13 wk, INH daily for 26 wk, or RPT once weekly for 13 or 26 wk or once fortnightly for 26 wk. The activity of RPT was significantly enhanced when INH was added at the same dosing frequency. In nude mice the response of M. tuberculosis infection to certain regimens was less favorable than that in normal mice, suggesting that preventive therapy may be less effective in severely immunodeficient hosts even during treatment. After chemotherapy was stopped, virtually all nude mice relapsed within 12 wk regardless of the regimen administered, whereas no or very few relapses were observed in normal mice that had been treated with RMP+PZA daily for 13 wk, or RPT alone or RPT+INH once weekly for 26 wk. The latter three regimens and RPT+INH once weekly for 13 wk may be applied for fixed-duration preventive therapy in human immunodeficiency virus (HIV)-negative subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Animals; Antitubercular Agents; Colony-Forming Units Assay; Drug Therapy, Combination; Female; Immunity; Isoniazid; Mice; Mice, Nude; Pyrazinamide; Rifampin; Tuberculosis

1994
Intermittent azithromycin for treatment of Mycobacterium avium infection in beige mice.
    Antimicrobial agents and chemotherapy, 1994, Volume: 38, Issue:8

    The activity of azithromycin (AZI) was evaluated in the beige mouse model of disseminated Mycobacterium avium infection. Mice were infected intravenously with approximately 10(7) viable avium ATCC 49601. AZI at 50, 100, or 200 mg/kg of body weight or clarithromycin (CLA) at 200 mg/kg was given by gavage 5 days per week for 4 weeks. Groups of treated mice were compared with untreated control animals. A dose-related reduction in cell counts in organs was observed with AZI treatment. AZI at 200 mg/kg was more active than CLA at 200 mg/kg against organisms in spleens. The activities of these two agents at 200 mg/kg were comparable against organisms in lungs. In a second study, AZI at 200 mg/kg was given daily for 5 days; this was followed by intermittent AZI treatment for the next 3 weeks. The activities of AZI given on a three-times- and five-times-per-week basis in the continuation phase were comparable. AZI given on a once-weekly basis was less active. The regimen of AZI given in combination with rifapentine on a once-weekly basis for 8 weeks showed promising activity. Clinical evaluation of AZI and rifapentine will help to define the roles of these agents in the treatment of disseminated M. avium complex infection.

    Topics: Animals; Azithromycin; Clarithromycin; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mycobacterium avium; Rifampin; Tuberculosis

1994
Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society.
    Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace, 1994, Volume: 49, Issue:4

    1. A 6-mo regimen consisting of isoniazid, rifampin, and pyrazinamide given for 2 mo followed by isoniazid and rifampin for 4 mo is the preferred treatment for patients with fully susceptible organisms who adhere to treatment. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should be included in the initial regimen until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance (i.e., there is less than 4% primary resistance to isoniazid in the community, and the patient has had no previous treatment with antituberculosis medications, is not from a country with a high prevalence of drug resistance, and has no known exposure to a drug-resistant case). This four-drug, 6-mo regimen is effective even when the infecting organism is resistant to INH. This recommendation applies to both HIV-infected and uninfected persons. However, in the presence of HIV infection it is critically important to assess the clinical and bacteriologic response. If there is evidence of a slow or suboptimal response, therapy should be prolonged as judged on a case by case basis. 2. Alternatively, a 9-mo regimen of isoniazid and rifampin is acceptable for persons who cannot or should not take pyrazinamide. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) should also be included until the results of drug susceptibility studies are available, unless there is little possibility of drug resistance (see Section 1 above). If INH resistance is demonstrated, rifampin and ethambutol should be continued for a minimum of 12 mo. 3. Consideration should be given to treating all patients with directly observed therapy (DOT). 4. Multiple-drug-resistant tuberculosis (i.e., resistance to at least isoniazid and rifampin) presents difficult treatment problems. Treatment must be individualized and based on susceptibility studies. In such cases, consultation with an expert in tuberculosis is recommended. 5. Children should be managed in essentially the same ways as adults using appropriately adjusted doses of the drugs. This document addresses specific important differences between the management of adults and children. 6. Extrapulmonary tuberculosis should be managed according to the principles and with the drug regimens outlined for pulmonary tuberculosis, except for children who have miliary tuberculosis, bone/joint tuberculosis, or tuberculous meningitis who should receive a mi

    Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Child; Clinical Protocols; Drug Monitoring; Ethambutol; Humans; Infant; Isoniazid; Patient Compliance; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

1994
Tuberculosis in cats.
    The Veterinary record, 1994, Apr-02, Volume: 134, Issue:14

    Topics: Animals; Cat Diseases; Cats; Mycobacterium bovis; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1994
Rifampin-induced nonresponsiveness of giant cell arteritis to prednisone treatment.
    Archives of internal medicine, 1994, Jul-11, Volume: 154, Issue:13

    Rifampin is an enzymatic inducer known to increase steroid metabolism. We studied two patients with giant cell arteritis in whom rifampin caused nonresponsiveness to prednisone treatment. A prednisone pharmacokinetics study was done. When rifampin-prednisone treatment must be used in giant cell arteritis, we propose increasing the prednisone dosage to 2 mg/kg per day.

    Topics: Aged; Female; Giant Cell Arteritis; Humans; Prednisone; Rifampin; Tuberculosis

1994
From the Food and Drug Administration.
    JAMA, 1994, Aug-03, Volume: 272, Issue:5

    Topics: Antitubercular Agents; Blood Donors; Drug Approval; Drug Combinations; Electromagnetic Phenomena; Equipment and Supplies; Equipment Failure; HIV Infections; HIV Seronegativity; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis; United States; United States Food and Drug Administration; Wheelchairs

1994
Tuberculosis in liver transplant patients.
    Transplantation, 1994, Aug-15, Volume: 58, Issue:3

    Tuberculosis has been increasing especially in urban areas and in immunosuppressed patients; however, the incidence and factors associated with tuberculosis in OLT patients are unknown. Five of 550 patients who underwent OLT at the Mount Sinai Medical Center during a 5-year period were noted to have tuberculosis. The mean age of the patients was 49.2 years; there were 3 males and 2 females and 3 were foreign born. One of 5 had a prior history of tuberculosis. Tuberculin skin tests performed before transplant revealed 1 positive and 2 anergic reactions. The preoperative chest x-ray revealed apical fibrosis in 2 patients and bilateral apical disease with a nodule in 1 patient. Tuberculosis developed from 2 to 57 months after surgery in 4/5 patients. One had miliary lesions of the peritoneum discovered at the time of OLT. One patient had recent contact with a patient with pulmonary tuberculosis. At presentation, fever was present in 4 of 5 patients, pulmonary lesions in 3 patients, meningitis in 2; during hospitalization, 1 had a liver abscess and disseminated intravascular coagulation and peripheral gangrene. Lymphocytosis was noted in the pleural (1), peritoneal (1), and cerebrospinal fluid (1). Acid-fast smears were positive in bronchoalveolar lavage fluid (1), peritoneal isolates (1), and liver biopsy (1). All patients had positive cultures for Mycobacterium tuberculosis. These isolates were all sensitive to isoniazid, streptomycin, rifampin, ethambutol, and pyrazinamide. Four of 5 patients were treated with isoniazid and rifampin, 2 received pyrazinamide, 2, amikacin, 2, ofloxacin, and 2, ethambutol. Three of 5 patients are doing well on antituberculous therapy and 2 expired with tuberculosis as the cause of death. In OLT patients with unexplained fever, tuberculosis including extrapulmonary and disseminated disease should be considered since the mortality rate is very high. Liver transplantation can be performed in the presence of active peritoneal tuberculosis with the use of judicious antituberculous therapy. The role of preventive therapy is controversial, though use in certain high risk patients is suggested.

    Topics: Adult; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Isoniazid; Liver Transplantation; Male; Middle Aged; Rifampin; Tuberculin Test; Tuberculosis

1994
Rifampin-resistant Mycobacterium kansasii.
    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 1994, Volume: 18, Issue:5

    We identified 36 rifampin-resistant Mycobacterium kansasii isolates, including 17 (4%) of 464 isolates recovered in Texas between 1989 and 1992. Of 29 patients infected with rifampin-resistant M. kansasii whose history of medication was known, 90% had previously received rifampin, and 58% of these patients had been treated with one or two effective drugs. Thirty-two percent of rifampin-resistant isolates recovered since 1989 were from patients who were seropositive for human immunodeficiency virus (HIV) infection. Twenty courses of therapy with a four-drug regimen determined on the basis of in vitro susceptibilities were administered to 16 patients from whom rifampin-resistant isolates were recovered; the therapy did not include surgery. Sputum cultures converted to negative as the result of 90% of treatments (time to conversion: mean, 11 weeks; range, 4-20 weeks). Bacteriologic relapses occurred in four of five patients who withdrew from therapy after being culture negative for < or = 6 months of therapy and in one of 12 patients who were culture negative for at least 12 months of therapy (mean, 16.3 months). This study suggests that the prognosis for cure of infection due to rifampin-resistant M. kansasii with chemotherapy alone is excellent, although the number of cases appears to be increasing, in part because of the HIV disease epidemic.

    Topics: Adult; Aged; Aged, 80 and over; Amikacin; Antitubercular Agents; Ciprofloxacin; Clinical Protocols; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Pyrazinamide; Pyridoxine; Rifampin; Streptomycin; Texas; Treatment Outcome; Tuberculosis

1994
Comparative in vivo activities of rifabutin and rifapentine against Mycobacterium avium complex.
    Antimicrobial agents and chemotherapy, 1994, Volume: 38, Issue:2

    The dose-response activity of rifabutin and the comparative activities of rifabutin and rifapentine were evaluated in the beige mouse model of disseminated Mycobacterium avium complex (MAC) infection. In the dose-response study, mice were infected intravenously with approximately 10(7) viable M. avium ATCC 49601. Treatment with rifabutin at 10, 20, or 40 mg/kg of body weight was started 7 days postinfection and was administered daily for 10 days. The mice were sacrificed 3 to 5 days after the last dose. Spleens, livers, and lungs were homogenized, and viable cell counts were determined by serial dilution and plating onto Middlebrook 7H10 agar. A dose-related reduction in MAC cell counts in the organs was noted for this MAC isolate. The comparative activities of rifabutin and rifapentine were determined against a total of five MAC isolates in the beige mouse model. Rifabutin or rifapentine (20 mg/kg each) was administered to infected mice for 10 days. Groups of treated mice were compared with untreated control animals. Despite favorable in vitro susceptibility results, rifabutin and rifapentine had activities in the spleens against only two of the five MAC isolates. For these two MAC isolates, rifabutin was more active than rifapentine. These agents had activities in the lungs against three of five isolates. Further study of rifabutin or rifapentine against a broader range of clinical isolates in a murine infection model may be useful as part of the continuing development of newer rifamycins as anti-MAC agents.

    Topics: Animals; Antitubercular Agents; Colony Count, Microbial; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Humans; Lung; Mice; Mice, Inbred C57BL; Mycobacterium avium; Mycobacterium avium Complex; Rifabutin; Rifampin; Tuberculosis

1994
Detecting multidrug resistant tuberculosis early.
    Lancet (London, England), 1993, Mar-13, Volume: 341, Issue:8846

    Topics: Drug Resistance, Microbial; Humans; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

1993
Antimycobacterial activity of methdilazine (Md), an antimicrobic phenothiazine.
    APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, 1993, Volume: 101, Issue:6

    Methdilazine (Md) could inhibit various Mycobacterium spp. at 5-15 micrograms/ml concentrations in vitro as well as in vivo. When Md was tested in combination with streptomycin (Sm), rifampicin (Rf) or methyl-DOPA (m-D), it showed synergistic effects only with respect to methyl-DOPA.

    Topics: Animals; Drug Interactions; Histamine H1 Antagonists; Humans; Male; Methyldopa; Mice; Mice, Inbred Strains; Microbial Sensitivity Tests; Mycobacterium; Phenothiazines; Rifampin; Streptomycin; Tuberculosis

1993
Transmission of multidrug-resistant Mycobacterium tuberculosis among persons with human immunodeficiency virus infection in an urban hospital: epidemiologic and restriction fragment length polymorphism analysis.
    The Journal of infectious diseases, 1993, Volume: 168, Issue:4

    From January 1990 to December 1991, 16 patients with multidrug-resistant tuberculosis (MDR-TB) caused by Mycobacterium tuberculosis resistant to isoniazid, rifampin, and streptomycin were diagnosed at Elmhurst Hospital. Compared with other TB patients, MDR-TB patients were more likely to have human immunodeficiency virus (HIV) infection (14/16 vs. 21/204, P < .001) and a prior admission (10/16 vs. 3/204, P < .001). HIV-infected patients hospitalized for > 10 days within three rooms of an infectious MDR-TB patient had higher risk of acquiring MDR-TB than did HIV-infected patients with shorter hospitalizations or locations further from the MDR-TB patient(s) (6/28 vs. 2/90, P < .001). Isolates of 6 of 8 MDR-TB patients in a chain of transmission were identical by restriction fragment length polymorphism DNA typing. Ambulation on the wards of inadequately masked TB patients and lack of negative pressure in isolation rooms probably facilitated transmission. This report documents nosocomial transmission of MDR-TB and underscores the need for effective isolation practices and facilities in health care institutions.

    Topics: AIDS-Related Opportunistic Infections; Cross Infection; DNA, Bacterial; Drug Resistance; Hospitals, Urban; Humans; Isoniazid; Mycobacterium tuberculosis; New York City; Polymorphism, Restriction Fragment Length; Rifampin; Streptomycin; Time Factors; Tuberculosis

1993
[Cephalosporins as possible methods of etiotropic therapy of tuberculosis].
    Problemy tuberkuleza, 1993, Issue:4

    Cephalosporin antibiotics cefamezin (I generation drug sensitive to beta-lactamase) and cefotaxime (III generation drug resistant to beta-lactamase) have been tested for antituberculous activity. The latter was found dependent on resistance to mycobacterial beta-lactamase. A minimal inhibiting concentration of cefotaxime was similar to that of etambutol and tisamid. Cefotaxime also enhanced tuberculostatic and bactericidal effect of isoniazid and rifampicin. Combination cefotaxime+isoniazid+rifampicin proved more effective than cefotaxime+etambutol+tisamid. The effectiveness against tuberculosis of the beta-lactamase resistant cephalosporin points to the validity of further research for active phthisiatric drugs among III generation cephalosporins.

    Topics: Animals; Cefazolin; Cefotaxime; Cells, Cultured; Cephalosporins; Culture Media; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Mice; Microbial Sensitivity Tests; Rifampin; Tuberculosis

1993
Short course chemotherapy for tuberculosis in children.
    Journal of tropical pediatrics, 1993, Volume: 39, Issue:6

    In order to determine the efficacy of short course chemotherapy (SCC) for tuberculosis in children, 83 newly diagnosed cases in children < 12 years old were given SCC and were prospectively followed for 1-3 years. Seventy-one cases were treated for 6-9 months as they had mild to moderate involvement. Twelve cases were treated for 12 months as they had meningitis (7), disseminated tuberculosis (2), or miliary tuberculosis (3). The results showed that none of the children, at the end of follow up, showed evidence of active tuberculosis. All children tolerated the drugs well, with side effects noticed being mild, namely transient hepatitis (4), vomiting (1), and skin rash (1). It is suggested that SCC for 6-9 months using isoniazid (INH) and rifampicin along with other drugs when necessary is highly effective in most cases of tuberculosis in children and has several advantages over conventional chemotherapy of 18 months or longer duration.

    Topics: Adolescent; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Pyrazinamide; Rifampin; Skin Diseases; Streptomycin; Tuberculosis; Vomiting

1993
[Tuberculosis of the parotid gland].
    Anales otorrinolaringologicos ibero-americanos, 1993, Volume: 20, Issue:4

    We present a case of parotid tuberculosis diagnosed through F.N.A.C. (fine needle aspiration cytology). Due to this rare extrapulmonary location of the tuberculosis, the AA. make a review of the last 12 years concerning literature together with a monographic study of the process.

    Topics: Demyelinating Diseases; Electromyography; Facial Nerve; Facial Paralysis; Female; Functional Laterality; Hemiplegia; Humans; Hypoglossal Nerve; Isoniazid; Middle Aged; Parotid Diseases; Parotid Gland; Pyridoxine; Rifampin; Sialography; Tuberculosis

1993
[Hepatic toxicity of antitubercular agents. Role of different drugs. 199 cases].
    Presse medicale (Paris, France : 1983), 1993, Sep-11, Volume: 22, Issue:26

    One hundred and ninety-nine cases of hepatic injury related to antituberculous treatment were analysed in order to assess the role played by each drug and to look for predisposing factors. This is a retrospective study of 169 cases reported in the literature and 30 cases reported to the regional pharmacovigilance centre of Paris Saint-Antoine. The mortality rate was related to the dose of isoniazid: it was 43 percent with a daily dose higher than 300 mg, and 9 percent with a daily dose of 300 mg or less (P < 0.001). Hepatic injury appeared significantly earlier in the case of rifampicin combination: 11 weeks without rifampicin and 2 weeks with rifampicin (P < 0.01). The role of pyrazinamide was difficult to determine because isoniazid and pyrazinamide were always used in combination. The influence of a preexisting liver disease could not be evaluated because of the small number of cases reported (8 cases). Alcoholism did not increase the mortality rate. Our results confirm the dose-dependent toxicity of isoniazid. Because of the short time elapsed before the apparent onset of hepatitis observed with the rifampicin combination, a close supervision of the patients should be exerted during the first weeks of treatment.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethambutol; Female; Humans; Infant; Isoniazid; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Streptomycin; Tuberculosis

1993
Effectiveness of rifampin, rifabutin, and rifapentine for preventive therapy of tuberculosis in mice.
    The American review of respiratory disease, 1993, Volume: 148, Issue:6 Pt 1

    To identify alternative regimens for preventive therapy of tuberculosis, the pharmacokinetics and antimicrobial activities of rifampin (RMP), rifabutin (RBT), and rifapentine (RPT) were compared in BCG-vaccinated and M. tuberculosis-infected immunocompetent mice. RPT showed the highest serum peak level (Cmax) and the longest half-life (t1/2), whereas RBT displayed the lowest Cmax and the shortest t1/2. On weight-to-weight basis, both RPT and RBT were more bactericidal than RMP. The activity of RMP was significantly reduced when the frequency of administration was reduced from six to three times weekly, whereas significant bactericidal activity was still observed in mice treated with RPT, 10 mg/kg up to once fortnightly, or RBT, 10 mg/kg twice weekly. Because the bactericidal activity of RBT, 10 mg/kg six times/wk for 6 wk, or RPT, 10 mg/kg two times/wk for 12 wk, was comparable to that of RMP, 10 mg/kg six times/wk for 12 wk in mice, the two regimens are appropriate for clinical trials of preventive therapy of tuberculosis.

    Topics: Animals; Antitubercular Agents; BCG Vaccine; Colony Count, Microbial; Female; Mice; Mycobacterium tuberculosis; Rifabutin; Rifampin; Spleen; Tuberculosis

1993
Turning intermittent regimens into daily regimens using blister-packs. An exploration in murine tuberculosis.
    Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1993, Volume: 74, Issue:5

    Blisterpacks might be used to present low cost intermittent regimens while maintaining an easily remembered daily frequency of opening blisters, by alternating blisters containing 2 of the drugs of a 4-drug regimen with blisters containing the remaining 2 drugs.. The efficacy of the alternating regimens was examined in murine tuberculosis.. 2 weeks after infection with Mycobacterium tuberculosis H37Rv, groups of mice were treated with rifampicin (R) 15 mg/kg, isoniazid (H) 25 mg/kg, pyrazinamide (Z) 300 mg/kg, ethambutol (E) 100 mg/kg three times weekly (RHZE3); RH/ZE, an alternating regimen of RH on days 1, 3 and 5 of the week and ZE on days 2, 4 and 6, RZ/HE or RE/HZ.. Spleen and lung bacillary counts at 7 and 12 weeks indicated large differences in the efficacy of the regimens: RZ/HE > RE/HZ > RHZE3 > RH/ZE. Serum assays showed that Rifampicin (RMP) levels were much lower after HRZE and slightly lower after RZ, RE and RH than after R alone, whereas levels were similar when R was given before the remaining drugs; also, the absorption of Z was slightly increased by R. A second experiment used the same 4 regimens but gave R before other drugs. The organ colony forming units counts at 6 and 12 weeks were then similar. A third experiment examined continuation phase regimens of R3, R2, R2H2 and R2H6 given after daily RHZ treatment for 4 weeks. It found R2H2 only slightly superior to R2H6 and R3 much better than R2.. 1. Alternating initial phase regimens were as effective as conventional intermittent regimens. 2. R3H6 might be an optimal continuation phase regimen for blisterpacks.

    Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Drug Packaging; Drug Therapy, Combination; Ethambutol; Isoniazid; Mice; Mice, Inbred BALB C; Pyrazinamide; Rifampin; Tuberculosis

1993
Phenytoin toxicity due to rifampicin induced hepatic dysfunction.
    The Journal of the Association of Physicians of India, 1993, Volume: 41, Issue:8

    Topics: Chemical and Drug Induced Liver Injury; Child; Drug Interactions; Epilepsy; Female; Humans; Isoniazid; Phenytoin; Rifampin; Tuberculosis

1993
Isoniazid and rifampin therapy for tuberculosis: what patients need to know.
    Medsurg nursing : official journal of the Academy of Medical-Surgical Nurses, 1993, Volume: 2, Issue:3

    Topics: Drug Interactions; Food; Humans; Isoniazid; Patient Education as Topic; Rifampin; Tuberculosis

1993
From the Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance: recommendations of the Advisory Council for the Elimination of Tuberculosis.
    JAMA, 1993, Aug-11, Volume: 270, Issue:6

    These recommendations update previous CDC/American Thoracic Society (ATS) recommendations for the treatment of tuberculosis (TB) among adults and children. The most notable changes are in response to the increasing prevalence of drug-resistant TB in the United States. These recommendations include the need for a) in vitro drug susceptibility testing of Mycobacterium tuberculosis isolates from all patients and reporting of these results to the health department, b) initial four-drug regimens for the treatment of TB, and c) initial directly observed therapy for persons with TB. Adherence to these recommendations will help prevent the occurrence of more cases of drug-resistant TB, reduce the occurrence of treatment failure, and reduce the transmission of TB in the United States.

    Topics: Adult; Antitubercular Agents; Child; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Female; Humans; Immunocompromised Host; Infant; Isoniazid; Mycobacterium tuberculosis; Pregnancy; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1993
[Analysis of drug sensitivity of M. tuberculosis strains isolated from patients treated for tuberculosis in 1982-1991].
    Pneumonologia i alergologia polska, 1993, Volume: 61, Issue:5-6

    Analysis of drug-sensitiveness of 822 M. tuberculosis strains isolated from patients with pulmonary tuberculosis treated in the Institute of Tuberculosis and Lung Diseases and in Pediatric Clinic of Medical Academy in Warsaw in 1982-1991 years was performed for isoniazid (INH), streptomycin (SM), rifampicin (RMP) and ethambutol (EMB). Drug sensitivity test was done on a basis of complexed proportional method according to Conethi and resistance index method according to Mitchinson. Examined strains were determined as resistant when the resistance index was 4 for INH, SM. RMP and EMB. During analysis the increase of resistance strains percentage (mean 25%) was observed in sputum-positive tuberculosis patients hospitalized in the Institute of Tuberculosis and Lung Diseases. The highest number of resistant strains was noticed in relation to CNH and RMP.

    Topics: Adult; Child; Ethambutol; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Species Specificity; Streptomycin; Tuberculosis

1993
Pharmacokinetic interaction between rifampin and zidovudine.
    Antimicrobial agents and chemotherapy, 1993, Volume: 37, Issue:7

    A potential pharmacokinetic interaction between rifampin (Rimactan, Rifadin) and zidovudine (AZT, Retrovir) was investigated in the population of human immunodeficiency virus-infected patients at our hospital. The results from four patients who were on long-term (> or = 6 months) combination therapy with zidovudine and rifampin are presented. In all cases of combined use of zidovudine and rifampin, a lower area under the plasma concentration-time curve (AUC) and, consequently, a higher apparent clearance of zidovudine were found, compared with a reference population of zidovudine users. Patients had a low to normal maximum concentration of zidovudine in plasma. Elimination half-lives were normal in all but one patient. Zidovudine glucuronide concentrations were determined in three patients and three control subjects. The patients all had relatively higher peak plasma concentrations and higher AUCs of zidovudine glucuronide than the control subjects. In one patient, zidovudine and zidovudine glucuronide were also measured 2.5 months after discontinuation of rifampin. The AUC of zidovudine increased by a factor of 2. These data are in agreement with an enzyme-inducing effect of rifampin on the glucuronidation of zidovudine. They indicate that long-term combination therapy of rifampin and zidovudine leads to increased clearance of zidovudine, which may have therapeutic consequences.

    Topics: Adult; Dose-Response Relationship, Drug; Drug Interactions; Humans; Male; Middle Aged; Rifampin; Tuberculosis; Zidovudine

1993
Current status of mycobacterial testing in clinical laboratories. Results of a questionnaire completed by participants in the College of American Pathologists Mycobacteriology E survey.
    Archives of pathology & laboratory medicine, 1993, Volume: 117, Issue:9

    To learn what methods are used in clinical microbiology laboratories for detection, identification, and susceptibility testing of mycobacteria, questions addressing these issues were added to the College of American Pathologists' Mycobacteriology E proficiency testing survey, and participants in the survey were asked to complete the questionnaire. Other questions related to numbers of mycobacteriology tests performed and the frequency with which drug-resistant Mycobacterium tuberculosis is isolated. Just over half of the respondents stained smears for acid-fast bacilli with the fluorochrome stain. Only 26% of respondents processed respiratory specimens daily, potentially providing results within 24 hours of receiving the specimen. The most rapid methods currently available for detection of mycobacteria and for identification of M tuberculosis, respectively, were used by 30% and 35% of the respondents. Half of the respondents who performed susceptibility testing on isolates of M tuberculosis used rapid methods. Approximately 26% of the respondents indicated that they usually provided a final identification of M tuberculosis within 21 days of receiving a specimen, and 11% indicated that identification and susceptibility test results were reported within 28 days. Participants' responses indicated that the mean number of specimens received for mycobacterial culture per month was higher during the first 5 months of 1992 than it had been in 1991. Moreover, the number of drug-resistant M tuberculosis isolated per month from January through May 1992 was about double the number isolated per month in 1991.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Bacteriological Techniques; Drug Resistance, Microbial; Humans; Isoniazid; Laboratories; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Surveys and Questionnaires; Time Factors; Tuberculosis

1993
The emergence of drug-resistant tuberculosis in New York City.
    The New England journal of medicine, 1993, Feb-25, Volume: 328, Issue:8

    In the past decade the incidence of tuberculosis has increased nationwide and more than doubled in New York City, where there have been recent nosocomial outbreaks of multidrug-resistant tuberculosis.. We collected information on every patient in New York City with a positive culture for Mycobacterium tuberculosis during April 1991. Drug-susceptibility testing was performed at the Centers for Disease Control and Prevention.. Of the 518 patients with positive cultures, 466 (90 percent) had isolates available for testing. Overall, 33 percent of these patients had isolates resistant to one or more antituberculosis drugs, 26 percent had isolates resistant to at least isoniazid, and 19 percent had isolates resistant to both isoniazid and rifampin. Of the 239 patients who had received antituberculosis therapy, 44 percent had isolates resistant to one or more drugs and 30 percent had isolates resistant to both isoniazid and rifampin. Among the patients who had never been treated, the proportion with resistance to one or more drugs increased from 10 percent in 1982 through 1984 to 23 percent in 1991 (P = 0.003). Patients who had never been treated and who were infected with the human immunodeficiency virus (HIV) or reported injection-drug use were more likely to have resistant isolates. Among patients with the acquired immunodeficiency syndrome, those with resistant isolates were more likely to die during follow-up through January 1992 (80 percent vs. 47 percent, P = 0.02). A history of antituberculosis therapy was the strongest predictor of the presence of resistant organisms (odds ratio, 2.7; P < 0.001).. There has been a marked increase in drug-resistant tuberculosis in New York City. Previously treated patients, those infected with HIV, and injection-drug users are at increased risk for drug resistance. Measures to control and prevent drug-resistant tuberculosis are urgently needed.

    Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Drug Resistance, Microbial; Female; Health Surveys; HIV Infections; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; New York City; Rifampin; Substance Abuse, Intravenous; Tuberculosis; Tuberculosis, Pulmonary; United States

1993
CDC recommends four-drug treatment of tuberculosis in multidrug-resistant era.
    American family physician, 1993, Sep-15, Volume: 48, Issue:4

    Topics: Adult; Centers for Disease Control and Prevention, U.S.; Child; Drug Therapy; Drug Therapy, Combination; Ethambutol; Female; Humans; Immunocompromised Host; Infant; Isoniazid; Pregnancy; Pregnancy Complications, Infectious; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary; United States

1993
Initial therapy for tuberculosis in the era of multidrug resistance. Recommendations of the Advisory Council for the Elimination of Tuberculosis.
    MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports, 1993, May-21, Volume: 42, Issue:RR-7

    These recommendations update previous CDC/American Thoracic Society (ATS) recommendations for the treatment of tuberculosis (TB) among adults and children. The most notable changes are in response to the increasing prevalence of drug-resistant TB in the United States. These recommendations include the need for a) in vitro drug susceptibility testing of Mycobacterium tuberculosis isolates from all patients and reporting of these results to the health department, b) initial four-drug regiments for the treatment of TB, and c) initial directly observed therapy for persons with TB. Adherence to these recommendations will help prevent the occurrence of more cases of drug-resistant TB, reduce the occurrence of treatment failure, and reduce the transmission of TB in the United States.

    Topics: Adult; Antitubercular Agents; Child; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Female; Humans; Immunocompromised Host; Infant; Isoniazid; Mycobacterium tuberculosis; Pregnancy; Pregnancy Complications, Infectious; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1993
Acute and long-term efficacy of antituberculous treatment in HIV-seropositive patients with tuberculosis: a study of 36 cases.
    The Journal of infection, 1993, Volume: 26, Issue:1

    Thirty-six consecutively observed HIV-seropositive patients with tuberculosis, including 31 patients with AIDS, who received antituberculous treatment, were followed up to evaluate its efficacy. Treatment with standard antituberculous regimens was intended except when an individual's condition required a modified therapeutic approach. Therapeutic failure occurred in five patients (14%) while on treatment, one also had a post-treatment relapse. Treatment failure was associated with drug resistance and non-compliance in three patients and in another two, both of whom died early in the course of their disease, with HIV-related conditions other than tuberculosis. The median relapse-free post-treatment follow-up time in 24 patients in whom treatment did not fail was 13 months (range 4-67). Standard antituberculous treatment is highly effective in the immediate and long-term treatment of HIV-related tuberculosis provided that drug susceptibility and treatment compliance are confirmed.

    Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Antitubercular Agents; Bisexuality; CD4-CD8 Ratio; Ethambutol; Female; HIV Seropositivity; Homosexuality; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Time Factors; Treatment Failure; Treatment Outcome; Tuberculosis

1993
[Tuberculosis treatment in 1992].
    Revue medicale de Liege, 1993, Volume: 48, Issue:3

    Topics: Anti-Bacterial Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

1993
Rationale for chemotherapy of tuberculosis and current recommendations.
    Indian pediatrics, 1992, Volume: 29, Issue:11

    Topics: Antitubercular Agents; Child; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Streptomycin; Time Factors; Tuberculosis

1992
Activity of clarithromycin against Mycobacterium avium complex infection in beige mice.
    Antimicrobial agents and chemotherapy, 1992, Volume: 36, Issue:11

    The activity of clarithromycin alone and in combination with other antimycobacterial agents was evaluated in the beige (C57BL/6J bgj/bgj) mouse model of disseminated Mycobacterium avium complex (MAC) infection. A dose-response experiment was performed with clarithromycin at 50, 100, 200, or 300 mg/kg of body weight administered daily by gavage to mice infected with approximately 10(7) viable MAC. A dose-related reduction in spleen and liver cell counts was noted with treatment at 50, 100, and 200 mg/kg. The difference in cell counts between treatment at 200 and 300 mg/kg was not significant. Clarithromycin at 200 mg/kg of body weight was found to have activity against three additional MAC isolates (MICs for the isolates ranged from 1 to 4 micrograms/ml by broth dilution). Clarithromycin at 200 mg/kg in combination with amikacin, ethambutol, temafloxacin, or rifampin did not result in increased activity beyond that seen with clarithromycin alone. Clarithromycin in combination with clofazimine or rifabutin resulted in an increase in activity beyond that seen with clarithromycin alone. The combination of clarithromycin with clofazimine or rifabutin should be considered for evaluation in the treatment of human MAC infections.

    Topics: Amikacin; Animals; Anti-Infective Agents; Antitubercular Agents; Clarithromycin; Clofazimine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethambutol; Female; Fluoroquinolones; Humans; Mice; Mice, Inbred C57BL; Mycobacterium avium; Mycobacterium avium Complex; Quinolones; Rifabutin; Rifampin; Rifamycins; Time Factors; Tuberculosis

1992
TLC G-65 in combination with other agents in the therapy of Mycobacterium avium infection in beige mice.
    The Journal of antimicrobial chemotherapy, 1992, Volume: 29, Issue:6

    The activity of TLC G-65 (a liposomal gentamicin preparation), alone and in combination with rifapentine, clarithromycin, clofazimine and ethambutol, was evaluated in the beige mouse (C57BL/6J--bgj/bgj) model of disseminated Mycobacterium avium infection. TLC G-65 was found to be more active than amikacin. The combination of rifapentine and TLC G-65 was more active than either agent alone. The activity of clarithromycin in combination with TLC G-65 was similar to that of either agent alone. Clofazimine improved the activity of TLC G-65 with respect to the spleen, while ethambutol improved the activity with respect to the liver. Clofazimine and ethambutol enhanced the activity of TLC G-65 against bacteria in the lungs. TLC G-65 in combination with rifapentine appears to be an attractive regimen for the treatment of infections caused by bacteria in the M. avium complex.

    Topics: Amikacin; Animals; Antitubercular Agents; Clarithromycin; Clofazimine; Culture Media; Drug Therapy, Combination; Erythromycin; Ethambutol; Gentamicins; Liposomes; Mice; Mice, Inbred C57BL; Mycobacterium avium; Rifampin; Tuberculosis

1992
Case holding in patients with tuberculosis in Botswana.
    BMJ (Clinical research ed.), 1992, Aug-08, Volume: 305, Issue:6849

    To evaluate the effectiveness of daily supervised short course chemotherapy in a national tuberculosis programme.. Observation of programme during 1984-90. In October 1986 short course chemotherapy was introduced with patients receiving treatment daily from staff in their nearest health facility.. Botswana national tuberculosis programme.. All patients with tuberculosis.. Proportions of patients complying with and defaulting from treatment (missing > or = 43 days' treatment).. 2938 cases of tuberculosis were recorded in 1990, 1528 of which were of sputum positive pulmonary disease. 2711 (92.3%) patients complied with treatment and 227 (7.7%) defaulted. Before introduction of short course chemotherapy compliance was about 60% compared with over 90% in 1987-90.. A programme using daily supervised short course chemotherapy integrated into the primary health care system is an effective method of treating tuberculosis. The costs of the programme need to be evaluated.

    Topics: Botswana; Drug Therapy, Combination; Humans; Isoniazid; National Health Programs; Patient Compliance; Primary Health Care; Pyrazinamide; Rifampin; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

1992
Drug combinations and the bioavailability of rifampicin.
    Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1992, Volume: 73, Issue:4

    Topics: Anti-Bacterial Agents; Biological Availability; Drug Therapy, Combination; Humans; Rifampin; Tuberculosis

1992
Clinical application of the polymerase chain reaction for a rapid diagnosis of Mycobacterium tuberculosis infection.
    Internal medicine (Tokyo, Japan), 1992, Volume: 31, Issue:8

    A gene amplification method of Mycobacterium tuberculosis DNA by the polymerase chain reaction (PCR) has been devised. A primer pair used in this study is 5'GTTGCCGTGGCGG TATCGG3' and 5'GCGACATTACGGGGCAGGTGG3', which brackets a 152-base region encoding the 65KD antigen, and a specific probe is 5'TTTGGGGTCATCTTTGGAGCG3'. The procedure could be completed within 2 days. The specificity and the sensitivity of the PCR for M. tuberculosis complex in identifying M. tuberculosis complex did not conflict with the conventional methods at all. Using this method, we could diagnose three cases of the disease, which had been very difficult to diagnose by the conventional methods, by detecting the DNA from the blood, liver biopsy specimen, lung aspirate, and pleural effusion.

    Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Base Sequence; DNA, Bacterial; Drug Therapy, Combination; Ethambutol; Female; HIV-1; Humans; Isoniazid; Male; Molecular Sequence Data; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis

1992
Culture-positive tuberculosis in Western Australia.
    Australian and New Zealand journal of medicine, 1992, Volume: 22, Issue:2

    Notifications of 485 patients with culture-positive tuberculosis (TB) in Western Australia from 1980 to 1989 inclusive have been analysed. In 478 (98.6%) the disease was caused by Mycobacterium tuberculosis hominis and in seven (1.4%) M. bovis. Most (78.5%) of the disease was pulmonary with 4.3% pleural and 17.2% extrapulmonary. The annual incidence decreased from 4.6 per 100,000 in 1980 to 2.5 in 1985 steadying thereafter around 3.3. The Aborigines had over four times the average incidence of the non-Aboriginal Australians but less than a quarter that of the Asians. In a total 297 migrants, 51% of 253 with data available had been in Australia for over five years. Initial drug resistance was found in 48 patients giving an overall rate of 9.9%. In 32 (66.7%), resistance was against a single drug, mainly isoniazid and in 11 (22.9%) against two drugs, predominantly isoniazid and streptomycin. The most disturbing finding was the occurrence of multiple-drug resistance including both isoniazid and rifampicin in five immigrants (10.4%). This study has provided useful baseline TB data, raised important issues such as chemoprophylaxis and drug resistance, and clearly indicates that the campaign against TB is far from over. Continual surveillance, monitoring and regular evaluation of existing policies should be maintained.

    Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Drug Resistance, Microbial; Emigration and Immigration; Female; Humans; Incidence; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Pleural; Tuberculosis, Pulmonary; Western Australia

1992
[Cold tuberculous retropharyngeal abscess].
    Anales otorrinolaringologicos ibero-americanos, 1992, Volume: 19, Issue:1

    The AA. present a report about a patient having a cold tuberculous abscess which symptomatologic manifested through dysphagia and cervico-brachialgia. Comments on the most remarkable aspects of these conditions.

    Topics: Abscess; Brachial Plexus Neuritis; Deglutition Disorders; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Middle Aged; Neck; Rifampin; Tuberculosis

1992
Pancreatic tuberculosis following renal transplantation.
    Nephron, 1992, Volume: 60, Issue:3

    Topics: Ethambutol; Female; Humans; Immunosuppression Therapy; Isoniazid; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pancreatic Diseases; Postoperative Complications; Rifampin; Transplantation, Homologous; Tuberculosis

1992
[Effectiveness of a liposomal form of rifampicin in the treatment of experimental tuberculosis in mice].
    Problemy tuberkuleza, 1992, Issue:1-2

    The therapeutic effectiveness of rifampicin as a free form and a component of multilamellar phosphatidylcholine cholesterol liposomes was studied on a model of generalized tuberculosis in BALB/c mice. Rifampicin as a liposomal form was found to have no advantages over its free form. Possible mechanisms of the phenomenon and prospects for using liposomes in the chemotherapy of tuberculosis are discussed.

    Topics: Animals; Drug Carriers; Liposomes; Male; Mice; Mice, Inbred BALB C; Rifampin; Tuberculosis

1992
Tuberculosis in the 1990's: resurgence, regimens, and resources.
    Southern medical journal, 1992, Volume: 85, Issue:6

    Physicians in the United States must maintain vigilance for the 25,000 annual new cases of tuberculosis, concentrated in the elderly, in immigrants, in migrant and minority populations, and in immunosuppressed patients. Tuberculosis rates in the South remain above the national average. Physicians diagnosing tuberculosis may also treat the disease, working with health departments, which can assist with drugs, follow-up tests, and contact investigation. Powerful short-course regimens have been standard treatments since 1986. The preferred combination is isoniazid, rifampin, and pyrazinamide daily for 2 months, followed by isoniazid and rifampin for 4 more months. A 9-month regimen of isoniazid and rifampin is equally effective. Supplementation or extension of these regimens is mandatory when drug resistance or immunosuppression, respectively, is likely. Isoniazid prophylaxis for 6 to 12 months continues to be a vital but often neglected preventive measure for those infected with Mycobacterium tuberculosis, but without active disease.

    Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Child; Drug Administration Schedule; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; False Negative Reactions; Humans; Isoniazid; Pyrazinamide; Radiography, Thoracic; Rifampin; Risk Factors; Streptomycin; Tuberculosis; United States

1992
Antagonism between isoniazid and the combination pyrazinamide-rifampin against tuberculosis infection in mice.
    Antimicrobial agents and chemotherapy, 1992, Volume: 36, Issue:3

    Mice that had been inoculated intravenously with 6.30 log10 Mycobacterium tuberculosis H37Rv 14 days earlier were administered one of three combinations of drugs, i.e., isoniazid (INH)-rifampin (RMP)-pyrazinamide (PZA), INH-RMP, and RMP-PZA, during an initial 2-month period to mimic the initial phase of chemotherapy for human tuberculosis and during a later 4-month period to mimic the continuation phase of chemotherapy. At the end of the initial phase, all three combined regimens were found to have been highly effective in terms of the number of CFUs in the spleens of infected mice. The bactericidal activities of INH-RMP-PZA and INH-RMP were similar, whereas that of RMP-PZA was significantly greater. The spleens of all of the mice that had been treated initially with INH-RMP-PZA were culture negative by the end of 6 months of treatment, regardless of the regimen employed during the continuation phase. However, after an additional period of 6 months without treatment, the proportion of spleen culture positivity, or relapse rate, was significantly smaller in the subgroup treated with RMP-PZA during the continuation phase than in the subgroups treated with INH-RMP-PZA or INH-RMP; the relapse rate did not differ significantly between the latter two subgroups. These results suggest that antagonism occurs between INH and the combination RMP-PZA during both the initial and continuation phases of chemotherapy, compromising the benefit conferred by the addition of PZA to the combined regimen. The preliminary pharmacokinetic analysis suggested that the pharmacological interaction between INH and RMP was very likely to be involved in the mechanism of antagonism, as concomitant treatment with INH had significantly reduced the peak serum level and the area under the serum concentration-time curve of RMP in mice.

    Topics: Animals; Colony Count, Microbial; Drug Combinations; Female; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Spleen; Tuberculosis

1992
Activity of rifapentine against Mycobacterium avium infection in beige mice.
    The Journal of antimicrobial chemotherapy, 1992, Volume: 29, Issue:5

    The activity of rifapentine (MDL 473) was evaluated in the beige (C57BL/6J-bgj/bgj) mouse model of disseminated Mycobacterium avium infection. Approximately 10(7) cfu of M. avium, serotype 1, were given iv. Seven days later treatment was started with intraperitoneal rifapentine at 20 mg/kg of body weight. Treatment was given daily for five days followed by twice weekly for three weeks. The mice were killed two days after the last dose. Spleens, livers and lungs were homogenized and cfu/organ determined. Analysis of variance and Tukey honestly significant difference tests indicated that rifapentine reduced cfu in each of the organs compared with untreated controls. A dose-response experiment was performed with a daily rifapentine dose of 10, 20 or 40 mg/kg administered intraperitoneally. Dose-related reductions in cfu counts were observed in each of the organs. The activity of oral rifapentine at 20 mg/kg was demonstrated in a comparative experiment with rifampicin at 20, 40 or 60 mg/kg. Rifapentine significantly reduced cfu counts in organs compared with rifampicin. Rifapentine should be considered for further evaluation in the treatment of M. avium complex infection in humans.

    Topics: Administration, Oral; Animals; Antitubercular Agents; Biological Availability; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Mycobacterium avium; Rifampin; Tuberculosis

1992
Transmission of multidrug-resistant tuberculosis among immunocompromised persons in a correctional system--New York, 1991.
    MMWR. Morbidity and mortality weekly report, 1992, Jul-17, Volume: 41, Issue:28

    During 1990 and 1991, nosocomial transmission of multidrug-resistant tuberculosis (MDR-TB) was documented in four hospitals in New York and Florida. Subsequently, additional MDR-TB outbreaks have been investigated by CDC. This report summarizes preliminary results of an investigation of transmission of MDR-TB in a correctional facility in New York.

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Ethionamide; HIV Seropositivity; Humans; Immunocompromised Host; Isoniazid; Kanamycin; Mycobacterium tuberculosis; New York; Prisons; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1992
From the Centers for Disease Control. Transmission of multidrug-resistant tuberculosis among immunocompromised persons, correctional system--New York, 1991.
    JAMA, 1992, Aug-19, Volume: 268, Issue:7

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Ethionamide; HIV Seropositivity; Humans; Immunocompromised Host; Isoniazid; Kanamycin; Mycobacterium tuberculosis; New York; Prisons; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1992
Primary and acquired drug resistance in adult black patients with tuberculosis in South Africa: results of a continuous national drug resistance surveillance programme involvement.
    Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1992, Volume: 73, Issue:2

    Drug resistance is a major problem in the treatment of tuberculosis, and monitoring programmes are essential in control of this disease. The extent of primary resistance in a community is an important indication of the effectiveness of treatment schedules. Since 1965 the Tuberculosis Research Institute (TBRI) of the South African Medical Research Council has performed 25 annual surveys of drug resistance in adult black tuberculosis patients where the disease is most prevalent. Methodology for patient selection, specimen collection, laboratory procedures and criteria for drug resistance were strictly adhered to. All specimens were processed in a central laboratory supervised by the same two technologists. Between 1965 and 1988 a total of 33,111 strains of Mycobacterium tuberculosis were isolated from new cases and 19,134 from old cases. Both primary and acquired resistance to the 5 major antituberculosis drugs has decreased dramatically. Sex and age do not influence resistance rates, while patients' ethnic origin and geographical location do. The results indicate that current tuberculosis treatment practices are satisfactory. The prevalence of primary drug resistance in black South Africans is now intermediate between those countries where eradication of tuberculosis is well advanced and those where the disease remains a public health problem. Also, it can be shown that comparable and clinically significant data can be obtained from a central laboratory employing unsophisticated and inexpensive drug susceptibility testing procedures.

    Topics: Black or African American; Black People; Drug Resistance, Microbial; Ethambutol; Ethionamide; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Rifampin; South Africa; Streptomycin; Tuberculosis

1992
Activity of two long-acting rifamycins, rifapentine and FCE 22807, in experimental murine tuberculosis.
    Tubercle and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 1992, Volume: 73, Issue:2

    The efficacy of the long-acting rifamycins, rifapentine (RPE) and FCE 22807 (FCE) in experimental murine tuberculosis was studied by counting viable bacilli in spleens. At 2 weeks after infection with Mycobacterium tuberculosis, strain H37Rv, treatment with isoniazid 25 mg/kg, rifampicin 10 mg/kg and pyrazinamide 150 mg/kg was given daily for 6 weeks. The mice were then divided into groups given RPE or FCE at intervals of 1, 2 or 3 weeks with spleen counts after 18 and 24 weeks of chemotherapy. The first experiment showed the great effect of the size of the dose of RPE, which, in once-weekly regimens, caused rapid sterilization at 16 mg/kg, less rapid sterilization at 10 mg/kg and incomplete activity at 6.25 mg/kg. Regimens of RPE given every 2 or 3 weeks were less effective, though 16 mg/kg fortnightly was as good as 6 mg/kg once-weekly. The second experiment compared RPE and FCE each given at 12 or 8 mg/kg. The results were similar though, at 8 mg/kg every 2 or 3 weeks, FCE was slightly more effective than RPE. Serum assays showed that the levels with 8 and 12 mg/kg FCE were lower than those produced even by 6.25 mg/kg RPE, suggesting that FCE would be a better drug than RPE if its bioavailability could be improved, and that the levels following 16 mg/kg RPE were similar to those found in man after 8 mg/kg RPE taken with a fat-rich meal, suggesting good prospects for effective once-fortnightly human treatment. The potential for long-acting rifamycins in the management of pulmonary tuberculosis is discussed.

    Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Rifamycins; Spleen; Tuberculosis

1992
Mycobacterium bovis (BCG) vaccination. Progressive disease in a patient asymptomatically infected with the human immunodeficiency virus.
    The Medical journal of Australia, 1992, Feb-17, Volume: 156, Issue:4

    To report a case of progressive disease caused by Mycobacterium bovis after BCG vaccination in a patient asymptomatically infected with the human immunodeficiency virus (HIV).. A 34-year-old white man about to commence employment as a developmental care worker had a BCG vaccination. Five months later, he had a positive result to a serological test for HIV antibody. Nine months after BCG vaccination, he presented with fever (38.7 degrees C), a large left axillary lymph node and a small left pleural effusion. The lymph node was biopsied and acid-fast bacilli observed in Ziehl-Neelsen stained smears. Culture grew Mycobacterium bovis (BCG).. He was successfully treated with isoniazid, rifampicin and ethambutol for a period of nine months.. BCG vaccination of asymptomatic HIV-positive patients is not recommended. The detection of those at risk for HIV infection before vaccination administration is essential. Self-exclusion based on information supplied to all potential recipients is likely to be the most effective method.

    Topics: Adult; BCG Vaccine; Ethambutol; HIV Infections; Humans; Isoniazid; Male; Mycobacterium bovis; Rifampin; Tuberculosis

1992
HIV prevalence, immunosuppression, and drug resistance in patients with tuberculosis in an area endemic for AIDS.
    AIDS (London, England), 1991, Volume: 5, Issue:4

    From October 1987 to June 1988, we attempted to determine the prevalence of HIV infection among patients hospitalized with tuberculosis and the extent of immunosuppression among those tuberculosis patients infected with HIV. Of 178 consecutive patients, 18-65 years of age, who were hospitalized with newly diagnosed, previously untreated tuberculosis, 46% (82 out of 178) had clinical or serological evidence of HIV infection, 30% (54 out of 178) were HIV-seronegative, and 24% (42 out of 178) could not be assessed for the presence of HIV infection. Among the HIV-seropositive patients without an AIDS-defining diagnosis by non-tuberculous criteria, the median CD4 lymphocyte (CD4) count was 133 x 10(6) cells/l (range: 11-677 x 10(6]; among the HIV-seronegative patients, the median CD4 count was 613 x 10(6) cells/l (range: 238-1614 x 10(6); P less than 0.001). Among the HIV-seropositive patients, those with disseminated tuberculosis (median CD4 = 79 x 10(6) cells/l) and those with pulmonary tuberculosis who had radiographic evidence of mediastinal or hilar adenopathy (median CD4 = 45 x 10(6) cells/l) had the most severe CD4 depletion, whereas those with localized extrapulmonary tuberculosis (median CD4 = 242 x 10(6) cells/l) and those with pulmonary tuberculosis without adenopathy (median CD4 = 299 x 10(6) cells/l) were less severely immunosuppressed. Of the 178 patients, 6% (11 out of 178) were infected with strains of Mycobacterium tuberculosis resistant to both isoniazid and rifampin.

    Topics: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Aged; CD4-Positive T-Lymphocytes; Drug Resistance, Microbial; Female; HIV Seropositivity; HIV Seroprevalence; Humans; Immune Tolerance; Isoniazid; Leukocyte Count; Male; Middle Aged; Mycobacterium tuberculosis; New York City; Rifampin; T-Lymphocytes, Regulatory; Tuberculosis

1991
Corticosteroids and tuberculosis.
    BMJ (Clinical research ed.), 1991, Nov-09, Volume: 303, Issue:6811

    Topics: Adrenal Insufficiency; Humans; Rifampin; Tuberculosis

1991
Stability of isoniazid, rifampin and pyrazinamide in suspensions used for the treatment of tuberculosis in children.
    The Pediatric infectious disease journal, 1991, Volume: 10, Issue:11

    The stability of monosuspensions, cosuspensions and multisuspensions of isoniazid (INH), pyrazinamide (PZA) and rifampin (RIF) has been evaluated by high pressure liquid chromatography over a period of 28 days both with and without the addition of vitamin C (20 micrograms/ml) and at ambient temperatures of 4 degrees C, 24 degrees C and 40 degrees C. At the end of 28 days greater than 90% of initial concentrations of INH, PZA and RIF in monosuspensions remained unchanged irrespective of ambient temperature as was the case with INH and PZA in cosuspension. The addition of RIF to either INH or PZA in cosuspension or together in multisuspension led to a marked fall in the concentration of one or more of the agents, an effect that was accentuated by the addition of vitamin C. In the case of a multisuspension of INH + RIF + PZA with vitamin C added, 41.7% (4 degrees C), 24.1% (24 degrees C) and 20.3% (40 degrees C) of initial INH concentrations and 1.9% (4 degrees C), 1.3% (24 degrees C) and 0.0% (40 degrees C) of initial RIF concentrations remained detectable after 28 days. The addition of vitamin C to monosuspensions of INH and PZA led to a marked decline in the amount of drug detectable and only in the case of RIF was greater than 90% of initial concentrations of the drug detectable after 28 days. The dispensing of cosuspensions or multisuspensions of antituberculosis agents containing RIF is inadvisable as is the addition of vitamin C in any form.

    Topics: Ascorbic Acid; Child; Chromatography, High Pressure Liquid; Drug Stability; Humans; Isoniazid; Pyrazinamide; Rifampin; Suspensions; Temperature; Tuberculosis

1991
AIDS and tuberculosis in Spain. A report of 140 cases.
    The Journal of infection, 1991, Volume: 23, Issue:2

    From January 1984 to October 1990, 140 of 392 (35.7%) patients with the acquired immunodeficiency syndrome (AIDS) were found to have had tuberculosis. One hundred and sixteen were intravenous drug abusers and 16 were homosexual men. Fever, cough, weight loss and generalised lymphadenopathy were common features of their illness. Tuberculin skin tests were negative in 74% and 55% had intraabdominal lymphadenopathy. The chest radiographs showed hilar lymphadenopathy and lower lobe interstitial or alveolar infiltrates, but rarely cavitation. Forty-one of our patients had pulmonary tuberculosis, 38 had extra pulmonary and in 61 it was disseminated. In 80 cases tuberculosis was the presenting feature of AIDS. Tuberculosis usually responded well to chemotherapy.

    Topics: Acquired Immunodeficiency Syndrome; Drug Therapy, Combination; Ethambutol; Female; Humans; Incidence; Isoniazid; Male; Prospective Studies; Pyrazinamide; Retrospective Studies; Rifampin; Risk Factors; Spain; Streptomycin; Substance Abuse, Intravenous; Tuberculosis; Tuberculosis, Pulmonary

1991
Can rifampicin be restarted in patients with rifampicin-induced thrombocytopenia?
    Tubercle, 1991, Volume: 72, Issue:4

    Topics: Adult; Humans; Male; Rifampin; Thrombocytopenia; Time Factors; Tuberculosis

1991
[Tuberculosis of the larynx, oral cavity and pharynx].
    Deutsche medizinische Wochenschrift (1946), 1991, Aug-02, Volume: 116, Issue:31-32

    A 44-year-old man, a heavy smoker over many years, complained of hoarseness for 8 weeks with weight loss and dysphagia. Malignant tumour of the pharynx was suspected. Examination revealed a swelling of the right upper lip, tumorous changes in the right buccal mucosa, about 6 x 6 cm in size, as well as enlargement of the cervical lymph-nodes. Microlaryngoscopy revealed a three-level tumour of the entire side of the right larynx. Histological examination of biopsies of the right false and true vocal cords as well as the buccal mucosa demonstrated numerous, partly caseous epithelioid granulomas with Langhans giant cells. Ziehl-Neelsen staining showed acid-fast rods. Combined tuberculostatic treatment with isoniazid, rifampicin, ethambutol and pyrazinamide achieved regression of all signs and symptoms within two months. This case emphasizes the need for including laryngeal tuberculosis in the differential diagnosis of seemingly malignant laryngeal tumours.

    Topics: Adult; Diagnosis, Differential; Drug Therapy, Combination; Endoscopy; Ethambutol; Humans; Isoniazid; Male; Pharyngeal Diseases; Pharyngeal Neoplasms; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Laryngeal; Tuberculosis, Oral

1991
Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection.
    The New England journal of medicine, 1991, Jan-31, Volume: 324, Issue:5

    Infection with the human immunodeficiency virus (HIV) increases the risk of tuberculosis and may interfere with the effectiveness of antituberculosis chemotherapy. To examine the outcomes in patients with both diagnoses, we conducted a retrospective study of all 132 patients listed in both the acquired immunodeficiency syndrome (AIDS) and tuberculosis case registries in San Francisco from 1981 through 1988.. At the time of the diagnosis of tuberculosis, 78 patients (59 percent) did not yet have a diagnosis of AIDS, 18 patients (14 percent) were given a concomitant diagnosis of AIDS (as determined by the presence of an AIDS-defining disease other than tuberculosis), and the remaining 36 patients (27 percent) already had AIDS. The manifestations of tuberculosis were entirely pulmonary in 50 patients (38 percent), entirely extrapulmonary in 40 patients (30 percent), and both pulmonary and extrapulmonary in 42 patients (32 percent). The treatment regimens were as follows: isoniazid and rifampin supplemented by ethambutol for the first two months, 52 patients; isoniazid and rifampin supplemented by pyrazinamide and ethambutol for the first two months, 39 patients; isoniazid and rifampin, 13 patients; isoniazid and rifampin supplemented by pyrazinamide for the first two months, 4 patients; and other drug regimens, 17 patients. The intended duration of treatment for patients whose regimen included pyrazinamide was six months, and for patients who did not receive pyrazinamide, nine months. Seven patients received no treatment because tuberculosis was first diagnosed after death. Sputum samples became clear of acid-fast organisms after a median of 10 weeks of therapy. Abnormalities on all chest radiographs taken after three months of treatment were stable or improved except for those of patients who had new nontuberculous infections. The only treatment failure occurred in a man infected with multiple drug-resistant organisms who did not comply with therapy. Adverse drug reactions occurred in 23 patients (18 percent). For all 125 treated patients, median survival was 16 months from the diagnosis of tuberculosis. Tuberculosis was a major contributor to death in 5 of the 7 untreated patients and 8 of the 125 treated patients. Three of 58 patients who completed therapy had a relapse (5 percent); compliance was poor in all 3.. Tuberculosis causes substantial mortality in patients with advanced HIV infection. In patients who comply with the regimen, conventional therapy results in rapid sterilization of sputum, radiographic improvement, and low rates of relapse.

    Topics: Acquired Immunodeficiency Syndrome; Adult; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Retrospective Studies; Rifampin; Sputum; Tuberculosis; Tuberculosis, Pulmonary

1991
[In vitro experiment showing that chemotherapy of tuberculosis by aminoglycoside antibiotics may influence successive chemotherapy with rifampicin].
    Kekkaku : [Tuberculosis], 1991, Volume: 66, Issue:1

    When Mycobacterium tuberculosis strain H37Rv was cultivated in Ogawa egg medium containing 5 micrograms/ml streptomycin and/or 10 micrograms/ml kanamycin, which were considered as subinhibitory, it was observed that growing bacterial population contained several times more rifampicin-resistant mutants than did the parent strain. The ratio of isoniazid-resistant mutants did not change by the above treatment. The finding suggests that, even without the use of rifampicin, the bacterial population of patients becomes more resistant to rifampicin by chemotherapy in the past with streptomycin or kanamycin. Furthermore, it was shown that the ratio of streptomycin-resistant mutants increased by pre-treatment with kanamycin and the ratio of kanamycin-resistant mutants by pre-treatment with streptomycin. Parent, susceptible bacterial population develops 4R-phenotype mutants which are resistant to four drugs, high concentrations of kanamycin, lividomycin and paraomomycin and a low concentration of capreomycin, whereas streptomycin-resistant mutant population does not develop the 4R mutants but develops only mutants with the KR phenotype which is almost mono-resistant to kanamycin.

    Topics: Anti-Bacterial Agents; Drug Interactions; Drug Resistance, Microbial; Kanamycin; Kanamycin Resistance; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1991
Memory T cell-mediated resistance to Mycobacterium tuberculosis infection in innately susceptible and resistant mice.
    Infection and immunity, 1991, Volume: 59, Issue:6

    The memory T cell immune response to Mycobacterium tuberculosis infection was examined in strains of mice which vary in their natural susceptibility to Mycobacterium bovis BCG infection. Naturally susceptible (NS) C57BL/6 and naturally resistant (NR) B6D2 F1 hybrid mice were infected with a sublethal dose of M. tuberculosis and then given antibiotic therapy beginning 2 weeks postinfection. T cells from both strains of mice transferred significant levels of resistance to syngeneic mice challenged aerogenically with M. tuberculosis. This memory response was not substantially reduced by depletion of either L3T4+ or Lyt2+ T cells from the donor mice but was ablated by depletion of both T cell subsets. Cyclophosphamide pretreatment of C57BL/6 memory T cell donors also ablated the resistance transferred to recipient mice. In contrast, B6D2 memory T cells were not affected by cyclophosphamide treatment, suggesting that differences may exist in the metabolic state of the memory T cells in the two donor strains, despite the fact that they both develop similar levels of acquired resistance to a subsequent tuberculous challenge.

    Topics: Animals; Cyclophosphamide; Immunity, Cellular; Immunization, Passive; Immunologic Memory; Immunotherapy, Adoptive; Isoniazid; Male; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Rifampin; T-Lymphocyte Subsets; T-Lymphocytes; Tuberculosis

1991
Hepatotoxicity of rifampin and isoniazid. Is it all drug-induced hepatitis?
    The American review of respiratory disease, 1991, Volume: 143, Issue:6

    Serologic markers for hepatitis viruses were studied in 40 children who developed acute hepatitis during antituberculosis therapy with rifampin and isoniazid, with the aim of assessing the contributory role of these viruses toward producing hepatic injury. Hepatitis A and B were confirmed in 7.5 and 35% patients, respectively, by IgM antibodies. Epidemiologic evidence suggested the possibility of non-A, non-B hepatitis in at least a few of the remaining 23 children. Hepatitis B was seen more often in children with severe tubercular disease (72%) and was largely (92.8%) parenterally transmitted. The study highlights that the endemicity of viral hepatitis in developing countries, among other factors, could also be responsible for the reported higher incidence of hepatotoxicity from developing countries and also for the increased risk of hepatotoxicity seen in severe tubercular disease.

    Topics: Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Hepatitis A; Hepatitis B; Hepatitis C; Humans; Infant; Isoniazid; Liver; Male; Rifampin; Tuberculosis

1991
[Drug therapy of intractable Mycobacterium infections].
    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine, 1990, Dec-10, Volume: 79, Issue:12

    Topics: Antibiotics, Antitubercular; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections, Nontuberculous; Rifampin; Streptomycin; Tuberculosis

1990
A 62-dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis. A twice-weekly, directly observed, and cost-effective regimen.
    Annals of internal medicine, 1990, Mar-15, Volume: 112, Issue:6

    To evaluate the efficacy and toxicity of a 62-dose, four-drug, 6-month, and directly observed regimen for treatment of pulmonary and extrapulmonary tuberculosis.. An open, nonblinded clinical trial, with intended follow-up of patients for 36 months after the completion of therapy.. A metropolitan tuberculosis clinic in a public health department.. From March 1981 through April 1989, we enrolled 160 patients with suspected or known tuberculosis; 35 of these patients were excluded from the analysis.. Isoniazid, rifampin, pyrazinamide, and streptomycin were administered daily for 2 weeks; these drugs were then given in higher doses twice weekly for 6 weeks, followed by isoniazid and rifampin twice weekly for 6 weeks, followed by isoniazid and rifampin twice weekly for 18 weeks. A total of 62 doses were administered, and all therapy was directly observed by a nurse or an outreach worker.. Of the 125 evaluable patients, 101 (81%) had pulmonary tuberculosis, 7 (6%) had both pulmonary and extrapulmonary involvement, and 17 (13%) had extrapulmonary disease only. Seventy-one (57%) patients had a history of recent alcoholism. There were two relapses (1.6% +/- 2.2%), occurring 6 and 56 months after the completion of therapy. The time at which sputum samples became culture negative in pulmonary patients ranged from 1 to 19 weeks (median, 4.6 weeks); 40% +/- 9.6% of patients were culture-negative after 4 weeks of therapy, 75% +/- 8.5% after 8 weeks, 94% +/- 4.7% after 12 weeks, 97% +/- 3.3% after 16 weeks, and 100% after 20 weeks. Adverse drug reactions included hyperuricemia (greater than 178 mumol/L [3 mg/dL] above normal) secondary to pyrazinamide in 80 patients (64%), twofold or greater elevations of aspartate aminotransferase in 21 patients (17%), 1.5-fold or greater elevations of alkaline phosphatase in 33 patients (27%), cutaneous abnormalities in 8 patients (6%), nausea in five patients (4%), and dizziness in 1 patient (1%).. This 62-dose, largely twice-weekly tuberculosis treatment regimen is efficacious and relatively nontoxic and is especially useful for patients in whom directly observed therapy is indicated.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Aspartate Aminotransferases; Cost-Benefit Analysis; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Sputum; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary

1990
[Tuberculosis: a disease that is difficult to eradicate. Description of a case].
    La Clinica terapeutica, 1990, Jul-15, Volume: 134, Issue:1

    The authors stress the recent increase of tuberculosis, especially in high-risk areas and populations. They illustrate the changes the disease has undergone lately, also with reference to a case they had occasion to observe. They describe 9-month and 6-month treatment schemes as well as the drugs that can be applied in cases of drug resistance which is rather frequent in AIDS patients.

    Topics: Acquired Immunodeficiency Syndrome; Antitubercular Agents; Diagnosis, Differential; Ethambutol; Female; Humans; Isoniazid; Middle Aged; Rifampin; Tuberculosis; Tuberculosis, Lymph Node

1990
Drug combinations and the bioavailability of rifampicin.
    Tubercle, 1990, Volume: 71, Issue:4

    Topics: Antitubercular Agents; Biological Availability; Drug Combinations; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

1990
[Drugs used in tuberculosis and leprosy].
    Nihon rinsho. Japanese journal of clinical medicine, 1990, Volume: 48, Issue:10

    Topics: Administration, Oral; Antibiotics, Antitubercular; Clofazimine; Dapsone; Humans; Injections, Intramuscular; Isoniazid; Leprostatic Agents; Leprosy; Rifampin; Streptomycin; Tuberculosis

1990
[Chemoprophylaxis of tuberculosis].
    La Revue du praticien, 1990, Mar-11, Volume: 40, Issue:8

    Chemoprophylaxis of tuberculosis may be primary or secondary. Primary chemoprophylaxis is intended for infants and children with negative tuberculin tests and exposed to contagion, in order to avoid primary tuberculosis. It lasts for three months and consists of oral isoniazide in one single daily dose of 5 to 10 mg/kg. Secondary chemoprophylaxis applies to all subjects, but principally to children, with a tuberculin test that has recently become positive in the absence of BCG vaccination. Its purpose is to protect against clinical tuberculosis. It lasts for six months and consists of isoniazid combined with rifampicin.

    Topics: Adolescent; Child; Child, Preschool; Drug Administration Schedule; Humans; Infant; Isoniazid; Rifampin; Tuberculosis

1990
Tuberculosis control and the AIDS epidemic in developing countries.
    Annals of internal medicine, 1990, Jul-15, Volume: 113, Issue:2

    Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Developing Countries; Diagnosis, Differential; Disease Outbreaks; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

1990
Salivary levels of isoniazid and rifampicin in tuberculous patients.
    Tubercle, 1990, Volume: 71, Issue:1

    Concentrations of isoniazid and rifampicin were determined in time-matched samples of saliva and serum from 30 tuberculous patients (18 with pulmonary tuberculosis and 12 with intestinal tuberculosis), comprising 18 slow and 12 rapid acetylators of isoniazid, following administration of isoniazid 300 mg and rifampicin 12 mg/kg. The diffusion of isoniazid into saliva was quite rapid and the salivary concentrations were similar to those in serum, suggesting that saliva could be used in place of serum for all pharmacokinetic studies with isoniazid. The salivary concentrations of rifampicin were much lower than those in serum, the mean peak concentrations being 0.9 and 8.5 microgram/ml, respectively. Further, there was evidence of a significant delay in the diffusion of rifampicin from serum to saliva.

    Topics: Adolescent; Adult; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Saliva; Tuberculosis; Tuberculosis, Gastrointestinal; Tuberculosis, Pulmonary

1990
Failure of tuberculosis chemotherapy in a human immunodeficiency virus-infected patient.
    The Journal of infectious diseases, 1990, Volume: 162, Issue:3

    Topics: Adult; HIV Infections; Humans; Isoniazid; Male; Rifampin; Tuberculosis

1990
Tuberculous brain infection located in an old cerebral infarct: CT changes with successful conservative therapy.
    Neuroradiology, 1990, Volume: 32, Issue:2

    A case of tuberculous brain infection following tuberculous meningitis in a 67-year-old man is presented. It was located in an old cerebral infarct associated with left internal carotid artery occlusion. CT demonstrated capsule enhancement in the left temporal area after iodinated contrast medium. Chemotherapy with INH, RFP and SM diminished the lesion and the capsule disappeared thirteen months later. It is suggested that a relatively long clinical history together with the appearance of a thick-walled abscess-like lesion on the CT scan is consistent with the diagnosis of tuberculous brain infection, perhaps an abscess.

    Topics: Aged; Brain Abscess; Cerebral Infarction; Humans; Isonicotinic Acids; Male; Rifampin; Streptomycin; Tomography, X-Ray Computed; Tuberculosis; Tuberculosis, Meningeal

1990
Drug resistance of Mycobacterium tuberculosis isolated from treated patients in Pakistan.
    Tubercle, 1989, Volume: 70, Issue:1

    An investigation was carried out to establish the extent of drug resistance among treated patients. A sample population of patients living in Lahore, Pakistan, which is a high prevalence area for tuberculosis, was studied. The total of 256 culture-positive cases in this study were divided into three groups according to the length of previous treatment. There was no significant difference in the antituberculosis treatment regimens or the drug resistance pattern among the three groups. All the patients had had at least three drugs for more than 6 months, and streptomycin and isoniazid were always included in the regimen. About one-third of the patients showed resistance to one or more drug, with the highest resistance being to streptomycin and INH. Resistance to rifampicin, which was introduced fairly recently in this area, was a little more than 5%, which is an increase from the last report.

    Topics: Adolescent; Adult; Aminosalicylic Acid; Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Pakistan; Pyrazinamide; Rifampin; Sputum; Streptomycin; Thioacetazone; Tuberculosis

1989
Problems of tuberculosis treatment in Thailand.
    Journal of the Medical Association of Thailand = Chotmaihet thangphaet, 1989, Volume: 72, Issue:11

    Problems of tuberculosis treatment in Thailand are an obstacle in the national tuberculosis control programme. Reasons concerning the problems on the health provider side being the most important are the budget and the health personnel attitude and behavior, convenience of service, distance of service, health provider-consumer social relation, social support and health service quality. On the health consumer side are patient attitude and behavior and patient economy. The most important understanding to the problems is the socio-economic status of the nation and health providers are responsible for the problems.

    Topics: Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation; Female; Humans; Isoniazid; Male; National Health Programs; Pyrazinamide; Rifampin; Streptomycin; Thailand; Thioacetazone; Tuberculosis

1989
Influence of BCG-induced immunity on the bactericidal activity of isoniazid and rifampicin in experimental tuberculosis of the mouse and guinea-pig.
    British journal of experimental pathology, 1989, Volume: 70, Issue:1

    The influence of previous BCG vaccination on the bactericidal activity of isoniazid and rifampicin has been studied using serial counts of viable tubercle bacilli in the spleens and lungs of mice and guinea-pigs infected intravenously with M. tuberculosis, strain H37Rv. In mice, BCG vaccination decreased the bactericidal activity of isoniazid in the spleen, but did not affect its activity in the lungs, where immunity is less strongly expressed. BCG did not influence the bactericidal activity of rifampicin in either organ. In contrast, previous BCG vaccination in the guinea-pig increased the bactericidal activity of isoniazid and rifampicin in the spleen and lungs. The differences between the animal species might result from the immune response being mainly bacteriostatic in the mouse but bactericidal in the guinea-pig.

    Topics: Animals; BCG Vaccine; Guinea Pigs; Immunity; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

1989
Relapses after stopping chemotherapy for experimental tuberculosis in genetically resistant and susceptible strains of mice.
    Clinical and experimental immunology, 1989, Volume: 76, Issue:3

    Three strains of mice (Swiss albinos, C57BL/6,C3H/OuJ) were injected intravenously with 3.7 x 10(6) colony forming units (CFU) of M. tuberculosis, H37RV, sensitive and resistant to antibiotics (90% of bacilli sensitive, 9% resistant to Streptomycin and 0.9% resistant to Kanamycin). Two weeks later, chemotherapy was started 6 days a week for a 6-month period with isoniazid (INH) and rifampicin (RMP). Twenty mice of each strain were killed at the end of the chemotherapy and the others were kept without antibiotics for a second 6-month follow-up period before being killed. The early multiplication of bacilli during the first 2 weeks following infection and before chemotherapy, was similar in the three strains of mice. Chemotherapy had the same apparent efficacy in the three strains of mice, nearly all the mice being cured as assessed by a negative spleen culture on Loewenstein-Jensen medium at the end of chemotherapy. But after the 6-month follow-up period, the C3H strain presented a statistically significantly higher level of positive spleen culture ('relapse') than seen in the C57BL/6 strain, and an increased number of mycobacteria per relapsing mouse spleen. It has been estimated with the help of resistant and sensitive bacilli that the relapses were due in most of the cases to the regrowth of one or very few bacilli, giving a clone. It seems that the C3H strain of mice, known to carry the Bcg-r allele of the Bcg gene, might be less able to develop a specific acquired resistance capable of stopping the delayed development of a highly virulent strain of mycobacteria.

    Topics: Animals; Anti-Bacterial Agents; Disease Susceptibility; Drug Therapy, Combination; Female; Immunity, Innate; Isoniazid; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mycobacterium bovis; Mycobacterium tuberculosis; Recurrence; Rifampin; Tuberculosis

1989
[The etiopathogenetic treatment of experimental tuberculosis using preparations with immunomodulating action].
    Zhurnal mikrobiologii, epidemiologii i immunobiologii, 1989, Issue:9

    The effectiveness of the complex chemotherapy of experimental tuberculosis in combination with the remedies of pathogenetic therapy has been studied. The immunomodulating action of levamisole, sodium succinate and the positive effect of RNAase on specific resistance in the complex treatment of guinea pigs infected with tuberculosis have been established. On the basis of the pronounced normalization of the systemic and specific resistance characteristics, as well as the clinical effect, the expediency of using levamisole and RNAase in the complex treatment of tuberculosis has been shown.

    Topics: Adjuvants, Immunologic; Animals; Drug Evaluation, Preclinical; Drug Therapy, Combination; Guinea Pigs; Immunity; Isoniazid; Levamisole; Male; Mycobacterium tuberculosis; Ribonucleases; Rifampin; Succinates; Succinic Acid; Time Factors; Tuberculosis

1989
Primary and acquired drug resistance in Mycobacterium tuberculosis strains in western region of Libyan Arab Jamahiriya.
    Tropical and geographical medicine, 1989, Volume: 41, Issue:4

    Drug resistance in Mycobacterium tuberculosis strains prevalent in the Western Region of Libyan Arab Jamahiriya was studied for the years 1984, 1985 and 1986 at the regional tuberculosis control centre at Gurgi, Tripoli. Records of resistance to streptomycin, isoniazid, ethambutol and rifampicin were analysed. Whereas primary drug resistance was observed in 5.1%, 19.5% and 3.8%, acquired drug resistance was found in 12.2%, 34.0% and 15.3% of the strains in 1984, 1985 and 1986 respectively. Only 3 out of 598 strains (1.2%) were found to show acquired resistance to rifampicin. No primary resistance to rifampicin was observed. The situation of drug resistance in pulmonary tuberculosis in the Jamahiriya is discussed.

    Topics: Drug Resistance, Microbial; Ethambutol; Female; Humans; Isoniazid; Libya; Male; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1989
Anaphylactoid drug reactions to ciprofloxacin and rifampicin in HIV-infected patients.
    Lancet (London, England), 1989, Apr-29, Volume: 1, Issue:8644

    Topics: Acquired Immunodeficiency Syndrome; Adult; Anaphylaxis; Ciprofloxacin; Humans; Male; Rifampin; Tuberculosis

1989
Venous thrombosis and rifampicin.
    Lancet (London, England), 1989, Aug-19, Volume: 2, Issue:8660

    In a retrospective analysis of clinically diagnosed and lower limb deep vein thrombosis (DVT) proven by contrast venography, DVT complicated admissions in 46 (3.4%) of 1366 adult patients treated in a tuberculosis hospital during 1986. Analysis of 7542 admissions during 1978-86 showed a relative risk of 4.74 in patients treated with regimens including rifampicin compared with other regimens. DVT was significantly more common in winter months and usually occurred within 2 weeks of treatment being started. This probable association between rifampicin and DVT does not contraindicate use of this drug, but measures to prevent DVT should be taken in inpatients receiving rifampicin.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Length of Stay; Male; Middle Aged; Retrospective Studies; Rifampin; Seasons; Thrombophlebitis; Tuberculosis

1989
Combination chemotherapy with ciprofloxacin for infection with Mycobacterium tuberculosis in mouse models.
    The American journal of medicine, 1989, Nov-30, Volume: 87, Issue:5A

    Topics: Animals; Ciprofloxacin; Disease Models, Animal; Drug Therapy, Combination; Isoniazid; Male; Mice; Rifampin; Tuberculosis

1989
[Tuberculosis in children in 1989].
    Pediatrie, 1989, Volume: 44, Issue:9

    Topics: Acquired Immunodeficiency Syndrome; Adolescent; Age Factors; Anti-Bacterial Agents; BCG Vaccine; Child; Child, Preschool; Drug Therapy, Combination; Humans; Infant; Infant, Newborn; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

1989
[Tuberculous ulcer of the tongue: clinical case].
    Odontologia chilena, 1989, Volume: 37, Issue:2

    A 26 year-old female was seeking treatment for a painless ulcerated lesion of the tongue developing 30 days before. No history of a sef biting in that area was told by the patient. Following a provisional diagnosis of tuberculous ulcer or a neoplasm, under local anesthesia, a segment of the lesion was excised and sent to histological diagnosis, which confirmed the existence of a tuberculous ulcer. Additionally, a chest roentgenogram disclosed the presence of an undiagnosed pulmonar tuberculous lesion. The patient underwent a successful treatment with rifampicin, isoniazide and pirazinamide, and two month after the initial diagnosis the oral lesion was almost absent, although the pulmonar lesion was still detected on the roentgenogram. Finally, a total disappearance of the pulmonar lesion was detected six month following drug treatment.

    Topics: Adult; Female; Humans; Isoniazid; Pyrazinamide; Rifampin; Tongue Diseases; Tuberculosis; Tuberculosis, Oral; Tuberculosis, Pulmonary; Ulcer

1989
Rifampin-associated thrombocytopenia secondary to poor compliance.
    DICP : the annals of pharmacotherapy, 1989, Volume: 23, Issue:5

    Rifampin can be associated with severe adverse effects such as hepatitis, acute renal failure, hemolytic anemia, and thrombocytopenia. Thrombocytopenia has traditionally been associated with intermittent therapy. This article reports the occurrence of rifampin-associated thrombocytopenia in an indigent patient after a four-month lapse in therapy for pulmonary tuberculosis. The patient's platelet count dropped rapidly to a level of 1000/mm3 after receiving a single 600 mg dose of rifampin. After returning to a normal level of greater than 100,000/mm3, the patient's platelets again dropped to 1200/mm3 with readministration of rifampin. The long-term therapy necessary to eradicate the Mycobacterium tuberculosis organism makes economic considerations important. This patient and other indigent patients who may be poor compliers because they are unable to buy the necessary medication may be at a higher risk for adverse reactions.

    Topics: Adult; Humans; Male; Patient Compliance; Platelet Count; Rifampin; Thrombocytopenia; Tuberculosis

1989
Systemic bacillus Calmette-Guérin infection, 'BCGitis', in patients treated by intravesical bacillus Calmette-Guérin therapy for bladder cancer.
    European urology, 1989, Volume: 16, Issue:3

    Among 169 patients treated for supeficial bladder tumor with 150 mg Pasteur-strain bacillus Calmette-Guérin (BCG) intravesical instillation, 5 cases of 'BCGitis' were observed, i.e. a severe systemic BCG infection with bronchopulmonary lesions and granulomatous hepatitis. In 4 cases, the complications appeared at the early stage of treatment (after the 3rd, 6th, 6th and 8th instillations, respectively). In 1 case, treated with monthly maintenance therapy for 2 years, BCGitis appeared 6 months after treatment had been completed and, in addition to pulmonary basal infiltrate and granulomatous hepatitis, intramedullary granulomatosis was observed. In 3 patients, trauma must be taken into consideration as BCGitis appeared after traumatic instillation with bleeding. All patients were cured by treatment with rifampicin, isoniazid and prednisone.

    Topics: Administration, Intravesical; Aged; BCG Vaccine; Carcinoma, Transitional Cell; Humans; Isoniazid; Male; Prednisolone; Rifampin; Time Factors; Tuberculosis; Urinary Bladder Neoplasms

1989
Nephrogenic diabetes insipidus and tubulointerstitial nephritis during continuous therapy with rifampin.
    American journal of kidney diseases : the official journal of the National Kidney Foundation, 1989, Volume: 14, Issue:3

    While receiving continuous daily rifampin therapy, a 57-year-old man developed acute renal failure and nephrogenic diabetes insipidus due to acute tubulointerstitial nephritis which was reversible by discontinuing the rifampin. Tubulointerstitial nephritis rarely develops during continuous rifampin therapy, and associated nephrogenic diabetes insipidus has not previously been reported. The majority of cases of tubulointerstitial nephritis due to rifampin have occurred following reintroduction of rifampin after an interruption in therapy. The clinical differences between patients developing tubulointerstitial nephritis during interrupted and continuous therapy are discussed.

    Topics: Acute Kidney Injury; Diabetes Insipidus; Humans; Male; Middle Aged; Nephritis, Interstitial; Rifampin; Tuberculosis

1989
[Recommendations for the therapy of tuberculosis. (Position: December, 1988)].
    Zeitschrift fur Erkrankungen der Atmungsorgane, 1989, Volume: 173, Issue:1

    Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1989
Less is more: short-course preventive therapy of tuberculosis.
    The American review of respiratory disease, 1989, Volume: 140, Issue:5

    Topics: Animals; Humans; Isoniazid; Mice; Rifampin; Tuberculosis

1989
Experimental short-course preventive therapy of tuberculosis with rifampin and pyrazinamide.
    The American review of respiratory disease, 1989, Volume: 140, Issue:5

    In a first experiment, the efficacy of a 6-month course of isoniazid (INH) alone in comparison with 2-month courses of rifampin (RMP) alone, RMP + pyrazinamide (PZA), or RMP + PZA + INH as preventive therapy of tuberculosis was evaluated in the mouse. To simulate the infected, non-diseased state of humans, a nonreplicating bacillary population of limited size was developed in the mouse. Mice were vaccinated intravenously with 2.74 log10 M. bovis BCG and infected a month later with 3.38 log10 M. tuberculosis. Treatment began 2 wk after infection when the mean size of the M. tuberculosis population was 4.98 +/- 0.26 log10 cfu in the spleen. After 2 months of therapy, the proportion of mice with positive spleen cultures was 100%, 50%, 0%, and 20% in those animals treated, respectively, with INH alone, RMP alone, RMP + PZA, or RMP + PZA + INH. After 6 months of therapy with INH alone, the proportion of mice with positive spleen cultures was 38%. In order to confirm the extreme activity of the combination RMP + PZA and to assess the value of 3 months of therapy with RMP, a second experiment was performed following similar procedures. On completion of treatment, the proportion of mice with positive spleen cultures was 100%, 20%, 0%, and 80% in those animals treated, respectively, for 6 months with INH alone, 3 months with RMP alone, or 2 months with RMP + PZA, or RMP + PZA + INH.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Animals; BCG Vaccine; Colony Count, Microbial; Drug Administration Schedule; Drug Therapy, Combination; Isoniazid; Mice; Pyrazinamide; Rifampin; Spleen; Time Factors; Tuberculosis

1989
[Activities of rifabutine and rifampicin against Mycobacterium avium complex infections in mice and in peritoneal macrophages].
    Kekkaku : [Tuberculosis], 1988, Volume: 63, Issue:3

    Topics: Animals; Antitubercular Agents; Female; Lung; Macrophages; Mice; Mice, Inbred Strains; Mycobacterium avium; Phagocytosis; Rifabutin; Rifampin; Rifamycins; Spleen; Tuberculosis

1988
Comparative in vitro and in vivo activity of rifabutin and rifampicin against Mycobacterium avium complex.
    Tubercle, 1988, Volume: 69, Issue:3

    In vitro antimicrobial activity of rifabutin and rifampicin against various mycobacteria, including the Mycobacterium avium complex, was evaluated by the agar dilution method, using 7H10 agar medium. The activity of rifabutin based on MIC50 and MIC90 was higher than that of rifampicin, against all the acid-fast organisms tested. Microbicidal activity of rifabutin against the M. avium complex phagocytosed in mouse peritoneal or alveolar macrophages was greater than that of rifampicin. Both rifabutin and rifampicin had therapeutic effects against murine infections induced by M. avium complex. Rifabutin was somewhat more effective than rifampicin in mice.

    Topics: Animals; In Vitro Techniques; Mice; Microbial Sensitivity Tests; Mycobacterium avium; Mycobacterium avium Complex; Rifabutin; Rifampin; Rifamycins; Tuberculosis

1988
The role of host factors for the chemotherapy of BCG infection in inbred strains of mice.
    APMIS : acta pathologica, microbiologica, et immunologica Scandinavica, 1988, Volume: 96, Issue:10

    Host factors have previously been considered to play a role in the efficacy of "incomplete" antituberculous chemotherapy. We investigated this aspect using a model of intravenous infection with M. bovis-BCG in three inbred strains of mice. Viable splenic counts of bacilli (CFU) were monitored following a three week regimen of rifampicin (R) and isoniazid (H) given either immediately or from three weeks after infection. At the end of the immediate (0-3 weeks) therapy the spleens of all mice were sterile and only a minority of animals had demonstrable CFU's at 23 weeks after infection. However, following the delayed-onset (3-6 weeks) therapy we found a pronounced relapse of BCG growth which was about 10 times higher in CBA/Ca and BALB/C than in C57B1/6 mice. These results indicated that host immunity which developed during the first three weeks after infection may have aggravated the relapse of bacterial growth following chemotherapy. This interpretation was corroborated by the finding that the immunosuppressive drug cyclosporin given concurrently with R/H reduced the splenic viable counts of BCG.

    Topics: Animals; Cyclosporins; Immunity; Isoniazid; Mice; Mice, Inbred Strains; Mycobacterium bovis; Rifampin; Time Factors; Tuberculosis

1988
Minimal inhibitory concentrations of isoniazid, rifampin, ethambutol, and streptomycin against Mycobacterium tuberculosis strains isolated before treatment of patients in Taiwan.
    The American review of respiratory disease, 1988, Volume: 138, Issue:4

    Minimal inhibitory concentrations (MICs) of isoniazid (INH), rifampin (RMP), ethambutol (EMB), and streptomycin (SM) for susceptible "wild" M. tuberculosis strains isolated from Taiwanese patients were within the limits previously reported for strains isolated in the United States. The highest agar-determined MICs (in 7H10 and 7H11 agar) corresponded well with the critical concentrations established for these media. The highest MICs found radiometrically in 7H12 broth were significantly lower than the critical concentrations proposed for this medium. On the basis of an evaluation of the highest broth-determined MICs found in this and in the previous study (1), we suggest that the following MICs, when determined radiometrically, should be used as breakpoints to classify the strain as "susceptible": for INH, 0.1 microgram/ml or less; for RMP, 0.5 microgram/ml or less; for EMB, 4.0 micrograms/ml or less; for SM, 2.0 micrograms/ml or less.

    Topics: Antitubercular Agents; China; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Osmolar Concentration; Rifampin; Streptomycin; Tuberculosis; United States

1988
Cell mediated and humoral immunity and light-chain proteinuria in rifampicin-treated tuberculous patients.
    Allergie und Immunologie, 1988, Volume: 34, Issue:4

    The present study was devoted to assess the humoral and cell mediated immune responsiveness in patients with pulmonary tuberculosis before and after rifampicin therapy. Skin test using PPD and PHA; Rosette forming cells test, serum IgG, M and A; and light chain proteinuria have been tested for 15 newly diagnosed tuberculous patients and 15 normal controls. Rifampicin showed an immunosuppressive effect on both cellular and humoral immune responses as well as by the advent of light chain proteinuria.

    Topics: Humans; Immunity; Immunity, Cellular; Immunoglobulin Light Chains; Lymphocyte Activation; Rifampin; Rosette Formation; Skin Tests; Tuberculosis

1988
[Therapeutic effect of DL-473 on experimental tuberculosis in mice].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 1988, Volume: 11, Issue:1

    Topics: Animals; Female; Male; Mice; Rifampin; Rifamycins; Tuberculosis

1988
[Addison crisis following administration of rifampicin in a patient with tuberculosis].
    Nederlands tijdschrift voor geneeskunde, 1988, Dec-17, Volume: 132, Issue:51

    Topics: Addison Disease; Adrenal Glands; Humans; Rifampin; Tomography, X-Ray Computed; Tuberculosis

1988
Single dose kinetics of rifampicin and isoniazid in well-nourished and malnourished patients of tuberculosis.
    International journal of clinical pharmacology, therapy, and toxicology, 1988, Volume: 26, Issue:8

    A single dose kinetics of isoniazid and rifampicin alone, and combination was studied in well-nourished and malnourished patients of tuberculosis. The elimination half-life of isoniazid was significantly increased when administered in combination with rifampicin in well-nourished and malnourished patients, while no significant difference was observed in any of the pharmacokinetic parameters of rifampicin in combination with isoniazid or alone in both groups of patients. Results are discussed on the basis of pharmacokinetic drug interaction.

    Topics: Acetylation; Adult; Female; Half-Life; Humans; Isoniazid; Male; Middle Aged; Nutrition Disorders; Phenotype; Rifampin; Spectrometry, Fluorescence; Tuberculosis

1988
Multidrug chemotherapy of tuberculosis in rhesus monkeys.
    Laboratory animal science, 1988, Volume: 38, Issue:1

    Occurrence of tuberculosis caused by Mycobacterium bovis in a colony of rhesus monkeys allowed evaluation of a modern multidrug therapeutic regimen. Fifteen tuberculin positive rhesus monkeys with disseminated tuberculosis were evaluated for extent of disease by radiographic techniques, physical examination and laparotomy prior to treatment. Monkeys were divided into treatment groups of 3, 6 and 12 months duration and were treated once daily with isoniazid, rifampin and ethambutol. All animals survived their treatment course, had marked clinical improvement and rapid resolution of radiographically demonstrable lesions. Lesion regression evaluated by necropsy and histopathology correlated positively with length of treatment interval. Mycobacterium bovis was not isolated from any animal following treatment. Multidrug chemotherapy of tuberculosis was considered successful and practical in rhesus monkeys at the 12 month treatment interval. Chemotherapy may provide a reasonable alternative to destruction of valuable animals infected with tuberculosis.

    Topics: Animals; Antitubercular Agents; Disease Outbreaks; Drug Therapy, Combination; Ethambutol; Female; Isoniazid; Macaca; Macaca mulatta; Male; Monkey Diseases; Mycobacterium bovis; Radiography; Rifampin; Tuberculosis

1988
Drugs for tuberculosis.
    The Medical letter on drugs and therapeutics, 1988, Apr-08, Volume: 30, Issue:763

    Topics: Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis

1988
Determination of rifampicin and its main metabolites in human plasma by high-performance liquid chromatography.
    Journal of chromatography, 1988, Apr-29, Volume: 426, Issue:2

    Topics: Adult; Chromatography, High Pressure Liquid; Humans; Male; Papaverine; Rifampin; Rifamycins; Tuberculosis

1988
Sensitivity to rifaximin and rifampicin of Mycobacterium tuberculosis isolated from guinea pigs treated orally with rifaximin.
    Chemioterapia : international journal of the Mediterranean Society of Chemotherapy, 1987, Volume: 6, Issue:2

    The in vitro sensitivity of the H 37 RV strain of Mycobacterium tuberculosis to rifaximin and rifampicin was determined by evaluating both the antimycobacterial activity of the two rifamycin derivatives after oral administration to infected guinea pigs and the influence of rifaximin on the susceptibility to rifampicin of the isolated strain from spleen, lungs and liver. The results showed that after oral treatment with rifaximin no changes regarding the sensitivity of the strain to rifaximin and rifampicin were seen.

    Topics: Animals; Drug Resistance, Microbial; Guinea Pigs; Male; Mycobacterium tuberculosis; Rifampin; Rifamycins; Rifaximin; Tuberculosis

1987
In vitro properties of rifapentine (MDL473) relevant to its use in intermittent chemotherapy of tuberculosis.
    Tubercle, 1987, Volume: 68, Issue:2

    In a comparison of in vitro properties of rifapentine (RIF) and rifampicin (RMP), the minimal inhibitory concentration of RIF against Mycobacterium tuberculosis in Tween-albumin liquid medium was usually 0.02 micrograms/ml, 2-3 times lower than for RMP; the bactericidal activity against a log phase culture was slightly less than that of RMP and the recovery after pulsed exposures to 1 microgram/ml of RIF or RMP lasting 6, 24 and 96 h was identical for the two rifamycins. These findings are used to interpret published data from the chronic experimental murine tuberculosis model and support the view that in the mouse, the efficacy of RIF in widely spaced intermittent chemotherapy is the result of its long half-life.

    Topics: Animals; Half-Life; In Vitro Techniques; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1987
The first joint THELEP-Sasakawa Memorial Health Foundation workshop on experimental chemotherapy of leprosy.
    International journal of leprosy and other mycobacterial diseases : official organ of the International Leprosy Association, 1987, Volume: 55, Issue:4 Suppl

    Topics: Dapsone; Drug Resistance, Microbial; Humans; Isoniazid; Leprosy; Mycobacterium leprae; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1987
[Isolated muscular tuberculosis in dermatomyositis treated with corticosteroids. Developing outbreak of dermatomyositis under rifampicin treatment. 2 cases].
    Annales de medecine interne, 1987, Volume: 138, Issue:7

    The authors report two cases of muscular tuberculosis in patients with dermatomyositis treated with steroids. Antituberculous therapy with Rifampicin led to a severe relapse of the dermatomyositis in both cases, suggesting enzymatic induction inhibiting the action of the steroids.

    Topics: Adrenal Cortex Hormones; Dermatomyositis; Humans; Male; Middle Aged; Muscular Diseases; Recurrence; Rifampin; Tuberculosis

1987
[Absorption and elimination of cyclopentyl-rifamycin in man].
    Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases, 1987, Volume: 10, Issue:5

    Topics: Absorption; Humans; Rifampin; Tuberculosis

1987
Pharmacokinetics of aldosterone in patients with Addison's disease: effect of rifampicin treatment on glucocorticoid and mineralocorticoid metabolism.
    Clinical endocrinology, 1987, Volume: 27, Issue:6

    Treatment of tuberculosis with rifampicin in patients with pre-existing adrenal failure has been reported to induce adrenal crisis due to alteration of cortisol metabolism by induction of hepatic mixed liver oxygenase enzymes. To determine whether mineralocorticoid metabolism is altered by rifampicin treatment, we established the pharmacokinetics of immunoreactive aldosterone. The metabolic clearance rate (MCR) and plasma half-life of this material were measured before and after 6 days of rifampicin treatment (600 mg/day) in seven patients with Addison's disease due to tuberculosis. Antipyrine clearance and urinary 6-beta-hydroxycortisol excretion was determined to demonstrate induction of the cytochrome P450 dependent enzymes. Infusion of aldosterone at a constant rate of 0.17 mg/h over 4.5 h produced steady state concentrations after 2 h, with no difference before and after rifampicin treatment (mean +/- SD, 1649 +/- 144 vs 1586 +/- 80 pg/ml, respectively). The disappearance curve of IR-aldosterone from plasma was biexponential. No change could be observed in the plasma half-lives (alpha-phase 29 +/- 1.9 min vs 30 +/- 1.5 min, beta-phase 129 +/- 3.2 min vs 126 +/- 4.3 min), the MCR (1.47 +/- 0.1 l/h/kg vs 1.46 +/- 0.1 l/h/kg), and the volume of distribution (9.9 +/- 1.9 vs 10.2 +/- 0.3 l). The antipyrine half-life decreased significantly from 12.2 +/- 2.6 h to 7.6 +/- 0.9 h (P less than 0.05) with a rise in antipyrine clearance from 0.38 +/- 0.07 to 0.80 +/- 0.23 ml/min/kg (P less than 0.05) and no change in the volume of distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Addison Disease; Adult; Aldosterone; Antipyrine; Female; Humans; Hydrocortisone; Male; Middle Aged; Rifampin; Tuberculosis

1987
Reduced incidence of tuberculosis by prophylactic chemotherapy in subjects showing strong reactions to tuberculin testing.
    Archives of disease in childhood, 1987, Volume: 62, Issue:10

    The introduction of chemoprophylaxis with rifampicin and isoniazid in 1981 significantly reduced the incidence of tuberculosis. Between 1978 and 1981 children accounted for 136 of 642 notified cases, and this was reduced to 55 of 418 between 1982 and 1986. This effect was most obvious among children from the Indian subcontinent who comprised 80.2% of the children treated. The incidence among white children was not affected. Few side effects occurred and only two of 339 (0.6%) later developed clinical tuberculosis. Chemoprophylaxis plays an important part in the management of tuberculosis in a district with a high incidence of the disease.

    Topics: Adolescent; Child; Child, Preschool; Drug Therapy, Combination; England; Humans; India; Infant; Infant, Newborn; Isoniazid; Rifampin; Tuberculin Test; Tuberculosis

1987
Antituberculous agents.
    Mayo Clinic proceedings, 1987, Volume: 62, Issue:12

    Antituberculous agents have radically improved the prognosis of patients with active tuberculosis. Generally, 6-month and 9-month regimens have been successful, and surgical therapy is rarely necessary. Extrapulmonary tuberculosis should be managed with the drug regimens outlined for pulmonary tuberculosis. The major cause of therapeutic failure is poor compliance of the patient in taking the medication regularly. The second major cause of treatment failure is resistance of tubercle bacilli to the antimicrobial agents used. When treatment failure is apparent, careful reassessment by physicians experienced in the treatment of tuberculosis is indicated. A single drug should never be added to a failing regimen. For prophylaxis, isoniazid, given for 6 to 12 months, is effective in most cases.

    Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1987
Association of leprosy and tuberculosis.
    The Journal of the Association of Physicians of India, 1987, Volume: 35, Issue:2

    Topics: Drug Resistance, Microbial; Female; Humans; Leprosy; Male; Rifampin; Tuberculosis

1987
Cost savings from alternative treatments for tuberculosis.
    Social science & medicine (1982), 1986, Volume: 23, Issue:9

    The cost effectiveness of short tuberculosis treatment regimes using rifampicin (R) or ethambutol (E) is calculated and compared to long regimes based on thiacetazone and isoniazid (TH). Although rifampicin and ethambutol are more costly per case they are only about one half the cost of the isoniazid based regimes per person effectively treated. This result is primarily derived from higher patient compliance with the short regimes. In addition, ambulatory treatment, where practical, is approximately one third the cost per person effectively treated of regimes using inpatient treatment for the first 2 months. Applied to 1982 data for Botswana, the analysis reveals that treating 80% of patients through ambulatory R and E regimes would have reduced total health expenditures for tuberculosis care by two thirds compared to inpatient regimes based on TH, and the number of people complying and cured would have doubled.

    Topics: Ambulatory Care; Antitubercular Agents; Botswana; Cost-Benefit Analysis; Ethambutol; Humans; Isoniazid; Patient Compliance; Retrospective Studies; Rifampin; Thioacetazone; Tuberculosis

1986
[Comparative effectiveness of the enteral and intravenous administration of rifampicin in treating experimental tuberculosis in rabbits].
    Antibiotiki i meditsinskaia biotekhnologiia = Antibiotics and medical biotechnology, 1986, Volume: 31, Issue:5

    The efficacy of intravenous and enteral administration of rifampicin was studied comparatively in treatment of hematogenic diseminated tuberculosis in rabbits. The drugs were administered in a dose of 10 mg/kg for 60 days. The functional state of the liver was studied in the time course by activity of urokinase, a hepatospecific enzyme and transaminases. Monotherapy with rifampicin capsules administered enterally resulted in death of 66.6 per cent of the animals due to tuberculosis during the first month of the treatment. Completion of the treatment course in 4 rabbits did not result in abacillation. When rifampicin was administered intravenously no deaths of the animals due to tuberculosis were recorded. Complete abacillation of the internal organs was observed in 37.5 per cent of the rabbits. The changes in activity of the indicator enzymes were transient and after discontinuation of the treatment came to normal.

    Topics: Administration, Oral; Animals; Drug Evaluation, Preclinical; Injections, Intravenous; Liver; Rabbits; Rifampin; Time Factors; Transaminases; Tuberculosis; Urocanate Hydratase

1986
[Routine use of 6-month antitubercular treatment in 300 patients].
    Presse medicale (Paris, France : 1983), 1986, Dec-06, Volume: 15, Issue:43

    Over a 2-year period, all patients with incipient tuberculosis seen in a hospital unit were given a 6-month treatment consisting of rifampicine, isoniazide, pyrazinamide and ethambutol. A retrospective study of these 300 patients showed that the treatment was effective, with no failure if taken for more than 2 months. Relapses were rare when the drugs were taken regularly, the responsible M. tuberculosis strain was sensitive, and there was no associated malignancy (present in 1.4% of the cases). The drugs were moderately well tolerated, and treatment had to be modified because of side-effects in 4.6% of the patients. It also appeared that 57% of the patients fully complied with the prescription, and 16% were lost sight of by the hospital unit. Treatment was altered in 36% of the cases, but in 16% changes were introduced by private doctors for reasons which retrospectively proved to be without medical grounds. It is concluded that this 6-month chemotherapeutic regimen was effective in more than 98% of the cases, and that the main problem in management of tuberculosis is the patient's compliance with treatment.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Drug Therapy, Combination; Drug Tolerance; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Pyrazinamide; Retrospective Studies; Rifampin; Time Factors; Tuberculosis

1986
Isoniazid, rifampin, and hepatotoxicity.
    The American review of respiratory disease, 1986, Volume: 133, Issue:6

    Topics: Acetylation; Asian; Chemical and Drug Induced Liver Injury; Drug Combinations; Drug Interactions; Humans; Isoniazid; Peripheral Nervous System Diseases; Rifampin; Risk; Time Factors; Tuberculosis

1986
Recombinant interferon-gamma and chemotherapy with isoniazid and rifampicin in experimental murine tuberculosis.
    British journal of experimental pathology, 1986, Volume: 67, Issue:4

    Viable bacterial counts in the lungs and spleens of mice infected intravenously with Mycobacterium tuberculosis, strain H37Rv were reduced by intravenous recombinant murine interferon-gamma (IFN-gamma) 1000-5000 u, but not by 200 u. Reduction in counts was greatest when IFN-gamma was given 1 day before infection and was not increased by additional doses in the preceding 2 days. The effect was complete in 1 day and was not increased by successive doses during the next week. Giving IFN-gamma in multilamellar liposomes further reduced the spleen viable counts, but this appeared due to the liposomes themselves and not to encapsulation of IFN-gamma within them. Only a minimal reduction in organ viable counts, not statistically significant, occurred when IFN-gamma was given 5 days after infection. Although IFN-gamma alone and isoniazid 25 mg/kg alone reduced the organ viable counts, combined treatment with IFN-gamma and isoniazid was no more bactericidal than isoniazid alone. Similarly, the bactericidal activity of rifampicin 25 mg/kg was not increased by simultaneous administration of IFN-gamma. There seems little likelihood that IFN-gamma would increase the efficacy of the early stages of the chemotherapy of tuberculosis.

    Topics: Animals; Drug Therapy, Combination; Interferon-gamma; Isoniazid; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Rifampin; Spleen; Time Factors; Tuberculosis

1986
Drug-resistant tuberculosis in Sierra Leone.
    Tubercle, 1986, Volume: 67, Issue:2

    Culture and sensitivity tests were performed on tubercle bacilli from patients with tuberculosis attending a provincial general hospital in Sierra Leone, who appeared clinically to have drug-resistant infections. Amongst the general intake of patients from 1978 to 1984 there was a 10.5% incidence of isoniazid resistance, with 7.7% of patients having strains resistant to both streptomycin and isoniazid, 1.3% resistant to rifampicin, and 0.8% resistant to ethambutol. Multiple drug resistance was more frequent than single drug resistance. This high incidence is largely due to inadequate and irregular supplies of first line drugs.

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sierra Leone; Streptomycin; Tuberculosis

1986
[New active drugs against the tuberculosis bacillus and other mycobacteria].
    Medicina, 1986, Volume: 46, Issue:1

    Topics: Amikacin; Anti-Bacterial Agents; Humans; Lactams; Mycobacterium; Mycobacterium avium; Mycobacterium tuberculosis; Nalidixic Acid; Nontuberculous Mycobacteria; Rifampin; Tuberculosis

1986
[Theoretical basis for the treatment of tuberculosis].
    Soins; la revue de reference infirmiere, 1986, Issue:491-492

    Topics: Antitubercular Agents; Drug Resistance; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1986
American Thoracic Society. Medical Section of the American Lung Association: Treatment of tuberculosis and tuberculosis infection in adults and children.
    The American review of respiratory disease, 1986, Volume: 134, Issue:2

    Treatment of tuberculosis: A 6-month regimen consisting of isoniazid, rifampin, and pyrazinamide given for 2 months followed by isoniazid and rifampin for 4 months is effective treatment in patients with fully susceptible organisms who comply with the treatment regimen. It may be advisable to include ethambutol in the initial phase when isoniazid resistance is suspected. A 9-month regimen consisting of isoniazid and rifampin is also highly successful. The need for an additional drug in the initial phase is not certain unless isoniazid resistance is suspected, in which case ethambutol should be included until susceptibility tests have been reported. In the presence of documented resistance to isoniazid, rifampin and ethambutol, perhaps supplemented initially by pyrazinamide, should be given for minimum of 12 months. Children should be treated in essentially the same ways as adults using appropriately adjusted doses of the drugs. However, consideration must be given to the important differences in the approach to management in children. Extrapulmonary tuberculosis should be managed according to the principles and with the drug regimens outlined to pulmonary tuberculosis. The major determinant of the outcome of treatment is patient compliance. Careful attention should be paid to measures designed to foster compliance and to ensure that patients take the drugs as prescribed. Treatment of tuberculous infection: Preventive therapy with isoniazid given for 6 to 12 months is effective in decreasing the risk of future tuberculosis. (ABSTRACT TRUNCATED AT 250 WORDS)

    Topics: Adult; Age Factors; Blood Cell Count; Blood Urea Nitrogen; Child; Creatinine; Drug Administration Schedule; Drug Resistance, Microbial; Ethambutol; Female; Humans; Isoniazid; Lactation; Liver; Mycobacterium bovis; Pregnancy; Pyrazinamide; Rifampin; Sputum; Streptomycin; Time Factors; Tuberculin; Tuberculosis

1986
Report of the joint leprosy-tuberculosis project in Paraguay.
    Leprosy review, 1986, Volume: 57 Suppl 3

    Topics: Dapsone; Drug Combinations; Drug Therapy, Combination; Humans; Isoniazid; Leprostatic Agents; Leprosy; Paraguay; Prothionamide; Rifampin; Tuberculosis

1986
Rifampin-induced release of hydrazine from isoniazid. A possible cause of hepatitis during treatment of tuberculosis with regimens containing isoniazid and rifampin.
    The American review of respiratory disease, 1986, Volume: 133, Issue:6

    The effect of daily administration of rifampin on the direct conversion of isoniazid to isonicotinic acid and hydrazine by isoniazid hydrolase was investigated in 6 slow and 8 rapid acetylators of isoniazid. The proportion of isoniazid metabolized through this direct pathway during the first 6 h was estimated from the ratio of total isonicotinic acid formed to acetylisoniazid in urine after administration of isoniazid or acetylisoniazid. In slow acetylators, this proportion was approximately 3% when isoniazid alone was administered and approximately 6% during the maximal phase of induction caused by the daily administration of rifampin in addition to isoniazid (p less than 0.001); in rapid acetylators, the proportions were considerably less (less than 1 and 2.5%, respectively), suggesting that isoniazid hydrolase was induced by rifampin. The increased formation of hydrazine, a known hepatotoxic agent in animals, could explain the substantially higher frequency of the occurrence of hepatitis in slow than in rapid acetylators among tuberculous patients treated with daily rifampin and isoniazid.

    Topics: Acetylation; Chemical and Drug Induced Liver Injury; Drug Combinations; Humans; Hydrazines; Isoniazid; Rifampin; Tuberculosis

1986
The bioavailability of isoniazid, rifampin, and pyrazinamide in two commercially available combined formulations designed for use in the short-course treatment of tuberculosis.
    The American review of respiratory disease, 1986, Volume: 133, Issue:6

    The bioavailability of isoniazid, rifampin, and pyrazinamide in 2 combined formulations of the 3 drugs (Rifater) for use primarily in the short-course chemotherapy of tuberculosis has been studied in Chinese patients in Singapore and Hong Kong. One formulation, containing 50 mg isoniazid, 120 mg rifampin, and 300 mg pyrazinamide per tablet is suitable for daily use, whereas the other, containing higher proportions of isoniazid and pyrazinamide, is designed for intermittent treatment, each tablet containing 125 mg isoniazid, 100 mg rifampin, and 375 mg pyrazinamide. Appropriate dosages for the Chinese patients, whose average weight was approximately 50 kg, were 5 and 6 tablets, respectively. Plasma concentrations of the 3 drugs after giving such dosages of the 2 combined formulations were compared in 16 patients, 8 in Singapore and 8 in Hong Kong, by means of a crossover study, with the concentrations obtained when identical doses of the 3 drugs were given using standard separate drug formulations. The concomitant urinary excretions of the drugs and their major metabolites were also estimated. Very similar results were obtained whether the drugs were given as the combined preparations or in their standard separate formulations, demonstrating the excellent bioavailability of all 3 drugs in each of the 2 combined formulations.

    Topics: Acetylation; Adolescent; Adult; Biological Availability; Drug Combinations; Humans; Isoniazid; Middle Aged; Osmolar Concentration; Phenotype; Pyrazinamide; Rifampin; Time Factors; Tuberculosis

1986
Hepatic mixed function oxidase induction during rifampicin/isoniazid therapy in Indian vegetarians.
    International journal of clinical pharmacology, therapy, and toxicology, 1986, Volume: 24, Issue:7

    To determine the effect of rifampicin therapy on hepatic oxidase activity in animal protein deficient patients antipyrine and quinine t 1/2 and 6B-hydroxycortisol (6B-OHF) excretion was studied in 8 Indian vegetarians during treatment for tuberculosis. In 4 patients at the start of treatment rifampicin/streptomycin caused a steady decline in by time antipyrine t 1/2 which was complete in 3 weeks, in one patient introduction of isoniazid produced a temporary reversal. After 4 months rifampicin/isoniazid 6B-OHF excretion was increased 2 to 10 fold in all patients although one followed serially showed a marked fall when isoniazid was begun. Decline in antipyrine t 1/2 persisted in 4 patients at the end of 18 months therapy and in one of these concurrent quinine t 1/2 confirmed partial isoniazid reversal of this decline. Rifampicin-mediated mixed function oxidase induction appeared similar to that reported for non-vegetarians and largely persists with combination therapy throughout treatment. Isoniazid can act as a competitive inhibitor of hepatic oxidase activity in some patients.

    Topics: Antipyrine; Diet, Vegetarian; Drug Therapy, Combination; Enzyme Induction; Female; Half-Life; Humans; Hydrocortisone; India; Isoniazid; Liver; Male; Mixed Function Oxygenases; Quinine; Rifampin; Streptomycin; Tuberculosis

1986
Amikacin, ethambutol, and rifampin for treatment of disseminated Mycobacterium avium-intracellulare infections in patients with acquired immune deficiency syndrome.
    Diagnostic microbiology and infectious disease, 1986, Volume: 5, Issue:3

    Synergistic combinations of achievable serum levels of amikacin, rifampin, and ethambutol were tested for their ability to inhibit growth of Mycobacterium avium-intracellulare strains isolated from seven patients with acquired immune deficiency syndrome. Even when the isolates were very resistant to the individual antimicrobial agents in vitro, growth was completely inhibited by all combinations of the three agents tested. Four of the patients treated with a combined regimen of amikacin, rifampin, and ethambutol showed clinical improvement. Synergistic antimicrobial susceptibility tests seem to more accurately represent the efficacy of combined regimens used to treat these extremely resistant mycobacteria than do conventional susceptibility determinations with individual antimicrobial agents.

    Topics: Acquired Immunodeficiency Syndrome; Amikacin; Drug Synergism; Drug Therapy, Combination; Ethambutol; Humans; Microbial Sensitivity Tests; Mycobacterium avium; Rifampin; Tuberculosis

1986
Triton WR-1339 as a biological-response modifier in mycobacterial infection.
    Japanese journal of medical science & biology, 1986, Volume: 39, Issue:2

    A non-ionic detergent, Triton WR-1339, prolonged markedly the survival time of mice infected fatally with virulent mycobacteria, though it exerted only a limited effect on the fate of tissue viable counts. The combined administration of Triton WR-1339 with lentinan (a glucan purified from the Japanese mushroom Lentinus edodes) was more effective than the single administration of each. This detergent was not lytic to red blood cells or lysosomes, but its substantial effect on the biomembrane was suggested by cold-shock experiment of hemolysis. It was considered that Triton WR-1339 is a biological-response modifier, possibly altering the interaction between the mycobacterial surface and the membrane structure of phagocytes.

    Topics: Animals; Cell Membrane; Detergents; Drug Therapy, Combination; Lentinan; Lung; Male; Mice; Mycobacterium; Polyethylene Glycols; Pyrazinamide; Rifampin; Spleen; Tuberculosis

1986
Tuberculosis policy--correction of facts.
    South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 1986, Oct-11, Volume: 70, Issue:8

    Topics: Humans; Rifampin; South Africa; Tuberculosis

1986
Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide.
    Tubercle, 1986, Volume: 67, Issue:2

    Results are presented of the incidence of hepatitis, nearly always with jaundice, among 1686 patients in clinical trials of the treatment of spinal tuberculosis, of tuberculosis meningitis and of pulmonary tuberculosis with short-course regimens containing rifampicin, isoniazid, streptomycin and pyrazinamide. The incidence was high in patients treated with daily regimens of isoniazid and rifampicin: 16-39% in children with tuberculous meningitis, 10% in patients with spinal tuberculosis (non-surgical cases), and 2-8% in those with pulmonary tuberculosis. Hepatitis, in those receiving rifampicin occurred more often in slow than in rapid acetylators of isoniazid, the proportions amongst those whose acetylator phenotype had been determined being 11% of 317 slow acetylators and 1% of 244 rapid acetylators. In children with tuberculous meningitis, the risk of hepatitis with isoniazid 20 mg/kg (39%) was higher than that with 12 mg/kg (16%), and appreciably lower in patients given rifampicin twice-weekly (5%) rather than daily (21%). There was no indication that pyrazinamide contributed to the hepatic toxicity.

    Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Humans; Infant; Isoniazid; Jaundice; Liver; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Meningeal; Tuberculosis, Pulmonary; Tuberculosis, Spinal

1986
Short-course chemotherapy for extrapulmonary tuberculosis. Nine years' experience.
    Annals of internal medicine, 1986, Volume: 104, Issue:1

    Short-course chemotherapy with isoniazid and rifampin is well established for pulmonary tuberculosis but not yet for extrapulmonary disease. We report our 9-year experience with short-course chemotherapy in treating 350 patients; 402 extrapulmonary sites were involved. Therapy was largely self-administered with careful monitoring by local public health nurses. Administration of drugs was directly supervised in less than 2% of patients. Short-course chemotherapy with isoniazid and rifampin for 9 months was successful in 95% of patients, equivalent to conventional therapy with two to three drugs for 18 to 24 months. It was found that early drainage and complete debridement of necrotic material in bone lesions enhances healing. Short-course chemotherapy has excellent patient acceptance, short duration, fewer doses, and modest toxicity. Our largely twice-weekly regimen has the additional advantages of reduced cost, fewer doses, and ease of supervision when needed.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Administration Schedule; Female; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1986
Pharmacokinetics of rifampin in children. II. Oral bioavailability.
    Therapeutic drug monitoring, 1986, Volume: 8, Issue:1

    The absolute bioavailability of oral rifampin was determined in 20 pediatric patients. Intravenous doses of rifampin (mean 287 mg/m2) were compared with p.o. doses (mean 324 mg/m2). Serum concentrations of rifampin, 25-O-desacetylrifampicin, and 3-formylrifamycin SV were determined by high performance liquid chromatography. Following a 1/2-h intravenous infusion, serum rifampin concentrations declined in a monoexponential fashion. Pharmacokinetic analysis of the rifampin serum concentration data indicated that only 50 +/- 22% of a freshly prepared p.o. suspension was absorbed. The rifampin elimination half-life following i.v. administration (2.25 +/- 0.64 h) was not different from that observed following p.o. dose administration (2.61 +/- 1.35 h). Peak rifampin concentrations were significantly higher following i.v. administration when corrected to a 300 mg/m2 dose (27.4 vs. 9.1 micrograms/ml, respectively, p less than 0.0001) than after p.o. administration. The peak concentration following a p.o. dose occurred at 2.0 +/- 0.9 h. The ratio of desacetylrifampicin to rifampin areas under the curves were similar for i.v. and p.o. routes of administration (0.23 vs. 0.19), suggesting linear metabolism of rifampin to this metabolite. 3-formylrifamycin SV concentrations were lower than those of desacetylrifampicin and were detectable in less than half of the patients. The results of this study indicate the need for larger p.o. doses when serum concentrations similar to those obtained following intravenous doses are desired.

    Topics: Administration, Oral; Biological Availability; Child, Preschool; Female; Humans; Infant; Injections, Intravenous; Kinetics; Male; Rifampin; Tuberculosis

1986
Cyclosporin and antituberculous therapy.
    Lancet (London, England), 1985, Jun-08, Volume: 1, Issue:8441

    Topics: Child; Cyclosporins; Drug Antagonism; Female; Graft Rejection; Humans; Immunosuppression Therapy; Kidney Transplantation; Rifampin; Tuberculosis

1985
[Rifampicine (2), Rifadine, Rimactan].
    Soins; la revue de reference infirmiere, 1985, Issue:454

    Topics: Humans; Rifampin; Tuberculosis

1985
[Rejection reaction and use of rifampicin in the treatment of tuberculosis in kidney transplantation].
    Nephrologie, 1985, Volume: 6, Issue:2

    Rifampicin is considered as one of the most potent antituberculous agents and is often used in renal transplant recipients. However, acute cellular rejection episodes were observed when rifampicin was prescribed in 4 tolerant renal transplant recipients. Acute rejection occurred in 3 out of the 5 patients, despite doubled daily dose of steroids. First, rifampicin is an enzymatic inducer and accelerates steroid metabolism. Secondly, rifampicin per se is an immunosuppressive drug, as already proved in animals. Rifampicin interferes with the active mechanisms involved in specific transplantation tolerance. In conclusion, we recommend a very cautious use of rifampicin in kidney transplant recipients.

    Topics: Adult; Graft Rejection; Humans; Kidney Transplantation; Male; Rifampin; Tuberculosis

1985
Isoniazid-induced pure red cell aplasia.
    The American review of respiratory disease, 1985, Volume: 131, Issue:6

    Pure red blood cell aplasia (PRCA) is an extremely rare side effect of isoniazid (INH). We have encountered 2 patients who developed anemia caused by PRCA. One was receiving INH preventive therapy and the other was being treated with INH and rifampin. On withdrawal of INH, the anemia responded rapidly. For unexplained anemia during INH therapy, PRCA should be considered as a cause.

    Topics: Aged; Bone Marrow; Drug Therapy, Combination; Humans; Isoniazid; Male; Middle Aged; Red-Cell Aplasia, Pure; Rifampin; Tuberculosis

1985
[Prevention of resistance to rifampicin by pyrazinamide in experimental tuberculosis in the mouse].
    Revue des maladies respiratoires, 1985, Volume: 2, Issue:4

    The capacity of Pyrazinamide (PZA) to prevent the selection of Rifampicin (RMP) resistant mutants was tested by the intravenous innoculation of 160 mice with 2 X 10(6) c.f.u. of M. tuberculosis, and two weeks later, the treatment of the mice either with 10 mg/kg/day RMP alone or with RMP + PZA 150 mg/kg/day. After three months of treatment, lungs and spleen were culture positive in respectively 95% and 90% of the mice treated with RMP alone and in 37% and 24% of the mice treated by RMP + PZA (p less than 10(-5). The strains isolated from lungs and spleen were resistant to Rifampicin in respectively 87% and 75% of the mice treated with RMP alone and in none of those treated with RMP + PZA.

    Topics: Animals; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Lung; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Spleen; Tuberculosis

1985
[The latest topics concerning pyrazinamide].
    Kekkaku : [Tuberculosis], 1985, Volume: 60, Issue:11

    Topics: Adolescent; Adult; Animals; Child; Drug Resistance, Microbial; Drug Synergism; Female; Humans; Isoniazid; Male; Mice; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

1985
Tuberculosis control practices in major metropolitan health departments in the United States. 3. Standard of practice in 1984.
    Chest, 1985, Volume: 87, Issue:2

    Twenty-eight metropolitan health departments in the United States reporting more than 200 cases annually were surveyed to determine the standard of practice in the control of pulmonary tuberculosis. The results were compared to previous surveys done in 1978 and 1980 to determine the impact of policy changes recommended by the American Thoracic Society, American College of Chest Physicians, and Centers for Disease Control and recent reports of innovative chemotherapeutic methods. A high degree of uniformity in chemoprophylaxis practices again was demonstrated. In contrast to our previous survey of 1980, most programs now use rifampin-containing regimens with short (less than 12 month) course chemotherapy as the primary initial treatment regimen for tuberculosis. Mean duration of treatment for tuberculosis decreased from 20.2 +/- 2.1 months in 1980 to 11.7 +/- 1.0 months in 1984. Intermittent chemotherapeutic regimens also were used more frequently in 1984. However, substantial variance from other recommended guidelines still is prevalent among the major metropolitan programs in the United States.

    Topics: Adolescent; Adult; Child; Drug Therapy; Drug Therapy, Combination; Ethambutol; Health Facilities; Health Policy; Health Surveys; Humans; Isoniazid; Public Health Administration; Rifampin; Tuberculosis; United States

1985
Should the dose of antituberculosis drugs be reduced in patients with liver disease?
    South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 1985, Apr-06, Volume: 67, Issue:14

    Topics: Humans; Isoniazid; Liver Diseases; Rifampin; Tuberculosis

1985
[Tuberculosis: some current problems].
    Revue medicale de Bruxelles, 1985, Volume: 6, Issue:4

    Topics: Belgium; Humans; Isoniazid; Rifampin; Tuberculosis

1985
[Immunologic reactivity and healing reactions in animals with experimental tuberculosis as affected by chemotherapy].
    Problemy tuberkuleza, 1985, Issue:5

    Topics: Animals; Antitubercular Agents; Drug Therapy, Combination; Guinea Pigs; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1985
Tuberculosis in an Indochinese refugee camp: epidemiology, management and therapeutic results.
    Tubercle, 1985, Volume: 66, Issue:3

    In a 3-year period tuberculosis was diagnosed in 629 patients in Thailand's largest camp for Kampuchean refugees: 62% had pulmonary disease and 38% extrapulmonary forms. Tuberculosis of lymph nodes was the most important extrapulmonary manifestation (50%). The mean annual notification rates were 0.5% and 0.24% for all forms and smear-positive pulmonary tuberculosis respectively. There was a steep rise in the annual notification rate with increasing age. A 6-month course of fully supervised chemotherapy efficiently counteracted defaulting, early absconding and initial drug resistance. Seventy-three per cent of all patients remained on chemotherapy for the planned period; only 2% of the smear-positive patients failed bacteriologically on chemotherapy. Of the patients with the most common forms of extrapulmonary disease, 90% showed a favourable response to chemotherapy.

    Topics: Adolescent; Adult; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Infant; Isoniazid; Middle Aged; Patient Compliance; Pregnancy; Pyrazinamide; Refugees; Rifampin; Streptomycin; Thailand; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary

1985
Leucopenia in rifampicin chemotherapy.
    The Journal of antimicrobial chemotherapy, 1985, Volume: 16, Issue:3

    Topics: Humans; Leukopenia; Random Allocation; Rifampin; Time Factors; Tuberculosis

1985
Clinical experience with short-course chemotherapy in patients with tubercular pleural effusion and lymphadenitis.
    Respiration; international review of thoracic diseases, 1985, Volume: 48, Issue:2

    Twenty-one patients with pleural effusion and 27 patients with lymphadenitis, both tubercular in origin, were administered isoniazid, rifampicin and ethambutol in a daily single dose for 9 months. 100% response was seen in patients with pleural effusion. In the case of tuberculous lymphadenitis the therapeutic response was unsatisfactory, and complete resolution of lymph nodes was achieved in 16 out of 27 patients only (59%). Drug treatment had to be extended for another 3 months which gave 89% response. In view of our present findings, short-course chemotherapy appears not to be the ideal mode of treatment for tuberculous lymphadenitis. There were no side effects from drug therapy in either group of patients.

    Topics: Adolescent; Adult; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Lymphadenitis; Male; Middle Aged; Pleural Effusion; Rifampin; Time Factors; Tuberculosis

1985
Evaluation of subdermal biodegradable implants incorporating rifampicin as a method of drug delivery in experimental tuberculosis of guinea pigs.
    Journal of medical microbiology, 1985, Volume: 20, Issue:3

    Conventional chemotherapy of tuberculosis and leprosy requires rifampicin to be administered orally. The long period of treatment and adverse side effects of the drug lead to poor compliance. To overcome this, subdermal implants incorporating rifampicin in pure and micro-encapsulated forms with biodegradable material were used as a new drug delivery system in experimental tuberculosis of guinea pigs. Two experiments were performed with 45-mg and 100-mg drug implants. Progress of infection was followed at intervals by studying necropsy scores and weights of the organs of predilection and levels of the drug in the blood were determined. There was a constant and sustained release of the drug in therapeutic concentrations for 30 and 50 days until the implants were completely assimilated without causing any damage to the implant site. The importance of multiple implants at long intervals is discussed.

    Topics: Animals; Drug Compounding; Drug Evaluation; Drug Implants; Guinea Pigs; Liver; Lung; Organ Size; Rifampin; Spleen; Time Factors; Tuberculosis

1985
Sarcoidosis of the larynx in a child.
    The Journal of otolaryngology, 1985, Volume: 14, Issue:6

    Sarcoidosis is a multisystem disease of unknown etiology characterized by non-caseating granulomatous inflammation of various organs, but most frequently involving the lungs of young adults. Sarcoidosis is rare in the pediatric age group, however numerous extensive reviews have been published. The most commonly seen initial manifestations in childhood are non-specific constitutional symptoms such as lethargy, fatigue and malaise, followed by cough, dyspnea, fever, weight loss, and lymphadenopathy in order of decreasing frequency. The diagnosis is one of exclusion and is established when clinical and radiological findings are supported by histological evidence of widespread non-caseating epithelial cell granulomas in more than one organ, or a positive Kveim test. Laryngeal involvement is usually part of the systemic disease, but isolated laryngeal sarcoidosis has been reported in adults. We report here a case of isolated laryngeal sarcoidosis in a 13 year old girl. The differential diagnosis and management are discussed.

    Topics: Adolescent; Diagnosis, Differential; Epiglottis; Female; Humans; Isoniazid; Laryngeal Diseases; Laryngeal Mucosa; Prednisone; Rifampin; Sarcoidosis; Tuberculosis

1985
Rifampicin-induced renal failure.
    Tubercle, 1985, Volume: 66, Issue:4

    Renal failure is a rare complication associated with the use of rifampicin for the treatment of tuberculosis, usually occurring well into the course of therapy. The following is a report of 2 cases of rifampicin-induced renal insufficiency. In the first case oligo-anuric renal failure occurred on the thirteenth day of treatment, after the patient had taken only 9 doses of medication. The second case occurred in a patient who developed renal failure while on daily therapy in the hospital. A literature review revealed 83 other reported cases of rifampicin-induced renal insufficiency. Intermittent or interrupted therapy appears to be a significant risk factor for the development of this complication.

    Topics: Acute Kidney Injury; Aged; Female; Humans; Male; Middle Aged; Rifampin; Risk; Tuberculosis

1985
Tuberculosis in hospital.
    The Journal of hospital infection, 1984, Volume: 5, Issue:2

    Topics: Adult; BCG Vaccine; Child; Cross Infection; Disease Outbreaks; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Occupational Diseases; Patient Isolation; Rifampin; Specimen Handling; Sterilization; Tuberculosis; Tuberculosis, Pulmonary; United Kingdom; Vaccination; Ventilators, Mechanical

1984
[Biological characteristics of rifampicin-resistant Mycobacterium tuberculosis].
    Antibiotiki, 1984, Volume: 29, Issue:3

    Eleven rifampicin resistant variants were obtained in vitro from rifampicin sensitive strains of M. tuberculosis. It was shown that the in-vitro development of the resistance to rifampicin was of the one-stage phenomenon type. The study on the morphological, tinctorial and cultural properties, catalase activity, cord factor and toxicity showed their identity in the initial rifampicin sensitive strains and the rifampicin resistant variants. The virulence of the rifampicin resistant variants for albino rats and rabbits did not significantly change either.

    Topics: Animals; Drug Resistance, Microbial; Guinea Pigs; Mice; Mycobacterium tuberculosis; Rabbits; Rifampin; Tuberculosis; Virulence

1984
[Resistance to antitubercular drugs in Chile].
    Revista medica de Chile, 1984, Volume: 112, Issue:1

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Humans; Immunity; Isoniazid; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1984
The usefulness of phage typing Mycobacterium tuberculosis isolates.
    The American review of respiratory disease, 1984, Volume: 130, Issue:6

    Mycobacteriophage typing of Mycobacterium tuberculosis isolates was used as an epidemiologic aid in investigating the transmission of tuberculosis in community, industrial, and institutional outbreaks. The technique was also useful in other situations, e.g., documenting congenital transmission of infection and distinguishing exogenous reinfection from endogenous reactivation. Additional studies are indicated to further explore the value of phage typing for tracking the transmission of tuberculosis in the community.

    Topics: Adolescent; Adult; Aged; Animal Diseases; Animals; Bacteriophage Typing; Child; Child, Preschool; Disease Outbreaks; Elephants; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacteriophages; Mycobacterium tuberculosis; Recurrence; Rifampin; Tuberculosis

1984
Preliminary observations on short-course chemotherapy in tuberculous serositis.
    Respiration; international review of thoracic diseases, 1984, Volume: 46, Issue:1

    Short-course chemotherapy has not been previously assessed in tuberculous serositis. In this study, 18 patients with tuberculous serositis were studied. 600 mg of rifampicin, 300 mg of isoniazid and 25 mg of pyridoxine were given daily for 6 months. 14 patients completed the therapeutic regimen and were evaluated. 11 of these showed excellent results on the long-term follow-up (18-24 months) and 3 of shorter-term follow-up (9-12 months). Short-course chemotherapy appears to be efficacious in the treatment of tuberculous serositis. However, further and larger trials are recommended.

    Topics: Adolescent; Adult; Aged; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyridoxamine; Rifampin; Serositis; Time Factors; Tuberculosis

1984
The problems of tuberculosis in the elderly.
    The Quarterly journal of medicine, 1984,Autumn, Volume: 53, Issue:212

    A prospective study of tuberculosis notifications from 1976 to 1980 in the North Staffordshire Health District (NSHD), an area with only a small immigrant population, has been carried out. The notification rate for all new cases of tuberculosis in white patients over 55 years of age in the NSHD was twice that reported for England and Wales by the Medical Research Council (1980). Of 433 cases in all ethnic groups 52 (12 per cent) were diagnosed only at necropsy. In addition 48 (11 per cent) died before treatment was completed. Tuberculosis was the only cause of death in 39 of these 100 cases and contributed to death in a further 19 cases, the site of disease being thoracic in 86. Of those who died before completion of treatment, tuberculosis was the cause of death or contributory in 23 and 16 of the 23 (70 per cent) had been on treatment for less than 13 weeks. Death occurred more commonly before or during treatment with increasing age. In a retrospective study of treatment during 1979 and 1980, major unwanted drug-induced effects occurred in 40 per cent of all treated cases in the over-65 age group, mostly related to rifampicin. The survey highlighted the problems of tuberculosis in the elderly white population. They present with advanced disease, are diagnosed late and their course is complicated by other disease and a poor tolerance of therapy.

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Bangladesh; England; Female; Humans; India; Male; Middle Aged; Pakistan; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

1984
Management of tuberculosis in elderly persons.
    Comprehensive therapy, 1984, Volume: 10, Issue:7

    Topics: Aged; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculin Test; Tuberculosis; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Osteoarticular; Tuberculosis, Pulmonary; Tuberculosis, Urogenital

1984
Tuberculoid granuloma of the pharynx.
    The Journal of laryngology and otology, 1984, Volume: 98, Issue:3

    Topics: Adult; Female; Granuloma; Humans; Isoniazid; Pharyngeal Diseases; Rifampin; Tuberculosis

1984
[Ambulatory therapy of tuberculosis].
    Minerva medica, 1984, Mar-17, Volume: 75, Issue:11

    Author debates the advantages of home treatment of tuberculosis and the question limits. These limits are essentially represented by a low compliance in many patients. At our Institute, we put in practice an home therapy trial of pulmonary and extra-pulmonary tuberculosis. Our treatment programme includes short-course chemotherapy (six or eight months of therapy) with rifampin, isoniazid and ethambutol associated or, instead of ethambutol, with morphazynamide. In 1982, 674 patients were treated according to this schedule. Previously we made a controlled clinical trial comparing home and hospital treatment of pulmonary tuberculosis in 50 patients newly diagnosed. The results of this study showed that both groups of patients entirely recovered at the same time. At last, Author points out that today politicians poorly know the importance of a therapeutic home programme.

    Topics: Adaptation, Psychological; Ambulatory Care; Drug Administration Schedule; Humans; Kidney Diseases; Pyrazines; Rifampin; Socioeconomic Factors; Tuberculosis

1984
[Activity of rifampicin administered daily and intermittently on experimental tuberculosis in mice].
    Pathologie-biologie, 1983, Volume: 31, Issue:5

    Intermittent regimens with rifampicin (RMP) for chemotherapy of pulmonary tuberculosis are cheaper and can be usually supervised more easily than daily regimens. They are recommended, specially, in developing countries. The present study is designed to evaluate the reduction of RMP activity as the interval between doses is increased in experimental mouse tuberculosis. The mice are given 10 mg/kg oral doses of RMP once, twice, three times or six times a week. The RMP activity is measured as the decrease of viable counts (cfu) in the spleen of mice. RMP given once a week has no activity neither in combination with isoniazid and streptomycin on a large population of organisms nor alone on a small population. RMP given alone twice a week has an activity slightly better than RMP given once a week. RMP given alone three times a week has a weak but not worthy activity: the mean number of cfu after a three times weekly treatment is significantly lower than the mean number of cfu in control (p less than 0.001) but significantly higher than the mean number of cfu after a six times weekly treatment (p less than 0.001). These experimental results are consistent with the experimental data on the effects of RMP on the RNA polymerase. They are not favourable to the intermittent administration of RMP in the chemotherapy of tuberculosis.

    Topics: Animals; Drug Administration Schedule; Female; Isoniazid; Mice; Rifampin; Time Factors; Tuberculosis

1983
[Tuberculostatic activity of various rifampicin derivatives in vitro and in vivo].
    Problemy tuberkuleza, 1983, Issue:6

    Topics: Animals; Drug Resistance, Microbial; Guinea Pigs; In Vitro Techniques; Mycobacterium tuberculosis; Rabbits; Rifampin; Tuberculosis; Tuberculosis, Hepatic; Tuberculosis, Lymph Node; Tuberculosis, Ocular; Tuberculosis, Splenic

1983
[Resistance of the Koch bacillus to antibacillary agents in the Department of the Lower Rhine].
    Revue francaise des maladies respiratoires, 1983, Volume: 11, Issue:5

    The aim of this work was to study drug resistance of M. tuberculosis to Streptomycin (SM), Isoniazid (INH), Ethambutol (EMB) and Rifampicin (RMP) in the department of the Bas-Rhin from 1971 to 1978. On 2,995 original culture plates which were positive, 1,561 antibiograms were performed at the C.E.R.P. The proportion of those tested has increased over the years from 27.8% in 1971 to 80.6% in 1978 because of the increasing number of laboratories participating in the study. The research is based on 1,511 cultures of M. tuberculosis and the population was split into two groups: 1,386 untreated subjects or treated for less than 15 days (primary resistance) and 125 subjects who had already been treated (acquired resistance). Over all the years, primary resistance to at least one drug was 6.9%. Primary resistance to SM was 3.0%, to INH 2.2% and to both 1.4% (the levels of primary resistance to EMB and RMP were practically nil). Acquired resistance to at least one of these antibiotics was 16.0% with the same order as for primary resistance: resistance to SM alone = 7.2%, to INH alone 4.0% and both together 2.4%. The proportions were greater than for primary resistance but concerned fewer subjects as only 8% of the population had been previously treated. There were no cases of primary or acquired resistance to Rifampicin alone.

    Topics: Adult; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1983
[Combined effect of tuberculosis and pesticides on the morphofunctional status of the liver].
    Problemy tuberkuleza, 1983, Issue:8

    Topics: Animals; Chemical and Drug Induced Liver Injury; Drug Interactions; Ethambutol; Liver; Organothiophosphorus Compounds; Rabbits; Rifampin; Tuberculosis

1983
[Activity of intermittently administered rifampicin and cyclopentyl rifamycin (or DL473) on experimental tuberculosis in the mouse].
    Revue francaise des maladies respiratoires, 1983, Volume: 11, Issue:6

    The results of recent experiences with experimental tuberculous chemotherapy in the mouse give information on the activity of rifampicin (RMP) administered intermittently and on the activity of Cyclopentyl-Rifampicin (or DL473). The activity of RMP decreases as one spaces the treatment without increasing the dose. These observations are compatible with the known facts concerning the mechanism of action of RMP on RNA polymerase, and are unfavourable as regards the intermittent administration of RMP. Cyclopentyl-Rifampicin, a new derivative of Rifamycine SV, administered once per week, is as active as RMP administered six days per week, both in the initial as well as the continuation phase of treatment.

    Topics: Animals; DNA-Directed RNA Polymerases; Drug Therapy, Combination; Female; Isoniazid; Mice; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1983
[Treatment modalities applied to tuberculosis patients in a French department. Hautes-Pyrénées, 1973 to 1980].
    Revue francaise des maladies respiratoires, 1983, Volume: 11, Issue:6

    This study of tuberculous treatment in a French department--Les Hautes Pyrenees--was carried out on 539 patients registered on an epidemiological card index from 1973 to 1980. Isoniazid, ethambutol and rifampicin were the drugs most commonly used and were prescribed in 96% of cases by Specialists in thoracic medicine. The mean duration of treatment was a little more than 12 months for the duration of the study. A quarter of the patients were admitted to hospital and this figure did not change during the study from one year to the next although the mean length of stay fell by half between 1973 and 1980, the longest stays in hospital were for social reasons.

    Topics: Ambulatory Care; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Ethionamide; Hospitalization; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1983
[Short-term chemotherapy for juvenile tuberculosis].
    Kekkaku : [Tuberculosis], 1983, Volume: 58, Issue:12

    Topics: Adolescent; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant; Isoniazid; Male; Rifampin; Tuberculosis; Tuberculosis, Lymph Node

1983
An overview of tuberculosis in the 1980s.
    Pennsylvania medicine, 1983, Volume: 86, Issue:2

    Topics: Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Patient Education as Topic; Pregnancy; Rifampin; Tuberculosis

1983
Antituberculous agents. Isoniazid, rifampin, streptomycin, ethambutol, and pyrazinamide.
    Mayo Clinic proceedings, 1983, Volume: 58, Issue:4

    Effective antituberculous drugs have radically improved the prognosis of the patient with active tuberculosis. Surgical therapy is rarely needed, and sanitoriums have largely vanished. Triple-drug therapy may be indicated initially for cavitary pulmonary disease, meningitis, miliary disease, and moderate to severe renal disease. Short-course therapy twice or three times weekly with isoniazid and rifampin may be used in cavitary pulmonary disease and probably in these other serious infections as well. Isoniazid alone is adequate for prophylaxis. The major cause of therapeutic failure is noncompliance of the patient in taking the medication regularly. The second major cause of treatment failure is resistance of tubercle bacilli to the antimicrobial agents used. When treatment failure is apparent, careful reassessment by physicians experienced in the treatment of tuberculosis is indicated. A single drug should never be added to a failing regimen.

    Topics: Antitubercular Agents; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1983
Calcium metabolism during rifampicin and isoniazid therapy.
    Tubercle, 1983, Volume: 64, Issue:1

    Topics: Calcium Metabolism Disorders; Drug Therapy, Combination; Female; Humans; Isoniazid; Rifampin; Tuberculosis

1983
[Relapse in tuberculosis].
    Kekkaku : [Tuberculosis], 1983, Volume: 58, Issue:2

    Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Recurrence; Rifampin; Tuberculosis

1983
Altered prednisolone pharmacokinetics in patients treated with rifampicin.
    Acta medica Scandinavica, 1983, Volume: 213, Issue:5

    The pharmacokinetics and protein binding of prednisolone were studied in 7 patients before and after 3 weeks of rifampicin therapy. The elimination half-time for prednisolone decreased by 45 +/- 8.1% (p less than 0.01), and the total body clearance of prednisolone increased by 91 +/- 26% (p less than 0.01). The area under the time-concentration curve (AUC) of total (free plus protein-bound) prednisolone decreased by 48 +/- 7.3% (p less than 0.01) and of free, unbound prednisolone by 57 +/- 9.8% (p less than 0.01). The reduction in AUC was greater for free than for total prednisolone (p less than 0.05) mainly due to the non-linear nature of prednisolone protein binding. There was no significant change in the volume of distribution. Because of the marked reduction in total and especially free prednisolone, the dosage should be adjusted accordingly if prednisolone and rifampicin are prescribed concomitantly.

    Topics: Adult; Aged; Drug Interactions; Female; Half-Life; Humans; Kinetics; Male; Middle Aged; Prednisolone; Protein Binding; Rifampin; Tuberculosis

1983
Therapy of tuberculosis.
    Journal of the National Medical Association, 1983, Volume: 75, Issue:7

    Despite its great decline in recent years as a cause of death, tuberculosis remains a curable and preventable disease. Remarkable progress has been made in understanding the pathogenesis and management of both pulmonary and extrathoracic disease. With the availability of multiple bactericidal drugs the length of treatment has been considerably shortened, while maintaining the high cure rate and low relapse rate. With the transfer of the treatment from the sanitoriums and specialized hospitals to mainstream outpatient medicine, it is incumbent upon all physicians who treat tuberculous patients to understand the actions of each drug and the most effective combinations.

    Topics: Adult; Aged; Antitubercular Agents; Child; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary

1983
Adverse drug reaction to sunset-yellow in rifampicin-isoniazid tablet.
    Lancet (London, England), 1982, Aug-14, Volume: 2, Issue:8294

    Topics: Azo Compounds; Excipients; Female; Gastrointestinal Diseases; Humans; Isoniazid; Middle Aged; Rifampin; Tablets; Tuberculosis

1982
[Abbreviated treatment of tuberculosis. Experience in large cities].
    Boletin de la Oficina Sanitaria Panamericana. Pan American Sanitary Bureau, 1982, Volume: 92, Issue:2

    Topics: Adolescent; Adult; Aged; Chile; Female; Humans; Male; Middle Aged; Patient Compliance; Recurrence; Rifampin; Tuberculosis; Urban Population

1982
The first infant to survive a generalized BCG infection.
    Acta paediatrica Scandinavica, 1982, Volume: 71, Issue:1

    A 17-month-old boy who contracted a severe generalized BCG infection is reported. He was treated for 2 years with streptomycin, isoniazide and rifampicin and is now, at the age of 5 years, apparently cured. The boy had an unexplained discrepancy between humoral and cellular PPD reactivity for several years, but conventional immunological studies including plasma immunoglobulin levels, blast transformation as well as MLC reactivity were all normal. This is, to the best of our knowledge, the first child reported who has survived a generalized BCG infection.

    Topics: Antibodies, Bacterial; B-Lymphocytes; Child, Preschool; Humans; Infant; Isoniazid; Lymphocyte Activation; Male; Mitogens; Mycobacterium bovis; Prognosis; Rifampin; Streptomycin; T-Lymphocytes; Tuberculosis; Viral Plaque Assay

1982
[Changes in the expert's assessment of tuberculosis. Traditional medical attitudes in expert testimony must be brought in line with the reality of improved therapy and prognosis].
    Fortschritte der Medizin, 1982, Mar-25, Volume: 100, Issue:12

    Topics: Expert Testimony; Humans; Insurance, Health, Reimbursement; Mycobacterium tuberculosis; Occupational Diseases; Prognosis; Rifampin; Risk; Tuberculosis; Virulence

1982
[Sterilizing activity of the main drugs on the mouse experimental tuberculosis (author's transl)].
    Pathologie-biologie, 1982, Volume: 30, Issue:6

    In a first experiment mice infected intravenously with 10(6) Mycobacterium tuberculosis were randomly treated either with isoniazid (INH) + rifampicin (RMP) 25 mg/kg or with INH + RMP + pyrazinamide (PZA) or with INH + RMP + PZA + streptomycin (SM). The decrease of the viable counts (CFU) in the lungs was similar with all three regimens. In a second experiment, mice were treated for six months either with INH + RMP 25 mg/kg or INH + RMP 10 mg/kg. After a follow-up of six months, mice were killed and their lungs and spleen cultivated. Positive cultures were obtained in 7.5 p. cent of the mice treated with the high dose of RMP and 36.5 p. cent in the mice treated with the low dose (p less than 0.05). A third experiment demonstrated that, during the first two months of treatment, adding PZA to INH + RMP 10 mg/kg increased significantly the overall effectiveness of INH + RMP 10 mg/kg combination. A fourth experiment demonstrated that after three initial months of INH + RMP 10 mg/kg, RMP alone was as effective as RMP + INH or RMP + INH + PZA. It may be concluded that RMP and PZA are both active on the intracellular population of Mycobacterium tuberculosis and that RMP is the only drug to act on persisting Mycobacterium tuberculosis in extracellular lesions.

    Topics: Animals; Antibiotics, Antitubercular; Drug Therapy, Combination; Female; Humans; Isoniazid; Lung; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Spleen; Streptomycin; Tuberculosis

1982
Present chemotherapy for tuberculosis.
    The Journal of infectious diseases, 1982, Volume: 146, Issue:5

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1982
[Treatment of tuberculosis].
    Soins; la revue de reference infirmiere, 1982, Volume: 27, Issue:9

    Topics: Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1982
[Rifadin].
    Soins; la revue de reference infirmiere, 1982, Volume: 27, Issue:9

    Topics: Drug Interactions; Humans; Rifampin; Tuberculosis

1982
[Serum rifampicin level in children with tuberculosis and in young mice].
    Pneumonologia polska, 1982, Volume: 50, Issue:11

    Topics: Adolescent; Adult; Age Factors; Animals; Biological Availability; Child; Child, Preschool; Female; Humans; Infant; Male; Mice; Rifampin; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

1982
[Antibacterian activity modifications of serum isoniazid when using it with rifampicin (author's transl)].
    Pathologie-biologie, 1982, Volume: 30, Issue:6

    When dosing isoniazid in patients' serum after ingestion, the authors find a difference in the isoniazid levels when isoniazid is used alone, then, when isoniazid is used simultaneously with rifampicin. The level decreases or increases according to the inactivation index. They analyse the therapeutic consequences which can result from it. They infer, from the practical point of view, the necessity of : dosing isoniazid after having ingested it simultaneously with rifampicin and not alone when the efficient therapeutic dose is to be determined ; testing serum levels during antituberculous therapy for an eventual readjustment.

    Topics: Acetylation; Drug Interactions; Drug Therapy, Combination; Humans; Isoniazid; Mycobacterium; Rifampin; Tuberculosis

1982
[Clinically primary tuberculosis of the tongue].
    Minerva medica, 1982, May-12, Volume: 73, Issue:20

    Topics: Ethambutol; Humans; Isoniazid; Lung; Male; Middle Aged; Mouth Mucosa; Radiography; Rifampin; Tongue Diseases; Tuberculosis; Tuberculosis, Oral

1982
Adverse drug reactions in TB therapy: risks and recommendations.
    Geriatrics, 1982, Volume: 37, Issue:7

    Topics: Adult; Age Factors; Aged; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Evaluation; Ethambutol; Humans; Isoniazid; Kidney Diseases; Middle Aged; Optic Neuritis; Rifampin; Risk; Streptomycin; Tuberculosis

1982
Calcium metabolism during rifampicin and isoniazid therapy for tuberculosis.
    Journal of the Royal Society of Medicine, 1982, Volume: 75, Issue:7

    Calcium metabolism was studied in 83 patients during eighteen months' rifampicin and isoniazid therapy for tuberculosis by measurements including calcium, alkaline phosphatase and 25-hydroxycholecalciferol (25-HCC). Five out of 52 Indian patients in the series were found to have osteomalacia, a prevalence probably no higher than in the Asian population in the UK at large. Moreover, osteomalacia responded to physiological supplementation with vitamin D. One European out of 31 had osteomalacia due to low vitamin D intake. Serum calcium was compared in 17 patients before and after six months of antituberculous chemotherapy but no significant difference was detected (P greater than 0.1). Two Indian patients were in positive calcium balance with low to normal plasma 25-HCC levels, indicating that an effect on 1,25 dihydroxyvitamin D activity during therapy was unlikely. It is concluded that rifampicin when combined with isoniazid has no significant effect on calcium metabolism over an eighteen-month treatment period.

    Topics: Adolescent; Adult; Calcium; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Osteomalacia; Rifampin; Tuberculosis; Vitamin D

1982
[Chemotherapy of tuberculosis (author's transl)].
    Zentralblatt fur Chirurgie, 1982, Volume: 107, Issue:5-6

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Rifampin; Streptomycin; Tuberculosis

1982
Parenteral rifampicin in tuberculous and severe non-mycobacterial infections. Clinical data on 237 patients.
    Chemotherapy, 1982, Volume: 28, Issue:3

    A parenteral formulation of rifampicin (Rimactan i.v., Ciba-Geigy, Basel, Switzerland) was administered to 237 critically ill or comatose patients, or patients with gastro-intestinal or absorption problems. There were 160 patients suffering from tuberculosis, 77 suffering from non-tuberculous (non-tb) infections including 30 cases of sepsis, 8 cases of bacterial meningitis and/or cerebral abscess and 9 patients with Legionnaires' disease. The usual daily dose of rifampicin was 450-600 mg, administered in most cases by i.v. bolus (122 cases) or i.v. drip infusion (79 cases) for a period of 1-113 days. Rifampicin was in all cases combined with one or more antimicrobial drug(s). The physicians considered the therapy as successful when the treatment with oral rifampicin could be instituted soon after parenteral administration or when the patients markedly improved their clinical condition. Of a total of 123 tuberculous patients for whom assessment of efficacy was possible, 100 (81.3%) showed favourable clinical results. Of 40 non-tb patients who could be analysed for clinical progress, 32 (80.0%) had a favourable outcome. Special attention should be drawn to the 11 patients with proven staphylococcal infections, of whom 10 were cured clinically and/or bacteriologically. Thrombophlebitis occurred in 10 out of the 237 (4.2%) patients, almost always in patients who were treated for more than 30 days. Systemic unwanted effects occurred in 14 (5.9%); the relationship to the treatment was not always established. Treatment was withdrawn due to unwanted effects in 5 (2.1%) of the 237 patients. Taking into account the severe, life-threatening infections reported, the results suggest that i.v. rifampicin is useful and in some critically ill patients even life-saving. Tolerability was good, even in long-term i.v. administration, although there seems to be the possibility that thrombophlebitis might develop if treatment is continued over 30 days.

    Topics: Adolescent; Adult; Aged; Bacterial Infections; Child; Child, Preschool; Female; Humans; Infant; Infusions, Parenteral; Injections, Intramuscular; Injections, Intravenous; Male; Middle Aged; Rifampin; Tuberculosis

1982
[Hepatotoxicity of the tuberculostatic combination INH+RMP+EMB in relation to drug metabolism in the liver].
    Die Medizinische Welt, 1982, Jun-25, Volume: 33, Issue:25

    Topics: Acetylation; Antitubercular Agents; Drug Interactions; Drug Therapy, Combination; Humans; Isoniazid; Liver; Rifampin; Transaminases; Tuberculosis

1982
Modern treatment of tuberculosis.
    Comprehensive therapy, 1982, Volume: 8, Issue:9

    Topics: Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

1982
Calcium metabolism during rifampicin and isoniazid therapy for tuberculosis.
    Journal of the Royal Society of Medicine, 1982, Volume: 75, Issue:11

    Topics: Calcium; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Tuberculosis

1982
Vitamin B12 estimation and rifampicin.
    Tubercle, 1982, Volume: 63, Issue:3

    Topics: Humans; Rifampin; Tuberculosis; Vitamin B 12

1982
[Sex-related differences in the level of rifampicin in humans and animals].
    Pneumonologia polska, 1982, Volume: 50, Issue:11

    Topics: Animals; Biological Availability; Female; Humans; Male; Mice; Rabbits; Rifampin; Sex Factors; Time Factors; Tuberculosis

1982
Potentiating action of rifampicin and isoniazid against Leishmania mexicana amazonensis.
    Lancet (London, England), 1981, May-23, Volume: 1, Issue:8230

    The treatment of the complex of diseases known as leishmaniasis, caused by infection with protozoal parasites, is often unsatisfactory. The response to chemotherapy depends not only on the species of infecting Leishmania but also on the immune reactions of the host. This creates difficulties in evaluating any new drug in clinical trials. In a Brazilian patient with diffuse cutaneous leishmaniasis, which classical antileishmanial drugs had failed to cure, antituberculous therapy of an intercurrent mycobacterial infection produced a striking remission of the leishmanial skin lesions. Subsequent studies in mice infected with the strain of L. mexicana amazonensis isolated from this patient showed that para-aminosalicylic acid was inactive and both rifampicin and isoniazid had only a moderate beneficial action. However, a pronounced degree of potentiation was observed when rifampicin and isoniazid were administered in combination. Clinical trials of this combination are recommended in further patients, as well as experimental studies on other antimycobacterial agents, alone and in various combinations.

    Topics: Brazil; Drug Synergism; Humans; Isoniazid; Leishmania; Leishmaniasis; Male; Rifampin; Tuberculosis

1981
Resistance to rifampicin and isoniazid in strains of Mycobacterium tuberculosis.
    Journal of clinical pathology, 1981, Volume: 34, Issue:8

    Drug susceptibility studies on strains of Mycobacterium tuberculosis isolated from widely different populations of patients and tested by two different techniques indicated that all 55 strains resistant to rifampicin were also resistant to isoniazid, while many strains resistant to isoniazid were found to be susceptible to rifampicin. This observation, which has as yet unknown laboratory and clinical significance, may be particularly useful in management of patients. Further studies are called for to establish this relation.

    Topics: Drug Resistance, Microbial; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Species Specificity; Tuberculosis

1981
Circulating immune complexes in tuberculosis.
    Thorax, 1981, Volume: 36, Issue:8

    Using a polyethylene glycol precipitation method, immune complexes were detected in 56% of patients with active tuberculosis. After antituberculous treatment, 29% remained positive for immune complexes, a frequency similar to that in a group of racially matched clinic controls (35%). In a study of 17 patients whose immune complex levels were determined soon after diagnosis and again when the therapy had ceased, there was a significant decrease in complexed IgM and Clq. Sequential studies of immune complex levels in tuberculosis merit further investigation, their persistence may indicate the continued presence of antigens, and their disappearance from the circulation may be a guide to successful treatment.

    Topics: Adolescent; Adult; Aged; Antigen-Antibody Complex; Child; Child, Preschool; Complement Activating Enzymes; Complement C1q; Female; Humans; Immunoglobulin G; Immunoglobulin M; Isoniazid; Longitudinal Studies; Male; Middle Aged; Rifampin; Tuberculosis

1981
Some thoughts on the present status and future prospects of chemotherapy of leprosy based on experience with treating tuberculosis.
    International journal of leprosy and other mycobacterial diseases : official organ of the International Leprosy Association, 1981, Volume: 49, Issue:3

    Topics: Dapsone; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Leprosy; Rifampin; Tuberculosis

1981
Current concept of short-term chemotherapy of tuberculosis.
    Journal of the Indian Medical Association, 1981, Feb-16, Volume: 76, Issue:4

    Topics: Drug Combinations; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Time Factors; Tuberculosis

1981
Effect of rifampicin treatment of Myobacterium avium infection in carbon tetrachloride treated rabbits.
    Indian journal of experimental biology, 1981, Volume: 19, Issue:2

    Topics: Animals; Carbon Tetrachloride Poisoning; Mycobacterium; Mycobacterium avium; Rabbits; Rifampin; Tuberculosis

1981
Intravenous use of rifampicin.
    European journal of respiratory diseases, 1981, Volume: 62, Issue:3

    Nineteen seriously ill patients with suspected or verified tuberculosis were treated with a new formulation of rifampicin for intravenous use. The normal dosage was 300 mg twice a day. Local reactions at the injection site were noted in four patients but no serious adverse reactions were observed. The serum concentrations were similar to those after the same dose given orally.

    Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Female; Humans; Infant; Injections, Intravenous; Kinetics; Male; Middle Aged; Rifampin; Time Factors; Tuberculosis

1981
[Hepatotoxicity of the rifampicin-isoniazid combination in children].
    Minerva pediatrica, 1981, Aug-31, Volume: 33, Issue:16

    Topics: Chemical and Drug Induced Liver Injury; Child, Preschool; Humans; Isoniazid; Liver; Male; Parotid Diseases; Rifampin; Tuberculosis; Tuberculosis, Oral

1981
Rimactan parenteral formulation in clinical use.
    The Journal of international medical research, 1981, Volume: 9, Issue:6

    Topics: Adolescent; Adult; Aged; Bacterial Infections; Child; Child, Preschool; Female; Humans; Infant; Infusions, Parenteral; Male; Middle Aged; Rifampin; Staphylococcal Infections; Tuberculosis; Tuberculosis, Pulmonary

1981
Antibacterial activity of DL 473, a new semisynthetic rifamycin derivative.
    The Journal of antibiotics, 1981, Volume: 34, Issue:8

    DL 473, a new semisynthetic rifamycin, was 2-10 times more active in vitro than rifampicin (RAMP) against several clinical isolates of Mycobacterium tuberculosis and only slightly less active than RAMP against Gram-positive and Gram-negative bacteria. It showed excellent therapeutic activity in mice in experimental infections caused by Staphylococcus aureus, Streptococcus pyogenes group A, Streptococcus pneumoniae and Klebsiella pneumoniae. In the experimental TB infection in the mouse DL 473 was clearly more active than isoniazide and RAMP, two of the most effective antitubercular drugs in current use. The LD50 in the mouse was significantly higher than that of RAMP and the half-life was about 5 times longer than that of RAMP.

    Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Dose-Response Relationship, Drug; Isoniazid; Mice; Microbial Sensitivity Tests; Rifampin; Tuberculosis

1981
Tuberculosis in chronic renal failure.
    Lancet (London, England), 1980, Apr-26, Volume: 1, Issue:8174

    Topics: Ethambutol; Humans; Isoniazid; Kidney Failure, Chronic; Mycobacterium avium; Rifampin; Tuberculosis

1980
Antituberculous drugs in pregnancy.
    Lancet (London, England), 1980, Dec-13, Volume: 2, Issue:8207

    Topics: Abnormalities, Drug-Induced; Animals; Antitubercular Agents; Female; Humans; Infant, Newborn; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Infectious; Rats; Rifampin; Risk; Tuberculosis

1980
Guidelines for short-course tuberculosis chemotherapy. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control Atlanta, Ga.
    Connecticut medicine, 1980, Volume: 44, Issue:8

    Topics: Centers for Disease Control and Prevention, U.S.; Drug Administration Schedule; Ethambutol; Humans; Isoniazid; Rifampin; Tuberculosis; United States

1980
Effect of chemotherapy on suppressor T cells in BCG-infected mice.
    Immunology, 1980, Volume: 40, Issue:4

    Specific pathogen-free B6D2 mice infected intravenously with 10(6) or 10(8) viable BCG Pasteur develop an anti-tuberculous immune response resulting in a progressive decline in viable BCG counts for the spleen and lung. Mice infected with 10(8) bacilli did not develop detectable levels of tuberculin hypersensitivity. Spleen cells harvested from both groups of mice at increasing time intervals after infection were T-cell enriched by nylon wool passage and tested for blast transformation following exposure to PHA or PPD. An early peak in tritiated thymidine uptake was observed following PPD exposure of cells from both the 10(6) and 10(8) groups. Cells from the latter group of animals developed a profound suppression to responsiveness to PPD throughout the remainder of the experiment. If the heavily infected mice were exposed to a regimen of 10 mg isoniazid plus 10 mg rifampin per 100 ml of drinking water for 30 days, the viable BCG population present within the lungs and spleen declined to near undetectable levels. This drop was associated with a decline in supressor T-cell activity demonstrated by appropriate cell-mixing experiments in vitro. The blastogenic responses to both PHA and PPD were substantially restored after 30 days of drug treatment. Treatment of the BCG infected mice within the first 7 days of infection prevented the development of the suppressor T-cell population.

    Topics: Animals; Drug Combinations; Isoniazid; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Mice; Mycobacterium bovis; Rifampin; Specific Pathogen-Free Organisms; Spleen; T-Lymphocytes, Regulatory; Tuberculosis

1980
The efficacy of short-course chemotherapy for tuberculosis.
    Bulletin of the Pan American Health Organization, 1980, Volume: 14, Issue:2

    Topics: Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1980
Choice of preventive treatment for isoniazid-resistant tuberculous infection. Use of decision analysis and the Delphi technique.
    JAMA, 1980, Dec-19, Volume: 244, Issue:24

    Proper care of persons infected with isoniazid-resistant tubercle bacilli is controversial because there are few data on the risks and benefits of the preventive treatment alternatives. Decision analysis was used to facilitate a comparison of outcomes using different strategies and the Delphi technique to obtain estimates of relevant probabilities. For all probabilities of isoniazid resistance, the observation and no-drug alternative is unsatisfactory because it sould result in a twofold to sevenfold greater number of tuberculosis cases than any of the drug regimens. With a low probability of isoniazid resistance, isoniazid is the preventive treatment of least cost and proved efficacy. As the probability of isoniazid resistance increases, more cases are prevented by rifampin-containing regimens, but at added cost. These findings can be used to formulate appropriate preventive treatment recommendations.

    Topics: Adolescent; Child; Child, Preschool; Cost-Benefit Analysis; Decision Making; Delphi Technique; Drug Resistance, Microbial; Drug Therapy; Drug Therapy, Combination; Humans; Infant; Isoniazid; Mycobacterium tuberculosis; Rifampin; Surveys and Questionnaires; Tuberculosis

1980
The effect of rifampicin on the pharmacokinetics of ethynylestradiol in women.
    Contraception, 1980, Volume: 21, Issue:2

    A single dose of Minovlar (50 microgram ethynylestradiol (EE) and 1 mg norethindrone acetate) was given to seven women during treatment with rifampicin (450-600 mg/day) and again one month after stopping rifampicin. Blood samples were taken at intervals over a 24-hour period. The area under the plasma EE versus time curve increased significantly on stopping rifampicin from 1014 +/- 317 pg/ml x h (mean +/- SE) to 1747 +/- 218 pg/ml x h (p less than 0.01). The terminal plasma half-life increased from 2.9 +/- 0.8 h to 6.3 +/- 1.4 h (p less than 0.005). The sex hormone binding globulin (S.H.B.G.) capacity was also reduced from 213.4 +/- 11.5 nmoles to 129.0 +/- 7.7 nmoles/1 after stopping rifampicin. In one patient starting rifampicin who was taking Minovlar as a long-term oral contraceptive, a fall in the plasma EE concentration was associated with a rise in the plasma follicle stimulating hormone concentration. These effects of rifampicin on EE pharmacokinetics are consistent with induction of the microsomal enzymes that metabolise EE.. 7 female patients between ages 18-42 who were receiving treatment with rifampicin (450-600 mg daily) for tuberculosis were given a single dose of Minovlar (50 mg ethynlestradiol (EE) and 1 mg norethindrone acetate) and given a dose 1 month after stopping rifampicin. Blood samples were taken at intervals over a 24-hour period. The area under the plasma EE versus time curve increased significantly on stopping rifampicin from 1014 + - 317 pg-ml x h (mean + - SE) to 1747 + - 218 pg-ml x h (p 0.01). The terminal plasma half-life increased from 2.9 + - 0.8 h to 6.3 + - 1.4 h (p 0.005). The sex hormone binding globulin capacity was reduced from 213.4 + - 11.5 nmoles to 129.0 + - 7.7 nmoles-1 after stopping rifampicin. In 1 patient starting rifampicin who was taking Minovlar as a long-term contraceptive, a decline in the plasma EE concentration was associated with an increase in the plasma follicle stimulating hormone concentration. Women taking oral contraceptive steroids and rifampicin at the same time are likely to suffer a decrease in the effectiveness of the OC. It is suggested that it is unwise for women taking rifampicin to use OCs as the sole method of contraception.

    Topics: Adolescent; Adult; Ethambutol; Ethinyl Estradiol; Female; Humans; Isoniazid; Kinetics; Norethindrone; Norethindrone Acetate; Rifampin; Sex Hormone-Binding Globulin; Tuberculosis

1980
Tuberculosis in patients with end-stage renal disease.
    The American journal of medicine, 1980, Volume: 68, Issue:1

    Ten patients with proved disease caused by Myocobacterium tuberculosis were identified over a 10 year period in a population of 172 adult patients undergoing long-term dialysis. The incidence of tuberculosis was 12 times greater than that prevailing in the general community during the period of the study and could not be accounted for solely by demographic factors. Diagnosis was obscured because the symptoms were nonspecific and attributable to uremia, intermediate strength (5 TU) tuberculin tests were often negative, the roentgenographic appearance of pulmonary disease was often atypical, and there was more frequent extrapulmonary involvement. Impaired cellular immunity due to advanced renal failure may predispose to the increased incidence of tuberculosis and the greater frequency of extrapulmonary disease observed. Treatment was safe and effective in these patients using 300 mg of isoniazid and 8 to 10 mg/kg of ethambutol daily. Eight patients survived longer than one year following the diagnosis of tuberculosis, and all were clinically cured. No deaths were directly attributed to tuberculosis. A high index of suspicion and aggressive evaluation may be necessary to diminish the significant mortality described previously in association with disseminated disease.

    Topics: Adult; Aged; Ethambutol; Female; Humans; Immunity, Cellular; Isoniazid; Kidney Failure, Chronic; Male; Middle Aged; Pyrazinamide; Renal Dialysis; Rifampin; Risk; Tuberculosis

1980
Tuberculosis in the elderly: treating the "white plague".
    Geriatrics, 1980, Volume: 35, Issue:3

    Topics: Adolescent; Adult; Age Factors; Aged; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Risk; Streptomycin; Tuberculin Test; Tuberculosis; Tuberculosis, Pulmonary; United States

1980
Acute cardiac failure during treatment with digitoxin--an interaction with rifampicin.
    British journal of clinical pharmacology, 1980, Volume: 10, Issue:1

    Topics: Digitoxin; Drug Interactions; Female; Half-Life; Heart Failure; Humans; Middle Aged; Rifampin; Tuberculosis

1980
American Thoracic Society. Medical Section of the American Lung Association. Guidelines for short-course tuberculosis chemotherapy.
    The American review of respiratory disease, 1980, Volume: 121, Issue:3

    Topics: Adult; Child; Humans; Isoniazid; Rifampin; Tuberculosis

1980
A service program of antituberculosis chemotherapy with five drugs for four months in the treatment of drug addicts and prisoners with pulmonary tuberculosis in Hong Kong. Hong Kong Chest Service/British Medical Research Council.
    The American review of respiratory disease, 1980, Volume: 122, Issue:3

    The results are reported of a service in Hong Kong of intensive antituberculosis chemotherapy with 5 drugs given daily for 4 months, or until discharge from hospital or release from prison if earlier, in the treatment of male Chinese drug addicts and prisoners who had pulmonary tuberculosis positive for acid-fast bacilli on microscopic examination of the sputum. Of 69 patients who received 4 months of chemotherapy, all those with sputum cultures negative for M. tuberculois initially, and more than 80% of those with positive cultures, 41% of whom had strains resistant to isoniazid, streptomycin, or both drugs, achieved quiescent disease, which was maintained for a year of follow-up. Some of the patients who received less than 4 months of chemotherapy also reponded well. Despite the 5 drugs, the frequency of adverse reactions to the regimen was low.

    Topics: Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Microbial; Ethambutol; Heroin Dependence; Hong Kong; Humans; Isoniazid; Male; Opioid-Related Disorders; Opium; Prisoners; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary

1980
False economy in tuberculosis treatment.
    South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde, 1980, Oct-11, Volume: 58, Issue:15

    Topics: Health Services; Humans; Rifampin; Tuberculosis

1980
Tuberculosis in the 1980s: a case for short-course chemotherapy.
    The New Zealand medical journal, 1979, Aug-22, Volume: 90, Issue:642

    Topics: Animals; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Humans; Hydrogen-Ion Concentration; Isoniazid; Mice; New Zealand; Pyrazinamide; Rifampin; Tuberculosis

1979
[The bacteriological principles of tuberculosis treatments].
    La Revue du praticien, 1979, Jun-11, Volume: 29, Issue:33

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1979
The cost of antituberculous drug regimens.
    The American review of respiratory disease, 1979, Volume: 120, Issue:3

    The relative costs of several highly effective short-course regimens have been compared for a developing and a developed country both for 1976 and 1978, with particular reference to the proportion of the total cost due to individual drugs. A convenient method of calculating costs for any individual country is provided. Of isoniazid, pyrazinamide, and rifampin, the 3 most important drugs in short-course chemotherapy, the cost and duration of the latter two have a major effect on the total cost. A decrease in the duration of a regimen from 9 to 6 months may decrease therapeutic effectiveness by as little as 5% or as much as 20%; the decrease in cost is often not proportional, because it depends on the drugs used in the continuation phase. The duration of pyrazinamide therapy has a considerable influence on cost, but the benefit of giving it beyond 2 months now needs to be re-evaluated. Factors that influence the choice of regimens are discussed. The importance of quality of the drugs, including purity and bioavailability, is stressed.

    Topics: Antitubercular Agents; Biological Availability; Drug Administration Schedule; Drug Therapy; Humans; Isoniazid; Long-Term Care; Pyrazinamide; Rifampin; Tuberculosis

1979
[Surveillance and complications of antituberculosis chemotherapy].
    La Revue du praticien, 1979, Jun-11, Volume: 29, Issue:33

    Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Hematologic Diseases; Humans; Isoniazid; Liver; Peripheral Nervous System Diseases; Psychoses, Substance-Induced; Rheumatic Diseases; Rifampin; Streptomycin; Tuberculosis

1979
Tuberculosis in renal transplant patients.
    Tubercle, 1979, Volume: 60, Issue:3

    Topics: Humans; Immunosuppressive Agents; Isoniazid; Kidney Transplantation; Postoperative Complications; Rifampin; Transplantation, Homologous; Tuberculosis

1979
[Pharmacodynamics of rifampicin--bacteriological and pharmacological action of rifampicin].
    Kekkaku : [Tuberculosis], 1979, Volume: 54, Issue:12

    Topics: Animals; Guinea Pigs; Humans; Lymphocyte Activation; Mice; Mycobacterium bovis; Rifampin; Tuberculosis

1979
[Effect of rifampicin on the nonspecific reactivity and natural resistence to tuberculosis in guinea pigs].
    Problemy tuberkuleza, 1979, Issue:1

    Topics: Animals; Antigen-Antibody Reactions; Drug Evaluation, Preclinical; Guinea Pigs; Immunity, Innate; Lymph Nodes; Rifampin; Spleen; Time Factors; Tuberculosis

1979
[Tuberculosis in Romania (author's transl)].
    Praxis und Klinik der Pneumologie, 1979, Volume: 33 Suppl 1

    The incidence of tuberculosis in Romania has decreased considerably over the past years, particularly since 1972 when the combined rifampicin-ethambutol-pyrazinamide therapy was introduced. During the period 1968-1977 it fell from 127.9 per 100,000 to 73.4 per 100,000. The incidence of relapses fell at a slower rate. The most endangered are the 20-24 years age-group and old people; but here again the number of cases tends to fall. Childhood tuberculosis showed a yearly decline by an average of 20%. Bacteriological examinations and diagnosis are assuming increased importance.

    Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Ethambutol; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Romania; Statistics as Topic; Tuberculosis

1979
[Liver function and anti-tuberculous drug therapy (author's transl)].
    Praxis und Klinik der Pneumologie, 1979, Volume: 33 Suppl 1

    Every year since 1972 all records pertaining to an unselected group of tuberculous patients were collected on August 1st and analysed with the view of establishing trends and detecting special problems associated with anti-tuberculous chemotherapy. One of the subjects of the analysis was to find the effects of chemotherapy on the global transaminase levels. The case material was divided into two groups: in group 1 rifampicin had been included in the therapy, in group 2 it had been omitted. In approximately 20% of the patients treated during 1976, 1977 and 1978 transaminase levels were already increased when they were admitted to hospital; in about 15% transaminase levels rose during treatment. The personal history of the patients showed that in 31% of the cases the disturbed liver function was attributable to alcohol abuse and that in 22% manifest damage to the liver had been diagnosed prior to admission. Despite these "unfavourable pre-conditions" antituberculous drug therapy succeeded in 50% of the patients in normalizing the transaminase levels, even if the original values had been fairly high. Further controlled studies have confirmed these observations but an interpretation of the results is not yet possible. Antituberculous drug therapy induced a rise in transaminase levels less frequently than it caused a return to normal of initially raised levels. As so many factors are involved it is impossible to single out any particular causal factor.

    Topics: Antitubercular Agents; Female; Humans; Liver Diseases, Alcoholic; Male; Rifampin; Transaminases; Tuberculosis

1979
[Deviation in cortisol metabolism induced by rifampicin. Therapeutic consequences in adrenal failure (author's transl)].
    La Nouvelle presse medicale, 1979, May-05, Volume: 8, Issue:20

    Deviation of cortisol metabolism in favour of its 6 beta-hydroxylated derivative was demonstrated in two patients with adrenal failure receiving substitution corticosteroid therapy and rifampicin. The existence of a frank increase in the metabolic clearance antipyrin was in favour of an hepatic enzyme induction. After rifampicin treatment was stopped, the 24 hour urinary excretion of 6 beta-OH-F returned to normal, demonstrating the responsability of the drug. This enzyme induction results in a need to increase the dose of hydrocortisone substitution therapy in patients with Addison's disease treated with rifampicin.

    Topics: Addison Disease; Adrenal Cortex Hormones; Adrenal Insufficiency; Adult; Aged; Antipyrine; Enzyme Induction; Humans; Hydrocortisone; Hydroxycorticosteroids; Liver; Male; Metabolic Clearance Rate; Rifampin; Steroid Hydroxylases; Tuberculosis

1979
[Indications, dosage and combinations of the major antitubercular drugs].
    La Revue du praticien, 1979, Jun-11, Volume: 29, Issue:33

    Topics: Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Tuberculosis

1979
[Virulence of rifampicin-resistent Mycobacterium tuberculosis].
    Problemy tuberkuleza, 1978, Issue:6

    Topics: Animals; Drug Resistance, Microbial; Guinea Pigs; Humans; In Vitro Techniques; Mice; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis; Virulence

1978
Clinical significance of precipitating anti-rifampicin antibodies.
    Scandinavian journal of respiratory diseases. Supplementum, 1978, Volume: 102

    Topics: Antibodies; Chemical Precipitation; Cross Reactions; Fever; Humans; Immunodiffusion; Rifampin; Time Factors; Tuberculosis

1978
[Short term chemotherapy of tuberculosis. Bactericidal mechanisms in short term chemotherapy].
    Bulletin of the International Union against Tuberculosis, 1978, Volume: 53, Issue:4

    Topics: Animals; Antitubercular Agents; Guinea Pigs; Humans; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Temperature; Tuberculosis

1978
[Treatment of tuberculosis].
    Soins; la revue de reference infirmiere, 1978, Sep-05, Volume: 23, Issue:17

    Topics: Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1978
[Report on the scientific conference of the European Region of International Union against Tuberculosis in combination with 70th anniversary of the Finnish Tuberculosis Association, June 14th to 17th 1977 (author's transl)].
    Zeitschrift fur Erkrankungen der Atmungsorgane, 1978, Volume: 152, Issue:2

    Topics: alpha 1-Antitrypsin; Anniversaries and Special Events; Antibody Formation; Congresses as Topic; Finland; Humans; Legislation, Medical; Lung Neoplasms; Public Relations; Rifampin; Scandinavian and Nordic Countries; Smoking; Societies, Medical; Tuberculosis; World Health Organization

1978
[Tasks and possibilities in the near future of consultation bureaus for the prevention of tuberculosis].
    Nederlands tijdschrift voor geneeskunde, 1978, Jan-07, Volume: 122, Issue:1

    Topics: Community Health Services; Ethambutol; History, 20th Century; Humans; Isoniazid; Netherlands; Rifampin; Transients and Migrants; Tuberculosis

1978
Rifampicin resistant strains of bacteria from tuberculosis patients treated with the drug.
    Microbiology and immunology, 1978, Volume: 22, Issue:9

    Topics: Drug Resistance, Microbial; Escherichia coli; Feces; Humans; Rifampin; Sputum; Staphylococcus aureus; Tuberculosis

1978
A recovered case of generalized BCG infection.
    Acta paediatrica Academiae Scientiarum Hungaricae, 1978, Volume: 19, Issue:3

    A female infant was at the age of 8 months admitted with muco-cutaneous candidiasis. The applied therapy was inefficacious. Subsequent examinations pointed to a combined humoral and cellular immunopathy. At the age of 7 years the patient was readmitted with abdominal complaints. Diagnostic laparotomy revealed a tuberculous mesenterial growth. The isolated agent proved to be a BCG strain. Antituberculous therapy was beneficial, the tumour dissappeared and full recovery was attained. The mycotic process remained unchanged and still needs continuous treatment.

    Topics: BCG Vaccine; Female; Humans; Infant; Laparotomy; Mesentery; Mycobacterium bovis; Rifampin; Streptomycin; Tuberculosis

1978
Long-term therapy with rifampin and the secondary antibody response to killed influenza vaccine.
    The American review of respiratory disease, 1978, Volume: 117, Issue:3

    The secondary antibody response was studied in 22 patients with tuberculosis, 11 of whom were taking rifampin as part of their antituberculous regimen. The mean duration of rifampin therapy was 12.7 months. Hemagglutination-inhibiting antibody titers to bivalent influenza vaccine were determined before, and 4 and 8 weeks after, vaccination. There was no significant difference in the number of patients who developed a 4-fold or greater increase in titer, or in the level of titer response between the rifampin and control groups. Long-term therapy with rifampin was not found to suppress the secondary antibody response to influenza vaccination.

    Topics: Antibodies, Viral; Humans; Immunosuppression Therapy; Influenza Vaccines; Rifampin; Tuberculosis

1978
Diseases of the respiratory system: tuberculosis.
    British medical journal, 1978, Mar-18, Volume: 1, Issue:6114

    Topics: Adrenal Cortex Hormones; Antitubercular Agents; Drug Combinations; Ethambutol; Humans; Isoniazid; Patient Compliance; Rifampin; Streptomycin; Tuberculosis

1978
Treatment of tuberculosis.
    British medical journal, 1978, Apr-22, Volume: 1, Issue:6119

    Topics: Attitude of Health Personnel; Humans; Isoniazid; Rifampin; Tuberculosis

1978
The sterilizing value of rifampicin and pyrazinamide in experimental short-course chemotherapy.
    Bulletin of the International Union against Tuberculosis, 1978, Volume: 53, Issue:1

    Topics: Drug Evaluation; Humans; Pyrazinamide; Rifampin; Tuberculosis

1978
[Comparative studies on therapeutic effect of rifampicin and isoniazid on experimental mouse tuberculosis (author's transl)].
    Kekkaku : [Tuberculosis], 1978, Volume: 53, Issue:4

    Topics: Animals; Drug Evaluation, Preclinical; Isoniazid; Male; Mice; Rifampin; Tuberculosis

1978
[An attempt to work out highly efficient short-course regimens by model experiments in mouse tuberculosis (author's transl)].
    Kekkaku : [Tuberculosis], 1978, Volume: 53, Issue:5

    Topics: Animals; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Isoniazid; Mice; Rifampin; Streptomycin; Tuberculosis

1978
[New methods of chemotherapy also for extrapulmonary tuberculosis?].
    Zeitschrift fur die gesamte innere Medizin und ihre Grenzgebiete, 1978, Oct-01, Volume: 33, Issue:19

    The chemotherapy of all forms of tuberculosis is basically performed according to homogeneous principles. Different opinions exist within the extrapulmonary forms particularly with regard to the duration of the treatment. Here, the so-called long-term therapy is frequently still postulated with 18--24 months. But newly developed, highly effective antituberculotic medicaments do not only allow but actually demand a shortening of the time of treatment in interest of the patient. Apparantly rifampicin and also pyrazin amide are able to effect on the germs in rest -- the persisters. Up to now the last mentioned gave the actual rise for the long-term application. Under the notion short-term therapy on the one hand by the application of the preparations mentioned and on the other hand basing on the experiences in the medicamentous treatment of the pulmonary tuberculosis now in the same measure the possiblity of a total duration of the therapy of on an average twelve months develops for the extrapulmonary manifestations of tuberculosis. Here, the two-phase regime is preferred with a continuous application of medicaments lasting for three months and following controlled phase with intermitting application of antituberculotics twice a week. The duration of application for rifampicin in these cases should neither trandgress nor be below three months.

    Topics: Female; Humans; Male; Pyrazinamide; Rifampin; Time; Tuberculosis; Tuberculosis, Urogenital

1978
[Tuberculosis of hematopoietic organs in the child. 2 cases with pulmonary involvement].
    Archives francaises de pediatrie, 1978, Volume: 35, Issue:9

    Topics: Adolescent; Child, Preschool; Drug Tolerance; Ethambutol; Female; Humans; Isoniazid; Male; Prognosis; Rifampin; Time Factors; Tuberculosis; Tuberculosis, Hepatic; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary; Tuberculosis, Splenic

1978
Can rifampicin use be safely extended? Evidence for non-emergence of resistant strains of Mycobacterium tuberculosis.
    Lancet (London, England), 1977, Apr-02, Volume: 1, Issue:8014

    Data on the incidence of primary resistance to rifampicin in Mycobacterium tuberculosis strains have been collected from various countries. Strains isolated from those countries where rifampicin is used for both tuberculous and non-tuberculous conditions (Italy, Argentina, Brazil, and Spain) did not show a higher incidence of primary resistance than did strains from other countries (France, U.K., and U.S.A.) where rifampicin use is confined to tuberculosis. It is concluded that there is no evidence to justify fears of an increased incidence of resistance to rifampicin in M. tuberculosis if rifampicin were used discreetly for treating non-tuberculous infections.

    Topics: Antitubercular Agents; Argentina; Brazil; Drug Resistance, Microbial; Humans; Infections; Italy; Mycobacterium tuberculosis; Rifampin; Spain; Tuberculosis; United States

1977
Treatment of tuberculosis in alcoholic patients.
    The American review of respiratory disease, 1977, Volume: 116, Issue:3

    Topics: Alcoholism; Hospitalization; Humans; Isoniazid; Long-Term Care; Patient Compliance; Rifampin; Social Work; Tuberculosis

1977
[Rifampicin in experimental tuberculosis].
    Antibiotiki, 1977, Volume: 22, Issue:1

    Topics: Animals; Body Weight; Drug Evaluation, Preclinical; Guinea Pigs; Liver; Lung; Mice; Organ Size; Rifampin; Spleen; Time Factors; Tuberculosis

1977
Tuberculosis.
    Wisconsin medical journal, 1977, Volume: 76, Issue:5

    Topics: Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1977
[Toxic hepatitis caused by rifampin and isoniazid in treatment of tuberculosis (author's transl)].
    Anales espanoles de pediatria, 1977, Volume: 10, Issue:2

    Five children with tuberculosis were treated with isoniazid (20 mg./Kg./day) and rifampin (15 mg./Kg./day). After five to twenty seven days of treatment they presented anorexia, vomiting and jaundice. Hepatomegaly was found in two of them. High indirect bilirubin, S.G.O.T. and S.G.P.T. and low prothrombin levels were present in all of them. Eight to thirty one days after withdrawal of rifampin, all patients were well and their laboratory data was normal.

    Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Child; Diagnosis, Differential; Female; Humans; Isoniazid; Male; Rifampin; Tuberculosis

1977
[INH and rifampicin dosage at the beginning of tuberculosis treatment].
    La Nouvelle presse medicale, 1977, Sep-17, Volume: 6, Issue:30

    Topics: Drug Tolerance; Ethambutol; Humans; Isoniazid; Rifampin; Tuberculosis

1977
[Experimental studies on the effective regimens of antituberculous drugs in the treatment of tuberculosis. II. Long-term chemotherapy in mice by daily and intermittent administration with changing drug combination (author's transl)].
    Kekkaku : [Tuberculosis], 1977, Volume: 52, Issue:8

    Topics: Animals; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Isoniazid; Mice; Rifampin; Tuberculosis

1977
[Studies on the relationship between the proliferation rate of infecting tubercle bacilli and the effectiveness of chemotherapy. I. Observations in a mouse experimental model using a streptomycin-dependent strain (author's transl)].
    Kekkaku : [Tuberculosis], 1977, Volume: 52, Issue:9

    Topics: Animals; Disease Models, Animal; Male; Mice; Mycobacterium; Rifampin; Streptomycin; Tuberculosis

1977
[Modification during treatment of the rate of acetylation of isoniazide clinically or biologically detectable hepatic damage (author's transl)].
    La Nouvelle presse medicale, 1977, Oct-01, Volume: 6, Issue:32

    The rate of acetylation of isoniazid is usually constant in a given subject. The authors report here a case where despite an adjusted initial dose there was a decrease in the rate of acetylation during treatment with INH-rifampicin and ethambutol, without hepatic involvement but accompanied by retrobulbar optic neuritis. The role of ethambutol and/or an overdose of isoniazid are discussed. The technique for its estimation is also described.

    Topics: Acetylation; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Liver; Male; Optic Neuritis; Rifampin; Tuberculosis

1977
Antituberculosis agents: isoniazid, rifampin, streptomycin, ethambutol.
    Mayo Clinic proceedings, 1977, Volume: 52, Issue:11

    Effective antituberculosis drugs have radically improved the prognosis of the patient with active tuberculosis. Surgical therapy is rarely needed, and sanatoria have largely vanished. Initially, triple-drug therapy is indicated in cavitary pulmonary disease and severe renal disease and it is generally used in miliary tuberculosis and meningitis. Use of one of the three drugs may be discontinued after there is evidence that the bacillary population has been decreased. Two-drug therapy is indicated for other active disease. Isoniazid alone is adequate for prophylaxis. The major cause of therapeutic failure is failure of the patient to take the antituberculosis medication regularly. The second major cause of treatment failure is resistance of tubercle bacilli to the antimicrobials used. When treatment failure is apparent, careful reassessment by experienced physicians is indicated. A single drug should never be added to a failing regimen.

    Topics: Antibiotics, Antitubercular; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1977
Editorial: Rifampicin: for tuberculosis only?
    Lancet (London, England), 1976, Feb-07, Volume: 1, Issue:7954

    Topics: Bacterial Infections; Drug Evaluation; Humans; Rifampin; Tuberculosis

1976
Letter: Rifampicin: for tuberculosis only?
    Lancet (London, England), 1976, Mar-20, Volume: 1, Issue:7960

    Topics: Animals; Bacterial Infections; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Guinea Pigs; Humans; Rifampin; Trimethoprim; Tuberculosis

1976
Interaction of rifampin and glucocorticoids. Adverse effect on renal allograft function.
    JAMA, 1976, Oct-25, Volume: 236, Issue:17

    Three renal transplant patients experienced progressive loss of renal allograft function during rifampin treatment for Mycobacterium tuberculosis. Previous studies have shown that rifampin causes induction of enzymes in hepatic microsomes that increase the catabolism of glucocorticoids. Evidence is presented that in our patients, the loss of renal allograft function during rifampin therapy was the result of decreased glucocorticoid effect presumably related to increased catabolism of the glucocorticoid drug they received. Thus, the adverse effects of rifampin on renal transplant function might be overcome by increasing the dose of glucocorticoid drug.

    Topics: Adult; Creatinine; Drug Interactions; Female; Follow-Up Studies; Glucocorticoids; Humans; Kidney; Kidney Transplantation; Male; Middle Aged; Rifampin; Transplantation, Homologous; Tuberculosis

1976
Emergence of rifampin-resistant Mycobacterium tuberculosis in Massachusetts.
    The Journal of infectious diseases, 1976, Volume: 133, Issue:1

    Tests of sensitivity to rifampin of over 2,200 strains of Mycobacterium tuberculosis demonstrated a progressive increase in the number of rifampin-resistant isolates during the past four years in Massachusetts. No resistant strains were isolated in 1971, but two strains resistant to 1 mug of rifampin/ml were isolated in 1972. Nine rifampin-resistant strains were isolated in 1973 and 16 were isolated in 1974. All but two of the resistant strains were isolated from patients who had received therapy for tuberculosis and had demonstrated resistance to other antituberculous agents. Rifampin-resistant strains were isolated from two patients, however, who had not received prior chemotherapy. Both strains were fully susceptible in vitro to other antituberculous drugs.

    Topics: Drug Resistance, Microbial; Female; Humans; In Vitro Techniques; Isoniazid; Male; Massachusetts; Middle Aged; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1976
[Bactericidal effect of rifampicin].
    Problemy tuberkuleza, 1976, Issue:9

    Topics: Animals; Cattle; Humans; In Vitro Techniques; Mycobacterium bovis; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Bovine

1976
Bactericidal activity in vitro and in the guinea-pig of isoniazid, rifampicin and ethambutol.
    Tubercle, 1976, Volume: 57, Issue:4

    Serial viable counts on Mycobacterium tuberculosis exposed in vitro to isoniazid, rifampicin and ethambutol in Tween-albumin liquid medium showed no bactericidal synergism between isoniazid and rifampicin and no influence of ethambutol on the bactericidal activity of isoniazid or isoniazid plus rifampicin. Guinea-pigs with moderately advanced experimental tuberculosis were treated fro 11 weeks with either (1) ethambutol, (2) isoniazid, (3) isoniazid plus ethambutol, (4) isoniazid plus rifampicin, (5) isonaiazid plus rifampic in plus ethambutol, or (6) no chemotherapy. The amount of tuberculous disease was scored and the spleen cultured in groups killed at intervals from 0--7 1/2 months after the end of chemotherapy. The regimens containing rifampicin were no more bactericidal during treatment than the corresponding regimens without rifampicin, but the onset of relapse after chemotherapy was delayed for at least 2 months following the rifampicin-containing regimens. Ethambutol alone did not protect guinea-pigs, nor did it influence the response to isoniazid or to isoniazid plus rifampicin. It was concluded that rifampicin may act selectively on a small proportion of the bacterial population and that it may be unnecessary to prescribe it for long periods in short course chemotherapy in man. Ethambutol does not appear likely to contribute to the sterilizing activity of short course regimens though it may prevent the emergence of drug resistance.

    Topics: Animals; Drug Therapy, Combination; Ethambutol; Guinea Pigs; Isoniazid; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

1976
Experimental investigations of bacteriological mechanisms in short course chemotherapy.
    Bulletin of the International Union against Tuberculosis, 1976, Volume: 51, Issue:1

    Topics: Animals; Drug Therapy, Combination; Guinea Pigs; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis

1976
Rifampin.
    Annals of internal medicine, 1976, Volume: 85, Issue:1

    In 1971, rifampin was approved for treatment of pulmonary tuberculosis and asymptomatic carriers of Neisseria meningitidis. At present, the approved indications remain the same. However, rifampin in conjunction with at least one other antituberculous drug may be of great value in therapy of extrapulmonary tuberculosis and infections due to other susceptible mycobacteria. In addition, results of clinical trials in leprosy have been highly encouraging. Rifampin appears to induce light chain proteinuria in a majority of patients and has been implicated in suppression of both humoral and cell-mediated immune responses. However, these effects appear to have been of little consequence to treated patients. A variety of possibly immunologically mediated reactions to rifampin has been closely associated with irregular administration of the drug. These reactions and hepatic toxcity may be preventable in many patients. Rifampin or one of its congeners, alone or in combination with other antibiotics, may prove useful in treatment of various infectious, and possibly malignant, diseases.

    Topics: Animals; Antibody Formation; Antineoplastic Agents; Antiviral Agents; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Resistance, Microbial; Drug Therapy, Combination; Forecasting; Humans; Immunity, Cellular; Immunosuppressive Agents; Leprosy; Liver; Meningococcal Infections; Mycobacterium Infections; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

1976
Tuberculosis management in the mid-1970s.
    JAMA, 1976, Jan-12, Volume: 235, Issue:2

    Topics: Ambulatory Care; Antitubercular Agents; Drug Resistance; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Patient Compliance; Rifampin; Self Medication; Sputum; Streptomycin; Time Factors; Tuberculosis; United States

1976
[Acute renal failure caused by rifampicin].
    Revista clinica espanola, 1976, Jul-31, Volume: 142, Issue:2

    Topics: Acute Kidney Injury; Humans; Male; Middle Aged; Rifampin; Tuberculosis

1976
Lack of association between rifampicin-dependent antibodies and bacteriological response during intermittent rifampicin treatment.
    The Journal of antimicrobial chemotherapy, 1976, Volume: 2, Issue:3

    Topics: Antibodies; Humans; Rifampin; Sputum; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

1976
Rifampin, oral contraceptives, and pregnancy.
    JAMA, 1976, Sep-20, Volume: 236, Issue:12

    Rifampin is a drug used in the treatment of tuberculosis. In the literature, there are reports of seven patients who became pregnant while taking a combination of rifampin and oral contraceptives. We report an eighth case involving a woman who became pregnant twice on this drug combination.

    Topics: Adult; Contraceptives, Oral; Female; Humans; Pregnancy; Pregnancy, Unwanted; Recurrence; Rifampin; Tuberculosis

1976
[Frequency, diagnosis, and course of hepatotoxic side effects of Rifampicin (author's transl)].
    Medizinische Klinik, 1976, Oct-22, Volume: 71, Issue:43

    In a retrospective study the following was found: Out of 111 patients suffering from tuberculosis and receiving a combined INH-therapy without Rifampicin 23% showed an increase of serum-transmainase activities, on the other hand out of 105 patients, treated with a combination including Rifampicin 74% did so. A pathological De Ritis ratio GOT/GPT was found in 31 among 59 comparable cases of Rifampicin-treated patients, and a pathological ratio GOT + GPT/AP in 22 among 37 cases before the transaminase-activities rose above normal. Development of a distinct toxic hepatic damage has to be anticipated in those cases, which show a De Ritis ratio below 0,5 or a GOT + GPT/AP ratio above 1,0 while transaminase-activity still is only slightly elevated. Liver biopsies taken from 10 patients showed no regular relation to the biochemical data.

    Topics: Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Isoniazid; Retrospective Studies; Rifampin; Time Factors; Tuberculosis

1976
[Effect of rifampicin on experimental tuberculosis].
    Problemy tuberkuleza, 1976, Issue:l

    Topics: Animals; Guinea Pigs; Rifampin; Tuberculosis

1976
New concepts in diagnosis and treatment of tuberculosis. Part II: current trends in treatment and management.
    The Nebraska medical journal, 1976, Volume: 61, Issue:12

    Topics: Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1976
Antibodies against rifampin in patients with tuberculosis after discontinuation of daily treatment.
    The American review of respiratory disease, 1976, Volume: 114, Issue:6

    The presence of antibodies to rifampin was determined in sera of patients with tuberculosis on daily treatment one day after discontinuation of treatment, one week later, 3 weeks later, and 8 weeks later. The highest number of positive patients was found in the third week.

    Topics: Animals; Antibody Formation; Antigen-Antibody Reactions; Humans; Rats; Rifampin; Time Factors; Tuberculosis

1976
[The results of liver biopsies during rifampicin therapy (author's transl)].
    Praxis der Pneumologie, 1976, Volume: 30, Issue:12

    Topics: Adult; Aged; Biopsy; Chemical and Drug Induced Liver Injury; Ethambutol; Female; Humans; Liver; Male; Middle Aged; Rifampin; Tuberculosis

1976
[Current aspects in treatment of tuberculosis].
    Duodecim; laaketieteellinen aikakauskirja, 1976, Volume: 92, Issue:10

    Topics: Adult; Child; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary

1976
[Anti-Tuberculous therapy with rifampicin and ethambutol during pregnancy (author's transl)].
    Praxis der Pneumologie, 1976, Volume: 30, Issue:1

    Topics: Abnormalities, Drug-Induced; Adult; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Infant, Newborn; Pregnancy; Pregnancy Complications, Infectious; Rifampin; Tuberculosis

1976
Letter: Short-course triple chemotherapy for tuberculosis.
    Lancet (London, England), 1975, Mar-29, Volume: 1, Issue:7909

    Topics: Adult; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Peritonitis, Tuberculous; Rifampin; Streptomycin; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

1975
Side effects of drugs used to treat tuberculosis.
    Scottish medical journal, 1975, Volume: 20, Issue:2

    Topics: Aminosalicylic Acids; Animals; Antitubercular Agents; Capreomycin; Chemical and Drug Induced Liver Injury; Cycloserine; Deafness; Drug Hypersensitivity; Ethambutol; Ethionamide; Gastrointestinal Diseases; Goiter; Humans; Isoniazid; Kanamycin; Liver; Mental Disorders; Mice; Nervous System Diseases; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Tuberculosis; Viomycin

1975
Letter: Permanent renal damage with rifampicin.
    Lancet (London, England), 1975, Jun-28, Volume: 1, Issue:7922

    Topics: Acute Kidney Injury; Adult; Female; Humans; Kidney Tubular Necrosis, Acute; Middle Aged; Rifampin; Time Factors; Tuberculosis

1975
The treatment of tuberculosis.
    The Practitioner, 1975, Volume: 215, Issue:1288

    Topics: Aminosalicylic Acids; Capreomycin; Ethambutol; Ethionamide; Humans; Isoniazid; Prothionamide; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Tuberculosis

1975
Light chain proteinuria and cellular mediated immunity in rifampin treated patients with tuberculosis.
    Chest, 1975, Volume: 67, Issue:4

    Light chain proteinuria was found in 9 of 17 tuberculosis patients treated with rifampin. Concomitant assay of cellular mediated immunity in these patients using skin test antigen and a lymphokine in vitro test provided results that were different. Response to Varidase skin test antigen was negative for all eight tuberculosis patients tested, but there occurred a hyper-responsiveness of the lymphocytes of these eight patients to phytomitogen (PHA-P). as well as of those of seven other tuberculous patients. This last finding may be related to time of testing and/or endogenous serum binding of rifampin which could have inhibited mitogen activity for the lymphocyte.

    Topics: Adult; Aged; Humans; Immunity, Cellular; Immunoglobulin Fragments; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; In Vitro Techniques; Lymphocyte Activation; Middle Aged; Proteinuria; Rifampin; Skin Tests; Tuberculosis

1975
The use of in-vitro and in-vivo experiments with Mycobacterium tuberculosis in helping to plan chemotherapy regimens.
    Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke, 1975, Jun-20, Volume: 95, Issue:17-18

    Topics: Animals; Drug Combinations; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Guinea Pigs; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1975
[Lepromatous leprosy after BCG vaccination].
    Medicina cutanea ibero-latino-americana, 1975, Volume: 3, Issue:5

    The authors describe an eruption of cutaneons nodules after a BCG vaccination. Investigation demonstrated that the lesions were caused by Lepromata. An increased number of B lymphocytes was observed in the bloodstream. Ryphampycin was used with good results.

    Topics: Adolescent; BCG Vaccine; Female; Humans; Leprosy; Rifampin; T-Lymphocytes; Tuberculosis

1975
Peripheral nervous system involvement in experimental tuberculosis.
    Pathologia et microbiologia, 1975, Volume: 42, Issue:2

    Following intravenous injection of mycobacteria in the mouse the bacilli are regularly found in the peripheral nervous system after the 5th day. The peripheral nerves and autonomic ganglia are involved at the level of the perineural cells and the sheath of Schwann. When the organisms are of low virulence (BCG, Mycobacterium intracellulare) the development of the nodules is limited. In the case of a virulent strain (Ravenel) extensive granulomas are found but epitheloid cells, always found in other organs, are constantly absent. In animals previously immunized, the bacilli seem to implant themselves as in the controls, but multiply more slowly; the nodules are more infrequent and the lymphoid infiltration appears earlier with the multiplication of interstitial cells.

    Topics: Animals; BCG Vaccine; Disease Models, Animal; Ganglia, Autonomic; Injections, Intravenous; Mice; Mycobacterium; Mycobacterium bovis; Peripheral Nerves; Rifampin; Schwann Cells; Tuberculosis; Virulence

1975
[Adverse effects of rifampicin and their biochemical principles].
    Deutsche medizinische Wochenschrift (1946), 1975, Jan-10, Volume: 100, Issue:2

    Topics: Acute Disease; Acute Kidney Injury; Anticoagulants; Contraceptives, Oral; Digitoxin; Female; Hemolysis; Humans; Nephritis, Interstitial; Rifampin; Thrombocytopenia; Tuberculosis

1975
[Comparison of rifampicin serum levels following its administration before breakfast and 3 hours after breakfast].
    Gruzlica i choroby pluc; tuberculosis et pneumonologia, 1975, Volume: 43, Issue:2

    Topics: Eating; Fasting; Humans; Male; Rifampin; Time Factors; Tuberculosis

1975
[Diagnostic usefulness of a chemical method of determination of rifampicin in urine].
    Gruzlica i choroby pluc; tuberculosis et pneumonologia, 1975, Volume: 43, Issue:2

    Topics: Female; Humans; Male; Methods; Rifampin; Spectrophotometry; Tuberculosis

1975
[New aspects of tuberculosis therapy].
    Schweizerische medizinische Wochenschrift, 1975, Feb-22, Volume: 105, Issue:8

    The introduction of ethambutol and rifampicin has modified the therapy of tuberculosis. Therapy in hospitals or sanatoria can be shortened, and intermittent regimens (once or twice weekly under supervision) are possible. Better knowledge of the side effects of particular drugs, particularly rifampicin, (such as allergic reactions in intermittent administration and reduced effect of oral contraceptives) has been gained. Instead of mere supervision, preventive chemotherapy is given in many cases such as in recently discovered fibrotic lesions and in high risk cases (silicosis, treatment with corticosteroids and immunosuppressive agents)minadequate treatment may lead to functional impairment such as fibrosis and cor pulmonale. These aspects are discussed and the resultant guidelines for the treatment of tuberculosis are presented.. The introduction of ethambutol and rifampicin has changed tuberculos is treatment, rendering possible ambulatory treatment with intermittent regimens. The steroid metabolic effects of Rifampicin, however, pose problems when tuberculostatic and contraceptive therapies are concurrent. It has been reported that metabolism of ethinyl estradiol is intensified by a factor of 4 during rifampicin therapy, explaining the cases of pregnancy occurring during simultaneous rifampicin and contraceptive therapy. Menstrual cycle disturbances have also been observed in patients treated only with Rifampicin. The author recommends that oral contraceptives and rifampicin not to be taken together; which course of therapy should be preferred depends on the ind ividual situation.

    Topics: Contraceptives, Oral; Ethambutol; Female; Humans; Isoniazid; Menstruation; Methods; Pulmonary Heart Disease; Rifampin; Streptomycin; Time Factors; Tuberculosis

1975
Tuberculosis. Chemoprophylaxis and treatment.
    Postgraduate medicine, 1975, Volume: 58, Issue:3

    Topics: Chemical and Drug Induced Liver Injury; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Patient Compliance; Rifampin; Streptomycin; Tuberculosis

1975
Topics in tuberculosis.
    Maryland state medical journal, 1975, Volume: 24, Issue:3

    Topics: Ambulatory Care; Female; Humans; Isoniazid; Maryland; Patient Care Planning; Pregnancy; Rifampin; Tuberculosis

1975
Proceedings: Latest results of East African/British Medical Research Council short course chemotherapy studies.
    Tubercle, 1975, Volume: 56, Issue:2

    Topics: Drug Evaluation; Humans; Isoniazid; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tuberculosis

1975
Rifampicin in clinical use.
    The Journal of antimicrobial chemotherapy, 1975, Volume: 1, Issue:4

    Topics: Aminosalicylic Acids; Drug Resistance, Microbial; Drug Therapy, Combination; England; Humans; Isoniazid; Rifampin; Staphylococcal Infections; Streptomycin; Substance-Related Disorders; Tuberculosis

1975
[Isoprodian in combination with ethambutol and rifampicin in the treatment of tuberculosis (author's transl)].
    Praxis der Pneumologie, 1975, Volume: 29, Issue:9

    Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Combinations; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Prothionamide; Rifampin; Sulfones; Tuberculosis

1975
[Treatment of tuberculosis].
    Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke, 1975, Dec-10, Volume: 95, Issue:34-36

    Topics: Aminosalicylic Acids; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1975
[Drug therapy of tuberculosis].
    Deutsche medizinische Wochenschrift (1946), 1974, Aug-09, Volume: 99, Issue:32

    Topics: Amides; Aminosalicylic Acids; Antitubercular Agents; Capreomycin; Drug Therapy, Combination; Ethambutol; Ethionamide; Humans; Isoniazid; Isonicotinic Acids; Kanamycin; Phenylthiourea; Pyrazinamide; Rifampin; Streptomycin; Tetracycline; Thiosemicarbazones; Tuberculosis; Viomycin

1974
Letter: Rifampicin and cortisone replacement therapy.
    Lancet (London, England), 1974, Oct-12, Volume: 2, Issue:7885

    Topics: Addison Disease; Aged; Cortisone; Drug Interactions; Female; Humans; Isoniazid; Recurrence; Rifampin; Streptomycin; Tuberculosis

1974
Binding of rifampicin by human plasma proteins.
    European journal of clinical pharmacology, 1974, Aug-23, Volume: 7, Issue:5

    Topics: Adult; Aged; Aminosalicylic Acids; Blood Proteins; Carbon Radioisotopes; Chromatography, Thin Layer; Dialysis; Ethambutol; Female; Fibrinogen; gamma-Globulins; Humans; Isoniazid; Male; Middle Aged; Protein Binding; Rifampin; Serum Albumin; Streptomycin; Tuberculosis

1974
Studies on lividomycin. I. In vitro antibacterial activities of LVDM against clinical isolates of Mycobacterium tuberculosis.
    The Japanese journal of antibiotics, 1974, Volume: 27, Issue:6

    Topics: Capreomycin; Cycloserine; Drug Resistance, Microbial; Ethambutol; Humans; Mycobacterium tuberculosis; Paromomycin; Rifampin; Sulfisoxazole; Tuberculosis; Viomycin

1974
The effect of chemotherapy for tuberculosis on immunity to tuberculosis.
    The Journal of infectious diseases, 1974, Volume: 129, Issue:4

    Topics: Animals; BCG Vaccine; Drug Resistance, Microbial; Female; Immunity, Maternally-Acquired; Immunization, Passive; Isoniazid; Lymphocyte Transfusion; Lymphocytes; Mycobacterium tuberculosis; Rats; Rifampin; Thoracic Duct; Transplantation, Homologous; Tuberculosis

1974
[Signes of adaptation under long-term combined antituberculous therapy (author's transl)].
    Schweizerische Rundschau fur Medizin Praxis = Revue suisse de medecine Praxis, 1974, Jan-15, Volume: 63, Issue:2

    Topics: Adaptation, Physiological; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Long-Term Care; Rifampin; Streptomycin; Transaminases; Tuberculosis

1974
Immunological memory in tuberculosis. I. Influence of persisting viable organisms.
    Cellular immunology, 1974, Volume: 14, Issue:3

    Topics: Animals; BCG Vaccine; Cortisone; Female; Hypersensitivity, Delayed; Immunity, Maternally-Acquired; Immunologic Memory; Isoniazid; Liver; Lung; Lymphocytes; Mycobacterium bovis; Mycobacterium tuberculosis; Rats; Rats, Inbred BN; Rats, Inbred Lew; Rifampin; Spleen; Time Factors; Tuberculin; Tuberculosis

1974
[Facial paralysis caused by tubercular otitis. Current therapeutic possibilities].
    JFORL. Journal francais d'oto-rhino-laryngologie; audiophonologie et chirurgie maxillo-faciale, 1974, Volume: 23, Issue:10

    Topics: Adult; Ethambutol; Facial Paralysis; Female; Humans; Isoniazid; Male; Otitis; Rifampin; Tuberculosis

1974
New antituberculosis drugs and concepts of prophylaxis.
    The Medical clinics of North America, 1974, Volume: 58, Issue:3

    Topics: Aminosalicylic Acids; Antitubercular Agents; Arthritis; Chemical and Drug Induced Liver Injury; Child; Cycloserine; Drug Hypersensitivity; Drug Resistance, Microbial; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Liver; Lupus Vulgaris; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tuberculin Test; Tuberculosis; Viomycin

1974
[Use of a isoniozid-rifompicin drug hepatotoxicity screening technic in tuberculosis therapy].
    La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris, 1974, Volume: 50, Issue:28

    Topics: Adult; Bilirubin; Chemical and Drug Induced Liver Injury; Clinical Enzyme Tests; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Isoenzymes; Isoniazid; Jaundice; L-Lactate Dehydrogenase; Male; Oxidoreductases; Rifampin; Transaminases; Tuberculosis

1974
Letter: Rifampicin and the pill.
    JAMA, 1974, May-13, Volume: 228, Issue:7

    Topics: Contraceptives, Oral; Female; Humans; Rifampin; Tuberculosis

1974
[Microscopic changes in liver in experimental tuberculosis in guinea pigs treated with rifampicin].
    Gruzlica i choroby pluc; tuberculosis et pneumonologia, 1974, Volume: 42, Issue:9

    Topics: Animals; Guinea Pigs; Liver; Rifampin; Tuberculosis

1974
[Survey of the tuberculosis problem in the Nordic countries. Are BCG vaccination and mass screening necessary?].
    Nordisk medicin, 1974, Volume: 89, Issue:7

    Topics: Adolescent; Adult; Aged; Aminosalicylic Acids; BCG Vaccine; Ethambutol; Female; Humans; Iceland; Infant, Newborn; Isoniazid; Male; Mass Chest X-Ray; Middle Aged; Registries; Retrospective Studies; Rifampin; Scandinavian and Nordic Countries; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary

1974
Intermittent chemotherapy for adults with tuberculosis.
    The American review of respiratory disease, 1974, Volume: 110, Issue:3

    Topics: Administration, Oral; Adult; Drug Resistance, Microbial; Ethambutol; Humans; Injections, Intramuscular; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis

1974
[The effects of antituberculosis drugs on the pharmacokinetics of digitoxin (author's transl)].
    Deutsche medizinische Wochenschrift (1946), 1974, Nov-22, Volume: 99, Issue:47

    Topics: Administration, Oral; Adult; Antitubercular Agents; Digitoxin; Drug Therapy, Combination; Ethambutol; Humans; Hydroxylation; Intestinal Absorption; Isoniazid; Kidney Tubules; Kinetics; Liver; Middle Aged; Protein Binding; Radioimmunoassay; Rifampin; Tuberculosis

1974
[Hematopoietic tuberculosis].
    Annales de medecine interne, 1974, Volume: 125, Issue:4

    Topics: Bone Marrow; Bone Marrow Examination; Cholestasis; Erythema; Ethambutol; Humans; Isoniazid; Leukopenia; Male; Middle Aged; Neutropenia; Peritonitis, Tuberculous; Rifampin; Streptomycin; Thrombocytopenia; Tuberculosis; Tuberculosis, Hepatic; Tuberculosis, Osteoarticular; Tuberculosis, Splenic; Vitamin B Complex

1974
[Local therapeutic trials of various forms of extrapulmonary tuberculosis using rifampicin suspension].
    Maroc medical, 1974, Volume: 54, Issue:579

    Topics: Administration, Topical; Adult; Humans; Male; Middle Aged; Pleural Effusion; Rifampin; Tuberculosis; Tuberculosis, Cutaneous; Tuberculosis, Lymph Node; Tuberculosis, Male Genital; Tuberculosis, Osteoarticular; Tuberculosis, Pleural; Tuberculosis, Spinal

1974
Acute renal failure following rifampicin administration.
    Scandinavian journal of respiratory diseases, 1974, Volume: 55, Issue:5

    Topics: Acute Kidney Injury; Adult; Aged; Complement Fixation Tests; Female; Humans; Male; Middle Aged; Renal Dialysis; Rifampin; Tuberculosis

1974
Experiences with rifampicin.
    Bulletin of the International Union against Tuberculosis, 1974, Volume: 49 suppl 1

    Topics: Drug Therapy, Combination; Ethambutol; Humans; Rifampin; Tuberculosis

1974
The impact of rifampicin on the treatment of tuberculosis.
    Bulletin of the International Union against Tuberculosis, 1974, Volume: 49 suppl 1

    Topics: Aminosalicylic Acids; Costs and Cost Analysis; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1974
Experiences with rifampicin.
    Bulletin of the International Union against Tuberculosis, 1974, Volume: 49 suppl 1

    Topics: Antitubercular Agents; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Humans; Rifampin; Tuberculosis

1974
Intermittent rifampicin treatment.
    Bulletin of the International Union against Tuberculosis, 1974, Volume: 49 suppl 1

    Topics: Antitubercular Agents; Costs and Cost Analysis; Finland; Humans; Rifampin; Time Factors; Tuberculosis

1974
[Classification of liver incidents occurring during antitubercular treatments which include rifampicin].
    Annales de medecine interne, 1974, Volume: 125, Issue:12

    Topics: Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Hepatitis A; Humans; Hyperbilirubinemia; Jaundice; Liver Diseases; Pruritus; Rifampin; Tuberculosis

1974
[Comparative histopathological studies of the results of continuous and intermittent treatment with rifampicin in experimental tuberculosis].
    Ftiziologia, 1974, Volume: 23, Issue:3

    Topics: Animals; Mycobacterium bovis; Rabbits; Rifampin; Time Factors; Tuberculosis

1974
Editorial: Rifampin in the treatment of tuberculosis.
    Canadian Medical Association journal, 1974, May-04, Volume: 110, Issue:9

    Topics: Canada; Drug Therapy, Combination; Emigration and Immigration; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1974
Upper respiratory tract tuberculosis. Sixteen cases in a general hospital.
    Annals of internal medicine, 1974, Volume: 80, Issue:6

    Topics: Aged; Diagnosis, Differential; Epiglottis; Esophageal Neoplasms; Hospitals, General; Humans; Ileocecal Valve; Isoniazid; Laryngeal Neoplasms; Laryngoscopy; Male; Otitis Media; Pharyngitis; Radiography; Respiratory Tract Infections; Rifampin; Tongue Diseases; Tonsillitis; Tuberculosis; Tuberculosis, Gastrointestinal; Tuberculosis, Laryngeal; Tuberculosis, Oral; Tuberculosis, Pulmonary

1974
Sensitivity to rifampicin: incidence, mechanism, and prevention.
    British medical journal, 1974, May-25, Volume: 2, Issue:5916

    Five out of 200 patients taking rifampicin 900 mg twice weekly and three out of 91 patients taking rifampicin who attended an immunology clinic developed intolerance to the drug. Antibodies to rifampicin, which were found in most cases, decreased steadily after the end of treatment but were detectable for up to 16 months. The dose of rifampicin and the blood levels are predominating factors in the occurrence of reactions. Thus the dose should be reduced in patients in whom rifampicin blood levels rise abnormally. When it is important to continue rifampicin treatment despite intolerance antibody titres within 24 hours after administration of the drug must be measured to find when they are lowest, which determines the "unreactive period," and when a further dose may be safely given.

    Topics: Antibodies; Antibody Formation; Binding Sites, Antibody; Biological Assay; Cell Membrane; Coombs Test; Dose-Response Relationship, Drug; Drug Hypersensitivity; Drug Tolerance; Erythrocytes; Humans; Isoniazid; Lymphocyte Activation; Rifampin; Time Factors; Tuberculosis

1974
[Detection of the effects of the rifampin-isoniazid combination on the human liver].
    La Nouvelle presse medicale, 1974, Mar-23, Volume: 3, Issue:12

    Topics: Chemical and Drug Induced Liver Injury; Drug Combinations; Drug Interactions; Female; Humans; Isoniazid; Liver; Male; Rifampin; Statistics as Topic; Transaminases; Tuberculosis

1974
[Jaundice and rifampicin. Critical study].
    La Nouvelle presse medicale, 1974, Mar-23, Volume: 3, Issue:12

    Topics: Antigen-Antibody Reactions; Chemical and Drug Induced Liver Injury; Drug Interactions; Female; Humans; Hyperbilirubinemia; Isoniazid; Male; Prognosis; Rifampin; Statistics as Topic; Transaminases; Tuberculosis

1974
Mycobacterium tuberculosis infection of the middle ear.
    Chest, 1974, Volume: 66, Issue:1

    Topics: Adult; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Otitis Media; Pyridoxine; Rifampin; Tuberculosis; Tuberculosis, Meningeal

1974
[Treatment of primary tuberculosis].
    Revue medicale de Liege, 1974, Jan-15, Volume: 29, Issue:2

    Topics: Administration, Oral; Adult; Aminosalicylic Acids; Antibody Formation; Antitubercular Agents; BCG Vaccine; Child; Child, Preschool; Drug Therapy, Combination; Ethambutol; Ethionamide; Humans; Immunity, Cellular; Infant; Isoniazid; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary

1974
[Complications of intermittent rifampicin treatment. Role of immuno-allergic factors. Study of 8 cases].
    La Nouvelle presse medicale, 1974, Jun-15, Volume: 3, Issue:24

    Topics: Dose-Response Relationship, Drug; Drug Hypersensitivity; Hemolysis; Humans; Rifampin; Tuberculosis

1974
Tuberculosis of the nose and paranasal sinuses.
    The Journal of laryngology and otology, 1974, Volume: 88, Issue:6

    Topics: Female; Humans; Isoniazid; Maxillary Sinus; Middle Aged; Nasal Mucosa; Nasal Polyps; Nose Diseases; Radiography; Rifampin; Streptomycin; Tuberculosis; Turbinates

1974
Initial treatment of tuberculosis with streptomycin and isoniazid combined with either aminosalyl or rifampicin.
    Scandinavian journal of respiratory diseases, 1973, Volume: 54, Issue:2

    Topics: Alcoholism; Aminosalicylic Acids; Bilirubin; Dihydrostreptomycin Sulfate; Humans; Isoniazid; Rifampin; Sputum; Transaminases; Tuberculosis; Tuberculosis, Pulmonary

1973
[Proceedings: Ambulatory chemotherapy of tuberculosis in Finland (organization)].
    Zeitschrift fur Erkrankungen der Atmungsorgane mit Folia bronchologica, 1973, Volume: 138, Issue:1

    Topics: Ambulatory Care; Aminosalicylic Acids; Antitubercular Agents; Capreomycin; Ethambutol; Ethionamide; Finland; Humans; Isoniazid; Patient Dropouts; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary

1973
Toxicologic and pharmacologic aspects of rifampin.
    Chest, 1973, Volume: 64, Issue:2

    Topics: Administration, Oral; Drug Interactions; Drug Resistance, Microbial; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

1973
A survey of mycobacterial isolates from the Randwick Chest Hospital, Sydney, in an 18-month period, 1970 to 1971.
    The Medical journal of Australia, 1973, Jun-09, Volume: 1, Issue:23

    Topics: Adult; Aged; Aminosalicylic Acids; Australia; Ethambutol; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium; Mycobacterium Infections; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1973
Endobronchial tuberculosis.
    Chest, 1973, Volume: 64, Issue:4

    Topics: Aged; Bronchial Diseases; Bronchoscopy; Ethambutol; Female; Humans; Isoniazid; Mycobacterium tuberculosis; Radiography; Rifampin; Sputum; Tracheal Diseases; Tuberculosis

1973
Tuberculosis in Acukland.
    The New Zealand medical journal, 1973, Dec-26, Volume: 78, Issue:505

    Topics: Adult; Age Factors; Aged; Antitubercular Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Ethnicity; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium bovis; Mycobacterium tuberculosis; New Zealand; Rifampin; Sex Factors; Sputum; Tuberculosis; Tuberculosis, Pulmonary

1973
[Effect of schizophyllan in experimental tuberculosis].
    The Japanese journal of antibiotics, 1973, Volume: 26, Issue:5

    Topics: Animals; Antitubercular Agents; Basidiomycota; Drug Evaluation, Preclinical; Drug Therapy, Combination; Ethambutol; Glycosaminoglycans; Liver; Lung; Lymph Nodes; Male; Mice; Polysaccharides; Rifampin; Spleen; Streptomycin; Tuberculosis

1973
Rifampicin effect on tuberculin hypersensitivity and humoral antibody response in tuberculous guinea-pigs.
    Zeitschrift fur Immunitatsforschung, experimentelle und klinische Immunologie, 1973, Volume: 144, Issue:5

    Topics: Animals; Antibody Formation; Guinea Pigs; Hypersensitivity, Delayed; Immunosuppression Therapy; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1973
Treatment of tuberculosis today in Nebraska.
    The Nebraska medical journal, 1973, Volume: 58, Issue:5

    Topics: Aminosalicylic Acids; Antitubercular Agents; Cycloserine; Drug Hypersensitivity; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Pyrazinamide; Pyridoxine; Rifampin; Sputum; Streptomycin; Tuberculosis; Viomycin

1973
[Liver tolerance of antitubercular treatment including rifampicin. Study on 214 cases].
    La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris, 1973, Jun-26, Volume: 49, Issue:30

    Topics: Adult; Biopsy, Needle; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Drug Tolerance; Female; Hepatitis A; Humans; Isoniazid; Jaundice; Liver; Male; Middle Aged; Rifampin; Tuberculosis

1973
[Cold thoracic abscess due to Histoplasma duboisii. Treatment using rifampicin].
    La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris, 1973, Nov-08, Volume: 49, Issue:45

    Topics: Abscess; Adult; Diagnosis, Differential; Ethambutol; Fluorescent Antibody Technique; Histoplasma; Histoplasmosis; Humans; Isoniazid; Male; Rifampin; Skin Tests; Thorax; Tuberculosis

1973
[The liver and rifampicin].
    Le Poumon et le coeur, 1973, Volume: 29, Issue:6

    Topics: Bilirubin; Biopsy; Chemical and Drug Induced Liver Injury; Drug Interactions; Ethambutol; Humans; Isoniazid; Liver; Phosphoric Monoester Hydrolases; Rifampin; Transaminases; Tuberculosis

1973
Drugs used in the management of tuberculosis. IV. Secondary tuberculostatic agents.
    The Australian nurses' journal. Royal Australian Nursing Federation, 1973, Volume: 2, Issue:11

    Topics: Antitubercular Agents; Ethambutol; Ethionamide; Rifampin; Tuberculosis

1973
[Comparative study of hepatic bilirubin and paranitrophenol glucuronyl transferase activity. 3. Effect of rifampicin alone or associated with streptomycin and isoniazid in man].
    Pathologie-biologie, 1973, Volume: 21, Issue:3

    Topics: Bilirubin; Enzyme Induction; Glucuronates; Humans; Isoniazid; Liver; Liver Function Tests; Microscopy, Electron; Nitrophenols; Rifampin; Streptomycin; Transferases; Tuberculosis

1973
Intermittent rifampicin treatment in experimental tuberculosis.
    Archives roumaines de pathologie experimentales et de microbiologie, 1973, Volume: 32, Issue:2

    Topics: Administration, Oral; Agglutination Tests; Animals; Antibodies, Bacterial; Blood Bactericidal Activity; Coombs Test; Disease Models, Animal; Fluorescent Antibody Technique; Guinea Pigs; Isoniazid; Rifampin; Spleen; Time Factors; Tuberculin Test; Tuberculosis

1973
Tuberculosis since Lettsom.
    Transactions of the Medical Society of London, 1973, Volume: 89

    Topics: Europe; History, 19th Century; History, 20th Century; Hydrotherapy; Rifampin; Streptomycin; Tuberculosis

1973
Tuberculosis complicated by pregnancy.
    American journal of obstetrics and gynecology, 1973, Feb-15, Volume: 115, Issue:4

    Topics: Adolescent; Adult; Aminosalicylic Acids; Anesthesia, General; Cross Infection; Delivery, Obstetric; Female; Fetus; Humans; Infant, Newborn; Isoniazid; Labor, Obstetric; Pregnancy; Pregnancy Complications, Infectious; Rifampin; Streptomycin; Tuberculin Test; Tuberculosis; Tuberculosis, Meningeal; Tuberculosis, Pulmonary

1973
[Treatment of experimental tuberculosis in guinea pigs by continuous and intermittent regimen with special reference to ethambutol and rifampicin].
    Gruzlica i choroby pluc; tuberculosis et pneumonologia, 1973, Volume: 41, Issue:1

    Topics: Animals; Drug Synergism; Ethambutol; Guinea Pigs; Isoniazid; Methods; Rifampin; Tuberculosis

1973
Light chain proteinuria and humoral immunoincompetence in tuberculous patients treated with rifampin.
    The American review of respiratory disease, 1973, Volume: 107, Issue:5

    Topics: Antibody Formation; Antigen-Antibody Reactions; Hemocyanins; Humans; Proteinuria; Rifampin; Salmonella; Tuberculosis; Tuberculosis, Pulmonary; Vaccines

1973
[Tubercular parotitis in childhood].
    Minerva pediatrica, 1973, Mar-03, Volume: 25, Issue:7

    Topics: Child, Preschool; Female; Humans; Parotid Gland; Radiography; Rifampin; Salivary Gland Diseases; Streptomycin; Tuberculosis

1973
[Antitubercular activity and concentrations of rifampicin and ethambutol in the organs].
    Vrachebnoe delo, 1973, Volume: 4

    Topics: Animals; Disease Models, Animal; Ethambutol; Mice; Rifampin; Tuberculosis

1973
[Two cases of auricular tuberculosis with facial paralysis].
    Annales d'oto-laryngologie et de chirurgie cervico faciale : bulletin de la Societe d'oto-laryngologie des hopitaux de Paris, 1973, Volume: 90, Issue:3

    Topics: Adolescent; Adult; Ear Diseases; Facial Paralysis; Female; Humans; Isoniazid; Labyrinth Diseases; Rifampin; Tuberculosis; Tuberculosis, Pulmonary; Vertigo

1973
[Results with rifampicin therapy of chronic tuberculosis].
    Orvosi hetilap, 1973, Sep-16, Volume: 114, Issue:37

    Topics: Adult; Aged; Antitubercular Agents; Chronic Disease; Drug Combinations; Female; Humans; Hungary; Male; Middle Aged; Rifampin; Tuberculosis

1973
[Liver toxicity of rifampicin].
    Die Medizinische Welt, 1973, Apr-27, Volume: 24, Issue:17

    Topics: Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Female; Humans; Liver; Male; Middle Aged; Rifampin; Tuberculosis

1973
Properties of lymphocytes which confer adoptive immunity to tuberculosis in rats.
    Immunology, 1973, Volume: 25, Issue:4

    Topics: Animals; BCG Vaccine; Female; Immunization, Passive; Lymphocytes; Rats; Rifampin; Thymidine; Tritium; Tuberculosis; Vinblastine

1973
[Rifampicin in the treatment of tuberculosis].
    Duodecim; laaketieteellinen aikakauskirja, 1973, Volume: 89, Issue:11

    Topics: Administration, Oral; Aminosalicylic Acids; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Time Factors; Tuberculosis

1973
Mycobacterium marinum (atypical acid-fast bacillus) infections of the hand.
    The Journal of bone and joint surgery. American volume, 1973, Volume: 55, Issue:5

    Topics: Adolescent; Adult; Amputation, Surgical; Debridement; Diagnosis, Differential; Ethambutol; Female; Fingers; Hand; Humans; Male; Middle Aged; Mycobacterium; Mycobacterium Infections; Osteomyelitis; Rifampin; Skin Diseases, Infectious; Skin Ulcer; Synovitis; Tuberculosis

1973
Editorial: Rifampicin.
    The Medical journal of Australia, 1973, Nov-10, Volume: 2, Issue:19

    Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Leprosy; Mycobacterium Infections; Rifampin; Time Factors; Tuberculosis

1973
[The liver and rifampicin].
    Les Cahiers de medecine, 1973, Jun-15, Volume: 14, Issue:6

    Topics: Chemical and Drug Induced Liver Injury; Humans; Jaundice; Liver; Rifampin; Tuberculosis

1973
[Modern treatment of tuberculosis].
    Lakartidningen, 1973, Nov-21, Volume: 70, Issue:47

    Topics: Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Recurrence; Rifampin; Streptomycin; Sweden; Tuberculosis

1973
[Recent developments in the treatment of tuberculosis].
    Schweizerische medizinische Wochenschrift, 1972, Feb-26, Volume: 102, Issue:8

    Topics: Antitubercular Agents; Drug Combinations; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Humans; Rifampin; Streptomycin; Thioacetazone; Tuberculosis

1972
[Rifampicin resistence and virulence of M. tuberculosis for guinea pigs].
    Zentralblatt fur Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene. Erste Abteilung Originale. Reihe A: Medizinische Mikrobiologie und Parasitologie, 1972, Volume: 219, Issue:1

    Topics: Animals; Drug Resistance, Microbial; Guinea Pigs; Injections, Subcutaneous; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Virulence

1972
[Involvement of adipose tissue in experimental tuberculosis of the mouse].
    Pathologia et microbiologia, 1972, Volume: 38, Issue:5

    Topics: Adipose Tissue; Adipose Tissue, Brown; Animals; Autopsy; BCG Vaccine; Disease Models, Animal; Histological Techniques; Macrophages; Mice; Mycobacterium bovis; Rifampin; Time Factors; Tuberculosis

1972
Evaluation of a new antituberculous agent. Rifampin (Rifadin, Rimactane).
    JAMA, 1972, Apr-17, Volume: 220, Issue:3

    Topics: Administration, Oral; Carrier State; Drug Interactions; Drug Resistance, Microbial; Drug Synergism; Female; Humans; Male; Mycobacterium Infections; Neisseria meningitidis; Pregnancy; Rifampin; Tuberculosis

1972
The effect of pulsed exposures to rifampin on the uptake of uridine- 14 C by Mycobacterium tuberculosis.
    The American review of respiratory disease, 1972, Volume: 105, Issue:4

    Topics: Animals; Bacteriological Techniques; Carbon Isotopes; Guinea Pigs; Mycobacterium tuberculosis; Rifampin; RNA Nucleotidyltransferases; RNA, Bacterial; Tuberculosis; Uridine

1972
[Critical concentration for definition of rifampicin resistance of tubercle bacilli].
    Kekkaku : [Tuberculosis], 1972, Volume: 47, Issue:5

    Topics: Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1972
[Pathomorphology of experimental tuberculosis induced by rifampicin-resistant mycobacteria].
    Problemy tuberkuleza, 1972, Volume: 50, Issue:7

    Topics: Animals; Drug Resistance, Microbial; Guinea Pigs; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1972
[Rifampicine in tuberculosis. Peculiarity of its experimental activity and new therapeutic prospects].
    Pathologie-biologie, 1972, Volume: 20, Issue:19

    Topics: Animals; Drug Resistance, Microbial; Humans; Isoniazid; Mice; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifampin; Streptomycin; Time Factors; Tuberculosis

1972
[Treatment of tuberculosis in childhood].
    Therapeutische Umschau. Revue therapeutique, 1972, Volume: 29, Issue:12

    Topics: Antitubercular Agents; Child; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1972
[Modern view on drug therapy of tuberculosis].
    Nederlands tijdschrift voor geneeskunde, 1972, Oct-07, Volume: 116, Issue:41

    Topics: Ethambutol; Humans; Isoniazid; Rifampin; Tuberculosis

1972
The Australian rifampicin trial.
    The Medical journal of Australia, 1972, Oct-14, Volume: 2, Issue:16

    Topics: Adult; Aged; Costs and Cost Analysis; Drug Resistance, Microbial; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Mycobacterium Infections; Rifampin; Sputum; Tuberculosis; Tuberculosis, Pulmonary

1972
[Antitubercular activity and pharmacokinetics of rifampicin].
    Antibiotiki, 1972, Volume: 17, Issue:7

    Topics: Animals; Guinea Pigs; Kinetics; Mice; Rifampin; Time Factors; Tuberculosis

1972
[Therapy of tuberculosis].
    Hippokrates, 1972, Volume: 43, Issue:4

    Topics: Antitubercular Agents; Drug Combinations; Ethambutol; Humans; Isoniazid; Rifampin; Tuberculosis

1972
[Rifampicin: a new antitubercular agent].
    Wiadomosci lekarskie (Warsaw, Poland : 1960), 1972, Feb-01, Volume: 25, Issue:3

    Topics: Chemical Phenomena; Chemistry; Drug Tolerance; Evaluation Studies as Topic; Humans; Rifampin; Tuberculosis

1972
Adverse reactions during rifampicin treatment.
    Scandinavian journal of respiratory diseases, 1972, Volume: 53, Issue:2

    Topics: Antigen-Antibody Reactions; Bilirubin; Drug Hypersensitivity; Humans; Liver; Rifampin; Time Factors; Transaminases; Tuberculosis

1972
Rifampicin and thrombocytopenia.
    Lancet (London, England), 1971, Jul-17, Volume: 2, Issue:7716

    Topics: Alcoholism; Chronic Disease; Humans; Liver Cirrhosis; Male; Middle Aged; Rifampin; Thrombocytopenia; Tuberculosis

1971
Rifampicin: an immunosuppressant?
    Lancet (London, England), 1971, Aug-14, Volume: 2, Issue:7720

    Topics: Culture Techniques; DNA; Humans; Immune Tolerance; Immunosuppression Therapy; Immunosuppressive Agents; Lymphocytes; Rifampin; Thymidine; Tuberculosis

1971
Laboratory aspects of intermittent drug therapy.
    Postgraduate medical journal, 1971, Volume: 47, Issue:553

    Topics: Animals; Ethionamide; Growth; Guinea Pigs; Humans; Isoniazid; Rifampin; Streptomycin; Thioacetazone; Time Factors; Tuberculosis

1971
New drugs in tuberculosis.
    Drugs, 1971, Volume: 1, Issue:5

    Topics: Capreomycin; Chemical and Drug Induced Liver Injury; Drug Combinations; Ethambutol; Gastrointestinal Diseases; Rifampin; Tuberculosis

1971
[Experimental studies on intermittent use of rifampicin alone or combined with other secondary antituberculous drugs].
    Kekkaku : [Tuberculosis], 1971, Volume: 46, Issue:5

    Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Antitubercular Agents; Body Weight; Ethambutol; Ethionamide; Injections, Intramuscular; Kanamycin; Lung; Mice; Organ Size; Pyrazinamide; Rifampin; Spleen; Tuberculosis; Viomycin

1971
[Jaundice and rifampicin].
    La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris, 1971, Apr-26, Volume: 47, Issue:20

    Topics: Aged; Chemical and Drug Induced Liver Injury; Female; Humans; Imipramine; Isoniazid; Jaundice; Liver; Male; Middle Aged; Rifampin; Tuberculosis; Tuberculosis, Miliary

1971
[Drug sensitivity of atypical Mycobacteria isolated from patients to antitubercular agents of the first and second order].
    Antibiotiki, 1971, Volume: 16, Issue:2

    Topics: Aminosalicylic Acids; Antitubercular Agents; Cycloserine; Depression, Chemical; Drug Resistance, Microbial; Ethambutol; Ethionamide; Humans; Isoniazid; Kanamycin; Microbial Sensitivity Tests; Mycobacterium; Rifampin; Streptomycin; Thiosemicarbazones; Tuberculosis; Viomycin

1971
[Advances and principles in tuberculostatic therapy].
    Der Internist, 1971, Volume: 12, Issue:8

    Topics: Adult; Aminosalicylic Acids; Antitubercular Agents; Cycloserine; Drug Resistance, Microbial; Ethambutol; Ethionamide; Female; Humans; Isoniazid; Kanamycin; Male; Microbial Sensitivity Tests; Middle Aged; Phenylthiourea; Pyrazinamide; Rifampin; Streptomycin; Thiosemicarbazones; Tuberculosis; Viomycin

1971
Rifampin: characteristics and role in the chemotherapy of tuberculosis.
    Annals of internal medicine, 1971, Volume: 74, Issue:5

    Topics: Animals; Haplorhini; Humans; Isoniazid; Mice; Mycobacterium tuberculosis; Research; Rifampin; Tuberculosis

1971
Mode of action of antituberculous agents and ultrastructure of mycobacteria.
    The science reports of the research institutes, Tohoku University. Ser. C, Medicine. Tohoku Daigaku, 1971, Volume: 18, Issue:1

    Topics: Animals; Antitubercular Agents; Cycloserine; Ethambutol; Isoniazid; Kanamycin; Mice; Microscopy, Electron; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1971
[Determination of rifomycin level in blood serum in tuberculous patients].
    Gruzlica i choroby pluc; tuberculosis et pneumonologia, 1971, Volume: 39, Issue:9

    Topics: Humans; Methods; Rifampin; Time Factors; Tuberculosis

1971
[Jaundice during rifampicin treatment].
    Journal de medecine de Lyon, 1971, May-20, Volume: 52, Issue:120

    Topics: Chemical and Drug Induced Liver Injury; Humans; Liver; Liver Function Tests; Rifampin; Tuberculosis

1971
[Our experience with Rifampicin].
    Praxis der Pneumologie, 1971, Volume: 25, Issue:10

    Topics: Ethambutol; Female; Humans; Male; Rifampin; Tuberculosis; Tuberculosis, Meningeal

1971
The effect of pyrazinamide, rifampicin and cycloserine on the blood levels and urinary excretion of isoniazid.
    Annals of clinical research, 1971, Volume: 3, Issue:5

    Topics: Cycloserine; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis

1971
Potentially serious side-effects of high-dose twice-weekly rifampicin.
    Postgraduate medical journal, 1971, Volume: 47, Issue:553

    Topics: Acute Kidney Injury; Adolescent; Adult; Antibodies; Child; Complement Fixation Tests; Epistaxis; Female; Fever; Humans; Isoniazid; Male; Middle Aged; Rifampin; Streptomycin; Thrombocytopenia; Tuberculosis

1971
Problems of drug resistance in tuberculosis--the newer anti-tuberculosis drugs.
    Postgraduate medical journal, 1971, Volume: 47, Issue:553

    Topics: Drug Combinations; Drug Resistance, Microbial; Ethambutol; Humans; Rifampin; Tuberculosis; United Kingdom; United States

1971
An experimental attempt of intensified chemotherapy with rifampicin combined with other drugs.
    The Japanese journal of tuberculosis and chest diseases, 1971, Volume: 17, Issue:1

    Topics: Administration, Oral; Animals; Drug Synergism; Ethambutol; Ethionamide; Female; Isoniazid; Mice; Mice, Inbred Strains; Rifampin; Tuberculosis

1971
[Standard therapy of tuberculosis].
    Deutsches medizinisches Journal, 1971, Jan-05, Volume: 22, Issue:1

    Topics: Antitubercular Agents; Body Weight; Drug-Related Side Effects and Adverse Reactions; Ethambutol; Humans; Isoniazid; Rifampin; Time Factors; Tuberculosis

1971
[Symposium: chemotherapy including new antitubercular agents].
    Kekkaku : [Tuberculosis], 1971, Volume: 46, Issue:2

    Topics: Aminosalicylic Acids; Antitubercular Agents; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1971
[Reduction of the blood level of rifampicin by phenobarbital].
    La Presse medicale, 1971, Feb-13, Volume: 79, Issue:8

    Topics: Humans; Phenobarbital; Rifampin; Tuberculosis

1971
[Changing picture of tuberculosis during a decade].
    Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke, 1971, Apr-30, Volume: 91, Issue:12

    Topics: Adult; Age Factors; Aged; Aminosalicylic Acids; Drug Resistance, Microbial; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Retrospective Studies; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary

1971
[The simultaneous use of rifampicin and other antitubercular agents with oral contraceptives].
    Praxis der Pneumologie, 1971, Volume: 25, Issue:5

    Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Contraceptives, Oral; Drug Hypersensitivity; Drug Tolerance; Female; Humans; Kidney Function Tests; Rifampin; Tuberculosis; Uterine Hemorrhage; Vision Disorders

1971
[Effect of combined rifampicin therapy on transaminases].
    Praxis der Pneumologie, 1971, Volume: 25, Issue:6

    Topics: Chemical and Drug Induced Liver Injury; Female; Humans; Rifampin; Transaminases; Tuberculosis

1971
The combination of rifampicin and other antituberculous agents in chronic murine tuberculosis.
    Chemotherapy, 1971, Volume: 16, Issue:3

    Topics: Animals; Cell Count; Chronic Disease; Disease Models, Animal; Drug Synergism; Ethambutol; Ethionamide; Isoniazid; Lung; Mice; Placebos; Rifampin; Streptomycin; Tuberculosis

1971
[The rational basis for the treatment of tuberculosis].
    Schweizerische medizinische Wochenschrift, 1971, Feb-13, Volume: 101, Issue:6

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Rifampin; Streptomycin; Tuberculosis

1971
[Rifampicin].
    Casopis lekaru ceskych, 1971, Jul-30, Volume: 110, Issue:31

    Topics: Administration, Oral; Chronic Disease; Humans; Rifampin; Tuberculosis

1971
Rifampicin and thrombocytopenia.
    British medical journal, 1971, Sep-11, Volume: 3, Issue:5775

    Topics: Female; Humans; Rifampin; Thrombocytopenia; Tuberculosis

1971
"Control of tuberculosis" up-to-date.
    The New England journal of medicine, 1971, Jun-17, Volume: 284, Issue:24

    Topics: Aminosalicylic Acids; Ethambutol; Humans; Isoniazid; Rifampin; Tuberculosis

1971
[Experimental study of rifampicin and ethambutol].
    Problemy tuberkuleza, 1971, Volume: 49, Issue:1

    Topics: Animals; Blood Bactericidal Activity; Ethambutol; Guinea Pigs; Humans; In Vitro Techniques; Isoniazid; Mice; Microbial Sensitivity Tests; Rabbits; Rifampin; Tuberculosis

1971
[How to oversee the treatment of tuberculosis?].
    La semaine des hopitaux : organe fonde par l'Association d'enseignement medical des hopitaux de Paris, 1970, Jun-08, Volume: 46, Issue:27

    Topics: Antitubercular Agents; Ethambutol; Ethionamide; Follow-Up Studies; Humans; Isoniazid; Long-Term Care; Male; Medication Errors; Middle Aged; Rifampin; Streptomycin; Tuberculosis

1970
[Preliminary studies on the determination of biologically active rifomycin using the platelet method].
    Gruzlica i choroby pluc; tuberculosis et pneumonologia, 1970, Volume: 38, Issue:6

    Topics: Animals; Bacteriological Techniques; Blood Platelets; Humans; Mycobacterium; Rifampin; Sarcina; Sheep; Tuberculosis

1970
[Current state of primary tuberculosis in children in Rhone department].
    Annales de pediatrie, 1970, Oct-02, Volume: 17, Issue:10

    Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Resistance, Microbial; Ethambutol; France; Humans; Infant; Mycobacterium tuberculosis; Radiography; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

1970
[Efficacy of rifampicin on experimental mouse tuberculosis].
    The Japanese journal of tuberculosis and chest diseases, 1970, Volume: 16, Issue:1

    Topics: Animals; Drug Resistance, Microbial; Mice; Mycobacterium; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1970
"Rifampin--now that the secret is out".
    The New England journal of medicine, 1970, Dec-10, Volume: 283, Issue:24

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1970
Suitability of rifampicin for intermittent administration in the treatment of tuberculosis.
    Tubercle, 1970, Volume: 51, Issue:1

    Topics: Analysis of Variance; Animals; Drug Resistance, Microbial; Guinea Pigs; Isoniazid; Mycobacterium tuberculosis; Rifampin; Spleen; Streptomycin; Tuberculosis; Tuberculosis, Hepatic

1970
Rifampicin in the treatment of experimental tuberculosis in mice: sterilization of tubercle bacilli in the tissues.
    Tubercle, 1970, Volume: 51, Issue:1

    Topics: Animals; Cortisone; Drug Synergism; Isoniazid; Lung; Male; Mice; Mycobacterium tuberculosis; Rifampin; Spleen; Tuberculosis

1970
[Durable character of the sterilization of experimental tuberculosis in mice by rifampicin-isoniazid association: cortisone test].
    Revue de tuberculose et de pneumologie, 1970, Volume: 34, Issue:2

    Topics: Animals; Cortisone; Drug Synergism; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Streptomycin; Time Factors; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Splenic

1970
Rifampicin in experimental investigations on mice.
    Antibiotica et chemotherapia. Fortschritte. Advances. Progres, 1970, Volume: 16

    Topics: Animals; Drug Combinations; Drug Resistance, Microbial; Evaluation Studies as Topic; Injections, Subcutaneous; Isoniazid; Lung; Mice; Mycobacterium tuberculosis; Rifampin; Spleen; Time Factors; Tuberculosis

1970
[Activity of rifampicin on experimental tuberculosis in mice. The development of resistance to rifampicin. Therapeutic effects of combinations of different drugs with rifampicin].
    Antibiotica et chemotherapia. Fortschritte. Advances. Progres, 1970, Volume: 16

    Topics: Animals; Drug Combinations; Drug Resistance, Microbial; Ethambutol; Ethionamide; Evaluation Studies as Topic; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis

1970
Experimental and clinical studies on the antituberculous activity of rifampicin alone or combined with other drugs.
    Antibiotica et chemotherapia. Fortschritte. Advances. Progres, 1970, Volume: 16

    Topics: Administration, Oral; Adolescent; Adult; Aminosalicylic Acids; Animals; Culture Media; Drug Combinations; Drug Resistance, Microbial; Ethambutol; Female; Guinea Pigs; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium; Mycobacterium tuberculosis; Organ Size; Rifampin; Spleen; Streptomycin; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

1970
Antimycobacterial activity of rifampicin.
    Antibiotica et chemotherapia. Fortschritte. Advances. Progres, 1970, Volume: 16

    Topics: Animals; Body Weight; Drug Combinations; Drug Resistance, Microbial; Evaluation Studies as Topic; Guinea Pigs; Humans; Lung; Mice; Microbial Sensitivity Tests; Mycobacterium; Mycobacterium bovis; Mycobacterium tuberculosis; Organ Size; Rifampin; Spleen; Sputum; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

1970
[Progress in the treatment of tuberculosis. Isoniazid plus rifomycin plus myambutol equals standard therapy].
    Deutsche medizinische Wochenschrift (1946), 1970, Jan-16, Volume: 95, Issue:3

    Topics: Aminosalicylic Acids; Antitubercular Agents; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis; Tuberculosis, Pulmonary

1970
Rifampicin.
    Drug and therapeutics bulletin, 1970, Jan-30, Volume: 8, Issue:3

    Topics: Female; Humans; Leprosy; Pregnancy; Rifampin; Tuberculosis

1970
[Current views on drug treatment of tuberculosis].
    Nordisk medicin, 1970, Jun-25, Volume: 83, Issue:26

    Topics: Antitubercular Agents; Ethambutol; Humans; Rifampin; Tuberculosis

1970
[Rifampicin--a new antitubercular drug].
    Gruzlica i choroby pluc; tuberculosis et pneumonologia, 1970, Volume: 38, Issue:2

    Topics: Antitubercular Agents; Rifampin; Tuberculosis

1970
[Monotherapy and combined therapy using rifampicin in 156 tuberculous patients].
    Praxis der Pneumologie, 1970, Volume: 24, Issue:3

    Topics: Adult; Aged; Antitubercular Agents; Female; Humans; Male; Middle Aged; Rifampin; Sputum; Tuberculosis; Tuberculosis, Laryngeal; Tuberculosis, Pulmonary

1970
Rifampin, new hope in the fight against tuberculosis.
    The New England journal of medicine, 1970, Sep-17, Volume: 283, Issue:12

    Topics: Humans; Isoniazid; Rifampin; Tuberculosis

1970
The action of rifampin alone and in combination with other antituberculous drugs.
    The American review of respiratory disease, 1970, Volume: 102, Issue:3

    Topics: Drug Resistance, Microbial; Drug Synergism; Ethambutol; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1970
[Modern chemotherapy of tuberculosis].
    Munchener medizinische Wochenschrift (1950), 1970, May-22, Volume: 112, Issue:21

    Topics: Adolescent; Adult; Age Factors; Antitubercular Agents; Berlin; Child; Child, Preschool; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Ethionamide; Humans; Infant; Isoniazid; Middle Aged; Rifampin; Streptomycin; Time Factors; Tuberculin Test; Tuberculosis

1970
[Pharmacogenetic and interaction-model with some usual antitubercular agents].
    Nordisk medicin, 1970, Sep-17, Volume: 84, Issue:38

    Topics: Aminosalicylic Acids; Humans; Isoniazid; Rifampin; Tuberculosis

1970
[New drugs in the treatment of primary tuberculosis].
    Annales de pediatrie, 1970, Oct-02, Volume: 17, Issue:10

    Topics: Aminosalicylic Acids; Child; Child, Preschool; Ethambutol; Female; France; Humans; Isoniazid; Male; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

1970
[Research on the protective action of rifampicin administered intermittently in experimental tuberculosis in guinea pigs].
    Annales de pediatrie, 1970, Oct-02, Volume: 17, Issue:10

    Topics: Animals; Guinea Pigs; Isoniazid; Rifampin; Tuberculosis

1970
[Clinical and therapeutic study of Rifampicine, apropos of 246 tuberculous patients treated with antibiotic association].
    Marseille medical, 1970, Volume: 107, Issue:10

    Topics: Anti-Bacterial Agents; Humans; Microbial Sensitivity Tests; Radiography; Rifampin; Tomography; Tuberculosis; Tuberculosis, Pulmonary

1970
[Antituberculous activity of rifampicin for the experimental tuberculosis of guinea pigs].
    Kekkaku : [Tuberculosis], 1970, Volume: 45, Issue:11

    Topics: Animals; Body Weight; Female; Guinea Pigs; Piperidines; Rifampin; Tuberculosis

1970
[Current views on drug treatment of tuberculosis].
    Duodecim; laaketieteellinen aikakauskirja, 1970, Volume: 86, Issue:21

    Topics: Adrenal Cortex Hormones; Aminosalicylic Acids; Anti-Bacterial Agents; Antitubercular Agents; Ethambutol; Ethionamide; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1970
Jaundice associated with rifampicin.
    Tubercle, 1970, Volume: 51, Issue:3

    Topics: Aged; Alkaline Phosphatase; Chemical and Drug Induced Liver Injury; Drug Synergism; Female; Humans; Isoniazid; Liver; Liver Function Tests; Middle Aged; Rifampin; Tuberculosis

1970
[A new and powerful anti-tubercular drug: rifampicin].
    Maroc medical, 1970, Volume: 537

    Topics: Drug Resistance, Microbial; Drug Synergism; Drug Tolerance; Ethambutol; Humans; Infusions, Parenteral; Isoniazid; Rifampin; Streptomyces; Tuberculosis

1970
[Jaundice epidemiology in 1,974 hospitalized tubercular patients, treated or untreated by rifampicin].
    Revue de tuberculose et de pneumologie, 1970, Volume: 34, Issue:2

    Topics: Drug Synergism; Humans; Isoniazid; Jaundice; Rifampin; Tuberculosis; Tuberculosis, Hepatic

1970
Specific action of some drugs on Bechterew nystagmus.
    Acta oto-rhino-laryngologica Belgica, 1970, Volume: 24, Issue:5

    Topics: Animals; Antitubercular Agents; Humans; Labyrinth Diseases; Nystagmus, Pathologic; Rabbits; Rifampin; Streptomycin; Tuberculosis

1970
[A new and powerful anti-tubercular drug: rifampicin].
    Voenno-meditsinskii zhurnal, 1970, Volume: 8

    Topics: Drug Resistance, Microbial; Drug Synergism; Drug Tolerance; Ethambutol; Humans; Infusions, Parenteral; Isoniazid; Rifampin; Streptomyces; Tuberculosis

1970
Rifampicin, isoniazid, ethambutol, ethionamide, and streptomycin in murine tuberculosis: comparative chemotherapeutic studies.
    Antibiotica et chemotherapia. Fortschritte. Advances. Progres, 1970, Volume: 16

    Topics: Administration, Oral; Animals; Drug Combinations; Ethambutol; Ethionamide; Evaluation Studies as Topic; Isoniazid; Mice; Rifampin; Streptomycin; Time Factors; Tuberculosis

1970
Consequences of the development of new antituberculous drugs for the treatment of tuberculosis.
    Antibiotica et chemotherapia. Fortschritte. Advances. Progres, 1970, Volume: 16

    Topics: Aminosalicylic Acids; Antitubercular Agents; Drug Combinations; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Rifampin; Streptomycin; Tuberculosis

1970
Experimental therapy with rifampicin.
    Antibiotica et chemotherapia. Fortschritte. Advances. Progres, 1970, Volume: 16

    Topics: Animals; Drug Combinations; Drug Resistance, Microbial; Ethambutol; Ethionamide; Isoniazid; Mice; Mycobacterium Infections; Phenylthiourea; Rifampin; Streptomycin; Time Factors; Tuberculosis

1970
The suitability of new drugs for intermittent chemotherapy of tuberculosis. An experimental study.
    Scandinavian journal of respiratory diseases. Supplementum, 1969, Volume: 69

    Topics: Animals; Ethambutol; Ethionamide; Guinea Pigs; Isoniazid; Mycobacterium tuberculosis; Rifampin; Streptomycin; Thioacetazone; Tuberculosis

1969
[Algodystrophy associated with antitubercular chemotherapy: 22 cases].
    Revue du rhumatisme et des maladies osteo-articulaires, 1969, Volume: 36, Issue:6

    Topics: Adult; Antitubercular Agents; Cycloserine; Ethambutol; Ethionamide; Female; Humans; Isoniazid; Male; Niacinamide; Pyrazinamide; Reflex Sympathetic Dystrophy; Rifampin; Tuberculosis; Vitamin B Deficiency

1969
Rifampin--a major new chemotherapeutic agent for the treatment of tuberculosis.
    The New England journal of medicine, 1969, Mar-13, Volume: 280, Issue:11

    Topics: Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Mycobacterium; Mycobacterium tuberculosis; Rifampin; Streptomyces; Streptomycin; Tuberculosis

1969
Experimental observations on the antimycobacterial activity of rifampin.
    Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.), 1969, Volume: 131, Issue:2

    Topics: Animals; Antitubercular Agents; Culture Media; Drug Synergism; In Vitro Techniques; Methods; Mice; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1969
[Drug therapy of tuberculosis. Advanced training and working conference at the Central Hospital Gauting of the State Insurance Company of Upper Bavaria on Nov. 9, 1968].
    Medizinische Klinik, 1969, Volume: 64, Issue:26

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Ethionamide; Germany, West; Hospitals, Convalescent; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1969
[Rifampicin inhibitory titer in wild strains of Mycobacterium and Rifampicin serum concentrations in tuberculous patients].
    Beitrage zur Klinik und Erforschung der Tuberkulose und der Lungenkrankheiten, 1969, Volume: 140, Issue:1

    Topics: Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1969
Rifampicin in daily and intermittent treatment of experimental murine tuberculosis, with emphasis on late results.
    Tubercle, 1969, Volume: 50, Issue:3

    Topics: Animals; Ethambutol; Ethionamide; Follow-Up Studies; Isoniazid; Lung; Mice; Mycobacterium tuberculosis; Rifampin; Spleen; Streptomycin; Tuberculosis

1969
Rifampicin in treatment of experimental tuberculosis in mice.
    Tubercle, 1969, Volume: 50, Issue:3

    Topics: Animals; Drug Synergism; Isoniazid; Lung; Male; Mice; Mycobacterium tuberculosis; Rifampin; Spleen; Tuberculosis

1969
Rifampicin activity "in vitro" and in established tuberculosis in mice.
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Animals; Drug Resistance, Microbial; Drug Synergism; In Vitro Techniques; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1969
[Incidence and significance of positive fluorescent bacilloscopy associated with negative cultures during treatment based on isoniazid or rifomycin in tubercular patients treated in the sanatorium].
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Drug Synergism; Hospitals, Special; Humans; Isoniazid; Microbial Sensitivity Tests; Microscopy, Fluorescence; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1969
[Rifomycin in treatment of tuberculosis with polyresistant mycobacteria: clinical and laboratory observations].
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Drug Resistance, Microbial; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1969
New treatment for tuberculosis.
    Nursing mirror and midwives journal, 1969, Dec-12, Volume: 130, Issue:24

    Topics: Antitubercular Agents; Rifampin; Tuberculosis

1969
[Intermittent treatment with Rifampicin in experimental tuberculosis in guinea pigs].
    Archivio di tisiologia e delle malattie dell'apparato respiratorio, 1969, Volume: 24, Issue:12

    Topics: Analysis of Variance; Animals; Guinea Pigs; Rifampin; Spleen; Tuberculosis

1969
Rifampicin.
    Tubercle, 1969, Volume: 50, Issue:3

    Topics: Bronchitis; Chronic Disease; Drug Resistance, Microbial; Drug Synergism; Economics, Medical; Ethambutol; Humans; Isoniazid; Rifampin; Tuberculosis

1969
[Round table discussion of Rifampicin. Turin, 18 December 1968].
    Minerva medica, 1969, Dec-01, Volume: 60, Issue:96

    Topics: Humans; Infections; Rifampin; Tuberculosis

1969
[The new antibiotic Rifampicin in the therapy of infectious diseases with special reference to acute respiratory tract infections].
    Minerva medica, 1969, Dec-01, Volume: 60, Issue:96

    Topics: Abscess; Adult; Aged; Female; Humans; Male; Middle Aged; Respiratory Tract Infections; Rifampin; Tonsillitis; Tuberculosis; Urinary Tract Infections

1969
Pharmacology--toxicology: introductory remarks on rifampicin.
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Humans; Rifampin; Tuberculosis

1969
Structure-activity relationships of rifamycin derivatives.
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Chemical Phenomena; Chemistry; Humans; Rifampin; Tuberculosis

1969
Comparison of rifampicin serum concentrations in men, following drug administration before or after breakfast.
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Humans; Rifampin; Tuberculosis

1969
[Pharmacokinetics of rifomycin].
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Animals; Guinea Pigs; Humans; Rifampin; Tuberculosis

1969
[Study of plasma levels of rifomycin and their variations (440 analyses)].
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Humans; Rifampin; Tuberculosis

1969
[Experimental research on otovestibular toxicity of rifomycin].
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Animals; Ear, Inner; Mice; Rabbits; Rifampin; Tuberculosis

1969
[Rifomycin in continuous and intermittent combined treatment of experimental tuberculosis in mice].
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Animals; Drug Synergism; Isoniazid; Mice; Rifampin; Streptomycin; Tuberculosis

1969
Rifampicin blood levels in man.
    Acta tuberculosea et pneumologica Belgica, 1969, Volume: 60, Issue:3

    Topics: Adult; Female; Humans; Male; Middle Aged; Rifampin; Tuberculosis

1969
Simple procedures for checking rifampin in urine.
    The American review of respiratory disease, 1969, Volume: 100, Issue:5

    Topics: Humans; Methods; Rifampin; Tuberculosis

1969
[Rifampicin].
    Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke, 1969, Dec-15, Volume: 89, Issue:24

    Topics: Rifampin; Tuberculosis

1969
[Tuberculoid leprosy treated with rifampicin].
    Bulletin de la Societe francaise de dermatologie et de syphiligraphie, 1969, Volume: 76, Issue:6

    Topics: Adult; Humans; Leprosy; Male; Rifampin; Tuberculosis

1969
[Rifampicin; its value and its limitations in tuberculosis, chronic or of severe onset, with or without associated ethambutol].
    Revue de tuberculose et de pneumologie, 1969, Volume: 33, Issue:2

    Topics: Adult; Aged; Drug Synergism; Ethambutol; Female; Humans; Male; Middle Aged; Rifampin; Tooth Diseases; Tuberculosis; Tuberculosis, Pulmonary

1969
[Observations on the use of Rifampicinin dermatovenereology].
    Minerva medica, 1969, Dec-01, Volume: 60, Issue:96

    Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Female; Humans; Lupus Vulgaris; Male; Middle Aged; Rifampin; Sexually Transmitted Diseases; Skin Diseases; Tuberculosis

1969
[Antitubercular chemotherapy and the progress realized by various new drugs].
    La Revue lyonnaise de medecine, 1969, May-15, Volume: 18, Issue:9

    Topics: Adult; Antitubercular Agents; Ethambutol; Humans; Male; Middle Aged; Pyrazines; Rifampin; Tuberculosis

1969
[Rifampicin and isoniazid in the intermittent treatment of experimental tuberculosis in guinea-pigs].
    Annali dell'Istituto "Carlo Forlanini", 1969, Volume: 29, Issue:1

    Topics: Animals; Drug Synergism; Guinea Pigs; Isoniazid; Rifampin; Tuberculin Test; Tuberculosis

1969
Chemotherapy of drug-resistant tuberculosis.
    British medical journal, 1969, Aug-30, Volume: 3, Issue:5669

    Topics: Anti-Bacterial Agents; Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Humans; Rifampin; Tuberculosis

1969
New drugs active against tuberculosis.
    Connecticut medicine, 1969, Volume: 33, Issue:8

    Topics: Animals; Ethambutol; Female; Humans; Mice; Rifampin; Tuberculosis

1969
Rifampicin desacetylation in the human organism.
    Arzneimittel-Forschung, 1969, Volume: 19, Issue:4

    Topics: Bile; Chromatography, Thin Layer; Humans; Rifampin; Spectrophotometry; Tuberculosis

1969
[Treatment with new antitubercular agents].
    Deutsche medizinische Wochenschrift (1946), 1968, Nov-22, Volume: 93, Issue:47

    Topics: Antitubercular Agents; Cycloserine; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Ethionamide; Humans; Mycobacterium tuberculosis; Phenylthiourea; Pyrazinamide; Rifampin; Thiosemicarbazones; Tuberculosis; Viomycin

1968
[Experimental evaluation of the antimycobacterial activity of rifampicin].
    Archivio di tisiologia e delle malattie dell'apparato respiratorio, 1968, Volume: 23, Issue:4

    Topics: Animals; Drug Synergism; Guinea Pigs; Isoniazid; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis

1968
[On the comparative effectiveness of rifampicin and INI treatment in guinea pigs inoculated with repeated microdoses of bacilli].
    Archivio di tisiologia e delle malattie dell'apparato respiratorio, 1968, Volume: 23, Issue:6

    Topics: Animals; Drug Resistance, Microbial; Guinea Pigs; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1968
[Chemotherapy of tuberculosis today with special consideration of capreomycin, ethambutol and rifampicin].
    Praxis der Pneumologie, 1968, Volume: 22, Issue:12

    Topics: Antitubercular Agents; Drug Resistance, Microbial; Ethambutol; Humans; Rifampin; Tuberculosis

1968
[Intermittent rifomycin therapy of experimental tuberculosis in guinea pigs].
    Annali dell'Istituto "Carlo Forlanini", 1968, Volume: 28, Issue:4

    Topics: Animals; Body Weight; Drug Synergism; Ethambutol; Guinea Pigs; Isoniazid; Rifampin; Tuberculosis

1968
Activity of rifampicin in experimental tuberculosis of the guinea pig.
    Chemotherapy, 1967, Volume: 12, Issue:6

    Topics: Animals; Antitubercular Agents; Guinea Pigs; Isoniazid; Lung Diseases; Lymph Nodes; Mycobacterium tuberculosis; Organ Size; Rifampin; Skin Ulcer; Spleen; Splenic Diseases; Tuberculin Test; Tuberculosis

1967
[Experimental research on the antimycobacterial activity of rifampicine: 3-(4-methyl-l-piperazinyl-iminomethyl)-rifomycin SV].
    Annali dell'Istituto "Carlo Forlanini", 1967, Volume: 27, Issue:2

    Topics: Animals; Guinea Pigs; In Vitro Techniques; Mice; Mycobacterium; Mycobacterium tuberculosis; Rifampin; Tuberculosis

1967
[On the bactericidal activity in vivo of Rifampicin alone or associated with isoniazid].
    Archivio di tisiologia e delle malattie dell'apparato respiratorio, 1967, Volume: 22, Issue:10

    Topics: Animals; Guinea Pigs; Isoniazid; Mycobacterium tuberculosis; Rifampin; Spleen; Tuberculosis

1967
[Activity of Rifampicin associated with other drugs on experimental tuberculosis in guinea pigs].
    Archivio di tisiologia e delle malattie dell'apparato respiratorio, 1967, Volume: 22, Issue:10

    Topics: Animals; Guinea Pigs; Isoniazid; Rifampin; Streptomycin; Tuberculosis

1967
[Serum levels of Rifampciin as a function of the posology and mode of administration].
    Archivio di tisiologia e delle malattie dell'apparato respiratorio, 1967, Volume: 22, Issue:5

    Topics: Female; Humans; Male; Rifampin; Tuberculosis

1967
Rifampicin: a new rifamycin. II. Laboratory studies on the antituberculous activity and preliminary clinical observations.
    Arzneimittel-Forschung, 1967, Volume: 17, Issue:5

    Topics: Adolescent; Adult; Aminosalicylic Acids; Animals; Guinea Pigs; Humans; Isoniazid; Mice; Middle Aged; Mycobacterium; Protein Binding; Rifampin; Streptomycin; Tuberculosis

1967
[The antimycobacterial activity of rifamycin B diethylamide].
    Archivio di tisiologia e delle malattie dell'apparato respiratorio, 1966, Volume: 21, Issue:5

    Topics: Animals; Guinea Pigs; Rifampin; Tuberculosis

1966
Chest diseases in Italy.
    Diseases of the chest, 1966, Volume: 50, Issue:2

    Topics: Antitubercular Agents; Bronchitis; Cycloserine; Humans; Italy; Lung Diseases; Lung Neoplasms; Pyrazines; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

1966
Chemotherapeutic activity of new derivatives of rifamycin.
    Antimicrobial agents and chemotherapy, 1966, Volume: 6

    Topics: Animals; Mice; Rifampin; Staphylococcal Infections; Tuberculosis

1966