rifampin and Tuberculosis--Pulmonary

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

In December 2022 World Health Organization released a new treatment for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) guideline. The main novelty of this update is two new recommendations (i) a 6-month treatment regimen composed of bedaquiline, pretomanid, linezolid (600 mg), and moxifloxacin (BPaLM) is recommended in place of the 9-month or longer (18-month) regimens in MDR/RR-TB patients, now including extensive pulmonary TB and extrapulmonary TB (except TB involving central nervous system, miliary TB and osteoarticular TB); (ii) the use of the 9-month all-oral regimen rather than longer (18-months) regimen is suggested in patients with MDR/RR-TB and in whom resistance to fluoroquinolones has been excluded. Longer (18-month) treatments remain a valid option in all cases in which shorter regimens cannot be implemented due to intolerance, drug-drug interactions, extensively drug-resistant tuberculosis, extensive forms of extrapulmonary TB, or previous failure. The new guidelines represent a milestone in MDR/RR-TB treatment landscape, setting the basis for a shorter, all-oral, more acceptable, equitable, and patient-centered model for MDR/RR-TB management. However, some challenges remain to be addressed to allow full implementation of the new recommendations.

Topics: Antitubercular Agents; Extensively Drug-Resistant Tuberculosis; Humans; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The GeneXpert MTB/RIF assay (Xpert) is a diagnostic tool that has been shown to significantly improve the accuracy of tuberculosis (TB) detection in clinical settings, with advanced sensitivity and specificity. Early detection of TB can be challenging, but Xpert has improved the efficacy of the diagnostic process. Nevertheless, the accuracy of Xpert varies according to different diagnostic specimens and TB infection sites. Therefore, the selection of adequate specimens is critical when using Xpert to identify suspected TB. As such, we have conducted a meta-analysis to evaluate the effectiveness of Xpert for diagnosis of different TB types using several specimens.. We conducted a comprehensive search of several electronic databases, including PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the World Health Organization clinical trials registry center, covering studies published from Jan 2008 to July 2022. Data were extracted using an adapted version of the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies. Where appropriate, meta-analysis was performed using random-effects models. The risk of bias and level of evidence was assessed using the Quality in Prognosis Studies tool and a modified version of the Grading of Recommendations Assessment, Development, and Evaluation. RStudio was utilized to analyze the results, employing the. After excluding duplicates, a total of 2163 studies were identified, and ultimately, 144 studies from 107 articles were included in the meta-analysis based on predetermined inclusion and exclusion criteria. Sensitivity, specificity and diagnostic accuracy were estimated for various specimens and TB types. In the case of pulmonary TB, Xpert using sputum (0.95 95%CI 0.91-0.98) and gastric juice (0.94 95%CI 0.84-0.99) demonstrated similarly high sensitivity, surpassing other specimen types. Additionally, Xpert exhibited high specificity for detecting TB across all specimen types. For bone and joint TB, Xpert, based on both biopsy and joint fluid specimens, demonstrated high accuracy in TB detection. Furthermore, Xpert effectively detected unclassified extrapulmonary TB and tuberculosis lymphadenitis. However, the Xpert accuracy was not satisfactory to distinguish TB meningitis, tuberculous pleuritis and unclassified TB.. Xpert has exhibited satisfactory diagnostic accuracy for most TB infections, but the efficacy of detection may vary depending on the specimens analyzed. Therefore, selecting appropriate specimens for Xpert analysis is essential, as using inadequate specimens can reduce the ability to distinguish TB.. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=370111, identifier CRD42022370111.

Topics: Antibiotics, Antitubercular; Humans; Latent Tuberculosis; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal; Tuberculosis, Pulmonary

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

To evaluate and update the evidence on the comparative efficacy and safety of antimicrobial drugs regimens for treating pulmonary drug-susceptible tuberculosis (DS-TB).. A systematic review was performed with searches in PubMed and Scopus (PROSPERO-CRD42019141463). We included randomised controlled trials comparing the effect of any antimicrobial regimen lasting at least 2 weeks. The outcomes of interest were culture conversion and incidence of adverse events. Bayesian network meta-analyses and surface under the cumulative ranking curve (SUCRA) analyses were performed. Results were reported as odds ratio with 95% credibility intervals.. Fifteen studies were included the meta-analysis (n = 7560 patients). No regimen was statistically more effective than the WHO standard approach (rifampicin, isoniazid, ethambutol, and pyrazinamide). The use of rifapentine 450 mg instead of rifampicin in the standard regimen demonstrated to be statistically safer than all other options for serious adverse events (e.g. hepatotoxicity, arthralgia) (OR ranging from 0.0 [Crl 0.00-0.04] to 0.0 [0.00-0.97]; SUCRA probabilities of 10%). Therapies containing rifapentine (Rp1500HEZ, Rp900HEZ) and moxifloxacin (RMEZ, RHMZ) are effective regarding culture conversion, but statistical uncertainty on their safety profile exists.. The WHO standard regimen remains an overall effective and safe alternative for DS-TB. For intensive phase treatments, drugs combinations with rifapentine and moxifloxacin seem to reduce treatment duration while maintaining efficacy.

Topics: Antitubercular Agents; Bayes Theorem; Drug Therapy, Combination; Humans; Moxifloxacin; Network Meta-Analysis; Rifampin; Tuberculosis, Pulmonary

The World Health Organization (WHO) End TB Strategy stresses universal access to drug susceptibility testing (DST). DST determines whether Mycobacterium tuberculosis bacteria are susceptible or resistant to drugs. Xpert MTB/XDR is a rapid nucleic acid amplification test for detection of tuberculosis and drug resistance in one test suitable for use in peripheral and intermediate level laboratories. In specimens where tuberculosis is detected by Xpert MTB/XDR, Xpert MTB/XDR can also detect resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin.. To assess the diagnostic accuracy of Xpert MTB/XDR for pulmonary tuberculosis in people with presumptive pulmonary tuberculosis (having signs and symptoms suggestive of tuberculosis, including cough, fever, weight loss, night sweats). To assess the diagnostic accuracy of Xpert MTB/XDR for resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin in people with tuberculosis detected by Xpert MTB/XDR, irrespective of rifampicin resistance (whether or not rifampicin resistance status was known) and with known rifampicin resistance.. We searched multiple databases to 23 September 2021. We limited searches to 2015 onwards as Xpert MTB/XDR was launched in 2020.. Diagnostic accuracy studies using sputum in adults with presumptive or confirmed pulmonary tuberculosis. Reference standards were culture (pulmonary tuberculosis detection); phenotypic DST (pDST), genotypic DST (gDST),composite (pDST and gDST) (drug resistance detection).. Two review authors independently reviewed reports for eligibility and extracted data using a standardized form. For multicentre studies, we anticipated variability in the type and frequency of mutations associated with resistance to a given drug at the different centres and considered each centre as an independent study cohort for quality assessment and analysis. We assessed methodological quality with QUADAS-2, judging risk of bias separately for each target condition and reference standard. For pulmonary tuberculosis detection, owing to heterogeneity in participant characteristics and observed specificity estimates, we reported a range of sensitivity and specificity estimates and did not perform a meta-analysis. For drug resistance detection, we performed meta-analyses by reference standard using bivariate random-effects models. Using GRADE, we assessed certainty of evidence of Xpert MTB/XDR accuracy for detection of resistance to isoniazid and fluoroquinolones in people irrespective of rifampicin resistance and to ethionamide and amikacin in people with known rifampicin resistance, reflecting real-world situations. We used pDST, except for ethionamide resistance where we considered gDST a better reference standard.. We included two multicentre studies from high multidrug-resistant/rifampicin-resistant tuberculosis burden countries, reporting on six independent study cohorts, involving 1228 participants for pulmonary tuberculosis detection and 1141 participants for drug resistance detection. The proportion of participants with rifampicin resistance in the two studies was 47.9% and 80.9%. For tuberculosis detection, we judged high risk of bias for patient selection owing to selective recruitment. For ethionamide resistance detection, we judged high risk of bias for the reference standard, both pDST and gDST, though we considered gDST a better reference standard. Pulmonary tuberculosis detection - Xpert MTB/XDR sensitivity range, 98.3% (96.1 to 99.5) to 98.9% (96.2 to 99.9) and specificity range, 22.5% (14.3 to 32.6) to 100.0% (86.3 to 100.0); median prevalence of pulmonary tuberculosis 91.3%, (interquartile range, 89.3% to 91.8%), (2 studies; 1 study reported on 2 cohorts, 1228 participants; very low-certainty evidence, sensitivity and specificity). Drug resistance detection People irrespective of rifampicin resistance - Isoniazid resistance: Xpert MTB/XDR summary sensitivity and specificity (95% confidence interval (CI)) were 94.2% (87.5 to 97.4) and 98.5% (92.6 to 99.7) against pDST, (6 cohorts, 1083 participants, moderate-certainty evidence, sensitivity and specificity). - Fluoroquinolone resistance: Xpert MTB/XDR summary sensitivity and specificity were 93.2% (88.1 to 96.2) and 98.0% (90.8 to 99.6) against pDST, (6 cohorts, 1021 participants; high-certainty evidence, sensitivity; moderate-certainty evidence, specificity). People with known rifampicin resistance - Ethionamide resistance: Xpert MTB/XDR summary sensitivity and specificity were 98.0% (74.2 to 99.9) and 99.7% (83.5 to 100.0) against gDST, (4 cohorts, 434 participants; very low-certainty evidence, sensitivity and specificity). - Amikacin resistance: Xpert MTB/XDR summary sensitivity and specificity were 86.1% (75.0 to 92.7) and 98.9% (93.0 to 99.8) against pDST, (4 cohorts, 490 participants; low-certainty evidence, sensitivity; high-certainty evidence, specificity). Of 1000 people with pulmonary tuberculosis, detected as tuberculosis by Xpert MTB/XDR: - where 50 have isoniazid resistance, 61 would have an Xpert MTB/XDR result indicating isoniazid resistance: of these, 14/61 (23%) would not have isoniazid resistance (FP); 939 (of 1000 people) would have a result indicating the absence of isoniazid resista. Review findings suggest that, in people determined by Xpert MTB/XDR to be tuberculosis-positive, Xpert MTB/XDR provides accurate results for detection of isoniazid and fluoroquinolone resistance and can assist with selection of an optimised treatment regimen. Given that Xpert MTB/XDR targets a limited number of resistance variants in specific genes, the test may perform differently in different settings. Findings in this review should be interpreted with caution. Sensitivity for detection of ethionamide resistance was based only on Xpert MTB/XDR detection of mutations in the inhA promoter region, a known limitation. High risk of bias limits our confidence in Xpert MTB/XDR accuracy for pulmonary tuberculosis. Xpert MTB/XDR's impact will depend on its ability to detect tuberculosis (required for DST), prevalence of resistance to a given drug, health care infrastructure, and access to other tests.

Topics: Adult; Amikacin; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Ethionamide; Fluoroquinolones; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Lymph Node; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Every year, an estimated one million children and young adolescents become ill with tuberculosis, and around 226,000 of those children die. Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that simultaneously detects Mycobacterium tuberculosis complex and rifampicin resistance. We previously published a Cochrane Review 'Xpert MTB/RIF and Xpert MTB/RIF Ultra assays for tuberculosis disease and rifampicin resistance in children'. The current review updates evidence on the diagnostic accuracy of Xpert Ultra in children presumed to have tuberculosis disease. Parts of this review update informed the 2022 WHO updated guidance on management of tuberculosis in children and adolescents.. To assess the diagnostic accuracy of Xpert Ultra for detecting: pulmonary tuberculosis, tuberculous meningitis, lymph node tuberculosis, and rifampicin resistance, in children with presumed tuberculosis. Secondary objectives To investigate potential sources of heterogeneity in accuracy estimates. For detection of tuberculosis, we considered age, comorbidity (HIV, severe pneumonia, and severe malnutrition), and specimen type as potential sources. To summarize the frequency of Xpert Ultra trace results.. We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, three other databases, and three trial registers without language restrictions to 9 March 2021.. Cross-sectional and cohort studies and randomized trials that evaluated Xpert Ultra in HIV-positive and HIV-negative children under 15 years of age. We included ongoing studies that helped us address the review objectives. We included studies evaluating sputum, gastric, stool, or nasopharyngeal specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), and fine needle aspirate or surgical biopsy tissue (lymph node tuberculosis). For detecting tuberculosis, reference standards were microbiological (culture) or composite reference standard; for stool, we also included Xpert Ultra performed on a routine respiratory specimen. For detecting rifampicin resistance, reference standards were drug susceptibility testing or MTBDRplus.. Two review authors independently extracted data and, using QUADAS-2, assessed methodological quality judging risk of bias separately for each target condition and reference standard. For each target condition, we used the bivariate model to estimate summary sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We summarized the frequency of Xpert Ultra trace results; trace represents detection of a very low quantity of Mycobacterium tuberculosis DNA. We assessed certainty of evidence using GRADE.. We identified 14 studies (11 new studies since the previous review). For detection of pulmonary tuberculosis, 335 data sets (25,937 participants) were available for analysis. We did not identify any studies that evaluated Xpert Ultra accuracy for tuberculous meningitis or lymph node tuberculosis. Three studies evaluated Xpert Ultra for detection of rifampicin resistance. Ten studies (71%) took place in countries with a high tuberculosis burden based on WHO classification. Overall, risk of bias was low. Detection of pulmonary tuberculosis Sputum, 5 studies Xpert Ultra summary sensitivity verified by culture was 75.3% (95% CI 64.3 to 83.8; 127 participants; high-certainty evidence), and specificity was 97.1% (95% CI 94.7 to 98.5; 1054 participants; high-certainty evidence). Gastric aspirate, 7 studies Xpert Ultra summary sensitivity verified by culture was 70.4% (95% CI 53.9 to 82.9; 120 participants; moderate-certainty evidence), and specificity was 94.1% (95% CI 84.8 to 97.8; 870 participants; moderate-certainty evidence). Stool, 6 studies Xpert Ultra summary sensitivity verified by culture was 56.1% (95% CI 39.1 to 71.7; 200 participants; moderate-certainty evidence), and specificity was 98.0% (95% CI 93.3 to 99.4; 1232 participants; high certainty-evidence). Nasopharyngeal aspirate, 4 studies Xpert Ultra summary sensitivity verified by culture was 43.7% (95% CI 26.7 to 62.2; 46 participants; very low-certainty evidence), and specificity was 97.5% (95% CI 93.6 to 99.0; 489 participants; high-certainty evidence). Xpert Ultra sensitivity was lower against a composite than a culture reference standard for all specimen types other than nasopharyngeal aspirate, while specificity was similar against both reference standards. Interpretation of results In theory, for a population of 1000 children: • where 100 have pulmonary tuberculosis in sputum (by culture): - 101 would be Xpert Ultra-positive, and of these, 26 (26%) would not have pulmonary tuberculosis (false positive); and - 899 would be Xpert Ultra-negative, and of these, 25 (3%) would have tuberculosis (false negative). • where 100 have pulmonary tuberculosis in gastric aspirate (by culture): - 123 would be Xpert Ultra-positive, and of these, 53 (43%) would not have pulmonary tuberculosis (false positive); and - 877 would be Xpert Ultra-negative, and of these, 30 (3%) would have tuberculosis (false negative). • where 100 have pulmonary tuberculosis in stool (by culture): - 74 would be Xpert Ultra-positive. We found Xpert Ultra sensitivity to vary by specimen type, with sputum having the highest sensitivity, followed by gastric aspirate and stool. Nasopharyngeal aspirate had the lowest sensitivity. Xpert Ultra specificity was high against both microbiological and composite reference standards. However, the evidence base is still limited, and findings may be imprecise and vary by study setting. Although we found Xpert Ultra accurate for detection of rifampicin resistance, results were based on a very small number of studies that included only three children with rifampicin resistance. Therefore, findings should be interpreted with caution. Our findings provide support for the use of Xpert Ultra as an initial rapid molecular diagnostic in children being evaluated for tuberculosis.

Topics: Adolescent; Antibiotics, Antitubercular; Child; Cross-Sectional Studies; HIV Infections; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Pulmonary

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

The performance of Xpert MTB/RIF using bronchoalveolar lavage fluid (BAL) for the diagnosis of pulmonary tuberculosis (PTB) remains unclear. Therefore, a systematic review/meta-analysis was conducted. Studies published before 31 December 2019 were retrieved from the PubMed, Embase, and Web of Science databases using the keywords "pulmonary tuberculosis," "Xpert MTB/RIF," and "BAL." Two independent evaluators extracted the data and assessed the bias risk of the included studies. A random-effects model was used to calculate the overall sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR, respectively), diagnostic odds ratio (DOR), and the area under the curve (AUC), as well as the respective 95% confidence intervals (CIs). Nineteen trials involving 3,019 participants met the inclusion criteria. Compared to the culture method, the pooled sensitivity, specificity, PLR, NLR, DOR, and the AUC with 95% CIs of Xpert MTB/RIF were 0.87 (0.84 to 0.90), 0.92 (0.91 to 0.93), 10.21 (5.78 to 18.02), 0.16 (0.12 to 0.22), 78.95 (38.59 to 161.53), and 0.9467 (0.9462 to 0.9472), respectively. Relative to the composite reference standard, the observed values were 0.69 (0.65 to 0.72), 0.98 (0.98 to 0.99), 37.50 (18.59 to 75.62), 0.30 (0.21 to 0.43), 171.98 (80.82 to 365.96), and 0.9691 (0.9683 to 0.9699), respectively. All subgroups, except children, showed high sensitivity and specificity. In conclusion, the use of Xpert MTB/RIF in the context of BAL samples has a high diagnostic performance for PTB (except for children) and may serve as an alternative rapid diagnostic tool.

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

Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Ultra) are World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. This review builds on our recent extensive Cochrane Review of Xpert MTB/RIF accuracy.. To compare the diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for the detection of pulmonary tuberculosis and detection of rifampicin resistance in adults with presumptive pulmonary tuberculosis. For pulmonary tuberculosis and rifampicin resistance, we also investigated potential sources of heterogeneity. We also summarized the frequency of Xpert Ultra trace-positive results, and estimated the accuracy of Xpert Ultra after repeat testing in those with trace-positive results.. We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, LILACS, Scopus, the WHO ICTRP, the ISRCTN registry, and ProQuest to 28 January 2020 with no language restriction.. We included diagnostic accuracy studies using respiratory specimens in adults with presumptive pulmonary tuberculosis that directly compared the index tests. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based drug susceptibility testing and line probe assays.. Two review authors independently extracted data using a standardized form, including data by smear and HIV status. We assessed risk of bias using QUADAS-2 and QUADAS-C. We performed meta-analyses comparing pooled sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection, and separately by reference standard. Most analyses used a bivariate random-effects model. For tuberculosis detection, we estimated accuracy in studies in participants who were not selected based on prior microscopy testing or history of tuberculosis. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarized Xpert Ultra trace results.. We identified nine studies (3500 participants): seven had unselected participants (2834 participants). All compared Xpert Ultra and Xpert MTB/RIF for pulmonary tuberculosis detection; seven studies used a paired comparative accuracy design, and two studies used a randomized design. Five studies compared Xpert Ultra and Xpert MTB/RIF for rifampicin resistance detection; four studies used a paired design, and one study used a randomized design. Of the nine included studies, seven (78%) were mainly or exclusively in high tuberculosis burden countries. For pulmonary tuberculosis detection, most studies had low risk of bias in all domains. Pulmonary tuberculosis detection Xpert Ultra pooled sensitivity and specificity (95% credible interval) against culture were 90.9% (86.2 to 94.7) and 95.6% (93.0 to 97.4) (7 studies, 2834 participants; high-certainty evidence) versus Xpert MTB/RIF pooled sensitivity and specificity of 84.7% (78.6 to 89.9) and 98.4% (97.0 to 99.3) (7 studies, 2835 participants; high-certainty evidence). The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at 6.3% (0.1 to 12.8) for sensitivity and -2.7% (-5.7 to -0.5) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss 9 cases, and Xpert MTB/RIF will miss 15 cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 40 with Xpert Ultra and 14 with Xpert MTB/RIF. In smear-negative, culture-positive participants, pooled sensitivity was 77.5% (67.6 to 85.6) for Xpert Ultra versus 60.6% (48.4 to 71.7) for Xpert MTB/RIF; pooled specificity was 95.8% (92.9 to 97.7) for Xpert Ultra versus 98.8% (97.7 to 99.5) for Xpert MTB/RIF (6 studies). In people living with HIV, pooled sensitivity was 87.6% (75.4 to 94.1) for Xpert Ultra versus 74.9% (58.7 to 86.2) for Xpert MTB/RIF; pooled specificity was 92.8% (82.3 to 97.0) for Xpert Ultra versus 99.7% (98.6 to 100.0) for Xpert MTB/RIF (3 studies). In participants with a history of tuberculosis, pooled sensitivity was 84.2% (72.5 to 91.7) for Xpert Ultra versus 81.8% (68.7 to 90.0) for Xpert MTB/RIF; pooled specificity was 88.2% (70.5 to 96.6) for Xpert Ultra versus 97.4% (91.7 to 99.5) for Xpert MTB/RIF (4 studies). The proportion of Ultra trace-positive results ranged from 3.0% to 30.4%. Data were insufficient to estimate the accuracy of X. Xpert Ultra has higher sensitivity and lower specificity than Xpert MTB/RIF for pulmonary tuberculosis, especially in smear-negative participants and people living with HIV. Xpert Ultra specificity was lower than that of Xpert MTB/RIF in participants with a history of tuberculosis. The sensitivity and specificity trade-off would be expected to vary by setting. For detection of rifampicin resistance, Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity. Ultra trace-positive results were common. Xpert Ultra and Xpert MTB/RIF provide accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multidrug-resistant tuberculosis.

Topics: Antibiotics, Antitubercular; Diagnostic Errors; Drug Resistance, Bacterial; Extensively Drug-Resistant Tuberculosis; False Negative Reactions; False Positive Reactions; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary

Tuberculosis is a leading cause of infectious disease-related death and is one of the top 10 causes of death worldwide. The World Health Organization (WHO) recommends the use of specific rapid molecular tests, including Xpert MTB/RIF or Xpert Ultra, as initial diagnostic tests for the detection of tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. However, the WHO estimates that nearly one-third of all active tuberculosis cases go undiagnosed and unreported. We were interested in whether a single test, Xpert MTB/RIF or Xpert Ultra, could be useful as a screening test to close this diagnostic gap and improve tuberculosis case detection.. To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for screening for pulmonary tuberculosis in adults, irrespective of signs or symptoms of pulmonary tuberculosis in high-risk groups and in the general population. Screening "irrespective of signs or symptoms" refers to screening of people who have not been assessed for the presence of tuberculosis symptoms (e.g. cough). To estimate the accuracy of Xpert MTB/RIF and Xpert Ultra for detecting rifampicin resistance in adults screened for tuberculosis, irrespective of signs and symptoms of pulmonary tuberculosis in high-risk groups and in the general population.. We searched 12 databases including the Cochrane Infectious Diseases Group Specialized Register, MEDLINE and Embase, on 19 March 2020 without language restrictions. We also reviewed reference lists of included articles and related Cochrane Reviews, and contacted researchers in the field to identify additional studies.. Cross-sectional and cohort studies in which adults (15 years and older) in high-risk groups (e.g. people living with HIV, household contacts of people with tuberculosis) or in the general population were screened for pulmonary tuberculosis using Xpert MTB/RIF or Xpert Ultra. For tuberculosis detection, the reference standard was culture. For rifampicin resistance detection, the reference standards were culture-based drug susceptibility testing and line probe assays.. Two review authors independently extracted data using a standardized form and assessed risk of bias and applicability using QUADAS-2. We used a bivariate random-effects model to estimate pooled sensitivity and specificity with 95% credible intervals (CrIs) separately for tuberculosis detection and rifampicin resistance detection. We estimated all models using a Bayesian approach. For tuberculosis detection, we first estimated screening accuracy in distinct high-risk groups, including people living with HIV, household contacts, people residing in prisons, and miners, and then in several high-risk groups combined.. We included a total of 21 studies: 18 studies (13,114 participants) evaluated Xpert MTB/RIF as a screening test for pulmonary tuberculosis and one study (571 participants) evaluated both Xpert MTB/RIF and Xpert Ultra. Three studies (159 participants) evaluated Xpert MTB/RIF for rifampicin resistance. Fifteen studies (75%) were conducted in high tuberculosis burden and 16 (80%) in high TB/HIV-burden countries. We judged most studies to have low risk of bias in all four QUADAS-2 domains and low concern for applicability. Xpert MTB/RIF and Xpert Ultra as screening tests for pulmonary tuberculosis In people living with HIV (12 studies), Xpert MTB/RIF pooled sensitivity and specificity (95% CrI) were 61.8% (53.6 to 69.9) (602 participants; moderate-certainty evidence) and 98.8% (98.0 to 99.4) (4173 participants; high-certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 40 would be Xpert MTB/RIF-positive; of these, 9 (22%) would not have tuberculosis (false-positives); and 960 would be Xpert MTB/RIF-negative; of these, 19 (2%) would have tuberculosis (false-negatives). In people living with HIV (1 study), Xpert Ultra sensitivity and specificity (95% CI) were 69% (57 to 80) (68 participants; very low-certainty evidence) and 98% (97 to 99) (503 participants; moderate-certainty evidence). Of 1000 people where 50 have tuberculosis on culture, 53 would be Xpert Ultra-positive; of these, 19 (36%) would not have tuberculosis (false-positives); and 947 would be Xpert Ultra-negative; of these, 16 (2%) would have tuberculosis (false-negatives). In non-hospitalized people in high-risk groups (5 studies), Xpert MTB/RIF pooled sensitivity and specificity were 69.4% (47.7 to 86.2) (337 participants, low-certainty evidence) and 98.8% (97.2 to 99.5) (8619 participants, moderate-certainty evidence). Of 1000 people where 10 have tuberculosis on culture, 19 would be Xpert MTB/RIF-positive; of these, 12 (63%) would not have tuberculosis (false-positives); and 981 would be Xpert MTB/RIF-negative; of these, 3 (0%) would have tuberculosis (false-negatives). We did not identify any studies using Xpert MTB/RIF or Xpert Ultra for screening in the general population. Xpert MTB/RIF as a screening test for rifampicin resistance Xpert MTB/RIF sensitivity was 81% and 100% (2 studies, 20 participants; very low-certainty evidence), and specificity was 94% to 100%, (3 studies, 139 participants; moderate-certainty evidence).. Of the high-risks groups evaluated, Xpert MTB/RIF applied as a screening test was accurate for tuberculosis in high tuberculosis burden settings. Sensitivity and specificity were similar in people living with HIV and non-hospitalized people in high-risk groups. In people living with HIV, Xpert Ultra sensitivity was slightly higher than that of Xpert MTB/RIF and specificity similar. As there was only one study of Xpert Ultra in this analysis, results should be interpreted with caution. There were no studies that evaluated the tests in people with diabetes mellitus and other groups considered at high-risk for tuberculosis, or in the general population.

Topics: Adult; Antibiotics, Antitubercular; Bacteriological Techniques; Bayes Theorem; Bias; Cohort Studies; Cross-Sectional Studies; Drug Resistance, Bacterial; False Negative Reactions; False Positive Reactions; HIV Infections; Humans; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

A growing amount of evidence suggests that the rifampicin dosing currently recommended for tuberculosis treatment could be associated with inadequate exposure and unfavourable outcomes. We aimed to compare clinical and microbiological efficacy and safety outcomes of standard and higher rifampicin dosing.. Data sources were MEDLINE, Google Scholar and the Cochrane Library. This was a systematic review and meta-analysis that included experimental or observational studies comparing 8-week sputum culture conversion, treatment failure, or safety outcomes in naïve patients with pulmonary tuberculosis treated with standard (10 mg/kg) or higher doses of rifampicin.. Of a total of 9683 citations screened, eight randomized controlled trials were included, accounting for 1897 subjects; the risk of bias was low in three studies, high in two and intermediate in three. At week 8 a higher proportion of patients in the high-dose group obtained a sputum culture conversion than those in the standard dose group (83.7% versus 80.6%, RR 1.06; 95%CI 1.01-1.12, p 0.028); this result was confirmed in the sub-analysis including patients treated with a rifampicin dose of ≥20 mg/kg, but not in those treated with 11-19 mg/kg. Events of treatment failure at end of treatment showed no significant difference between the two groups (RR 0.84; 95%CI 0.59-1.21, p 0.362). In the analysis evaluating safety outcome, the difference in the occurrence of a grade 3 or 4 liver toxicity or adverse drug reactions leading to discontinuation was not significant at the statistical analysis among the groups (7.2% versus 5.4%, RR 1.19; 95%CI 0.81-1.73, p 0.370, and 1.5% versus 0.6%, RR 2.31; 95%CI 0.65-8.21, p 0.195, respectively). No statistical heterogeneity among studies was observed for each outcome.. High doses of rifampicin were associated with an increased rate of sputum culture conversion at 8 weeks of treatment, particularly in patients receiving ≥20 mg/kg.

Topics: Antitubercular Agents; Dose-Response Relationship, Drug; Humans; Rifampin; Tuberculosis, Pulmonary

The World Health Organization (WHO) recommends Xpert MTB/RIF in place of smear microscopy to diagnose tuberculosis (TB), and many countries have adopted it into their diagnostic algorithms. However, it is not clear whether the greater accuracy of the test translates into improved health outcomes.. To assess the impact of Xpert MTB/RIF on patient outcomes in people being investigated for tuberculosis.. We searched the following databases, without language restriction, from 2007 to 24 July 2020: Cochrane Infectious Disease Group (CIDG) Specialized Register; CENTRAL; MEDLINE OVID; Embase OVID; CINAHL EBSCO; LILACS BIREME; Science Citation Index Expanded (Web of Science), Social Sciences citation index (Web of Science), and Conference Proceedings Citation Index - Social Science & Humanities (Web of Science). We also searched the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the Pan African Clinical Trials Registry for ongoing trials.. We included individual- and cluster-randomized trials, and before-after studies, in participants being investigated for tuberculosis. We analysed the randomized and non-randomized studies separately.  DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted data, using a piloted data extraction tool. We assessed the risk of bias using Cochrane and Effective Practice and Organisation of Care (EPOC) tools. We used random effects meta-analysis to allow for heterogeneity between studies in setting and design.  The certainty of the  evidence in the randomized trials was assessed by GRADE.. We included 12 studies: eight were randomized controlled trials (RCTs), and four were before-and-after studies. Most included RCTs had a low risk of bias in most domains of the Cochrane 'Risk of bias' tool. There was inconclusive evidence of an effect of Xpert MTB/RIF on all-cause mortality, both overall (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.75 to 1.05; 5 RCTs, 9932 participants, moderate-certainty evidence), and restricted to studies with six-month follow-up (RR 0.98, 95% CI 0.78 to 1.22; 3 RCTs, 8143 participants; moderate-certainty evidence). There was probably a reduction in mortality in participants known to be infected with HIV (odds ratio (OR) 0.80, 95% CI 0.67 to 0.96; 5 RCTs, 5855 participants; moderate-certainty evidence). It is uncertain whether Xpert MTB/RIF has no or a modest effect on the proportion of participants starting tuberculosis treatment who had a successful treatment outcome (OR) 1.10, 95% CI 0.96 to 1.26; 3RCTs, 4802 participants; moderate-certainty evidence). There was also inconclusive evidence of an effect on the  proportion of participants who were treated for tuberculosis (RR 1.10, 95% CI 0.98 to 1.23; 5 RCTs, 8793 participants; moderate-certainty evidence). The proportion of participants treated for tuberculosis who had bacteriological confirmation was probably higher in the Xpert MTB/RIF group (RR 1.44, 95% CI 1.29 to 1.61; 6 RCTs, 2068 participants; moderate-certainty evidence). The proportion of participants with bacteriological confirmation who were lost to follow-up pre-treatment was probably reduced (RR 0.59, 95% CI 0.41 to 0.85; 3 RCTs, 1217 participants; moderate-certainty evidence).. We were unable to confidently rule in or rule out the effect on all-cause mortality of using Xpert MTB/RIF rather than smear microscopy. Xpert MTB/RIF probably reduces mortality among participants known to be infected with HIV. We are uncertain whether Xpert MTB/RIF has a modest effect or not on the proportion treated or, among those treated, on the proportion with a successful outcome. It probably does not have a substantial effect on these outcomes. Xpert MTB/RIF probably increases both the proportion of treated participants who had bacteriological confirmation, and the proportion with a laboratory-confirmed diagnosis who were treated. These findings may inform decisions about uptake alongside evidence on cost-effectiveness and implementation.. La Organización Mundial de la Salud (OMS) recomienda la Xpert MTB/RIF en lugar de la baciloscopia para diagnosticar la tuberculosis (TB) y muchos países la han adoptado en sus algoritmos de diagnóstico. Sin embargo, no está claro si la mayor exactitud de la prueba se traduce en mejores desenlaces de salud.. Evaluar el impacto de la Xpert MTB/RIF en los desenlaces de las personas sometidas a pruebas para la tuberculosis. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las siguientes bases de datos, sin restricción de idioma, desde 2007 hasta el 24 de julio de 2020: Registro especializado del Grupo Cochrane de Enfermedades infecciosas (Cochrane Infectious Disease Group [CIDG]); CENTRAL; MEDLINE OVID; Embase OVID; CINAHL EBSCO; LILACS BIREME; Science Citation Index Expanded (Web of Science), Social Sciences citation index (Web of Science), y Conference Proceedings Citation Index ‐ Social Science & Humanities (Web of Science). También se buscaron ensayos en curso en la Plataforma de registros internacionales de ensayos clínicos de la OMS, en ClinicalTrials.gov y en el Pan African Clinical Trials Registry. CRITERIOS DE SELECCIÓN: Se incluyeron ensayos aleatorizados individuales y por conglomerados, y estudios tipo antes y después (before‐after studie), con participantes sometidos a pruebas para la tuberculosis. Los estudios aleatorizados y no aleatorizados se analizaron por separado. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, extrajeron los datos de cada estudio mediante una herramienta de extracción de datos analizada. El riesgo de sesgo se evaluó mediante las herramientas de Cochrane y del Grupo Cochrane para una Práctica y organización sanitarias efectivas (Effective Practice and Organisation of Care [EPOC]). Se utilizó el metanálisis de efectos aleatorios para considerar la heterogeneidad entre los estudios en cuanto al contexto y el diseño. La certeza de la evidencia en los ensayos aleatorizados se evaluó mediante el método GRADE.. Se incluyeron 12 estudios: ocho eran ensayos controlados aleatorizados (ECA) y cuatro eran estudios tipo antes y después. La mayoría de los ECA incluidos tenían un bajo riesgo de sesgo en la mayoría de los dominios de la herramienta Cochrane "Risk of bias". Hubo evidencia no concluyente de un efecto de la Xpert MTB/RIF sobre la mortalidad por todas las causas, tanto en general (razón de riesgos [RR] 0,89; intervalo de confianza [IC] del 95%: 0,75 a 1,05; cinco ECA, 9932 participantes, evidencia de certeza moderada), como limitada a los estudios con seguimiento de seis meses (RR 0,98; IC del 95%: 0,78 a 1,22; tres ECA, 8143 participantes; evidencia de certeza moderada). Probablemente hubo una reducción de la mortalidad en los participantes que se sabía que estaban infectados por el VIH (odds ratio [OR] 0,80; IC del 95%: 0,67 a 0,96; cinco ECA, 5855 participantes; evidencia de certeza moderada). No está claro si la Xpert MTB/RIF no tiene efectos o tiene un efecto modesto sobre la proporción de participantes que inician el tratamiento de la tuberculosis y que tienen un desenlace exitoso del tratamiento (OR 1,10; IC del 95%: 0,96 a 1,26; tres ECA, 4802 participantes; evidencia de certeza moderada). También hubo evidencia no concluyente de un efecto sobre el porcentaje de participantes que recibieron tratamiento para la tuberculosis (RR 1,10; IC del 95%: 0,98 a 1,23; cinco ECA, 8793 participantes; evidencia de certeza moderada). Es probable que la proporción de participantes tratados por tuberculosis que tuvieron confirmación bacteriológica fuera mayor en el grupo de Xpert MTB/RIF (RR 1,44; IC del 95%: 1,29 a 1,61; seis ECA, 2068 participantes; evidencia de certeza moderada). Es probable que se redujera la proporción de participantes con confirmación bacteriológica que se perdió durante el seguimiento previo al tratamiento (RR 0,59; IC del 95%: 0,41 a 0,85; tres ECA, 1217 participantes; evidencia de certeza moderada).. No fue posible descartar con seguridad el efecto sobre la mortalidad por todas las causas del uso de Xpert MTB/RIF en lugar de la baciloscopia. La Xpert MTB/RIF probablemente reduce la mortalidad en los participantes que se sabe que están infectados por el VIH. No hay certeza con respecto a si la Xpert MTB/RIF tiene un efecto modesto o no en la proporción tratada o, entre los tratados, en la proporción con un desenlace exitoso. Probablemente no tenga un efecto importante sobre estos desenlaces. La Xpert MTB/RIF probablemente aumenta la proporción de participantes tratados que tenían confirmación bacteriológica, así como la de aquellos con un diagnóstico confirmado por el laboratorio que fueron tratados. Estos hallazgos podrían servir de base para las decisiones sobre la adopción de la prueba, junto con la evidencia sobre la coste‐efectividad y la aplicación.

Topics: Antibiotics, Antitubercular; Bias; Confidence Intervals; Controlled Before-After Studies; Drug Resistance, Bacterial; HIV Infections; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Odds Ratio; Randomized Controlled Trials as Topic; Reagent Kits, Diagnostic; Real-Time Polymerase Chain Reaction; Rifampin; Tuberculosis, Pulmonary

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

The re-engineered Xpert MTB/RIF Ultra (Xpert Ultra) assay was developed due to the poor sensitivity of the Xpert MTB/RIF assay for the detection of tuberculosis (TB) in some conditions. This new assay has been recommended by the World Health Organization since 2017. A systematic review and meta-analysis was performed to assess the accuracy of Xpert Ultra for the detection of TB and rifampicin (RIF) resistance.. The Medline (via PubMed), Embase (via OvidSP), ISI Web of Science, Cochrane Central Register of Controlled Trials, and Scopus databases were screened for original articles. Summary sensitivity and specificity were calculated with a bivariate mixed-effects model. A Fagan nomogram was used to assess the clinical utility. The sources of heterogeneity were investigated by meta-regression and subgroup analyses.. Sixteen studies were identified. The summary diagnostic accuracy of Xpert Ultra for the diagnosis of TB were as follows: sensitivity 87.2% (95% confidence interval (CI) 82.5-90.8%) and specificity 96.5% (95% CI 95.1-97.5%). For the detection of RIF resistance, sensitivity was 95.1% (95% CI 91.6-97.2%) and specificity was 98.9% (95% CI 97.6-99.5%). Meta-regression showed that the category of population, TB prevalence, reference standard, sample state, sample type, and study design attributed to the heterogeneity. Subgroup analyses found good performance of Xpert Ultra in settings with a low TB burden.. As a rapid and highly sensitive test for the detection of TB and simultaneous detection of RIF resistance, Xpert Ultra exhibits a viable alternative in sensitivities in both pulmonary TB (PTB) and extrapulmonary TB (EPTB), which was proved to be higher than Xpert in the comparative analysis, and also shows a good performance in the detection of RIF resistance. Additional studies with comparative consistency tests are needed to precisely describe this finding for more forms of EPTB.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Bacterial Proteins; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary; Young Adult

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

Intracranial tuberculomas are rare yet lethal forms of tuberculosis. Diagnosis is often difficult because of its nonspecific symptoms and radiological findings.. This study aims to perform a literature review of multiple tuberculomas to improve disease recognition and management in immunocompetent patients along with presenting a case report on the topic.. Scopus, LILACS, Ovid MEDLINE and EMBASE.. Case reports and case series up to December 2018 in English, Spanish, and Portuguese focusing on intracranial tuberculomas in adult and pediatric immunocompetent patients. Data on presentation, diagnostic workup, and treatment was analyzed.. Cochrane Collaboration/Cochrane Handbook and PRISMA guidelines.. Twenty reports involving 21 patients were included. Most patients were male (57.14%). The average age at diagnosis was 26.9 ± 14.9 years. Headache was the most common presenting symptom (52.4%; 11/21), followed by motor weakness (47.6%; 10/21) and vomiting (23.8%; 5/21). MRI was the most used image technique (17/21). Most lesions occurring in the cerebral hemispheres (16/21); we found five or more lesions in 66.6% (14/21) of the patients. The majority treated with anti-tuberculous drugs resulted in a favorable outcome.. Immunocompetent patients living in TB endemic areas whose clinical evaluation and neuroimaging findings are compatible with tuberculoma should undergo anti-tubercular treatment despite a lack of bacteriological confirmation.

Topics: Antitubercular Agents; Blindness; Brain; Brain Diseases; Cerebellar Ataxia; Dexamethasone; Drug Therapy, Combination; Endemic Diseases; Ethambutol; Female; Glucocorticoids; Humans; Immunocompetence; Isoniazid; Magnetic Resonance Imaging; Nausea; Nystagmus, Pathologic; Peru; Pyrazinamide; Quadriplegia; Rifampin; Tomography, X-Ray Computed; Tuberculoma, Intracranial; Tuberculosis, Pulmonary; Vomiting; Young Adult

Every year, at least one million children become ill with tuberculosis and around 200,000 children die. Xpert MTB/RIF and Xpert Ultra are World Health Organization (WHO)-recommended rapid molecular tests that simultaneously detect tuberculosis and rifampicin resistance in adults and children with signs and symptoms of tuberculosis, at lower health system levels. To inform updated WHO guidelines on molecular assays, we performed a systematic review on the diagnostic accuracy of these tests in children presumed to have active tuberculosis.. Primary objectives • To determine the diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for (a) pulmonary tuberculosis in children presumed to have tuberculosis; (b) tuberculous meningitis in children presumed to have tuberculosis; (c) lymph node tuberculosis in children presumed to have tuberculosis; and (d) rifampicin resistance in children presumed to have tuberculosis - For tuberculosis detection, index tests were used as the initial test, replacing standard practice (i.e. smear microscopy or culture) - For detection of rifampicin resistance, index tests replaced culture-based drug susceptibility testing as the initial test Secondary objectives • To compare the accuracy of Xpert MTB/RIF and Xpert Ultra for each of the four target conditions • To investigate potential sources of heterogeneity in accuracy estimates - For tuberculosis detection, we considered age, disease severity, smear-test status, HIV status, clinical setting, specimen type, high tuberculosis burden, and high tuberculosis/HIV burden - For detection of rifampicin resistance, we considered multi-drug-resistant tuberculosis burden • To compare multiple Xpert MTB/RIF or Xpert Ultra results (repeated testing) with the initial Xpert MTB/RIF or Xpert Ultra result SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, the WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and the International Standard Randomized Controlled Trials Number (ISRCTN) Registry up to 29 April 2019, without language restrictions.. Randomized trials, cross-sectional trials, and cohort studies evaluating Xpert MTB/RIF or Xpert Ultra in HIV-positive and HIV-negative children younger than 15 years. Reference standards comprised culture or a composite reference standard for tuberculosis and drug susceptibility testing or MTBDRplus (molecular assay for detection of Mycobacterium tuberculosis and drug resistance) for rifampicin resistance. We included studies evaluating sputum, gastric aspirate, stool, nasopharyngeal or bronchial lavage specimens (pulmonary tuberculosis), cerebrospinal fluid (tuberculous meningitis), fine needle aspirates, or surgical biopsy tissue (lymph node tuberculosis).. Two review authors independently extracted data and assessed study quality using the Quality Assessment of Studies of Diagnostic Accuracy - Revised (QUADAS-2). For each target condition, we used the bivariate model to estimate pooled sensitivity and specificity with 95% confidence intervals (CIs). We stratified all analyses by type of reference standard. We assessed certainty of evidence using the GRADE approach.. For pulmonary tuberculosis, 299 data sets (68,544 participants) were available for analysis; for tuberculous meningitis, 10 data sets (423 participants) were available; for lymph node tuberculosis, 10 data sets (318 participants) were available; and for rifampicin resistance, 14 data sets (326 participants) were available. Thirty-nine studies (80%) took place in countries with high tuberculosis burden. Risk of bias was low except for the reference standard domain, for which risk of bias was unclear because many studies collected only one specimen for culture. Detection of pulmonary tuberculosis For sputum specimens, Xpert MTB/RIF pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 64.6% (55.3% to 72.9%) (23 studies, 493 participants; moderate-certainty evidence) and 99.0% (98.1% to 99.5%) (23 studies, 6119 participants; moderate-certainty evidence). For other specimen types (nasopharyngeal aspirate, 4 studies; gastric aspirate, 14 studies; stool, 11 studies), Xpert MTB/RIF pooled sensitivity ranged between 45.7% and 73.0%, and pooled specificity ranged between 98.1% and 99.6%. For sputum specimens, Xpert Ultra pooled sensitivity (95% CI) and specificity (95% CI) verified by culture were 72.8% (64.7% to 79.6%) (3 studies, 136 participants; low-certainty evidence) and 97.5% (95.8% to 98.5%) (3 studies, 551 participants; high-certainty evidence). For nasopharyngeal specimens, Xpert Ultra sensitivity (95% CI) and specificity (95% CI) were 45.7% (28.9% to 63.3%) and 97.5% (93.7% to 99.3%) (1 study, 195 participants). For all specimen types, Xpert MTB/RIF and Xpert Ultra sensitivity were lower against a composite reference standard than against culture. Detection of tuberculous meningitis For cerebrospinal fluid, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 54.0% (95% CI 27.8% to 78.2%) (6 studies, 28 participants; very low-certainty evidence) and 93.8% (95% CI 84.5% to 97.6%) (6 studies, 213 participants; low-certainty evidence). Detection of lymph node tuberculosis For lymph node aspirates or biopsies, Xpert MTB/RIF pooled sensitivity and specificity, verified by culture, were 90.4% (95% CI 55.7% to 98.6%) (6 studies, 68 participants; very low-certainty evidence) and 89.8% (95% CI 71.5% to 96.8%) (6 studies, 142 participants; low-certainty evidence). Detection of rifampicin resistance Xpert MTB/RIF pooled sensitivity and specificity were 90.0% (67.6% to 97.5%) (6 studies, 20 participants; low-certainty. We found Xpert MTB/RIF sensitivity to vary by specimen type, with gastric aspirate specimens having the highest sensitivity followed by sputum and stool, and nasopharyngeal specimens the lowest; specificity in all specimens was > 98%. Compared with Xpert MTB/RIF, Xpert Ultra sensitivity in sputum was higher and specificity slightly lower. Xpert MTB/RIF was accurate for detection of rifampicin resistance. Xpert MTB/RIF was sensitive for diagnosing lymph node tuberculosis. For children with presumed tuberculous meningitis, treatment decisions should be based on the entirety of clinical information and treatment should not be withheld based solely on an Xpert MTB/RIF result. The small numbers of studies and participants, particularly for Xpert Ultra, limits our confidence in the precision of these estimates.

Topics: Adolescent; Antibiotics, Antitubercular; Bias; Child; Feces; Gastrointestinal Contents; Humans; Molecular Typing; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Lymph Node; Tuberculosis, Meningeal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Despite broad uptake of antiretroviral therapy (ART), tuberculosis (TB) incidence and mortality among people with HIV remain unacceptably high. Short-course regimens for TB, incorporating both novel and established drugs, offer the potential to enhance adherence and completion rates, thereby reducing the global TB burden. This review will outline short-course regimens for TB among patients with HIV.. After many years without new agents, there is now active testing of many novel drugs to treat TB, both for latent infection and active disease. Though not all studies have included patients with HIV, many have, and there are ongoing trials to address key implementation challenges such as potent drug-drug interactions with ART. The goal of short-course regimens for TB is to enhance treatment completion without compromising efficacy. Particularly among patients with HIV, studying these shortened regimens and integrating them into clinical care are of urgent importance. There are now multiple short-course regimens for latent infection and active disease that are safe and effective among patients with HIV.

Topics: Anti-HIV Agents; Antitubercular Agents; Drug Interactions; Extensively Drug-Resistant Tuberculosis; HIV Infections; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

The Abbott RealTime MTB (Abbott-RT) and Abbott RealTime MTB RIF/INH Resistance (Abbott-RIF/INH) assays have been introduced for the detection of tuberculosis (TB) and drug-resistant tuberculosis (DR-TB). We performed a systematic review and meta-analysis to assess the accuracy of Abbott-RT and Abbott-RIF/INH for the detection of TB and DR-TB.. The Ovid MEDLINE, EMBASE, Cochrane and Web of Science databases were searched to identify eligible articles for the systematic review. The pooled analyses were calculated with a bivariate model. Hierarchical summary receiver operating characteristic curves and the area under the curve (AUC) were used to summarize overall diagnostic performance. Deeks' test was performed to evaluate potential publication bias.. For the Abbott-RT assay, 9 studies including 3, 640 patients met the study criteria. The pooled sensitivity of Abbott-RT for detecting TB was 0.96 (95% CI: 0.88-0.99) and specificity was 0.97 (95% CI: 0.93-0.99). For DR-TB, four studies were included to evaluate the diagnosis accuracy of Abbott-RIF/INH. The pooled sensitivity was 0.88 (95% CI, 0.82-0.93) and specificity was 0.99 (95% CI, 0.96-0.99). No publication bias was found.. Both Abbott-RT and Abbott-RIF/INH assays have good sensitivity, specificity and accuracy for the diagnosis of TB and DR-TB.

Topics: Anti-Bacterial Agents; Diagnostic Techniques and Procedures; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Invasive collection methods are often required to obtain samples for the microbiological evaluation of children with presumptive pulmonary tuberculosis (PTB). Nucleic acid amplification testing of easier-to-collect stool samples could be a noninvasive method of diagnosing PTB. We conducted a systematic review and meta-analysis to evaluate the diagnostic accuracy of testing stool with the Xpert MTB/RIF assay ("stool Xpert") for childhood PTB. Four databases were searched for publications from January 2008 to June 2018. Studies assessing the diagnostic accuracy among children of stool Xpert compared to a microbiological reference standard of conventional specimens tested by mycobacterial culture or Xpert were eligible. Bivariate random-effects meta-analyses were performed to calculate pooled sensitivity and specificity of stool Xpert against the reference standard. From 1,589 citations, 9 studies (

Topics: Adolescent; Age Factors; Child; Child, Preschool; Feces; Humans; Infant; Infant, Newborn; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Publication Bias; Reference Values; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary

Xpert MTB/RIF (Xpert MTB/RIF) and Xpert MTB/RIF Ultra (Xpert Ultra), the newest version, are the only World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in persons with signs and symptoms of tuberculosis, at lower health system levels. A previous Cochrane Review found Xpert MTB/RIF sensitive and specific for tuberculosis (Steingart 2014). Since the previous review, new studies have been published. We performed a review update for an upcoming WHO policy review.. To determine diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for tuberculosis in adults with presumptive pulmonary tuberculosis (PTB) and for rifampicin resistance in adults with presumptive rifampicin-resistant tuberculosis.. We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, to 11 October 2018, without language restriction.. Randomized trials, cross-sectional, and cohort studies using respiratory specimens that evaluated Xpert MTB/RIF, Xpert Ultra, or both against the reference standard, culture for tuberculosis and culture-based drug susceptibility testing or MTBDRplus for rifampicin resistance.. Four review authors independently extracted data using a standardized form. When possible, we also extracted data by smear and HIV status. We assessed study quality using QUADAS-2 and performed meta-analyses to estimate pooled sensitivity and specificity separately for tuberculosis and rifampicin resistance. We investigated potential sources of heterogeneity. Most analyses used a bivariate random-effects model. For tuberculosis detection, we first estimated accuracy using all included studies and then only the subset of studies where participants were unselected, i.e. not selected based on prior microscopy testing.. We identified in total 95 studies (77 new studies since the previous review): 86 studies (42,091 participants) evaluated Xpert MTB/RIF for tuberculosis and 57 studies (8287 participants) for rifampicin resistance. One study compared Xpert MTB/RIF and Xpert Ultra on the same participant specimen.Tuberculosis detectionOf the total 86 studies, 45 took place in high tuberculosis burden and 50 in high TB/HIV burden countries. Most studies had low risk of bias.Xpert MTB/RIF pooled sensitivity and specificity (95% credible Interval (CrI)) were 85% (82% to 88%) and 98% (97% to 98%), (70 studies, 37,237 unselected participants; high-certainty evidence). We found similar accuracy when we included all studies.For a population of 1000 people where 100 have tuberculosis on culture, 103 would be Xpert MTB/RIF-positive and 18 (17%) would not have tuberculosis (false-positives); 897 would be Xpert MTB/RIF-negative and 15 (2%) would have tuberculosis (false-negatives).Xpert Ultra sensitivity (95% confidence interval (CI)) was 88% (85% to 91%) versus Xpert MTB/RIF 83% (79% to 86%); Xpert Ultra specificity was 96% (94% to 97%) versus Xpert MTB/RIF 98% (97% to 99%), (1 study, 1439 participants; moderate-certainty evidence).Xpert MTB/RIF pooled sensitivity was 98% (97% to 98%) in smear-positive and 67% (62% to 72%) in smear-negative, culture-positive participants, (45 studies). Xpert MTB/RIF pooled sensitivity was 88% (83% to 92%) in HIV-negative and 81% (75% to 86%) in HIV-positive participants; specificities were similar 98% (97% to 99%), (14 studies).Rifampicin resistance detectionXpert MTB/RIF pooled sensitivity and specificity (95% Crl) were 96% (94% to 97%) and 98% (98% to 99%), (48 studies, 8020 participants; high-certainty evidence).For a population of 1000 people where 100 have rifampicin-resistant tuberculosis, 114 would be positive for rifampicin-resistant tuberculosis and 18 (16%) would not have rifampicin resistance (false-positives); 886 would be would be negative for rifampicin-resistant tuberculosis and four (0.4%) would have rifampicin resistance (false-negatives).Xpert Ultra sensitivity (95% CI) was 95% (90% to 98%) versus Xpert MTB/RIF 95% (91% to 98%); Xpert Ultra specificity was 98% (97% to 99%) versus Xpert MTB/RIF 98% (96% to 99%), (1 study, 551 participants; moderate-certainty evidence).. We found Xpert MTB/RIF to be sensitive and specific for diagnosing PTB and rifampicin resistance, consistent with findings reported previously. Xpert MTB/RIF was more sensitive for tuberculosis in smear-positive than smear-negative participants and HIV-negative than HIV-positive participants. Compared with Xpert MTB/RIF, Xpert Ultra had higher sensitivity and lower specificity for tuberculosis and similar sensitivity and specificity for rifampicin resistance (1 study). Xpert MTB/RIF and Xpert Ultra provide accurate results and can allow rapid initiation of treatment for multidrug-resistant tuberculosis.

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

In high-income countries, the presentation of tuberculosis is changing, primarily because of migration, and understanding the specific health needs of susceptible populations is becoming increasingly important. Although disseminated tuberculosis is well documented in HIV-positive patients, the disease is poorly described and less expected in HIV-negative individuals. In this Grand Round, we report eight HIV-negative refugees, who presented with extensively disseminated tuberculosis. We discuss the multifactorial causes, such as deprivations during long journeys, precarious living conditions, and the experience of violence, which might add to nutritional factors and chronic disorders, eventually resulting in a state of predisposition to immune deficiency. We also show that disseminated tuberculosis is often difficult to diagnose when pulmonary symptoms are absent. Communication difficulties between refugees and health-care workers are another major hurdle, and every effort should be made to get a valid patient history. This medical history is crucial to guide imaging and other diagnostic procedures to establish a definite diagnosis, which should be confirmed by a positive tuberculosis culture. Because many of these patients are at risk for multidrug-resistant tuberculosis, drug susceptibility testing is imperative to guide therapy. In the absence of treatment guidelines for this entity, clinicians can determine treatment duration according to recommendations provided for extrapulmonary tuberculosis and affected organs. Paradoxical expansion of tuberculous lesions during therapy should be treated with corticosteroids. In many cases, treatment duration must be individualised and might even exceed 12 months.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Ethambutol; Fluorine Radioisotopes; HIV Infections; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Positron Emission Tomography Computed Tomography; Pyrazinamide; Refugees; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

To estimate the diagnostic accuracy of Xpert MTB/RIF for rifampicin resistance in different regions, a meta-analysis was carried out.. Several databases were searched for relevant studies up to March 3, 2019. A bivariate random-effects model was used to estimate the diagnostic accuracy.. We identified 97 studies involving 26,037 samples for the diagnosis of rifampicin resistance. The pooled sensitivity, specificity and AUC of Xpert MTB/RIF for rifampicin resistance detection were 0.93 (95% CI 0.90-0.95), 0.98 (95% CI 0.96-0.98) and 0.99 (95% CI 0.97-0.99), respectively. For different regions, the pooled sensitivity were 0.94(95% CI 0.89-0.97) and 0.92 (95% CI 0.88-0.94), the pooled specificity were 0.98 (95% CI 0.94-1.00) and 0.98 (95% CI 0.96-0.99), and the AUC were 0.99 (95% CI 0.98-1.00) and 0.99 (95% CI 0.97-0.99) in high and middle/low income countries, respectively. The pooled sensitivity were 0.91 (95% CI 0.87-0.94) and 0.91 (95% CI 0.86-0.94), the pooled specificity were 0.98 (95% CI 0.96-0.99) and 0.98 (95% CI 0.96-0.99), and the AUC were 0.98 (95% CI 0.97-0.99) and 0.99 (95% CI 0.97-0.99) in high TB burden and middle/low prevalence countries, respectively.. The diagnostic accuracy of Xpert MTB/RIF for rifampicin resistance detection was excellent.

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

Topics: Antibiotics, Antitubercular; Drug Resistance, Multiple, Bacterial; Humans; Iran; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Drug delivery via the inhaled route has advantages for treating local and systemic diseases. Pulmonary drug delivery may have potential in treating tuberculosis (TB), which is mainly localised in the lung (pulmonary tuberculosis ∼75%) while also affecting other organs (extra-pulmonary tuberculosis). Currently, rifampicin, a first-line anti-tubercular drug, is given orally and the maximum daily oral dose is the lesser of 10 mg/kg or 600 mg. Since only a small fraction of this dose is available in the lung, concentrations may frequently fail to reach bactericidal levels, and therefore, contribute to the development of multi-drug resistant pulmonary TB. Pulmonary delivery of rifampicin, either alone or in addition to the standard oral dose, has the potential to achieve a high concentration of rifampicin in the lung at a relatively low administered dose that is sufficient to kill bacteria and reduce the development of drug resistance. As yet, no clinical study in humans has reported the pharmacokinetics or the efficacy of pulmonary delivery of rifampicin for TB. This review discusses the opportunities and challenges of rifampicin delivery via the inhaled route and important considerations for future clinical studies on high dose inhaled rifampicin are illustrated.

Topics: Administration, Inhalation; Animals; Antitubercular Agents; Clinical Studies as Topic; Humans; Rifampin; Tuberculosis, Pulmonary

Uptake of preventive treatment for tuberculosis (TB) remains poor. A 3-month regimen of rifapentine (RPT) plus isoniazid (INH) (3HP) could facilitate its scale-up. We conducted a systematic review to assess the effects of 3HP compared with daily 6- or 9-month INH monotherapy.. We searched the following databases to identify randomised controlled trials: PubMed, Embase, the Web of Science, Cochrane Central Register of Controlled Trials, three ongoing trial registers and conference abstracts up to 24 January 2017. Where possible, we pooled data using a random-effects model.. Four studies were included. Of those, we included two studies that compared 3HP with daily 6- or 9-month INH (6/9H) among adults with human immunodeficiency virus (HIV) co-infection, one among HIV-negative adults and one among predominantly HIV-negative children and adolescents. Risk of active TB was not significantly different between 3HP and 6/9H (risk ratio [RR] 0.73, 95%CI 0.23-2.29, in adults with HIV; RR 0.44, 95%CI 0.18-1.07, in adults without HIV; RR 0.13, 95%CI 0.01-2.54, in children and adolescents). Risk of hepatotoxicity was significantly lower in the 3HP group among adults with HIV (RR 0.26, 95%CI 0.12-0.55) and those without HIV (RR 0.16, 95%CI 0.10-0.27). 3HP was also associated with a higher completion rate in all subgroups.. HP was shown to have a preventive effect similar to that of INH monotherapy, with fewer adverse events and higher completion rates. 3HP can contribute significantly to the scale-up of preventive treatment.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Child; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; HIV Seronegativity; Humans; Isoniazid; Latent Tuberculosis; Rifampin; Tuberculosis, Pulmonary

As we move into the era of the Sustainable Development Goals (SDGs), the World Health Organization (WHO) has developed the End TB strategy 2016-2035 with a goal to end the global epidemic of tuberculosis (TB) by 2035. Achieving the targets laid out in the Strategy will require strengthening of the whole TB diagnosis and treatment cascade, including improved case detection, the establishment of universal drug susceptibility testing and rapid treatment initiation. An estimated 3.9% of new TB cases and 21% of previously treated cases had rifampicin-resistant (RR) or multidrug-resistant (MDR) TB in 2015. These levels have remained stable over time, although limited data are available from major high burden settings. In addition to the emergence of drug resistance due to inadequate treatment, there is growing evidence that direct transmission is a large contributor to the RR/MDR-TB epidemic. Only 340,000 of the estimated 580,000 incident cases of RR/MDR-TB were notified to WHO in 2015. Among these, only 125,000 were initiated on second-line treatment. RR/MDR-TB epidemics are likely to be driven by direct transmission. The most important risk factor for MDR-TB is a history of previous treatment. Other risk factors vary according to setting but can include hospitalisation, incarceration and HIV infection. Children have the same risk of MDR-TB as adults and represent a diagnostic and treatment challenge. Rapid molecular technologies have revolutionized the diagnosis of drug-resistant TB. Until capacity can be established to test every TB patient for rifampicin resistance, countries should focus on gradually expanding their coverage of testing. DNA sequencing technologies are being increasingly incorporated into patient management and drug resistance surveillance. They offer additional benefits over conventional culture-based phenotypic testing, including a faster turn-around time for results, assessment of resistance patterns to a range of drugs, and investigation of strain clustering and transmission.

Topics: Adult; Antitubercular Agents; Child; Drug Resistance, Multiple, Bacterial; Epidemics; Extensively Drug-Resistant Tuberculosis; Hospitalization; Humans; Mycobacterium tuberculosis; Rifampin; Risk Factors; Sequence Analysis, DNA; Tuberculosis, Pulmonary; World Health Organization

Drug Resistant Tuberculosis (DRTB) is an emerging problem world-wide. In order to control the disease and decrease the number of cases overtime a prompt diagnosis followed by an appropriate treatment should be provided to patients. Phenotypic DST based on liquid automated culture has greatly reduced the time needed to generate reliable data but has the drawback to be expensive and prone to contamination in the absence of appropriate infrastructures. In the past 10 years molecular biology tools have been developed. Those tools target the main mutations responsible for DRTB and are now globally accessible in term of cost and infrastructures needed for the implementation. The dissemination of the Xpert MTB/rif has radically increased the capacity to perform the detection of rifampicin resistant TB cases. One of the main challenges for the large scale implementation of molecular based tests is the emergence of conflicting results between phenotypic and genotypic tests. This mines the confidence of clinicians in the molecular tests and delays the initiation of an appropriate treatment. A new technique is revolutionizing the genotypic approach to DST: the WGS by Next-Generation Sequencing technologies. This methodology promises to become the solution for a rapid access to universal DST, able indeed to overcome the limitations of the current phenotypic and genotypic assays. Today the use of the generated information is still challenging in decentralized facilities due to the lack of automation for sample processing and standardization in the analysis.The growing knowledge of the molecular mechanisms at the basis of drug resistance and the introduction of high-performing user-friendly tools at peripheral level should allow the very much needed accurate diagnosis of DRTB in the near future.

Topics: Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Evolution, Molecular; Genes, Bacterial; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Phenotype; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Whole Genome Sequencing

The results of some reports have suggested that treatment of isoniazid-resistant tuberculosis with the recommended regimens of first-line drugs might be suboptimal. We updated a previous systematic review of treatment outcomes associated with use of first-line drugs in patients with tuberculosis resistant to isoniazid but not rifampicin.. In this systematic review, we updated the results of a previous review to include randomised trials and cohort studies published in English, French, or Spanish to March 31, 2015, containing results of standardised treatment of patients with bacteriologically confirmed isoniazid-resistant tuberculosis (but not multidrug-resistant tuberculosis-ie, not resistant to rifampicin) in whom failure and relapse were bacteriologically confirmed. Results in patients with drug-sensitive tuberculosis included in the same studies were also analysed. We pooled treatment outcomes with random-effects meta-analysis.. We identified 19 cohort studies and 33 trials with 3744 patients with isoniazid-resistant tuberculosis and 19 012 patients with drug-sensitive disease. The pooled rates of failure or relapse, or both, and acquired drug resistance with all drug regimens were 15% (95% CI 12-18) and 3·6% (2-5), respectively, in patients with isoniazid-resistant tuberculosis and 4% (3-5) and 0·6% (0·3-0·9) in those with drug-sensitive tuberculosis. Of patients with initial isoniazid-resistant tuberculosis with acquired drug resistance, 96% (93-99) had acquired multidrug-resistant disease. Treatment of isoniazid-resistant tuberculosis with the WHO standard regimen for new patients resulted in treatment failure, relapse, and acquired multidrug resistance in 11% (6-17), 10% (5-15) and 8% (3-13), respectively; treatment with the standard WHO regimen for previously treated patients resulted in treatment failure in 6% (2-10), relapse in 5% (2-8), and acquisition of multidrug resistance in 3% (0-6). For patients with drug-sensitive disease treated with the standard retreatment regimen the rates were 1% (0-2), 5% (4-7), and 0·3% (0-0·6).. Treatment of isoniazid-resistant tuberculosis with first-line drugs resulted in suboptimal outcomes, supporting the need for better regimens. Standardised empirical treatment of new cases could be contributing substantially to the multidrug-resistant epidemic, particularly in settings where the prevalence of isoniazid resistance is high.. Canadian Institutes of Health Research.

Topics: Antitubercular Agents; Canada; Humans; Isoniazid; Recurrence; Retreatment; Rifampin; Treatment Failure; Tuberculosis, Pulmonary

The management of latent tuberculosis (LTBI) in children represents an important issue for paediatricians because of the disease burden, the lack of a gold standard for the diagnosis and the high annual risk of progression to active disease. Areas covered: A review of English language articles on LTBI in children, published between the 1st of January 2010 and the 1st of July 2016, was conducted using multiple keywords and standardized terminology in PubMed database. This review provides an updated overview of the available tests for LTBI diagnosis in children, management strategies and treatment options. Expert commentary: Two tests are available for LTBI diagnosis: tuberculin skin test and interferon-gamma release assays, both with a suboptimal specificity and sensitivity, and both with the lack of capability in distinguishing between infection and disease. Several new markers have been identified but further studies are needed. Among all treatment regimes, because of the high safety and efficacy profile showed and to avoid the poor completion rate, the treatment with a three-month course of isoniazid and rifampicin is currently recommended. New vaccines are needed because of the spread of the disease despite BCG vaccination in high risk countries. Currently, 15 new vaccines are in the pipeline.

Topics: Antitubercular Agents; Biomarkers; Chemokine CXCL10; Child; Disease Management; Enzyme-Linked Immunosorbent Assay; Enzyme-Linked Immunospot Assay; Humans; Interferon-gamma; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Rifampin; Tuberculin Test; Tuberculosis Vaccines; Tuberculosis, Pulmonary

Only 25% of multidrug-resistant tuberculosis (MDR-TB) cases are currently diagnosed. Line probe assays (LPAs) enable rapid drug-susceptibility testing for rifampicin (RIF) and isoniazid (INH) resistance and Mycobacterium tuberculosis detection. Genotype MTBDRplusV1 was WHO-endorsed in 2008 but newer LPAs have since been developed.This systematic review evaluated three LPAs: Hain Genotype MTBDRplusV1, MTBDRplusV2 and Nipro NTM+MDRTB. Study quality was assessed with QUADAS-2. Bivariate random-effects meta-analyses were performed for direct and indirect testing. Results for RIF and INH resistance were compared to phenotypic and composite (incorporating sequencing) reference standards. M. tuberculosis detection results were compared to culture.74 unique studies were included. For RIF resistance (21 225 samples), pooled sensitivity and specificity (with 95% confidence intervals) were 96.7% (95.6-97.5%) and 98.8% (98.2-99.2%). For INH resistance (20 954 samples), pooled sensitivity and specificity were 90.2% (88.2-91.9%) and 99.2% (98.7-99.5%). Results were similar for direct and indirect testing and across LPAs. Using a composite reference standard, specificity increased marginally. For M. tuberculosis detection (3451 samples), pooled sensitivity was 94% (89.4-99.4%) for smear-positive specimens and 44% (20.2-71.7%) for smear-negative specimens.In patients with pulmonary TB, LPAs have high sensitivity and specificity for RIF resistance and high specificity and good sensitivity for INH resistance. This meta-analysis provides evidence for policy and practice.

Topics: Antitubercular Agents; DNA Probes; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The global roll-out of Xpert MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) has changed the diagnostic landscape of tuberculosis (TB). More than 16 million tests have been performed in 122 countries since 2011, and detection of multidrug-resistant TB has increased three- to eight-fold compared to conventional testing. The roll-out has galvanised stakeholders, from donors to civil society, and paved the way for universal drug susceptibility testing. It has attracted new product developers to TB, resulting in a robust molecular diagnostics pipeline. However, the roll-out has also highlighted gaps that have constrained scale-up and limited impact on patient outcomes. The roll-out has been hampered by high costs for under-funded programmes, unavailability of a complete solution package (notably comprehensive training, quality assurance, implementation plans, inadequate service and maintenance support) and lack of impact assessment. Insufficient focus has been afforded to effective linkage to care of diagnosed patients, and clinical impact has been blunted by weak health systems. In many countries the private sector plays a dominant role in TB control, yet this sector has limited access to subsidised pricing. In light of these lessons, we advocate for a comprehensive diagnostics implementation approach, including increased engagement of in-country stakeholders for product launch and roll-out, broader systems strengthening in preparation for new technologies, as well as quality impact data from programmatic settings.

Topics: Antibiotics, Antitubercular; Communicable Disease Control; Drug Resistance, Bacterial; Global Health; Health Care Costs; Health Policy; Humans; Mycobacterium tuberculosis; Point-of-Care Testing; Private Sector; Quality Assurance, Health Care; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a pauci-immune necrotizing vasculitis that involves small vessels. Herein, we report an extremely rare case of rifampicin (RFP)-induced AAV. A 42-yearold female was transferred to the West China Hospital due to cough with phlegm for 3 months, fever for 1 month, and fatigue for 2 weeks. The patient was diagnosed with pulmonary tuberculosis (TB) and received anti-TB treatment with isoniazid, RFP, ethambutol, and pyrazinamide (PZA) at her local hospital. After 5 days of anti-TB treatment, her creatinine level rose to 420.2 μmol/L from a normal level prior to anti-TB treatment. Serum proteinase 3 (PR3)-ANCA was positive. After discontinuing the anti-TB drugs and administering protective renal treatment, her renal function improved, whereas PR3-ANCA remained positive. With RFP rechallenge after transfer to our hospital, the patient developed oliguria. Her urine volume increased gradually after RFP was discontinued 3 days later. Therefore, RFPinduced AAV was suspected. Eventually, the patient received prednisone and anti-TB therapy, including isoniazid, ethambutol, PZA, and moxifloxacin. After 2 months, PZA was discontinued. During 6 months of normal, and PR3-ANCA became negative at 4 months. This outcome is characteristic of RFP-induced AAV.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antitubercular Agents; Female; Follow-Up Studies; Humans; Kidney Function Tests; Prednisone; Rifampin; Tuberculosis, Pulmonary

Compared with smear microscopy, the Xpert MTB/RIF assay (Xpert), with superior accuracy and capacity to diagnose rifampicin resistance, has advanced TB diagnostic capability. However, recent trials of Xpert impact have not demonstrated reductions in patient morbidity and mortality. We conducted a narrative review of Xpert impact trials to summarize which patient-relevant outcomes Xpert has improved and explore reasons for no observed morbidity or mortality reductions. We searched PubMed, Google Scholar, Cochrane Library and Embase and identified eight trials meeting inclusion criteria: three individually randomized, three cluster-randomized, and two pre-post trials. In six trials Xpert increased diagnostic yield of bacteriologically-confirmed TB from sputa and in four trials Xpert shortened time to TB treatment. However, all-cause mortality was similar between arms in all six trials reporting this outcome, and the only trial to assess Xpert impact on morbidity reported no impact. Trial characteristics that might explain lack of observed impact on morbidity and mortality include: higher rates of empiric TB treatment in microscopy compared with Xpert arms, enrollment of study populations not comprised exclusively of populations most likely to benefit from Xpert, and health system weaknesses. So far as equipoise exists, future trials that address past limitations are needed to inform Xpert use in resource-limited settings.

Topics: Antitubercular Agents; Bacterial Typing Techniques; Drug Resistance, Bacterial; HIV Infections; Humans; Mycobacterium tuberculosis; Patient Selection; Polymerase Chain Reaction; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Human immunodeficiency virus (HIV) epidemic has undoubtedly increased the incidence of tuberculosis (TB) globally, posing a formidable global health challenge affecting 1.2 million cases. Pulmonary TB assumes utmost significance in the programmatic perspective as it is readily transmissible as well as easily diagnosable. HIV complicates every aspect of pulmonary tuberculosis from diagnosis to treatment, demanding a different approach to effectively tackle both the diseases. In order to control these converging epidemics, it is important to diagnose early, initiate appropriate therapy for both infections, prevent transmission and administer preventive therapy. Liquid culture methods and nucleic acid amplification tests for TB confirmation have replaced conventional solid media, enabling quicker and simultaneous detection of mycobacterium and its drug sensitivity profile Unique problems posed by the syndemic include Acquired rifampicin resistance, drug-drug interactions, malabsorption of drugs and immune reconstitution inflammatory syndrome or paradoxical reaction that complicate dual and concomitant therapy. While the antiretroviral therapy armamentarium is constantly reinforced by discovery of newer and safer drugs every year, only a few drugs for anti tuberculosis treatment have successfully emerged. These include bedaquiline, delamanid and pretomanid which have entered phase III B trials and are also available through conditional access national programmes. The current guidelines by WHO to start Antiretroviral therapy irrespective of CD4+ cell count based on benefits cited by recent trials could go a long way in preventing various complications caused by the deadly duo. This review provides a consolidated gist of the advancements, concepts and updates that have emerged in the management of HIV-associated pulmonary TB for maximizing efficacy, offering latest solutions for tackling drug-drug interactions and remedial measures for immune reconstitution inflammatory syndrome.

Topics: Anti-Retroviral Agents; Antitubercular Agents; Coinfection; Drug Interactions; HIV Infections; Humans; Mycobacterium tuberculosis; Rifampin; Risk Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The lack of capacity to provide laboratory confirmation of a diagnosis of tuberculosis disease (TB) is contributing to enormous gaps in the ability to find, treat and follow TB patients. WHO estimates that globally only about 57% of the notified new cases of pulmonary TB in 2012 and about 19% of rifampicin-resistant TB cases were laboratory confirmed. The Cepheid Xpert(®) MTB/RIF assay has been credited with revolutionizing laboratory testing to aid in the diagnosis of TB and rifampicin-resistant TB. This semi-automated test can detect both the causative agent of TB and mutations that confer rifampicin resistance from clinical specimens within 2 h after starting the test. In this article, we review the performance of the test, its pathway to regulatory approval and endorsement, guidelines for its use and lessons learned from the implementation of the test in low-burden, high-resource countries and in high-burden, low-resource countries.

Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Evaluation Studies as Topic; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Tuberculosis, Pulmonary

Children were often the forgotten victims of the global tuberculosis (TB) epidemic, neglected by traditional TB services as well as maternal and child health initiatives. Luckily this is changing with a greater focus on children and the issues regarding their optimal management. A common misconception is that children with TB are always difficult to diagnose and treat. New diagnostic tools are urgently needed, but most children with TB in high-burden settings can be diagnosed with available approaches and treatment outcomes are generally excellent. Increased TB awareness, appropriate training of health care workers and inclusion in integrated management of childhood illness strategies will improve the access and quality of care that children receive. This review highlights what needs to be done to ensure that no child unnecessarily dies from TB and provides a brief overview of new advances in the field.

Topics: Antitubercular Agents; BCG Vaccine; Child; Global Health; Health Knowledge, Attitudes, Practice; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Vaccination

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

Drug-resistant tuberculosis (TB), especially multidrug-resistant (MDR, resistance to rifampicin and isoniazid) disease, is associated with a worse patient outcome. Drug resistance diagnosed using microbiological culture takes days to weeks, as TB bacteria grow slowly. Rapid molecular tests for drug resistance detection (1 day) are commercially available and may promote faster initiation of appropriate treatment.. To (1) conduct a systematic review of evidence regarding diagnostic accuracy of molecular genetic tests for drug resistance, (2) conduct a health-economic evaluation of screening and diagnostic strategies, including comparison of alternative models of service provision and assessment of the value of targeting rapid testing at high-risk subgroups, and (3) construct a transmission-dynamic mathematical model that translates the estimates of diagnostic accuracy into estimates of clinical impact.. A standardised search strategy identified relevant studies from EMBASE, PubMed, MEDLINE, Bioscience Information Service (BIOSIS), System for Information on Grey Literature in Europe Social Policy & Practice (SIGLE) and Web of Science, published between 1 January 2000 and 15 August 2013. Additional 'grey' sources were included. Quality was assessed using quality assessment of diagnostic accuracy studies version 2 (QUADAS-2). For each diagnostic strategy and population subgroup, a care pathway was constructed to specify which medical treatments and health services that individuals would receive from presentation to the point where they either did or did not complete TB treatment successfully. A total cost was estimated from a health service perspective for each care pathway, and the health impact was estimated in terms of the mean discounted quality-adjusted life-years (QALYs) lost as a result of disease and treatment. Costs and QALYs were both discounted at 3.5% per year. An integrated transmission-dynamic and economic model was used to evaluate the cost-effectiveness of introducing rapid molecular testing (in addition to culture and drug sensitivity testing). Probabilistic sensitivity analysis was performed to evaluate the impact on cost-effectiveness of diagnostic and treatment time delays, diagnosis and treatment costs, and associated QALYs.. A total of 8922 titles and abstracts were identified, with 557 papers being potentially eligible. Of these, 56 studies contained sufficient test information for analysis. All three commercial tests performed well when detecting drug resistance in clinical samples, although with evidence of heterogeneity between studies. Pooled sensitivity for GenoType® MTBDRplus (Hain Lifescience, Nehren, Germany) (isoniazid and rifampicin resistance), INNO-LiPA Rif.TB® (Fujirebio Europe, Ghent, Belgium) (rifampicin resistance) and Xpert® MTB/RIF (Cepheid Inc., Sunnyvale, CA, USA) (rifampicin resistance) was 83.4%, 94.6%, 95.4% and 96.8%, respectively; equivalent pooled specificity was 99.6%, 98.2%, 99.7% and 98.4%, respectively. Results of the transmission model suggest that all of the rapid assays considered here, if added to the current diagnostic pathway, would be cost-saving and achieve a reduction in expected QALY loss compared with current practice. GenoType MTBDRplus appeared to be the most cost-effective of the rapid tests in the South Asian population, although results were similar for GeneXpert. In all other scenarios GeneXpert appeared to be the most cost-effective strategy.. Rapid molecular tests for rifampicin and isoniazid resistance were sensitive and specific. They may also be cost-effective when added to culture drug susceptibility testing in the UK. There is global interest in point-of-care testing and further work is needed to review the performance of emerging tests and the wider health-economic impact of decentralised testing in clinics and primary care, as well as non-health-care settings, such as shelters and prisons.. This study is registered as PROSPERO CRD42011001537.. The National Institute for Health Research Health Technology Assessment programme.

Topics: Antitubercular Agents; Bacteriological Techniques; Cost-Benefit Analysis; Drug Resistance, Microbial; Humans; Isoniazid; Models, Econometric; Nucleic Acid Amplification Techniques; Patient Acceptance of Health Care; Quality-Adjusted Life Years; Rifampin; Sequence Analysis; State Medicine; Technology Assessment, Biomedical; Time Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; United Kingdom

Several systematic reviews suggest that intermittent pulmonary tuberculosis (TB) chemotherapy is effective, but intensity (daily versus intermittent) and duration of rifampicin use (intensive phase only versus both phases) have not been distinguished. In addition, the various outcomes (success, failure, relapse, and default) have only selectively been evaluated.. We conducted a meta-analysis of proportions using all four outcomes as multi-category proportions to examine the effectiveness of WHO category 1 TB treatment regimens. Database searches of studies reporting treatment outcomes of HIV negative subjects were included and stratified by intensity of therapy and duration of rifampicin therapy. Using a bias-adjusted statistical model, we pooled proportions of the four treatment outcome categories using a method that handles multi-category proportions.. A total of 27 studies comprising of 48 data sets with 10,624 participants were studied. Overall, treatment success was similar among patients treated with intermittent (I/I) (88%) (95% CI, 81-92) and daily (D/D) (90%) (95% CI, 84-95) regimens. Default was significantly less with I/I (0%) (95% CI, 0-2) compared to D/D regimens (5%) (95% CI, 1-9). Nevertheless, I/I relapse rates (7%) (95% CI, 3-11) were higher than D/D relapse rates (1%) (95% CI, 0-3).. Treatment regimens that are offered completely intermittently versus completely daily are associated with a trade-off between treatment relapse and treatment default. There is a possibility that I/I regimens can be improved by increasing treatment duration, and this needs to be urgently addressed by future studies.

Topics: Databases, Factual; Female; Humans; Male; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

To supplement previous state-of-art reviews on anti-tuberculosis treatment and to pave the way forward with reference to the current status, we systematically reviewed published literature on clinical research on tuberculosis (TB) over the past decade in the treatment of drug-susceptible and multidrug-resistant TB (MDR-TB), with a focus on drugs, dosing factors and regimens. Our review was restricted to Phase II/III clinical trials, cohort and case-control studies, and systematic reviews of clinical studies. TB programmatic and patient behavioural factors, non-TB drugs, adjunctive surgery, new vaccines, immunotherapy, antiretroviral therapy and management of latent tuberculous infection are outside the scope of this review. An algorithm was used to systematically search PubMed for relevant articles published in English from 1 January 2005 to 31 December 2014. Articles without evaluated factors (drugs, dosing factors and regimens) or comparative analysis of specified anti-tuberculosis treatment outcomes were excluded. Of the 399 articles initially identified, 294 were excluded. The main findings of the remaining 105 articles are described under two categories: presumed drug-susceptible TB and MDR-TB. Fifty-nine articles included under drug-susceptible TB were divided into 12 subcategories: isoniazid, rifampicin, pyrazinamide, fluoroquinolones, fixed-dose combination drugs, dosing frequency, treatment phases, treatment duration, experimental regimens for pulmonary (surrogate markers vs. clinical outcomes) and extra-pulmonary TB. Forty-nine articles included under MDR-TB were divided into seven subcategories: fluoroquinolones, pyrazinamide, second-line injectable drugs, World Health Organization Group 4 and Group 5 drugs, MDR-TB regimens and novel drugs. Clinical research in the last decade and ongoing trials might furnish new paradigms for improving the treatment of this recalcitrant ancient disease.

Topics: Antitubercular Agents; Biomedical Research; Clinical Trials as Topic; Drug Therapy, Combination; Fluoroquinolones; Humans; Isoniazid; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; World Health Organization

The Xpert MTB/RIF assay has been recommended by WHO to replace conventional microscopy, culture, and drug resistance tests. It simultaneously detects both Mycobacterium tuberculosis infection (TB) and resistance to rifampicin (RIF) within two hours. The objective was to review the available research studies on the accuracy of the Xpert MTB/RIF assay for diagnosing pulmonary TB and RIF-resistance in children.. A comprehensive search of Pubmed and Embase was performed up to October 28, 2014. We identified published articles estimating the diagnostic accuracy of the Xpert MTB/RIF assay in children with or without HIV using culture or culture plus clinical TB as standard reference. QUADAS-2 tool was used to evaluate the quality of the studies. A summary estimation for sensitivity, specificity, diagnostic odds ratios (DOR), and the area under the summary ROC curve (AUC) was performed. Meta-analysis was used to establish the overall accuracy.. 11 diagnostic studies with 3801 patients were included in the systematic review. The overall analysis revealed a moderate sensitivity and high specificity of 65% (95% CI: 61 - 69%) and 99% (95% CI: 98 - 99%), respectively, and a pooled diagnostic odds ratio of 164.09 (95% CI: 111.89 - 240.64). The AUC value was found to be 0.94. The pooled sensitivity and specificity for paediatric rifampicin resistance were 94.0% (95% CI: 80.0 - 93.0%) and 99.0% (95% CI: 95.0 - 98.0%), respectively. Hence, the Xpert MTB/RIF assay has good diagnostic and rifampicin performance for paediatric pulmonary tuberculosis.. The Xpert MTB/RIF is sensitive and specific for diagnosing paediatric pulmonary TB. It is also effective in detecting rifamnicin resistance. It can, therefore, be used as an initial diagnostic tool.

Topics: Antitubercular Agents; Child; Drug Resistance, Bacterial; Humans; Rifampin; Tuberculosis, Pulmonary

Tuberculosis (TB) remains rampant throughout the world, in large part due to the lengthy treatment times of current therapeutic options. Rifapentine, a rifamycin antibiotic, is currently approved for intermittent dosing in the treatment of TB. Recent animal studies have shown that more frequent administration of rifapentine could shorten treatment times, for both latent and active TB infection. However, these results were not replicated in a subsequent human clinical trial.. This review analyses the evidence for more frequent administration of rifapentine and the reasons for the apparent lack of efficacy in shortening treatment times in human patients. Inhaled delivery is discussed as a potential option to achieve the therapeutic effect of rifapentine by overcoming the barriers associated with oral administration of this drug. Avenues for developing an inhalable form of rifapentine are also presented.. Rifapentine is a promising active pharmaceutical ingredient with potential to accelerate treatment of TB if delivered by inhaled administration. Progression of current fundamental work on inhaled anti-tubercular therapies to human clinical trials is essential for determining their role in future treatment regimens. While the ultimate goal for global TB control is a vaccine, a short and effective treatment option is equally crucial.

Topics: Administration, Inhalation; Animals; Antitubercular Agents; Drug Administration Schedule; Humans; Rifampin; Tuberculosis, Pulmonary

Accurate, rapid detection of tuberculosis (TB) and TB drug resistance is critical for improving patient care and decreasing TB transmission. Xpert® MTB/RIF assay is an automated test that can detect both TB and rifampicin resistance, generally within two hours after starting the test, with minimal hands-on technical time. The World Health Organization (WHO) issued initial recommendations on Xpert® MTB/RIF in early 2011. A Cochrane Review on the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB and rifampicin resistance was published January 2013. We performed this updated Cochrane Review as part of a WHO process to develop updated guidelines on the use of the test.. To assess the diagnostic accuracy of Xpert® MTB/RIF for pulmonary TB (TB detection), where Xpert® MTB/RIF was used as both an initial test replacing microscopy and an add-on test following a negative smear microscopy result.To assess the diagnostic accuracy of Xpert® MTB/RIF for rifampicin resistance detection, where Xpert® MTB/RIF was used as the initial test replacing culture-based drug susceptibility testing (DST).The populations of interest were adults presumed to have pulmonary, rifampicin-resistant or multidrug-resistant TB (MDR-TB), with or without HIV infection. The settings of interest were intermediate- and peripheral-level laboratories. The latter may be associated with primary health care facilities.. We searched for publications in any language up to 7 February 2013 in the following databases: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; ISI Web of Knowledge; MEDION; LILACS; BIOSIS; and SCOPUS. We also searched the metaRegister of Controlled Trials (mRCT) and the search portal of the WHO International Clinical Trials Registry Platform to identify ongoing trials.. We included randomized controlled trials, cross-sectional studies, and cohort studies using respiratory specimens that allowed for extraction of data evaluating Xpert® MTB/RIF against the reference standard. We excluded gastric fluid specimens. The reference standard for TB was culture and for rifampicin resistance was phenotypic culture-based DST.. For each study, two review authors independently extracted data using a standardized form. When possible, we extracted data for subgroups by smear and HIV status. We assessed the quality of studies using QUADAS-2 and carried out meta-analyses to estimate pooled sensitivity and specificity of Xpert® MTB/RIF separately for TB detection and rifampicin resistance detection. For TB detection, we performed the majority of analyses using a bivariate random-effects model and compared the sensitivity of Xpert® MTB/RIF and smear microscopy against culture as reference standard. For rifampicin resistance detection, we undertook univariate meta-analyses for sensitivity and specificity separately to include studies in which no rifampicin resistance was detected.. We included 27 unique studies (integrating nine new studies) involving 9557 participants. Sixteen studies (59%) were performed in low- or middle-income countries. For all QUADAS-2 domains, most studies were at low risk of bias and low concern regarding applicability.As an initial test replacing smear microscopy, Xpert® MTB/RIF pooled sensitivity was 89% [95% Credible Interval (CrI) 85% to 92%] and pooled specificity 99% (95% CrI 98% to 99%), (22 studies, 8998 participants: 2953 confirmed TB, 6045 non-TB).As an add-on test following a negative smear microscopy result, Xpert®MTB/RIF pooled sensitivity was 67% (95% CrI 60% to 74%) and pooled specificity 99% (95% CrI 98% to 99%; 21 studies, 6950 participants).For smear-positive, culture-positive TB, Xpert® MTB/RIF pooled sensitivity was 98% (95% CrI 97% to 99%; 21 studies, 1936 participants).For people with HIV infection, Xpert® MTB/RIF pooled sensitivity was 79% (95% CrI 70% to 86%; 7 studies, 1789 participants), and for people without HIV infection, it was 86% (95% CrI 76% to 92%; 7 studies, 1470 participants). Comparison with smear microscopy In comparison with smear microscopy, Xpert® MTB/RIF increased TB detection among culture-confirmed cases by 23% (95% CrI 15% to 32%; 21 studies, 8880 participants).For TB detection, if pooled sensitivity estimates for Xpert® MTB/RIF and smear microscopy are applied to a hypothetical cohort of 1000 patients where 10% of those with symptoms have TB, Xpert® MTB/RIF will diagnose 88 cases and miss 12 cases, whereas sputum microscopy will diagnose 65 cases and miss 35 cases. Rifampicin resistance For rifampicin resistance detection, Xpert® MTB/RIF pooled sensitivity was 95% (95% CrI 90% to 97%; 17 studies, 555 rifampicin resistance positives) and pooled specificity was 98% (95% CrI 97% to 99%; 24 studies, 2411 rifampicin resistance negatives). Among 180 specimens with nontuberculous mycobacteria (NTM), Xpert® MTB/RIF was positive in only one specimen that grew NTM (14 studies, 2626 participants).For rifampicin resistance detection, if the pooled accuracy estimates for Xpert® MTB/RIF are applied to a hypothetical cohort of 1000 individuals where 15% of those with symptoms are rifampicin resistant, Xpert® MTB/RIF would correctly identify 143 individuals as rifampicin resistant and miss eight cases, and correctly identify 833 individuals as rifampicin susceptible and misclassify 17 individuals as resistant. Where 5% of those with symptoms are rifampicin resistant, Xpert® MTB/. In adults thought to have TB, with or without HIV infection, Xpert® MTB/RIF is sensitive and specific. Compared with smear microscopy, Xpert® MTB/RIF substantially increases TB detection among culture-confirmed cases. Xpert® MTB/RIF has higher sensitivity for TB detection in smear-positive than smear-negative patients. Nonetheless, this test may be valuable as an add-on test following smear microscopy in patients previously found to be smear-negative. For rifampicin resistance detection, Xpert® MTB/RIF provides accurate results and can allow rapid initiation of MDR-TB treatment, pending results from conventional culture and DST. The tests are expensive, so current research evaluating the use of Xpert® MTB/RIF in TB programmes in high TB burden settings will help evaluate how this investment may help start treatment promptly and improve outcomes.

Topics: Adult; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Tuberculosis, Pulmonary

Although the evidence base regarding the use of the Xpert MTB/RIF assay for diagnosis of pulmonary tuberculosis (TB) when testing respiratory samples is well established, the evidence base for its diagnostic accuracy for extrapulmonary and sputum-scarce pulmonary TB when testing non-respiratory samples is less clearly defined.. A systematic literature search of 7 electronic databases (Medline, EMBASE, ISI Web of Science, BIOSIS, Global Health Database, Scopus and Cochrane Database) was conducted to identify studies of the diagnostic accuracy of the Xpert assay when testing non-respiratory samples compared with a culture-based reference standard. Data were extracted and study quality was assessed using the QUADAS-2 tool. Sensitivities and specificities were calculated on a per-sample basis, stratified by sample type and smear microscopy status and summarised using forest plots. Pooled estimates were calculated for groups with sufficient data.. Twenty-seven studies with a total of 6,026 non-respiratory samples were included. Among the 23 studies comparing Xpert and culture done on the same samples, sensitivity was very heterogeneous with a median sensitivity of 0.83 (IQR, 0.68-0.94) whereas specificities were typically very high (median, 0.98; IQR, 0.89-1.00). The pooled summary estimates of sensitivity when testing smear-positive and smear-negative samples were 0.95 (95% CI 0.91-1.00) and 0.69 (95% CI 0.60-0.80), respectively. Pooled summary estimates of sensitivity varied substantially between sample types: lymph node tissue, 0.96 (95% CI, 0.72-0.99); tissue samples of all types, 0.88 (95% CI, 0.76-0.94); pleural fluid, 0.34 (95% CI, 0.24-0.44); gastric aspirates for diagnosis of sputum-scarce pulmonary TB, 0.78 (IQR, 0.68 - 0.85). Median sensitivities when testing cerebrospinal fluid and non-pleural serous fluid samples were 0.85 (IQR, 0.75-1.00) and 0.67 (IQR, 0.00-1.00), respectively.. Xpert detects with high specificity the vast majority of EPTB cases with smear-positive non-respiratory samples and approximately two-thirds of those with smear-negative samples. Xpert is a useful rule-in diagnostic test for EPTB, especially when testing cerebrospinal fluid and tissue samples. In addition, it has a high sensitivity for detecting pulmonary TB when using gastric aspirate samples. These findings support recent WHO guidelines regarding the use of Xpert for TB diagnosis from non-respiratory samples.

Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Exudates and Transudates; Feces; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary

Accurate and rapid detection of tuberculosis (TB) and drug resistance are critical for improving patient care and decreasing the spread of TB. Xpert® MTB/RIF assay (Xpert) is a rapid, automated test that can detect both TB and rifampicin resistance, within two hours after starting the test, with minimal hands-on technical time, but is more expensive than conventional sputum microscopy.. To assess the diagnostic accuracy of Xpert for pulmonary TB (TB detection), both where Xpert was used as an initial test replacing microscopy, and where Xpert was used as an add-on test following a negative smear microscopy result.To assess the diagnostic accuracy of Xpert for rifampicin resistance detection where Xpert was used as the initial test, replacing conventional culture-based drug susceptibility testing.The population of interest was adults suspected of having pulmonary TB or multidrug-resistant TB (MDR-TB), with or without HIV infection.. We performed a comprehensive search of the following databases: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; ISI Web of Knowledge; MEDION; LILACS; BIOSIS; and SCOPUS. We also searched the metaRegister of Controlled Trials (mRCT) and the search portal of the WHO International Clinical Trials Registry Platform to identify ongoing trials. We performed searches on 25 September 2011 and we repeated them on 15 December 2011, without language restriction.. We included randomized controlled trials, cross-sectional, and cohort studies that used respiratory specimens to compare Xpert with culture for detecting TB and Xpert with conventional phenotypic drug susceptibility testing for detecting rifampicin resistance.. For each study, two review authors independently extracted a set of data using a standardized data extraction form. When possible, we extracted data for subgroups by smear and HIV status. We assessed the quality of studies using the QUADAS-2 tool. We carried out meta-analyses to estimate the pooled sensitivity and specificity of Xpert separately for TB detection and rifampicin resistance detection using a bivariate random-effects model. We estimated the median pooled sensitivity and specificity and their 95% credible intervals (CrI).. We identified 18 unique studies as eligible for this review, including two multicentre international studies, one with five and the other with six distinct study centres. The majority of studies (55.6%) were performed in low-income and middle-income countries. In 17 of the 18 studies, Xpert was performed by trained technicians in reference laboratories.When used as an initial test replacing smear microscopy (15 studies, 7517 participants), Xpert achieved a pooled sensitivity of 88% (95% CrI 83% to 92%) and pooled specificity of 98% (95% CrI 97% to 99%). As an add-on test following a negative smear microscopy result (14 studies, 5719 participants), Xpert yielded a pooled sensitivity of 67% (95% CrI 58% to 74%) and pooled specificity of 98% (95% CrI 97% to 99%). In clinical subgroups, we found the following accuracy estimates: the pooled sensitivity was 98% (95% CrI 97% to 99%) for smear-positive, culture-positive TB and 68% (95% CrI 59% to 75%) for smear-negative, culture-positive TB (15 studies); the pooled sensitivity was 80% (95% CrI 67% to 88%) in people living with HIV and 89% (95% CrI 81% to 94%) in people without HIV infection (four studies). For rifampicin resistance detection (11 studies, 2340 participants), Xpert achieved a pooled sensitivity of 94% (95% CrI 87% to 97%) and pooled specificity of 98% (95% CrI 97% to 99%). In a separate analysis, Xpert could distinguish between TB and nontuberculous mycobacteria (NTM) in clinical samples with high accuracy: among 139 specimens with NTM, Xpert was positive in only one specimen that grew NTM.In a hypothetical cohort of 1000 individuals suspected of having rifampicin resistance (a proxy for MDR-TB), where the prevalence of rifampicin resistance is 30%, we estimated that on average Xpert would wrongly identify 14 patients as being rifampicin resistant. In comparison, where the prevalence of rifampicin resistance is only 2%, we estimated that the number of individuals wrongly identified as rifampicin resistant would increase to 20, an increase of 43%.. This review shows that Xpert used as an initial diagnostic test for TB detection and rifampicin resistance detection in patients suspected of having TB, MDR-TB, or HIV-associated TB is sensitive and specific. Xpert may also be valuable as an add-on test following microscopy for patients who have previously been found to be smear-negative. An Xpert result that is positive for rifampicin resistance should be carefully interpreted and take into consideration the risk of MDR-TB in a given patient and the expected prevalence of MDR-TB in a given setting.Studies in this review mainly assessed sensitivity and specificity of the test when used in reference laboratories in research investigations. Most studies were performed in high TB burden countries. Ongoing use of Xpert in high TB burden countries will contribute to the evidence base on the diagnostic accuracy and clinical impact of Xpert in routine programmatic and peripheral health care settings, including settings where the test is performed at the point of care.

Topics: Adult; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Tuberculosis, Pulmonary

Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.

Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Cost of Illness; Cost-Benefit Analysis; Drug Resistance, Bacterial; Global Health; Health Care Costs; Humans; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Point-of-Care Systems; Predictive Value of Tests; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rifampicin remains one of the first-line drugs used in tuberculosis therapy. This drug's potential to induce the hepatic cytochrome P450 oxidative enzyme system increases the risk of drug-drug interactions. Thus, although the presence of comorbidities typically necessitates the use of multiple drugs, the co-administration of rifampicin and warfarin may lead to adverse drug events. We report a bleeding episode after termination of the co-administration of rifampicin and warfarin and detail the challenges related to international normalized ratio (INR) monitoring.. A 59-year-old Brazilian woman chronically treated with warfarin for atrial fibrillation (therapeutic INR range: 2.0-3.0) was referred to a multidisciplinary anticoagulation clinic at a university hospital. She showed anticoagulation resistance at the beginning of rifampicin therapy, as demonstrated by repeated subtherapeutic INR values. Three months of sequential increases in the warfarin dosage were necessary to reach a therapeutic INR, and frequent visits to the anticoagulation clinic were needed to educate the patient about her pharmacotherapy and to perform the warfarin dosage adjustments. The warfarin dosage also had to be doubled at the beginning of rifampicin therapy. However, four weeks after rifampicin discontinuation, an excessively high INR was observed (7.22), with three-day macroscopic hematuria and the need for an immediate reduction in the warfarin dosage. A therapeutic and stable INR was eventually attained at 50% of the warfarin dosage used by the patient during tuberculosis therapy.. The present case exemplifies the influence of rifampicin therapy on warfarin dosage requirements and the increased risk of bleeding after rifampicin discontinuation. Additionally, this case highlights the need for warfarin weekly monitoring after stopping rifampicin until the maintenance dose of warfarin has decreased to the amount administered before rifampicin use. In particular, patients with cardiovascular diseases and active tuberculosis represent a group with a substantial risk of drug-drug interactions. Learning how to predict and monitor drug-drug interactions may help reduce the incidence of clinically significant adverse drug events.

Topics: Antibiotics, Antitubercular; Anticoagulants; Atrial Fibrillation; Drug Interactions; Female; Hematuria; Humans; Middle Aged; Rifampin; Tuberculosis, Pulmonary; Warfarin

Preventing active tuberculosis (TB) from developing in people with latent tuberculosis infection (LTBI) is important for global TB control. Isoniazid (INH) for six to nine months has 60% to 90% protective efficacy, but the treatment period is long, liver toxicity is a problem, and completion rates outside trials are only around 50%. Rifampicin or rifamycin-combination treatments are shorter and may result in higher completion rates.. To compare the effects of rifampicin monotherapy or rifamycin-combination therapy versus INH monotherapy for preventing active TB in HIV-negative people at risk of developing active TB.. We searched the Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; clinical trials registries; regional databases; conference proceedings; and references, without language restrictions to December 2012; and contacted experts for relevant published, unpublished and ongoing trials.. Randomized controlled trials (RCTs) of HIV-negative adults and children at risk of active TB treated with rifampicin, or rifamycin-combination therapy with or without INH (any dose or duration), compared with INH for six to nine months.. At least two authors independently screened and selected trials, assessed risk of bias, and extracted data. We sought clarifications from trial authors. We pooled relative risks (RRs) with their 95% confidence intervals (CIs), using a random-effects model if heterogeneity was significant. We assessed overall evidence quality using the GRADE approach.. Ten trials are included, enrolling 10,717 adults and children, mostly HIV-negative (2% HIV-positive), with a follow-up period ranging from two to five years. Rifampicin (three/four months) vs. INH (six months)Five trials published between 1992 to 2012 compared these regimens, and one small 1992 trial in adults with silicosis did not detect a difference in the occurrence of TB over five years of follow up (one trial, 312 participants; very low quality evidence). However, more people in these trials completed the shorter course (RR 1.19, 95% CI 1.01 to 1.30; five trials, 1768 participants; moderate quality evidence). Treatment-limiting adverse events were not significantly different (four trials, 1674 participants; very low quality evidence), but rifampicin caused less hepatotoxicity (RR 0.12, 95% CI 0.05 to 0.30; four trials, 1674 participants; moderate quality evidence). Rifampicin plus INH (three months) vs. INH (six months)The 1992 silicosis trial did not detect a difference between people receiving rifampicin plus INH compared to INH alone for occurrence of active TB (one trial, 328 participants; very low quality evidence). Adherence was similar in this and a 1998 trial in people without silicosis (two trials, 524 participants; high quality evidence). No difference was detected for treatment-limiting adverse events (two trials, 536 participants; low quality evidence), or hepatotoxicity (two trials, 536 participants; low quality evidence). Rifampicin plus pyrazinamide (two months) vs. INH (six months)Three small trials published in 1994, 2003, and 2005 compared these two regimens, and two reported a low occurrence of active TB, with no statistically significant differences between treatment regimens (two trials, 176 participants; very low quality evidence) though, apart from one child from the 1994 trial, these data on active TB were from the 2003 trial in adults with silicosis. Adherence with both regimens was low with no statistically significant differences (four trials, 700 participants; very low quality evidence). However, people receiving rifampicin plus pyrazinamide had more treatment-limiting adverse events (RR 3.61, 95% CI 1.82 to 7.19; two trials, 368 participants; high quality evidence), and hepatotoxicity (RR 4.59, 95% 2.14 to 9.85; three trials, 540 participants; moderate quality evidence). Weekly, directly-observed rifapentine plus INH (three months) vs. daily, self-administered INH (nine months)A large trial conducted from 2001 to 2008 am. Trials to date of shortened prophylactic regimens using rifampicin alone have not demonstrated higher rates of active TB when compared to longer regimens with INH. Treatment completion is probably higher and adverse events may be fewer with shorter rifampicin regimens. Shortened regimens of rifampicin with INH may offer no advantage over longer INH regimens. Rifampicin combined with pyrazinamide is associated with more adverse events. A weekly regimen of rifapentine plus INH has higher completion rates, and less liver toxicity, though treatment discontinuation due to adverse events is probably more likely than with INH.

Topics: Adult; Antibiotics, Antitubercular; Child; Directly Observed Therapy; Drug Administration Schedule; HIV Seronegativity; Humans; Isoniazid; Latent Tuberculosis; Randomized Controlled Trials as Topic; Rifabutin; Rifampin; Tuberculosis, Pulmonary

New drugs and regimens with the potential to transform tuberculosis treatment are presently in early stage clinical trials.. The goal of the present study was to infer the required duration of these treatments.. A meta-regression model was developed to predict relapse risk using treatment duration and month 2 sputum culture positive rate as predictors, based on published historical data from 24 studies describing 58 regimens in 7793 patients. Regimens in which rifampin was administered for the first 2 months but not subsequently were excluded. The model treated study as a random effect.. The model predicted that new regimens of 4 or 5 months duration with rates of culture positivity after 2 months of 1% or 3%, would yield relapse rates of 4.0% or 4.1%, respectively. In both cases, the upper limit of the 2-sided 80% prediction interval for relapse for a hypothetical trial with 680 subjects per arm was <10%. Analysis using this model of published month 2 data for moxifloxacin-containing regimens indicated they would result in relapse rates similar to standard therapy only if administered for ≥5 months.. This model is proposed to inform the required duration of treatment of new TB regimens, potentially hastening their accelerated approval by several years.

Topics: Follow-Up Studies; Humans; Meta-Analysis as Topic; Microbiological Techniques; Mycobacterium tuberculosis; Prognosis; Pyrazinamide; Recurrence; Regression Analysis; Rifampin; Risk Factors; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB). However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection.. We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB.. We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI) assay, Nitrate Reductase Assay (NRA) and MODS tests): for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%.. In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests.. Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.

Topics: Antitubercular Agents; Bias; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Predictive Value of Tests; Reagent Kits, Diagnostic; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

A 47-year-old man diagnosed with pulmonary tuberculosis was referred to our hospital. Rifampicin, isoniazid, pyrazinamide and ethambutol were administered, and the patient's symptoms promptly improved. On the 19th hospital day, he developed acute kidney injury with a fever and chills. Renal biopsy specimens indicated tubulointerstitial nephritis. Suspecting rifampicin-induced acute kidney injury, we discontinued the rifampicin and administered levofloxacin in its place. The patient's serum creatinine level subsequently gradually improved. We herein report this case and review eight cases reported in Japan. We found that the rifampicin toxicity appeared at both the initial administration and readministration. All eight patients presented with proteinuria.

Topics: Acute Kidney Injury; Antitubercular Agents; Creatinine; Drug Therapy, Combination; Humans; Japan; Male; Middle Aged; Nephritis, Interstitial; Rifampin; Tuberculosis, Pulmonary

A review of the records of patients seen between 2004 and 2011 at the Dermatology Clinic of the São Paulo University Medical School showed that only two leprosy patients had been co-infected with tuberculosis (TB). One patient showed a type 1 leprosy reaction during the first 3 months of treatment of pleural TB and in the other patient, pulmonary TB was diagnosed during the first 3 months of treatment of a type 1 leprosy reaction. Both patients showed normal cellular immune response tests, including those of the interferon-gamma (IFN-γ)/interleukin 12 (IL-12) axis. Although both mycobacterial infections are endemic in developing countries like Brazil, the co-infection has hardly been reported in the last decade. There is no suitable explanation for this observation. The reports on the interaction between the two mycobacteria are highly speculative: some studies suggest that leprosy, especially the anergic form, would predispose to TB, whereas other investigations suggested an antagonism between the two diseases.

Topics: Adult; Brazil; Coinfection; Female; Humans; Immunity, Cellular; Interferon-gamma; Interleukin-12; Isoniazid; Leprosy; Male; Middle Aged; Prednisone; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pleural; Tuberculosis, Pulmonary; White People

Fixed-dose combination (FDC) formulations are currently recommended for the treatment of active tuberculosis (TB). We have conducted a systematic review to evaluate the risk of treatment failure or disease relapse, acquired drug resistance, bacterial conversion after 2 months of treatment, adverse events, adherence and treatment satisfaction associated with treatment of active TB using FDC or separate drug formulations. We searched four electronic databases for randomised controlled trials and cohort studies. Results from trials that directly compared FDC to separate drug formulations were pooled. Results from other studies were reported separately. We identified 2450 citations from which 15 controlled trials and four additional relevant studies were included. In the 15 trials there were no differences in acquired drug resistance, bacterial conversion after 2 months of treatment or adverse drug reactions with FDC or separate drug formulations. There was a trend toward higher risk of failure or relapse with FDC (pooled relative risk 1.28 (95% CI 0.99-1.7)). Based on individual study results, only one of two trials that assessed treatment satisfaction, and none of five that assessed patient adherence, favoured FDCs. Although FDC formulations simplify TB therapy, the current evidence does not indicate that these formulations improve treatment outcomes among patients with active TB.

Topics: Antitubercular Agents; Drug Combinations; Drug Resistance, Bacterial; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Treatment Failure; Tuberculosis, Pulmonary

To provide a descriptive synthesis of the evidence assessing the efficacy and safety of higher doses of rifampin (RMP) for the treatment of pulmonary tuberculosis (TB).. Systematic review of randomized controlled trials that evaluate a range of RMP doses, including doses higher than standard (>10 mg/kg or >600 mg), used as part of combination drug therapies for pulmonary TB. Two reviewers applied inclusion criteria, assessed trial quality and extracted data. Inclusion criteria were smear- or culture-confirmed pulmonary TB, and English and French language articles. Exclusion criteria were RMP monotherapy and smear-negative TB. Outcomes included were sputum culture conversion, treatment failure, recurrence and adverse events, including hepatotoxicity and flu-like syndrome.. Of 14 trials (4256 participants) identified, 12 were conducted before 1980. Four trials were considered high quality according to published guidelines. Study characteristics, including history of prior TB treatment, dose of RMP, duration of treatment, timing of introduction of intervention treatment, concomitant drugs, and duration of follow-up, varied, making synthesis of efficacy data challenging. Several trials suggested an advantage in terms of likelihood of culture conversion among patients receiving at least 900 mg RMP. However, an increased incidence of flu-like syndrome was seen when RMP doses of 900 mg and higher were given intermittently.. Historical trials suggest that higher than standard RMP dosing results in improved culture conversion rates. Phase 2 and 3 clinical trials evaluating higher doses of RMP and other rifamycins are needed to confirm efficacy and assure tolerability. Pharmacokinetic studies will be needed to inform the development of such trials.

Topics: Animals; Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Humans; Recurrence; Rifampin; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

The dosages of antituberculosis agents recommended for treatment of childhood tuberculosis often reflect those for adult patients with similar mg/kg body weight dosages and ranges advised. Literature relating to the pharmacokinetics and pharmacodynamics of rifampicin (RMP) is reviewed and the serum concentrations reached by adults, both patients and healthy volunteers and children, established or not established on RMP, compared. Straight line regression of maximum RMP serum concentrations (C(max)) on dosage, weighted for the number of individuals, found slopes (SE) of 1.025 (0.067) and 0.881 (0.046) respectively for adult volunteers not established and established on RMP (P = 0.076), and similarly 0.748 (0.057) and 0.684 (0.038) respectively for adult patients (P < 0.001) and 0.622 (0.050) and 0.368 (0.041) respectively for children (P < 0.001). These results indicate that for equivalent RMP dosages adult patients reach a lower C(max) than adult volunteers and that adults, both volunteers and patients established on RMP reach higher C(max) values than children; children established on RMP require approximately twice the mg/kg body weight dosage of RMP to reach serum concentrations equivalent to those of adults. It is noteworthy that many adult patients receiving currently recommended RMP dosages also do not reach the often recommended RMP 2 h serum concentration of 8 μg/mL.

Topics: Adult; Antitubercular Agents; Biological Availability; Child; Dose-Response Relationship, Drug; Drug Dosage Calculations; Female; Humans; Male; Practice Guidelines as Topic; Rifampin; Tuberculosis, Pulmonary

A case of isoniazid induced gynecomastia is being reported in an 18-year old male, who received a re-treatment regimen for the relapse of pulmonary tuberculosis (TB). At the end of two months of the treatment, the patient developed a painless unilateral gynecomastia, which completely disappeared after a month of the cessation of isoniazid. A review of literature on isoniazid induced gynecomastia is discussed.

Topics: Adolescent; Anti-Bacterial Agents; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Gynecomastia; Humans; Isoniazid; Male; Pyrazinamide; Retreatment; Rifampin; Sputum; Streptomycin; Treatment Outcome; Tuberculosis, Pulmonary

While we wait for improved new anti-tuberculosis drugs, the main aim for improving current treatment should be to optimize the use of the two current drugs, rifampicin and the pro-drug pyrazinamide, which are responsible to a similar extent for the entire sterilizing activity of current therapy. The rifamycin activity could be improved by increasing the dose size of rifampicin or by daily dosing with long acting rifapentine. Increasing the dose size of pyrazinamide is limited by toxicity but an alternative approach is to use inhalation with pyrazinoic acid, as an adjunct to standard oral therapy. This would acidify pulmonary lesions, thus increasing the bactericidal activity of the orally administered pyrazinamide. Because pyrazinoic acid is the active moiety, it should also increase overall pyrazinamide activity and, because most resistance arises in the pncA gene that converts pyrazinamide to pyrazinoic acid, it should act on most pyrazinamide resistant strains. Inhalation technology allows delivery of drug to lesions rapidly and without first pass toxicity. The properties of drug containing microparticles and nanoparticles during inhalation and storage are reviewed. Spray-dried larger Trojan particles in which the smaller encapsulated particles can reside should be able to improve localisation within alveoli and avoid some storage problems.

Topics: Administration, Inhalation; Antitubercular Agents; Area Under Curve; Biological Availability; Dosage Forms; Humans; Lung; Multicenter Studies as Topic; Particle Size; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

We report a case of a 61-year-old Filipino-American male who developed pulmonary tuberculosis after travel to the Philippines. His history, presentation, imaging findings, and clinical course are presented as well as a discussion of the interesting imaging features in his case. Our case highlights the importance of having a high index of suspicion for tuberculosis in the setting of "bronchiectatic air bronchograms" as well as the value of computed tomography (CT) imaging in pulmonary tuberculosis.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Bronchiectasis; Bronchoalveolar Lavage; Bronchoscopy; Diagnosis, Differential; Ethambutol; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Radiography; Rifampin; Tuberculosis, Pulmonary

Renal transplant recipients are prone to a variety of infections due a persistent immunodepleted state. Incidence of tuberculosis in this population is much higher compared with the general population. While pulmonary tuberculosis still remains the commonest form in this population, renal allograft tuberculosis is very rare. We report two cases of isolated allograft tuberculosis and one case of allograft tuberculosis with coexistent pleuro-pulmonary and bone marrow involvement. All three cases had presented with pyrexia of unknown origin, wherein despite extensive investigations the cause was not found. In two cases the diagnosis was confirmed on histology. Two cases responded to non-rifampicin-based modified antitubercular treatment and one to conventional four-drug Rifampicin-based regimen. Graft function improved in two cases while in one case the graft was lost. Tuberculosis involving the renal allograft is a potential cause for graft dysfunction/loss and requires a high index of suspicion for diagnosis. Timely detection and early institution of therapy can help save the renal allograft.

Topics: Adult; Antibiotics, Antitubercular; Biopsy; Bone Marrow; Drug Therapy, Combination; Female; Fever of Unknown Origin; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Rifampin; Transplantation, Homologous; Treatment Outcome; Tuberculosis, Pleural; Tuberculosis, Pulmonary; Tuberculosis, Renal; Ultrasonography, Doppler, Color

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

To evaluate the efficacy and safety of rifapentine (RPT) vs. rifampicin (RMP) for the treatment of pulmonary tuberculosis (PTB).. Systematic review of randomised controlled trials (RCTs) that compared combination drug regimens containing RPT with those containing RMP for the treatment of drug-susceptible or previously untreated PTB.. Nine RCTs were identified. Statistically significant differences were not found in the cure rates, severe adverse effects, severe hepatotoxicity or bacteriological relapse rates between the regimens containing once- or twice-weekly RPT and those containing daily RMP for human immunodeficiency virus (HIV) negative patients, but were found in the bacteriological relapse rates between regimens containing once-weekly or less frequent RPT and those containing twice- or thrice-weekly RMP: the pooled relative risks in the two subgroups were respectively 1.71 (95%CI 1.13-2.58, P = 0.01) and 2.44 (95%CI 1.15-5.18, P = 0.02). The trial for HIV-positive patients did not show significant differences in the sputum conversion rate, severe adverse effects or bacteriological relapse rate between the RPT- and RMP-containing regimens; four of the five relapses were associated with the RPT-containing regimen, but none of the three relapses with the RMP-containing regimen produced monoresistance to rifamycin (RIF).. Once- or twice-weekly RPT and daily RMP have similar efficacy and safety for the treatment of HIV-negative PTB, but once-weekly or less frequent use of RPT, in comparison with twice- or thrice-weekly RMP, increases the risk of bacteriological relapse. RPT might increase the risk of resistance to RIF in HIV-positive patients.

Topics: Antitubercular Agents; Humans; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Pulmonary

Treatment regimens for active tuberculosis (TB) that are intermittent, or use rifampin during only the initial phase, offer practical advantages, but their efficacy has been questioned. We conducted a systematic review of treatment regimens for active TB, to assess the effect of duration and intermittency of rifampin use on TB treatment outcomes.. PubMed, Embase, and the Cochrane CENTRAL database for clinical trials were searched for randomized controlled trials, published in English, French, or Spanish, between 1965 and June 2008. Selected studies utilized standardized treatment with rifampin-containing regimens. Studies reported bacteriologically confirmed failure and/or relapse in previously untreated patients with bacteriologically confirmed pulmonary TB. Pooled cumulative incidences of treatment outcomes and association with risk factors were computed with stratified random effects meta-analyses. Meta-regression was performed using a negative binomial regression model. A total of 57 trials with 312 arms and 21,472 participants were included in the analysis. Regimens utilizing rifampin only for the first 1-2 mo had significantly higher rates of failure, relapse, and acquired drug resistance, as compared to regimens that used rifampin for 6 mo. This was particularly evident when there was initial drug resistance to isoniazid, streptomycin, or both. On the other hand, there was little evidence of difference in failure or relapse with daily or intermittent schedules of treatment administration, although there was insufficient published evidence of the efficacy of twice-weekly rifampin administration throughout therapy.. TB treatment outcomes were significantly worse with shorter duration of rifampin, or with initial drug resistance to isoniazid and/or streptomycin. Treatment outcomes were similar with all intermittent schedules evaluated, but there is insufficient evidence to support administration of treatment twice weekly throughout therapy.

Topics: Antibiotics, Antitubercular; Drug Administration Schedule; Drug Resistance, Bacterial; Humans; Isoniazid; Randomized Controlled Trials as Topic; Recurrence; Regression Analysis; Rifampin; Risk Factors; Streptomycin; Treatment Failure; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Cohort Studies; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Isoniazid; Randomized Controlled Trials as Topic; Recurrence; Rifampin; Streptomycin; Treatment Failure; Tuberculosis, Pulmonary

Silicosis, the most prevalent of the pneumoconioses, is caused by inhalation of crystalline silica particles. Silica-exposed workers, with or without silicosis, are at increased risk for tuberculosis and nontuberculous mycobacteria-related diseases. The risk of a patient with silicosis developing tuberculosis is higher (2.8 to 39 times higher, depending on the severity of the silicosis) than that found for healthy controls. Various regimens for tuberculosis chemoprophylaxis in patients with silicosis have been studied, all of which present similar efficacy and overall risk reduction to about one half of that obtained with placebo. Long-term regimens have potential side effects (particularly hepatotoxicity). In addition, the use of such regimens can jeopardize adherence to treatment. The current guidelines recommend that tuberculin skin tests be performed, and, if positive, that chemoprophylaxis be instituted. There are several possible regimens, varying in terms of the drugs prescribed, as well as in terms of treatment duration. We recommend the use of isoniazid at 300 mg/day (or 10 mg/kg/day) for six months for patients with silicosis, as well as for healthy patients with periods of exposure to silica longer than 10 years and strongly positive tuberculin skin test results (induration > or = 10 mm). Nevertheless, further studies are necessary so that indications, drugs, doses and duration of chemoprophylaxis regimens can be more properly defined.

Topics: Antibiotics, Antitubercular; Brazil; Humans; Isoniazid; Occupational Exposure; Pyrazinamide; Rifampin; Silicon Dioxide; Silicosis; Silicotuberculosis; Tuberculosis, Pulmonary

Chemotherapy of pulmonary MAC (Mycobacterium avium complex) infection has been almost universally agreed with the multidrugs regimen that contains Clarithromycin (CAM), Rifampin (RFP), Ethambtol (EB), and aminoglycoside in case of advanced stage. One of the reason for the multidrugs regimen which is similar to tuberculous chemotherapy is to inhibit the emersion of resistant MAC strain. The other reasons, enhancement of anti microbial activity and response to polyclonal infection are unique to the MAC chemotherapy. In the current MAC chemotherapy, both CAM and aminoglycoside are main axes because only they can suppress the growth of MAC alone respectively. Efficacy of CAM was revealed through the randomized controlled trials of disseminated MAC infection with HIV and that consequences applied to pulmonary MAC infection treatment. CAM is not effective unless exceed 2 microg/ml blood concentration. RFP decreases CAM blood concentration remarkably, but the regimens contained RFP and CAM are superior clinically to the regimens without RFP. There seemed to be unknown pharmacological mechanisms with RFP. Although the advantage of aminoglycosides is easily achieved high blood concentration, if aminoglycoside dosage is exceed 15 mg/kg, the possibility of auditory disturbance increase. About the duration of MAC chemotherapy, many guidelines recommended that one year continuation after the negative conversion of sputum culture. It is not the evidence but an expert opinion. We often experience recurrences several months later after the all drugs are ceased. The interval days to positive conversion of sputum culture from the day of completion of chemotherapy are randomly distributed with weibull's equation. It suggests that exogenous re-infection may cause the recurrence of pulmonary MAC infection as pointed out by Wallace Jr. Considering these issues, we have the conception of pulmonary MAC infection chemotherapy as follows. 1. Full dose induction chemotherapy (two years). 2. Maintenance chemotherapy (one year). 3. Preventive chemotherapy (one year). These conceptions have to be the problem validated. However, these current chemotherapies are not effective adequately, we need the combination treatment with surgical resection when indicated as a localized focus for example. Generally chemotherapy could not cured the destructed bronchial lesion due to MAC infection as like as local bronchiectasis or cavities. Consequently, the chemotherapy just after the surgical resec

Topics: Aminoglycosides; Antitubercular Agents; Clarithromycin; Combined Modality Therapy; Drug Therapy, Combination; Ethambutol; Evidence-Based Medicine; Humans; Mycobacterium avium-intracellulare Infection; Practice Guidelines as Topic; Rifampin; Secondary Prevention; Time Factors; Tuberculosis, Pulmonary

The World Health Organization estimates that up to 50 million persons worldwide may be infected with drug resistant strains of TB. The fatality rate of MDR-TB is 20-80%. Drug resistant tuberculosis cases are on the rise in Pakistan. The reasons for this menace are multiple including improper prescription, compliance and over the counter sale of anti-TB drugs. The treatment cost of drug-resistant TB is high, both to the individual patient and society. This article is written to create awareness about the available second line drugs and those in the pipeline. Considering the fact that resistant tuberculosis is difficult to manage, it is suggested that these drugs should only be used after consultation with a physician experienced in the treatment of drug resistant TB. The most frequent mistake made by treating physicians is addition of one drug in the failing regimen. At present, 27 potential anti-TB drugs are at various stages of development. The aim is that by 2010 at least one of these molecules completes the journey and should come in the market.

Topics: Antitubercular Agents; Fluoroquinolones; Humans; Rifabutin; Rifampin; Treatment Failure; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The current 6-month tuberculosis (TB) therapy is suboptimal with significant side effects and a poor patient compliance problem that frequently selects drug-resistant organisms. The increasing drug-resistant TB problem highlights the need to develop new and more effective drugs. Significant progress has been made recently with several new drug candidates currently in clinical trials. Improved understanding of persister biology and development of persister drugs are likely to be important for developing a more effective therapy.

Topics: Adamantane; AIDS-Related Opportunistic Infections; Animals; Anti-Bacterial Agents; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Drugs, Investigational; Ethylenediamines; Extensively Drug-Resistant Tuberculosis; Fluoroquinolones; Humans; Isoniazid; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Rifampin; Treatment Refusal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rifamycins are an essential component of modern short-course regimens for treating tuberculosis. Rifabutin has favourable pharmacokinetic and pharmacodynamic properties and is less prone to drug-drug interactions than rifampicin. It could contribute to shortening of therapy or simplify treatment in HIV-positive people who also need antiretroviral drugs.. To compare combination drug regimens containing rifabutin with those containing rifampicin for treating pulmonary tuberculosis. We searched Cochrane Infectious Diseases Group Specialized Register (January 2007), CENTRAL (The Cochrane Library 2006, Issue 4), MEDLINE (1966 to January 2007), EMBASE (1974 to January 2007), and LILACS (1982 to January 2007). We also searched the Indian Journal of Tuberculosis (1983 to 2006), conference abstracts, reference lists, and unpublished data on file at Pfizer Inc.. Randomized and quasi-randomized trials including participants with sputum smear and/or culture-confirmed tuberculosis that compared a rifabutin-containing with an otherwise identical rifampicin-containing regimen.. Two authors independently assessed study eligibility and methodological quality, and extracted data. Dichotomous data were analysed and combined using relative risks (RR) with 95% confidence intervals (CI) using a fixed-effect model. Subgroup analyses were carried out according to rifabutin dose.. Five trials with a total of 924 participants met the inclusion criteria; 5% of participants were HIV positive. Only one small trial was methodologically adequate. The two largest trials (818 participants) had unclear allocation concealment and included < 90% of randomized participants in the analysis. There was no statistically significant difference in between the regimens for cure (RR 1.00, 95% CI 0.96 to 1.04; 553 participants, 2 trials) or relapse (RR 1.23, 95% CI 0.45 to 3.35; 448 participants, 2 trials). The number of adverse events was not significantly different (RR 1.42, 95% CI 0.88 to 2.31; 714 participants, 3 trials), though the RR increased with rifabutin dose: 150 mg (RR 0.98, 95% CI 0.45 to 2.12; 264 participants, 2 trials); and 300 mg (RR 1.78, 95% CI 0.94 to 3.34; 450 participants, 2 trials). However, lack of dose adjustment by weight in the relevant trials complicates interpretation of this relationship.. The replacement of rifampicin by rifabutin for first-line treatment of tuberculosis is not supported by the current evidence. HIV-positive people with tuberculosis, the group most likely to benefit from the rifabutin use, are under-represented in trials to date, and further trials in this group would be useful.

Topics: Antibiotics, Antitubercular; Humans; Randomized Controlled Trials as Topic; Rifabutin; Rifampin; Tuberculosis, Pulmonary; Uveitis

In the last decade, multidrug-resistant tuberculosis (MDR-TB, defined as resistance to at least isoniazid and rifampicin) has become an epidemiological issue of first priority at the global level. Case management needs to be simplified and standardised, as in many countries MDR-TB cases cannot receive individualised attention from specialist physicians. However, before any decision can be made on standardisation, a careful analysis must first be made of the evidence and controversies behind the various published recommendations. Unfortunately, the controversies outweigh the evidence. The difficulties lie not only in the absence of controlled trials to validate specific recommendations, but also in the very different and even contradictory results found in the literature. It is therefore essential to analyse these discrepancies before developing rational, uniform recommendations. The analysis should encompass the most essential and controversial issues regarding the management of MDR-TB patients: 1) confirmation of diagnosis in a suspected MDR-TB patient, and determination of the value of drug susceptibility testing; 2) the number of anti-tuberculosis drugs required to treat MDR-TB; 3) the most rational use of effective drugs against tuberculosis; 4) the advisable length of parenteral drug administration or of the initial phase of treatment; 5) the contribution of surgery to the management of MDR-TB patients; and 6) the optimal regimen for treating MDR-TB: standardised vs. individualised regimens. The evidence and controversies regarding each of the above questions are analysed with the aim of facilitating decision making in the treatment of these complex patients.

Topics: Antibiotics, Antitubercular; Case Management; Clinical Trials as Topic; Drug Administration Routes; Humans; Isoniazid; Microbial Sensitivity Tests; Rifampin; Time Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rifapentine is a recently approved antituberculosis drug that has not yet been widely used in clinical settings. Clinical data support intermittent use of rifapentine with isoniazid during the continuation phase of tuberculosis treatment. Patients with culture-positive, noncavitary, pulmonary tuberculosis whose sputum smear is negative for acid-fast bacilli at the end of the 2-month intensive treatment phase are eligible for rifapentine therapy. Rifapentine should not be used in human immunodeficiency virus-infected patients, given their increased risk of developing rifampin resistance with currently recommended dosages. Rifapentine is not currently recommended for children aged <12 years, pregnant or lactating women, or individuals with culture-negative or extrapulmonary tuberculosis. Rifapentine (600 mg) is administered once weekly with isoniazid (900 mg) during the continuation phase of treatment. This combination should only be given under direct observation. As with rifampin, drug-drug interactions are common, and regular patient monitoring is required. Ease of administration makes this regimen attractive both for tuberculosis-control programs and for patients.

Topics: Antitubercular Agents; Humans; Rifampin; Tuberculosis, Pulmonary

Multidrug-resistant tuberculosis (MDR-TB) is an increasing global problem, with most cases arising from a mixture of physician error and patient non-compliance during treatment of susceptible TB. The extent and burden of MDR-TB varies significantly from country to country and region to region. As with TB itself, the overwhelming burden of MDR-TB is in high-burden resource-poor countries. The diagnosis depends on confirming the drug susceptibility pattern of isolated organisms, which is often only possible in resource-rich settings. There should be a strong suspicion of drug resistance, including MDR-TB, in persons with a history of prior treatment or in treatment failure cases. Treatment in developed countries is expensive and involves an individualized regimen based on drug susceptibility data and use of reserve drugs. In resource-poor settings a WHO retreatment regimen may be used, but increasingly the move is to a directly observed treatment based 'DOTS-plus' regimen in a supported national TB programme. However, even where such treatment is given, the outcome for patients is significantly worse than that for fully susceptible TB and has a much higher cost.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Developed Countries; Developing Countries; Humans; Isoniazid; Patient Compliance; Rifampin; Risk Factors; Treatment Failure; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

To summarize, using meta-analysis, the accuracy of bacteriophage-based assays for the detection of rifampicin resistance in Mycobacterium tuberculosis.. By searching multiple databases and sources we identified a total of 21 studies eligible for meta-analysis. Of these, 14 studies used phage amplification assays (including eight studies on the commercial FASTPlaque-TB kits), and seven used luciferase reporter phage (LRP) assays. Sensitivity, specificity, and agreement between phage assay and reference standard (e.g. agar proportion method or BACTEC 460) results were the main outcomes of interest.. When performed on culture isolates (N=19 studies), phage assays appear to have relatively high sensitivity and specificity. Eleven of 19 (58%) studies reported sensitivity and specificity estimates > or =95%, and 13 of 19 (68%) studies reported > or =95% agreement with reference standard results. Specificity estimates were slightly lower and more variable than sensitivity; 5 of 19 (26%) studies reported specificity <90%. Only two studies performed phage assays directly on sputum specimens; although one study reported sensitivity and specificity of 100 and 99%, respectively, another reported sensitivity of 86% and specificity of 73%.. Current evidence is largely restricted to the use of phage assays for the detection of rifampicin resistance in culture isolates. When used on culture isolates, these assays appear to have high sensitivity, but variable and slightly lower specificity. In contrast, evidence is lacking on the accuracy of these assays when they are directly applied to sputum specimens. If phage-based assays can be directly used on clinical specimens and if they are shown to have high accuracy, they have the potential to improve the diagnosis of MDR-TB. However, before phage assays can be successfully used in routine practice, several concerns have to be addressed, including unexplained false positives in some studies, potential for contamination and indeterminate results.

Topics: Antibiotics, Antitubercular; Culture Media; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacteriophages; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Rifampin; Sensitivity and Specificity; Time Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Since the introduction of rifampicin, it has been believed that pulmonary tuberculosis can be cured with medication alone. However, if tubercle bacilli are resistant to isoniazid and rifampicin, the success rate of medical treatment falls considerably. These bacilli are defined as multidrug-resistant tuberculosis (MDR-TB) and have been of great concern. To improve the outcome of chemotherapy in patients with MDR-TB, adjuvant resectional surgery has been advocated. Currently the most common indication for pulmonary resection in patients with tuberculosis is MDR-TB. Pulmonary resection for MDR-TB achieves a high cure rate with low morbidity and mortality. The majority of the MDR-TB patients in the previously reported surgical series were middle-aged, and pulmonary resection for MDR-TB has not been performed on the octogenarians. The oldest patient in our series was 65 years old. Nevertheless, pulmonary resection is worth considering for an octogenarian infected with MRD-TB because pulmonary resection achieves a high success rate with low morbidity and mortality.

Topics: Aged; Aged, 80 and over; Antitubercular Agents; Combined Modality Therapy; Drug Resistance, Multiple; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pneumonectomy; Postoperative Care; Rifampin; Tuberculosis, Pulmonary

A 2-month regimen of rifampin and pyrazinamide (2RZ) became an accepted alternative for treatment of latent tuberculosis (TB) after initial studies in HIV-seropositive patients demonstrated safety and efficacy. Once this alternative came into widespread use, however, a number of cases of severe and fatal hepatitis associated with 2RZ were reported. Although the initial experience with HIV-seropositive patients was encouraging, subsequent research demonstrated that the risk of 2RZ-associated hepatitis is considerably greater than the risk of hepatitis associated with isoniazid treatment for latent TB. Updated guidelines now recommend only restricted use of the 2RZ regimen for latent TB, with careful supervision.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Pulmonary

A 65-year-old man was admitted to hospital for treatment of pulmonary tuberculosis. He was treated with isoniazid (INH), rifampicin (RFP), ethambutol (EB), and pyrazinamide (PZA). On the 14th day, he developed a fever and interstitial pneumonia, which improved promptly after discontinuation of the antituberculous drugs. Drug lymphocyte stimulation tests against INH, RFP and PZA were negative. However, the provocation test on INH (only) was positive, leading to a diagnosis of pneumonitis caused by INH. We then tried desensitization of INH over a period of two weeks, which was successful and occurred without any clinical event. In the past, five cases of INH-induced pneumonitis were reported, but desensitization of INH did not occur in any. We conclude that physicians should be aware not only of paradoxical reactions but also of drug-induced pneumonitis when a new pulmonary infiltrate develops in the course of tuberculosis treatment. Furthermore, drug desensitization may be possible in some cases of drug-induced pneumonitis.

Topics: Aged; Antibiotics, Antitubercular; Antitubercular Agents; Desensitization, Immunologic; Ethambutol; Humans; Isoniazid; Male; Pneumonia; Rifampin; Tuberculosis, Pulmonary

Several rifamycin derivatives have been developed during the last 15 years for the treatment of mycobacterial infections. For tuberculosis, rifabutin (RFB) showed strong activity and seemed to be suitable when tuberculosis patients were also treated for their AIDS infection. Rifapentine (RPT) was evaluated in patients with or without AIDS for its intermittent use. It displayed promising activity but must be strengthened in situations, such as AIDS or patients without AIDS but with cavities. Rifalazil (RLZ) has been evaluated in mice but the dosages used were much higher than those tolerated by patients. Regarding Mycobacterium avium infections, RFB showed significant prophylactic activity in humans, RPT displayed some activity in mice and RLZ showed modest activity in mice.

Topics: AIDS-Related Opportunistic Infections; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; France; Humans; Meta-Analysis as Topic; Mycobacterium avium-intracellulare Infection; Randomized Controlled Trials as Topic; Rifampin; Switzerland; Tuberculosis, Pulmonary

Tuberculosis (TB) is one of the most common infectious diseases worldwide. Data from WHO show that one third of the world population is estimated to be infected with Mycobacterium Tuberculosis (TM). TB remains an important problem for adults and children in Lithuania as number of new diagnosed children's TB cases vary between 16.7-21.8 per 100 000 population. The aim of this article is to present the TB pneumonia in childhood: peculiarities of clinical forms, symptoms, diagnostics, treatment and results. The diagnosis of TB in children more often is made on epidemiological data, supposed by clinical symptoms, tuberculin skin test and chest radiography results, rather than bacteriological data. Clinical symptoms of TB pneumonia are mostly similar to atypical pneumonia, caused by Mycoplasma pneumoniae and Chlamydia pneumoniae. We discussed similarities and differences between atypical and TB pneumonia, based on 10-year data of our patient ill with atypical and TB pneumonia, (123 - 63.7%) and (69 - 36.3%) respectively. Chemotherapy of TB is directed towards the eradication of TM. The main principle of TB chemotherapy is regular, directly controlled and long-term usage of several antituberculous drugs. The child, ill with TB, is totally cured, when he has no clinical symptoms or laboratory findings specific for TB and is able to return to his normal social life. Two clinical cases of children ill with TB pneumonia are discussed as well. We hope that this article and two clinical cases would remind pediatricians and family doctors to be aware of still possible TB in childhood.

Topics: Administration, Oral; Age Factors; Antibiotics, Antitubercular; Antitubercular Agents; Child; Child, Preschool; Diagnosis, Differential; Ethambutol; Humans; Injections, Intravenous; Isoniazid; Lithuania; Male; Mycobacterium tuberculosis; Radiography, Thoracic; Rifampin; Sputum; Streptomycin; Time Factors; Tuberculosis, Pulmonary

We experienced 4 cases of agranulocytosis due to anti-tuberculosis drugs (rifampicin [RFP], isoniazid [INH], ethambutol [EB], streptomycin [SM] or pyrazinamide [PZA]) among some 6,400 tuberculosis patients who underwent chemotherapy over the past 20 years from 1981 to 2002 in our hospital, and the incidence rate of agranulocytosis was estimated at 0.06%. The 4 cases of agranulocytosis were as follows. CASE 1: A 51-year-old woman with right chest pain and fever was admitted to our hospital on Jan 4, 2001. The white blood cell (WBC) count was 5,200/microliter. The tubercle bacilli were cultured in her sputum. The treatment with INH 0.3, RFP 0.45, EB 0.75, PZA 1.2 g/day, allopurinol and teprenone was started on Jan 13. Pyrazinamide and allopurinol were stopped because of hyper-uric acidemia on Feb 7. Agranulocytosis and eosinophilia (WBC 1,300 [Neut 1%, Ly 57%, Eos 35%]) developed on Feb 13. All drugs were withdrawn and G-CSF drug nartograstim 100 micrograms was injected subcutaneously for 3 days. The WBC recovered to normal level and she was thereafter treated with INH, EB and Levofloxacin (LVFX) without any further trouble. Agranulocytosis in this case was supposed to be due to RFP. CASE 2: A 66-year-old man who had had nephrotic syndrome and hypothyroidism and has been treated with prednisolone 10 mg/day was admitted to our hospital on Aug 9, 2000 because of miliary tuberculosis. The tubercle bacilli were cultured in his sputum and the treatment with INH 0.3, RFP 0.45, and EB 0.75 g/day were started on Aug 10, but it was withdrawn on Aug 17 because of general skin eruption. After re-starting treatment with EB and INH on Aug 24, RFP was added in small dosage (0.05 g) on Oct 12, but agranulomatosis (WBC 2,300/microliter [Neut 2%]) developed on Nov 21, and all drugs were withdrawn again. The G-CSF drug filgrastim was used once subcutaneously, and WBC recovered immediately. He was thereafter treated with INH, EB, LVFX successfully. Agranulocytosis was supposed to be due to RFP. CASE 3: A 60-year-old woman without symptoms had abnormal chest roentgenograph, and consulted with our hospital on Aug 26, 2002. The broncho-alveolar lavage fluid was smear and culture-negative, but PCR-TB positive, and the case was diagnosed as pulmonary tuberculosis. Treatment with INH 0.3, RFP 0.45, EB 0.75, PZA 1.2 g/day, alloprinol 300 mg and rebamipide 300 mg/day was started on Sept. 5, 2002. Late in September, she complained of appetite loss. The laboratory data on Oct 3 reveale

Topics: Aged; Agranulocytosis; Antitubercular Agents; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

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

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

One third of the world population has been infected with Mycobacterium tuberculosis, and the number of tuberculosis will increase worldwide without more effective programs of tuberculosis control. Despite of the presence of very potent anti-tuberculosis drugs the global tuberculosis situation is still very serious, and such gloomy feature are caused, at least partly, by the failures in the treatment of tuberculosis. The most important factor for the failure in chemotherapy is incompliance of the patients to the regimens. History of the chemotherapy of tuberculosis can be said as the history of the efforts to reduce such defaulters. Modern chemotherapy of tuberculosis has started from the discovery of streptomycin. Streptomycin monotherapy could improve temporally symptoms and bacteriological status, but could not cure the patients with moderately advanced pulmonary tuberculosis because of the emerge of drug-resistant tuberculosis. This problem was overcome by combining use of para-aminosalicylate and/or isoniazid developed later on. About 97% of patients with pulmonary tuberculosis became bacteriologically quiescent by the 12 months of streptomycin, para-aminosalicylate and isoniazid. Since 1950s through 1970s three drug combination of streptomycin, para-aminosalicylate and isoniazid had been the standard regimen for the treatment of tuberculosis. By the introduction of rifampicin, the duration of chemotherapy could be shortened to 9 months. Subsequent to the successful animal experiments carried out by Grosset which demonstrated that the addition of pyrazinamide for initial 2 months to the standard two-drug combination (isoniazid and rifampicin) could remarkably shorten the duration of chemotherapy, many clinical trials have been done all over the world to compare the efficacy and safety of pyrazinamide-containing intensified short-course regimen with those of standard regimen without pyrazinamide. Sputum negative conversion rates after 2 months of treatment with PZA-regimen was 70-95%, and the relapse rates after the completion of the treatment course were less than 4%. The incidence of adverse events was less than 4%. The pyrazinamide-containing 6 months short-course regimens has been established as a new standard regimen for the initial treatment of pulmonary tuberculosis worldwide. But, in Japan, this regimen had not been adapted as the standard until April 1996 because of undue fear for high incidence of liver toxicity induced by pyrazinamide. Howev

Topics: Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Risk Factors; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Few data address the outcomes of patients who have multidrug-resistant tuberculosis (MDR-TB), defined as resistance to at least isoniazid and rifampin, and who receive a standard World Health Organization (WHO) recommended retreatment regimen after relapse or failure with initial treatment. In this case series, we examined treatment outcomes of a convenience sample of 42 relapse or failure patients who had documented MDR-TB and who had received a standard WHO retreatment regimen (2SHRZE/1HRZE/5H3R3E3). One patient died of tuberculosis in the last month of treatment; the remaining 41 patients completed retreatment. Of the 42, 14 (33%) were sputum smear-negative on completion of therapy. The proportion of patients cured of MDR-TB with the WHO retreatment regimen was similar to historic outcomes when no chemotherapy for TB was given.

Topics: Adolescent; Adult; Antitubercular Agents; Clinical Protocols; Female; Humans; Isoniazid; Male; Middle Aged; Recurrence; Retreatment; Rifampin; Treatment Failure; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Vietnam; World Health Organization

The number of people infected with tuberculosis continues to rise worldwide. Rifampicin-containing treatment regimens can achieve high cure rates. Intermittent drug treatment delivered in the community has the potential to improve adherence to treatment.. The objective of this review was to compare the effectiveness of rifampicin-containing short-course chemotherapy regimens, given two or three times a week, with similar regimens given daily in adult patients with pulmonary tuberculosis.. We searched the Cochrane Infectious Diseases Group specialized trials register, The Cochrane Controlled Trials Register, MEDLINE, and reference lists of articles. We contacted experts in the field.. Randomized and quasi-randomized trials of any multiple drug regimen containing rifampicin in patients with confirmed pulmonary tuberculosis. Treatment had to be given up to three times a week for up to nine months, with any initial daily dosing period not more than one month, and was compared to daily dosing throughout for the same period.. Two reviewers independently assessed trial eligibility and quality.. One trial involving 399 patients was included. The trial compared treatment three times per week with daily treatment for six months. There was no difference in cure rate (198 out of 199 people in the intermittent group compared to all 200 in the daily group), but 5 patients relapsed in the group receiving intermittent therapy compared to one in the group receiving the daily regimen.. There is not enough evidence to assess the equivalence of effect between fully intermittent, rifampicin-containing short-course chemotherapy and similar daily therapy in patients with pulmonary tuberculosis. Larger randomized studies are required to establish the equivalence of fully intermittent, short-course chemotherapy, with daily regimens.

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Pulmonary

The highest burden of human immunodeficiency virus (HIV) related tuberculosis (TB) is in sub-Saharan Africa. HIV complicates several areas of TB control, one of which involves treatment and treatment outcome. Large patient numbers cause congestion on TB wards, there is increased morbidity, an increased risk of adverse drug reactions, an increased case fatality, and an increased recurrence of TB after treatment completion. TB Control Programmes have responded to these problems by taking actions such as abolishing thioacetazone and decentralising the initial phase of treatment to peripheral health centres and the community. Despite this response, there are three major on-going concerns which need to be addressed by research studies. There is a need to reduce case fatality rates focusing on 1) stronger treatment regimens, 2) adequacy of rifampicin levels when intermittent treatment regimens are used, and 3) adjunctive treatments. There is a need to reduce recurrent rates of TB by 1) determining the relative role of re-infection and reactivation as a cause of recurrence, 2) assessing the importance of duration and type of anti-TB treatment for the first episode of TB, and 3) determining the role of secondary isoniazid preventive therapy. There is a need to evaluate how best to decentralise treatment from the perspective of the health service and the patient. Research studies should be relevant to the needs and resources of TB control programmes, and should include pharmacokinetic studies, controlled clinical trials and operational research, including economic analysis and social science evaluation.

Topics: Africa South of the Sahara; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Government Programs; Humans; Isoniazid; Recurrence; Rifampin; Risk Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The number of people infected with tuberculosis continues to rise world-wide. Rifampicin-containing treatment regimens can achieve high cure rates. Intermittent drug treatment delivered in the community has the potential to improve adherence to treatment.. The objective of this review was to compare the effectiveness of rifampicin-containing short-course chemotherapy regimens, given two or three times a week, with similar regimens given daily in patients with pulmonary tuberculosis.. We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, and reference lists of articles. We contacted experts in the field.. Randomised and quasi-randomised trials of any multi-drug regimen containing rifampicin in patients with confirmed pulmonary tuberculosis. Treatment had to be given up to three times a week for up to nine months, with any initial daily dosing period not more than one month, and was compared to daily dosing throughout for the same period.. Two reviewers independently assessed trial eligibility and quality.. One trial involving 399 patients was included. The trial compared treatment three times per week with daily treatment for six months. There was no difference in cure rate (198 out of 199 people in the intermittent group compared to all 200 in the daily group), but 5 patients relapsed in the group receiving intermittent therapy compared to one in the group receiving the daily regimen.. There is not enough evidence to assess the equivalence of effect between fully intermittent, rifampicin-containing short-course chemotherapy and similar daily therapy in patients with pulmonary tuberculosis. Larger randomised studies are required to establish the effectiveness of fully intermittent, short-course chemotherapy.

Topics: Antitubercular Agents; Drug Administration Schedule; Humans; Rifampin; Tuberculosis, Pulmonary

The number of people infected with tuberculosis continues to rise world-wide. Rifampicin-containing treatment regimens can achieve high cure rates. Intermittent drug treatment delivered in the community has the potential to improve adherence to treatment.. The objective of this review was to compare the effectiveness of rifampicin-containing short-course chemotherapy regimens, given two or three times a week, with similar regimens given daily in patients with pulmonary tuberculosis.. We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, and reference lists of articles. We contacted experts in the field.. Randomised and quasi-randomised trials of any multi-drug regimen containing rifampicin in patients with confirmed pulmonary tuberculosis. Treatment had to be given up to three times a week for up to nine months, with any initial daily dosing period not more than one month, and was compared to daily dosing throughout for the same period.. Two reviewers independently assessed trial eligibility and quality.. One trial involving 399 patients was included. The trial compared treatment three times per week with daily treatment for six months. There was no difference in cure rate (198 out of 199 people in the intermittent group compared to all 200 in the daily group), but 5 patients relapsed in the group receiving intermittent therapy compared to one in the group receiving the daily regimen.. There is not enough evidence to assess the equivalence of effect between fully intermittent, rifampicin-containing short-course chemotherapy and similar daily therapy in patients with pulmonary tuberculosis. Larger randomised studies are required to establish the equivalence of fully intermittent, short-course chemotherapy, with daily regimens.

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Pulmonary

Topics: Antibiotics, Antitubercular; Drug Therapy, Combination; Humans; Mycobacterium avium-intracellulare Infection; Rifabutin; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

A 71-year-old woman was treated for a relapsing pulmonary tuberculosis with reinstitution of rifampicin after a medication-free interval of 2 years. After ingestion of the second dose, she developed severe hemolytic anemia and acute renal failure (ARF) necessitating dialysis. We demonstrated the presence in the patient's serum of rifampicin-dependent immunoglobulin G (IgG) and IgM antibodies, which caused red blood cell lysis through interaction with the I antigen on the erythrocyte surface. A review of the literature yielded 48 cases of rifampicin-associated renal failure. A subgroup of 37 patients could be distinguished, which, analogous to our case, suddenly developed ARF and frequently also developed hemolytic anemia and/or thrombocytopenia during intermittent or interrupted treatment. Regarding the pathogenesis of the ARF, renal biopsy consistently revealed tubular lesions. Although intravascular hemolysis with hemoglobinuria may play a role, it is not uniformly present. Our demonstration of an antibody with anti-I specificity provides a possible explanation. The I antigen is also expressed on tubular epithelium and may, therefore, be the target structure through which rifampicin-antibody complexes lead to tubular cell destruction. The other cases of rifampicin-associated ARF were unrelated to this subgroup: two cases of rapidly progressive glomerulonephritis, five cases of acute interstitial nephritis, and four cases of light chain proteinuria were recorded.

Topics: Acute Kidney Injury; Aged; Anemia, Hemolytic; Antibiotics, Antitubercular; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Rifampin; Time Factors; Tuberculosis, Pulmonary

A 6-month regimen consisting of isoniazid (INH. 0.3-0.5 g).rifampicin (RFP. 0.3-0.45 g).pyrazinamide (PZA. 1.2-2.0 g) and streptomycin (SM. 0.75 g) or ethambutol (EB. 0.75-1.0 g) given for 2 month followed by isoniazid and rifampicin for 4 month is the preferred treatment for patients with fully susceptible organism, who adhere to treatment. Consideration should be given to treating all patients with directly observed treatment.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Drug Administration Schedule; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

The current practice of using INH for tuberculosis prevention is limited by the necessity for at least 6 months of therapy and the problem of INH-induced hepatitis, particularly in older individuals and those with chronic liver disease. Bacteriologic models suggest that, in their persistent form, tubercle bacilli are relatively resistant to INH but become more sensitive to other drugs. Similarly, animal models of latent tuberculosis have suggested that alternative, short-course combinations such as RIF/PZA may be effective, and clinical trials of that two-drug regimen are continuing. At the present time, 3 months of daily RIF, 2 months of RIF/PZA, and 3 months of rifabutin can be considered reasonable alternatives to INH in selected patients. Routine use of these agents in preference to INH cannot yet be endorsed, however, as the standard of care. Without highly effective vaccines for tuberculosis, an important strategy for breaking the cycle of tuberculosis transmission lies in inexpensive, convenient, and effective preventive therapy.

Topics: Animals; Anti-Bacterial Agents; Antibiotic Prophylaxis; Antitubercular Agents; Chronic Disease; Clinical Trials as Topic; Disease Models, Animal; Drug Therapy, Combination; Humans; Isoniazid; Mice; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: AIDS-Related Opportunistic Infections; Animals; Antibiotics, Antitubercular; HIV-1; Humans; Rifabutin; Rifampin; Tuberculosis, Pulmonary

Topics: Acute Disease; Addison Disease; Adrenal Insufficiency; Adult; Antibiotics, Antitubercular; Drug Therapy, Combination; Female; Humans; Rifampin; Tuberculosis, Pulmonary

Tuberculosis is once more a subject of world wide preoccupation; since 1985 a disturbing recrudescence of this disease has been noted in numerous countries related to population growth and the worsening of poverty in those countries without natural resources, and disadvantaged groups living on the margins of society in rich countries, along with the occurrence of an epidemic of HIV (VIH). In numerous developed countries where tuberculosis no longer represents a public health problem, the care services have little by little been closed or re-orientated and the principles of treatment of tuberculosis have been forgotten. The direct consequence of this has often been inadequate treatment and its corollary: the emergence of strains multiresistant to Isoniazid and Rifampicin. If the current epidemiological tendencies are confirmed and no supplementary action is taken, the WHO (OMS) has estimated that during the ten years between 1990 and the millennium there will be 88 million new cases of tuberculosis and 30 million people will die of tuberculosis. However the tendencies can be reversed and tuberculosis could still be eliminated. The struggle against tuberculosis is a world wide emergency and the hope of controlling the situation before an increase in multiresistant strains which would render the trend irreversible, rests on a general application of correct and coherent national programmes. Such a programme as the UICTMR model had already been carried out as has the proof of their efficacy.

Topics: AIDS-Related Opportunistic Infections; Antitubercular Agents; Developed Countries; Developing Countries; Global Health; Health Promotion; HIV Infections; Humans; Incidence; Isoniazid; Population Growth; Poverty; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; World Health Organization

Changing incidence and nature of mycobacterial infections subsequent to the historical regression of tuberculosis and the acquired human immunodeficiency syndrome (AIDS) epidemic, as well as the development of new technical tools for molecular biology, have profoundly modified the methods used for the bacteriological diagnosis of mycobacteria infections. Although microscopic search for acid-fast bacilli, culture and antibiotic resistance tests on Löwenstein-Jensen medium remain the reference methods, more rapid and sophisticated methods are now available. Culture on radiolabeled media using the Bactec system has shortened the delay for positive culture and interpretable antibiotic sensitivity tests. Molecular techniques allow: 1) rapid identification of the most frequently isolated mycobacteria strains, including the most frequent laboratory contaminant M. gordonae, with genome probes; 2) genome typing of M. tuberculosis strains to trace interhuman transmission, detect recurrence or exogenous reinfection or demonstrate laboratory contamination; 3) rapid detection of rifampicin resistance; and 4) direct detection of M. tuberculosis and M. avium in pathological specimens. The role of mycobacteria in the environment causing opportunistic infections, atypical mycobacteria or non-tuberculosis mycobacteria (NTM), particularly the aviaire complex, has grown considerably. Isolation and identification relies on methods used to detect bacilli as well as blood cultures and analysis of fecal matter. NTM are naturally resistant to most of the antituberculosis antibiotics but are sometimes sensitive to aminoglycosides, fluoroquinolones or new macrolides.

Topics: AIDS-Related Opportunistic Infections; Aminoglycosides; Anti-Bacterial Agents; Anti-Infective Agents; Antitubercular Agents; Bacteriological Techniques; Culture Media; Drug Resistance, Microbial; Fluoroquinolones; Genome, Bacterial; Humans; Incidence; Macrolides; Microbial Sensitivity Tests; Molecular Biology; Mycobacterium avium; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Radiopharmaceuticals; Recurrence; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

All patients with a positive reaction to the tuberculin skin test should be evaluated for weight loss, night sweats, fever, chronic cough and other signs of active tuberculosis. Chest radiographs should also be obtained in these patients. All converters receiving isoniazid should be examined monthly for signs of hepatitis and neurotoxicity. Liver function tests should be obtained at initiation of isoniazid therapy and again during the first two to four months in patients age 35 or older or with a history of alcoholism, liver disease or intravenous drug use. All cases of active tuberculosis should be reported to the local public health department. Most patients with active tuberculosis should receive isoniazid, rifampin, ethambutol and pyrazinamide daily for two weeks, followed by directly observed administration twice weekly for six additional weeks. If sputum cultures show no resistance after two months of therapy, pyrazinamide and ethambutol may be discontinued, with isoniazid and rifampin taken for an additional 16 weeks. Patients with human immunodeficiency virus infection or acquired immunodeficiency syndrome should receive the initial treatment for at least nine to 12 months, and isoniazid and rifampin for at least six months after culture conversion has occurred.

Topics: Algorithms; Ambulatory Care; Antitubercular Agents; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Mass Screening; Population Surveillance; Pyrazinamide; Rifampin; Sensitivity and Specificity; Streptomycin; Tuberculin Test; Tuberculosis, Pulmonary; United States

This article reviews recent studies conducted outside the United States assessing the efficacy and safety of rifabutin in the treatment of tuberculosis (TB) in HIV-infected patients, in patients with newly diagnosed TB, and in patients with multidrug-resistant TB. A 6-month pilot study of 50 Ugandan patients with TB associated with HIV infection showed that rifabutin and rifampin were similarly effective with regard to conversion of sputum-smear findings (sputum conversion) and in bringing about clinical and radiologic improvement. Compared with rifampin, rifabutin showed potential for reducing the time to sputum conversion for these patients. Multicenter studies in five countries compared two rifabutin dosages (150 mg/d and 300 mg/d) with rifampin as part of a combination regimen for treatment of newly diagnosed TB in 935 patients. Rifabutin compared favorably with rifampin in sputum conversion; administration of 150 mg/d of rifabutin yielded good results and the fewest adverse effects. The use of rifabutin by 270 patients in five countries who had multidrug-resistant TB (approximately 90% of isolates tested were resistant to rifampin and isoniazid) was assessed in another study. For the majority of these patients, signs and symptoms diminished; one-third had bacteriologic conversions.

Topics: AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Clinical Trials as Topic; Humans; Pilot Projects; Rifabutin; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Developing Countries; Humans; Isoniazid; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Clinical Trials as Topic; Colony Count, Microbial; Drug Evaluation; Humans; Mycobacterium tuberculosis; Paromomycin; Recurrence; Rifabutin; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

During the last decade, there has been a marked increase in the number of gravity of tuberculosis cases both in developing countries and in industrialized nations. This is, in part, due to the acquired immune deficiency syndrome (AIDS) pandemic, but global economic depression, increased homelessness and declining control programmes have also contributed. One of the more insidious consequences of this resurgence has been the recent emergence and nosocomial transmission of multidrug-resistant strains of Mycobacterium tuberculosis, thus raising the possibility that untreatable forms of the disease may become widespread. Somewhat surprisingly, given the difficulties of working with this slow-growing pathogen, remarkable progress has been made in a relatively short time, in understanding the molecular epidemiology, the genetic basis, and the biochemical mechanisms of drug resistance. Furthermore, a number of promising molecular tools are now available to help counter tuberculosis and to further understanding.

Topics: AIDS-Related Opportunistic Infections; Amino Acid Sequence; Antitubercular Agents; Cross Infection; Developing Countries; Drug Resistance, Multiple; Humans; Microbial Sensitivity Tests; Molecular Sequence Data; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Risk Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

In the report, 4 patients with similar Hexheimer's reaction during initial chemotherapy for pulmonary tuberculosis were presented. The literatures on clinical manifestations, predisposing factors, pathogenic mechanism, pathological changes, diagnosis and management of Hexheimer's reaction are reviewed.

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Child, Preschool; Female; Humans; Isoniazid; Lymphadenitis; Male; Pleurisy; Rifampin; Tuberculosis, Pulmonary

Rifabutin is a derivative of rifamycin S with activity against mycobacteria including atypical organisms such as Mycobacterium avium and M. intracellulare, also referred to as Mycobacterium avium-intracellulare complex (MAC). To date, rifabutin is the only drug to have been studied in large prospective placebo-controlled trials that has been shown to significantly reduce the incidence of disseminated MAC infection when administered prophylactically as a single agent to patients with acquired immune deficiency syndrome (AIDS). Initial studies also indicate that rifabutin may be a useful component of multiple drug regimens for the treatment of MAC infection, although further studies combining rifabutin with other recently available antimycobacterial drugs are required to determine the most effective regimens. When rifabutin is combined with at least two other antimycobacterial drugs, the combination appears to be of similar efficacy to rifampicin (rifampin)-containing regimens in patients with newly diagnosed pulmonary tuberculosis. Since available therapy for MAC infection in patients with AIDS is still suboptimal, rifabutin, at present the only first-line agent for prophylaxis against disseminated MAC infection in patients with advanced human immunodeficiency virus (HIV) infection, has the potential to make a valuable contribution to the continuing attempts to preserve the quality of life of patients with AIDS.

Topics: AIDS-Related Opportunistic Infections; Animals; Bacteria; Biological Availability; Drug Interactions; Half-Life; Humans; Intestinal Absorption; Metabolic Clearance Rate; Mycobacterium avium-intracellulare Infection; Rifabutin; Rifampin; Tissue Distribution; Tuberculosis, Pulmonary

Two patients with liver failure secondary to isoniazid hepatotoxicity were successfully treated with orthotopic liver transplantation. A 49-year-old man received isoniazid prophylaxis for a positive tuberculin test, and a 60-year-old woman was treated for active pulmonary tuberculosis with isoniazid, rifampin, and pyrazinamide. Both patients developed hepatic failure 4 and 1.5 months after initiation of antituberculous drug therapy, respectively. Liver transplantation was performed for progressive hepatic failure and was successful in both patients. The patient with active pulmonary tuberculosis was successfully treated with a modified antituberculous drug regimen while taking standard doses of immunosuppressive drugs after transplantation. In conclusion, liver transplantation is feasible and effective therapy for patients with isoniazid-induced hepatic failure, and active pulmonary tuberculosis may represent a relative rather than absolute contraindication to transplantation.

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Hepatic Encephalopathy; Humans; Isoniazid; Liver Failure; Liver Transplantation; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

We describe two cases of pulmonary infection due to Mycobacterium xenopi (M. xenopi). Both cases were men, ages 61 and 54 yr. In the first patient, lung infection due to M. xenopi occurred after gastrectomy. The second patient had an inactive M. tuberculosis infection. Both had pulmonary symptoms including cough, sputum and fever. Each chest X-ray showed an infiltrative shadow with a cavity in a unilateral, upper lobe. Isolates from both patients were studied not only by microbiological characteristics but also by DNA-DNA hybridization. All isolates were susceptible to streptomycin and kanamycin. In the first case, the patient had initially received rifampicin, isoniazid and ethambutol despite in vitro susceptibility patterns, however, there was no response and a new infiltrative shadow appeared in the contralateral lobe. With a multiple drug regimen based on in vitro susceptibility, clinical and roentgenographic improvements were achieved. The second patient showed a favorable response to the initial chemotherapy. Pulmonary infection due to M. xenopi can generally be successfully treated with drugs to which the organisms show in vitro sensitivity. We also reviewed the other two cases reported in Japan.

Topics: Bacterial Typing Techniques; Clarithromycin; Cycloserine; DNA Probes; Drug Resistance, Microbial; Gastrectomy; Humans; Isoniazid; Kanamycin; Male; Middle Aged; Mycobacterium Infections; Respiratory Tract Infections; Rifampin; Streptomycin; Tuberculosis, Pulmonary

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

The optimization of the therapy of lung tuberculosis and asthma bronchiale was supported since 1955 by clinical-pharmacological investigations. The prerequisites therefore--using highly specific methods of distribution and quantification in biological material till to the synthesis of 3H-INH and 3H-RMP were introduced step by step. The investigations--in most cases estimations of the nonbiotransformated part of antituberculotic drugs and theophylline had following purposes: security of the necessary dose especially in the case of INH (hereditary INH-polymorphismus), proof of a sufficient permeation of INH and RMP in the tuberculous kidney, control of the usefulness or uselessness of the INH-depot-preparations, relations between the concentration in the serum and dose respectively of the appearance of side effects, estimation of bioavailability and pharmacokinetic parameters during the development of an useful retard-preparation of theophylline.

Topics: Antitubercular Agents; Asthma; Biotransformation; Ethionamide; Humans; Isoniazid; Metabolic Clearance Rate; Rifampin; Theophylline; Tuberculosis, Pulmonary

The here described investigations show correspondingly that the administration of isoniazid, rifampicin and pyrazinamide in a fixed combination of the administration of the individual substances is bioequivalent under pharmacokinetic aspects. Further investigations on large populations of patients must, however, still confirm whether or not the advantages of the fix combination striven for or theoretically to be expected can be proved in practice.

Topics: Biological Availability; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Due to the scarcity of published articles on short-course chemotherapeutic regimens for pediatric pulmonary tuberculosis, the following study has been carried out: Twenty-five children diagnosed of pulmonary tuberculosis were administered a short course therapeutic regimen consisting of three tuberculostatics for the first two month (isoniazid, rifampicin and pyrazinamide) and only two (isoniazid and rifampicin) for the following four months. The results were compared with those obtained from a control group of twenty-five children receiving the "classical" therapy: two drugs (isoniazid and rifampicin) for a nine month period. The statistical analysis did not demonstrate any significant difference related to evolution, duration and complications of the disease, between both groups. Therefore, this short course therapeutic regimen could be accepted for pediatric pulmonary tuberculosis.

Topics: Antitubercular Agents; BCG Vaccine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Infant, Newborn; Isoniazid; Rifampin; Time Factors; Tuberculosis, Pulmonary

Tuberculosis, once considered a problem solved, is now dramatically on the rise. New approaches to chemotherapy will hopefully help to control this again serious problem. This article reviews the current status of tuberculosis chemotherapy, including the management of drug-resistant cases.

Topics: Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

The treatment of pulmonary TB due to bacilli sensitive to antituberculous treatment should lead to 100 p. 100 therapeutic success. However, this result implies a good bacteriological knowledge of the Koch bacillus, of antituberculous drugs, of therapeutic strategy, of the duration of treatment and, finally, of the reasons for failure. The association of isoniazide (5 mg/kg/day), rifampicin (10 mg/kg/day) and ethambutol (20 mg/kg/day for the first two months) sterilizes tuberculous lesions in 9 months. The introduction of a fourth antituberculous drug, pyrazinamide (35 mg/kg/day for the first two months) enables the duration of treatment to be reduced to 6 months without any loss of efficiency. Tuberculous relapses, sometimes due to polyresistant bacilli, pose difficult problems requiring detailed bacteriological studies of antibiotic sensitivity. Specific measures have to be taken (adaptation of dosage, contra-indications of certain drugs) with respect to the individual patient (elderly patients, pregnant or lactating women). Surgery has a role to play, especially in the treatment of sequellae. Admission to a sanatorium is reserved for infectious cases at the beginning of treatment and for patients living in poor conditions. The cover of social security is essential for successful treatment. Tuberculous is a compulsory notifiable disease.

Topics: Aminoglycosides; Antitubercular Agents; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Thioamides; Tuberculosis, Pleural; Tuberculosis, Pulmonary

There is no solid evidence that pregnancy has an adverse effect on tuberculosis. With early diagnosis and prompt, adequate chemotherapy, the outcome of pregnancy in a woman with tuberculosis is likely to be good. Routine therapeutic abortion is not indicated. Data in the literature do not support the notion that pregnancy is a major risk factor for the development of tuberculosis, although no well-designed studies have been conducted. Screening of pregnant patients for tuberculosis should be based on consideration of other proved risk factors not on the fact of pregnancy. Preventive therapy should be given during the second and third trimesters of pregnancy to selected patients at high risk of progressive disease developing. Treatment of disease should be instituted promptly when disease is detected. The preferred regimens are INH-EMB, INH-RIF, or INH-EMB-RIF, although other drugs may be needed if the disease is recurrent or if there is resistance to these primary drugs. Mothers taking antituberculosis drugs can nurse their infants with little risk. With proper medical management, both tuberculosis and pregnancy can be expected to reach a happy conclusion in virtually all cases.

Topics: Drug Therapy, Combination; Ethambutol; Female; Humans; Infant, Newborn; Isoniazid; Mass Screening; Pregnancy; Pregnancy Complications, Infectious; Prognosis; Rifampin; Risk; Streptomycin; Tuberculin Test; Tuberculosis, Miliary; Tuberculosis, Pulmonary

In the United States, an increasing proportion of all forms of reactivation tuberculosis occurs in patients over the age of 60 years. Atypical presentations and presence of chronic illness obscure the diagnosis of tuberculosis in the elderly. Prompt diagnosis requires a high index of suspicion and aggressive procedures for diagnostic microbiology. Short-course (9 months) chemotherapy with isoniazid and rifampin is the treatment of choice for elderly patients with uncomplicated pulmonary tuberculosis. Isoniazid chemoprophylaxis is recommended for selected elderly patients.

Topics: Aged; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Pyridoxine; Rifampin; Streptomycin; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Osteoarticular; Tuberculosis, Pulmonary; Tuberculosis, Urogenital; United States

Topics: Adult; Aged; Amantadine; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Cephalosporins; Cyclophosphamide; Drug Combinations; Erythromycin; Ethambutol; Humans; Metronidazole; Pyrazinamide; Respiratory Tract Diseases; Respiratory Tract Infections; Rifampin; Trimethoprim; Tuberculosis, Pulmonary

Topics: Animals; Humans; Isoniazid; Mice; Recurrence; Rifampin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Chemical Phenomena; Chemistry; Ethambutol; Humans; Isoniazid; Kinetics; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Aged; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Animals; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Isoniazid; Mice; Pyrazinamide; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

Topics: Animals; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Animals; Antitubercular Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Guinea Pigs; Humans; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Alcohol Drinking; Carrier State; Chemical and Drug Induced Liver Injury; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculin Test; Tuberculosis, Pulmonary

The pregnant woman with tuberculosis who requires treatment presents a therapeutic dilemma; therefore, we reviewed all available literature on pregnant women treated with isoniazid (INH), ethambutol (EMB), rifampin (RMP), or streptomycin (SM) and report here on the relative safety of these drugs and whether the risk of teratogenesis justifies abortion on medical grounds. Other than the ototoxicity of SM, none of these drugs in normal dosages are proved teratogens to human fetuses. We recommend the use of INH in combination with EMB for a pregnant woman with tuberculosis, if the disease is not extensive. If a third drug is warranted, then RMP could be added. Because of its ototoxicity, SM should not be used, unless RMP is contraindicated or proves unsatisfactory. Routine therapeutic abortion is not medically indicated for a pregnant woman who is taking first-line antituberculosis drugs.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Antitubercular Agents; Ethambutol; Female; Hearing Disorders; Humans; Isoniazid; Limb Deformities, Congenital; Pregnancy; Pregnancy Complications, Infectious; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acid; Antitubercular Agents; Clinical Trials as Topic; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Patient Dropouts; Rifampin; Streptomycin; Thioacetazone; Tuberculosis, Pulmonary

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

Topics: BCG Vaccine; Child; Child, Preschool; Ethambutol; Germany, West; Humans; Infant; Infant, Newborn; Isoniazid; Rifampin; Risk; Streptomycin; Tuberculin Test; Tuberculosis, Pulmonary

This paper reviews hepatic toxicity during chemoprophylactic treatment with isoniazid alone, and during the treatment or retreatment of active pulmonary tuberculosis with regimens containing one or more of the drugs isoniazid, rifampicin and pyrazinamide. Chemoprophylaxis with isoniazid carries a risk of drug-induced hepatitis, and this risk needs to be weighed against the advantages of preventing tuberculosis morbidity. The risks of hepatitis during standard treatment based on isoniazid are very small, and most patients who develop hepatitis recover. Moreover, it is often doubtful whether hepatitis is in fact drug-induced, and a proportion of patients who develop it already have liver disease at the time treatment is started. The risks are acceptable in the treatment of bacteriologically active disease. There is no consistent evidence that giving rifampicin with isoniazid in the initial treatment of tuberculosis increases the risk of hepatitis; in particular, transient abnormalities in the results of tests of liver function during the early weeks of treatment do not imply serious toxicity; patients who are rapid acetylators of isoniazid are not, as has been suggested, exposed to any special risk, and patients with known liver disease can also be treated without undue risk. Retreatment regimens based on rifampicin plus ethambutol carry a low risk of hepatitis, even though patients who need retreating have often experience toxicity during their initial treatment. Frist-line or second-line regimens containing pyrazinamide in currently accepted dosages, given daily or intermittently, carry a low and acceptable risk of hepatic toxicity. Finally, current studies of daily and intermittent short-course regimens based on isoniazid, rifampicin and pyrazinamide will extend our knowledge of hepatic toxicity. Because such regimens involve small total quantitites of drugs given over short periods they are likely to give rise to less hepatic toxicity than regimens of standard duration.

Topics: Acetylation; Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Liver Function Tests; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Factors affecting the success and failure of tuberculosis (TB) treatment programs are reviewed. Topics covered include incidences of primary and secondary resistance; methods and probability of bacteriologic transfer of resistance; factors affecting delivery of successful treatment of TB; and retreatment concepts, history and regimens for TB relapse and treatment failures. Isoniazid, rifampin and ethambutol hydrochloride produce a high percentage of cure in initial and retreatment TB therapy. Attention to patient compliance should be emphasized to assure effective treatment.

Topics: Aminosalicylic Acid; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Ethambutol; Humans; Recurrence; Rifampin; Tuberculosis, Pulmonary

Topics: Acute Kidney Injury; Anemia, Hemolytic; Digestive System; Humans; Influenza, Human; Liver; Rifampin; Skin; Syndrome; Thrombocytopenia; Tuberculosis, Pulmonary

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

Topics: Adult; Aged; Chromatography, Gas; Drug Interactions; Feces; Female; Heroin Dependence; Humans; Liver; Male; Mass Spectrometry; Methadone; Methods; Middle Aged; Naloxone; Rifampin; Substance Withdrawal Syndrome; Tuberculosis, Pulmonary

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

Topics: Antitubercular Agents; Aspirin; Bacteriological Techniques; BCG Vaccine; Drug Therapy, Combination; Ethambutol; Hospitalization; Humans; Isoniazid; Length of Stay; Mycobacterium tuberculosis; Outpatient Clinics, Hospital; Pyrazinamide; Rifampin; Streptomycin; Time Factors; Tuberculin Test; Tuberculosis, Pulmonary

Topics: Adult; Amides; Antitubercular Agents; Ethambutol; Evaluation Studies as Topic; False Negative Reactions; Female; Humans; Isoniazid; Isonicotinic Acids; Male; Placebos; Pregnancy; Recurrence; Rifampin; Time Factors; Tuberculin Test; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Age Factors; Aged; Drug Administration Schedule; Drug Therapy, Combination; Female; Fever; Humans; Isoniazid; Leukocytosis; Lymphopenia; Male; Middle Aged; Purpura, Thrombocytopenic; Rifampin; Sex Factors; Tuberculosis, Pulmonary

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

Topics: Antitubercular Agents; Drug Combinations; Ethambutol; Humans; Isoniazid; Isonicotinic Acids; Microbial Sensitivity Tests; Prognosis; Prospective Studies; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; BCG Vaccine; Child, Preschool; China; Cycloserine; Drug Resistance, Microbial; Ethionamide; Health Education; Hong Kong; Hospitalization; Humans; Hypersensitivity; Infant; Infant Mortality; Infant, Newborn; Isoniazid; Pyrazinamide; Racial Groups; Research; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Alcoholism; Aminosalicylic Acids; Bilirubin; Drug Therapy, Combination; Humans; Isoniazid; Patient Dropouts; Rifampin; Streptomycin; Time Factors; Transaminases; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Costs and Cost Analysis; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Rifampin; Self Medication; Streptomycin; Thioacetazone; Tuberculosis, Pulmonary

Topics: Animals; Antitubercular Agents; Drug Resistance; Guinea Pigs; Humans; Male; Mice; Pneumonectomy; Rifampin; Tuberculosis, Pulmonary

Rifampin is a potent antituberculous drug. In the treatment of drug-resistant tuberculosis it is highly effective provided it is given in combination with other drugs to which the patient's organisms are sensitive. Rifampin and ethambutol is a particularly powerful combination and will achieve almost 100% sputum conversion. It seems likely that rifampin will replace streptomycin, and ethambutol will replace PAS in first-treatment cases. Optimum first-line treatment will thus consist of rifampin, INH and ethambutol, with the probability of almost 100% success and the possibility also that the total duration of treatment may be considerably reduced. Rifampin is well tolerated but it may give rise to liver dysfunction and thrombocytopenia in a small proportion of patients. Patients treated with rifampin must be kept under close supervision because of the risk of side effects and, more important, because irregular treatment may lead to the development of rifampin-resistant organisms.

Topics: Adult; Aged; Animals; Drug Combinations; Ethambutol; Female; Humans; Isoniazid; Jaundice; Male; Mice; Middle Aged; Mycobacterium tuberculosis; Pregnancy; Rifampin; Thrombocytopenia; Tuberculosis, Pulmonary

Topics: Administration, Oral; Animals; Drug Resistance, Microbial; Humans; Mice; Mycobacterium tuberculosis; Recurrence; Rifampin; RNA Nucleotidyltransferases; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Animals; Culture Media; Ethambutol; Follow-Up Studies; Guinea Pigs; Half-Life; Humans; Isoniazid; Mycobacterium tuberculosis; Rabbits; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Antitubercular Agents; Clinical Trials as Topic; Ethambutol; Ethionamide; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

Topics: Aged; Aminosalicylic Acids; Capreomycin; Chemical Phenomena; Chemistry; Color Perception; Drug Therapy, Combination; Ethambutol; Eye; Eye Diseases; Female; Humans; Isoniazid; Kidney Failure, Chronic; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary; Visual Acuity; Visual Fields

Topics: Aminosalicylic Acids; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Cycloserine; Drug Resistance, Microbial; Drug Synergism; Drug Tolerance; Hemorrhagic Disorders; Humans; Isoniazid; Kanamycin; Phenylthiourea; Purpura, Thrombocytopenic; Pyrazines; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary

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

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

Topics: Administration, Oral; Aminosalicylic Acids; Animals; Antitubercular Agents; Ethambutol; Guinea Pigs; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antitubercular Agents; Bronchitis; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Humans; Microbial Sensitivity Tests; Pneumonia; Respiratory Tract Infections; Rifampin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Drug Resistance, Microbial; Humans; Methods; Microbial Sensitivity Tests; Mycobacterium; Mycobacterium Infections; Rifampin; Tuberculosis, Pulmonary

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

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

Topics: Adolescent; Child; Child, Preschool; Drug Resistance, Microbial; Drug Synergism; Drug Tolerance; Ethambutol; Female; Germany, West; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Ethambutol; Humans; Phenylthiourea; Rifampin; Tuberculosis, Pulmonary

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

Topics: Animals; Antitubercular Agents; Drug Therapy, Combination; Isoniazid; Mice; Nitroimidazoles; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Tuberculosis is usually treated with a 6-month rifampin-based regimen. Whether a strategy involving shorter initial treatment may lead to similar outcomes is unclear.. In this adaptive, open-label, noninferiority trial, we randomly assigned participants with rifampin-susceptible pulmonary tuberculosis to undergo either standard treatment (rifampin and isoniazid for 24 weeks with pyrazinamide and ethambutol for the first 8 weeks) or a strategy involving initial treatment with an 8-week regimen, extended treatment for persistent clinical disease, monitoring after treatment, and retreatment for relapse. There were four strategy groups with different initial regimens; noninferiority was assessed in the two strategy groups with complete enrollment, which had initial regimens of high-dose rifampin-linezolid and bedaquiline-linezolid (each with isoniazid, pyrazinamide, and ethambutol). The primary outcome was a composite of death, ongoing treatment, or active disease at week 96. The noninferiority margin was 12 percentage points.. Of the 674 participants in the intention-to-treat population, 4 (0.6%) withdrew consent or were lost to follow-up. A primary-outcome event occurred in 7 of the 181 participants (3.9%) in the standard-treatment group, as compared with 21 of the 184 participants (11.4%) in the strategy group with an initial rifampin-linezolid regimen (adjusted difference, 7.4 percentage points; 97.5% confidence interval [CI], 1.7 to 13.2; noninferiority not met) and 11 of the 189 participants (5.8%) in the strategy group with an initial bedaquiline-linezolid regimen (adjusted difference, 0.8 percentage points; 97.5% CI, -3.4 to 5.1; noninferiority met). The mean total duration of treatment was 180 days in the standard-treatment group, 106 days in the rifampin-linezolid strategy group, and 85 days in the bedaquiline-linezolid strategy group. The incidences of grade 3 or 4 adverse events and serious adverse events were similar in the three groups.. A strategy involving initial treatment with an 8-week bedaquiline-linezolid regimen was noninferior to standard treatment for tuberculosis with respect to clinical outcomes. The strategy was associated with a shorter total duration of treatment and with no evident safety concerns. (Funded by the Singapore National Medical Research Council and others; TRUNCATE-TB ClinicalTrials.gov number, NCT03474198.).

Topics: Antitubercular Agents; Diarylquinolines; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Linezolid; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted.. This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited.. This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB.. ClinicalTrials.gov NCT04485156 . Registered on July 24, 2020.

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Multicenter Studies as Topic; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Rifampicin-resistant tuberculosis (RR-TB) treatment requires combination treatment, which frequently causes serious adverse events and globally results in not much more than 60% treatment success. In Niger, a high cure rate was obtained with a RR-TB treatment strategy based on a second-line injectable drug (SLID)-containing Short Treatment Regimen (STR), with linezolid replacing the SLID in patients with ototoxicity. Given the availability of novel anti-tuberculosis drugs, WHO recommends all-oral RR-TB treatment. Considering the high level of success with the Niger treatment strategy, it would only be justified to replace it in case robust evidence shows that the WHO all-oral bedaquiline/linezolid (BDQ/LZD)-containing STR (experimental arm) performs better than the Niger RR-TB treatment strategy, (control arm) in terms of safety, effectiveness and adherence.. A pragmatic randomised clinical trial (RCT) using stratified block randomisation, conducted between April 2021 and March 2024, prospectively enrols participants diagnosed with RR-TB in one of the four RR-TB units of the nation. Depending of the month in which patients are diagnosed with RR-TB, patients with FQ-susceptible RR-TB are enrolled in either the experimental arm or control arm.. To increase the feasibility of conducting a RCT, embedded in routine activities of all Niger's RR-TB Units, we used a creative trial design. We randomised by monthly blocks, whereby the regimen used changes every month, using the month of RR-TB diagnosis as stratifying variable. This approach was deemed feasible for Niger's national tuberculosis programme, as it simplifies the work of the clinicians running the RR-TB units. Our creative design may serve as an example for other national programs. Findings will inform national and international RR-TB treatment guidelines, and will also strengthen the evidence-base on how to develop robust RR-TB treatment regimens.. Pan African Clinical Trial Register PACTR202203645724919 . Registered on 15 March 2022.

Topics: Antitubercular Agents; Humans; Linezolid; Niger; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed.. We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points.. Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%).. In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

Topics: Administration, Oral; Adolescent; Adult; Antitubercular Agents; Drug Therapy, Combination; Humans; Linezolid; Moxifloxacin; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Direct bronchial spread of tuberculosis was extensively described in pre-antibiotic human pathology literature but this description has been overlooked in the post-antibiotic era, in which most pathology data come from animal models that emphasise the granuloma. Modern techniques, such as [. In this observational analysis, we analysed data from PredictTB, an ongoing, prospective, randomised clinical trial that examined sequential baseline and week 4 FDG-PET-CT scans from participants successfully treated (sputum culture negative 18 months after enrolment) for drug-susceptible pulmonary tuberculosis in South Africa and China. Participants who were aged 18-75 years, GeneXpert MTB/RIF positive for tuberculosis and negative for rifampicin resistance, had not yet started tuberculosis treatment, had not been treated for active tuberculosis within the previous 3 years, and met basic safety laboratory criteria were included and participants with diabetes, HIV infection, or with extrapulmonary tuberculosis including pleural tuberculosis were excluded. Scans were assessed by two readers for the location of tuberculosis lesions (eg, cavities and consolidations), bronchial thickening patterns, and changes from baseline to week 4 of treatment.. Among the first 124 participants (enrolled from June 22, 2017, to Sept 27, 2018) who were successfully treated, 161 primarily apical cavitary lesions were identified at baseline. Bronchial thickening and inflammation linking non-cavitary consolidative lesions to cavities were observed in 121 (98%) of 124 participants' baseline PET-CT scans. After 4 weeks of treatment, 21 (17%) of 124 participants had new or expanding lesions linked to cavities via bronchial inflammation that were not present at baseline, particularly participants with two or more cavities at baseline and participants from South Africa.. In participants with pulmonary tuberculosis who were subsequently cured, the location of cavitary and non-cavitary lesions at baseline and new lesions at week 4 of treatment suggest a cavitary origin of disease and bronchial spread through the lungs. Bronchial spread from cavities might play a larger role in the spread of pulmonary tuberculosis than has been appreciated. Elucidating cavity lesion dynamics and. Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials Partnership, China Ministry of Science and Technology, National Natural Science Foundation of China, and National Institutes of Health.. For the Chinese, Afrikaans and Xhosa translations of the abstract see Supplementary Materials section.

Topics: Anti-Bacterial Agents; Fluorodeoxyglucose F18; HIV Infections; Humans; Inflammation; Positron Emission Tomography Computed Tomography; Prospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary; United States

The aim was to evaluate the efficacy, safety and completion rate of 3-month, once-weekly rifapentine and isoniazid for tuberculosis (TB) prevention among Chinese silicosis patients.. Male silicosis patients without human immunodeficiency virus infection, aged 18 years to 65 years, with or without latent TB infection, were randomized 1:1 to receive rifapentine/isoniazid under direct observation (3RPT/INH group) or were untreated (observation group). Active TB incidence was compared between the two groups with 37 months of follow-up. Safety profile and complete rates were evaluated.. A total of 1227 adults with silicosis were screened; 513 eligible participants were enrolled and assigned to 3RPT/INH (n = 254) vs. observation (n = 259). Twenty-eight participants were diagnosed with active TB, and 9 and 19 in the 3RPT/INH group and observation groups, respectively. In the intention-to-treat analysis, the cumulative active TB rate was 3.5% (9/254) in the 3RPT/INH group and 7.3% (19/259) in the observation group (log rank p 0.055). On per protocol analysis, the cumulative active TB rates were 0.7% (1/139) and 7.3% (19/259), respectively (log rank p 0.01). Owing to an unexpected high frequency of adverse events (70.4%) and Grade 3 or 4 AEs (7.9%), the completion rate of the 3RPT/INH regimen was 54.7% (139/254). Twenty-six (10.8%) participants had flu-like systemic drug reactions; five (2.1%) experienced hepatotoxicity.. Weekly rifapentine/isoniazid prophylaxis prevented active TB among Chinese people with silicosis when taken, irrespective of LTBI screening; efficacy was reduced by lack of compliance. The regimen must be used with caution because of the high rates of adverse effects.. ClinicalTrials.gov number: NCT02430259.

Topics: Antitubercular Agents; Area Under Curve; China; Drug Administration Schedule; Half-Life; Humans; Isoniazid; Male; Medication Adherence; Middle Aged; Rifampin; Silicosis; Tuberculosis, Pulmonary

Xpert® MTB/RIF has been widely used for tuberculosis (TB) diagnosis in Brazil, since 2014. This prospective observational study aimed to evaluate the performance of Xpert in different contexts during a two-year period: (i) laboratory and clinical/epidemiological diagnosis; (ii) HIV-positive and -negative populations; (iii) type of specimens: pulmonary and extrapulmonary. Overall, 924 specimens from 743 patients were evaluated. The performance of the assays was evaluated considering culture (Lowenstein Jensen or LJ medium) results and composite reference standard (CRS) classification as gold standard. According to CRS evaluation, 219 cases (29.5%) were classified as positive cases, 157 (21.1%) as 'possible TB', and 367 (49.3%) as 'not TB'. Based on culture, Xpert and AFB smear achieved a sensitivity of 96% and 62%, respectively, while based on CRS, the sensitivities of Xpert, AFB smear, and culture were 40.7%, 20%, and 25%, respectively. The pooled sensitivity and specificity of Xpert were 96% and 94%, respectively. Metric evaluations were similar between pulmonary and extrapulmonary samples against culture, whereas compared to CRS, the sensitivities were 44.6% and 29.3% for the pulmonary and extrapulmonary cases, respectively. The Xpert detected 42/69 (60.9%) patients with confirmed TB and negative culture on LJ medium, and 52/69 (75.4%) patients with negative AFB smear results. There was no significant difference in the diagnostic accuracy based on the types of specimens and population (positive- and negative-HIV). Molecular testing detected 13 cases of TB in culture-negative patients with severe immunosuppression. Resistance to rifampicin was detected in seven samples. Herein, Xpert showed improved detection of pulmonary and extrapulmonary TB cases, both among HIV-positive and -negative patients, even in cases with advanced immunosuppression, thereby performing better than multiple other diagnostic parameters.

Topics: Adult; Aged; Brazil; Drug Resistance, Bacterial; Female; Humans; Immunocompromised Host; Male; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary

Rifapentine-based regimens have potent antimycobacterial activity that may allow for a shorter course in patients with drug-susceptible pulmonary tuberculosis.. In an open-label, phase 3, randomized, controlled trial involving persons with newly diagnosed pulmonary tuberculosis from 13 countries, we compared two 4-month rifapentine-based regimens with a standard 6-month regimen consisting of rifampin, isoniazid, pyrazinamide, and ethambutol (control) using a noninferiority margin of 6.6 percentage points. In one 4-month regimen, rifampin was replaced with rifapentine; in the other, rifampin was replaced with rifapentine and ethambutol with moxifloxacin. The primary efficacy outcome was survival free of tuberculosis at 12 months.. Among 2516 participants who had undergone randomization, 2343 had a culture positive for. The efficacy of a 4-month rifapentine-based regimen containing moxifloxacin was noninferior to the standard 6-month regimen in the treatment of tuberculosis. (Funded by the Centers for Disease Control and Prevention and others; Study 31/A5349 ClinicalTrials.gov number, NCT02410772.).

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Child; Confidence Intervals; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Moxifloxacin; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Pulmonary; Young Adult

To determine the efficacy and safety of add-on dry powder for inhalation (DPI) of combined anti-TB agents prepared as a particulate system (study group) compared with placebo DPI (control group) in patients diagnosed with pulmonary TB.. This study was a randomized, placebo-controlled, double-blinded parallel design. Subjects were pulmonary TB patients, new or re-treatment, aged 18 years or older. The eligible patients were randomly allocated (1:1) to either the study group or the control group using stratified blocked randomization. The add-on DPI of combined anti-TB therapy (each capsule contained isoniazid 5 mg, rifampicin 2 mg, pyrazinamide 16 mg, and levofloxacin 2 mg) was used throughout the course of the standard oral anti-TB treatment. The primary outcome was Mycobacterium tuberculosis (MTB) sputum culture conversion measured after receiving treatment for eight weeks. Secondary outcomes were clinical signs and symptoms of pulmonary TB and adverse drug reactions (ADRs) related to anti-TB agents. The percentages of patients who achieved the primary outcome were compared (95% confidence interval). All analyses were performed using the modified intention-to-treat principle.. 91 patients were randomly allocated: 44 to the study group and 47 to the control group. Important baseline data (%peak expiratory flow rate, chest X-ray findings, resistance to anti-TB agents, renal and liver function tests) were similar between the two groups. Although the percentages of patients who achieved the primary outcome were similar in both groups (34/44 [77.3%] in the study group and (34/47 [72.3%] in the control group; relative risk [RR] 1.07, 95% CI 0.84-1.36; p = 0.589), the study group patients seemed to achieve the primary outcome earlier than the control group (22/44 [50.0%] vs 15/47 [31.9%]; RR 1.57, 95% CI 0.94-2.61; p = 0.079) at the end of week 4. Cough was significantly lower in the study group than in the control group (23/44 [52.3%] vs 43/47 [91.5%]; RR 0.57, 95% CI 0.43-0.77; p < 0.001) at week 4 of treatment. Hemoptysis was found in approximately half of each group at baseline. The percentage of patients having hemoptysis was substantially reduced at week 2 of treatment (5 [11.4%] in the study group and 11 [23.0%] in the control group, p = 0.132). Regarding safety outcomes, no dyspnea or severe ADRs were reported. Adverse events (AEs) related to oral anti-TB agents, (e.g. liver function tests) were in normal ranges in most patients in both groups during the treatment. The incidences of common AEs reported (e.g. anorexia, dizziness, numbness, arthralgia, rash, and itching) were similar between the two groups, while the incidences of nausea and vomiting were significantly lower in the study group than the control group (38.6% vs 74.5%, p = 0.001, and 43.2% vs 66.0%, p = 0.029, respectively).. Add-on combined anti-TB DPI therapy to the standard oral anti-TB treatment did not increase MTB sputum culture conversion at two months of treatment. However, the percentage of patients having cough in the study group was significantly lower than in the control group at two months after treatment. A reduction in cough might represent adequate response to treatment, and result in a decreased risk of spread of infection. Combined anti-TB DPI therapy was safe. Further study investigated in a larger sample using higher strengths of DPI therapy is required.

Topics: Dry Powder Inhalers; Humans; Isoniazid; Levofloxacin; Powders; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Tuberculosis preventive therapy for persons with HIV infection is effective, but its durability is uncertain.. To compare treatment completion rates of weekly isoniazid-rifapentine for 3 months versus daily isoniazid for 6 months as well as the effectiveness of the 3-month rifapentine-isoniazid regimen given annually for 2 years versus once.. Randomized trial. (ClinicalTrials.gov: NCT02980016).. South Africa, Ethiopia, and Mozambique.. Persons with HIV infection who were receiving antiretroviral therapy, were aged 2 years or older, and did not have active tuberculosis.. Participants were randomly assigned to receive weekly rifapentine-isoniazid for 3 months, given either annually for 2 years or once, or daily isoniazid for 6 months. Participants were screened for tuberculosis symptoms at months 0 to 3 and 12 of each study year and at months 12 and 24 using chest radiography and sputum culture.. Treatment completion was assessed using pill counts. Tuberculosis incidence was measured over 24 months.. Between November 2016 and November 2017, 4027 participants were enrolled; 4014 were included in the analyses (median age, 41 years; 69.5% women; all using antiretroviral therapy). Treatment completion in the first year for the combined rifapentine-isoniazid groups (. If rifapentine-isoniazid is effective in curing subclinical tuberculosis, then the intensive tuberculosis screening at month 12 may have reduced its effectiveness.. Treatment completion was higher with rifapentine-isoniazid for 3 months compared with isoniazid for 6 months. In settings with high tuberculosis transmission, a second round of preventive therapy did not provide additional benefit to persons receiving antiretroviral therapy.. The U.S. Agency for International Development through the CHALLENGE TB grant to the KNCV Tuberculosis Foundation.

Topics: Adolescent; Adult; Anti-HIV Agents; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethiopia; Female; HIV Infections; Humans; Isoniazid; Male; Mozambique; Rifampin; South Africa; Tuberculosis, Pulmonary; Young Adult

Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen.. S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority.. This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels.. NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1.

Topics: Adolescent; Adult; Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Equivalence Trials as Topic; Ethambutol; Female; HIV Infections; Humans; Male; Middle Aged; Moxifloxacin; Rifampin; Tuberculosis, Pulmonary; Young Adult

Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. From November 2014 to November 2016, we randomized 114 drug-sensitive treatment-naive pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid at 300 mg once daily (QD), 300 mg twice daily (BD), 600 mg QD, 600 mg BD, 1,200 mg QD, 1,200 mg three times per week (TIW), or a combination of isoniazid, rifampin, pyrazinamide, and ethambutol. Sixteen-hour sputum samples were collected overnight, and bactericidal activity was characterized by the daily percentage change in time to positivity (TTP) and the daily rate of change in log

Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Linezolid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; South Africa; Sputum; Tuberculosis, Pulmonary

To investigate the factors associated with rifampicin-resistant tuberculosis among drug resistant tuberculosis patients and to determine the correlation of rifampicin-resistant TB with MDR-TB in a high MDR-TB burden province of china.. A retrospective longitudinal analysis on four surveys of anti-TB drug resistance done in 1998, 2003, 2008, and 2013 in Zhejiang province, China. 4289 sputum-smear microscopy positive suspected tuberculosis patients were eligible at 30 investigation points, chosen by stratified random sampling at survey sites from all over the province. Culturing samples in L-J medium and the drug-susceptibility testing for the 4 first-line anti-TB drugs were performed to all patients. Multivariate logistic regression was carried out to determine the factors associated with the rifampicin-resistance in the study population.. Overall, there were 3832 patients with positive mycobacterial cultures, and 2813 of the isolates (73.4%) were susceptible to all 4 first-line drugs. Analysis of rifampin monoresistant (RMR) TB indicated the prevalence was 1.1% in new cases and 3.4% in previously treated cases. Among the 359 rifampicin resistant TB (RR-TB) cases, 279 (77.7%) were also resistant to isoniazid, indicating MDR-TB. From 1998 to 2013, the proportion of MDR-TB among rifampicin-resistant TB cases varied between 80.0% and 87.5% (P for trend: 0.768) among previously treated cases and varied from 68.6% to 79.5% (P for trend: 0.403) among new cases. Among previously treated patients, those who received treatment for less than 6 months were less likely to have drug resistant TB (OR: 0.40, 95% CI: 0.16-0.97) or MDR-TB (OR: 0.24, 95% CI: 0.07-0.81). Patients who received anti-TB treatment in a general hospital were less likely to develop MDR-TB than those treated in a TB clinic (OR: 0.08, 95% CI: 0.01-0.72).. This study highlights a high proportion of RMR-TB among new RR-TB cases in Zhejiang, China. The management of treatment with rapid and accurate diagnosis of MDR-TB other than only relying on RIF susceptibility testing is crucial for improving adherence and outcomes in patients with drug-resistant TB.

Topics: Adolescent; Adult; China; Female; Humans; Longitudinal Studies; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Prevalence; Retrospective Studies; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Administration, Oral; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethambutol; Humans; Imidazoles; Isoniazid; Mycobacterium tuberculosis; Piperidines; Pyrazinamide; Pyridines; Rifampin; Tuberculosis, Pulmonary

To address the multifaceted challenges associated with tuberculosis (TB) in-person directly observed therapy (DOT), the World Health Organization recently recommended that countries maximize the use of digital adherence technologies. Sub-Saharan Africa needs to investigate the effectiveness of such technologies in local contexts and proactively contribute to global decisions around patient-centered TB care. This study aims to evaluate the effectiveness of pillbox-enabled self-administered therapy (SAT) compared to standard DOT on adherence to TB medication and treatment outcomes in Ethiopia. It also aims to assess the usability, acceptability, and cost-effectiveness of the intervention from the patient and provider perspectives.. This is a multicenter, randomized, controlled, open-label, superiority, effectiveness-implementation hybrid, mixed-methods, two-arm trial. The study is designed to enroll 144 outpatients with new or previously treated, bacteriologically confirmed, drug-sensitive pulmonary TB who are eligible to start the standard 6-month first-line anti-TB regimen. Participants in the intervention arm (n = 72) will receive 15 days of HRZE-isoniazid, rifampicin, pyrazinamide, and ethambutol-fixed-dose combination therapy in the evriMED500 medication event reminder monitor device for self-administration. When returned, providers will count any remaining tablets in the device, download the pill-taking data, and refill based on preset criteria. Participants can consult the provider in cases of illness or adverse events outside of scheduled visits. Providers will handle participants in the control arm (n = 72) according to the standard in-person DOT. Both arms will be followed up throughout the 2-month intensive phase. The primary outcomes will be medication adherence and sputum conversion. Adherence to medication will be calculated as the proportion of patients who missed doses in the intervention (pill count) versus DOT (direct observation) arms, confirmed further by IsoScreen urine isoniazid test and a self-report of adherence on eight-item Morisky Medication Adherence Scale. Sputum conversion is defined as the proportion of patients with smear conversion following the intensive phase in intervention versus DOT arms, confirmed further by pre-post intensive phase BACTEC MGIT TB liquid culture. Pre-post treatment MGIT drug susceptibility testing will determine whether resistance to anti-TB drugs could have impacted culture conversion. Secondary outcomes will include other clinical outcomes (treatment not completed, death, or loss to follow-up), cost-effectiveness-individual and societal costs with quality-adjusted life years-and acceptability and usability of the intervention by patients and providers.. This study will be the first in Ethiopia, and of the first three in sub-Saharan Africa, to determine whether electronic pillbox-enabled SAT improves adherence to TB medication and treatment outcomes, all without affecting the inherent dignity and economic wellbeing of patients with TB.. ClinicalTrials.gov, NCT04216420. Registered on 2 January 2020.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Cost-Benefit Analysis; Directly Observed Therapy; Electrical Equipment and Supplies; Equivalence Trials as Topic; Ethambutol; Ethiopia; Female; Follow-Up Studies; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Multicenter Studies as Topic; Mycobacterium tuberculosis; Patient Acceptance of Health Care; Prospective Studies; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Self Administration; Sputum; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

The phase III REMoxTB study prospectively enrolled HIV-positive (with CD4+ count > 250 cells, not on anti-retroviral therapy) and HIV-negative patients. We investigated the incidence of adverse events and cure rates according to HIV status for patients receiving standard TB therapy in the trial.. Forty-two HIV-positive cases were matched to 220 HIV-negative controls by age, gender, ethnicity, and trial site using coarsened exact matching. Grade 3 and 4 adverse events (AEs) were summarised by MedDRA System Organ Class. Kaplan-Meier curves for time to first grade 3 or 4 AE were constructed according to HIV status with hazard ratios calculated. Patients were considered cured if they were culture negative 18 months after commencing therapy with ≥2 consecutive negative culture results.. Twenty of 42 (47.6%) HIV-positive and 34 of 220 (15.5%) HIV-negative patients experienced ≥1 grade 3 or 4 AE, respectively. The majority of these were hepatobiliary disorders that accounted for 12 of 40 (30.0%) events occurring in 6 of 42 (14.3%) HIV-positive patients and for 15 of 60 (25.0%) events occurring in 9 of 220 (4.1%) HIV-negative patients. The median time to first grade 3 or 4 AE was 54 days (IQR 15.5-59.0) for HIV-positive and 29.5 days (IQR 9.0-119.0) for HIV-negative patients, respectively. The hazard ratio for experiencing a grade 3 or 4 AE among HIV-positive patients was 3.25 (95% CI 1.87-5.66, p < 0.01). Cure rates were similar, with 38 of 42 (90.5%) HIV-positive and 195 of 220 (88.6%) HIV-negative patients (p = 0.73) cured at 18 months.. HIV-positive patients receiving standard TB therapy in the REMoxTB study were at greater risk of adverse events during treatment but cure rates were similar when compared to a matched sample of HIV-negative patients.

Topics: Adult; Antitubercular Agents; Ethambutol; Female; HIV Seropositivity; Humans; Incidence; Isoniazid; Linear Models; Male; Multivariate Analysis; Prospective Studies; Pyrazinamide; Rifampin; Risk Factors; Treatment Outcome; Tuberculosis, Pulmonary; United Kingdom

Drug-resistant tuberculosis (DR-TB) remains a major global health problem. Early treatment of TB is critical; in the absence of rapid- susceptibility testing, the empiric selection of drugs should be guided by clinical data. This study aimed to determine the clinical predictors of DR-TB. From September 2010 to August 2017, sociodemographic and clinical characteristics were collected from 144 patients with tuberculosis at the Hospital Civil de Guadalajara, Mexico. Isolates were subjected to drug-susceptibility testing. Clinical predictors of DR-TB were determined using univariate and multivariate analysis. Any drug, isoniazid, and rifampin resistance rates were 47.7, 23.0, and 11.6%, respectively. The visualization of cavities and nodules through either chest radiography or computed tomography were independent predictors of DR-TB. In conclusion, early detection of DR-TB in this population could be based on multiple cavities being observed using chest imaging. This study's results can be applied to future patients with TB in our community to optimize the DR-TB diagnostic process.

Topics: Adult; Antitubercular Agents; Female; Humans; Isoniazid; Male; Mexico; Middle Aged; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

To measure the association between phenotypic drug resistance and the risk of tuberculosis infection and disease among household contacts of patients with pulmonary tuberculosis.. 106 district health centers in Lima, Peru between September 2009 and September 2012.. Prospective cohort study.. 10 160 household contacts of 3339 index patients with tuberculosis were classified on the basis of the drug resistance profile of the patient: 6189 were exposed to drug susceptible strains of. Tuberculosis infection (positive tuberculin skin test) and the incidence of active disease (diagnosed by positive sputum smear or chest radiograph) after 12 months of follow-up.. Household contacts exposed to patients with multidrug resistant tuberculosis had an 8% (95% confidence interval 4% to 13%) higher risk of infection by the end of follow-up compared with household contacts of patients with drug sensitive tuberculosis. The relative hazard of incident tuberculosis disease did not differ among household contacts exposed to multidrug resistant tuberculosis and those exposed to drug sensitive tuberculosis (adjusted hazard ratio 1.28, 95% confidence interval 0.9 to 1.83).. Household contacts of patients with multidrug resistant tuberculosis were at higher risk of tuberculosis infection than contacts exposed to drug sensitive tuberculosis. The risk of developing tuberculosis disease did not differ among contacts in both groups. The evidence invites guideline producers to take action by targeting drug resistant and drug sensitive tuberculosis, such as early detection and effective treatment of infection and disease.. ClinicalTrials.gov NCT00676754.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Child, Preschool; Contact Tracing; Disease Progression; Female; Follow-Up Studies; Humans; Incidence; Infant; Infant, Newborn; Isoniazid; Kaplan-Meier Estimate; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Peru; Prospective Studies; Rifampin; Sputum; Tuberculin Test; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Linezolid improves the treatment outcomes of multidrug-resistant tuberculosis substantially. We investigated whether use of linezolid instead of ethambutol increases the proportion of sputum culture conversion at 8 weeks of treatment in patients with pulmonary tuberculosis.. We did a phase 2, multicentre, randomised, open-label trial for patients with pulmonary tuberculosis at the three affiliated hospitals to Seoul National University and National Medical Center (Seoul-Seongnam, South Korea). Patients, aged 20-80 years, with a positive sputum for pulmonary tuberculosis, but without resistance to rifampicin, and current treatment administered for 7 days or fewer, were randomly assigned at a 1:1:1 ratio into three groups. The control group received ethambutol (2 months) with isoniazid, rifampicin, and pyrazinamide. The second group used linezolid (600 mg/day) for 2 weeks and the third group for 4 weeks instead of ethambutol for 2 months. We used a minimisation method to randomise, and stratified according to institution, cavitation on chest radiographs, and diabetes. The primary endpoint was the proportion of patients with negative culture conversion of sputum in liquid media after 8 weeks of treatment. The results of this trial were analysed primarily in the modified intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01994460.. Between Feb 19, 2014, and Jan 13, 2017, a total of 429 patients were enrolled and 428 were randomly assigned into either the control group (142 patients), the linezolid 2 weeks group (143 patients), or the linezolid 4 weeks group (143 patients). Among them, 401 were eligible for primary efficacy analyses. In the modified intention-to-treat analyses, negative cultures in liquid media at 8 weeks of treatment were observed in 103 (76·9%) of 134 control patients, 111 (82·2%) of 135 in the linezolid 2 weeks group, and 100 (75·8%) of 132 in the linezolid 4 weeks groups. The difference from the control group was 5.4% (95% CI -4·3 to 15·0, p=0·28) for the linezolid 2 weeks group and -1·1% (-11·3 to 9·1, p=0·83) for the linezolid 4 weeks group. Numbers of patients who experienced at least one adverse event were similar across the groups (86 [62·8%] of 137 in control, 79 [57·2%] of 138 in the linezolid 2 weeks group, and 75 [62·0%] of 121 in the linezolid 4 weeks group). Resistance to linezolid was not identified in any patient.. Higher rates of culture conversion at 8 weeks of treatment with short-term use of linezolid were not observed. However, safety analyses and the resistance profile suggested the potential role of linezolid in shortening of treatment for drug-susceptible tuberculosis.. Ministry of Health and Welfare, South Korea.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Drug Substitution; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Linezolid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Delamanid is one of two recently approved drugs for the treatment of multidrug-resistant tuberculosis. We aimed to evaluate the safety and efficacy of delamanid in the first 6 months of treatment.. This randomised, double-blind, placebo-controlled, phase 3 trial was done at 17 sites in seven countries (Estonia, Latvia, Lithuania, Moldova, Peru, the Philippines, and South Africa). We enrolled eligible adults (>18 years) with pulmonary multidrug-resistant tuberculosis to receive, in combination with an optimised background regimen developed according to WHO and national guidelines, either oral delamanid (100 mg twice daily) for 2 months followed by 200 mg once daily for 4 months or placebo (same regimen). Patients were centrally randomised (2:1) and stratified by risk category for delayed sputum culture conversion. Primary outcomes were the time to sputum culture conversion over 6 months and the difference in the distribution of time to sputum culture conversion over 6 months between the two groups, as assessed in the modified intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424670.. Between Sept 2, 2011, and Nov 27, 2013, we screened 714 patients, of whom 511 were randomly assigned (341 to delamanid plus optimised background regimen [delamanid group] and 170 to placebo plus optimised background regimen [placebo group]) and formed the safety analysis population. 327 patients were culture-positive for multidrug-resistant tuberculosis at baseline and comprised the efficacy analysis population (226 in the delamanid group and 101 in the placebo group). Median time to sputum culture conversion did not differ between the two groups (p=0·0562; modified Peto-Peto), with 51 days (IQR 29-98) in the delamanid group and 57 days (43-85) in the placebo group; the hazard ratio was 1·17 (95% CI 0·91-1·51, p=0·2157). 501 (98·0%) of 511 patients had at least one treatment-emergent adverse event. 136 (26·6%) of 511 patients had at least one serious treatment-emergent adverse event; the incidence was similar between treatment groups (89 [26·1%] of 341 patients for delamanid and 47 [27·6%] of 170 for placebo). Deaths related to treatment-emergent adverse events were similar between groups (15 [4·4%] of 341 for delamanid and six [3·5%] of 170 for placebo). No deaths were considered to be related to delamanid.. The reduction in median time to sputum culture conversion over 6 months was not significant in the primary analysis. Delamanid was well tolerated with a highly characterised safety profile. Further evaluation of delamanid is needed to determine its role in a rapidly evolving standard of care.. Otsuka Pharmaceutical.

Topics: Antitubercular Agents; Double-Blind Method; Drug Administration Schedule; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Nitroimidazoles; Oxazoles; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Antitubercular Agents; Carboxylic Ester Hydrolases; Constitutive Androstane Receptor; Female; HIV Infections; Humans; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Pharmacogenomic Testing; Polymorphism, Single Nucleotide; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Rifampin; Tuberculosis, Pulmonary; Young Adult

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

Vitamin D deficiency may contribute to the therapeutic failure of antituberculosis therapy (ATT). The aim of this study is to explore the role of adding cholecalciferol to the standard ATT in improving the therapeutic outcome among the naïve patients with pulmonary tuberculosis (TB).. A randomized, controlled, clinical study, which included 496 naïve patients with pulmonary TB, was carried out. The patients were randomly allocated to two groups. Group-A included 247 patients who received ATT, while group-B included 249 patients who received ATT with cholecalciferol.. The rate of therapeutic failure among the study population was 29.4%; it was significantly lower among patients of group-B compared to those of group-A (22.1% (95% CI 14.7-26.2) vs 38.1% (95% CI 31.5-46.1), p 0.036). In addition, the rate of early therapeutic response was significantly higher among patients of group-B compared to those of group-A (35.3% (95% CI 29.6-42.3) vs 19.4% (95% CI 15.1-24.6), p 0.041). Incidence rate of adverse effects was 19.3%; it was higher (although not statistically significant) among patients of group-A compared to those of group-B (21.9% vs 16.9%).. In conclusion, cholecalciferol-augmented ATT can be more efficacious in treating naïve patients with pulmonary TB compared to the standard ATT. In addition, adding vitamin D3 to ATT provides extra protection against the hepatic and muscular adverse effects of ATT.

Topics: Adult; Antitubercular Agents; Cholecalciferol; Drug Therapy, Combination; Egypt; Ethambutol; Female; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Treatment Failure; Treatment Outcome; Tuberculosis, Pulmonary; Vitamins; Young Adult

Shorter duration of treatment for the management of drug-susceptible pulmonary tuberculosis (TB) would be a significant improvement in the care of patients suffering from the disease. Besides newer drugs and regimens, other modalities like host-directed therapy are also being suggested to reach this goal. This study's objective is to assess the efficacy and safety of metformin-containing anti-TB treatment (ATT) regimen in comparison to the standard 6-month ATT regimen in the treatment of patients with newly diagnosed sputum smear-positive drug-sensitive pulmonary TB.. We are conducting a multicentric, randomised open-label controlled clinical trial to achieve the study objective. The intervention group will receive isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) along with 1000 mg of daily metformin (Met) for the first 2 months while the control group will receive only HRZE. After 2 months, both the groups will receive HRE daily for 4 months. The primary endpoint is time to sputum culture conversion. Secondary endpoints will include time to detection of. The ethics committee of the participating institutes have approved the study. Results from this trial will contribute to evidence towards constructing a shorter, effective and safe regimen for patients with TB. The results will be shared widely with the National Programme managers, policymakers and stakeholders through open access publications, dissemination meetings, conference abstracts and policy briefs. This is expected to provide a new standard of care for drug-sensitive patients with pulmonary TB who will not only reduce the number of clinic visits and lost to follow-up of patients from treatment but also reduce the burden on the healthcare system.. CTRI/2018/01/011176; Pre-results.

Topics: Adult; Antibiotics, Antitubercular; Drug Combinations; Drug Therapy, Combination; Ethambutol; Humans; India; Isoniazid; Metformin; Multicenter Studies as Topic; Mycobacterium tuberculosis; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Pulmonary

Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011.. We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for. Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively.. In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.).

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Medication Adherence; Middle Aged; Moxifloxacin; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Pyrazinamide (PZA) -including regimen had not been fully recommended for late elderly patients with tuberculosis (TB) by Japanese Society for Tuberculosis until 2018. Studies on the safety of adding PZA to other first-line TB drugs for late elderly patients are limited. In this prospective randomized open-label study, we aimed to assess the safety of regimen including PZA for patients aged 80 or older. Patients in their eighties with smear-positive pulmonary TB without any liver diseases were randomly assigned to HRE (isoniazid, rifampicin, ethambutol) group or HREZ (HRE and PZA) group. The primary endpoint was discontinuation or interruption rate of treatment due to liver injury. Other endpoint included overall rate of liver injury, time to culture conversion, and overall mortality. Eighty-nine patients were assigned to either HRE group (n = 45) or HREZ group (n = 44). Clinical background was not different in two groups including age, smear grade, body weight, serum albumin, and activity degree. Discontinuation of treatment due to liver injury occurred in 15.6% of HRE group and 9.1% of HREZ group, which showed no statistical difference. Incidence of liver injury was also comparable between two groups. Overall mortality was statistically higher in HREZ group (3 in HRE vs. 10 in HREZ), although all deaths seemed to be irrelevant to PZA use. Time to culture conversion was significantly shorter in HREZ group (43.6 days vs. 30.2 days). In conclusion, regimen including PZA seems to be safe for late elderly patients with pulmonary TB.

Topics: Age Factors; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Humans; Incidence; Isoniazid; Male; Mycobacterium tuberculosis; Prospective Studies; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

The benefit of daily over thrice-weekly antituberculosis therapy among HIV-positive patients with pulmonary tuberculosis (TB) who are receiving antiretroviral therapy remains unproven.. To compare the efficacy and safety of daily, part-daily, and intermittent antituberculosis therapy regimens in the treatment of HIV-associated pulmonary TB.. This open-label, randomized clinical trial was conducted by the National Institute for Research in Tuberculosis, south India. Adults infected with HIV with newly diagnosed, culture-positive, pulmonary TB were enrolled between September 14, 2009, and January 18, 2016.. Patients were randomized to daily, part-daily, and intermittent antituberculosis therapy regimens, stratified by baseline CD4 lymphocyte count and sputum smear grade. Antiretroviral therapy was initiated as per national guidelines. Clinical and sputum microbiological examinations of patients were performed monthly until 18 months after randomization. Adverse events were recorded using standard criteria.. The primary outcome was favorable response, defined as treatment completion with all available sputum cultures negative for Mycobacterium tuberculosis during the last 2 months of treatment. Unfavorable responses included treatment failures, dropouts, deaths, and toxic effects among regimens.. Of 331 patients (251 [76%] male; mean [SD] age, 39 [9] years; mean [SD] HIV viral load, 4.9 [1.2] log10 copies/mL; and median [interquartile range] CD4 lymphocyte count, 138 [69-248] cells/μL), favorable responses were experienced by 91% (89 of 98), 80% (77 of 96), and 77% (75 of 98) in the daily, part-daily, and intermittent regimens, respectively. With the difference in outcome between daily and intermittent regimens crossing the O'Brien-Fleming group sequential boundaries and acquired rifampicin resistance emergence (n = 4) confined to the intermittent group, the data safety monitoring committee halted the study. A total of 18 patients died and 18 patients dropped out during the treatment period in the 3 regimens. Six, 4, and 6 patients in the daily, part-daily, and intermittent regimens, respectively, had TB recurrence.. Among HIV-positive patients with pulmonary TB receiving antiretroviral therapy, a daily anti-TB regimen proved superior to a thrice-weekly regimen in terms of efficacy and emergence of rifampicin resistance.. clinicaltrials.gov Identifier: NCT00933790.

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; CD4 Lymphocyte Count; Directly Observed Therapy; Drug Administration Schedule; Ethambutol; Female; HIV Infections; Humans; Immune Reconstitution Inflammatory Syndrome; Isoniazid; Male; Middle Aged; Patient Dropouts; Proportional Hazards Models; Rifampin; Streptomycin; Treatment Failure; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Viral Load

The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs.. We enrolled HIV-infected Ugandans with pulmonary tuberculosis. Estimation of first-line antituberculosis drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of tuberculosis treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion.. We enrolled 268 HIV-infected patients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of tuberculosis treatment (hazard ratio, 0.54; 95% confidence interval, .37-.77; P = .001) or by the end of follow-up (0.61; .44-.85; P = .003). Patients in the highest quartile for area under the rifampicin and isoniazid concentration-time curves for were twice as likely to experience sputum conversion than those in the lowest quartile. Rifampicin and isoniazid concentrations below the thresholds and weight <55 kg were both risk factors for unfavorable tuberculosis treatment outcomes. Only 4.4% of the participants had treatment failure.. Although low antituberculosis drug concentrations did not translate to a high proportion of patients with treatment failure, the association between low concentrations of rifampicin and isoniazid and delayed culture conversion may have implications for tuberculosis transmission. Clinical Trials Registration: NCT01782950.

Topics: Adult; Antitubercular Agents; Coinfection; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Male; Prospective Studies; Rifampin; Risk Factors; Sputum; Treatment Failure; Treatment Outcome; Tuberculosis, Pulmonary; Uganda

Xpert MTB/RIF is increasingly used in many countries as the initial diagnostic test for tuberculosis (TB). Few studies have evaluated the effect of Xpert on TB diagnosis under programmatic conditions in Brazil. The aim of the present study was to evaluate the impact of introduction of Xpert MTB/RIF on TB diagnosis in a city with high TB incidence in Brazil.. We included patients evaluated with conventional diagnostic tests during one year before Xpert introduction (pre-Xpert group) and patients evaluated using Xpert during one year after the test introduction (post-Xpert group).. 620 patients met the inclusion criteria (208 in the pre-Xpert group and 412 in the post-Xpert group) and were included in the analysis. The time until TB diagnosis was shorter in post-Xpert group (0.7 day, IQR: 0.5-1.0 day) than in pre-Xpert group (2.0 days, IQR: 2.0-2.0 days) (p<0.0001). Atypical disease characteristics, such as less weight loss, fever, dyspnea, night sweats, and hemoptysis; a negative sputum smear; a negative culture, and a chest X-ray atypical of TB were more common in post-Xpert group than in pre-Xpert group (p<0.0001 for all).. We found that the implementation of the Xpert MTB/RIF assay, under programmatic conditions, improve and facilitate TB diagnosis, especially in cases with atypical disease manifestations. These results are likely to be generalizable to settings with a similar high TB incidence.

Topics: Adult; Antitubercular Agents; Brazil; Comorbidity; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Incidence; Male; Middle Aged; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Predictive Value of Tests; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Treatment Outcome; Tuberculosis, Pulmonary; Urban Population

The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure-response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin.. Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates.. The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25-10.3 days.. A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin.. NCT01392911.

Topics: Adult; Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Humans; Middle Aged; Models, Theoretical; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis, Pulmonary; Young Adult

In the experimental arm of the OFLOTUB trial, gatifloxacin replaced ethambutol in the standard 4-month regimen for drug-susceptible pulmonary tuberculosis. The study included a nested pharmacokinetic (PK) study. We sought to determine if PK variability played a role in patient outcomes.. Patients recruited in the trial were followed for 24 months, and relapse ascertained using spoligotyping. Blood was drawn for drug concentrations on 2 separate days during the first 2 months of therapy, and compartmental PK analyses was performed. Failure to attain sustained sputum culture conversion at the end of treatment, relapse, or death during follow-up defined therapy failure. In addition to standard statistical analyses, we utilized an ensemble of machine-learning methods to identify patterns and predictors of therapy failure from among 27 clinical and laboratory features.. Of 126 patients, 95 (75%) had favorable outcomes and 19 (15%) failed therapy, relapsed, or died. Pyrazinamide and rifampicin peak concentrations and area under the concentration-time curves (AUCs) were ranked higher (more important) than gatifloxacin AUCs. The distribution of individual drug concentrations and their ranking varied significantly between South African and West African trial sites; however, drug concentrations still accounted for 31% and 75% of variance of outcomes, respectively. We identified a 3-way antagonistic interaction of pyrazinamide, gatifloxacin, and rifampicin concentrations. These negative interactions disappeared if rifampicin peak concentration was above 7 mg/L.. Concentration-dependent antagonism contributed to death, relapse, and therapy failure but was abrogated by high rifampicin concentrations. Therefore, increasing both rifampin and gatifloxacin doses could improve outcomes.. NCT00216385.

Topics: Adolescent; Adult; Antitubercular Agents; Artificial Intelligence; Dose-Response Relationship, Drug; Female; Gatifloxacin; Humans; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Young Adult

We conducted a single-center retrospective cohort study to evaluate whether the HbA1c level on admission could predict the in-hospital treatment outcome of smear-positive non-multi-drug-resistant HIV-negative culture-proven pulmonary tuberculosis inpatients. Our standard regimens under the direct observation were HRZE or HRE for the first two months followed by combination therapy with isoniazid and rifampicin. Our cohort consisted of consecutive 239 patients consisted of 147 men and 92 women with a median age of 73 years. The HbA1c level of patients whose HbA1c was above 7.0% on admission showed clear declining trends after admission. HbA1c on admission had no Spearman's rank correlation with time to discharge alive (r = 0.17) and time to becoming non-infective (r = 0.17). By Kaplan-Meier curves and a log-rank trend test, HbA1c quartile subgroups showed no association with times to discharge alive (p = 0.431), becoming non-infective (p = 0.113), and in-hospital death (p = 0.427). Based on multi-variate Cox analysis, HbA1c on admission had no significant impact on time to discharge alive (hazard ratio = 1.03, 95% CI 0.89-1.20, p = 0.659), becoming non-infective (hazard ratio = 0.93, 95% CI 0.80-1.06, p = 0.277), and in-hospital death (hazard ratio = 0.68, 0.43-1.07, p = 0.097). In conclusion, the HbA1c level on admission did not seem to affect in-hospital tuberculosis treatment outcomes in Japanese cohort.

Topics: Adult; Aged; Aged, 80 and over; Female; Glycated Hemoglobin; HIV; Humans; Isoniazid; Male; Middle Aged; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Point-of-care (POC) diagnostics have the potential to reduce pretreatment loss to follow-up and delays to initiation of appropriate tuberculosis (TB) treatment.. To evaluate the effect of a POC diagnostic strategy on initiation of appropriate TB treatment.. We conducted a cluster-randomized trial of adults with cough who were HIV positive and/or at high risk of drug-resistant TB. Two-week time blocks were randomized to two strategies: (1) Xpert MTB/RIF test (Cepheid, Sunnyvale, CA) performed at a district hospital laboratory or (2) POC Xpert MTB/RIF test performed at a primary health care clinic. All participants provided two sputum specimens: one for the Xpert test and the other for culture as a reference standard. The primary outcome was the proportion of participants with culture-positive pulmonary tuberculosis (PTB) initiated on appropriate TB treatment within 30 days.. Between August 22, 2011, and March 1, 2013, 36 two-week blocks were randomized, and 1,297 individuals were enrolled (646 in the laboratory arm, 651 in the POC arm), 159 (12.4%) of whom had culture-positive PTB. The proportions of participants with culture-positive PTB initiated on appropriate TB treatment within 30 days were 76.5% in the laboratory arm and 79.5% in the POC arm (odds ratio, 1.13; 95% confidence interval, 0.51-2.53; P = 0.76; risk difference, 3.1%; 95% confidence interval, -16.2 to 10.1). The median time to initiation of appropriate treatment was 7 days (laboratory) versus 1 day (POC).. POC positioning of the Xpert test led to more rapid initiation of appropriate TB treatment. Achieving one-stop diagnosis and treatment for all people with TB will require simpler, more sensitive diagnostics and broader strengthening of health systems. Clinical trial registered with www.isrctn.com (ISRCTN 18642314) and www.sanctr.gov.za (DOH-27-0711-3568).

Topics: Adult; Antibiotics, Antitubercular; Female; Humans; Male; Middle Aged; Point-of-Care Systems; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

In a multiple-dose-ranging trial, we previously evaluated higher doses of rifampin in patients for 2 weeks. The objectives of the current study were to administer higher doses of rifampin for a longer period to compare the pharmacokinetics, safety/tolerability, and bacteriological activity of such regimens. In a double-blind, randomized, placebo-controlled, phase II clinical trial, 150 Tanzanian patients with tuberculosis (TB) were randomized to receive either 600 mg (approximately 10 mg/kg of body weight), 900 mg, or 1,200 mg rifampin combined with standard doses of isoniazid, pyrazinamide, and ethambutol administered daily for 2 months. Intensive pharmacokinetic sampling occurred in 63 patients after 6 weeks of treatment, and safety/tolerability was assessed. The bacteriological response was assessed by culture conversion in liquid and solid media. Geometric mean total exposures (area under the concentration-versus-time curve up to 24 h after the dose) were 24.6, 50.8, and 76.1 mg · h/liter in the 600-mg, 900-mg, and 1,200-mg groups, respectively, reflecting a nonlinear increase in exposure with the dose (

Topics: Adult; Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Anti-tuberculosis drug-induced liver injury (ATLI) is common during the treatment of tuberculosis (TB). As an important enzyme in the metabolism of many drugs, UGT2B7 (uridine diphosphate glucuronyl transferase 2B7) was associated with drug-induced liver disorder. This study investigated the association between the polymorphisms of UGT2B7 and ATLI in Chinese Han. Totally, 280 newly diagnosed TB patients had been followed up for 3 months after the prescription of anti-TB therapy. Tag-single-nucleotide polymorphism (tag-SNPs) (rs10028494 and rs7668282) were genotyped with the MassARRAY platform. The associations between tag-SNPs and ATLI risk were analyzed by logistic regression analysis adjusting for confounding factors. In this prospective study, 33 patients were lost to follow-up, and 24 patients were diagnosed with ATLI and considered as the case group. The remaining 223 subjects without ATLI were considered as the control group. No significant association was observed in allele and genotype frequencies of UGT2B7 between the two groups. This study is the first attempt to investigate the association of genetic polymorphisms of UGT2B7 with ATLI in Chinese Han. There is no significant association between UGT2B7 polymorphisms and ATLI in Chinese Han.

Topics: Adult; Antitubercular Agents; Asian People; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Genetic Predisposition to Disease; Glucuronosyltransferase; Humans; Isoniazid; Male; Middle Aged; Polymorphism, Single Nucleotide; Pyrazinamide; Rifampin; Risk; Tuberculosis, Pulmonary; Young Adult

More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study.

Topics: Adult; Aged; Antitubercular Agents; Biomarkers; Drug Combinations; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Severity of Illness Index; Treatment Outcome; Tuberculosis, Pulmonary

The overall goals for treatment of Tuberculosis (TB) are to cure individual patient and to minimize the transmission of Mycobacterium tuberculosis. At the time of study conduction, the standard treatment for newly diagnosed tuberculosis patients consisted of an intensive phase for two months with four drugs (HRZE), followed by continuation phase for four months with two drugs (HR). Rifampicin, which is very effective against Mycobacterium tuberculosis, in both the phases of treatment, has certain concerns, which includes, decreased bioavailability with chronic use and hepatotoxicity. To overcome these concerns a new boosted formulation of Rifampicin (Risorine) with bio-enhancer Piperine was developed. Piperine has been found to increase bioavailability of several drugs including Amoxicillin, Cefotaxime, Theophylline and Propranolol. Risorine is a fixed dose combination that contains Rifampicin 200 mg + Isoniazid 300 mg + Piperine 10 mg.. The aim of the present study was to validate the therapeutic efficacy and tolerability of Risorine formulation containing regimen with a conventional regimen in the management of patients with newly diagnosed pulmonary tuberculosis.. Total 216 patients with sputum positive and treatment naïve pulmonary tuberculosis were enrolled in the study after fulfillment of inclusion / exclusion criteria. These patients were randomized to receive either a conventional anti-TB therapy (n = 117) or a similar regimen containing Risorine (n = 99) for 6 months. During the study period, symptomatic improvement, sputum conversion and radiological improvement were monitored at regular intervals.. Of the 216 enrolled patients, 75% in the Risorine group and 79% in the control group completed the study. At 4 weeks the sputum conversion rate was significantly superior in Risorine group (93%) than the control group (84%), which was consistence throughout the study. Cure rate at the end of 24 weeks, was higher in Risorine group (92%) than in the control group (82%). Elevation of liver enzymes were observed in 3 patients in the Risorine group and in 9 patients in control group.. Risorine, a novel formulation of low dose Rifampicin (200 mg), a bio enhancer Piperine (10 mg) and standard dose Isoniazid (300 mg) when given along with Ethambutol and Pyrazinamide was comparable in efficacy with standard WHO therapy using conventional formulation. Risorine provides more Rifampicin in blood compare to GI tract as well as maintaining higher blood levels on chronic therapy compared to conventional Rifampicin with better safety profile. Risorine gives higher sputum conversion rate during the Intensive Phase which is maintained till the end of study. Further a trend was also noticed towards better tolerability with newer formulation, Risorine. H = Isoniazid, R = Rifampicin, Z = Pyrazinamide and E = Ethambutol.

Topics: Adult; Alkaloids; Antibiotics, Antitubercular; Benzodioxoles; Drug Combinations; Female; Humans; Isoniazid; Male; Piperidines; Polyunsaturated Alkamides; Rifampin; Sputum; Tuberculosis, Pulmonary

Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis.. We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15-20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15-20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186).. Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22-2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3-5 adverse events, with similar proportions in each arm.. A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost.. The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC).

Topics: Adamantane; Adult; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Ethylenediamines; Female; Fluoroquinolones; Humans; Isoniazid; Male; Moxifloxacin; Pyrazinamide; Rifampin; South Africa; Tanzania; Tuberculosis, Pulmonary

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses.

Topics: Adult; Antibiotics, Antitubercular; Dose-Response Relationship, Drug; Female; Humans; Male; Rifampin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Bacterial Load; Bacterial Proteins; Colony Count, Microbial; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Gene Expression; Humans; Models, Statistical; Mutation Rate; Mycobacterium tuberculosis; Rifampin; Tissue Distribution; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB.. Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400 mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and again 4 weeks after treatment completion, when given alone as a single dose. Moxifloxacin concentration-time data were analysed using non-linear mixed-effects models.. We included 58 patients; 42 (72.4%) were HIV co-infected and 40 (95%) of these were on efavirenz-based ART. Moxifloxacin pharmacokinetics was best described using a two-compartment disposition model with first-order lagged absorption and elimination using a semi-mechanistic model describing hepatic extraction. Oral clearance (CL/F) of moxifloxacin during rifampicin-based TB treatment was 24.3 L/h for a typical patient (fat-free mass of 47 kg), resulting in an AUC of 16.5 mg·h/L. This exposure was 7.8% lower than the AUC following the single dose of moxifloxacin given alone after TB treatment completion. In HIV-co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4%, resulting in a further 30% reduction in moxifloxacin AUC.. Moxifloxacin clearance was high and plasma concentrations low in our patients overall. Moxifloxacin AUC was further decreased by co-administration of efavirenz-based ART and, to a lesser extent, rifampicin. The clinical relevance of the low moxifloxacin concentrations for TB treatment outcomes and the need for moxifloxacin dose adjustment in the presence of rifampicin and efavirenz co-treatment need further investigation.

Topics: Adult; Africa; Alkynes; Anti-HIV Agents; Antibiotics, Antitubercular; Benzoxazines; Coinfection; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Female; Fluoroquinolones; HIV Infections; Humans; Male; Moxifloxacin; Reverse Transcriptase Inhibitors; Rifampin; Tuberculosis, Pulmonary

Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.).

Topics: Adult; Antitubercular Agents; Area Under Curve; CD4 Lymphocyte Count; Coinfection; Ethambutol; Female; Gene Expression; HIV Infections; Humans; Isoniazid; Liver-Specific Organic Anion Transporter 1; Male; Monte Carlo Method; Organic Anion Transporters; Polymorphism, Single Nucleotide; Pyrazinamide; Rifabutin; Rifampin; Sex Factors; Tuberculosis, Pulmonary

There are limited pharmacokinetic data for use of the first-line antituberculosis drugs during infancy (<12 months of age), when drug disposition may differ. Intensive pharmacokinetic sampling was performed in infants routinely receiving antituberculosis treatment, including rifampin, isoniazid, pyrazinamide, and ethambutol, using World Health Organization-recommended doses. Regulatory-approved single-drug formulations, including two rifampin suspensions, were used on the sampling day. Assays were conducted using liquid chromatography-mass spectrometry; pharmacokinetic parameters were generated using noncompartmental analysis. Thirty-nine infants were studied; 14 (36%) had culture-confirmed tuberculosis. Fifteen (38%) were premature (<37 weeks gestation); 5 (13%) were HIV infected. The mean corrected age and weight were 6.6 months and 6.45 kg, respectively. The mean maximum plasma concentrations (Cmax) for rifampin, isoniazid, pyrazinamide, and ethambutol were 2.9, 7.9, 41.9, and 1.3 μg/ml, respectively (current recommended adult target concentrations: 8 to 24, 3 to 6, 20 to 50, and 2 to 6 μg/ml, respectively), and the mean areas under the concentration-time curves from 0 to 8 h (AUC0-8) were 12.1, 24.7, 239.4, and 5.1 μg · h/ml, respectively. After adjusting for age and weight, rifampin exposures for the two formulations used differed inCmax(geometric mean ratio [GMR],2.55; 95% confidence interval [CI], 1.47 to 4.41;P= 0.001) and AUC0-8(GMR, 2.52; 95% CI, 1.34 to 4.73;P= 0.005). HIV status was associated with lower pyrazinamideCmax(GMR, 0.85; 95% CI, 0.75 to 0.96;P= 0.013) and AUC0-8(GMR, 0.79; 95% CI, 0.69 to 0.90;P< 0.001) values. No other important differences were observed due to age, weight, prematurity, ethnicity, or gender. In summary, isoniazid and pyrazinamide concentrations in infants compared well with proposed adult target concentrations; ethambutol concentrations were lower but similar to previously reported pediatric studies. The low rifampin exposures require further investigation. (This study has been registered at ClinicalTrials.gov under registration no. NCT01637558.).

Topics: Anti-Bacterial Agents; Area Under Curve; Coinfection; Drug Dosage Calculations; Ethambutol; Female; HIV; HIV Infections; Humans; Infant; Infant, Newborn; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Practice Guidelines as Topic; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

The objective of this prospective study was to evaluate the diagnosis and treatment of latent tuberculosis infection (LTBI) in adult close contacts of active pulmonary tuberculosis (TB) patients in Korea.. Adult close contacts of active pulmonary TB patients were recruited at a regional tertiary hospital in Korea. The participants were tested for LTBI using the tuberculin skin test (TST) and/or QuantiFERON-TB Gold (QFT-G) test. LTBI patients, who consented to treatment, were randomly assigned to receive isoniazid for 9 months (9INH) or rifampin for 4 months (4RIF).. We examined 189 adult close contacts (> 18 years) of 107 active pulmonary TB patients. The TST and QFT-G were positive (≥ 10 mm) in 75/183 (39.7%) and 45/118 (38.1%) tested participants, respectively. Among 88 TST or QFT-G positive LTBI participants, 45 participants were randomly assigned to receive 4RIF (n = 21) or 9INH (n = 24), respectively. The average treatment duration for the 4RIF and 9INH groups was 3.3 ± 1.3 and 6.1 ± 2.7 months, respectively. Treatment was completed in 25 participants (4RIF, n = 16; 9INH, n = 9). LTBI participants who accepted treatment were more likely to be women and have more cavitary lesions on the chest radiographs of index cases and positive TST and QFT-G results compared to those who refused treatment.. About 40% of adult close contacts of active pulmonary TB patients had LTBI; about 50% of these LTBI participants agreed to treatment.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Contact Tracing; Drug Administration Schedule; Female; Humans; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Male; Medication Adherence; Middle Aged; Predictive Value of Tests; Prospective Studies; Republic of Korea; Rifampin; Tertiary Care Centers; Time Factors; Treatment Outcome; Tuberculin Test; Tuberculosis, Pulmonary; Young Adult

Randomised Phase IIB clinical trial.. To assess whether increasing the dose of rifampicin (RMP) from 10 mg/kg to 15 or 20 mg/kg results in an increase in grade 3 or 4 hepatic adverse events and/or serious adverse events (SAE).. Three hundred human immunodeficiency virus negative patients with newly diagnosed microscopy-positive pulmonary tuberculosis (TB) were randomly assigned to one of three regimens: 1) the control regimen (R10), comprising daily ethambutol (EMB), isoniazid (INH), RMP and pyrazinamide for 8 weeks, followed by INH and RMP daily for 18 weeks; 2) Study Regimen 1 (R15), as above, with the RMP dose increased to 15 mg/kg body weight daily for the first 16 weeks; and 3) Study Regimen 2 (R20), as above, with RMP increased to 20 mg/kg. Serum alanine transferase (ALT) levels were measured at regular intervals.. There were seven grade 3 increases in ALT levels, 1/100 (1%) among R10 arm patients, 2/100 (2%) in the R15 arm and 4/100 (4%) in the R20 arm (trend test P = 0.15). One (R15) patient developed jaundice, requiring treatment modification. There were no grade 4 ALT increases. There was a non-significant increase in culture negativity at 8 weeks with increasing RMP dosage: 75% (69/92) in R10, 82.5% (66/80) in R15 and 83.1% (76/91) R20 patients (P = 0.16).. No significant increase in adverse events occurred when the RMP dose was increased from 10 mg/kg to 15 mg/kg or 20 mg/kg.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Dose-Response Relationship, Drug; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment.. Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment.. 121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm).. For intensive phase daily tuberculosis treatment in combination with isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin.. www.ClinicalTrials.gov NCT00728507.

Topics: Adult; Antitubercular Agents; Case-Control Studies; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Isoniazid; Male; Middle Aged; Moxifloxacin; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

There are limited data on the performance of the use of fixed-dose combination (FDC) TB drugs when used under programmatic settings in high TB-endemic countries. We evaluated the efficacy and safety of FDC versus loose formulation (LF) TB treatment regimens for treatment of pulmonary TB (PTB) in the context of actual medical practice in prevailing conditions within programmatic settings in five sites in two high TB-burden African countries.. A two-arm, single-blind, randomized clinical trial comparing FDCs with separate LFs involving 1000 adults newly diagnosed with culture positive PTB was conducted at five sites in two African countries between 2007 and 2011. Participants were randomized to receive daily treatment with anti-TB drugs given as either FDC or separate LFs for 24 weeks (intensive phase- 8 weeks of isoniazid, rifampicin, ethambutol and pyrazinamide; continuation phase- 16 weeks of rifampicin and isoniazid). Primary outcome measures were microbiological cure and safety at the end of six months' treatment; pre-specified non-inferiority margin for difference in cure rate was 4%. The primary efficacy analysis was based on the modified intent to treat (mITT) cohort comprising all randomized patients with a positive baseline culture result for TB and who received at least one dose of study treatment. Patients missing end of treatment culture results were considered failures. Further analyses were done in which mITT patients without an end of treatment (EOT) culture were excluded in a complete case analysis (mITTcc) and a per protocol cohort analysis defined as mITTcc patients who received at least 95% of their intended doses and had an EOT culture result.. In the mITT analysis, the cure rate in the FDC group was 86.7% (398/459) and in the LF group 85.2% (396/465) (difference 1.5-% (90% confidence interval (CI) (-2.2%- 5.3%)). Per Protocol analysis showed similar results: FDC 98.9% (359/363) versus LF 96.9% (345/356), (difference 2.0% (90% CI: 0.1%- 3.8%)). The two arms showed no significant differences in terms of safety, early culture conversion and patient adherence to treatment.. The comparison of the two drug regimens satisfied the pre-specified non-inferiority criterion. Our results support the WHO recommendations for the use of FDC in the context of actual medical practice within health services in high TB-endemic countries.. ISRCTN Registry 95204603.

Topics: Adult; Africa; Aged; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

In 2012, as a pilot for Botswana's national Xpert MTB/RIF (Xpert) rollout plans, intensified tuberculosis (TB) case finding (ICF) activities were strengthened at 22 HIV treatment clinics prior to phased activation of 13 Xpert instruments. Together, the strengthened ICF intervention and Xpert activation are referred to as the "Xpert package".. The evaluation, called the Xpert Package Rollout Evaluation using a Stepped-wedge design (XPRES), has two key objectives: (1) to compare sensitivity of microscopy-based and Xpert-based pulmonary TB diagnostic algorithms in diagnosing sputum culture-positive TB; and (2) to evaluate impact of the "Xpert package" on all-cause, 6-month, adult antiretroviral therapy (ART) mortality. A pragmatic, stepped-wedge cluster-randomized trial design was chosen. The design involves enrollment of three cohorts: (1) cohort R, a retrospective cohort of all study clinic ART enrollees in the 24 months before study initiation (July 31, 2012); (2) cohort A, a prospective cohort of all consenting patients presenting to study clinics after study initiation, who received the ICF intervention and the microscopy-based TB diagnostic algorithm; and (3) cohort B, a prospective cohort of all consenting patients presenting to study clinics after Xpert activation, who received the ICF intervention and the Xpert-based TB diagnostic algorithm. TB diagnostic sensitivity will be compared between TB culture-positive enrollees in cohorts A and B. All-cause, 6-month ART-mortality will be compared between cohorts R and B. With anticipated cohort R, A, and B sample sizes of about 10,131, 1,878, and 4,258, respectively, the study is estimated to have >80 % power to detect differences in pre-versus post-Xpert TB diagnostic sensitivity if pre-Xpert sensitivity is ≤52.5 % and post-Xpert sensitivity ≥82.5 %, and >80 % power to detect a 40 % reduction in all-cause, 6-month, ART mortality between cohorts R and B if cohort R mortality is ≥13/100 person-years.. Only one small previous trial (N = 424) among ART enrolees in Zimbabwe evaluated, in a secondary analysis, Xpert impact on all-cause 6-month ART mortality. No mortality impact was observed. This Botswana trial, with its larger sample size and powered specifically to detect differences in all-cause 6-month ART mortality, remains well-positioned to contribute understanding of Xpert impact.. Retrospectively registered at ClinicalTrials.gov: NCT02538952 .

Topics: Adult; Ambulatory Care Facilities; Anti-HIV Agents; Botswana; Humans; Microscopy; Mycobacterium tuberculosis; Prospective Studies; Radiography, Thoracic; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.. We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.. Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase.. A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively).. Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).

Topics: Adolescent; Adult; Africa; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Asia; Drug Administration Schedule; Drug Therapy, Combination; Europe; Female; Humans; Male; Middle Aged; North America; Rifampin; Single-Blind Method; South America; Treatment Outcome; Tuberculosis, Pulmonary

SQ109, an asymmetrical diamine, is a novel anti-TB drug candidate. This first study in patients was done to determine safety, tolerability, pharmacokinetics and bacteriological effect of different doses of SQ109 alone and in combination with rifampicin when administered over 14 days.. Smear-positive pulmonary TB patients were randomized into six groups of 15 to receive once-daily oral treatment with 75, 150 or 300 mg of SQ109, rifampicin (10 mg/kg body weight), rifampicin plus 150 mg of SQ109, or rifampicin plus 300 mg of SQ109 for 14 days. Patients were hospitalized for supervised treatment, regular clinical, biochemical and electrocardiographic safety assessments, pharmacokinetic profiling and daily overnight sputum collection.. SQ109 was safe and generally well tolerated. Mild to moderate dose-dependent gastrointestinal complaints were the most frequent adverse events. No relevant QT prolongation was noted. Maximum SQ109 plasma concentrations were lower than MICs. Exposure to SQ109 (AUC0-24) increased by drug accumulation upon repeated administration in the SQ109 monotherapy groups. Co-administration of SQ109 150 mg with rifampicin resulted in decreasing SQ109 exposures from day 1 to day 14. A higher (300 mg) dose of SQ109 largely outweighed the evolving inductive effect of rifampicin. The daily fall in log cfu/mL of sputum (95% CI) was 0.093 (0.126-0.059) with rifampicin, 0.133 (0.166-0.100) with rifampicin plus 150 mg of SQ109 and 0.089 (0.121-0.057) with rifampicin plus 300 mg of SQ109. Treatments with SQ109 alone showed no significant activity.. SQ109 alone or with rifampicin was safe over 14 days. Upon co-administration with rifampicin, 300 mg of SQ109 yielded a higher exposure than the 150 mg dose. SQ109 did not appear to be active alone or to enhance the activity of rifampicin during the 14 days of treatment.

Topics: Adamantane; Adult; Antitubercular Agents; Drug Therapy, Combination; Ethylenediamines; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

Rifampin at a dose of 10 mg/kg was introduced in 1971 based on pharmacokinetic, toxicity, and cost considerations. Available data in mice and humans showed that an increase in dose may shorten the duration of tuberculosis treatment.. To evaluate the safety and tolerability, the pharmacokinetics, and the extended early bactericidal activity of increasing doses of rifampin.. Patients with drug-susceptible tuberculosis were enrolled into a control group of eight patients receiving the standard dose of 10 mg/kg rifampin, followed by consecutive experimental groups with 15 patients each receiving rifampin 20, 25, 30, and 35 mg/kg, respectively, for 14 days. In all patients isoniazid, pyrazinamide, and ethambutol were added in standard doses for the second 7 days of treatment. Safety, pharmacokinetics of rifampin, and fall in bacterial load were assessed.. Grade 1 and 2 adverse events were equally distributed between the five dose groups; there were five grade 3 events of which one was a possibly related hepatotoxicity. Areas under the time-concentration curves and peak serum concentrations of rifampin showed a more than proportional increase with dose. The daily fall in bacterial load over 14 days was 0.176, 0.168, 0.167, 0.265, and 0.261 log10 colony-forming units/ml sputum in the 10, 20, 25, 30, and 35 mg/kg groups, respectively.. Two weeks of rifampin up to 35 mg/kg was safe and well tolerated. There was a nonlinear increase in exposure to rifampin without an apparent ceiling effect and a greater estimated fall in bacterial load in the higher dosing groups. Clinical trial registered with www.clinicaltrials.gov (NCT 01392911).

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Bacterial Load; Drug Dosage Calculations; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Young Adult

New antituberculosis regimens are urgently needed to shorten tuberculosis treatment. Following on from favourable assessment in a 2 week study, we investigated a novel regimen for efficacy and safety in drug-susceptible and multidrug-resistant (MDR) tuberculosis during the first 8 weeks of treatment.. We did this phase 2b study of bactericidal activity--defined as the decrease in colony forming units (CFUs) of Mycobacterium tuberculosis in the sputum of patients with microscopy smear-positive pulmonary tuberculosis-at eight sites in South Africa and Tanzania. We enrolled treatment-naive patients with drug-susceptible, pulmonary tuberculosis, who were randomly assigned by computer-generated sequences to receive either 8 weeks of moxifloxacin, 100 mg pretomanid (formerly known as PA-824), and pyrazinamide (MPa100Z regimen); moxifloxacin, 200 mg pretomanid, and pyrazinamide (MPa200Z regimen); or the current standard care for drug-susceptible pulmonary tuberculosis, isoniazid, rifampicin, PZA, and ethambutol (HRZE regimen). A group of patients with MDR tuberculosis received MPa200Z (DRMPa200Z group). The primary outcome was bactericidal activity measured by the mean daily rate of reduction in M tuberculosis CFUs per mL overnight sputum collected once a week, with joint Bayesian non-linear mixed-effects regression modelling. We also assessed safety and tolerability by monitoring adverse events. This study is registered with ClinicalTrials.gov, number NCT01498419.. Between March 24, 2012, and July 26, 2013 we enrolled 207 patients and randomly assigned them to treatment groups; we assigned 60 patients to the MPa100Z regimen, 62 to the MPa200Z regimen, and 59 to the HRZE regimen. We non-randomly assigned 26 patients with drug-resistant tuberculosis to the DRMPa200Z regimen. In patients with drug-susceptible tuberculosis, the bactericidal activity of MPa200Z (n=54) on days 0-56 (0·155, 95% Bayesian credibility interval 0·133-0·178) was significantly greater than for HRZE (n=54, 0·112, 0·093-0·131). DRMPa200Z (n=9) had bactericidal activity of 0·117 (0·070-0·174). The bactericidal activity on days 7-14 was strongly associated with bactericidal activity on days 7-56. Frequencies of adverse events were similar to standard treatment in all groups. The most common adverse event was hyperuricaemia in 59 (29%) patients (17 [28%] patients in MPa100Z group, 17 [27%] patients in MPa200Z group, 17 [29%] patients. in HRZE group, and 8 [31%] patients in DRMPa200Z group). Other common adverse events were nausea in (14 [23%] patients in MPa100Z group, 8 [13%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 8 [31%] patients in DRMPa200Z group) and vomiting (7 [12%] patients in MPa100Z group, 7 [11%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 4 [15%] patients in DRMPa200Z group). No on-treatment electrocardiogram occurrences of corrected QT interval more than 500 ms (an indicator of potential of ventricular tachyarrhythmia) were reported. No phenotypic resistance developed to any of the drugs in the regimen.. The combination of moxifloxacin, pretomanid, and pyrazinamide, was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment. Results were consistent between drug-susceptible and MDR tuberculosis. This new regimen is ready to enter phase 3 trials in patients with drug-susceptible tuberculosis and MDR-tuberculosis, with the goal of shortening and simplifying treatment.. Global Alliance for TB Drug Development.

Topics: Adolescent; Adult; Antitubercular Agents; Colony Count, Microbial; Drug Therapy, Combination; Ethambutol; Female; Fluoroquinolones; Humans; Isoniazid; Male; Moxifloxacin; Nitroimidazoles; Pyrazinamide; Rifampin; South Africa; Sputum; Tanzania; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Rifapentine (RPT) has potent activity against Mycobacterium tuberculosis; however, the optimal dose for anti-tuberculosis treatment is unknown.. To determine the antimicrobial activity, safety and tolerability of RPT 450 mg or 600 mg administered daily during the first 8 weeks of treatment for pulmonary tuberculosis (TB).. In a two-stage, randomised open-label study, adults with sputum smear-positive TB were randomised to receive RPT 450 mg, RPT 600 mg or rifampicin (RMP) 600 mg daily for 8 weeks with isoniazid, pyrazinamide and ethambutol. The primary endpoint was sputum culture status on Löwenstein-Jensen (LJ) medium at completion of 8 weeks of treatment.. A total of 153 participants were enrolled. Both RPT regimens met pre-specified criteria to advance to stage 2. At completion of 8 weeks of treatment, LJ culture conversion occurred in 85% (35/41), 96% (43/45) and 94% (34/36) of participants in the RPT 450 mg, RPT 600 mg and RMP groups, respectively. The proportions of participants discontinuing treatment were similar (respectively 1/54 [2.0%], 1/51 [2.0%] and 4/48 [8.3%] in the RPT 450 mg, RPT 600 mg and RMP groups), as were ⩾grade 3 adverse events (0/54 [0%], 1/51 [2.0%] and 4/48 [8.3%]).. There was a trend towards greater efficacy with RPT 600 mg than with RPT 450 mg. Daily RPT was safe and well-tolerated.

Topics: Adult; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; South Africa; Sputum; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

We compared the pharmacokinetics of rifampicin (RMP) during daily and intermittent (thrice weekly) anti-tuberculosis treatment in human immunodeficiency virus infected tuberculosis patients. Patients treated with a thrice-weekly regimen had significantly lower plasma peak concentration, area under the time concentration curve from 0 to 24 h and higher oral clearance of RMP than those treated with the daily regimen. The median values were respectively 3.7 and 6.4 μg/ml (P < 0.001), 20.7 and 29.4 μg/ml.h (P = 0.03) and 21.7 and 15.3 ml/min (P = 0.03).

Topics: Adult; Antitubercular Agents; CD4 Lymphocyte Count; Drug Administration Schedule; Female; HIV Infections; Humans; India; Male; Prospective Studies; Rifampin; Tuberculosis, Pulmonary

In South Africa, sputum smear microscopy has been replaced with Xpert MTB/RIF as the initial diagnostic test for tuberculosis. In a pragmatic parallel cluster-randomised trial, we evaluated the effect on patient and programme outcomes.. We randomly allocated 20 laboratories (clusters) in medium-burden districts of South Africa to either an Xpert (immediate Xpert) or microscopy (Xpert deferred) group (1:1), stratified by province. At two primary care clinics per laboratory, a systematic sample of adults giving sputum for tuberculosis investigation was assessed for eligibility. The primary outcome was mortality at 6 months from enrolment. Masking of participants' group allocation was not possible because of the pragmatic trial design. The trial is registered with the ISRCTN registry (ISRCTN68905568) and the South African Clinical Trial Register (DOH-27-1011-3849).. Between June and November, 2012, 4972 people were screened, and 4656 (93·6%) enrolled (median age 36 years; 2891 [62%] female; 2212 [62%] reported being HIV-positive). There was no difference between the Xpert and microscopy groups with respect to mortality at 6 months (91/2324 [3·9%] vs 116/2332 [5·0%], respectively; adjusted risk ratio [aRR] 1·10, 95% CI 0·75-1·62]).. Xpert did not reduce mortality at 6 months compared with sputum microscopy. Improving outcomes in drug-sensitive tuberculosis programmes might require not only better diagnostic tests but also better linkage to care.. Bill & Melinda Gates Foundation.

Topics: Adult; Analysis of Variance; Antitubercular Agents; Comorbidity; Drug Resistance, Bacterial; Endpoint Determination; Female; HIV Infections; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mortality; Outcome and Process Assessment, Health Care; Rifampin; South Africa; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

To observe the clinical effect on type 2 diabetes mellitus (T2DM) complicated with pulmonary tuberculosis (TB) of insulin, isoniazid, rifampicin, pyrazinamide and ethambutol (conventional medication) administered together with Qi-boosting and Yin-nourishing decoction derived from Traditional Chinese Medicine (TCM).. A total of 60 patients with T2DM complicated with pulmonary TB were randomly and equally divided into positive control group and treatment group. The control group was treated with Western conventional regiment (WCR): insulin, isoniazid, rifampicin, pyrazinamide, and ethambutol, whereas the treatment group was given both WCR and Qi-boosting and Yin-nourishing decoction prepared from TCM.. After the treatment, 20 (66.7%) and 11 (36.7%) cases showed sputum bacteria negative conversion in the WCR plus TCM group and WCM group respectively (P < 0.05). A total of 25 (83.3%) and 18 (60%) cases showed improvement in lung lesion in the WCR plus TCM group and WCM group respectively (P < 0.05). Compared with WCR group, fasting plasma glucose and 2-hour postprandial blood glucose levels in the WCR plus TCM group significantly decreased (P < 0.05 and P < 0.01, respectively).. Qi-boosting and Yin-nourishing decoction combined with the Western medication showed better curative effect in treating T2DM complicated with pulmonary TB compared with the group using the conventional Western Medicine alone.

Topics: Adult; Aged; Antitubercular Agents; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Drugs, Chinese Herbal; Ethambutol; Female; Humans; Hypoglycemic Agents; Insulin; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Dormant, slow-growing, antibiotic-tolerant Mycobacterium tuberculosis undermine the shortening of tuberculosis treatment to less than 6 months and are thought to be characterised by intracellular lipid bodies. Antibiotic effects on such persisting bacilli escape evaluation as they cannot be readily cultured. We identified cells containing lipid bodies in sputum smears from 86 newly diagnosed pulmonary tuberculosis patients and monitored these cells daily in 42 patients over the first 14 days of treatment with rifampicin, the experimental compound SQ-109, or both agents combined. Counts of Nile-Red-positive lipid-body containing cells were correlated with those of Auramine-O-positive cells and colony forming units of viable Mycobacterium tuberculosis on agar plates. Rifampicin but not SQ-109 significantly reduced colony forming units but all treatments distinctively and significantly changed the proportions of lipid body-containing bacilli and viable Mycobacterium tuberculosis. Monitoring lipid-body containing bacilli in sputum during treatment with experimental antituberculosis regimens may identify putative treatment-shortening regimens.

Topics: Adamantane; Antitubercular Agents; Bacterial Load; Benzophenoneidum; Colony Count, Microbial; Drug Monitoring; Drug Therapy, Combination; Ethylenediamines; Fluorescent Dyes; Humans; Lipid Droplets; Microscopy, Fluorescence; Mycobacterium tuberculosis; Oxazines; Predictive Value of Tests; Rifampin; South Africa; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Patients with Mycobacterium avium complex pulmonary disease are frequently administered a combination of clarithromycin, ethambutol, and rifampicin. However, rifampicin is known to reduce the serum levels of clarithromycin. It remains unclear whether a reduction in clarithromycin serum levels influences the clinical outcome of the Mycobacterium avium complex pulmonary disease treatment regimen.. To compare a three-drug regimen (clarithromycin, ethambutol, and rifampicin) to a two-drug regimen (clarithromycin and ethambutol) for the treatment of Mycobacterium avium lung disease.. In a preliminary open-label study, we randomly assigned newly diagnosed, but as-yet untreated, patients with disease caused by Mycobacterium avium complex without HIV infection to either the three-drug or the two-drug regimen for 12 months. The primary endpoint was the conversion of sputum cultures to negative after 12 months of treatment. Patient data were analyzed using the intention-to-treat method.. Of 119 eligible patients, 59 were assigned to the three-drug regimen and 60 to the two-drug regimen. The rate of sputum culture conversion was 40.6% with the three-drug regimen and 55.0% with the two-drug regimen (difference, -14.4% [95% confidence interval, -32.1 to 3.4]). The incidence of adverse events leading to the discontinuation of treatment was 37.2 and 26.6% for the three-drug and the two-drug regimens, respectively.. This preliminary study suggests that treatment with clarithromycin and ethambutol is not inferior to treatment with clarithromycin, ethambutol, and rifampicin for Mycobacterium avium complex lung disease. Our findings justify a larger clinical trial to compare long-term clinical outcomes for the two treatment regimens. Clinical trial registered with http://www.umin.ac.jp/english/ (UMIN000002819).

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Antibiotics, Antitubercular; Antitubercular Agents; Clarithromycin; Drug Therapy, Combination; Ethambutol; Female; Humans; Male; Middle Aged; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

The quantification of antituberculosis drug concentrations in multinational trials currently requires the collection of modest blood volumes, centrifugation, aliquoting of plasma, freezing, and keeping samples frozen during shipping. We prospectively enrolled healthy individuals into the Tuberculosis Trials Consortium Study 29B, a phase I dose escalation study of rifapentine, a rifamycin under evaluation in tuberculosis treatment trials. We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying rifapentine in whole blood on dried blood spots (DBS) to facilitate pharmacokinetic/pharmacodynamic analyses in clinical trials. Paired plasma and whole-blood samples were collected by venipuncture, and whole blood was spotted on Whatman protein saver 903 cards. The methods were optimized for plasma and then validated for DBS. The analytical measuring range for quantification of rifapentine and its metabolite was 50 to 80,000 ng/ml in whole-blood DBS. The analyte was stable on the cards for 11 weeks with a desiccant at room temperature and protected from light. The method concordance for paired plasma and whole-blood DBS samples was determined after correcting for participant hematocrit or population-based estimates of bias from Bland-Altman plots. The application of either correction factor resulted in acceptable correlation between plasma and whole-blood DBS (Passing-Bablok regression corrected for hematocrit; y = 0.98x + 356). Concentrations of rifapentine may be determined from whole-blood DBS collected via venipuncture after normalization in order to account for the dilutional effects of red blood cells. Additional studies are focused on the application of this methodology to capillary blood collected by finger stick. The simplicity of processing, storage, shipping, and low blood volume makes whole-blood DBS attractive for rifapentine pharmacokinetic evaluations, especially in international and pediatric trials.

Topics: Antitubercular Agents; Chromatography, Liquid; Dried Blood Spot Testing; Drug Monitoring; High-Throughput Screening Assays; Humans; Prospective Studies; Reproducibility of Results; Rifampin; Tandem Mass Spectrometry; Tuberculosis, Pulmonary

Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis.. We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization.. Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group.. The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.).

Topics: Adult; Antitubercular Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Fluoroquinolones; HIV Seropositivity; Humans; Isoniazid; Kaplan-Meier Estimate; Male; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Young Adult

Study C was an open-label, non-inferiority, randomised controlled trial of fixed-dose combination (FDC) or separate drugs given during the intensive phase of treatment to 1585 patients with smear-positive pulmonary tuberculosis conducted at 11 sites in Africa, Asia and Latin America. Thirty months post-randomisation, the failure/relapse rates in the per protocol population were 7.4% of 591 patients on FDCs and 6.5% of 587 patients on separate drugs; the site-adjusted difference was 0.3% (90%CI -1.8 to 2.3). In the modified intention-to-treat analysis, the corresponding results were respectively 17.9% of 683 and 16.1% of 671; the site-adjusted difference was 2.0% (90%CI -1.2 to 5.2).

Topics: Africa; Antitubercular Agents; Asia; Dose-Response Relationship, Drug; Drug Combinations; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Latin America; Male; Pyrazinamide; Recurrence; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis.. We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country.. A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen.. Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.).

Topics: Adult; Antitubercular Agents; Blood Glucose; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Fluoroquinolones; Gatifloxacin; Humans; Intention to Treat Analysis; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed.. We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals.. We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4).. The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

Topics: Adolescent; Adult; Antitubercular Agents; Coinfection; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Fluoroquinolones; HIV Seropositivity; Humans; Isoniazid; Kaplan-Meier Estimate; Male; Middle Aged; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Young Adult

A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of ≥125 for the area under the concentration time curve to infinity (AUC0-∞) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC0-∞ of 41.2 μg · h/ml decreased on average by 14.3% (90% confidence interval [CI], -90.5% to +61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an fAUC/MIC of ≥125 only when the MIC was <0.125 μg/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. NCT00216385.).

Topics: Adult; Antitubercular Agents; Area Under Curve; Coinfection; Drug Administration Schedule; Drug Dosage Calculations; Drug Synergism; Drug Therapy, Combination; Female; Fluoroquinolones; Gatifloxacin; HIV Infections; Humans; Isoniazid; Male; Monte Carlo Method; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

To describe HIV RNA levels during tuberculosis (TB) infection in patients co-infected with TB and HIV. Moreover, to examine the p24 antigen profile during TB treatment.. We examined the changes in CD4 cell count, HIV RNA, and p24 levels during anti-tuberculous therapy in a group of TB/HIV-1 co-infected and HIV-untreated patients from Guinea-Bissau.. A total of 365 TB patients were enrolled, of whom 76 were co-infected with HIV-1 and 19 were dually infected with HIV-1 + HIV-2. No significant changes in CD4, HIV RNA, or p24 levels were found during 8 months of TB treatment. HIV RNA levels correlated well with p24 (Spearman's R(2)=0.52, p<0.00001) and both markers were strong predictors of mortality. Initial HIV RNA levels correlated with a clinical TB severity index--the TBscore (Spearman's R(2)=0.23, p=0.02)--and the TBscore decreased dramatically during TB treatment although HIV RNA levels remained unchanged.. We found no significant changes in CD4, HIV RNA, or p24 antigen levels during 8 months of TB treatment among TB/HIV co-infected individuals, who did not receive antiretroviral treatment. The markers were unaffected by a strong improvement in TBscore and all three markers showed predictive capacity for mortality risk.

Topics: Adult; Antitubercular Agents; Biomarkers; CD4 Lymphocyte Count; Coinfection; Dietary Supplements; Drug Therapy, Combination; Ethambutol; Female; Guinea-Bissau; HIV Core Protein p24; HIV Infections; HIV-1; HIV-2; Humans; Isoniazid; Kaplan-Meier Estimate; Male; Middle Aged; Pyrazinamide; Rifampin; RNA, Viral; Tuberculosis, Pulmonary; Vitamin D; Young Adult

To evaluate the effect of rifampicin-based tuberculosis (TB) treatment on the pharmacokinetics of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet, and vice versa, in Tanzanian TB-HIV-coinfected patients.. This was a Phase II open-label multiple dose pharmacokinetic and safety study. This study was conducted in TB-HIV-coinfected Tanzanian patients who started TB treatment (rifampicin/isoniazid/pyrazinamide/ethambutol) at week 1 to week 8 and continued with rifampicin and isoniazid for another 16 weeks. Antiretroviral treatment (ART) of efavirenz/tenofovir/emtricitabine in a fixed-dose combination tablet was started at week 4 after initiation of TB treatment. A 24-h pharmacokinetic sampling curve was recorded at week 8 (with TB treatment) and week 28 (ART alone). For TB drugs, blood samples at 2 and 5 h post-dose were taken at week 3 (TB treatment alone) and week 8 (with ART).. A total of 25 patients (56% male) completed the study; 21 had evaluable pharmacokinetic profiles. The area under the concentration-time curve 0-24 h post-dose of efavirenz, tenofovir and emtricitabine were slightly higher when these drugs were coadministered with TB drugs; geometric mean ratios (90% CI) were 1.08 (0.90, 1.30), 1.13 (0.93, 1.38) and 1.05 (0.85, 1.29), respectively. For TB drugs, equivalence was suggested for peak plasma concentrations when administered with and without efavirenz/tenofovir/emtricitabine. Adverse events were mostly mild and no serious adverse events or drug discontinuations were reported.. Coadministration of efavirenz, tenofovir and emtricitabine with a standard first-line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are coinfected with HIV.

Topics: Adenine; Adult; Alkynes; Anti-HIV Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Deoxycytidine; Drug Combinations; Drug Therapy, Combination; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Male; Organophosphonates; Oxazines; Pyrazinamide; Reverse Transcriptase Inhibitors; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Days to positivity in automated liquid mycobacterial culture have been shown to correlate with mycobacterial load and have been proposed as a useful biomarker for treatment responses in tuberculosis. However, there is currently no quantitative method or model to analyze the change in days to positivity with time on treatment. The objectives of this study were to describe the decline in numbers of mycobacteria in sputum collected once weekly for 8 weeks from patients on treatment for tuberculosis using days to positivity in liquid culture. One hundred forty-four patients with smear-positive pulmonary tuberculosis were recruited from a tuberculosis clinic in Cape Town, South Africa. A nonlinear mixed-effects repeated-time-to-event modeling approach was used to analyze the time-to-positivity data. A biexponential model described the decline in the estimated number of bacteria in patients' sputum samples, while a logistic model with a lag time described the growth of the bacteria in liquid culture. At baseline, the estimated number of rapidly killed bacteria is typically 41 times higher than that of those that are killed slowly. The time to kill half of the rapidly killed bacteria was about 1.8 days, while it was 39 days for slowly killed bacteria. Patients with lung cavitation had higher bacterial loads than patients without lung cavitation. The model successfully described the increase in days to positivity as treatment progressed, differentiating between bacteria that are killed rapidly and those that are killed slowly. Our model can be used to analyze similar data from studies testing new drug regimens.

Topics: Antimalarials; Bacterial Load; Bacteriological Techniques; Diagnostic Techniques, Respiratory System; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

The currently recommended doses of rifampin are believed to be at the lower end of the dose-response curve. Rifampin induces its own metabolism, although the effect of dose on the extent of autoinduction is not known. This study aimed to investigate rifampin autoinduction using a semimechanistic pharmacokinetic-enzyme turnover model. Four different structural basic models were explored to assess whether different scaling methods affected the final covariate selection procedure. Covariates were selected by using a linearized approach. The final model included the allometric scaling of oral clearance and apparent volume of distribution. Although HIV infection was associated with a 30% increase in the apparent volume of distribution, simulations demonstrated that the effect of HIV on rifampin exposure was slight. Model-based simulations showed close-to-maximum induction achieved after 450-mg daily dosing, since negligible increases in oral clearance were observed following the 600-mg/day regimen. Thus, dosing above 600 mg/day is unlikely to result in higher magnitudes of autoinduction. In a typical 55-kg male without HIV infection, the oral clearance, which was 7.76 liters · h⁻¹ at the first dose, increased 1.82- and 1.85-fold at steady state after daily dosing with 450 and 600 mg, respectively. Corresponding reductions of 41 and 42%, respectively, in the area under the concentration-versus-time curve from 0 to 24 h were estimated. The turnover of the inducible process was estimated to have a half-life of approximately 8 days in a typical patient. Assuming 5 half-lives to steady state, this corresponds to a duration of approximately 40 days to reach the induced state for rifampin autoinduction.

Topics: Adolescent; Adult; Aged; Aging; Algorithms; Antitubercular Agents; Area Under Curve; Computer Simulation; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Half-Life; HIV Infections; Humans; Linear Models; Male; Middle Aged; Models, Statistical; Rifampin; Sex Characteristics; Software; Stochastic Processes; Tuberculosis, Pulmonary; Young Adult

PA-824 is a novel nitroimidazo-oxazine under evaluation as an antituberculosis agent. A dose-ranging randomized study was conducted to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive adult pulmonary-tuberculosis patients to find the lowest dose giving optimal bactericidal activity (EBA). Fifteen patients per cohort received oral PA-824 in doses of 50 mg, 100 mg, 150 mg, or 200 mg per kg body weight per day for 14 days. Eight subjects received once-daily standard antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) as a positive control. The primary efficacy endpoint was the mean rate of decline in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log(10) CFU/day/ml sputum (± standard deviation). The mean 14-day EBA of HRZE was consistent with previous studies (0.177 ± 0.042), and that of PA-824 at 50 mg, 100 mg, 150 mg, and 200 mg was 0.063 ± 0.058, 0.091 ± 0.073, 0.078 ± 0.074, and 0.112 ± 0.070, respectively. Although the study was not powered for testing the difference between arms, there was a trend toward significance, indicating a lower EBA at the 50-mg dose. Serum PA-824 levels were approximately dose proportional with respect to the area under the time-concentration curve. All doses were safe and well tolerated with no dose-limiting adverse events or clinically significant QTc changes. A dose of 100 mg to 200 mg PA-824 daily appears to be safe and efficacious and will be further evaluated as a component of novel antituberculosis regimens for drug-sensitive and drug-resistant tuberculosis.

Topics: Adolescent; Adult; Antitubercular Agents; Drug Administration Schedule; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Nitroimidazoles; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Young Adult

We described the population pharmacokinetics of moxifloxacin and the effect of high-dose intermittent rifapentine in patients with pulmonary tuberculosis who were randomized to a continuation-phase regimen of 400 mg moxifloxacin and 900 mg rifapentine twice weekly or 400 mg moxifloxacin and 1,200 mg rifapentine once weekly. A two-compartment model with transit absorption best described moxifloxacin pharmacokinetics. Although rifapentine increased the clearance of moxifloxacin by 8% during antituberculosis treatment compared to that after treatment completion without rifapentine, it did not result in a clinically significant change in moxifloxacin exposure.

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Aza Compounds; Drug Administration Schedule; Drug Therapy, Combination; Fluoroquinolones; Humans; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Rifampin; Tuberculosis, Pulmonary

Damien Foundation tuberculosis (TB) control projects in Bangladesh.. To assess the effectiveness of extending the intensive phase (P1) of treatment by 1 month for patients who are smear-positive after 2 months of a 6-month regimen containing rifampicin (RMP) throughout.. Prospective operational study randomising P1 extension for new smear-positive cases with any number of acid-fast bacilli in the 2-month smear (2M+). Smear-defined failures and relapses underwent culture and drug susceptibility testing in addition to DNA sequencing of the rpoB gene before and after treatment.. Of 16,708 patients evaluated, 12,967 were smear-negative at 2 months (2M-); 1871 and 1870 2M+ were randomised to no extension or extension. Respectively 0.3% (95%CI 0.2-0.4), 1.2% (95%CI 0.7-1.8) and 2.0% (95%CI 1.4-2.8) smear- and culture-positive failures, and 1.2% (95%CI 1.0-1.4), 2.6% (95%CI 1.9-3.4) and 0.9% (95%CI 0.5-1.4) relapses were detected. Extension significantly reversed the relative risk (RR) of relapse of 2M+ vs. 2M- patients from 2.2 (95%CI 1.6-3.0) to 0.7 (95%CI 0.4-1.2). The RR for failure remained high, at 7.3 (95%CI 4.7-11.5) with and 4.2 (95%CI 2.5-7.2) without extension. More multi-drug resistance was found after extension, but acquired RMP resistance was similar in all arms. The fair sensitivity of the 2-month smear for failure or relapse (40%) was offset by a very low positive predictive value (3%).. Extension of P1 is very inefficient with this 6-month regimen. Operational research should define appropriate algorithms allowing an earlier switch to the next higher regimen for those in need, using follow-up smears for screening.

Topics: Antitubercular Agents; Bangladesh; Drug Administration Schedule; Humans; Microbial Sensitivity Tests; Predictive Value of Tests; Prospective Studies; Rifampin; Secondary Prevention; Sensitivity and Specificity; Sequence Analysis, DNA; Sputum; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rifapentine administered 5 days per week has potent activity in mouse models of antituberculosis chemotherapy, but efficacy and safety data are limited in humans. We compared the antimicrobial activity and safety of rifapentine vs rifampin during the first 8 weeks of pulmonary tuberculosis treatment.. In total, 531 adults with sputum smear-positive pulmonary tuberculosis were randomized to rifapentine 10 mg/kg/dose or rifampin 10 mg/kg/dose, administered 5 days per week for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. Coprimary outcomes were negative sputum culture on liquid and on solid media at completion of intensive phase.. Negative cultures on solid media occurred in 145 of 174 participants (83.3%) in the rifampin group and 171 of 198 participants (86.4%) in the rifapentine group (difference, 3.0%; 95% confidence interval [CI]: -4.3, 10.5); negative cultures in liquid media occurred in 110 of 169 (65.1%) in the rifampin group and 133 of 196 (67.9%) in the rifapentine group (difference, 2.8%; 95% CI: -6.9, 12.4). Among 529 participants who received study therapy, 40 of 254 participants (15.7%) in the rifampin group and 40 of 275 participants (14.5%) in the rifapentine group prematurely discontinued treatment (P=.79).. The rifapentine regimen was safe but not significantly more active than a standard rifampin regimen, by the surrogate endpoint of culture status at completion of intensive phase. Assessment of higher exposures to rifapentine for tuberculosis treatment is warranted.. NCT00694629.

Topics: Adult; Antibiotics, Antitubercular; Drug Substitution; Female; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Fixed-dose combinations (FDCs) of drugs for treatment of tuberculosis have been advocated to prevent the emergence of drug resistance.. To assess the efficacy and safety of a 4-drug FDC for the treatment of tuberculosis.. The Study C trial, a parallel-group, open-label, noninferiority, randomized controlled trial conducted in 11 sites in Africa, Asia, and Latin America between 2003 and 2008. Patients were 1585 adults with newly diagnosed smear-positive pulmonary tuberculosis.. Patients were randomized to receive daily treatment with 4 drugs (rifampicin, isoniazid, pyrazinamide, ethambutol) given as an FDC (n = 798 patients) or separately (n = 787) in the 8-week intensive phase of treatment.. Favorable treatment outcome, defined as negative culture result at 18 months post randomization and not having already been classified as unfavorable. Noninferiority was dependent on consistent results from a per-protocol and modified intention-to-treat analysis, using 2 different models for the latter, classifying all changes of treatment or refusal to continue treatment (eg, bacteriological failure/relapse, adverse event, default, drug resistance) as unfavorable (model 1) and classifying changes of treatment for reasons other than therapeutic outcomes according to their 18-month bacteriological outcome if available (post hoc model 2). The prespecified noninferiority margin was 4%.. In the per-protocol analysis, 555 of 591 patients (93.9%) had a favorable outcome in the FDC group vs 548 of 579 (94.6%) in the separate-drugs group (risk difference, -0.7% [90% confidence interval {CI}, -3.0% to 1.5%]). In the model 1 analysis, 570 of 684 patients (83.3%) had a favorable outcome in the FDC group vs 563 of 664 (84.8%) in the separate-drugs group (risk difference, -1.5% [90% CI, -4.7% to 1.8%]). In the post hoc model 2 analysis, 591 of 658 patients (89.8%) in the FDC group and 589 of 647 (91.0%) in the separate-drugs group had a favorable outcome (risk difference, -1.2% [90% CI, -3.9% to 1.5%]). Adverse events related to trial drugs were similarly distributed among treatment groups.. Compared with a regimen of separately administered drugs, a 4-drug FDC regimen for treatment of tuberculosis satisfied prespecified noninferiority criteria in 2 of 3 analyses. Although the results do not demonstrate full noninferiority of the FDCs compared with single drugs given separately using the strict definition applied in this trial, use of FDCs is preferred because of potential advantages associated with the administration of FDCs compared with separate-drug formulations.. clinicaltrials.gov Identifier: NCT00216333.

Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

An 8-month isoniazid (INH, H) and ethambutol (EMB, E) based regimen recommended by the World Health Organization (WHO) had never been evaluated in a randomised controlled multicentre trial.. To compare, in a non-inferiority study design, two 8-month INH+EMB-based regimens with a standard INH and rifampicin (RMP, R) based regimen.. A total of 1355 patients with newly diagnosed smear-positive pulmonary tuberculosis were randomly allocated to receive 1) daily EMB, INH, RMP and pyrazinamide (PZA, Z) for 2 months, followed by EMB+INH for 6 months (2EHRZ/6HE); 2) the same drugs in the intensive phase but given three times weekly, followed by the same continuation phase of daily EMB+INH (2(EHRZ)(3)/6HE); or 3) a control regimen with the same intensive phase as in regimen 1, followed by 4 months of daily RMP+INH (2EHRZ/4HR). All patients were to be seen and sputum examinations for microscopy and culture carried out at regular intervals up to 30 months after randomisation.. At 30 months, failure/relapse rates were 11.7% of 281 2EHRZ/6HE, 15.3% of 301 2(EHRZ)(3)/6HE and 6.0% of 282 2EHRZ/4HR patients (χ(2), 2 degrees of freedom = 12.8, P = 0.002).. These results confirm earlier findings demonstrating the inferiority of the INH+EMB-based regimens to the standard 6-month regimen. The WHO has withdrawn its recommendation of these regimens.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Drug Combinations; Drug Therapy, Combination; Ethambutol; Female; Humans; Intention to Treat Analysis; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Sputum; Treatment Failure; Tuberculosis, Pulmonary; World Health Organization; Young Adult

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

South African guidelines recommend protease-inhibitor-based antiretroviral therapy (ART) with lopinavir-ritonavir for human immunodeficiency virus (HIV)-infected children <36 months of age. We investigated factors associated with viral suppression and mortality among young children initiating ART.. Treatment-naive, ART-eligible, HIV-infected children (aged 6-104 weeks) were enrolled in an ART strategies trial in South Africa and initiated protease-inhibitor-based ART. Mortality and the probability of viral suppression (defined as HIV RNA load of <400 copies/mL) by 39 weeks after ART initiation were investigated.. Of 254 children who initiated ART, 99 (39%) were cotreated for tuberculosis during follow-up. The mortality rate was 14%. Factors predicting mortality were lower pre-ART weight-for-age z score and higher HIV RNA load. By 39 weeks, 84% of surviving children achieved viral suppression. Children who were not cotreated for tuberculosis were more likely to achieve viral suppression (94.8%) than were children who were receiving cotreatment at ART initiation (74.2%) or who started tuberculosis cotreatment after ART initiation (51.6%; P < .001). Other factors predicting lower probability of viral suppression were lower pre-ART weight- and length-for-age z score, higher HIV RNA load, and World Health Organization disease stage.. High rates of viral suppression can be achieved among infants and young children who initiate protease-inhibitor-based ART. Cotreatment for tuberculosis reduced viral suppression. How best to treat HIV-infected children who require tuberculosis treatment warrants urgent investigation.

Topics: Antiretroviral Therapy, Highly Active; Antitubercular Agents; Child, Preschool; Drug Therapy, Combination; Ethionamide; Female; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Infant; Isoniazid; Kaplan-Meier Estimate; Lopinavir; Male; Pyrimidinones; Rifampin; Ritonavir; RNA, Viral; South Africa; Tuberculosis, Pulmonary; Viral Load

Isoniazid, rifampicin, and pyrazinamide, the first-line antituberculosis (anti-TB) drugs, are associated with hepatotoxicity.. To study the hepatoprotective effect of N-acetylcysteine (NAC) on liver injury induced by anti-TB drugs.. A randomized clinical trial was conducted on 60 new TB patients who were aged 60 years or more. Patients were randomized into two groups. In group I (n=32), drug regimen included daily doses of isoniazid, rifampicin, pyrazinamide, and ethambutol. Patients in group II (n=28) were treated with the same regimen and NAC. The patients were followed up for 2 weeks. Liver enzymes and bilirubins were measured at baseline, after 1 and 2 weeks of treatment, and whenever the patients presented with clinical symptoms of hepatotoxicity.. The mean+/-SD values of aspartate aminotransferase and alanine aminotransferase were significantly higher in group I than in group II after 1 and 2 weeks of treatment. Hepatotoxicity occurred in 12 patients with (37.5%) group I and none in group II. The mean duration of treatment before the onset of hepatotoxicity was 4.67+/-4.58 days.. NAC protects against anti-TB drug-induced hepatotoxicity.

Topics: Acetylcysteine; Aged; Aged, 80 and over; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Drug Interactions; Drug Therapy, Combination; Ethambutol; Female; Free Radical Scavengers; Humans; Isoniazid; Liver; Male; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Vitamin D deficiency is associated with susceptibility to active tuberculosis (TB) in many settings. In vitro studies and studies on human volunteers showed that two of the first-line anti-tuberculosis drugs, isoniazid and rifampicin, reduce 25-hydroxy vitamin D (25[OH]D) concentrations.. To study changes in vitamin D status during treatment of Tanzanian hospitalised patients with pulmonary TB (PTB).. We compared serum 25[OH]D concentrations in 81 Tanzanian PTB patients before and after 2 months of treatment.. Median serum 25[OH]D concentrations increased from 91 nmol/l at baseline to 101 nmol/l after 2 months of TB treatment (median increase 6.0 nmol/l, IQR -0.7-25.0, P = 0.001). Median serum parathyroid hormone concentrations increased from 1.6 to 2.0 pmol/l (median increase 0.46, IQR -0.2-1.1, P < 0.001).. 25[OH]D serum concentrations increased during the first 2 months of TB treatment in 81 PTB patients in northern Tanzania. Improved dietary intake and increased sunlight exposure may have contributed to the increased 25[OH]D concentrations.

Topics: Adult; Antitubercular Agents; Calcifediol; Female; Hospitalization; Humans; Isoniazid; Male; Parathyroid Hormone; Rifampin; Sunlight; Tanzania; Tuberculosis, Pulmonary; Vitamin D; Vitamin D Deficiency; Vitamins

Evaluation of early bactericidal activity (EBA) by the determination of a fall in viable colony-forming units (CFU) of Mycobacterium tuberculosis in sputum is a first step in the clinical study of new antituberculosis agents. The time to detection (TTD) of growth in liquid media is more sensitive and could substitute for CFU counting on solid media. Overnight sputum samples collected during the evaluation of the novel agent TMC207 in comparison to isoniazid and rifampicin were studied. For the determination of CFU, we incubated 10-fold dilutions of homogenized sputum on selective 7H10 agar. The TTD was measured by incubating decontaminated sputum in the BACTEC MGIT 960 system. The fall in bacillary load over 7 days determined by CFU counting closely matched the prolongation of the TTD in the BACTEC MGIT 960 system. The CFU counts correlated significantly with the TTD. While the ranking of agents and different dosages of TMC207 was similar, the highest dose of TMC207 showed markedly better activity when measured by the TTD than CFU counting when compared to the activity of isoniazid. Automated TTD could augment, or, in future, replace, CFU counting to determine sputum bacillary load in EBA clinical trials pending a more formal evaluation of the correlation of the measurements.

Topics: Adolescent; Adult; Antitubercular Agents; Colony Count, Microbial; Culture Media; Diarylquinolines; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Quinolines; Rifampin; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

The present study evaluated the possible protective role of Livina (a polyherbal preparation) against anti-tubercular therapy (ATT)-induced liver dysfunction in patients of pulmonary tuberculosis. Patients were given intensive phase treatment with 4-drugs (rifampicin, INH, pyrazinamide and ethambutol) used for anti-tubercular therapy for 2 months, followed by a 4-month continuous phase treatment with 2 drugs (rifampicin and INH) under clinical advice and supervision. Both qualitative and quantitative measures of liver function were assessed, at different time intervals, before and after ATT. Analysis of data showed that the incidence of qualitative manifestations of liver dysfunction were greater in the placebo treated group as compared to the test drug group. None of the patients of either group showed clinical jaundice. Most signific changes ant were observed in the SGOT and SGPT levels in the placebo group, wherein the levels of both enzymes were higher at 4 and 8 weeks post-ATT, as compared to the respective baseline (0 week) values. When Livina (2 capsules twice daily) was given with ATT drugs, incidence of qualitative manifestation of liver dysfunction was insignificant and SGOT and SGPT levels were also significantly lower than the placebo+AITT drugs treated group. These results indicate that the test drug (Livina) was efficacious, against ATT-induced hepatic dysfunction in patients of pulmonary tuberculosis.

Topics: Adolescent; Adult; Alanine Transaminase; Antitubercular Agents; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Combinations; Ethambutol; Follow-Up Studies; Humans; Liver Diseases; Liver Function Tests; Middle Aged; Phytotherapy; Plant Preparations; Plants, Medicinal; Prospective Studies; Pyrazinamide; Rifampin; Single-Blind Method; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

New treatments are needed to shorten the time required to cure tuberculosis and to treat drug-resistant strains. The fluoroquinolone moxifloxacin is a promising new agent that might have additive activity to existing antituberculosis agents. We assessed the activity and safety of moxifloxacin in the initial stage of tuberculosis treatment.. We undertook a phase II, double-blind, randomised controlled trial of a regimen that included moxifloxacin in adults with sputum smear-positive tuberculosis at one hospital in Rio de Janeiro, Brazil. 170 participants received isoniazid, rifampicin, and pyrazinamide at standard doses and were assigned by permuted block randomisation to receive either moxifloxacin (400 mg) with an ethambutol placebo (n=85) or ethambutol (15-20 mg/kg) plus moxifloxacin placebo (n=85) 5 days per week for 8 weeks. The primary endpoint was the proportion of patients whose sputum culture had converted to negative by week 8. Analysis was by modified intention to treat (ITT); patients whose baseline cultures were negative, contaminated, or contained drug-resistant Mycobacterium tuberculosis were excluded from the analysis. Additionally, all missing 8-week results were deemed treatment failures. This study is registered with ClinicalTrials.gov, number NCT00082173.. 74 patients assigned to the moxifloxacin group and 72 in the ethambutol group were included in the modified ITT population. 125 patients had 8-week data (moxifloxacin n=64, ethambutol n=61); the main reason for absence of data was culture contamination. At 8 weeks, culture conversion to negative had occurred in 59 (80%) of 74 patients in the moxifloxacin group compared with 45 (63%) of 72 in the ethambutol group (difference 17.2%, 95% CI 2.8-31.7; p=0.03). There were 16 adverse events (eight in each group) in 12 patients. Only one event was judged related to study drug (grade 3 cutaneous reaction in the ethambutol group).. Moxifloxacin improved culture conversion in the initial phase of tuberculosis treatment. Trials to assess whether moxifloxacin can be used to shorten the duration of tuberculosis treatment are justified.

Topics: Adult; Antitubercular Agents; Aza Compounds; Brazil; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Fluoroquinolones; Humans; Isoniazid; Kaplan-Meier Estimate; Logistic Models; Male; Moxifloxacin; Multivariate Analysis; Pyrazinamide; Quinolines; Rifampin; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

To compare the efficacy, safety and acceptability of two short-course regimens of isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) given either as fixed-dose combination (4-FDC) tablets or as single tablets (ST) in patients with newly diagnosed pulmonary tuberculosis (PTB).. This randomised, open, multicentre, multinational study was conducted in 26 centres and included 1159 patients with smear-positive PTB. 4-FDC daily for 2 months then H+R for 4 months, or single preparations of H, R, Z and E for 2 months followed by H and R for 4 months were administered daily. Sputum smear conversion rates at 2, 4 and 6 months (end of treatment [EOT], primary endpoint) and at 9 and 12 months (follow-up) were measured, together with adverse events and the acceptability of the formulations.. Smear conversion rates for 4-FDC and ST at EOT were 80.4% (468/582 patients) vs. 82.7% (477/577) in the intent-to-treat (ITT) population, and 98.1% (404/412) vs. 98.6% (416/422) in the per-protocol (PP) subgroup. Non-inferiority of 4-FDC was demonstrated at month 2, EOT and follow-up in both the ITT and the PP populations. Overall numbers of adverse events were not significantly different between the groups.. The efficacy of the 4-FDC regimen was non-inferior to that of the ST regimens, but patient acceptability significantly improved with 4-FDC.

Topics: Adult; Antitubercular Agents; Drug Combinations; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Patient Satisfaction; Pyrazinamide; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

Clinico-roentgenologic and bacteriologic efficacy and safety of rifapex (rifapentin) were investigated in the complex therapy of 90 patients with newly recorded drug-susceptible tuberculosis. Pifapex was shown to be effective in the treatment of the patients during the acute phase of the disease, during the treatment completeness and during the short preoperative period.

Topics: Adult; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Radiography; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Cavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients.. To assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months.. This study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment.. Enrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10).. Shortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.

Topics: Adult; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Kaplan-Meier Estimate; Male; Mycobacterium tuberculosis; Proportional Hazards Models; Pyrazinamide; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

To evaluate the efficacy and safety of short-term treatment including fluoroquinolones anti-tuberculosis drugs for rifampicin resistant pulmonary tuberculosis (TB) in those areas carrying out the 'TB control project'.. TB cases involved in this study were from TB drug resistance surveillance in Heilongjiang province, Zhejiang province and Shenzhen city from 2004 to 2006. TB cases with rifampicin resistant were randomly divided into the treatment group (including fluoroquinolones anti-tuberculosis drugs group) and the control group (re-treatment regimen group). The treatment group was treated with 3RFT AM Ofx Pto PAS-INH/5RFT Ofx Pto PAS-INH while the control group was treated with 3 H3R3Z3E3S3/5 H3R3E3. Efficacy of short-term treatment was analyzed by per-protocol analysis (PP analysis) and intention-to-treat analysis (ITT analysis) while drug adverse reactions was also observed.. (1) 154 patients with rifampicin resistant pulmonary tuberculosis were recruited among them, 25 (16.2%) were only resistant to rifampicin, 114 (74.0%) to MDR-TB and 15 (9.8%) to others (resistant R+S, resistant R+E and resistant R+E+S). 114 TB cases completed the full course of treatment,with 71 in the treatment group and 43 in the control group. (2) Sputum negative conversion rate of the treatment group and the control group were 78.9% and 65.1% (chi2CMH = 4.558, P = 0.011) respectively, by per-protocol analysis. Sputum negative conversion rate of the treatment group and the control group were 65.9% and 40.6% (chi2CMH = 0.272, P = 0.001) respectively, by intention-to-treat analysis. The sputum negative conversion rate of the treatment group was higher than in the control group when treating rifampicin resistant pulmonary tuberculosis and MDR-TB patients. (3) Three patients withdrew in each of the two groups because of adverse effects to the drugs. Rates of adverse reaction to drugs appeared to be 23.9% (17/71) and 18.6% (8/43) in the treatment and in the control groups, with no statistically significant difference between the two groups.. The efficacy of treatment including fluoroquinolones anti-tuberculosis drugs group seemed better than the re-treatment regimen group in treating patients with rifampicin resistant pulmonary tuberculosis and those MDR-TB patients.

Topics: Adult; Aged; Antitubercular Agents; China; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Male; Middle Aged; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log(10) decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log(10) CFU counts (+/- standard deviation) from baseline to day 7 were 0.04 +/- 0.46 for 25 mg TMC207 (n = 14), 0.26 +/- 0.64 for 100 mg TMC207 (n = 14), 0.77 +/- 0.58 for 400 mg TMC207 (n = 14), 1.88 +/- 0.74 for INH (n = 11), and 1.70 +/- 0.71 for RIF (n = 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.

Topics: Administration, Oral; Adolescent; Adult; Antitubercular Agents; Area Under Curve; Diarylquinolines; Dose-Response Relationship, Drug; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Mycobacterium tuberculosis; Quinolines; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

To evaluate the relapse rate after treatment of a twice weekly intermittent chemotherapy during continuation phase in the patients with pulmonary tuberculosis in two years period after completion of chemotherapy.. The patients with drug susceptible pulmonary tuberculosis treated with 2HRZE/4H2R2 under the supervision by the pharmacists or the patients treated with 2HRZE/4HR by self-administration were followed-up for two years after completion of chemotherapy.. A total number of 135 pulmonary tuberculosis patients were treated with 2HRZE/4H2R2, 3 of 135 discontinued this intermittent treatment, and 11 of 135 completed chemotherapy was excluded from the relapse analysis, 105 out of the remaining 121 were followed-up for more than 6 months. On the other hand 240 patients were treated with 2HRZE/4HR, 37 out of 240 were excluded from the analysis, 147 of the remaining 203 were followed-up for more than 6 months. The relapse rate of this intermittent chemotherapy 1.89/100 person-year was similar to the relapse rate 1.86/100 person-year among 147 treated with daily regimen by self-administration. This difference was not statistically significant (z = 0.36, P = 0.14).. As regards relapse rate, this 2HRZE/4H2R2 regimen is effective and useful for the expansion of DOT, and it should be expanded nationally in Japan.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Self Administration; Tuberculosis, Pulmonary

The treatment of fibrocavitatory pulmonary infection due to Mycobacterium avium complex and Mycobacterium malmoense poses a challenge. This study assessed microbial, inflammatory, radiographic, and clinical outcomes for a standardized 24-month triple-drug regime. Following treatment completion, all patients had fewer symptoms, experienced a reduction in systemic inflammation, and had negative sputum mycobacterial culture results.

Topics: Aged; Anti-Bacterial Agents; Blood Sedimentation; Ciprofloxacin; Clarithromycin; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Female; Humans; Lung; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium avium; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Radiography; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

Pyrazinamide (PZA) is one of the first-line drugs in anti-tuberculosis treatment. In the present study, PZA serum levels in 34 children aged 1 to 14 years were measured either after oral application of PZA alone or after combination therapy with isoniazid and rifampicin. Serum levels did not differ statistically with age, in PZA monotherapy or in combination therapy. With a dosage of 30 mg/kg PZA, efficient serum levels were reached. Because PZA is distributed uniformly in the body, serum levels are related to body weight, and a dose of 30 mg/kg bodyweight is appropriate in children.

Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Therapy, Combination; Humans; Infant; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Moxifloxacin- and rifapentine-based regimens are under investigation for the treatment of tuberculosis. However, rifapentine may induce enzymes that metabolize moxifloxacin, resulting in decreased moxifloxacin concentrations. In this phase I, two-period, sequential-design study, 13 subjects received 400 mg moxifloxacin daily for 4 days followed by daily moxifloxacin coadministered with 900 mg rifapentine thrice weekly. Pharmacokinetic analyses were performed after the 4th and 19th doses of moxifloxacin and after the 1st and 7th doses of rifapentine. For moxifloxacin, the mean area under the concentration-time curve from 0 to 24 h (AUC(0-24)) decreased by 17.2% (P = 0.0006) when the drug was coadministered with rifapentine, and the mean half-life (t(1/2)) decreased from 11.1 to 8.9 h (P = 0.0033). For rifapentine, the mean AUC(0-48) after seven thrice-weekly doses decreased by 20.3% (P = 0.0035) compared to the AUC(0-48) after the first dose, and the mean t(1/2) decreased from 18.5 to 14.8 h (P = 0.0004). The AUC(0-48) for the 25-desacetyl-rifapentine metabolite diminished 21%. Two days after completing the study drugs, one subject developed a fever and hepatitis, and another developed a flu-like illness with a rash. In conclusion, rifapentine modestly reduced moxifloxacin concentrations. Changes consistent with rifapentine autoinduction of metabolism were seen. Adverse reactions in two subjects may have represented rifamycin hypersensitivity syndrome, although some features were atypical.

Topics: Adult; Antitubercular Agents; Aza Compounds; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Drug Tolerance; Female; Fluoroquinolones; Humans; Male; Middle Aged; Moxifloxacin; Quinolines; Rifampin; Safety; Tuberculosis, Pulmonary; Young Adult

The mainstays of treatment for pulmonary disease caused by opportunist mycobacteria are rifampicin (R) and ethambutol (E). The role of macrolides, quinolones and immunotherapy with Mycobacterium vaccae is not clear. A trial was undertaken to compare clarithromycin (Clari) and ciprofloxacin (Cipro) as third drugs added to [corrected] 2 years of treatment with R and E for pulmonary disease caused by M avium-intracellulare (MAC), M malmoense and M xenopi (REClari and RECipro). An optional comparison of immunotherapy with M vaccae vs no immunotherapy was also performed.. Progress was monitored annually during the 2 years of treatment and for 3 years thereafter. If the patient was not improving at 1 year the regimen was supplemented by the addition of the drug not received in the original allocation of treatment.. 371 patients (186 REClari, 185 RECipro) entered the study (170 MAC, 167 M malmoense, 34 M xenopi). All-cause mortality was high for both groups (44% REClari, 43% RECipro); for MAC it was higher with REClari than with RECipro (48% vs 29%) but for M malmoense (42% vs 56%) and M xenopi (29% vs 47%) it was higher with RECipro (p = 0.006). 3% died from their mycobacterial disease (REClari = RECipro). At the end of treatment, 4% of REClari and 10% of RECipro patients still had positive cultures. Among those with negative cultures at the end of treatment, 6% of the REClari group and 4% of the RECipro group had relapsed. At 5 years 30% of the REClari group were known to have completed treatment as allocated and to be alive and cured compared with 21% of the RECipro group (p = 0.04), but this difference was principally due to those with M malmoense (REClari 38%, RECipro 20%). Patients with MAC or M xenopi were more likely to have a poor outcome than those with M malmoense (p = 0.004), with no difference between REClari and RECipro. Overall, 20% in each group were unable to tolerate the regimen allocated, Cipro being associated with more unwanted effects than Clari (16% vs 9%, p = 0.05). No significant differences in outcomes were found between M vaccae-treated patients and those not treated with M vaccae immunotherapy.. Considering all three species together, there were no differences in outcome between the REClari and RECipro groups. Immunotherapy did not improve outcome. New therapies, optimised management of co-morbid conditions and a more holistic approach must be explored in the hope of improving outcome.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Antitubercular Agents; Ciprofloxacin; Clarithromycin; Drug Therapy, Combination; Ethambutol; Female; Humans; Immunotherapy; Male; Middle Aged; Opportunistic Infections; Rifampin; Tuberculosis, Pulmonary

We compared the nutritional status of individuals with human immunodeficiency virus (HIV) infection alone, individuals with HIV infection and tuberculosis (after completion of antituberculosis treatment), and HIV-negative individuals and found that malnutrition, anemia, and hypoalbuminemia were most pronounced among HIV-positive patients with tuberculosis. Weight loss was associated with loss of fat in female patients and with loss of body cell mass in male patients.

Topics: Adult; AIDS-Related Opportunistic Infections; Anemia; Antitubercular Agents; Body Composition; Drug Therapy, Combination; Ethambutol; HIV Infections; HIV Seronegativity; Humans; Hypoalbuminemia; India; Isoniazid; Malnutrition; Nutritional Status; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

To evaluate the clinical and therapeutic value of 4 and 3 drug fixed dose combinations verses single drug formulations to treat pulmonary tuberculosis patients. The occurrence of adverse effects was also monitored. A total of 293 patients having sputum positive pulmonary tuberculosis were enrolled (Male: 187 and Female: 106). Patients with renal, hepatic, diabetic, cardiac problem and pregnancy were excluded from study. Patients were randomly selected into three groups (A, B, C). Group A and B were given FDCs and group C was given single drug formulations. All patients received 4 drugs in the intensive phase and 3 drugs in the continuation phase. Group A showed the highest percentage of patients who achieved sputum conversion (98.9%). The numbers of days taken to achieve sputum conversion on average were the least for Group B (32 days). When comparing the adverse effects, the patients of Group C suffered the most, with 22 patients who vomited repeatedly, 3 complaining of itching, 2 with Jaundice and 1 dead. There was no significant difference in the efficacy among the three treatment regimens. However the side effects observed in all three groups strongly indicate that FDCs are safer for treating TB patients. There were no side effects in the continuation phase.

Topics: Adolescent; Adult; Antitubercular Agents; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Educational Status; Employment; Ethambutol; Humans; Isoniazid; Middle Aged; Pakistan; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Rifampin is a key drug for tuberculosis (TB) treatment. The available data suggest that the currently applied 10-mg/kg of body weight dose of rifampin may be too low and that increasing the dose may shorten the treatment duration. A double-blind randomized phase II clinical trial was performed to investigate the effect of a higher dose of rifampin in terms of pharmacokinetics and tolerability. Fifty newly diagnosed adult Indonesian TB patients were randomized to receive a standard (450-mg, i.e., 10-mg/kg in Indonesian patients) or higher (600-mg) dose of rifampin in addition to other TB drugs. A full pharmacokinetic curve for rifampin, pyrazinamide, and ethambutol was recorded after 6 weeks of daily TB treatment. Tolerability was assessed during the 6-month treatment period. The geometric means of exposure to rifampin (area under the concentration-time curve from 0 to 24 h [AUC(0-24)]) were increased by 65% (P < 0.001) in the higher-dose group (79.7 mg.h/liter) compared to the standard-dose group (48.5 mg.h/liter). Maximum rifampin concentrations (C(max)) were 15.6 mg/liter versus 10.5 mg/liter (49% increase; P < 0.001). The percentage of patients for whom the rifampin C(max) was > or =8 mg/liter was 96% versus 79% (P = 0.094). The pharmacokinetics of pyrazinamide and ethambutol were similar in both groups. Mild (grade 1 or 2) hepatotoxicity was more common in the higher-dose group (46 versus 20%; P = 0.054), but no patient developed severe hepatotoxicity. Increasing the rifampin dose was associated with a more than dose-proportional increase in the mean AUC(0-24) and C(max) of rifampin without affecting the incidence of serious adverse effects. Follow-up studies are warranted to assess whether high-dose rifampin may enable shortening of TB treatment.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Area Under Curve; Biological Availability; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Drug Tolerance; Ethambutol; Female; Half-Life; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Radiography, Thoracic; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

We studied the early bactericidal activity of twice the standard dose of rifampin in subjects with pulmonary tuberculosis evidenced by positive smears. The observed mean 2-day activity was almost double that reported at the standard dose. Further studies are warranted to establish whether higher rifampin doses might assist in shortening tuberculosis treatment.

Topics: Adolescent; Adult; Antitubercular Agents; Colony Count, Microbial; Dose-Response Relationship, Drug; Female; Humans; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Specimen Handling; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Tuberculosis Research Centre, Chennai and Madurai, South India.. To assess response to treatment, relapse and emergence of MDR TB in newly diagnosed patients with sputum-positive tuberculosis using an intermittent intensive phase followed by a non-rifampicin continuation phase.. Patients were treated in a controlled clinical trial with 2HRZE3/6HE with thrice-weekly direct dosing in the intensive phase and once-weekly with six doses self-administered in the continuation phase. Clinical and bacteriologic evaluation was done every month for 24 months.. The overall outcome was good, with 92% favourable response (cure) and 4.8% relapse in 450 patients including 103 who did not receive extension of intensive phase for positive smear, 38 with initial H-resistant cultures, 4 with MDR TB and 15 who received less than 75% of chemotherapy. In 392 patients with drug-susceptible cultures, 96%were cured and only 4% relapsed. There was no emergence of MDR TB among failures and relapses; toxicity was low.. Newly-diagnosed Category I patients can be effectively treated with this regimen without emergence of MDR TB. It has immense potential in programmes where directly observed therapy cannot be ensured throughout, and when rifampicin is contraindicated in HIV-TB patients who require concomitant therapy with anti-retroviral

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

The long duration of the current tuberculosis (TB) treatment is demanding and warrants the development of new drugs. Moxifloxacin shows promising results and may be combined with rifampicin to shorten the duration of TB treatment. Rifampicin induces the phase II metabolic enzymes that are involved in the biotransformation of moxifloxacin. Therefore, the interaction between rifampicin and moxifloxacin should be investigated.. Nineteen Indonesian patients with pulmonary TB who were in the last month of their TB treatment completed a 1-arm, 2-period, fixed-order pharmacokinetic study. In phase 1 of the study, they received 400 mg of moxifloxacin every day for 5 days in addition to 450 mg of rifampicin and 600 mg of isoniazid 3 times per week. In phase 2 of the study, after a 1-month washout period, patients received moxifloxacin for another 5 days (without rifampicin and isoniazid). A 24-h pharmacokinetic curve for moxifloxacin was recorded on the last day of both study periods, and its pharmacokinetic parameters were evaluated for an interaction with rifampicin, using a bioequivalence approach.. Coadministration of moxifloxacin with rifampicin and isoniazid resulted in an almost uniform decrease in moxifloxacin exposure (in 18 of 19 patients). The geometric means for the ratio of phase 1 area under the curve to phase 2 area under the curve and for the ratio of phase 1 peak plasma concentration to phase 2 peak plasma concentration were 0.69 (90% confidence interval, 0.65-0.74) and 0.68 (90% confidence interval, 0.64-0.73), respectively. The median time to reach peak plasma concentration for moxifloxacin was prolonged from 1 h to 2.5 h when combined with rifampicin and isoniazid (P=.003).. Coadministration of moxifloxacin with intermittently administered rifampicin and isoniazid results in reduced moxifloxacin plasma concentrations, which is most likely the result of induced glucuronidation or sulphation by rifampicin. Further studies are warranted to evaluate the impact of the interaction on the outcome of TB treatment.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Aza Compounds; Drug Interactions; Female; Fluoroquinolones; Humans; Indonesia; Isoniazid; Male; Middle Aged; Moxifloxacin; Plasma; Quinolines; Rifampin; Tuberculosis, Pulmonary

To assess whether adrenocortical function was compromised in patients with active tuberculosis (TB) during the first 5 days of therapy with either a rifampicin-based or ciprofloxacin-based regimen.. Patients were randomised into two groups of 10 each. Adrenocortical function was compared in both groups by the measurement of biochemical indices, electrolytes, osmolality and pituitary-adrenocortical hormones. Adrenal reserve was assessed by intravenous 250 mug adrenocorticotropin hormone (ACTH) stimulation tests.. Department of Medicine, Johannesburg Hospital.. Twenty hospitalised patients who were diagnosed with TB.. Respiratory rate, pulse rate and blood pressure were recorded, and urinary sodium and osmolality were measured. Serum ACTH, cortisol, dehydroepiandrosterone- sulphate (DHEA-S) and aldosterone were assayed.. None of the patients demonstrated biochemical evidence of overt adrenal insufficiency. There were no significant differences between the two groups before or during therapy for any biochemical indices, electrolytes, hormones or calculated osmolality. Mean basal cortisol concentrations were substantially elevated and DHEA-S levels were consistently subnormal, resulting in a high cortisol/ DHEA-S ratio. In the ciprofloxacin group, cortisol responses to ACTH stimulation on day 1 were not significantly lower than on day 5. In the rifampicin group, cortisol concentrations decreased at each time point on day 5 compared with day 1 (p = 0.001). However, a significantly higher mean incremental rise from the basal cortisol concentration was measured on day 5 at 60 minutes (p = 0.04). In the entire cohort of 20 patients, 40% demonstrated an incremental cortisol rise of < 250 nmol/l after ACTH stimulation on day 1.. Rifampicin did not additionally impair adrenocortical function during the initial period of therapy. The high cortisol/DHEA-S ratio might be of clinical relevance.

Topics: Adrenal Cortex; Adrenocorticotropic Hormone; Adult; Aldosterone; Antibiotics, Antitubercular; Biomarkers; Ciprofloxacin; Dehydroepiandrosterone Sulfate; Female; Follow-Up Studies; Humans; Hydrocortisone; Immunoassay; Inpatients; Male; Pilot Projects; Prospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Treatment of latent tuberculosis (TB) infection with weekly rifapentine and isoniazid is a potentially effective alternative to current therapies.. To compare the efficacy of weekly rifapentine/isoniazid to daily rifampin/pyrazinamide in preventing TB in household contacts of patients with pulmonary TB in Brazil.. Contacts of patients with TB were randomized to rifapentine 900 mg/isoniazid 900 mg once weekly for 12 wk or rifampin 450-600 mg/pyrazinamide 750-1,500 mg daily for 8 wk and followed for at least 2 yr.. TB rates, adverse events, and adherence to therapy.. A total of 399 household contacts were enrolled, 206 in the rifapentine/isoniazid arm and 193 in the rifampin/pyrazinamide arm. The median age was 34 yr, median weight was 63 kg, 60% of participants were female, and only one patient was HIV infected. Rifapentine/isoniazid was well tolerated, but the trial was halted by the investigators before completion because of unanticipated hepatotoxicity in the rifampin/pyrazinamide arm. Twenty of 193 participants (10%) receiving rifampin/pyrazinamide experienced grade 3 or 4 hepatotoxicity, compared with 2 of 206 participants (1%) on rifapentine/isoniazid (p<0.001). There were no hospitalizations or deaths due to hepatotoxicity, and all participants' liver enzyme levels returned to normal during follow-up. During follow-up, four cases of active TB developed, three in the rifapentine/isoniazid group and one in the rifampin/pyrazinamide group (1.46 vs. 0.52%; difference, 0.94%; 95% confidence interval, -1.6 to 3.7%).. Rifapentine/isoniazid was better tolerated than rifampin/pyrazinamide and was associated with good protection against TB. Rifapentine/isoniazid weekly for 12 wk is likely a promising therapy for latent TB infection.

Topics: Adult; Antitubercular Agents; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Incidence; Isoniazid; Male; Pyrazinamide; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Mycobacterium avium complex pulmonary disease (MAC-PD) is associated with substantial morbidity, and standard daily multidrug therapy is difficult to tolerate.. To characterize response to a three-times-weekly (TIW) regimen of clarithromycin, ethambutol, and rifampin.. A 1-yr prospective noncomparative trial of TIW treatment was conducted during 2000-2003 in 17 U.S. cities. Participants were 91 HIV-negative adults, diagnosed with moderate to severe MAC-PD, who originally participated in a trial of an inhaled IFN-gamma treatment. Improvement in sputum culture, high-resolution computed tomography (HRCT), and symptoms were assessed.. Treatment response rates (and median response times) were 44% (2 mo or longer) for culture, 60% (5.5-11.5 mo) for HRCT, and 53% (8.5 mo) for symptoms. Having noncavitary, compared with cavitary, disease increased culture response by 4.0 times (95% confidence interval [CI], 1.7-9.2) and HRCT response by 4.9 times (95% CI, 1.9-13.0). Culture response was 1.5 times (95% CI, 1.1-2.2) higher for older subjects and 2.2 times (95% CI, 1.0-4.7) higher for previously untreated subjects. Being smear-negative increased culture response by 2.3 times (95% CI, 1.1-5.2) but decreased HRCT response by 4.4 times (95% CI, 1.7-11.5). Increasing ethambutol use by 5 mo increased culture response by 1.5 times (95% CI, 1.0-2.1) but decreased symptom response. Not having chronic obstructive pulmonary disease, bronchiectasis, or poor lung function increased symptom response by 1.9 to 3.9 times.. TIW therapy was less effective for MAC-PD patients with cavitary disease and a history of chronic obstructive pulmonary disease, bronchiectasis, or previous treatment for MAC-PD. Further research is needed to study the long-term outcomes of TIW treatment.

Topics: Aged; Antitubercular Agents; Bronchiectasis; Clarithromycin; Double-Blind Method; Drug Therapy, Combination; Ethambutol; Female; Forced Expiratory Flow Rates; Forced Expiratory Volume; Humans; Male; Middle Aged; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Prospective Studies; Radiography; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

To evaluate the efficiency of chemotherapy used in patients with pulmonary tuberculosis by the results of a rapid detection of drug resistance (DR) to isoniazid and rifampicin on a "TB-Biochip" test system versus the standard treatment with its subsequent correction by the data of determination of Mycobacterium tuberculosis (MBT) resistance by the absolute concentration technique (ACT), the study included 208 patients with pulmonary tuberculosis. The patients were divided into 2 groups: 1) those in whom MBT sensitivity to antituberculous agents was determined on a "TB-Biochip" test system to detect mutations in the MBT genes rpoB, katG, inhA, ahpC that were responsible for MBT sensitivity to rifampicin and isoniazid and by ACT; 2) those in whom this was determined by only ACT. The results of a test for MBT sensitivity to rifampicin and isoniazid were obtained within 2 days before chemotherapy in Group 1 and 2 months after chemotherapy in Group 2. In Group 1, antituberculous chemotherapy was used, by taking into account MBT sensitivity to isoniazid, rifampicin, or their combination; in Group 2, the drugs were given by the standard regimens with their subsequent correction following 2 months by the results of ACT. The timely initiation of treatment with reserve drugs in the detection of drug sensitivity in MBT could achieve higher therapeutic efficiency and in a shorter space of time.

Topics: Adult; DNA Mutational Analysis; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Point Mutation; Rifampin; Severity of Illness Index; Treatment Outcome; Tuberculosis, Pulmonary

To evaluate the curative effect and safety of a long course regimen containing Chinese-made rifabutin as compared to the regimen containing rifapentine in the treatment of multi-drug resistant pulmonary tuberculosis.. During 18 month treatment, 130 patients with multi-drug resistant pulmonary tuberculosis were divided into a treatment group (rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide, amikacin for 3 months, rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide for 6 months, rifabutin, pasiniazide, levofloxacin, ethambutol for 9 months), and a control group (rifapentine, pasiniazide, levofloxacin, ethambutol, ethionamide, amikacin for 3 months, rifabutin, pasiniazide, levofloxacin, ethambutol, ethionamide for 6 months, rifabutin, pasiniazide, levofloxacin, ethambutol for 9 months) with proportion 1:1 random, and parallel compared method.. After intensive phase, the sputum negative conversion rates (smear negative, culture negative) of the treatment group and the control group were 41.54% (27/65) and 35.94% (23/65), chi(2) = 2.42, P > 0.05, respectively. The remarkable effective rates in chest X-ray of the two groups were all 10.77% (7/65), chi(2) = 0.01, P > 0.05, and the effective rates were 67.69% (44/65) and 56.92% (37/65), chi(2) = 1.44, P > 0.05, respectively. At the end of the treatment, the sputum negative conversion rate (smear negative, culture negative) of the treatment group was 75.0% (48/65), and of the control group was 65.08% (41/65), chi(2) = 1.88, P > 0.05. The remarkable effective rates in chest X-ray of the two groups were 46.15% (30/65) and 44.62% (29/65), chi(2) = 0.02, P > 0.05, and the effective rates were 76.92% (50/65) and 73.85% (48/65), chi(2) = 0.19, P > 0.05, respectively. The cavity closure rates were 23.64% (13/55) and 33.33% (17/51), chi(2) = 0.00, P > 0.05, respectively.. Regimens containing rifabutin or rifapentine. are very effective in sputum negative conversion rate, lesion absorption and cavity closing for the treatment of multi-drug resistant pulmonary tuberculosis, with good safety and tolerance.

Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Rifabutin; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Nine public health care centres in four Spanish cities.. To evaluate the efficacy and safety of 2 months of rifampicin (R) plus pyrazinamide (Z) therapy (2RZ) compared with a 6-month course of isoniazid therapy (6H) for treating latent tuberculosis infection (LTBI).. Multicentered, randomised, comparative and prospective trial conducted in HIV-seronegative contacts of infectious pulmonary TB cases.. Of 352 individuals, 199 received 6H and 153 2RZ; 73% of contacts receiving 6H and 71% receiving 2RZ completed treatment (P = 0.73). Treatment interruption due to hepatotoxicity (ALT/AST > 5 times upper limit of normal) was observed in 10% of contacts in the 2RZ group and in 2.5% of the 6H group (P = 0.007). This higher than expected rate of hepatotoxicity in the 2RZ arm led to premature termination of the study. Severe or fatal liver injury was not detected. Liver function tests normalised after discontinuation of treatment. We conclude that the use of RZ should only be considered when other regimens are unsuitable and intensive monitoring of liver function is feasible.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; HIV; HIV Antibodies; HIV Seronegativity; Humans; Infant; Male; Prospective Studies; Pyrazinamide; Rifampin; Spain; Treatment Outcome; Tuberculin Test; Tuberculosis, Pulmonary

Comparison of the early bactericidal activity (EBA) of rifapentine and its pharmacokinetics with those of rifampin to determine the cause of poor clinical response and regrowth between doses, leading to rifamycin monoresistance at relapse.. Determination of the dose size of rifapentine that gives sufficient drug exposure to prevent regrowth.. EBA study over initial 5 days of treatment of 123 patients, half at Durban and half at Cape Town, who received single rifapentine doses of 300, 600, 900, or 1,200 mg rifapentine or five daily doses of 150, 300, or 600 mg rifampin, with a pharmacokinetic study on 58 patients measuring standard parameters for each dose size of rifamycin and their desacetyl metabolites.. The EBAs for both rifamycins were similar, with a linear relationship to log dose at lower doses and a curvilinear response at higher doses giving a plateau at 1,136 mg rifapentine. The area under the concentration-time curve (AUC) divided by the minimal inhibitory concentration (MIC) agreed well for both rifamycins on the assumption that the only free 2% of free rifapentine and the 14% of free rifampin after plasma binding were active in the lesions.. Only the free proportions of the rifamycins were active in lesions. From consideration of the pulse size and the duration of the postantibiotic lag, a 1,200-mg dose of rifapentine seemed necessary to improve response and to prevent regrowth between doses, and hence rifamycin monoresistance.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Area Under Curve; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Rifamycins; Secondary Prevention; South Africa; Sputum; Time Factors; Tuberculosis, Pulmonary

This report presents the 5-year follow-up of 137 children with respiratory tuberculosis enrolled in a randomised clinical trial of two different anti-tuberculosis regimens 9HR and 2HRZ3/4RH2. Both regimens had similar cure rates, with low relapse rates and mortality. Of 134 children followed up to 5 years, 86% had normal radiographs, with more sequelae in the 9HR group (15% vs. 1.5%, P < 0.01). One patient relapsed and there was one accidental death. Short-course chemotherapy in children is safe, effective and well tolerated, and leads to excellent long-term results, with a small proportion of children left with radiological sequelae.

Topics: Antitubercular Agents; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Humans; Infant; Isoniazid; Pyrazinamide; Rifampin; Statistics, Nonparametric; Tuberculosis, Pulmonary

The pharmacokinetics of rifampin and ethambutol in HIV-infected patients with tuberculosis (TB) are incompletely characterized. We examined the pharmacokinetics of rifampin and ethambutol in a cohort of patients with HIV-related TB who were treated in the United States.. Serum drug concentrations were determined 2, 6, and 10 h after dosing in 36 HIV-infected patients with TB who were taking rifampin and in 49 who were taking ethambutol. Observed serum concentrations were compared with published normal ranges and published data.. With daily dosing of rifampin (600 mg), 26 (77%) of 34 patients (95% confidence interval [CI], 59%-89%]) had a low maximum concentration of rifampin (<8 microg/mL), and 12 (35%; 95% CI, 20%-54%) had a very low maximum concentration (<4 microg/mL). With intermittent rifampin dosing (600 mg), 13 (68%) of 19 patients (95% CI, 44%-85%) had a low maximum concentration of rifampin, and 5 (26%; 95% CI, 11%-50%) had a very low maximum concentration. With daily ethambutol dosing (20 mg/kg), 33 (69%) of 48 patients (95% CI, 55%-81%) had a low maximum concentration of ethambutol (<2 microg/mL), and 18 (38%; 95% CI, 24%-53%) had a very low maximum concentration (<1 microg/mL). With intermittent ethambutol dosing (50 mg/kg twice weekly or 30 mg/kg thrice weekly), 13 (72%) of 18 patients (95% CI, 47%-88%) had a low maximum concentration of ethambutol (<4 microg/mL), and 5 (28%; 95% CI, 12%-54%]) had a very low maximum concentration (<2 microg/mL).. In HIV-infected patients with TB who are receiving rifampin and ethambutol, low maximum concentrations of rifampin and ethambutol were common. For patients with HIV-related TB, therapeutic monitoring of rifampin and ethambutol levels may help clinicians achieve target serum concentrations.

Topics: Adult; Antitubercular Agents; Area Under Curve; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Half-Life; HIV Infections; Humans; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

The pharmacokinetics of rifapentine at 600, 900, and 1,200 mg were studied during once-weekly continuation phase therapy in 35 patients with tuberculosis. Mean area under the plasma concentration-time curve (AUC(0-infinity)) increased significantly with dose (rifapentine AUC(0- infinity): 296, 410, and 477 microg.hour/ml at 600, 900, and 1,200 mg, respectively; p = 0.02 by linear regression). In multivariate stepwise regression analyses, AUC(0-infinity) values for rifapentine and the active 25-desacetyl metabolite were associated with drug dose and plasma albumin concentration, and were lower among men and among white individuals. Fifty-four percent of patients had total (free and protein-bound) plasma concentrations of rifapentine and of desacetyl rifapentine detected for more than 36 hours after clearance of concurrently administered isoniazid. Serious adverse effects of therapy in these study patients were infrequent (1 of 35 cases; 3%) and not linked with higher rifapentine AUC(0-infinity) or peak concentration. The present pharmacokinetic study supports further trials to determine the optimal rifapentine dose for treatment of tuberculosis.

Topics: Adult; Antibiotics, Antitubercular; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Humans; Isoniazid; Male; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

To evaluate the efficacy of split-drug regimens for treatment of patients with sputum smear-positive pulmonary tuberculosis in south India.. Randomized controlled clinical trial where eligible patients were randomly allocated to: (i) 2RE(3)HZ(3)(alt)/4RH(2) (split I): rifampicin plus ethambutol given on one day and isoniazid plus pyrazinamide the next day for first 2 months followed by rifampicin plus isoniazid twice weekly for 4 months, or (ii) 3RE(3)HZ(3)(alt)/3RH(2) (split II): similar to regimen 1, except duration was 3 months in each phase, or (iii) 2REHZ(3)/4RH(2) (control): rifampicin, isoniazid, ethambutol and pyrazinamide, given thrice weekly for 2 months followed by isoniazid and rifampicin twice weekly for 4 months. All patients were followed up clinically and bacteriologically every month up to 2 years and every 6 months for up to 5 years.. A favourable response (cultures negative for Mycobacterium tuberculosis during the last 2 months of treatment) was observed in 91% of 407 patients in split I, 94% of 415 in split II and 89% of 418 in the control regimen. Ninety-one per cent of 370 patients in split I, 93% of 389 in split II and 90% of 370 in control regimens had quiescent disease at the end of 60 months. Gastrointestinal symptoms were more frequent under the control regimen (P = 0.01).. Split-drug regimens were as effective as the control regimen in terms of favourable response at the end of treatment and quiescent disease at 5 years, and caused fewer gastrointestinal side-effects.

Topics: Adult; Antitubercular Agents; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Risk Factors; Survival Analysis; Treatment Outcome; Tuberculosis, Pulmonary

Plasma levels of pyridoxal phosphate (PLP) were determined in 20 patients with pulmonary tuberculosis before and after one week of drug therapy including isoniazid. At baseline, body mass index and PLP levels were reduced in 10 and 18 patients, respectively. After 7 days of therapy, PLP levels decreased (P < 0.001) in all but one subject who inadvertently received pyridoxine supplementation. The decreased PLP levels occurred despite a significant improvement in the acute phase response (increased albumin [P < 0.001] and reduced C-reactive protein levels [P < 0.01]). This study indicates the need for possible routine pyridoxine supplementation in patients with newly diagnosed tuberculosis.

Topics: Adult; Antitubercular Agents; Ethambutol; Female; Follow-Up Studies; HIV Infections; Humans; Isoniazid; Male; Pyrazinamide; Pyridoxine; Rifampin; Time Factors; Tuberculosis, Pulmonary

To characterise the pharmacokinetics of two consecutive doses of rifapentine (RPT) in patients diagnosed with pulmonary tuberculosis at a South African hospital.. Forty-five patients received RPT doses of 600, 750 and 900 mg, based on body weight, after receiving a soup-based meal. Doses were administered to each subject on study days 1 and 5. All patients had already received not less than 4 weeks and not more than 6 weeks of standard antimycobacterial therapy (including isoniazid, rifampicin, pyrazinamide and ethambutol). Serial blood samples were collected between 0 and 72 h post-dose. RPT and 25-desacetyl-RPT concentrations were determined using validated high performance liquid chromatography methods. The plasma concentration-time data were analysed using a noncompartmental approach and compared to healthy volunteer data from a previous study.. Median peak plasma concentrations for RPT in the patient cohort were 15.19 and 15.48 microg/ml on study days 1 and 5, respectively. Time to reach these concentrations was 5.00 and 5.08 h and plasma elimination half-lives were 11.63 and 12.03 h, respectively. Areas under the plasma concentration-time curve (0-72 h) were 355.81 and 371.89 microg x h/ml on the two occasions, respectively.. A 15 mg/kg dose of RPT was well absorbed and well tolerated. The variability observed between individuals and between occasions was small, and similar to that seen in data from previous studies in healthy volunteers.

Topics: Administration, Oral; Adolescent; Adult; Antibiotics, Antitubercular; Drug Administration Schedule; Female; Half-Life; Humans; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Recurrence of active tuberculosis after treatment can be due to relapse of infection with the same strain or reinfection with a new strain of Mycobacterium tuberculosis. The proportion of recurrent tuberculosis cases caused by reinfection has varied widely in previous studies. We evaluated cases of recurrent tuberculosis in two prospective clinical trials: a randomized study of two regimens for the last 4 months of treatment (n = 1,075) and a study of a twice-weekly rifabutin-containing regimen for human immunodeficiency virus-infected tuberculosis (n = 169). Isolates at diagnosis and from positive cultures after treatment completion underwent genotyping using IS6110 (with secondary genotyping for isolates with less than six copies of IS6110). Of 85 patients having a positive culture after completing treatment, 6 (7.1%) were classified as false-positive cultures by a review committee blinded to treatment assignment. Of the remaining 75 cases with recurrent tuberculosis and genotyping data available, 72 (96%; 95% confidence interval, 88.8-99.2%) paired isolates had the same genotype; only 3 (4%; 95% confidence interval, 0.8-11.2%) had a different genotype and were categorized as reinfection. We conclude that recurrent tuberculosis in the United States and Canada, countries with low rates of tuberculosis, is rarely due to reinfection with a new strain of M. tuberculosis.

Topics: Adult; Antitubercular Agents; Canada; Female; Genotype; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Prospective Studies; Recurrence; Rifampin; Tuberculosis, Pulmonary; United States

Forty-nine adolescents with active pulmonary tuberculosis were followed up to assess the biological chip test for the detection of rifampicin resistance in Mycobacterium tuberculosis (MBT). Rifampicin resistance (rpo B gene mutation) was detected in 22 (44.9%) patients. Disseminated processes were detected in a larger proportion of the patients with rifampicin resistance than in those with MBT susceptibility (63.6 and 40.7%, respectively (p < 0.05). Comparison of the data on MBT resistance and susceptibility, which had been obtained by bacteriological studies (nutrient medium cultuvations) and the biological chip test, revealed their agreement in 50% of the cases. A response could be showed after 2-3 months in the former case and after 2-3 days in the latter case. With the biological chip test, the resistance of MBT to rifampicin was additionally established in 38.7% of the patients with negative cultivation tests on admission and during therapy. Follow-ups have demonstrated that MBT resistance to rifampicin preserves longer with the biological microchip test than that with nutrient medium cultivation.

Topics: Adolescent; Antitubercular Agents; Drug Resistance, Bacterial; Humans; Lab-On-A-Chip Devices; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tuberculosis (TB) is increasing in the world and drug-resistant (DR) disease beckons new treatments.. To evaluate the action of interferon (IFN) gamma as immunoadjuvant to chemotherapy on pulmonary DR-TB patients, a pilot, open label clinical trial was carried out in the Cuban reference ward for the management of this disease. The eight subjects existing in the country at the moment received, as in-patients, 1 x 10(6) IU of recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to the indicated chemotherapy, according to their antibiograms and WHO guidelines. Sputum samples collection for direct smear observation and culture as well as routine clinical and thorax radiography assessments were done monthly.. Sputum smears and cultures became negative for acid-fast-bacilli before three months of treatment in all patients. Lesion size was reduced at the end of 6 months treatment; the lesions disappeared in one case. Clinical improvement was also evident; body mass index increased in general. Interferon gamma was well tolerated. Few adverse events were registered, mostly mild; fever and arthralgias prevailed.. These data suggest that IFN gamma is useful and well tolerated as adjunctive therapy in patients with DR-TB. Further controlled clinical trials are encouraged.

Topics: Adjuvants, Immunologic; Adult; Amikacin; Antitubercular Agents; Ciprofloxacin; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Ethionamide; Female; Follow-Up Studies; Humans; Interferon-gamma; Kanamycin; Male; Middle Aged; Mycobacterium tuberculosis; Pilot Projects; Pyrazinamide; Radiography; Recombinant Proteins; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

Tuberculosis Centre, University Medical Centre, Groningen, The Netherlands.. To study intralesional concentrations of isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA) in tuberculous pleural effusions and psoas abscesses, and to compare these to reference serum values and minimal inhibitory concentration (MIC).. Intralesional concentrations were measured 2 h after drug administration (six pleural effusions, 10 psoas abscesses).. A wide range of concentrations was found for pleural effusions and psoas abscesses. Concentrations were below MIC values in none of 15 patients for INH, in two of 13 for RMP, and in eight of nine for PZA. The Cmax:MIC ratio was always >4 for INH, in four of 13 for RMP, and in none of nine for PZA. In 5/8 patients receiving all three drugs, both RMP and PZA had Cmax:MIC ratios <4, indicating sub-therapeutic drug levels.. Penetration of INH was always sufficient, penetration of RMP mostly below the desired ratio, and for PZA on average 10 times too low. Five of eight patients on all three drugs had Cmax:MIC ratios <4. This indicates intralesional sub-therapeutic drug levels for RMP and PZA, and local monotherapy with INH. This could induce drug resistance. Drainage as additional therapy seems indicated.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Netherlands; Pleural Effusion; Psoas Abscess; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Young Adult

Regional lymphotropic therapy involving 10% isoniazid administration was included into multimodality treatment in 250 patients with pulmonary tuberculosis and comorbidity. The findings have indicated that the lymphotropic therapy during the use of rifampicin, streptomycin, ethambutol enhances the efficiency of chemotherapy in different forms of pulmonary tuberculosis, including the latter concurrent with hepatic lesion or diabetes mellitus. Lymphotropic therapy is particularly beneficial to patients with poor drug tolerability. The use of lymphotropic isoniazid in the multimodality treatment of pulmonary tuberculosis leads to the earlier disappearance of the symptoms of tuberculous intoxication (by 1-1.5 months) in 80-92% of the patients, to abacillation in the same periods, to the increased frequency of decay cavity closure by an average of 15% as compared to the conventional treatment, and, in most cases, to the normalization of the biochemical parameters of hepatic function.

Topics: Administration, Oral; Antitubercular Agents; Diabetes Complications; Ethambutol; Humans; Hypoglycemic Agents; Injections, Intralymphatic; Injections, Intramuscular; Insulin; Isoniazid; Liver Diseases; Lymphatic System; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Over the period, 1st October 1999 to 30th April 2002 a clinical trial of the modified short-course chemotherapy (SCC) in newly diagnosed cases of pulmonary tuberculosis with human immunodeficiency virus (HIV) infection in Ibadan, Nigeria was carried out. The modified SCC used was adopted by World Health Organisation (WHO)/International Union against Tuberculosis and Lung Diseases (IUALTD) for developing countries and also by the Nigerian National Tuberculosis and Leprosy Control Programmed (NTLCP). The regimen used consisted of ethambutol (E), isoniazid (H), rifampicin (R) and pyrazinamide (Z) in the intensive phase of 2 months. The continuation phase was 6 months of ethambutol (E) and isoniazid(H), i.e. 2EHRZ/6EH. Sputum conversion was 90% at the second month of treatment and there was no bacteriological relapse after 18 months of follow-up. Side effects were few and consisted mainly of acne vulgaris in 20 (22.5%) of 89 patients during the continuation phase. It is concluded that this modified 8-month chemotherapy regimen adopted by NTLCP is efficacious in treatment of smear positive pulmonary tuberculosis (PTB) patients with background HIV infection.

Topics: Acne Vulgaris; Adolescent; Adult; Age Distribution; Aged; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Nigeria; Pyrazinamide; Radiography; Rifampin; Tuberculosis, Pulmonary

To explore the feasibility of domestic fixed-dose combinations as antituberculosis therapy applied in the National Tuberculosis Program.. A randomized control trial was conducted and 422 smear-positive pulmonary tuberculosis patients were randomly distributed into 2 groups. The trial group was treated daily with rifampicin, isoniazid and pyrazinamide tablets (including 120 mg rifampicin, 80 mg isoniazid and 250 mg pyrazinamide) in the first 2 months and rifampicin and isoniazid tables (including 300 mg rifampicin, 150 mg isoniazid) in the subsequent 4 months. The control group was treated by full 6-month standard regimens (2HRZE/4H3R3).. The demographic data and the disease status were similar between the 2 groups before treatment. The rate of conversion from positive to negative cases in the trial group after therapy was 91.6% at 2 months, 97.2% at 3 months, and 97.7% at 6 months, while that of the control group was 87.3%, 97.5%, and 98.0% respectively. The difference in the conversion rates between the two groups was not statistically significant (chi2 = 2. 05, chi2 = 0.03, chi2 = 0.04, P > 0.05). The incidence of skin rash as an adverse effect was less common in the trial group as compared to the control group (Fisher's exact P = 0.024 33) .. Domestic fixed-dose combinations as supplementary anti-tuberculous therapy could be used in the National Tuberculosis Program, but further study is needed for widespread application.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Protocols; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

To understand why once-weekly isoniazid/rifapentine therapy for tuberculosis was less effective than twice-weekly isoniazid/rifampin, we studied human immunodeficiency virus-seronegative patients with either failure (n = 4), relapse (n = 35), or cure (n = 94), recruited from a comparative treatment trial. In multivariate analyses that were adjusted for severity of disease, low plasma concentrations of isoniazid were associated with failure/relapse with once-weekly isoniazid/rifapentine (median isoniazid area under the concentration-time curve for 12 hours after the dose [AUC(0-12)] was 36 microg x hour/ml in failure/relapse versus 56 microg x hour/ml in control cases p = 0.005), but not with twice-weekly isoniazid/rifampin. Furthermore, two patients who relapsed with Mycobacterium tuberculosis monoresistant to rifamycin had very low concentrations of isoniazid. Finally, isoniazid acetylator status determined by N-acetyltransferase type 2 genotype was associated with outcome with once-weekly isoniazid/rifapentine (p = 0.03) but not twice-weekly isoniazid/rifampin. No rifamycin pharmacokinetic parameter was consistently and significantly associated with outcome (p > 0.10). Because low isoniazid concentrations were associated with failure/relapse, a drug with consistently greater area under the concentration-time curve than isoniazid may be needed to achieve highly active once-weekly therapy with rifapentine.

Topics: Adult; Analysis of Variance; Antibiotics, Antitubercular; Antitubercular Agents; Biological Availability; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; HIV Seronegativity; Humans; Isoniazid; Male; Middle Aged; Multivariate Analysis; Probability; Recurrence; Reference Values; Rifampin; Severity of Illness Index; Treatment Failure; Treatment Outcome; Tuberculosis, Pulmonary

To evaluate the effects of combined anti-tuberculosis treatment including isoniazid (INH), rifampicin (RMP), ethambutol (EMB) and pyrazinamide (PZA), on the pharmacokinetics of theophylline during the initial phase of treatment.. Prospective, controlled clinical study.. Twenty patients with pulmonary tuberculosis received 7.35 mg/kg/day of aminophylline intravenously combined with anti-tuberculosis agents. The first theophylline serum concentration was measured before administration of INH, RMP, EMB and PZA, and samples were obtained once daily for 6 consecutive days after initiation of treatment. All patients in this study were non-smokers with normal hepatic and renal function, and they were not given any other drugs that could affect the clearance of theophylline.. The concentration and half-life of theophylline was decreased and its clearance was increased significantly at days 5-7 after administration of antituberculosis agents compared to before the therapy was started.. These results suggest that patients with asthma or chronic obstructive pulmonary disease administered combinations of anti-tuberculosis agents and theophylline during the initial phase of tuberculosis treatment should be monitored closely for changes in theophylline concentration, and that the dose of theophylline should be adjusted accordingly.

Topics: Adult; Aged; Antitubercular Agents; Bronchodilator Agents; Drug Interactions; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Theophylline; Time Factors; Tuberculosis, Pulmonary

To evaluate the clinical response to antituberculosis chemotherapy rapidly.. Sputum viable counts from a previously published clinical trial comparing a standard regimen and one containing isoniazid, rifampicin and ciprofloxacin were re-evaluated using an exponential decay model. The results were fitted to a one or two phase exponential decline. The decline in viable counts followed a curve described by a single-phase exponential decay model. From these data the time taken to reduce the viable count by 50% (vt50) was calculated to estimate the bactericidal effect of the regimens.. This method shows promise as a means for early identification of patients who are responding poorly as a result of resistance or poor immune response and for comparing anti-tuberculosis regimens in clinical trials. The failure to show a two-phase exponential decay curve suggested that either the sputum does not contain bacteria upon which only drugs with a sterilising activity act or that they are not present in sufficient numbers to have a significant impact on the total viable count. Further studies are required to understand the physiological state of organisms being sampled in sputum.

Topics: Antitubercular Agents; Cell Survival; Ciprofloxacin; Drug Administration Schedule; Humans; Isoniazid; Microbial Sensitivity Tests; Models, Statistical; Rifampin; Sputum; Tuberculosis, Pulmonary

Patients in whom acid-fast bacilli smear-positive pulmonary tuberculosis was newly diagnosed were randomized to receive 400 mg moxifloxacin, 300 mg isonaizid, or 600 mg rifampin daily for 5 days. Sixteen-hour overnight sputa collections were made for the 2 days before and for 5 days of monotherapy. Bactericidal activity was estimated by the time taken to kill 50% of viable bacilli (vt50) and the fall in sputum viable count during the first 2 days designated as the early bactericidal activity (EBA). The mean vt50 of moxifloxacin was 0.88 days (95% confidence interval [CI], 0.43-1.33 days) and the mean EBA was 0.53 (95% CI 0.28-0.79). For the isoniazid group, the mean vt50 was 0.46 days (95% CI, 0.31-0.61 days) and the mean EBA was 0.77 (95% CI, 0.54-1.00). For rifampin, the mean vt50 was 0.71 days (95% CI, 0.48-0.95 days) and the mean EBA was 0.28 (95% CI, 0.15-0.41). Using the EBA method, isoniazid was significantly more active than rifampin (p < 0.01) but not moxifloxacin. Using the vt50 method, isoniazid was more active than both rifampin and moxifloxacin (p = 0.03). Moxifloxacin has an activity similar to rifampin in human subjects with pulmonary tuberculosis, suggesting that it should undergo further assessment as part of a short course regimen for the treatment of drug-susceptible tuberculosis.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Aza Compounds; Female; Fluoroquinolones; Humans; Inhibitory Concentration 50; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Moxifloxacin; Mycobacterium tuberculosis; Quinolines; Rifampin; Sputum; Tuberculosis, Pulmonary

It has been postulated that deficient or incomplete clinical and/or microbiological response to tuberculosis treatment is associated with cell-mediated immunological dysfunction involving monocytes and macrophages. A phase 2 safety trial was conducted by treating patients with either recombinant human granulocyte-macrophage colony-stimulating factor (rhu-GM-CSF) or a placebo, both in combination with anti-tuberculosis chemotherapy. Thirty-one patients with documented pulmonary tuberculosis were treated with rifampin/isoniazid for six months, plus pyrazinamide for the first two months. At the beginning of treatment, rhu-GM-CSF (125mg/M(2)) was randomly assigned to 16 patients and injected subcutaneously twice weekly for four weeks; the other 15 patients received a placebo. The patients were accompanied in the hospital for two weeks, then monthly on an out patient basis, for 12 months. Clinical outcomes were similar in both groups, with no difference in acid-fast bacilli (AFB) clearance in sputum at the end of the fourth week of treatment. Nevertheless, a trend to faster conversion to negative was observed in the rhu-GM-CSF group until the eighth week of treatment (p=0.07), after which all patients converted to AFB negative. Adverse events in the rhu-GM-CSF group were local skin inflammation and an increase in the leukocyte count after each injection, returning to normal 72 hours after rhu-GM-CSF injection. Three patients developed SGOP and SGPT > 2.5 times the normal values. All patients included in the GM-CSF group were culture negative at six months, except one who had primary TB resistance. None of the patients had to discontinue the treatment in either group. We conclude that rhu-GM-CSF adjuvant immunotherapy could be safely explored in a phase 3 trial with patients who have active tuberculosis.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Antitubercular Agents; Double-Blind Method; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

The multicomponent drug Mairin-P that contains isoniazid, 60 mg, rifampicin, 120 mg, pyrazinamide, 300 mg, and ethambutol hydrochloride, 225 mg, has been pharmacokinetically and clinically studied. There was no significant difference in the pharmacokinetic parameters of rifampicin as a component of Mairin-P and in combination with antitubercuous agents as free dosage forms. Treatment of first detected patients with pulmonary tuberculosis who isolate drug-sensitive Mycobacterium tuberculosis with Mairin-P is as effective as conventional treatment regimens with antituberculous drugs. Adverse reactions, including non-correctable one, due to the use of Mairin-P occur less frequently than to that of antituberculous drugs.

Topics: Adolescent; Adult; Drug Combinations; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Radiography; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week.. We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drug-susceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat.. 1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin twice a week (relative risk 1.64, 95% CI 1.04-2.58, p=0.04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2.8, 95% CI 1.7-4.6); cavitation on chest radiography (3.0, 1.6-5.9); being underweight (3.0, 1.8-4.9); bilateral pulmonary involvement (1.8, 1.0-3.1); and being a non-Hispanic white person (1.8, 1.1-3.0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1.34; 0.83-2.18; p=0.23). Of participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the twice a week group (relative risk 1.15; 95% CI 0.38-3.50; p=0.81). Rates of adverse events and death were similar in the two treatment groups.. Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.

Topics: Antibiotics, Antitubercular; Drug Administration Schedule; Drug Therapy, Combination; Ethnicity; Female; Humans; Isoniazid; Male; Middle Aged; Radiography, Thoracic; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

Veterans General Hospital-Taipei, Taiwan.. To assess the efficacy and safety of a fixed-dose combination (FDC) of Rifater (RFT)/Rifinah (RFN) in the treatment of newly diagnosed smear-positive pulmonary tuberculosis.. Patients were randomly assigned to two 6-month short-course chemotherapy regimens. One group of patients was treated with FDCs and another was given the four component drugs (INH, RMP, EMB and PZA) as separate formulations.. The 105 patients enrolled in the study were divided into two treatment groups. Fifty-one patients who had completed treatment without interruption, 26 in the FDC group and 25 in the separate regimen, were eligible for analysis at the end of 2 years. Among the patients with a drug susceptibility test result available, four in the FDC group had bacilli resistant to pyrazinamide. In the separate regimen group, two patients had bacilli resistant to ethambutol and six had bacilli resistant to pyrazinamide. The two regimens were of similar effectiveness with regard to sputum conversion, compliance and radiological improvement. No patient with FDC treatment developed gastointestinal symptoms, visual disturbance or peripheral neuropathy (P < 0.05). However, FDC treatment resulted in drug-induced fever in one patient. One patient (3.8%) in the FDC group relapsed 5 months after completing treatment.. This study suggests that the two regimens had similar effectiveness in the treatment of smear-positive pulmonary tuberculosis. However, the fewer adverse drug events among those patients treated with the FDC regimen suggests that it has a better safety profile.

Topics: Adult; Antitubercular Agents; Drug Combinations; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Patient Compliance; Pyrazinamide; Rifampin; Sputum; Taiwan; Tuberculosis, Pulmonary

Several therapeutic regimens for drug-resistant tuberculosis have been suggested, most of them with a total duration of 18-24 months.. To report our experience using a shorter regimen.. Fifty patients with drug-resistant pulmonary tuberculosis were managed by withdrawing all anti-tuberculosis drugs until the results of a drug sensitivity test were obtained (approximately 3 months), and then a 12-month self-administered regimen with four to six anti-tuberculosis drugs at full daily doses was initiated, based primarily on the sensitivity test and secondarily on the history of previous treatment.. In 31 patients treatment was completed as planned, in six it was irregular and 13 definitively abandoned it. In the best scenario, 90.3% (28/31) of patients with full treatment were cured; this outcome was similar for both multidrug-resistant (MDR, n = 18, 88.9%) and non-MDR (n = 13, 92.3%) patients. Six months later, the relapse rate was 4.8%, and after a 5-year follow-up 14 out of 18 cured patients who were located remained asymptomatic (77.8%). If the worst scenario was applied, a 62.0% cure rate (31/50) was obtained.. A 12-month regimen with a minimum of four anti-tuberculosis agents at full dose, essentially selected on drug sensitivity testing, could be an alternative option for the treatment of drug-resistant pulmonary tuberculosis.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Drug Administration Schedule; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Outcome Assessment, Health Care; Prospective Studies; Pyrazinamide; Rifampin; Streptomycin; Time Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The aim of our study was to evaluate and compare the therapeutic efficacy & safety profile of three different antituberculous regimens for pulmonary tuberculosis. The study sample size included 90 newly diagnosed, sputum positive patients of pulmonary. tuberculosis. 30 each from different groups. The parameters studied were, therapeutic efficacy included weight gain, cough, sputum examination and safety profile: nausea, vomiting, anorexia, gastritis, hepatitis, jaundice diarrhoea, rashes, dizziness, tingling & numbness, flu like symptoms & joint aches. Group-I showed statistically significant weight gain when compared to Group-II. Improvement in cough and conversion to smear negative were seen in 100% of patients in Group-I, 83.3% of patients in Group-II and 93.3% of patients in Group-III. Therapeutic efficacy was highest with Group I regimen, followed by Group III and Group II which was least efficacious. Group II also registered; the maximum cost and highest incidence of adverse effects.

Topics: Adult; Antitubercular Agents; Dizziness; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Gastritis; Humans; Hypesthesia; Isoniazid; Male; Nausea; Pyrazinamide; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis, Pulmonary

Recommended treatment of childhood tuberculosis is 6 months in duration with at least 3 drugs. We studied a regimen requiring as few as 58 doses, given entirely by directly observed therapy (DOT), under program conditions.. An observational trial was conducted to determine the effectiveness of a completely DOT 6-month regimen for pulmonary, pleural and lymph node tuberculosis in children with the use of 2 weeks of daily isoniazid, rifampin and pyrazinamide therapy; then 6 weeks of twice weekly isoniazid, rifampin and pyrazinamide therapy; followed by 16 weeks of twice weekly isoniazid and rifampin. All therapy was given by workers from the health department, and patients were followed by the Children's Tuberculosis Clinic in Houston, TX. Patients were evaluated for changes in symptoms, weight, clinical or radiographic findings and adherence to therapy.. Of the 175 evaluable children (159 pulmonary/thoracic node, 4 pleural, 12 cervical lymph node), 81% of children completed treatment in 6 months. Of the 33 patients who received extended treatment, 3 did so because of physician choice, 17 had an inadequate response to initial therapy, 2 had significant adverse reactions to drugs and 16 had poor adherence to the DOT. Only 37% of patients had complete resolution of disease at the end of treatment, but all continued to improve after therapy was stopped. There was only 1 patient who relapsed after 4 years.. This regimen had results comparable with those of 6-month regimens with longer durations of daily therapy. Determining treatment response in pediatric tuberculosis is difficult because of the slow resolution of chest radiograph abnormalities. DOT is an important aspect of treatment but does not solve all problems with treatment adherence.

Topics: Adolescent; Antibiotics, Antitubercular; Antitubercular Agents; Child; Child, Preschool; Directly Observed Therapy; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant; Isoniazid; Male; Patient Compliance; Pyrazinamide; Recurrence; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Clinical trial in 672 patients with newly diagnosed pulmonary tuberculosis in Hong Kong. After an initial 2 months of a four-drug intensive phase consisting of thrice-weekly streptomycin, isoniazid, rifampicin and pyrazinamide (SHRZ), a random allocation was made to a continuation phase of once-weekly 600 mg rifapentine + 15 mg/kg isoniazid (HRp1), HRp1 given in 2 of every 3 weeks (HRp1.2/3), or to thrice-weekly isoniazid + rifampicin (HR3), the standard treatment in Hong Kong.. Final report evaluating adverse events (46 relapses and one failure) after 5 years and the prognostic influence of various factors.. Kaplan-Meier analysis of adverse events and Cox proportional hazards analysis of prognostic factors.. The two rifapentine regimens, HRp1 and HRp1.2/3 had similar final rates of adverse events of 10.8% and 11.7%, respectively, compared to 4.2% for the HR3 regimen (P = 0.02 and 0.009, respectively). In the initial univariate proportional hazards analysis, adverse events were significantly related to the regimen, age, sex, pretreatment radiographic extent of disease and cavitation, and also to sputum culture at 2 months. In the final multivariate analysis, after step-wise removal of non-significant factors, adverse events were related only to the regimen, patients' sex and pretreatment radiographic extent of disease. Elderly male patients were more at risk of an adverse event, as were those with more severe disease. Adverse events occurred at life table rates of 9.0% in patients with drug-sensitive strains and in 8.9% of those with initially isoniazid-resistant organisms at 5 years.. The two rifapentine regimens were unsatisfactory because of their high incidence of adverse events. Isoniazid appeared not to contribute to preventing relapse. Further studies with increased rifapentine dosage are necessary.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Antitubercular Agents; Child; Drug Therapy, Combination; Female; Hong Kong; Humans; Isoniazid; Life Tables; Male; Middle Aged; Prognosis; Proportional Hazards Models; Pyrazinamide; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis, Pulmonary

A clinical study was carried out between January 1996 and December 1997 in Iwo Nigeria to determine among others the types and frequency of occurrence of side-effects of anti-tuberculous drugs in the 8-month regimen recommended by the Nigerian National Tuberculosis Control Programme Committee (NTCP) for newly diagnosed (ND) Pulmonary Tuberculosis (PTB) cases. This was compared with a 6-month regimen used within the same population of ND PTB subjects at Iwo Nigeria. 65 (13%) of the 500 patients in group one on the 8-month regimen had various side-effects while 7 (14%) of the 50 patients in group two on the 6-month regimen manifested various side-effects. The side-effects rate and frequencies were similar and in both, they were mild and did not materially lead to major change of the anti-tuberculous medications. The regimen used in this study in group one (NTCP recommended) and group two recorded low incidence of side-effects. It confirmed that Directly Observed Treatment Short-course (DOTS) when applied with the recommended regimen by the Nigerian NTCP is effective and is characterised by low and minor side-effects.

Topics: Adolescent; Adult; Antitubercular Agents; Clinical Protocols; Directly Observed Therapy; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Nigeria; Pyrazinamide; Rifampin; Time Factors; Tuberculosis, Pulmonary

The treatment of pulmonary disease caused by opportunist mycobacteria is controversial. It is uncertain whether in vitro sensitivity testing predicts clinical response in the way it does for Mycobacterium tuberculosis. The literature suggests that the combination of rifampicin (R) and ethambutol (E) is important whereas isoniazid (H) may not be, but to date there have been no published reports of randomised controlled trials in the treatment of these conditions. The British Thoracic Society has conducted the first such trial, a randomised study of two regimens in HIV negative patients with pulmonary disease caused by M avium intracellulare (MAC), M malmoense, and M xenopi.. When two positive cultures were confirmed by the Mycobacterium Reference Laboratories for England, Wales and Scotland, the coordinating physician invited the patient's physician to enrol the patient. Patients were also recruited from Scandinavia. Randomisation to 2 years of treatment with RE or REH was performed from lists held in the coordinator's office. Clinical, bacteriological, and radiological progress was monitored at set intervals up to 5 years.. From October 1987 to December 1992, 141 physicians entered 223 patients (106 with M malmoense, 75 with MAC, 42 with M xenopi). At entry the RE and REH groups were comparable over a range of demographic and clinical features. For each species there was no significant difference between RE and REH in the number of deaths, but when the three species were combined there were fewer deaths from the mycobacterial disease with RE (1% v 8%, p=0.018, odds ratio 0.10, exact 95% CI 0.00 to 0.76). For M malmoense the failure of treatment/relapse rates did not differ appreciably between the regimens, but for MAC there were fewer failures of treatment/relapses with REH (16% v 41%, p=0.033) With M xenopi there was a non-significant trend in the same direction (5% v 18%, p=0.41) and when all three species were combined there was a significant difference in favour of REH (11% v 22%, p=0.033). There was no correlation between failure of treatment/relapse and in vitro resistance. M xenopi was associated with the greatest mortality (57% at 5 years), MAC was the most difficult to eradicate, and M malmoense had the most favourable outlook (42% known to be alive and cured at 5 years).. The results of susceptibility tests performed by the modal resistance method do not correlate with the patient's response to chemotherapy. RE and REH are tolerated better than previous regimens containing second or third line anti-mycobacterial drugs. Treatment of M malmoense with RE for 2 years is preferable to REH. The addition of H reduces the failure of treatment/relapse rates for MAC and has a tendency to do so also for M xenopi, but there is a suggestion that REH is associated with higher death rates overall. Better regimens are required.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; HIV Seronegativity; Humans; Isoniazid; Male; Middle Aged; Mycobacterium avium; Mycobacterium avium Complex; Mycobacterium Infections, Nontuberculous; Mycobacterium xenopi; Opportunistic Infections; Prospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Clarithromycin; Drug Therapy, Combination; Ethambutol; Female; Humans; Male; Middle Aged; Mycobacterium avium-intracellulare Infection; Rifampin; Roxithromycin; Treatment Outcome; Tuberculosis, Pulmonary

Treatment of latent infection is needed to protect HIV-infected individuals against tuberculosis. A previous report addressed short-term efficacy of three regimens in HIV-infected adults. We now report on long-term efficacy of the study regimens.. Three daily self-administered regimens were compared in a randomized placebo-controlled trial in 2736 purified protein derivative (PPD)-positive and anergic HIV-infected adults. PPD-positive subjects were treated with isoniazid (INH) for 6 months (6H), INH plus rifampicin for 3 months (3HR), INH plus rifampicin and pyrazinamide for 3 months (3HRZ), or placebo for 6 months. Anergic subjects were randomized to 6H or placebo.. 6H initially protected against tuberculosis in PPD-positive individuals; however, benefit was lost within the first year of treatment. Sustained benefit was observed in persons receiving 3HR and 3HRZ. In a Cox regression analysis, the adjusted relative risk for tuberculosis compared with placebo was 0.67 [95% confidence interval (CI), 0.42-1.07] for 6H, 0.49 (95% CI, 0.29-0.82) for 3HR, and 0.41 (95% CI, 0.22-0.76) for 3HRZ. When the rifampicin-containing regimens were combined, the adjusted relative risk for tuberculosis compared with placebo was 0.46 (95% CI, 0.29-0.71). Among anergic subjects, a modest degree of protection with 6H was present (adjusted relative risk, 0.61; 95% CI, 0.32-1.16). Treatment of latent tuberculosis infection had no effect on mortality.. Six months of INH provided short-term protection against tuberculosis in PPD-positive HIV-infected adults. Three month regimens including INH plus rifampicin or INH, rifampicin and pyrazinamide provided sustained protection for up to 3 years.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Therapy, Combination; Female; HIV Infections; Humans; Incidence; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculin Test; Tuberculosis, Pulmonary

Clinical trial amongst 762 patients with newly diagnosed pulmonary tuberculosis in Hong Kong. After an initial 2 months of a four-drug intensive phase consisting of streptomycin, isoniazid, rifampicin and pyrazinamide (SHRZ), a random allocation in continuation to once-weekly rifapentine + isoniazid (HRp1), HRp1 given in 2 of every 3 weeks (HRp1.2/3), or to three times weekly isoniazid + rifampicin (HR3).. Interim report evaluating progress of study and the role of isoniazid in the continuation phase.. Kaplan-Meier analysis and response of patients related to susceptibility of pretreatment organisms to isoniazid and to rate of isoniazid acetylation determined by NAT2 genotyping.. In the 30-month follow-up, rates for adverse treatment events (failure and relapse) were 4.2% in the HR3, 10.2% in the HRp1 and 11.2% in the HRp1.2/3 series (P = 0.02 for HR3 vs HRp1 and P = 0.01 for HR3 vs HRp1.2/3). Occurrence of adverse events was not related to initial susceptibility to isoniazid nor to the rate of acetylation of isoniazid.. The two rifapentine regimens had similar final rates of adverse events which were unsatisfactory. Isoniazid had little or no activity in the continuation phase, indicating that no improvement of the continuation regimen is likely to be obtained by alteration of the isoniazid dosage.

Topics: Acetylation; Antitubercular Agents; Arylamine N-Acetyltransferase; Drug Therapy, Combination; Genotype; Hong Kong; Humans; Isoniazid; Polymorphism, Restriction Fragment Length; Rifampin; Tuberculosis, Pulmonary

Treating childhood tuberculosis places a large burden on health services, and ways of lessening this were sought.. A randomized controlled trial was conducted to determine the effectiveness of fully intermittent twice weekly treatment for intrathoracic childhood tuberculosis and its effect on adherence to treatment, in comparison with daily (weekday) treatment. The setting was a district of Cape Town, South Africa, an area of high incident tuberculosis. We randomized 206 children with confirmed (4%), probable (94%) and suspected (2%) intrathoracic tuberculosis: 89 (median age, 25 months) received intermittent treatment; and 117 (median age, 28 months) received daily treatment. Intermittent treatment (twice weekly for 6 months) was isoniazid 15 mg/kg/dose, rifampin 15 mg/kg/dose and pyrazinamide 55 mg/kg/dose for 2 months, followed by isoniazid and rifampin only for 4 months. Daily treatment was isoniazid 10 mg/kg/day, rifampin 10 mg/kg/day and pyrazinamide 25 mg/kg/day on weekdays for 6 months.. At 6 months 97% of subjects were discharged, with treatment outcomes in the two groups equivalent at that time (P = 0.90) and at the 18- to 30-month follow-up. One relapse occurred in the twice weekly group (P = 0.25). Adherence was equivalent; 70 children (79%) on intermittent and 90 (77%) on daily treatment took 75% or more of the prescribed doses (P = 0.90). Nonadherence over the full course of therapy was significantly associated with nonadherence during the first month of treatment (P = 0.0002) and household crowding (P = 0.002).. Six month fully intermittent antituberculosis treatment is an effective and acceptable alternative to daily treatment.

Topics: Antitubercular Agents; Child, Preschool; Drug Administration Schedule; Female; Humans; Infant; Isoniazid; Male; Patient Compliance; Pyrazinamide; Rifampin; South Africa; Treatment Outcome; Tuberculosis, Pulmonary

The early bactericidal activities (EBAs) of 300 mg isoniazid, 18.5 mg isoniazid, 600 mg rifampicin and 800 mg ofloxacin given daily to 262 patients with newly diagnosed pulmonary tuberculosis in Cape Town, Nairobi, Madras and Hong Kong were measured by counting cfu and total acid-fast bacilli in sputum collections taken pre-treatment (S1), at 2 days (S3) and at 5 days (S6). In Cape Town, Nairobi and Madras, the cfu findings suggested that isoniazid produced a massive kill, perhaps of actively growing organisms, during the first 2 days (mean S1-S3 EBAs of 0.636-1.006) but was almost inactive thereafter (mean S3-S6 EBAs of 0.000-0.081), whereas rifampicin maintained moderate activity against slowly growing organisms throughout the 5 days (mean S3-S6 EBAs of 0.242-0.305). This finding suggests that EBAs measured during the 2-5 day interval might be able to assess the sterilizing activity of drugs. Ofloxacin had moderately high mean S1-S3 EBAs of 0.130-0.391. However, in Hong Kong rifampicin appeared to be the most bactericidal drug from the start, possibly because patients had more chronic disease. A method of adjusting the cfu EBAs using total counts was devised which decreased the variability between patients within a treatment group without altering the mean cfu EBA. This resulted in a large gain in precision in Hong Kong, suggesting that their estimates were greatly affected by type II variation, due to dilution of pus by saliva and bronchial secretions, whereas small or no gains were obtained in the other three centres, suggesting that the main cause of variability was type I, due to other factors.

Topics: Adult; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Hong Kong; Humans; India; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Ofloxacin; Rifampin; South Africa; Sputum; Tuberculosis, Pulmonary

Over a 3 year period 3rd of April 1995 and 6th of April 1998 a controlled clinical trial of the modified short-course chemotherapy (SSC) in newly diagnosed cases of pulmonary tuberculosis in Nigeria was carried out. Between The SCC used was the one adopted from World Health Organisation/International Union Against Tuberculosis and Lung Diseases for developing countries by the Nigerian National Tuberculosis and Leprosy Control Programme (NTLCP). The regimen used consisted of streptomycin (S), isoniazid (H), Rifampicin (R) and pyrazinamide (Z) in the initial or intensive phase of 2 months. Ethambutol (E) was sometimes substituted for streptomycin. The continuation phase was 6 months of thiacetazone, (T) and isoniazid (H), i.e., 2SHRZ/6TH or 2EHRZ/6TH. Sputum conversion was 90% at the second month of treatment and there was no bacteriological relapse after 18 months of follow-up. Side effects were few and consisted mainly of acne vulgaris which occurred in twenty (20.6%) of 97 patients during the continuation phase. It is concluded that the 8-month chemotherapy regimen adopted by NTLCP is efficacious in treatment of smearpositive pulmonary tuberculosis (PTB).

Topics: Adolescent; Adult; Antitubercular Agents; Developing Countries; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Male; Middle Aged; Nigeria; Pyrazinamide; Rifampin; Sputum; Streptomycin; Thioacetazone; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary; Urban Health; World Health Organization

Rifampin is the cornerstone of short-course chemotherapy for the treatment of tuberculosis (TB). Rifampin monoresistance (RMR) is less common than resistance to isoniazid alone or in combination with other antituberculous medications. We conducted a retrospective case-control study to identify risk factors for RMR-TB. Complete records for 21 of a total of 26 RMR patients from 1990 to 1997 were available for review, and were compared with those of 48 patients with drug-susceptible TB, controlling for year of diagnosis. Cases more frequently had a history of TB than did controls (61% versus 22%, p < 0.01), and were more often human immunodeficiency virus (HIV) positive (81% versus 46%, p = 0.02). With control for HIV status, cases were more likely to have extrapulmonary involvement (47.6% versus 11.6%, p = 0.05). Four cases (19%) and one control (2. 1%) died (p = 0.02) during hospitalization. Cases more often had a history of incarceration (71.4% versus 37.5%, p = 0.09). Among the 13 cases with a history of TB, five had evidence of malabsorption (vomiting and/or diarrhea), versus none of the 11 controls with prior TB. These data support the hypothesis that RMR is seen primarily in individuals with a history of TB and who are HIV positive. Cases were frequently noncompliant with previous treatment for TB, had a history of incarceration, and had poor outcomes.

Topics: Adult; Aged; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Case-Control Studies; CD4 Lymphocyte Count; Drug Resistance, Microbial; Female; Follow-Up Studies; HIV; HIV Seropositivity; Humans; Length of Stay; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Risk Factors; Treatment Outcome; Tuberculosis, Pulmonary

Singapore Tuberculosis Service.. To assess the acceptability, efficacy and relapse rate of a combined formulation of three drugs--isoniazid, rifampicin and pyrazinamide (Rifater)--given in the initial phase of chemotherapy in three 6-month regimens (2SHRZ/4H3R3, 1SHRZ/5H3R3 and 2HRZ/4H3R3) under direct observation for all patients.. A randomised, controlled, unblinded study comparing a group of patients treated with Rifater and another given the three component drugs as separate formulations.. The 310 patients admitted to the study were divided into two groups of 155 patients. The frequency of side effects was similar in both groups. Of 271 patients with drug-sensitive strains who had completed treatment without interruption, sputum cultures converted in all patients. At the end of 5 years, there were 15 relapses: three (2.2%) in the separate drugs group and 12 (9.3%) in the Rifater group. Exclusion of two cases in the Rifater group, one with silicotuberculosis and another with no bacteriological confirmation of diagnosis, gave a relapse rate of 7.9% (P = 0.03 for the comparison of relapse rates in the two groups).. A combined formulation of three drugs given daily in the initial phase of 6-month short-course therapy, followed by intermittent treatment with isoniazid and rifampicin given three times a week under direct observation for all patients, appears to be less effective than treatment with the component drugs given as separate formulations.

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Combinations; Follow-Up Studies; Humans; Isoniazid; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Rifapentine is a cyclopentyl-substituted rifamycin whose serum half-life is five times that of rifampin. The US Public Health Service Study 22 compared a once-weekly regimen of isoniazid and rifapentine with twice weekly isoniazid and rifampin in the continuation phase (the last 4 months) of treatment for pulmonary tuberculosis in HIV-seropositive and HIV-seronegative patients. This report concerns only the HIV-seropositive part of the trial, which has ended. The HIV-seronegative part will stop follow-up in 2001.. Adults with culture-positive, drug-susceptible pulmonary tuberculosis who completed 2 months of four-drug (isoniazid, rifampin, pyrazinamide, ethambutol) treatment (induction phase) were randomly assigned 900 mg isoniazid and 600 mg rifapentine once weekly, or 900 mg isoniazid and 600 mg rifampin twice weekly. All therapy was directly observed. Statistical analysis used univariate, Kaplan-Meier, and logistic and proportional hazards regression methods.. 71 HIV-seropositive patients were enrolled: 61 completed therapy and were assessed for relapse. Five of 30 patients in the once-weekly isoniazid/rifapentine group relapsed, compared with three of 31 patients in the twice-weekly isoniazid/rifampin group (log rank chi2=0.69, p=0.41). However, four of five relapses in the once-weekly isoniazid/rifapentine group had monoresistance to rifamycin, compared with none of three in the rifampin group (p=0.05). Patients who relapsed with rifamycin monoresistance were younger (median age 29 vs 41 years), had lower baseline CD4 cell counts (median 16 vs 144 microL), and were more likely to have extrapulmonary involvement (75% vs 18%, p=0.03) and concomitant therapy with antifungal agents (75% vs 9%, p=0.006). No rifamycin monoresistant relapse has occurred among 1004 HIV-seronegative patients enrolled to date.. Relapse with rifamycin monoresistant tuberculosis occurred among HIV-seropositive tuberculosis patients treated with a once-weekly isoniazid/rifapentine continuation-phase regimen. Until more effective regimens have been identified and assessed in clinical trials, HIV-seropositive people with tuberculosis should not be treated with a once-weekly isoniazid/rifapentine regimen.

Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Recurrence; Rifampin; Time Factors; Tuberculosis, Pulmonary

Two small, placebo-controlled studies of immunotherapy with heat killed Mycobacterium vaccae added to routine chemotherapy for pulmonary tuberculosis, together involving 40 HIV seronegative patients, were carried out in Argentina. The immunotherapy was associated with reduced sputum smear positivity of AFB at 1 month and a greater reduction in ESR at 2 months. In the first study radiological improvement was better (P < 0.05) among immunotherapy recipients. In the second study, weight regain and time to become apyrexial were measured and were found to be improved amongst immunotherapy recipients (P < 0.05). In the first month of treatment the levels of IgG to the 65 kDa and 70 kDa heat-shock proteins showed greater falls following immunotherapy (P < 0.05 and P < 0.001, respectively). On admission serum cytokine levels of interleukins 4 and 10 (IL-4, IL-10), interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) were grossly raised in comparison with a matched control group (P < 0.001). After 1 month. Levels of IL-4, IL-10 and TNF-alpha fell (P < 0.001, P < 0.01 and P < 0.01, respectively) and levels of IFN-gamma rose more (P = 0.005) in immunotherapy recipients than in those receiving chemotherapy alone. The results are in accord with a switch towards a TH1 immunological status and clinical benefit for immunotherapy recipients.

Topics: Adjuvants, Immunologic; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Argentina; BCG Vaccine; Drug Therapy, Combination; Female; Humans; Immunotherapy; Isoniazid; Male; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Tuberculosis is a common complication of HIV-1 infection, especially in developing countries. Practical and effective chemoprophylaxis regimens for HIV-1-related tuberculosis are needed. Our aim was to test the efficacy of isoniazid versus rifampicin with pyrazinamide for prevention of tuberculosis in HIV-1-positive individuals.. We compared the efficacy of 6 months of isoniazid with 2 months of rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1-seropositive individuals. Eligible participants were aged 16-77 years, HIV-1 seropositive, had a positive purified-protein derivative (PPD) skin test reaction of at least 5 mm, and had a normal chest radiograph. Participants were randomly assigned partially supervised twice weekly isoniazid for 24 weeks or twice weekly rifampicin and pyrazinamide for 8 weeks. Participants were followed up for up to 4 years for the development of tuberculosis and survival.. Tuberculosis developed in 14 (3.8%) of 370 participants assigned isoniazid and 19 (5.0%) of 380 participants assigned rifampicin and pyrazinamide (Cox model rate ratio 1.3 [95% CI 0.7-2.7]). The Kaplan-Meier estimate of the risk of tuberculosis during the first 10 months after entry was 3.7% among participants who received rifampicin and pyrazinamide compared with 1.0% (p=0.03) among participants who received isoniazid, and 5.4% versus 5.1%, respectively (p=0.9) at 36 months after entry. Higher rates of tuberculosis were observed in people with baseline CD4 percentages (of total lymphocytes) of less than 20 (rate ratio 4.0 [95% CI 1.8-9.0]). There were no significant differences in total mortality at any time.. Twice-weekly isoniazid preventive therapy for 6 months or rifampicin and pyrazinamide for 2 months provided similar overall protection against tuberculosis in HIV-1-infected, PPD-positive adults. The better protection among recipients of isoniazid during the first 10 months was most likely secondary to the longer duration of chemoprophylaxis. Preventive therapy for HIV-1-seropositive, PPD-positive individuals could be practical in developing countries with a once weekly clinic visit, but optimum duration of chemoprophylaxis has not been determined.

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Administration Schedule; Female; Follow-Up Studies; HIV Infections; HIV-1; Humans; Isoniazid; Male; Prospective Studies; Pyrazinamide; Rifampin; Time Factors; Tuberculosis, Pulmonary

This study examined whether adding levofloxacin to a standard four-drug regimen improved the 8-week culture response and compared effectiveness of 9 versus 6 months of intermittent therapy for human immunodeficiency virus-related pansusceptible pulmonary tuberculosis. Patients were randomized to receive either four or five drugs, the fifth being levofloxacin. Patients who completed induction therapy were randomized to complete 9 versus 6 months of intermittent therapy with isoniazid and rifampin. In the randomized induction phase, 97.3% of patients in the four-drug group and 95.8% in the five-drug group had sputum culture conversion at 8 weeks (P = 1.00). In the continuation phase, one patient (2%) assigned to 9 months and two patients (3.9%) assigned to 6 months of therapy had treatment failure/relapse (P = 1.00). In conclusion, this study showed that levofloxacin added no benefit to a highly effective, largely intermittent, four-drug induction regimen. Both 9 and 6 months of intermittent therapy were associated with low treatment failure/relapse rates.

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Levofloxacin; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Ofloxacin; Pyrazinamide; Recurrence; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

A randomized comparison has been made of three times weekly rifampin plus isoniazid (HR3) with rifapentine plus isoniazid given once weekly (HRp1) or on 2 of 3 wk (HRp1.2/3) in the continuation phase of 6-mo regimens (each starting with an initial 2 mo of 4-drug therapy) for the treatment of pulmonary tuberculosis in 672 Chinese patients in Hong Kong. Because of poor bioavailability of the rifapentine used (produced in China), its dose size was increased from 600 mg initially to about 750 mg in the last third of patients to obtain serum concentrations similar to those with rifapentine of Western origin; all doses were given after a meal promoting absorption. After initial exclusions, an intent to treat analysis, done on the remaining 592 patients, showed 45 adverse treatment events in 7 of 190 HR3 patients, in 17 of 199 HRp1 patients, and in 21 of 203 HRp1.2/3 patients; of these, 42 were bacteriological or radiographic relapses after the end of treatment (HR3 versus HRp1, p = 0.04; HR3 versus HRp1.2/3, p = 0.01). Patients with organisms initially sensitive or resistant to isoniazid or streptomycin had similar relapse rates. The high relapse rate in the HRp1 regimen suggests that the rifapentine dose should be increased. Similarity of relapse rates, 8.9% and 10.4%, after the HRp1 and HRp1.2/3 regimens, respectively, indicates that irregularity in taking rifapentine/isoniazid could be tolerated. The few adverse side effects in the continuation phase in the rifapentine regimens were less frequent than in the HR3 regimen.

Topics: Adolescent; Adult; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis, Pulmonary

To investigate the effects of rifampicin on the pharmacokinetics of itraconazole in humans.. Our study was conducted with six healthy normal volunteers and three AIDS patients. All subjects received a 200 mg single dose of oral itraconazole on day 1 and day 15 and 600 mg of oral rifampicin once daily from day 2 to day 15. Itraconazole pharmacokinetics studies were carried out on day 1 (phase 1) and day 15 (phase 2). The limit of detection for itraconazole concentration was 16 ng x ml(-1).. Concentrations itraconazole were higher when it was administered alone than when it was administered with rifampicin. Coadministration of rifampicin resulted in undetectable levels of itraconazole in all subjects except one normal volunteer. The mean AUC0-24 was 3.28 vs 0.39 microg x h x ml(-1) in phase 1 and 2, respectively, in healthy normal volunteers. Therefore, the estimated minimum decrease of the mean AUC0-24 of itraconazole in phase 2 was approximately 88% compared with phase 1. The mean AUC0-24 was 1.07 vs 0.38 microg x h x ml(-1) in phase 1 and 2, respectively, in AIDS patients. Therefore, the estimated minimum decrease of the mean AUC0-24 of itraconazole in phase 2 was approximately 64% compared with phase 1.. Rifampicin has a very strong inducing effect on the metabolism of itraconazole, so that these two drugs should not be administered concomitantly.

Topics: Adult; AIDS-Related Opportunistic Infections; Antifungal Agents; Antitubercular Agents; Drug Interactions; Female; Humans; Itraconazole; Male; Middle Aged; Reference Values; Rifampin; Tuberculosis, Pulmonary

A randomized double-blind placebo-controlled trial was conducted to estimate the efficacy of preventive therapy for tuberculosis (TB) in HIV-infected adults in Lusaka, Zambia. The main outcome measures were the incidence of TB, mortality and adverse drug reactions.. During a 2 year period, 1053 HIV-positive individuals without evidence of clinical TB were randomly assigned to receive 6 months of isoniazid twice a week (H), or 3 months of rifampicin twice a week (R) plus pyrazinamide (Z), or a placebo. Therapy was taken twice a week and was self administered. Subjects presenting with symptoms during the follow-up period were investigated for TB.. The 1053 subjects in the study were followed up for a total of 1631 person-years (median = 1.8 years). Twenty-nine subjects were taken off treatment as a result of adverse drug reactions. A total of 96 cases of TB/probable TB (59 TB and 37 probable TB) were diagnosed during the study period and 185 deaths were reported. One hundred and fifteen subjects (11%) did not return to the study clinic at any time after enrolment. The incidence of TB was lower in those subjects on preventive therapy (H and RZ groups combined) compared with those on placebo (rate ratio = 0.60, 95% CI: 0.36-1.01, P = 0.057), as was the incidence of TB/probable TB (rate ratio = 0.60, 95% CI: 0.40-0.89, P = 0.013). The effect of preventive therapy was greater in those with a tuberculin skin test (TST) of 5 mm or greater, in those with a lymphocyte count of 2x10(9)/l or higher, and in those with haemoglobin of 10 g/dl or higher. There was no difference in mortality rates between the preventive therapy and placebo groups. The effect of preventive therapy declined after the first year of the study so that by 18 months the rates of TB in the treated groups were similar to that in the placebo group.. This study has demonstrated that preventive therapy with either twice weekly isoniazid for 6 months or a combination of rifampicin and pyrazinamide for 3 months reduced the incidence of TB in HIV-infected persons in Zambia. No effect was observed on mortality. The effect was greatest in persons who had a positive TST or a lymphocyte count of 2x10(9)/l or greater, indicating that preventive therapy may be more effective in people with less advanced immunosuppression. The limited duration of the protective effect reported in this study raises the question of the need for lifelong preventive therapy or re-prophylaxis.

Topics: Adult; AIDS-Related Opportunistic Infections; Antibiotic Prophylaxis; Antibiotics, Antitubercular; Antitubercular Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Incidence; Isoniazid; Male; Patient Compliance; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculin Test; Tuberculosis, Pulmonary; Zambia

To assess the therapeutic efficacy of rifapentine (L), to reduce the duration of treatment and the frequency of drug administration, and to observe the influence on efficacy and adverse reactions of using pyrazinamide (Z) through whole-course.. Two 5-month regimens respectively including rifampin (R) and L and two whole course intermittent regimens were designed as following: I: 2SHRZ/3R2H2Z2; II: 2SHRZ/3L1H2Z2; III: 2S3H3R3Z3/4L1H2Z2; IV: 2S3H3R3Z3/4L1H2E2. A total of 366 newly-diagnosed bacillary pulmonary tuberculosis patients were admitted and randomly allocated.. 339 cases completed the prescribed short course chemotherapy. The sputum conversion rates at the end of the treatment of groups I, II, III and IV were 97.0%, 94.1%, 100.0% and 97.2% respectively. X-ray resolution rates were 96.0%, 97.6%, 100.0% and 94.4% respectively. Cavity-close rates of the 5-month regimens and the 6-month regimens were 77% and 76%. Comparing the results among groups, there were no statistically significant differences (P > 0.05), and no obvious side-effect was found. 305 patients have been followed up for 3 years since completion of the chemotherapy. The bacteriological relapse and bacteriological relapse with deterioration on chest X-ray in groups I, II, III and IV were seen in 2,3,6 and 3 cases respectively.. Domestic-made rifapentine is a long-acting, highly effective antituberculosis drug. It is unnecessary to use Z in continuation phase, and it is possible to shorten the duration to 5 months with the appropriate combination of essential drugs, which is worthwhile for further study.

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Humans; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Sputum; Tuberculosis, Pulmonary

To assess antituberculous efficacy, patients' compliance and application perspective of fixed-dose compounds rifater/rifinah in China.. Three hundred eight new smear positive pulmonary tuberculosis patients were randomly allocated with a ratio of 2 to 1 into treatment group (227 cases, receiving 2RIFATER/4RIFINAH regimen) and controls (81 cases, 2HRZ/4HR) for observation.. The sputum negative conversion rates at the 2nd month in the treatment group and the controls were 91.2% and 86.4% respectively, and at the end of the chemotherapy 98.7% and 97.5%. Chest radiography showed remarkable improvement. The resolution of pulmonary lesions in the treatment group and the controls accounted for 95.2% and 93.8% respectively, with cavity closure rates of 68.6% in the treatment group and 67.9% in the controls. The drug adverse reaction rates were 8.9% in both groups, and the default rates were 4.3% and 7.8% respectively.. Fixed-dose compounds rifater/rifinah show excellent therapeutic efficacy, safety and compliance in antituberculous chemotherapy, which could be recommended for wider use in tuberculosis control in China.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Infection with the human immunodeficiency virus (HIV) greatly increases the risk of reactivation tuberculosis. We evaluated the safety and efficacy of three preventive-therapy regimens in a setting where exposure to tuberculosis is common.. We performed a randomized, placebo-controlled trial in 2736 HIV-infected adults recruited in Kampala, Uganda. Subjects with positive tuberculin skin tests (induration, > or =5 mm) with purified protein derivative (PPD) were randomly assigned to one of four regimens: placebo (464 subjects), isoniazid daily for six months (536), isoniazid and rifampin daily for three months (556), or isoniazid, rifampin, and pyrazinamide daily for three months (462). Subjects with anergy (0 mm induration in reaction to PPD and candida antigens) were randomly assigned to receive either placebo (323 subjects) or six months of isoniazid (395). The medications were dispensed monthly and were self-administered.. Among the PPD-positive subjects, the incidence of tuberculosis in the three groups that received preventive therapy was lower than the rate in the placebo group (P=0.002 by the log-rank test). The relative risk of tuberculosis with isoniazid alone, as compared with placebo, was 0.33 (95 percent confidence interval, 0.14 to 0.77); with isoniazid and rifampin, 0.40 (0.18 to 0.86); and with isoniazid, rifampin, and pyrazinamide, 0.51 (0.24 to 1.08). Among the subjects with anergy, the relative risk of tuberculosis was 0.83 (95 percent confidence interval, 0.34 to 2.04) with isoniazid as compared with placebo. Side effects were more common with the multidrug regimens, and particularly with the regimen containing pyrazinamide. Survival did not differ among the groups, but the subjects with anergy had a higher mortality rate than the PPD-positive subjects.. A six-month course of isoniazid confers short-term protection against tuberculosis among PPD-positive, HIV-infected adults. Multidrug regimens with isoniazid and rifampin taken for three months also reduce the risk of tuberculosis.

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Risk; Treatment Outcome; Tuberculin Test; Tuberculosis, Pulmonary

Prospective randomised clinical trial comparing the safety and efficacy of rifampicin- and thiacetazone-containing regimens in human immunodeficiency virus (HIV)-infected adults with pulmonary tuberculosis (TB) at the National Tuberculosis Treatment Centre, Kampala, Uganda.. To assess demographic, clinical and laboratory risk factors associated with toxicity during treatment with streptomycin, thiacetazone and isoniazid (STH) of HIV-1 infected adults with pulmonary TB.. Nested case-control study of all subjects randomized to the STH treatment arm. Baseline demographic, clinical, microbiological, hematological and radiographic characteristics were compared between subjects who developed and those who did not develop adverse drug reactions (ADR).. Of the 90 subjects randomized to STH, 13 developed ADR yielding an incidence rate of 19.6 events per 100 person years of observation (PYO). Eleven of the 13 ADR were cutaneous hypersensitivity reactions, including one fatal case of Stevens-Johnson syndrome. Eight of 13 patients who developed ADR were tuberculin anergic, compared to 12 of 77 patients who did not develop ADR (P < 0.001). An absolute lymphocyte count below 2000 cells/mm3 was also associated with ADR (P = 0.02).. Initial anergy to tuberculin and lymphocytopenia, markers of advanced HIV infection and immunosuppression, were associated with increased risk for adverse drug reactions during STH chemotherapy.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Case-Control Studies; Clonal Anergy; Confidence Intervals; Developing Countries; Drug Eruptions; Drug Therapy, Combination; Female; HIV-1; Humans; Incidence; Jaundice; Lymphopenia; Male; Middle Aged; Odds Ratio; Prospective Studies; Rifampin; Risk Factors; Stevens-Johnson Syndrome; Survival Rate; Thioacetazone; Tuberculosis, Pulmonary; Uganda

A study conducted by the Uganda-Case Western Reserve University Research Collaboration in Kampala, Uganda, a country with high incidence rates of tuberculosis (TB) and human immunodeficiency virus type 1 (HIV-1) infection.. To assess clinical, microbiologic and radiographic factors associated with risk for relapse in HIV-infected adults treated for initial episodes of pulmonary TB.. Nested case-control study within a randomized prospective clinical trial comparing the safety and efficacy of thiacetazone- and rifampicin-containing regimens for TB treatment in HIV-infected adults.. The analysis was based on 119 patients who completed therapy. Median follow-up for all subjects was 22.3 months. Ten patients relapsed a median of 12.7 months after the end of therapy; seven of these were initially treated with the thiacetazone (T)-containing regimen. Each relapse case was matched to four controls by length of follow-up after initial TB treatment. In a univariate analysis risk for relapse was associated with treatment with the T-containing regimen (OR = 4.2, P = 0.08), age > or = 30 yrs (OR = 2.9, P = 0.16), and irregular compliance (OR = 3.6, P = 0.1). Baseline anergy on Mantoux tuberculin skin testing, cavitary disease, radiographic extent of disease and sputum bacillary burden, two month culture negativity, and residual cavitary disease at the end of treatment did not differ between relapses and controls.. Older HIV-1 infected patients, those with poor treatment compliance, and those being treated with T-containing regimens, may be at increased risk for relapse after TB treatment and require closer post-treatment surveillance. Risk for relapse in HIV-infected adults with pulmonary TB after treatment with a nine month rifampicin-containing regimen was low (3.1 per 100 person-years observation) compared with those treated with a thiacetazone-containing regimen (10.1 per 100 person-years observation).

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Case-Control Studies; Developing Countries; Drug Therapy, Combination; Female; Follow-Up Studies; HIV-1; Humans; Logistic Models; Lung; Male; Middle Aged; Patient Compliance; Prospective Studies; Radiography; Recurrence; Rifampin; Risk Factors; Sputum; Survival Rate; Thioacetazone; Tuberculosis, Pulmonary; Uganda

To describe the clinical response to antituberculosis therapy in HIV-1 disease, 49 HIV-1 positive Ugandan adults (mean age 29.4 years; 68% men) with active pulmonary tuberculosis (PTB) were studied in a trial of rifampicin containing short-course antituberculosisis regimens. At presentation, 18 patients were PPD non-reactors (PPD skin test induration < 2mm), ten patients (20%) had non-cavitary lung disease. The mean CD4 lymphocyte count at presentation was 339/microliters (+/- SD 275). Among patients with abnormal baseline clinical values, the median time to resolution of fever, weight gain of 10%, increase of haemoglobin to 10g/dl and of Karnofsky performance score (KPS) to 80 occurred before sputum smear and culture conversion. Short-term survival was associated with: baseline lymphocytes < 1200/microliters, (Odds ratio (OR) 17.5), CD4+ lymphocytes < 200/microliters (OR 9.8), cavitary lung disease, (OR 0.6), atypical chest radiograph, (OR 6.7), and PPD non-reactivity, (OR 13.5), PPD non-reactivity and non-cavitary disease were associated with significantly lower CD4 lymphocyte counts. Affordable serial measurements parallel the response to therapy and predict survival in HIV-associated PTB.. Tuberculosis (TB) is the most often seen and serious opportunistic infection in HIV-1-infected individuals in developing countries. Infection with HIV-1 predisposes individuals to TB, both progressive primary and reactivation disease. To describe the clinical response to anti-TB therapy in HIV-1 disease, 49 HIV-1-positive Ugandan adults of mean age 29.4 years with active pulmonary TB (PTB) were studied in a trial of rifampicin containing short-course anti-TB regimens. At presentation, 18 patients were PPD skin test nonreactive, and 39 had cavitary lung disease. The mean CD4 lymphocyte count at presentation was 339/mcl. Among patients with abnormal baseline clinical values, the median time to resolution of fever, weight gain of 10%, increase of hemoglobin to 10 g/dl, and Karnofsky performance score (KPS) to 80 occurred before sputum smear and culture conversion. Short-term survival was associated with baseline lymphocytes of less than 1200/mcl, cavitary lung disease, atypical chest radiograph, and PPD nonreactivity. PPD nonreactivity and noncavitary disease were associated with significantly lower CD4 lymphocyte counts. Study findings demonstrate that the careful monitoring of clinical symptoms and simple, inexpensive, and widely available laboratory markers permit the satisfactory evaluation of early clinical response to anti-TB therapy in HIV-1-infected patients with pulmonary TB.

Topics: Adult; Aged; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; CD4 Lymphocyte Count; Disease Progression; Female; HIV Seropositivity; HIV-1; Humans; Male; Middle Aged; Predictive Value of Tests; Radiography; Rifampin; Survival Analysis; Tuberculin Test; Tuberculosis, Pulmonary; Uganda

The Tuberculosis Research Centre, Chennai, and its unit at Madurai, South India.. To design oral short-course regimens for the treatment of sputum-positive pulmonary tuberculosis that could be more easily implemented under field conditions.. A total of 1203 patients was randomly allocated to one of three regimens. I (2EHRZ7/6EH7): 8-month daily regimen of ethambutol (E), isoniazid (H), rifampicin (R) and pyrazinamide (Z) for 2 months, followed by E and H for 6 months. II (2EHRZ2/4EHR2): 6-month twice-weekly regimen with the same four drugs for 2 months, followed by EHR for 4 months. III (2HRZ2/4HR2): similar to Reg. II, but without ethambutol. In Reg. I, drugs were given completely unsupervised. Regs. II and III were either completely or partially supervised.. Drug-susceptible group: At the end of treatment, 3.6% of 305 patients in Reg. I, 0.4% of 263 in Reg. II and 9.3% of 257 in Reg. III had an unfavourable bacteriological response. By 24 months after start of treatment, 5% of 290 in Reg. I, 11% of 258 in Reg. II and 10% of 229 in Reg. III had a bacteriological relapse requiring treatment. Giving the twice-weekly regimens partly unsupervised did not influence the response to treatment, emergence of drug resistance or relapse rates. Isoniazid resistant group: Unfavourable response and relapse with Reg. I (94 patients) was 17% and 8%, with Reg. II (59 patients) 20% and 25%, and with Reg. III (74 patients) 62% and 15%, respectively.. A fully unsupervised ethambutol-containing regimen given daily for 8 months (Reg. I) was found to be very effective even in the presence of isoniazid-resistant bacilli. With the ethambutol-containing twice-weekly regimen, the response at the end of treatment was near 100%, but the relapse rate was high (11%). The non-ethambutol twice-weekly regimen was not satisfactory. All three regimens failed in the presence of bacilli resistant to rifampicin and isoniazid.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antitubercular Agents; Child; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Sputum; Tuberculosis, Pulmonary

Although endobronchial tuberculosis frequently causes bronchial stenosis, there are no specific therapies to prevent the sequelae. The use of corticosteroids remains controversial and there have been no prospective comparative studies about the effectiveness of corticosteroids. This study was undertaken in order to determine the effectiveness of corticosteroids in the prevention of complications of endobronchial tuberculosis. Thirty-four patients with endobronchial tuberculosis who were admitted to Chung-Ang University hospital from March 1991 to December 1995 were evaluated prospectively to determine the effect of corticosteroid in the treatment of endobronchial tuberculosis. All patients were randomly divided into two groups: group 1 (n=17, anti-tuberculosis chemotherapy only) and group 2 (n=17, combining anti-tuberculosis chemotherapy with oral corticosteroid). Serial bronchoscopies, pulmonary function tests and chest roentgenograms were analyzed every 2 months until the complete resolution of endobronchial tuberculosis. Before treatment commenced there were no significant differences between the two groups with respect to sex, mean age, pulmonary function, chest roentgenogram and morphologic patterns of endobronchial lesion. After treatment, the healing rate of bronchoscopic findings and changes in pulmonary function showed no significant differences between the two groups. Radiologic improvements were observed in all eight patients (five in group 1 and three in group 2) with segmental atelectasis on chest roentgenograms after 2 months of treatment. This study suggests that corticosteroid therapy would not influence the outcome of endobronchial tuberculosis and that prompt treatment with early diagnosis, before formation of fibrosis would be necessary to prevent complications of endobronchial tuberculosis, such as bronchostenosis.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Bronchoscopy; Chi-Square Distribution; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Glucocorticoids; Humans; Isoniazid; Lung; Male; Middle Aged; Prednisolone; Prospective Studies; Pyrazinamide; Radiography; Respiratory Function Tests; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis, Pulmonary

To evaluate the long-term efficacy of full course intermittent short-course chemotherapy [2H3R3Z3S3(E3)/4H3R3], which has first been used in the National Tuberculosis Control Programme with the loan from the World Bank and its satisfactory short-term efficacy has been achieved, on new smear positive tuberculosis patients.. All new smear positive tuberculosis patients, registered by 56 counties of 12 project provinces and autonomous regions in 1992, were investigated to find out the bacteriological relapse rate 2 years after treatment.. One hundred thirty five out of 4400 patients followed up were found smear positive, with a relapse rate of 3.1%.. The result suggests that the chemotherapy should be given a priority in the National Tuberculosis Control Programme because of its high cure rate.

Topics: Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Follow-Up Studies; Humans; Isoniazid; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary

The fluoroquinolones are promising new antituberculous agents. A randomized controlled trial of 200 adult patients with sputum smear-positive pulmonary tuberculosis was conducted in Tanzania. Patients received either a trial regimen (HRC) consisting of isoniazid (300 mg), rifampin (600 mg), and ciprofloxacin (750 mg) or a control regimen (HRZE) consisting of isoniazid (300 mg), rifampin (600 mg), pyrazinamide (25 mg/kg), and ethambutol (15 mg/kg). The 168 evaluable patients all had negative smears and cultures by month 6, but the time to conversion to negativity was longer for the HRC group than for the HRZE group because of the poor response of patients infected with human immunodeficiency virus (HIV) to the HRC regimen. Relapse was more frequent in the HRC group. The sterilizing activity of ciprofloxacin does not appear to be equal to that of the combination of pyrazinamide and ethambutol, but the difference in outcome was significant only among HIV-infected patients.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-Infective Agents; Antitubercular Agents; Ciprofloxacin; Ethambutol; Female; HIV-1; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Time Factors; Tuberculosis, Pulmonary

The aim of this study was to know the demographic profile of the new cases of tuberculosis (TB) and evaluate the current status of resistance to antituberculous drugs in Madrid, Spain.. A transversal study was carried out in 8 hospitals (6 general hospitals) during 6 months. The clinical data of patients over 14 years old who presented a positive culture for Mycobacterium tuberculosis were collected in a protocolized method; the study on sensitivity to 5 drugs was independently and centrally performed (proportions method).. 467 patients (339 from general hospitals), were included. In respect to the latter patients, 71% were under the age of 45 years and 36% presented coinfection with the human immunodeficiency virus (HIV). A sensitivity study was performed in 419 strains. Forty strains showed resistance to one or more of the antituberculous drugs; 13 were from the same center (CIC) in which a nosocomial outbreak of multiresistent TB had been detected among HIV infected patients. Resistence to more than one drug was observed in 29 cases (6.9%) and to rifampicine (RIF) and isoniacide (INH) in 24 patients (5.7%). On excluding the patients from the CIC these values were 16 (4.1%) and 13 (3.3%), respectively. Ninety-two percent of the strains with resistence to RIF + INH were from HIV positive patients. The rate of primary resistence to iNH in the patients with TB without HIV infection was 2.7%. This rate was 9.3% in those with HIV infection, and was 5.7% on excluding CIC cases. In patients with HIV infection most of the strains with primary resistence to INH also presented primary resistance to RIF.. More than one third of the patients with TB diagnosed in the general hospitals in Madrid, presented coinfection with HIV. In this population, the initial treatment for TB should probably begin with 4 drugs while awaiting the obliged sensitivity study.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Drug Resistance, Multiple; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Spain; Streptomycin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

To compare the pharmacokinetic parameters and the clinical efficacy of isoniazid, administered in 10 mg/kg or 5 mg/kg to children suffering from pulmonary tuberculosis.. A randomized, open, controlled clinical trial.. Teaching hospital in New Delhi.. Twenty children suffering from pulmonary tuberculosis in the age group 6-12 years.. A three drug antitubercular regimen comprising of rifampicin (10 mg/kg), pyrazinamide (30 mg/kg) and isoniazid in a dose of either 10 mg/kg (Group I) or 5 mg/kg (Group II) was administered for fourteen days. On day fifteen serial blood samples were collected at 0,1,2,3,6 and 24 h of isoniazid administration and analyzed spectrofluorometrically.. Serum isoniazid concentrations and clinical response in both the groups.. In both the groups, serum concentration of isoniazid were above the therapeutic range (0.5-2 micrograms/ml) at 6 h following drug administration. The minimum serum concentration of isoniazid was within or above minimum inhibitory concentration of the drug at 24 h in both the groups. The time to achieve maximum serum concentration, elimination half life, elimination rate constant, mean residence time, volume of distribution at steady state and plasma drug clearance were also comparable. At the end of 6 months follow up, all children showed comparable clinical and radiological improvement.. Isoniazid in a dose of 5 mg/kg administered with other antitubercular drugs appears adequate for treatment of pulmonary tuberculosis in children.

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Child; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

To evaluate a monthly 'pulse' of rifampicin plus pyrazinamide plus streptomycin in the continuation phase of a short-course antituberculosis regimen.. Randomised controlled trial of two 7-month chemotherapy regimens.. Inpatient chemotherapy and outpatient follow-up in Tanzania.. Smear-positive pulmonary tuberculosis.. All patients received streptomycin plus rifampicin plus isoniazid plus pyrazinamide daily for 6 weeks followed by isoniazid daily for 24 weeks; 50%, at random, received additional doses of rifampicin, pyrazinamide and streptomycin every 4 weeks in the continuation phase. Follow-up continued for 23 months after cessation of chemotherapy.. Bacteriological failure rate at the end of chemotherapy and relapse rate after stopping.. Of the 266 patients with fully sensitive strains before treatment there was one failure in each series during chemotherapy; after stopping, 5% of the 114 who received the supplement relapsed bacteriologically compared with 10% of the 113 who did not (95% CI for the difference -0.02% to + 11.3%). The results in the 37 patients with strains resistant to isoniazid pretreatment were not as good, but similar for the two regimens.. This study was not large enough to demonstrate a significant reduction in the relapse rate from 10% to 5%. If such a reduction were confirmed in a larger study it would represent an important improvement in efficacy. further, in an outpatient setting, the additional monthly doses might improve attendance.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Black People; Body Weight; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Isonicotinic Acids; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

Tuberculosis was diagnosed in 26 patients (6 females and 20 males) undergoing maintenance hemodialysis, with an incidence of 23.6%. Infection was characterized clinically by a very insidious onset, the main symptoms being anorexia, loss of weight and low-grade fever, a very high sedimentation rate and lymphocytes predominant in the peripheral circulation, pleural and peritoneal fluids. Pulmonary tuberculosis was seen in 18 patients (70%), 10 of whom presented with pleural effusions. There were extrapulmonary presentations in 8 of the 26 patients (30%). Most of the patients developed the disease about 1 year from the start of their dialysis treatment. With early therapy all patients survived their tuberculosis disease and no recurrence was seen in up to 5 years of follow-up. Despite earlier reports of high mortality, we suggest that awareness of the increased incidence of tuberculosis in dialysis patients, together with its unusual presentation and consequent early diagnosis, results in a very good prognosis.

Topics: Adult; Aged; Antibiotics, Antitubercular; Antitubercular Agents; Ethambutol; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Cavity; Prognosis; Radiography; Renal Dialysis; Rifampin; Tuberculosis, Pulmonary

To determine the frequency and magnitude of below normal apparent peak serum concentrations for antituberculosis drugs in patients with AIDS and CD4 cell counts less than 200 cells/mm3. We also explored the data for potential relationships between response variables and patient characteristics.. Prospective study of consecutive patients seen in tuberculosis clinics.. Five urban tuberculosis clinics in four major metropolitan areas.. Twenty-six patients diagnosed with HIV infection and receiving treatment for active tuberculosis were eligible.. After 2 weeks or more of therapy, blood was collected 2 hours after observed doses of the antituberculosis drugs. Serum samples were frozen, shipped to National Jewish Center in Denver, and analyzed by HPLC or GC. Serum concentrations were compared with the proposed normal ranges. Data were analyzed to determine correlations between antituberculosis drug serum concentrations and patient characteristics.. Low-2-hour serum concentrations were common for antituberculosis drugs, particularly rifampin and ethambutol. Absorption of isoniazid was generally high. Potential drug-drug interactions were found between rifampin and fluconazole (fluconazole appears to increase rifampin concentrations) and between pyrazinamide and zidovudine (zidovudine may lower pyrazinamide concentrations). Patients receiving pyrazinamide had lower rifampin concentrations than those not receiving pyrazinamide.. Low antituberculosis drug serum concentrations occur frequently during the treatment of tuberculosis in patients with AIDS. Additional research is required for patients with drug-resistant tuberculosis, and to clarify the nature of the potential drug-drug interactions.

Topics: Adult; Anti-HIV Agents; Antifungal Agents; Antitubercular Agents; Drug Interactions; Female; Fluconazole; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Zidovudine

The efficacy and safety of rifabutin (RBT) and rifampicin (RMP) were compared in 298 patients with newly diagnosed pulmonary tuberculosis. In the initial 8-wk phase, all patients received isoniazid 400 mg/d, ethambutol 1200 mg/d, and pyrazinamide 2 g/d and were randomly allocated to receive either RMP 600 mg/d or RBT 300 mg/d. In the 16-wk continuation phase, patients received intermittent treatment (twice weekly) with isoniazid 600 mg/d, ethambutol 2400 mg/d and either RMP 600 mg/d or RBT 300 mg/d. Two hundred twenty-five (RMP = 118; RBT = 107) patients completed the 24-wk treatment period (evaluable patient population). Bacteriologic conversion rates in the RMP and RBT groups were 87.7 versus 92.0% at Week 8, 99.1 versus 99.0% at Week 12, 93.5 versus 93.8% at Week 24, and 89.8 versus 95.3% at the last valid observation. The mean time to first bacteriologic conversion was 14.1 wk in the RMP group and 14.3 wk in the RBT group. None of these differences was significant. Adverse events were reported by four patients (five events) in the RMP group and six patients (six events) in the RBT group. Those events thought to be associated with RMP were increased SGOT and leucopenia and, with RBT, increased SGOT and thrombocytopenia. Two hundred four patients entered the follow-up phase, and, of these, 95 (RMP = 49; RBT = 46) completed the scheduled 24-mo period. The overall rate of relapse was 3.8% (4/106) for the RMP group and 5.1% (5/98) for the RBT group. These differences were not significant. All relapsed patients, except for two who could not be traced, were successfully retreated. We conclude that the efficacy and tolerability of RBT is equivalent to that of RMP in the treatment of newly diagnosed uncomplicated tuberculosis, and that RBT can be effectively administered in a part-daily, part-intermittent dosage schedule.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Random Allocation; Rifabutin; Rifampin; Safety; Tuberculosis, Pulmonary

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Clarithromycin; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Humans; Kanamycin; Mycobacterium avium-intracellulare Infection; Ofloxacin; Pilot Projects; Rifampin; Tuberculosis, Pulmonary

The Matiben Chest Clinic at the West Algiers University Teaching Hospital, and 3 outpatient clinics specializing in tuberculosis and lung disease in Algiers.. To determine the tolerance and efficacy of a fixed proportion combination of 3 antituberculosis drugs (per tablet: 50 mg isoniazid + 120 mg rifampicin + 300 mg pyrazinamide) given during the first 2 months of a daily 6-month chemotherapy regimen.. Random prospective treatment trial comparing a group of 124 patients receiving the triple combination with another group of 126 patients receiving the 3 drugs separately during the initial treatment phase. The continuation phase was identical for the 2 groups. Comparison of tolerance in the first 2 months, and of the failure and relapse rates (respectively at the end of treatment and 24 months after the end of treatment).. During the first 2 months side-effects were significantly more common in the group receiving the drugs separately. At the end of treatment and during the following 24 months there were no significant differences in the cumulative rates of observed failures and relapses (2% and 1%).. The triple combination studied could replace the separate drugs in the initial treatment phase in countries where the bioavailability of the drugs used has been proven.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Antitubercular Agents; Drug Therapy, Combination; Drug Tolerance; Female; Humans; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Recurrence; Rifampin; Tuberculosis, Pulmonary

This pilot study was conducted at the Joint Clinical Research Centre (JCRC) in Kampala, Uganda, where tuberculosis (TB) is an epidemic health problem aggravated by the HIV-1 pandemic.. To evaluate the feasibility of a larger phase III trial utilizing rifabutin as a substitute for rifampicin in short-course therapy for pulmonary TB.. Single-blind randomized trial in 50 patients with new onset smear- and culture-positive pulmonary tuberculosis and HIV-1 infection. Comparison of daily, intermittently supervised 6-month treatment regimens of rifabutin versus rifampicin, together with isoniazid, ethambutol and pyrazinamide.. Rifabutin- and rifampicin-containing regimens had comparable efficiency. However, rifabutin-treated patients had significantly more rapid clearance of acid-fast bacilli from sputum at 2 months (P < 0.05, Fisher exact test) and over the entire study period (P < 0.05, logrank test) than rifampicin-treated patients. The presence of cavitary disease was associated with a longer sputum conversion time for patients treated with either regimen. No major adverse events requiring dosage reduction or withdrawal of any study medication were seen in either treatment group. Mean absolute peripheral blood CD4 T lymphocyte counts increased by 28% from week 0 to week 12 in all subjects (334-427/microliters, respectively). An unexpected finding was the isolation of Mycobacterium africanum from 49% of the sputum cultures. This is the first report indicating a high prevalence of M. africanum in human TB in Uganda.. Short-course antituberculosis regimens containing rifabutin or rifampicin are both safe and efficacious in the treatment of HIV-1 associated tuberculosis. Rifabutin-containing regimens were associated with earlier sputum smear and culture conversion.

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Therapy, Combination; Female; HIV-1; Humans; Male; Mycobacterium tuberculosis; Pilot Projects; Retrospective Studies; Rifabutin; Rifampin; Single-Blind Method; Sputum; Tuberculosis, Pulmonary

Tuberculosis is still a major public health threat in Thailand. The introduction of a short course of chemotherapy at national level might help reduce the magnitude of the problem. In order to assess the efficacy and toleration of two different regimens of chemotherapy under field conditions, a comparative clinically controlled trial was conducted at the Central Chest Hospital in Nonthaburi, Thailand. From January 1988 to August 1990, 199, newly diagnosed, untreated, sputum positive tuberculosis patients were allocated randomly to two treatment groups; in Group A, 97 patients received Rifater daily for the first 2 months, followed by Rifinah daily for 4 months (2 Rifater/4 Rifinah). In Group B, 102 patients received Rifater supplemented by ethambutol daily for the first 2 months followed by thiacetazone and isoniazid daily for 6 months (2 Rifater EMB/6 HT.) Treatment results were very satisfactory in both groups. At the end of treatment conversion rates were 100 per cent in Group A, and 99 per cent in Group B. After a period of 36 months following completion of treatment, relapse rates of 3 per cent for Group A and 4 per cent for Group B were observed. Adverse reactions were minimal in both groups, but acne formation and gastrointestinal symptoms were noticed more in Group B, suggestive of thiacetazone side effects. This study shows that, the 6-months regimen is as effective as the 8-months regimen. Although the 8-months regimen is cheaper, it causes more gastrointestinal disturbance and skin reaction which might led to less patient compliance and result in a lower cure rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Antitubercular Agents; Drug Combinations; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Thailand; Treatment Outcome; Tuberculosis, Pulmonary

The results of the treatment 33 patients for smear-positive pulmonary tuberculosis with Isoniazid, Rifampicin, Pyrazinamide and Streptomycin administrated during first two weeks daily, from 3 to 8 week also with these four drugs but in a little higher doses twice weekly and next Isoniazid and Rifampicin during 9-26 weeks also twice weekly as in standard Polish model were described. After therapy with above described regimen all patients became smear-negative and radiological improvement was observed. Drugs in higher doses were well tolerated. Only abnormality in laboratory findings was temporary elevated level of uric acid, which recovered to normal values before the end of therapy. Costs of antituberculous drugs were used in this regimen is approximately 35% lower than standard model in Poland.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary; Uric Acid

Concomitant feeding and administration of antituberculosis medication has been proposed to increase compliance (by decreasing pyrazinamide associated nausea) and improve nutritional status. Food may however decrease the oral bioavailability of rifampicin and isoniazid.. A triple-crossover pharmacokinetic study in 27 patients with tuberculosis (15 males and 12 females) compared the bioavailability of rifampicin, isoniazid and pyrazinamide without food (control) with that when taken with a high carbohydrate (CHO) or high lipid (LIPID) diet.. the CHO diet decreased isoniazid bioavailability. The maximum measured drug concentration (Cm) was decreased by 20% (P = 0.0002) and the area under the concentration-time curve to 8 h (AUC8) by 19% (P = 0.01). The CHO diet increased the time to maximum measured drug concentration (Tmax) for rifampicin by 21% (P = 0.03). The LIPID diet decreased the Cm of isoniazid by 9% (P = 0.03). Individual patient bioavailability on each meal was compared to the no-food control. A decrease of Cm or AUC8 of greater than 20% was considered significant. The bioavailability of isoniazid and rifampicin was decreased by food in a high percentage (33-56%) of patients.. Concomitant feeding may thus have an important adverse effect on the therapy of tuberculosis and the desirability of this practice is called into question.

Topics: Adolescent; Adult; Biological Availability; Cross-Over Studies; Dietary Carbohydrates; Dietary Fats; Female; Food; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Chest Clinic, Sant Pau Hospital, Barcelona, Spain.. To assess the therapeutic response of pulmonary disease due to Mycobacterium kansasii to 12 and 18 months of chemotherapy.. 28 patients with criteria of pulmonary disease caused by M. kansasii not associated with HIV-infection were identified in our department in the period 1985-91 (24 male, 4 female, mean age 56 +/- 12 years). 14 patients were treated with rifampicin-isoniazid-ethambutol daily for 12 months (ethambutol only for the first 6 months), and 14 with the same regimen for 18 months. The follow-up after treatment was 12-30 months.. All patients showed improvement of radiographic manifestation of disease and sputum conversion (mean time: 4.5 +/- 2 months). The adverse drug effects were minimal. No failures were detected, and only one patient (3.5%), in the group of 12-month chemotherapy, relapsed after finishing the treatment.. Our findings suggest that pulmonary disease due to M. kansasii has an effective response to 12-month chemotherapy regimen and that it is not necessary to prolong the administration of ethambutol for more than 6 months.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Prospective Studies; Rifampin; Time Factors; Tuberculosis, Pulmonary

To assess the response to therapy for tuberculosis using rifampicin-containing short-course chemotherapy, and to compare recurrence and mortality rates in seronegative persons and those with HIV-1, HIV-2, and dual serologic reactivity in West Africa.. A cohort of 835 adult patients (167 HIV-1-positive, 143 HIV-2-positive, 243 dual-reactive, 282 HIV-negative) with smear-positive pulmonary tuberculosis was followed for 2 years under programme conditions. Standard self-administered treatment was daily rifampicin and isoniazid for 6 months, and in addition pyrazinamide during the first 2 months. Outcomes evaluated were rates of completion of therapy, cure, failure of treatment, recurrence after cure, and mortality.. HIV-positive patients had lower rates of completion of therapy (65-73%) than seronegative patients (79%), mainly because of increased mortality. Among patients completing therapy, failure of treatment was similarly low in HIV-positive (2%) and seronegative patients (1%). Recurrence rates after cure did not differ significantly in the 18 months of follow-up in the four serologic groups (3-7%). The respective mortality rates for HIV-1-positive, HIV-2-positive, and dually reactive patients were 20.3, 8.3, and 25.5 per 100 person-years (PY), compared with 2.2 per 100 PY among seronegatives.. Rifampicin-containing short-course chemotherapy for pulmonary tuberculosis is associated with similar cure and recurrence rates in HIV-positive and HIV-negative persons completing 6 months of therapy. HIV-2 infection is associated with more favourable survival than HIV-1 infection or dual reactivity, even when AIDS-defining illness is already present. However, mortality is significantly increased in all seropositive groups compared with HIV-negative tuberculosis patients; thus, establishing the causes of this increased mortality is a priority.

Topics: Adolescent; Adult; Africa, Western; AIDS-Related Opportunistic Infections; Antibiotics, Antitubercular; Antitubercular Agents; Drug Therapy, Combination; Female; Follow-Up Studies; HIV Seronegativity; HIV Seropositivity; HIV-1; HIV-2; Humans; Isoniazid; Male; Pyrazinamide; Recurrence; Rifampin; Treatment Failure; Tuberculosis, Pulmonary

We studied 266 patients with drug-resistant pulmonary tuberculosis at national sanatoria in Japan. The patients included 218 men (mean age, 58 years) and 48 women (mean age, 62 years). The levels of isoniazid and rifampicin resistance were determined at 1 mcg/mL and 50 mcg/mL, respectively. The results were as follows. (1) Most patients with drug-resistant pulmonary tuberculosis were middle-aged or past middle-aged. (2) There were many cases of drug-resistant pulmonary tuberculosis in previously treated tuberculosis patients with active disease and several cases in previously untreated pulmonary tuberculosis patients. However, in some previously untreated patients active tuberculosis was convert relatively easily to inactive tuberculosis. (3) Concerning life style, bachelors who drank heavily were more likely to develop drug-resistant pulmonary tuberculosis. (4) Most cases of drug-resistant pulmonary tuberculosis had at least one cavity on chest radiographs. (5) Several patients with drug-resistant tuberculosis left the hospital against the advice of their attending doctors; therefore, it was difficult to treat their illnesses. (6) In more than half the cases in which Mycobacterium tuberculosis was resistant to isoniazid and rifampicin, tolerance to streptomycin and ethanbutol was also seen. (7) When patients with drug-resistant pulmonary tuberculosis continued to have tuberculous bacilli in their sputum after 3 months of chemotherapy, there was a tendency for them to expectorate tuberculous bacilli in their sputum. For these drug-resistant tuberculosis patients, we must pay attention not only to the medical aspects but also to the social aspects of their disease.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Female; Humans; Isoniazid; Life Style; Male; Middle Aged; Prognosis; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Drug Resistance, Microbial; Humans; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Rifabutin; Rifampin; Tuberculosis, Pulmonary

Among HIV-positive patients who received treatment for active tuberculosis, thiacetazone has been associated with cutaneous hypersensitivity and recurrent tuberculosis. No controlled trials have investigated the safety and efficacy of thiacetazone-containing regimens compared with alternative regimens among patients with HIV. In a randomised clinical trial of 191 HIV-positive patients with active pulmonary tuberculosis, we examined the safety and short-term efficacy of isoniazid, rifampicin, and pyrazinamide for two months followed by isoniazid and rifampicin for seven months (RHZ) compared with streptomycin, thiacetazone, and isoniazid for two months followed by thiacetazone and isoniazid for ten months (STH). Between May, 1990, and September, 1991, 191 HIV-positive adult Ugandan patients with acid-fast bacilli sputum smear-positive pulmonary tuberculosis (93% confirmed by culture) received either STH or RHZ. Subjects had a standard evaluation that included Mantoux skin test, complete blood count with differential white blood cell count, and chest radiography. After starting therapy, subjects were followed-up over one year for three outcomes: complications of anti-tuberculosis therapy, early sterilisation of cultures, and survival. Of 191 eligible subjects, 90 received STH and 101 received RHZ. The overall one-year survival was similar for STH and RHZ (65% vs 72%), but when controlled for baseline differences in Mantoux reaction size and absolute lymphocyte count, the relative risk of death for STH compared with RHZ was 1.57 (95% CI 1.0-2.48). Overall, 12 adverse drug reactions occurred in the STH arm (18.2 reactions per 100 person years [PYO]) compared with one in the RHZ arm (1.6 reactions per 100 PYO) for a relative risk of 11.7 (95% CI 1.52-90.0). 10 cutaneous reactions occurred in the STH arm (15.2 events per 100 PYO) compared with one event in the RHZ arm (1.6 events per 100 PYO) for a relative risk of 9.7 (95% CI: 1.24, 75.8). A greater proportion of RHZ patients compared with STH patients had sterilised their sputum within two months (74% vs 37%, p < 0.001). In developing countries, rifampicin-containing regimens should be given, when possible, to HIV-positive patients to reduce drug toxicity and to prolong survival.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Drug Eruptions; Drug Hypersensitivity; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Survival Rate; Thioacetazone; Tuberculosis, Pulmonary; Uganda

Reduced chemotherapy courses (6-10 months) were studied for effectivity in 108 children with advanced intrathoracic tuberculosis. Intramuscular isoniazid, pyrazinamide+rifampicin produced a complete response in 87.9% of the cases who suffered side effects 2 times less frequently. The overall treatment course became shorter by 2-3 months. The treatment of 157 children with destructive pulmonary tuberculosis required long-term (12 months and more) treatment with employment of all the tuberculostatic armory and surgical intervention in 15.3% of the cases.

Topics: Administration, Oral; Child; Child, Preschool; Drug Therapy, Combination; Ethambutol; Follow-Up Studies; Humans; Injections, Intramuscular; Isoniazid; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Mycobacterium kansasii infection responds well to antituberculous drugs, and in the initial phase of treatment, many patients with M. kansasii infection are regarded as tuberculosis. This study was carried out to know whether the regimen of chemotherapy be continued or changed after the confirmation of diagnosis as M. kansasii infection. The treatment result of 107 cases with M. kansasii infection of the lung encountered at Fukujuji Hospital was compared with that of pulmonary tuberculosis. Sputum culture of all patients treated with drug regimens containing RFP converted to negative within 3 months after starting chemotherapy, while sputum culture of many patients treated with regimens not containing RFP converted to negative 4 months or later after the start of chemotherapy. Hence, the effectiveness of RFP in treating M. kansasii infection was confirmed. Among 65 patients with no relapse during a follow-up period of at least one year after the completion of chemotherapy, 58 patients (89.2%) were treated with drug regimens containing INH and RFP, and the treatment of 40 patients (61.5%) was finished within 12 months. Among three patients deteriorated during chemotherapy or relapsed within one year after the completion of chemotherapy, two patients were treated with drug regimens containing RFP and one of them had serious complications. The chemotherapy regimen for tuberculosis is considered to be sufficient for the initial treatment of pulmonary disease caused by M. kansasii.

Topics: Adult; Aged; Antitubercular Agents; Female; Humans; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Rifampin; Tuberculosis, Pulmonary

Efficacy of preventive chemotherapy in tuberculosis-infected children depends to a great extend on medical compliance and drug tolerability. Two new short-course chemoprevention-regimes of tuberculosis--four months Rifampin (A) and two months Rifampin plus Pyrazinamide (B)--were compared with the well established regimen of six months Isoniacid (C). 150 children (mean age 3.6 years with Tb conversion) were randomly allocated to these three regimens. 13 patients were non-compliant, in terms of interview, urinary INH-test strips, urine colour and prescription frequency: 7 in group C and 3 in group A and B, respectively. Adverse effects were observed in 5 patients: 3 in group C and 1 in group A and B. 1 child (group B) developed tuberculosis two years after stopping short course chemoprevention. Good compliance (94%) as well as neglectable risks of adverse effects (2%) justify further controlled studies to evaluate the efficacy of short course chemoprevention in childhood.

Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant; Isoniazid; Male; Pilot Projects; Pyrazinamide; Rifampin; Tuberculin Test; Tuberculosis, Pulmonary

From January 1991 to December 1992, 419 patients with pulmonary tuberculosis were initially treated at Fukujuji Hospital. Among them, 190 patients, who were younger than 80 years old and had pulmonary tuberculosis with cavities or infiltration of extension 2 or 3, and/or were sputum-smear positive, had been treated by 6-month short course regimen containing pyrazinamide, 2HRS(E)Z/4HRE. And were eligible for the evaluation of the clinical usefulness of pyrazinamide-containing regimen for the initial treatment of pulmonary tuberculosis. The dose of pyrazinamide was 1.2 g per day irrespective of body weight. The patients of this treatment group consisted of 151 males and 39 females, and mean age of the males was 45.3 and that of the females was 43.8 years old. At the start of the treatment, 74% of the cases were smear positive, 70% were cavitary, and 6 cases each showed primary resistance to isoniazid and to streptomycin, respectively, and only one case showed resistance to both of isoniazid and streptomycin. There was no primary resistant case to either rifampicin or ethambutol. Bacteriologic negative conversion rates were 95% and 90% after 2 months of treatment by PZA-containing regimen and by the standard regimen, respectively, and treatment durations required to achieve the negative conversion of all cases were 3 and 6 months for respective regimens. Of 90 patients who completed 6-month PZA-containing regimen and could be followed-up, only one bacteriologic relapse (1.1%) was noticed. Elevation of serum GPT level higher than 150 IU/ml during the treatment was noticed in 6.3% of 175 cases under PZA-containing regimen in comparison with 4.0% of 174 cases under the standard regimen (not significant). The interval between the onset of the treatment and the detection of abnormal liver function was much shorter (mean 31.3 days) in the PZA-containing regimen than in the standard regimens (mean 63.4 days). Hyperuricaemia (> 10 mg/ml) was noticed in 46.7% of 57 males and 59.4% of 19 females tested, but pyrazinamide was not discontinued in any case due to arthralgia. These results clearly show that pyrazinamide can be used rather safely for Japanese tuberculosis patients. If the pyrazinamide-containing regimen [2HRS(E)Z/4HRE] is adopted as the new standard regimen in place of on-going standard regimen in Japan, 6HRS(E)/3HR, the duration of chemotherapy could be shortened by three months with the same level of both efficacy and safety. We recommended pyrazinamide-c

Topics: Adolescent; Adult; Aged; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Patients with newly-diagnosed drug-sensitive, radiographically active and bacteriologically confirmed pulmonary tuberculosis recruited at 6 centres in Argentina, Brazil and Thailand.. To assess the efficacy, tolerability and toxicity of two regimens containing different daily dosages of rifabutin in comparison with rifampicin.. Multicentred, randomised, comparative study. In each group, study medications were administered daily for 6 months combined with isoniazid (6 months), and with pyrazinamide and ethambutol (both stopped after 2 months). Treatment success patients were followed-up for up to 2 years.. A total of 520 patients were enrolled and randomly assigned to receive either rifampicin (n = 175), or rifabutin 150 mg (n = 174) or rifabutin 300 mg (n = 171). Considering all patients with positive baseline culture, the success rates at the last valid observation for each patient were 89%, 94% and 92% in the rifampicin, rifabutin 150 mg, and rifabutin 300 mg groups, respectively. The median time to culture conversion was comparable in the 3 groups and was 34 days for rifampicin and 37 days for each of the rifabutin groups. During the drug-free follow-up period, one relapse occurred in the rifampicin group, and two in each of the rifabutin groups. The 3 treatment schedules appeared well tolerated. No patients had to discontinue therapy because of an adverse event in the rifabutin 150 mg group, compared to one in the rifampicin and 5 in the rifabutin 300 mg group.. All 3 regimens proved effective and well tolerated. Rifabutin at 150 mg/d showed the best risk-to-benefit ratio, in that this group had the highest proportion of patients completing treatment, the highest bacteriological conversion rates and the lowest incidence of adverse events.

Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Rifabutin; Rifampin; Sputum; Tuberculosis, Pulmonary

The paper presents the therapeutical results of 82 adolescents suffering from respiratory tuberculosis. During multi-modality therapy by using tuberculin, oliphen plus prednisolone there were clear-cut changes in immunological parameters, an increase in therapeutical efficiency and an average 3-month reduction in hospital stay.

Topics: Administration, Oral; Adolescent; Antibiotics, Antitubercular; Antioxidants; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Isoniazid; Lipid Peroxidation; Male; Phenyl Ethers; Prednisolone; Rifampin; Streptomycin; T-Lymphocytes; Treatment Outcome; Tuberculin; Tuberculosis, Pulmonary

Topics: Adult; Antifungal Agents; Aspergillosis; Azoles; Candidiasis; Cyclosporine; Drug Interactions; Erythromycin; Female; Humans; Kidney Transplantation; Legionnaires' Disease; Male; Middle Aged; Opportunistic Infections; Postoperative Complications; Rifampin; Streptococcal Infections; Tuberculosis, Pulmonary

The purpose of this study was to determine the efficacy and toxicity of a standard antituberculosis regimen in patients with human immunodeficiency virus (HIV) infection. We prospectively evaluated 89 patients with tuberculosis and HIV infection at an urban medical center. Eighty-two patients received isoniazid, rifampin, and pyrazinamide, with or without ethambutol, for 2 mo, followed by isoniazid and rifampin for 7 mo. Seven patients received other regimens because of drug resistance or intolerance. Therapy was self-administered in 57 patients and directly observed in 32 cases. All patients showed rapid clinical improvement during the first month of therapy, and sputum cultures reverted to negative after 3 mo in 52 of 54 patients from whom specimens were obtained. Adverse reactions to isoniazid or rifampin prompted alterations in antituberculosis regimens in five patients (6%). Forty patients (45%) died during follow-up, and tuberculosis was a potential contributory cause of death in three cases. Treatment failure occurred in five patients (6%), four of whom were noncompliant with therapy. The fifty patient had an isoniazid-resistant organism. No relapses occurred in 916 patient-months of follow-up posttreatment. We thus conclude that the 9-mo regimen used for treatment of drug-susceptible tuberculosis in HIV-infected patients is effective and well tolerated.

Topics: Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; HIV-1; Humans; Isoniazid; Los Angeles; Male; Mycobacterium tuberculosis; Patient Compliance; Prospective Studies; Pyrazinamide; Remission Induction; Rifampin; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

For the purpose to compare the effectiveness of SM and EB as a third drug in the standard regimens and to know whether the addition of SM twice weekly to INH and RFP could be acceptable for the treatment of pulmonary tuberculosis, the efficacy, adverse effects and results of long-term follow-up of the groups consisting of 105 patients treated with SM twice weekly for 6 months in addition to INH and RFP for 9 months (S2 group) and 107 patients treated with EB for 6 months in addition to INH and RFP for 9 months (E group) were observed. The speed of negative conversion of sputum and that of X-ray findings improvement were slightly faster in S2 group than E group but the difference was statistically not significant. The incidence of adverse effects such as elevation of serum transaminase values, gastrointestinal troubles, drug allergy and others was not similar in two groups. The relapse was observed in 2 cases of S2 group and 5 cases of E group. We concluded that SM twice weekly to INH and RFP is similarly effective as EB in combination with INH and RFP, and the this regimen could be used as standard regimen for pulmonary tuberculosis.

Topics: Adult; Aged; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Pulmonary

The activity of rifabutin and rifampicin against rapidly growing, extra-cellular Mycobacterium tuberculosis in cavity walls was measured by counting colony-forming units (cfu) in the sputum of 74 patients with newly diagnosed, severe pulmonary tuberculosis during the first 2 days of daily chemotherapy. The fall in counts, (log10 cfu/mL sputum/day), was termed the early bactericidal activity (EBA). The EBA, a highly reproducible measure within groups of 10-13 patients, was -0.015 for a low EBA reference group (who received no chemotherapy) and 0.495 for a high EBA reference group (who received 300 mg isoniazid daily). The EBAs in patients receiving 300 and 600 mg rifabutin were 0.014 and 0.075, and for those taking 150, 300 and 600 mg rifampicin 0.021, 0.150 and 0.204, respectively. Weight-for-weight, the ratio rifabutin to rifampicin producing the same EBA was estimated to be 2.73 (95% confidence limits 1.96-3.78). Determination of the EBA is a rapid and economical method of comparing the potency in human lesions of drugs of the same type before embarking on a conventional clinical trial.

Topics: Adolescent; Adult; Colony Count, Microbial; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifabutin; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

A clinical study about the efficacy of rifapentine in the treatment and 3 years' follow up on initial pulmonary tuberculous patient. Altogether 267 patients of initial pulmonary tuberculosis with positive smears were randomly divided into 3 groups; Group I with DL473 twice-weekly (2HE+L2/7H2L2), Group IIARFp twice-weekly (2HE+R2/7H2R2) and Group IIBRFP daily (2HRE/7HR) for controls. Results are: the conversion rate to smear negative are 96.0%, 96.4% and 97.1% respectively (P > 0.05); the sputum conversion rate by cultures are 98.0%, 95.7% and 96.4% respectively (P > 0.05). From X-Ray pictures, the treatment effect of Group I are similar to that of Group IIB. But in Group I with less side action were observed. The relapse rate of the three groups are 2.6%, 3.8% and 3.1% respectively (P > 0.05). From this investigation, we can draw a conclusion that the twice-weekly of rifapentine has at least an effect similar to rifampicin given daily. Further investigation of DL473 once weekly will soon be followed.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Antitubercular Agents; Drug Therapy, Combination; Ethionamide; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

The early bactericidal and sterilizing activities of ciprofloxacin were evaluated in the treatment of adult patients with smear positive pulmonary tuberculosis. Two randomized prospective studies were performed in Northern Tanzania. In study 1, ten patients received either 750 mg ciprofloxacin or 300 ng isoniazid daily for 7 days. Counts of colony-forming units (cfu) of Mycobacterium tuberculosis in early morning sputum were performed. In study 2, twenty patients received either a standard regimen of rifampin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E) (regimen HRZE) or a trial regimen of ciprofloxacin (C), isoniazid (H), and rifampin (R) (regimen HRC). Sputum colony counts were performed for 8 wk. Patients were tested for antibodies to human immunodeficiency virus (HIV)-1. The results demonstrate that ciprofloxacin alone has useful early bactericidal activity, resulting in a mean daily fall of 0.20 log10cfu/ml/day during 7 days compared with 0.25 log10cfu/ml/day for isoniazid. When HRZE and HRC regimens were compared, the HRC regimen appeared to be inferior in its sterilizing ability, with a culture conversion rate of 67% at 2 months compared with 100% for HRZE. The difference in outcome was most marked in HIV-1 positive patients. The role of ciprofloxacin in combination regimens may be as a bactericidal rather than a sterilizing agent.

Topics: Adult; Aged; Ciprofloxacin; Drug Therapy, Combination; Ethambutol; Female; HIV Seropositivity; HIV-1; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

310 patients with pulmonary tuberculosis disseminating bacteria received isoniazid, rifampicin, streptomycin (ethambutol) and pirazinamid in different regimens and dosage forms. The drugs were administered in sequence or simultaneously, in single or divided doses. The best time and number characteristics as regards the discharge negativation were obtained in pirazinamid administration at a single dose daily or each other day irrespective of other drugs intake. 100 patients were given isoniazid, rifampicin and pirazinamid in multicomponent form tricox (Jemis, India). Tricox proved effective under additional administration of isoniazid in the same dose as was fixed in tricox.

Topics: Antitubercular Agents; Dosage Forms; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Rifampicin and pyrazinamide constitute an important part of drug regimens advocated for tuberculosis therapy, along with INH and streptomycin/ethambutol. The International Union against Tuberculosis and Lung Disease has also suggested the inclusion of these two drugs as part of short course chemotherapy for tuberculosis. Hence this study was undertaken to evaluate the influence of pyrazinamide on rifampicin kinetics when the two are given together. In a randomized, cross-over, single dose study, 16 patients with untreated pulmonary tuberculosis, after an overnight fast, were administered either rifampicin 450 mg + INH 300 mg (study A) or rifampicin 450 mg + INH 300 mg+pyrazinamide 1500 mg (study B). Blood samples were collected for serum rifampicin estimation at 0, 0.5, 2, 4, 6 and 8 h. Various pharmacokinetic parameters (Cmax, Tmax, t1/2, Kel, area under plasma concentration time curve (AUC), Vd & Cpl of rifampicin) were calculated. It was observed that rifampicin concentration in study A in contrast to study B was significantly higher at 6 h (P < 0.01) and 8 h (P < 0.05), while there were no significant differences in serum rifampicin concentration at 0.5, 2 and 4 h. A significant difference was also observed in AUC and Cpl. In study A, AUC was higher (P < 0.05), while Cpl was lower (P < 0.02), than in study B. From the above data it appears that on concomitant administration of pyrazinamide in patients on rifampicin therapy, AUC of rifampicin is decreased while its clearance is increased.

Topics: Adult; Anti-Bacterial Agents; Drug Interactions; Drug Therapy, Combination; Humans; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

A study was carried out in six human volunteers, to assess the blood kinetics of isoniazid, rifampicin and pyrazinamide, administered in a fixed-triple combination intended for use in intermittent chemotherapy of tuberculosis. The formulation employed contained 125 mg of isoniazid (H), 100 mg of rifampicin (R) and 375 mg of pyrazinamide (Z) per tablet; six tablets were administered to every subject, giving a total dosage of 750 mg of isoniazid, 600 mg of rifampicin and 2,250 mg of pyrazinamide. In each subject, the same dose of each drug was administered individually in separate sessions and the results compared. The results indicated that, at the level of dose of the intermittent tablet, no negative interactions between the drugs were observed.

Topics: Adult; Biological Availability; Capsules; Drug Administration Schedule; Drug Combinations; Half-Life; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Tablets; Tuberculosis, Pulmonary

The frequency of infection with multidrug-resistant Mycobacterium tuberculosis is increasing. We reviewed the clinical courses of 171 patients with pulmonary disease due to M. tuberculosis resistant to rifampin and isoniazid who were referred to our hospital between 1973 and 1983. The patients' records were analyzed retrospectively. Their regimens were selected individually and preferably included three medications that they had not been given previously and to which the strain was fully susceptible.. The 171 patients (median age, 46 years) had previously received a median of six drugs and shed bacilli that were resistant to a median of six drugs. Thus, their regimens were frequently not optimal. Of 134 patients with sufficient follow-up data, 87 (65 percent) responded to chemotherapy (as indicated by negative sputum cultures for at least three consecutive months); 47 patients (35 percent) had no response, as shown by continually positive cultures. The median stay in the hospital was more than seven months. In a multivariate analysis, an unfavorable response was significantly associated with a greater number of drugs received before the current course of therapy (odds ratio, 4.0; 95 percent confidence interval, 1.6 to 9.9; P < 0.001) and with male sex (odds ratio, 2.5; 95 percent confidence interval, 1.1 to 6.2; P < 0.03). Twelve of the patients with responses subsequently had relapses. The overall response rate was 56 percent over a mean period of 51 months. Of the 171 patients, 63 (37 percent) died, and 37 of these deaths were attributed to tuberculosis.. For patients with pulmonary tuberculosis that is resistant to rifampin and isoniazid, even the best available treatment is often unsuccessful. Only about half of such patients eventually have negative sputum cultures despite carefully selected regimens administered for extended periods. Failure to control this resistant infection is associated with high mortality and ominous implications for the public health.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Resistance, Microbial; Female; Humans; Isoniazid; Male; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Recurrence; Retrospective Studies; Rifampin; Sputum; Tuberculosis, Pulmonary

A prospective multicentre open study has been conducted in France in order to assess the efficacy and tolerability of an antimycobacterial regimen including rifabutin in the treatment of patients with pulmonary tuberculosis due to rifampicin and isoniazid resistant bacilli. Patients were treated with daily rifabutin (450-600 mg), associated with companion drugs to which the organisms remained susceptible; in most cases the regimen included a fluoroquinolone. The duration of treatment was initially scheduled for a minimum period of 12 months after sputum culture conversion. Thirty nine patients were enrolled, 23 of whom were treated for at least 12 months. Culture conversion was obtained at the end of the twelfth month in 14 out of 23 patients. Twenty one out of 39 patients experienced adverse events. These were, however, serious enough to discontinue treatment in only four patients. These results suggest that an antimycobacterial combination including rifabutin might contribute to the treatment of multi-resistant pulmonary tuberculosis.

Topics: Adult; Antitubercular Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins; Time Factors; Tuberculosis, Pulmonary

Previously untreated patients with smear-positive pulmonary tuberculosis were randomly allocated to treatment with 600, 300, 150 or 75 mg doses of rifabutin (LM427, ansamycin), 600, 300 or 150 mg of rifampicin, 300 mg isoniazid or to no drug daily for 2 days. The fall in viable counts of Mycobacterium tuberculosis in sputum collections during the 2 days, termed the early bactericidal activity (EBA), was estimated from counts of colony-forming units (cfu) on selective 7H-11 agar medium. The EBA for rifabutin ranged from -0.039 (an increase in counts) to 0.049 log10 cfu/ml/day whereas the EBA increased from 0.071 for 150 mg rifampicin to 0.293 log10 cfu/ml/day for 600 mg rifampicin and was 0.43 log10 cfu/ml/day for 300 mg isoniazid. The difference between the EBAs for rifabutin and rifampicin just attained significance (P = 0.05) suggesting that rifabutin was inactive or less active than rifampicin against the extracellular bacilli in pulmonary cavities. Peak plasma concentrations of rifabutin after the initial doses were found to be proportional to dose size and were approximately 7 times lower than those after the same dose size of rifampicin. The lower EBA of rifabutin as compared to rifampicin is probably due to the low plasma concentrations which are not fully compensated for by slightly greater antituberculosis activity of rifabutin in vitro.

Topics: Adolescent; Adult; Antitubercular Agents; Colony Count, Microbial; Dose-Response Relationship, Drug; Hong Kong; Humans; Isoniazid; Mycobacterium tuberculosis; Rifabutin; Rifampin; Rifamycins; Sputum; Tuberculosis, Pulmonary

A study of rifabutin in the retreatment of patients with chronic pulmonary tuberculosis whose strains of tubercle bacilli were resistant to all three of the drugs isoniazid, streptomycin, and rifampicin, and usually to others as well, was undertaken in 22 Chinese patients in Hong Kong. They were arranged in 11 pairs such that the resistance pattern of the strains for both patients was the same or closely similar. One of each pair was allocated at random to receive rifabutin (B) daily and the other rifampicin (R) daily. The two members of each pair were also prescribed the same or similar companion drugs, selected on the basis of the results of susceptibility tests and of the history of previous antituberculosis chemotherapy. The bacteriological results showed no evidence of a sustained benefit in any patient. A temporary response was seen on sputum smear examination in 14 patients (7B, 7R), of whom 10 (5B, 5R) had a period of smear-negativity, and on sputum culture examination in 10 patients (5B, 5R), of whom 3 (2B, 1R) had a period of culture-negativity. The duration of response was longer for the B patient in 5 pairs and for the R patient in 5. Two patients (both B) had rifabutin-susceptible strains on admission to the study; their temporary responses were among the best and were associated with the emergence of rifabutin resistance, suggesting that rifabutin may have contributed to their response. A total of 17 patients, including 7 not in the paired comparison, were subsequently retreated with ofloxacin; 10 showed a response, disease becoming and remaining quiescent in 3.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antitubercular Agents; Chronic Disease; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Ofloxacin; Rifabutin; Rifampin; Rifamycins; Sputum; Streptomycin; Treatment Outcome; Tuberculosis, Pulmonary

Nineteen randomized patients, treated with isoniazid (INH, CAS 54-85-3) for tuberculosis chemoprophylaxis or isoniazid plus rifampicin (RMP, CAS 13292-46-1) combination for tuberculosis therapy, were studied in order to explore the effects of these drugs on fibrinogen and antithrombin III blood levels. Other hepatic biology indices were also measured (aminotransferases, alkaline phosphatase, prothrombin time etc). The results suggested a relationship between INH or INH + RMP administration and fibrinogen as well as antithrombin III blood levels. The data indicate a protective effect of the RMP synchronous administration (by enzyme induction mechanisms) in the preservation of fibrinogen blood levels.

Topics: Adult; Antithrombin III; Blood Coagulation; Drug Combinations; Enzymes; Female; Fibrinogen; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

The efficacy of ofloxacin, rifampicin and isoniazid was prospectively compared with the regimen of ethambutol, rifampicin and isoniazid for the primary treatment of pulmonary tuberculosis in 124 patients. All drugs were given orally daily for nine months. Culture conversion rates three months after starting treatment were 98 percent in the ofloxacin group and 94 percent in the ethambutol group; by six months all patients in both groups were culture-negative. Significant radiological improvement of pulmonary infiltrates was observed in 83 percent of the ofloxacin group and 85 percent of the ethambutol group one year after starting treatment. No relapse in either group was observed during a two-year follow-up period after the cessation of chemotherapy. Ofloxacin appears to be as useful as ethambutol in the treatment of pulmonary tuberculosis when either drug is combined with isoniazid and rifampicin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Drug Combinations; Drug Resistance, Microbial; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Ofloxacin; Prospective Studies; Rifampin; Time Factors; Tuberculosis, Pulmonary

Newly diagnosed patients of pulmonary tuberculosis (n = 112) were put on a rifampicin-containing drug regimen. Fifty six patients were also given a placebo tablet twice daily while the other fifty-six were given ranitidine 150 mg twice daily. Gastric pH, gastric emptying time, serum rifampicin levels, urinary total and unchanged rifampicin, serum bilirubin and ALT levels were measured serially. Clinical record of adverse symptoms was maintained. Ranitidine increased the basal as well as post-drug gastric pH without altering the gastric emptying time. Concomitant administration of ranitidine and rifampicin did not alter the absorption, metabolism or excretion of the latter but reduced the frequency of gastrointestinal symptoms.

Topics: Adult; Alanine Transaminase; Bilirubin; Drug Interactions; Female; Gastric Acidity Determination; Gastrointestinal Motility; Humans; Male; Middle Aged; Ranitidine; Rifampin; Tuberculosis, Pulmonary

A double-blind placebo-controlled trial of antituberculosis chemoprophylaxis was undertaken in sillicotic subjects in Hong Kong where there is a high prevalence of both silicosis and tuberculosis. During 1981 to 1987, 679 Chinese men with silicosis, with no history of previous antituberculosis chemotherapy and no evidence of active tuberculosis, were admitted to the trial and have been studied for between 2 and 5 yr. They were allocated at random to four series-rifampin for 12 wk (R3), isoniazid and rifampin for 12 wk (HR3), isoniazid alone for 24 wk (H6), or placebo (Pl)--in a double-blind design with matching placebos for isoniazid and rifampin as appropriate. Active pulmonary tuberculosis developed more frequently during the 5 yr in the placebo series than in the three chemoprophylaxis series (p less than 0.01, log-rank test), but there were no significant differences between the chemoprophylaxis series. The estimated proportions of patients with active pulmonary disease in the placebo series were 9% at 2 yr, 15% at 3 yr, 20% at 4 yr, and 27% at 5 yr. In contrast, in the three chemoprophylaxis series combined they were 5, 8, 10, and 13%, respectively. Thus, although chemoprophylaxis halved the proportion of patients in whom tuberculosis developed, this proportion was still substantial. There was no evidence that chemoprophylaxis led to the selection of drug-resistant strains of bacilli. Adverse effects were reported with a similar frequency in all four series, suggesting that few were drug related. During the first 12 wk, hepatic toxicity was reported in 8 (1%) patients (3 HR3, 3 H6, and 2 Pl), but only 1 (H6) had symptomatic hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Alanine Transaminase; Disease Susceptibility; Double-Blind Method; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Rifampin; Silicosis; Tuberculosis, Pulmonary

In a study in Hong Kong 1,386 Chinese patients with sputum smear-positive pulmonary tuberculosis were allocated at random to four 6-month regimens of chemotherapy, all given three times weekly from the start and all containing isoniazid (H) and rifampin (R) throughout. Three contained streptomycin (S) for the first 4 months and pyrazinamide (Z) for 2 months (Z2), 4 months (Z4), or 6 months (Z6); the fourth contained pyrazinamide for 6 months but no streptomycin (Z6noS). Every dose of all four regimens was given under the direct supervision of clinic staff on a predominantly outpatient basis. During the later part of the intake patients were allocated at random to be given their HRZ either as a combined formulation (Rifater), each tablet containing 125 mg isoniazid, 100 mg rifampin, and 375 mg pyrazinamide, or as the three drugs separately. Among 892 assessable patients with drug-susceptible strains of tubercle bacilli pretreatment, bacteriologic failure during chemotherapy occurred in 4, all Z6noS (2% of 224; p less than 0.005 for the comparison with the S-containing regimens). During 30 months of follow-up after the end of chemotherapy, bacteriologic relapse occurred in 2 (3%) of 71 Z2, 2 (3%) of 72 Z4, 4 (6%) of 66 Z6, and 6 (9%) of 64 Z6noS patients allocated to Rifater, and in 4 (3%) of 149 Z2, 8 (6%) of 133 Z4, 2 (1%) of 142 Z6, and 6 (4%) of 135 Z6noS patients allocated to separate drugs. In the relapse rates there were no significant differences between the Rifater and separate drug regimens, the different durations of pyrazinamide, or the regimens with and without streptomycin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Drug Administration Schedule; Drug Combinations; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

In a study in Singapore 310 patients with sputum smear-positive pulmonary tuberculosis were allocated at random to daily chemotherapy with streptomycin, isoniazid, rifampin, and pyrazinamide (1) for 2 months (2SHRZ), (2) for 1 month (1SHRZ), or (3) for 2 months without streptomycin (2HRZ). This was followed for all patients by three times weekly isoniazid and rifampin to a total duration of 6 months. During the initial period of daily chemotherapy the patients were also allocated at random to be given their HRZ either as a combined formulation (Rifater), each tablet containing 50 mg isoniazid, 120 mg rifampin, and 300 mg pyrazinamide, or as three separate drugs. During the Rifater versus separate drugs comparison the most common spontaneous complaints were of nausea and vomiting, reported by 8% of 155 patients receiving Rifater and 7% of 155 separate drugs. Other adverse effects were also reported in similar proportions in the two series. Among 271 patients with drug-susceptible strains of tubercle bacilli pretreatment there were no bacteriologic failures during chemotherapy. During 18 months of subsequent follow-up bacteriologic relapse occurred in 3 (7%) of 46 2SHRZ, 2 (5%) of 42 1SHRZ, and 3 (8%) of 40 2HRZ patients allocated to Rifater and in 0 of 47 2SHRZ, 1 (2%) of 46 1SHRZ, and 1 (2%) of 44 2HRZ patients allocated to separate drugs. There was no evidence of therapeutic benefit from continuing SHRZ administration beyond 1 month or from adding streptomycin to HRZ. The relapse rates were slightly higher in the Rifater series (p = 0.04). Further follow-up and results from other studies are therefore needed fully to assess the combined preparation.

Topics: Adolescent; Adult; Drug Combinations; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Patient Compliance; Pyrazinamide; Recurrence; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

The results of a complex treatment of 126 patients with destructive pulmonary tuberculosis have been studied. The chemotherapy regimen of 72 patients comprised intramuscular administration of a 10% isoniazid solution and 54 received isoniazid orally. Both groups of patients were identical in the clinical pattern of pulmonary tuberculosis and treatment conditions. Treatment effectiveness proved to be higher in Group I patients in whom the hospital stay was mainly 6 months. With oral isoniazid, it was longer and 24% of patients (versus 9.7% in Group I) required more prolonged therapy. Clinical manifestations, which were identical in both groups in the pre-treatment period, subsided earlier when isoniazid was administered intramuscularly. Hence, intramuscular administration of 10% isoniazid solution, as compared with its oral use, raises the effectiveness of chemotherapy and decreases the terms of a hospital treatment.

Topics: Adult; Aged; Drug Therapy, Combination; Ethambutol; Humans; Injections, Intramuscular; Isoniazid; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Two chemotherapy regimens of 28 weeks (6M) and 36 weeks (8M) duration were compared in patients with previously untreated pulmonary tuberculosis in 30 health districts of Algeria. In the 6M regimen, patients received isoniazid plus rifampicin daily throughout with streptomycin and pyrazinamide in addition for the first 8 weeks. In the 8M regimen patients received isoniazid daily throughout plus rifampicin for the first 16 weeks and streptomycin and pyrazinamide as well for the first 8 weeks. The districts were allocated to apply either the 6M or the 8M regimen to all eligible patients. However, 22% of eligible patients were not admitted, the most common reason being oversight on the part of the personnel in the local health centres. A total of 2218 (977 6M, 1241 8M) patients was admitted and the results were assessed 2 years after the due date of completion of chemotherapy, irrespective of whether or not management had deviated from the study protocol. An appreciable proportion of patients (25% of 6M, 29% of 8M) could not be assessed because they failed to attend for follow-up or the collection of specimens was overlooked or because of difficulties in the transport of specimens to the reference laboratory in Algiers, and a further 5% and 4% of patients died. Of those who were assessable 7 (1%) of 731 6M and 15 (2%) of 875 8M were classified as having an unfavourable response during or after chemotherapy because they had one or more positive cultures. In addition 16 (2%) 6M and 18 (2%) 8M patients had received additional chemotherapy for failure, relapse or the development of non-pulmonary lesions but had achieved a favourable status. Of 1018 (488 6M, 530 8M) patients assessed who had fully sensitive strains pretreatment and completed treatment as planned, 97% in both series had a favourable status 2 years after their chemotherapy was due to be completed. In patients with initial strains resistant to isoniazid the results were less good in the 8M than the 6M series: none of the 19 6M compared with 5 of 26 in the 8M series having an unfavourable outcome suggesting that the duration of rifampicin may have been important in patients with initial isoniazid resistance. A slightly higher proportion of patients on the 8M regimen defaulted during chemotherapy (9.3% compared with 6.7% in the 6M regimen) but there was no difference between the regimens in other measures of compliance.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adolescent; Adult; Aged; Algeria; Antitubercular Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

In order to know the adequate duration of the chemotherapy with two drugs (INH + RFP) for pulmonary tuberculosis with non-cavitary minimal radiological findings (minimal case), 278 cases with minimal lesion which had completed 9 months' chemotherapy, were observed for more than six months up to 5 years (mean duration = 54.4 months). Of them, 60 cases were bacteriologically confirmed by smear and/or culture examination. Many cases showed further improvement in radiological findings even after the end of the chemotherapy. Of 180 cases of initially infiltrative type (GAKKEN B type), 10 cases showed the enlargement of shadow radiologically, but were not regarded as relapsed cases, because they remained bacteriologically negative and the shadow improved in 1-2 months without additional chemotherapy. Only 3 cases (1.1%) were regarded as relapsed cases because of the positive bacteriological conversion and aggravation of the shadow. They were initially sputum negative. It can be concluded that for radiological minimal cases, nine months is enough for the duration of chemotherapy when the INH-RFP regimen is used.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Child; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

250 patients suffering from pulmonary tuberculosis who were smear positive received a chemotherapy regime for 6 months combining Rifampicin and Isoniazid every day with a daily supplement of Pyrazinamide for the first 8 weeks. The three drugs given in the initial phase of treatment were administered either separately or in combined preparations according to the 2 controlled randomised groups. During the maintenance phase the drugs were given in a combined form in fixed proportions in the 2 groups. 6 months after the end of treatment the bacteriological results were similar in the 2 groups in the 144 cases which were analysed. Amongst 137 cases with bacilli which were initially sensitive to Isoniazid (68 cases with separate medicines at the beginning and 69 with combined drugs) there was no failure at 6 months, nor any relapse during the course of the first period of surveillance. Amongst 7 cases with bacilli which were originally resistant to Isoniazid (4 and 3 respectively), there were 2 failures at 6 months one in each group with acquired resistance to Rifampicin observed at the time of the failure. There was no difference in the therapeutic results observed whatever the presentation of drugs used during the initial phase of treatment.

Topics: Drug Combinations; Drug Resistance, Microbial; Follow-Up Studies; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Random Allocation; Rifampin; Tuberculosis, Pulmonary

A controlled study of three short-course regimens was undertaken in South Indian patients with newly diagnosed, sputum-positive pulmonary tuberculosis. The patients were allocated at random to one of three regimens: a) Rifampicin, streptomycin, isoniazid and pyrazinamide daily for 3 months (R3); b) the same regimen as above but followed by streptomycin, isoniazid and pyrazinamide twice-weekly for a further period of 2 months (R5); c) the same as R5 but without rifampicin (Z5). A bacteriological relapse requiring treatment occurred by 5 years in 16.8% of 113 R3, 5.2% of 97 R5, and 20.0% of 115 Z5 patients with organisms sensitive to streptomycin and isoniazid initially. The differences in the relapse rates between the R3 and R5 regimens and the R5 and Z5 regimens were statistically significant (p less than 0.01 for both). Considering patients with organisms initially resistant to streptomycin or isoniazid or both, 7 of 52 patients (4 R3, 2 R5, 1 Z5) had a bacteriological relapse requiring retreatment.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Microbial; Follow-Up Studies; Humans; Isoniazid; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

To determine the effectiveness, toxicity, and acceptability of a 6-month antituberculous regimen compared with a 9-month regimen.. A nonblinded, unbalanced, randomized, multicenter clinical trial.. Twenty-two tuberculosis clinics in public health departments and hospitals in the United States.. Patients were eligible if Mycobacterium tuberculosis, isolated from sputum cultures, was susceptible to study drugs. Of 1451 patients enrolled, 75% (617 of 823) assigned to the 6-month regimen and 71% (445 of 628) assigned to the 9-month regimen were eligible.. Patients took self-administered isoniazid and rifampin daily for 24 weeks (6-month regimen) or 36 weeks (9-month regimen). In addition, patients assigned to the 6-month regimen took self-administered pyrazinamide daily during the first 8 weeks.. Patients on the 6-month regimen converted more rapidly than patients on the 9-month regimen (94.6% compared with 89.9% after 16 weeks of therapy, with a difference of 4.7% [95% CI, 0.7% to 8.7%]); had similar rates of adverse drug reactions (7.7% compared with 6.4%, with a difference of 1.3% [95% CI, 0.0% to 4.6%]); had lower noncompliance rates (16.8% compared with 29.2%, with a difference of 12.4% [95% CI, 6.8% to 18.0%]); and had similar relapse rates 96 weeks after completing therapy (3.5% compared with 2.8%, with a difference of 0.7% [95% CI, 0.0% to 3.9%]). A significantly greater proportion of patients assigned to the 6-month regimen successfully completed therapy (61.4% compared with 50.6%; chi 2 = 11.976).. Our results suggest that this 6-month regimen is similar in effectiveness, toxicity, and acceptability to the 9-month regimen for treating pulmonary tuberculosis.

Topics: Adult; Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Data Interpretation, Statistical; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Multicenter Studies as Topic; Patient Compliance; Proportional Hazards Models; Pyrazinamide; Randomized Controlled Trials as Topic; Recurrence; Rifampin; Sputum; Survival Rate; Tuberculosis, Pulmonary; United States

The effectiveness of a tablet containing a combination of rifampicin, isoniazid and pyrazinamide (Rifater; Mer-National) in the treatment of pulmonary tuberculosis was examined by comparing it with a previously evaluated four-drug regimen. Of 150 black goldminers with a first case of pulmonary tuberculosis, 69 were randomly allocated to receive the combination tablet (RHZ), 5 tablets per day on weekdays for 100 treatment-days, and 81 the four-drug regimen (streptomycin, rifampicin, isoniazid and pyrazinamide) (RHZS). Non-compliance was detected in 42% of the RHZ group and in 16% of the RHZS group. Two patients in the RHZ group and 4 in the RHZS group had to have their treatment altered because routine investigations revealed drug-resistant mycobacteria. Treatment was unsuccessful in 10 patients in the RHZ group, with 4 men failing to complete the regimen and being lost to follow-up, 3 cases of failure of conversion of sputum on the regimen, and 3 relapses. The results for the RHZS group were similar, with 4 failures to complete the regimen, 2 treatment failures and 4 relapses. Evaluation of RHZ showed it to be comparable with a previously evaluated, successful short-course regimen (RHZS). The high incidence of non-compliance probably reflects reduced supervision of this wholly oral regimen.

Topics: Adult; Antitubercular Agents; Drug Combinations; Drug Therapy, Combination; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Streptomycin; Tablets; Tuberculosis, Pulmonary

The outcomes of tisamid treatment of newly diagnosed patients with bacillary pulmonary tuberculosis were analysed. To estimate the efficacy of tisamid and its administration indications, chemotherapy of the patients was performed with the use of two therapeutic regimens. Isoniazid, rifampicin and streptomycin (or ethambutol) were given to 73 patients, while other 72 ones were treated with the same drugs plus tisamid. The patients in each group were subdivided into slow, rapid and homozygotic (the most rapid) acetylators. Tisamid, when prescribed to newly-discovered patients with destructive tuberculosis, accelerates recovery, by excluding the risk of a hepatotoxic action. Tisamid in a combined treatment with isoniazid, rifampicin and streptomycin is mostly recommended for patients with a rapid acetylation phenotype, i.e. the cases for whom a short-term chemotherapy is possible.

Topics: Adult; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

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

A randomised controlled trial compared the effectiveness and toxicity in pulmonary tuberculosis of two drug regimens containing rifampicin and isoniazid given daily or twice-weekly for 4 months after a 2-month period of intensive treatment with daily isoniazid, rifampicin, and pyrazinamide. 667 patients with newly diagnosed pulmonary tuberculosis were randomly allocated to continue daily treatment with isoniazid (400 mg) and rifampicin (600 mg) or to twice-weekly treatment with isoniazid (900 mg) and rifampicin (600 mg). 544 of the 667 patients (81%) completed the 6-month course (287 of 337 [85%] treated daily and 257 of 330 [79%] treated twice-weekly). Drug toxicity was not a great problem; the treatment was permanently discontinued in only 2% of patients. There was no significant difference at the end of months 5 and/or 6 of chemotherapy between the groups treated daily and twice-weekly in the proportions with bacteriological failure (at least one positive sputum culture with more than 20 colonies) or who had died from tuberculosis (17 [6%] vs 10 [3%]). Nor was there a significant difference in the relapse rate (17 [7%] treated daily vs 10 [4%] treated twice-weekly) during follow-up of 12 months. Thus, the twice-weekly regimen was at least as effective as the daily regimen for treatment of pulmonary tuberculosis.

Topics: Administration, Oral; Brazil; Costs and Cost Analysis; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Follow-Up Studies; Humans; Isoniazid; Patient Compliance; Randomized Controlled Trials as Topic; Rifampin; Time Factors; Tuberculosis, Pulmonary

In Hong Kong, 627 adult Chinese patients with newly diagnosed pulmonary tuberculosis received, for the first 2 months of chemotherapy, streptomycin together with isoniazid, rifampin, and pyrazinamide allocated at random to be given either as a combined formulation or separately. Each tablet of the combined formulation, which was designed for intermittent use, contained 125 mg of isoniazid, 100 mg of rifampin, and 375 mg of pyrazinamide. Patients weighing 42 kg or less received 5 tablets per dose, 43 to 57 kg, 6 tablets per dose, and 58 kg or more, 7 tablets per dose. The dosage of each drug was very similar whether it was given combined or separately. During the 2 months, spontaneous complaints, the commonest of which were nausea and vomiting, were made by 38% of patients receiving the combined and 39% receiving the separate formulations; 1% compared with 5%, respectively, complained that the tablets or capsules were too many, too large, difficult to swallow or that they stuck in the throat (p less than 0.05), and 32% compared with 45% regularly brought their own drink (usually milk or fruit juice) to the clinic to help them swallow their medicament (p less than 0.01). Only 14% of patients in each group missed one or more doses through default. Reported adverse reactions were mainly trivial, 4% of patients receiving the combined and 7% receiving the separate formulations having the administration of one or more drugs terminated. Thus, the differences between the combined and separate formulations showed a small advantage to the combined formulation in terms of acceptability to patients.

Topics: Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Humans; Isoniazid; Patient Compliance; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

250 patients suffering from smear positive pulmonary tuberculosis who had never been treated before, received a six-month regimen combining isoniazid and rifampicin every day with a supplement of pyrazinamide for the first eight weeks of treatment. The three drugs given during the initial phase of therapy were administered in two different forms: either as separate tablets or in a form combining all three drugs in fixed proportions (each tablet contained 50 mg of isoniazid, 120 mg of rifampicin and 300 mg of pyrazinamide). The patients were randomised into two groups of 125 receiving one or other combination of medications with the dose adapted for their weight. An analysis of the results at the end of the second month of treatment was carried out on 240 cases who could be analysed for tolerance and acceptability and in 193 cases who were analysed for the efficacy of therapy as judged by negative cultures. The treatment results were excellent in both groups, as was patient acceptability. The level of side effects was significantly lower in the group receiving combined medication (p less than 0.02). Both groups gave a similar proportion of negative cultures at the end of two months. The combined medicaments studied are thus well tolerated and at least as effective as individual drugs. They may thus replace them.

Topics: Adolescent; Adult; Antitubercular Agents; Clinical Trials as Topic; Drug Combinations; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Random Allocation; Rifampin; Tuberculosis, Pulmonary

Of 1,710 Chinese patients with radiologically active pulmonary tuberculosis but with sputum negative for acid-fast bacilli on four or more initial microscopic examinations who were studied for 5 yr, 592 (35%) had one or more initial sputum cultures positive for Mycobacterium tuberculosis. These 592 patients were randomly allocated to receive streptomycin, isoniazid, rifampin, and pyrazinamide daily for 4 months or 3 times a week for either 4 or 6 months. The remaining 1,118 patients with all their initial cultures negative were randomly allocated to receive the same four drugs daily for 3 months or 3 times a week for either 3 or 4 months. There were no bacteriologic failures during chemotherapy, and the relapse rates for the 4-month regimens during the 5 yr were 2% in 293 patients with drug-susceptible cultures initially (95% confidence limits, 1 to 5%); 8% in 59 patients with cultures resistant to isoniazid, streptomycin, or both drugs, but susceptible to rifampin initially; and 4% in 325 patients with all their cultures negative initially (95% confidence limits, 1 to 7%). The combined relapse rate for the 3-month regimens was 7% in 709 patients with all their cultures negative initially (95% confidence limits, 5 to 9%). In Hong Kong, 4 months of chemotherapy is now used routinely in the treatment of patients with smear-negative pulmonary tuberculosis, whether their initial sputum cultures are positive or negative.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Female; Hong Kong; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Random Allocation; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

Treatment of tuberculosis should be as short and as simple as possible in order to improve patient compliance; and combinations of at least three drugs should be used in order to kill the different populations of mycobacteria and to avoid development of drug resistance.--In a controlled multicentre study two regimens were compared in 93 patients with newly-diagnosed pulmonary tuberculosis: 1) Six-month therapy (47 cases): Daily rifampicin and isoniazid, supplemented with pyrazinamide for the first 2 months. A tablet with a fixed combination of 120 mg rifampicin, 50 mg isoniazid and 300 mg pyrazinamide (Rifater) was used. 2) Present Swiss standard therapy (46 cases): Daily rifampicin, isoniazid and ethambutol for 2 months followed by rifampicin and isoniazid for 7 months.--The time-course of culture negativation and the frequency of adverse events were similar in the two groups. During a follow-up period of at least two years only one relapse was observed in the six-month regimen, 3 months after completion of treatment. This was one of three patients with pretreatment resistance to isoniazid. Nevertheless, two of them were cured with the six-month regimen containing Rifater.--Patient compliance, assessed during outpatient treatment by detecting isoniazid metabolites in the urine, was very good (93% of tests were positive in each group).--These results with a follow-up of more than 2 years, indicate that short-course therapy of 6 months duration with the fixed combination tablet may be recommended as treatment of choice in pulmonary tuberculosis except in cases of isoniazid resistance and other special situations (i.e. large cavitations, large number of viable bacilli).

Topics: Adult; Antitubercular Agents; Drug Combinations; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Multicenter Studies as Topic; Patient Compliance; Prospective Studies; Pyrazinamide; Recurrence; Rifampin; Time Factors; Tuberculosis, Pulmonary

Due to the scarcity of published articles on short-course chemotherapeutic regimens for pediatric pulmonary tuberculosis, the following study has been carried out: Twenty-five children diagnosed of pulmonary tuberculosis were administered a short course therapeutic regimen consisting of three tuberculostatics for the first two month (isoniazid, rifampicin and pyrazinamide) and only two (isoniazid and rifampicin) for the following four months. The results were compared with those obtained from a control group of twenty-five children receiving the "classical" therapy: two drugs (isoniazid and rifampicin) for a nine month period. The statistical analysis did not demonstrate any significant difference related to evolution, duration and complications of the disease, between both groups. Therefore, this short course therapeutic regimen could be accepted for pediatric pulmonary tuberculosis.

Topics: Antitubercular Agents; BCG Vaccine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Infant, Newborn; Isoniazid; Rifampin; Time Factors; Tuberculosis, Pulmonary

Schoolchildren were Mantoux-tested with 2 TU freeze-dried PPD RT23, and the strong reactors with indurations of 14.0 mm or more were selected for treatment with one of three different fixed drug combinations containing isoniazid or with placebo for 2 to 6 months. The initial tuberculin test was repeated after 8, 14, and 27 months. Of the 8,934 black schoolchildren initially tested, 5,165 did not react to the skin test, 2,898 had indurations up to 14.0 mm, and 871 reacted strongly. Of these strong reactors, 808 were allocated to four preventive treatment groups. On completion of treatment, the mean tuberculin reaction for all groups was significantly decreased. Because the placebo group showed changes similar to those seen in the other treatment groups, the tuberculin skin test is probably not suitable for monitoring the success of preventive therapy. Differences between skin test results before and after treatment when retesting only strong reactors are caused by a combination of effects that are difficult to distinguish. Assuming random variation in tuberculin sensitivity, the decrease can be explained as a combined effect of regression to the mean and some boosting. The increased reaction sizes in the subsequent Mantoux tests are explained by the booster phenomenon and possibly by reinfection. When using a cutting point for deriving a positive reactor, the chance of being selected for preventive treatment may depend primarily on the moment in time when the test is done. Thus, all reactors with no recent BCG vaccination should equally be considered for treatment.

Topics: Adolescent; Child; Dapsone; Drug Combinations; Ethambutol; Female; Humans; Hypersensitivity, Delayed; Isoniazid; Male; Placebos; Prothionamide; Random Allocation; Rifampin; Tuberculin Test; Tuberculosis, Pulmonary

In a study in Singapore, patients of Chinese, Malay, and Indian ethnic origin with sputum-smear-positive pulmonary tuberculosis were allocated at random to daily treatment with streptomycin, isoniazid, rifampin, and pyrazinamide for 2 months (2SHRZ), for 1 month (1SHRZ), or for 2 months without streptomycin (2HRZ), followed, for all patients, by 3-times-weekly isoniazid and rifampin (H3 R3) up to 6 months. As previously reported, all except 1 of 319 patients with drug-susceptible tubercle bacilli pretreatment had a favorable bacteriologic status at the end of chemotherapy, and among the 300 patients assessed up to 30 months (24 months after the end of chemotherapy), there was only 1 bacteriologic relapse in each series, giving an overall therapeutic failure rate of only 1.3%. Follow-up has been continued at 6-month intervals up to 5 yr. During the 5 yr, the total relapse rate for patients with drug-susceptible strains pretreatment was 2.4% of 297 patients (95% confidence limits, 1.0 to 4.8%). Among the 31 patients with strains resistant to isoniazid, streptomycin, or both drugs pretreatment, there were no failures during chemotherapy and 4 (13%) subsequent relapses.

Topics: Antitubercular Agents; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Follow-Up Studies; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Patients with pulmonary tuberculosis who were failures of primary chemotherapy with strains resistant to isoniazid or to isoniazid and streptomycin were allocated at random to receive a regimen of rifampicin and ethambutol for 6 (4RE) or 9 months (7RE), supplemented in both treatment series by streptomycin plus pyrazinamide for the first 2 months. The patients were treated in hospital for the first 2 months and thereafter treatment was supervised on a daily basis in the nearest health institution by an appointed member of staff or at home by responsible members of the community. A total of 306 patients was admitted and 226 patients remained for analysis at the end of chemotherapy, 179 with a strain resistant to isoniazid alone and 47 with a strain resistant to isoniazid and streptomycin. There were only two failures at the end of chemotherapy, one in the 6-month series who had resistance to both isoniazid and streptomycin pretreatment, and one in the 9-month series who had resistance to isoniazid alone. For the 144 patients with initial resistance to isoniazid alone assessed up to 30 months, the relapse rates were low in both series: 4% for the 72 patients in the 6-month series and 3% for the 72 patients in the 9-month series. However, for the 34 patients with resistance to both drugs, three of the 14 in the 6-month but none of 20 in the 9-month series relapsed.

Topics: Adolescent; Adult; Clinical Trials as Topic; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Tuberculosis, Pulmonary

One daily and 3 thrice weekly retreatment regimens given for 12 months under programme conditions were compared. The daily regimen was rifampicin and ethambutol (RE7). The three intermittent regimens also contained rifampicin and ethambutol: one of them, rifampicin and ethambutol throughout (RE3); the next one supplemented with pyrazinamide for the first 3 months (REZ3); the last one supplemented with prothionamide for the first 3 months (REPt3). The pyrazinamide containing regimen was subdivided into ordinary and high dose groups. The subjects for retreatment were those who have had, at least, more than 6 months of initial triple chemotherapy of isoniazid, PAS and streptomycin at the health centres, and failed to convert to bacteriologically negative status. Among 419 patients who were available for sensitivity tests before commencing retreatment, 393 (94.3%) were resistant to isoniazid. Six hundred and seventy-four patients (674) were allocated randomly to the regimens: 64 patients were excluded due to various pretreatment reasons and 109 did not complete 12 months of chemotherapy. There remain 501 patients who completed their retreatment. As assessed at 12 months, a bacteriologically favourable response was achieved in 68% of 135 RE7 patients, 62% of 129 RE3 patients, 74% of 132 REZ3 patients, and in 79% of 108 REPt3 patients. Adverse reactions were uncommon: 4% in RE7, 5% in RE3 and 9% in REZ3, but 32% in REPt3. Relapse rates during 2 years after termination of chemotherapy were 15% in RE7, 14% in RE3 and REZ3, and 26% in REPt3, as calculated by life table analysis.

Topics: Adolescent; Adult; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Male; Prothionamide; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Three regimens of 9 months' duration, 2 containing Isoprodian (isoniazid, prothionamide and dapsone) and either rifampicin or pyrazinamide and the third, a former standard regimen, isoniazid, streptomycin and pyrazinamide, were allocated at random to 436 untreated African tuberculosis patients. In the course of the trial 83 were excluded for various reasons and 93 were lost. After 3 months of hospitalization, patients took either Isoprodian or isoniazid at home for 6 months and were then followed up for 24 months. The Isoprodian plus rifampicin regimen achieved 97% bacteriological cure, the Isoprodian plus pyrazinamide regimen 86% and the standard regimen 91%. Of 35 patients found to harbour drug-resistant strains 22 were cured. There were 15 relapses in all. Absconding was the most common cause of failure.

Topics: Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Dapsone; Drug Combinations; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Prothionamide; Pyrazinamide; Radiography; Recurrence; Rifampin; Sputum; Tuberculosis, Pulmonary

This is the first prospective clinical trial recorded to date of short-course chemotherapy in pulmonary tuberculosis complicated by pneumoconiosis. Forty-eight anthrasillicotic and 11 silicotic patients with previously untreated pulmonary tuberculosis completed 9-month, short-course chemotherapy regimens: 2 months of daily streptomycin, isoniazid, rifampicin, and pyrazinamide followed by daily isoniazid and rifampicin for 7 months (2SHRZ/7HR). There were 3 treatment failures (5%). The remaining 56 patients (95%) all had their sputum converted within 4 months (mean, 1.5 months). Bacteriologic relapses were noted in 3 patients (5%) after 18 to 40 months of follow-up (mean, 28.4 months). The relapses occurred within 7 months after chemotherapy was stopped. There were 2 deaths from nontuberculosis causes during the follow-up period. Fifty-one patients (90%) remained bacteriologically sterile for 28.4 +/- 6.1 months. These results suggest that the 2SHRZ/7HR regimen is satisfactory in treating anthrasilicotic or silicotic patients with pulmonary tuberculosis, though antituberculosis chemotherapy seemed less effective in patients with pneumoconiosis than in those without pneumoconiosis.

Topics: Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Isoniazid; Middle Aged; Pneumoconiosis; Prospective Studies; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Combinations; Female; Humans; Isoniazid; Male; Patient Compliance; Pyrazinamide; Random Allocation; Rifampin; Tuberculosis, Pulmonary

Despite previous findings to the contrary in uncontrolled studies, we have found in a randomized trial that rifampicin does not suppress the tuberculin reaction in patients with tuberculosis.

Topics: Humans; Random Allocation; Rifampin; Tuberculin Test; Tuberculosis, Pulmonary

In a study of 41 African Zulus with acute pulmonary tuberculosis, 55% were found to have a suboptimal cortisol response to Synacthen and all had very low plasma dehydroepiandrosterone levels. Following a 2-week course of antituberculous chemotherapy there was an improvement in adrenal corticosteroid function with a reduction to 30% of those showing an impaired cortisol response to Synacthen, but adrenal androgen function did not improve in any. Patients who received rifampicin as part of their treatment appeared to show less improvement in adrenal corticosteroid function when compared to a group who received antituberculous treatment which did not include rifampicin.

Topics: Acute Disease; Adolescent; Adrenal Glands; Adrenocorticotropic Hormone; Adult; Aged; Child; Child, Preschool; Ethambutol; Female; Humans; Hydrocortisone; Infant; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

During the past decade, six short-course (6-month) chemotherapy regimens were studied in which drugs were given daily and intermittently. Four regimens containing isoniazid, rifampin, and ethambutol caused little toxicity but yielded relapse rates (8-21%) which were unacceptably high. The safety of giving rifampin (450 or 600 mg) twice weekly was confirmed, however, and there was evidence that daily therapy during the 4-month continuation phase was no more effective than twice weekly isoniazid and rifampin. Once weekly therapy during the continuation phase was clearly inadequate. The use of four drugs (isoniazid, rifampin, pyrazinamide, and streptomycin) given daily during the initial 2 months of therapy followed by 4 months of twice weekly isoniazid and rifampin resulted in a nearly 100% cure rate. However, this regimen was not well tolerated by patients. Deleting streptomycin improved the tolerability of the regimen but appears to have slightly increased the frequency of treatment failure and relapse. A suggested model for choosing treatment regimens is presented.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary

The bacteriological relapse rates up to 30 months after the start of chemotherapy have been compared for 4 daily short-course regimens for pulmonary tuberculosis. All 4 had the same initial 2-month intensive phase of streptomycin, isoniazid, rifampicin and pyrazinamide (SHRZ) followed by isoniazid plus rifampicin for 4 months (4HR), or isoniazid plus pyrazinamide for 4 months (4HZ), or isoniazid alone for 4 months (4H), or isoniazid alone for 6 months (6H). In patients with fully sensitive strains pretreatment, the 6-month regimen with rifampicin throughout (4HR) was highly effective, only 2% of 166 patients relapsing bacteriologically in 24 months of follow-up after stopping chemotherapy. This regimen was significantly better than the 4H regimen which had a relapse rate of 10% in 156 patients (P less than 0.02) and the 4HZ regimen which had a relapse rate of 8% in 164 patients (P = 0.05). The 6H regimen was also highly effective, only 3% of the 123 patients relapsing, compared with 10% of the 156 on the 4H regimen (P = 0.06). The relapse rate of the regimen with pyrazinamide throughout (4HZ), was not significantly different from that of either of the regimens with isoniazid alone in the continuation phase. All except 3 (1 4HR, 1 4HZ, 1 4H) of the 36 relapses were with fully drug-sensitive strains. In patients with strains resistant to isoniazid alone pretreatment none of the 23 on the 4HR or 4HZ regimens had an unfavourable bacteriological status at the end of chemotherapy compared with 8 of the 17 patients (P less than 0.005) on 4H or 6H regimens. Of the patients assessed, 3 of 20 receiving rifampicin or pyrazinamide throughout relapsed compared with 2 of 8 who did not.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Tuberculosis, Pulmonary

A controlled comparison of 3 short-course regimens was undertaken in patients with newly diagnosed, sputum-positive, pulmonary tuberculosis in South India. The regimens were: R3: rifampin plus streptomycin plus isoniazid plus pyrazinamide daily for 3 months; 5: the same as regimen R3 followed by streptomycin plus isoniazid plus pyrazinamide twice weekly for 2 months; Z5: the same as regimen R5 but without rifampin. The distributions of various pretreatment characteristics were similar in the 3 series. At the end of treatment, 6 patients (3 R3, 3 Z5) of 694 (228 R3, 230 R5, 236 Z5) with drug-sensitive organisms initially were classified as having an unfavorable response. By 24 months (21 months of follow-up for the R3 regimen and 19 months for the R5 and Z5 regimens), a bacteriologic relapse requiring treatment occurred in 20% of 200 R3, 4% of 187 R5, and 13% of 199 Z5 patients, the difference between the R3 and R5 series being highly significant (p = 0.00001). Considering patients with cultures initially resistant to isoniazid, 4 of 57 in the R3 and R5 series combined had an unfavorable response to treatment compared with 13 of 26 in the Z5 series (p less than 0.0001). Of the 4 patients with an unfavorable response in the R3 and R5 series combined, resistance to rifampin emerged in 2. Complaints of arthralgia were made by 45% of the R3 and R5 patients combined and 70% of the Z5 patients (p less than 0.00001). However, chemotherapy was modified in only 5 and 12%, respectively. Jaundice occurred in 7% of the R3 and R5 patients and 1% of the Z5 patients (p less than 0.00001).

Topics: Adolescent; Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Dizziness; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; India; Isoniazid; Joint Diseases; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Humans; Rifampin; Tuberculosis, Pulmonary

Forty-six patients with positive sputum cultures for Mycobacterium avium complex and cavitary disease were placed on a 4-drug regimen consisting of isoniazid, rifampin, and ethambutol daily and streptomycin twice weekly. Forty-two (91.3%) converted their sputum to negative and 4 (8.7%) failed to convert. All of the 4 nonconverters had prior subtotal gastrectomy. Twenty-two patients were available for long-term follow-up: 12 patients completed 24 months of chemotherapy, all experienced sputum conversion, but 2 reactivated, 1 at 9 and the other at 27 months after termination of chemotherapy. These 2 patients had prior subtotal gastrectomy. Ten patients completed 18 months of chemotherapy with sputum conversion, 2 of these reactivated but had not had prior subtotal gastrectomy. In this group of patients, subtotal gastrectomy appeared to be an adverse risk factor for both initial treatment response and reactivation in pulmonary disease caused by Mycobacterium avium complex.

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Mycobacterium avium; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

Three short-course regimens, all comprising isoniazide (H), rifampicine (R), streptomycine (S) and pyrazinamide (Z), are compared in a randomized prospective cooperative clinical trial. The drugs are given daily in a 3-month regimen (3-HRSZ), twice a week in a 6-month regimen (6-HRSZ2), and in a further two-phase 6-month regimen the 4 drugs are administered 3 times a week for the first 3 months followed by the administration of HSZ twice a week (without R) for further 3 months (3-HRSZ3/3-HSZ2). The number of patients admitted to study is 80, 144 and 139 respectively. The 3-month regimen has been stopped because of a high rate of relapses. 17 p.c. of the patients admitted have to be excluded from analysis for various reasons, out of these 5.8 p.c. because of adverse reactions. Two thirds of the patients had heavily positive sputum cultures at the start. 300 patients completed therapy. At the end of therapy cultures were negative in 94 p.c., 100 p.c. and 99 p.c. respectively. The rate of bacteriological relapses is 19 p.c. in 3-HRSZ, 9 p.c. in 3-HRSZ3/3-HSZ2 and 3 p.c. in 6-HRSZ2, during a follow-up period of 3-4 years after completing therapy. The acceptability was good in all treatment groups. Adverse reactions like "flu" were rarely observed. Increased blood urea was common but in general without clinical symptoms. Elevation of ALAT and ASAT was relatively frequent but mostly transient and without clinical importance. The results served as basis for the new "Recommendation for Treatment of Tuberculosis" and are interpreted with regard to practical consequences and possibilities for further rationalisation of treatment.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Middle Aged; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Tuberculosis, Pulmonary

A controlled clinical trial of daily short course (6-month) chemotherapy in newly diagnosed cases of pulmonary tuberculosis in Nigerians was carried out. The three regimens used contained streptomycin, isoniazid, rifampicin and pyrazinamide in the initial phase; and isoniazid plus rifampicin or isoniazid plus rifampicin and/or pyrazinamide in the continuation phase. Sputum culture conversion was satisfactory after 2 and 6 months of treatment and no positive cultures were found one year after treatment had been completed. Side effects were few and consisted mainly of arthralgia, possibly associated with pyrazinamide.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Nigeria; Pyrazinamide; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

In a study in Singapore, Chinese, Malay, and Indian patients with sputum-smear-positive pulmonary tuberculosis were allocated at random to daily treatment with streptomycin, isoniazid, rifampin, and pyrazinamide for 2 months (2SHRZ), 1 month (1SHRZ), or 2 months without streptomycin (2HRZ), followed, for all patients, by 3-times-weekly isoniazid and rifampin (H3R3) up to 6 months. At 2 months, the culture-negativity rate for the 2SHRZ series was statistically significantly higher than for either of the other 2 series. All 319 patients with drug-sensitive tubercle bacilli pretreatment had a favorable bacteriologic response during chemotherapy except for one 2SHRZ/H3R3 patient, and among the 300 patients assessed during 24 months of follow-up after chemotherapy there was only 1 bacteriologic relapse in each series, giving an overall therapeutic failure rate of only 1%. Thus, the 2SHRZ combination had the highest early sterilizing activity, but the potent continuation therapy compensated for the initial inferiority of the other 2 regimens. Among the 32 patients with tubercle bacilli resistant pretreatment to isoniazid, streptomycin, or both drugs, there were no failures during chemotherapy and 3 subsequent relapses among the 30 assessed during 24 months of follow-up. Eleven (3%) of the 420 patients who started chemotherapy on their allocated regimen had hepatitis with jaundice during chemotherapy. However, 2 of these had cirrhosis pretreatment and 1 was a chronic alcoholic.

Topics: Adolescent; Adult; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Two 6-month daily regimens of chemotherapy for smear-positive pulmonary tuberculosis were compared in Tanzania. Both had the same initial 2-month intensive phase of streptomycin, isoniazid, rifampicin, and pyrazinamide, and the continuation phase was either thiacetazone plus isoniazid or isoniazid alone. All patients were hospital inpatients for 6 months, solely to ensure that chemotherapy was fully supervised throughout. The patients were followed up to 24 months after stopping chemotherapy. In patients with fully sensitive strains pretreatment, there were no failures during chemotherapy on either regimen; the bacteriologic relapse rates were 3% for the 105 patients receiving thiacetazone plus isoniazid in the continuation phase, and 11% for the 100 patients receiving isoniazid alone (p less than 0.05). Possible adverse reactions were reported in the initial phase in 5 (1.6%) of 319 patients who started treatment, and in 2 of 306 who started the continuation phase, chemotherapy being modified in 5 of the 7 patients.

Topics: Adolescent; Adult; Clinical Trials as Topic; Drug Resistance, Microbial; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tanzania; Tuberculosis, Pulmonary

To measure the effectiveness of treatment for pulmonary tuberculosis in Peru we evaluated the fate of 2,669 patients who had tuberculosis diagnosed in 1981. Two regimens were used: (1) isoniazid, rifampin, pyrazinamide, and streptomycin daily for 2 months, then either isoniazid and streptomycin twice a week or isoniazid and thiacetazone daily for 6 months; and (2) isoniazid, streptomycin, and thiacetazone daily for 2 months, then either isoniazid and streptomycin twice weekly or isoniazid and thiacetazone daily for 10 months. Patients were not assigned at random to the 2 treatment regimens; thus, the results cannot be directly compared. In the 8-month group, 70% had a favorable outcome, 14% abandoned, 9% failed, 3% died, and 3% relapsed. In the 12-month group, 53% had a favorable outcome, 34% abandoned, 6% failed, 4% died, and 2% relapsed. In patients who did not abandon treatment, the results of both regimens were nearly identical. Patients in both groups who had been treated previously had significantly lower rates of cure than those not treated previously.

Topics: Adolescent; Adult; Antitubercular Agents; Child; Child, Preschool; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Infant; Infant, Newborn; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

190 patients with positive cultures for M. tuberculosis were treated in the initial phase as inpatients for 2-3 months at random with either pyrazinamide (Z) or ethambutol (E) in combination with isoniazid (H) and rifampicin (R). In the continuation phase as out-patients they were treated by their family doctor for a further seven months with a new randomization using either R or E combined with H. Regular controls of drug intake using urine test strips were 97% positive. The patients treated with Z showed a tendency to more rapid conversion to negative cultures despite the significantly shorter duration of initial-phase treatment. During the average observation period of 33 months after commencing therapy there were five relapses (without development of drug resistance). The distribution over the four patient groups did not allow statistical conclusions to be drawn. All of the relapses occurred during the first year after the treatment ended. All relapsing patients showed an unusually long delay (108 days) before the tuberculosis cultures proved negative, in comparison with only 48 days in all patients. The relapse rate of 3.6% equals comparable controlled studies in the literature of the last four years, in which patients were initially hospitalized for two months or received medication under direct supervision as out-patients. The family doctors treated their patients on average for ten months instead of the nine months recommended in the treatment scheme ("doctor's compliance"). This seems to be a direct consequence of the earlier recommendations in favour of a longer duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Prospective Studies; Pyrazinamide; Random Allocation; Rifampin; Tuberculosis, Pulmonary

Three anti-tuberculous regimens were compared in Algiers. The three regimens use Isoniazid and Rifampicin every day for six months; two of them used a third drug, Ethambutol or Pyrazinamide for the first three months. The results at 12 months after cessation of chemotherapy have already been reported. At 30 months (or 24 months after the end of treatment) the results were analysed for 513 cases: in 27 cases (5%) there was a relapse or therapy failed. Of 21 relapses 13 occurred in the first six months of follow up, four during the next six months, three during the third and one in the final six months. No further relapse was seen between the thirtieth and forty second months. All the cases of failure or relapse had received an additive chemotherapy. Two patients were on chemotherapy again for a relapse noted in under six months; the other 25 patients had a satisfactory outcome after receiving a regime of six to 12 months containing Rifampicin in 21 cases or a regime 12 months without Rifampicin in four cases. There was no statistically significant difference between the three therapeutic series for those cases with tubercle bacilli initially sensitive to the antituberculous drugs. On the other hand, for primary Isoniazid resistance a third drug is essential during the initial treatment. In the overall analysis pyrazinamide was as effective as Ethambutol in avoiding failure due to primary drug resistance and relapses up to 30 months.

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Drug Administration Schedule; Drug Therapy, Combination; Humans; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Uric Acid

We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic "first-pass" effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.

Topics: Administration, Oral; Adolescent; Adult; Aged; Biological Availability; Drug Therapy, Combination; Ethambutol; Female; Humans; Infusions, Parenteral; Isoniazid; Male; Metabolic Clearance Rate; Middle Aged; Rifampin; Rifamycins; Tuberculosis, Pulmonary

In an area where default from out-patient treatment for tuberculosis is very frequent and leads to 16% known failures on the 2SHT/16HT regimen, a 1-year follow-up study was carried out on 201 new sputum smear-positive patients who were hospitalised for the first 2 months of treatment. The first 103 patients were treated with 2SHT/10HT and the remaining 98 with 2SHRZ/10HT. In the first group 15 (17%) out of 89 traced patients were sputum-positive on a single smear after 1 year, compared with 1 (1%) out of 78 in the second group (P less than 0.001).

Topics: Adult; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Eswatini; Female; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

In a multicenter trial of 2 regimens for treatment of pulmonary tuberculosis, all patients received 300 mg of isoniazid (INH) and 600 mg of rifampin (RIF) daily for 6 months (the Initial Phase). During the next 9 months (the Maintenance Phase) patients received either daily INH (300 mg) and ethambutol (EMB) (15 mg per kg body weight) or matching placebos. Of the 672 patients who met the admission criteria, only 309 (46%) completed the Initial and Maintenance Phases. Approximately 20% of the patients failed to keep their appointments. Adverse drug reaction, most commonly hepatotoxicity, accounted for the withdrawal of 37 patients (5.5%). No visual toxicity caused by EMB was observed. During the Maintenance Phase, 3 patients who were taking INH and EMB, and 16 who were taking placebos, developed relapses, i.e., 2 or more positive cultures. The significant difference in relapse rate between regimens (Fisher's exact test, p less than 0.001) demonstrates the inadequacy of INH-RIF given alone for only 6 months.

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Patient Compliance; Random Allocation; Rifampin; Tuberculosis, Pulmonary; United States

A 6-month short-course chemotherapy regimen and a 12-month standard duration regimen have been compared in the treatment of pulmonary tuberculosis in a rural area of Algeria in a population with a relatively high proportion of nomads. The 6-month regimen was isoniazid and rifampicin throughout, with ethambutol and pyrazinamide in addition for an initial 2-month intensive phase. The 12-month regimen was isoniazid and ethambutol throughout, supplemented by streptomycin during the first month. All 601 patients admitted had one or more sputum smears positive on examination in the local laboratory. Most patients were admitted to hospital initially for 1 to 2 months, where they received their chemotherapy under full supervision; thereafter, it was self-administered. In both nomads and settled residents known to have fully sensitive strains pretreatment, the 6-month regimen was highly effective, with no failures during chemotherapy and only 3% relapses after stopping chemotherapy in 131 patients compared with a combined failure rate during chemotherapy and relapse rate of 17% in the 154 patients receiving the 12-month regimen (p less than 0.001). The results in patients with isoniazid-resistant strains pretreatment were also significantly better for the 6-month than for the 12-month regimen, none of 15 and 7 of 15 patients, respectively, being classified as failures or relapses.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Algeria; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Hospitalization; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Rural Population; Streptomycin; Tuberculosis, Pulmonary

Topics: Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Rifampin; Sputum; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Injections, Intravenous; Male; Rifampin; Tuberculosis, Pulmonary

Topics: Ambulatory Care; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Female; Humans; Male; Middle Aged; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

Two 6-month regimens of isoniazid and rifampicin supplemented for the first 2 months by streptomycin and pyrazinamide (SHRZ6 regimen), or by ethambutol and pyrazinamide (EHRZ6 regimen), were compared with a 9-month regimen of isoniazid and rifampicin supplemented for the first 2 months by ethambutol (EHR9 regimen). All 444 patients who completed chemotherapy had negative sputum cultures by the end of treatment. Of these, 373 have been followed for a minimum duration of 36 months after the end of chemotherapy. Relapses have occurred in two of 119 SHRZ6 patients, four of 127 EHRZ6 patients and two of 127 EHR9 patients. These results demonstrate that the two 6-month regimens are as effective as the currently recommended 9-month regimen. They are equally well tolerated and have the advantages of being shorter and cheaper. The Research Committee of the British Thoracic Society now recommends the use of either of the two 6-month regimens as an alternative to the currently recommended 9-month regimen.

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Follow-Up Studies; Humans; Isoniazid; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary

The success of short-course chemotherapy for tuberculosis, the similarity between Mycobacterium tuberculosis and M. kansasii and the effectiveness of rifampin against the latter organism prompted a comparison of the diseases due to these organisms to assess the feasibility of a prospective trial of short-course chemotherapy in patients with mycobacteriosis kansasii. The two groups of patients were matched for age, sex and time of diagnosis. The patients with mycobacteriosis kansasii more frequently had underlying obstructive pulmonary disease. The clinical course of mycobacteriosis kansasii was more indolent, with a slower rate of improvement according to the chest x-ray films and a longer time before sputum smears and cultures became negative. M. kansasii was significantly more resistant to all the antibiotics, including rifampin. Although these differences from tuberculosis suggest that an equally short course of therapy may not be effective for patients with mycobacteriosis kansasii, the outcome was good in compliant patients who were given the three most effective major drugs for 12 months after the sputum smears and cultures had become negative. Therefore, a trial of modified short-course chemotherapy is recommended for patients with mycobacteriosis kansasii.

Topics: Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Microbial; Female; Humans; Male; Middle Aged; Mycobacterium Infections; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Prospective Studies; Rifampin; Time Factors; Tuberculosis, Pulmonary

In a previous study, we have shown that a 6-month regimen consisting of 2 months of isoniazid, rifampin, pyrazinamide, and streptomycin administered daily (2IRSZ) followed by 4 months of isoniazid and rifampin administered twice weekly (4I2R2) yielded no relapses after 30 months of follow-up. In order to assess the contribution of streptomycin to this treatment regimen, 213 patients with newly detected smear-positive pulmonary tuberculosis were randomly assigned to the following two 6-month treatment regimens: 2IRZ/4I2R2 and 2IRSZ/4I2R2. One hundred seventy-two of the 213 patients (81%) completed therapy, i.e., 116 of 135 patients (86%) treated with 2IRZ/4I2R2 and 56 of 78 patients (72%) treated with 2IRSZ/4I2R2. Adverse reactions requiring withdrawal of drugs for 7 days or longer were observed in 4.2% of patients (3.7% receiving the 2IRZ/4I2R2 regimen and 5.1% receiving the 2IRSZ/4I2R2 regimen). At the end of treatment, all patients in the 2IRZ/I2R2 series had negative smears and cultures. Two of the 116 patients (1.7%) in the 2IRZ/I2R2 series developed isoniazid resistance in the fourth month of treatment and remained sputum positive at the end of treatment. In the follow-up period, 4 patients (3.4%) treated with 2IRZ/4I2R2 relapsed and 1 (1.8%) treated with 2IRSZ/4I2R2 relapsed. The only significant difference between the 2 regimens was the higher dropout rate among those assigned to the 2IRSZ/4I2R2 regimen.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Therapy, Combination; Evaluation Studies as Topic; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Administration Schedule; Humans; Isoniazid; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Prednisolone; Pyrazinamide; Random Allocation; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

Four daily short-course chemotherapy regimens (three 6-month and one 8-month) for pulmonary tuberculosis have been compared. All four had the same initial 2-month intensive phase of streptomycin, isoniazid, rifampicin and pyrazinamide (SHRZ). The continuation phase of the 6-month regimens was: 1) isoniazid and rifampicin (4HR), or 2) isoniazid and pyrazinamide (4HZ), or 3) isoniazid alone (4H) and of the 8-month regimen 4) isoniazid alone (6H). All patients have been followed up for 12 months after stopping chemotherapy. In patients with fully sensitive strains pretreatment the 6-month regimen with rifampicin throughout (4 HR) was highly effective with a bacteriological relapse rate of 2% of 167 patients, significantly better (P less than 0.01) than the rate of 9% of 158 patients in the 6-month regimen with isoniazid alone in the continuation phase (4H). The 8-month regimen (6H) was also highly effective, with a relapse rate of 3% of 119 patients but was not significantly better (p greater than 0.1) than the 6-month isoniazid regimen (4H). The regimen with pyrazinamide throughout (4HZ) had a relapse rate of 4% of 165 patients, not significantly different from any of the other regimens. An important finding in the two regimens with isoniazid alone in the continuation phase (4H and 6H) was that 1 of the 2 failures during chemotherapy and 17 of the 18 bacteriological relapses after stopping occurred with strains still sensitive to isoniazid. In patients with strains resistant to isoniazid pretreatment, 8 of 19 patients on the 4H or 6H regimens had an unfavourable response during chemotherapy compared with none of 26 on the HR or HZ regimens (P less than 0.005). Of the 851 patients who started treatment, 24 developed possible adverse reactions but only 6 required modification of their chemotherapy.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

A cooperative french trial in the treatment of pulmonary tuberculosis has compared the efficacy and the tolerance of daily antituberculous regimes, one of short duration of 18 weeks (HRSZ/HRZ), the other of standard duration of 9 months (HRE). Of 204 patients included in the trial 180 were analysed. No significant difference was found between the two regimes regarding either biological tolerance or clinical outcome. Four relapses were seen within 24 months of the onset of treatment, two in each regime, which shows that 18 weeks treatment is ethically acceptable. Such short course therapy is useful in those patients who would sometimes find prolonged therapy difficult or would be likely to abandon treatment prematurely.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

The relapse rate after short course chemotherapy is usually assessed by cases that are available for analysis, with a delay which rarely exceeds 3 years from the time of instituting therapy. This level may be disputed if too many are lost to follow up or non-compliers appearing late. To understand the true failure rate we strove to trace every patient in a trial carried out between 1969 and 1973, consisting of three groups of patients treated with the same chemotherapy: Isoniazid (450 mg/day), Rifampicin (600 mg/day) given every day but for differing durations: 6 months (Group A), 9 months (Group B), 12 months (Group C), with either daily Ethambutol or Streptomycin in addition for the first three months. Amongst the 356 patients in the trial 86 were eliminated for failure to comply with the protocol, either due to a mishap or change of treatment. Amongst the 270 remaining patients, 248 were traced with a mean delay of post-therapy follow up of 101 months for patients still living and of 72 months for patients who had died in the intervening period, but of non-tuberculous disease. In the 242 old patients whose disease could be evaluated, the number of bacteriological relapses was 4/81 (6.2 %) in group A, and 2/85 (2.3 %) in group B and 2/76 (2.6 %) in group C. There was no significant differences between the groups. From these results it is seen that the Isoniazid/Rifampicin combination given daily for 6 months is a powerful combination with few failures. Maintaining such chemotherapy for 12 months does not seem to yield substantial gains. In conclusion nine months of chemotherapy with this regime offers a sufficiently ample guarantee of cure.

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Follow-Up Studies; Humans; Isoniazid; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Administration, Oral; Adult; Female; Humans; Injections, Intravenous; Male; Rifampin; Tuberculosis, Pulmonary

Recent experience suggests that the duration of chemotherapy of tuberculosis can be shortened to 6-9 months, without an increase in the relapse rate, if the treatment if started with 3 or 4 drugs including isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA). In a controlled study of culture-positive advanced pulmonary tuberculosis we have compared treatment regimens with PZA in a dosage of less than 2 g and with ethambutol (EMB). 113 patients were given, in random order for 2-3 months, either PZA (25 mg/kg body weight) or EMB (25 mg/kg) together with RMP (450 or 600 mg) and INH (5 mg/kg). The last two drugs were given for a total of 9 months. Patients treated with PZA showed a (not significantly) earlier conversion to negative cultures after an average of 7 weeks. After 18 months follow-up there have been no relapses on these regimens. 2 patients, both treated with EMB, did not respond to therapy. Drug-induced hepatitis was seen in 5 patients with PZA and in 2 patients with EMB. The hepatitis was always observed during the first month of therapy and was fully reversible. Three of the 4 patients with clinically apparent hepatitis were over 70 years of age. Three patients with elevated uric acid levels had arthralgia which led in one of them to termination of therapy. The preliminary results of our study show that the treatment regimen with PZA does not lead to a higher rate of side effects if used with particular moderation in older patients.

Topics: Adult; Aged; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Middle Aged; Pyrazinamide; Random Allocation; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Administration, Oral; Adult; Biological Availability; Drug Therapy, Combination; Ethambutol; Female; Humans; Injections, Intravenous; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

Two 6-month regimens of isoniazid and rifampicin supplemented for the first 2 months by streptomycin and pyrazinamide or by ethambutol and pyrazinamide were compared with a 9-month regimen of isoniazid and rifampicin supplemented for the first 2 months by ethambutol. All 444 patients who completed chemotherapy had negative sputum cultures by the end of treatment. Of these, 393 have been followed for 24 months after the end of chemotherapy. Relapse has occurred in 1 of 125 SHRZ6 patients, 3 of 132 EHRZ6, and 2 of 136 EHR9 patients. These observations suggest that both 5-month regimens are as effective as the currently recommended 9-month regimen and have the advantages of being shorter, cheaper, and equally well tolerated.

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Follow-Up Studies; Humans; Isoniazid; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Aged; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Humans; Middle Aged; Rifampin; Tuberculosis, Pulmonary; USSR

Patients with culture-positive pulmonary tuberculosis were allocated at random into two groups for a three-phase regimen in original course chemotherapy. The first group was given rifampicin (RMP) plus isoniazid (INH) plus ethambutol until sensitivity tests were completed, then RMP plus INH until culture conversion, thereafter INH alone for four months. The second group received the same drugs until obtaining culture conversion, thereafter IHN alone for a period lasting two years after onset of chemotherapy. One hundred sixty-eight patients were available for the final assessment after a five-year follow-up after culture conversion. Two bacteriologic relapses occurred among the two-year scheme patients, none in the short-course patients.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Time Factors; Tuberculosis, Pulmonary

There is extensive favorable worldwide experience with short-course chemotherapy (SCC) for pulmonary tuberculosis. It has not yet been shown, however, that daily, unsupervised SCC would be efficacious in the United States, especially in large urban centers where compliance rates are poor and alcohol abuse is common. From January 1977 to February 1980, 75 patients began treatment using SCC combining isoniazid and rifampin for nine months, accompanied by ethambutol during the first 60 days. This report describes results achieved under "field conditions" with all medications self-administered except during the first few days of hospitalization. Forty-nine patients successfully completed this regimen. No patients failed chemotherapy during treatment and no relapses have occurred during follow-up through June 1981. There were no serious drug-related side effects. This study supports the results of similar studies conducted in other countries and provides further evidence that this regimen can be adopted more widely in this country.

Topics: Adult; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Rifampin; Self Administration; Tuberculosis, Pulmonary

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

Topics: Antitubercular Agents; Clinical Trials as Topic; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Aged; Antitubercular Agents; Dapsone; Drug Combinations; Drug Therapy, Combination; Humans; Isoniazid; Isonicotinic Acids; Male; Middle Aged; Prothionamide; Pyrazinamide; Radiography; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acid; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Ethionamide; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis, Pulmonary

We compared the bacteriologic relapse between 5 and 28 months for five 4-month chemotherapeutic regimens for pulmonary tuberculosis. The regimens were: (1) streptomycin plus isoniazid plus rifampin plus pyrazinamide daily for 8 wk followed by isoniazid plus rifampin plus pyrazinamide daily for 9 wk; (2) the same 4 initial drugs for 8 wk followed by isoniazid plus rifampin daily for 9 wk; (3) the same 4 initial drugs for 8 wk followed by isoniazid plus pyrazinamide daily for 9 wk; (4) the same 4 drugs for 8 wk followed by isoniazid daily for 9 wk; (5) the same as regimen 4; but without streptomycin for the first 8 wk. The first 2 regimens, in which rifampin was given for 4 months, had relapse rates of 16 and 11%, respectively, but the rates were much higher for the regimens in which rifampin was given for only 2 months (32 and 30 %, respectively). The addition of pyrazinamide in the continuation phase had no effect on relapse rate. Removal of the streptomycin (regimen 5) resulted in a relapse rate of 40%, but this was not significantly higher than that (30%) after regimen 4 (p = 0.2).

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Middle Aged; Pyrazinamide; Random Allocation; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary

The results of six-month courses of chemotherapy with daily isoniazid and rifampicin, supplemented for the first two months by either streptomycin and pyrazinamide (EHRZ6 regimen), or by ethambutol and pyrazinamide (EHRZ6 regimen), in patients with culture-positive pulmonary tuberculosis have been studied. These results have been compared with those of a nine-month regimen of daily isoniazid and rifampicin supplemented by ethambutol for the first two months (EHR9 regimen). All patients in the three regimens achieved negative cultures before the end of chemotherapy but the rate of sputum conversion was significantly more rapid with the two pyrazinamide-containing regimens. Of the 287 patients on the SHRZ6 and EHRZ6 regimens who completed chemotherapy, 77% had achieved negative cultures at two months and 98% at three months, compared with 64% and 88% respectively of the 157 patients on the EHR9 regimen. Adverse drug reactions were not a serious problem. Of the 234 patients who started treatment with the SHRZ6 and EHRZ6 regimens, 14 (4%) developed hepatitis; among the 177 patients in the EHR9 group (who did not receive pyrazinamide), the incidence of hepatitis was also 4%. Thus the addition of pyrazinamide to regimens containing rifampicin and isoniazid did not increase the incidence of hepatitis. However, the incidence of adverse effect other than hepatitis was increased in the pyrazinamide-containing regimens, the most common being skin rashes. These results indicate that six-month regimens containing pyrazinamide do not produce undue toxicity and are worthy of further study. Their usefulness in routine clinical practice will not become clear until a further period of follow-up of patients in this study had established the incidence of subsequent relapse.

Topics: Adolescent; Adult; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

In a study in Singapore, Chinese, Malay and Indian patients with pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampicin, and pyrazinamide followed by daily isoniazid, and rifampicin either with pyrazinamide (SHRZ/HRZ) or without it (SHRZ/HR), allocated at random. Both regimens were given for either 6 or 4 months by random allocation. All 330 patients with drug-sensitive tubercle bacilli pretreatment had a favourable bacteriological response during chemotherapy. After chemotherapy none of 78 SHRZ/HRZ patients and only 2 of 80 SHRZ/HR patients treated for 6 months relapsed bacteriologically, but 9 (11%) of 79 SHRZ/HRZ and 6 (8%) of 77 SHRZ/HR patients treated for 4 months relapsed. Of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs pretreatment, only 1 had an unfavourable response during chemotherapy; none of 9 patients treated for 6 months and 2 of 22 treated for 4 months relapsed bacteriologically after stopping chemotherapy.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Middle Aged; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Ethambutol; Female; Hepatitis; Humans; Isoniazid; Liver Function Tests; Male; Pyrazinamide; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary; United Kingdom

Topics: Adolescent; Adult; Aged; Arkansas; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Hypersensitivity; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

A total of 302 Chinese patients were diagnosed on clinical and radiographic grounds by chest physicians from the Hong Kong Chest Service as having radiographically active pulmonary tuberculosis, but had sputum negative for acid-fast bacilli on 5 recent microscopical examinations. They were not given antituberculosis chemotherapy until active disease had been confirmed by positive bacteriological findings, or by radiographic or clinical deterioration during close observation. Of the 283 patients assessed up to 30 months, 200 (71%) had active disease confirmed and had chemotherapy started during the 30 months. A further 42 (15%) had evidence of changing lesions on serial chest radiography, and hence of recently active disease. A number of characteristics of the patients and of their bacteriological and radiographic status were tested singly and in combination for association with the presence of active disease confirmed on admission or at any time during the 30 months. Patients with radiographic lesions which were larger and classified as "active" on independent radiological assessment, and with a history of blood-streaked sputum or frank haemoptysis were more likely to have unquestionably active disease on admission or at some time during the 30 months, than patients without these characteristics.

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Radiography; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

A 100-day interrupted regimen is described which is a useful and efficacious treatment for pulmonary tuberculosis. It is well tolerated, guarantees treatment supervision, and has acceptable relapse rates under normal programme conditions. The 5-day-a-week administration makes it particularly suitable for industrial medical services as well as for other outpatient health care clinical services.

Topics: Adult; Antibiotics, Antitubercular; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Follow-Up Studies; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adult; Age Factors; Antitubercular Agents; Female; Humans; Liver; Male; Middle Aged; Pancreas; Rifampin; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Follow-Up Studies; Humans; Isoniazid; Recurrence; Remission, Spontaneous; Rifampin; Societies, Medical; Streptomycin; Time Factors; Tuberculosis, Pulmonary; United Kingdom

Four short-course chemotherapy regimens for pulmonary tuberculosis have been compared: (1) streptomycin, isoniazid, rifampicin and pyrazinamide daily for 2 months followed by daily thiacetazone plus isoniazid; (2) the same 4 drugs daily for 1 month followed by thiacetazone plus isoniazid; (3) the same 4 drugs daily for 1 month followed by twice-weekly streptomycin, isoniazid and pyrazinamide; (4) the first regimen but without pyrazinamide in the initial intensive phase. Each regimen was given for 6 and 8 months and patients were followed up to 30 months. When given for 6 months the regimen with a 2-month 4-drug intensive phase had a bacteriological relapse rate of 13% and when given for 8 months there were no relapses. When pyrazinamide was omitted in the first 2 months the relapse rates were 18% for the 6-month and 6% for the 8-month series. The regimen with the 4-drug initial phase shortened to 1 month had relapse rates of 18% and 7% respectively if the continuation phase was thiacetazone plus isoniazid. However, the relapse rates were lower, 9% and 2% respectively, when the continuation phase was twice-weekly streptomycin, isoniazid and pyrazinamide.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

An analysis is presented of the side effects which occurred in 530 patients treated with 6 months chemotherapy for newly detected pulmonary tuberculosis. Five treatment regimens were used. The initial phase of treatment consisted of daily isoniazid, rifampicin and ethambutol (HRE) or isoniazid, rifampicin, streptomycin and pyrazinamide (HRSZ) given for 2 months. The second phase of treatment consisted of isoniazid and rifampicin given twice weekly (H2R2) or isoniazid, rifampicin and ethambutol given daily (4HRE) or intermittently (H1R1E1 or H2R2E2) for 4 months. Side effects were detected in 66 (12.4%) patients. Hepatotoxic reactions occurred in 48 (9%) patients, mainly of amild and transient nature and the majority were attributable to isoniazid. The 'flu like' syndrome occurred in only 2 patients both during the daily phase of treatment, and it was not encountered in patients taking rifampicin intermittently (dose 600 mg). Inclusion of pyrazinamide in the initial phase of 1 regimen did not result in an increase of frequency of side effects. In 56% of patients on pyrazinamide the serum uric acid concentration was elevated but there was no arthralgia. Drug toxicity leading to alteration or withdrawal of treatment occurred in only 10 (1.8%) patients. This study shows that with these 6 month regimens the overall risk of drug toxicity was low, and less than that associated with more conventional treatment regimens.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Middle Aged; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Aged; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium; Rifampin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aminosalicylic Acid; Antibiotics, Antitubercular; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aminosalicylic Acid; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Ethambutol; Hospitalization; Humans; Isoniazid; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Pulmonary

A history of alcoholism is often regarded as a relative contraindication to the use of isoniazid and rifampin in patients with tuberculosis. To test the validity of this assumption the outcome of 6 months of rifampin-isoniazid therapy was analyzed for the first 531 eligible patients enrolled in a U.S. Public Health Service Cooperative Trial of Short-Course Chemotherapy of Pulmonary Tuberculosis. In this study, data were available to classify a patient as an alcoholic in the following 2 ways: (1) patient's statement that he was a moderate, heavy, or excessive user of alcohol, or (2) patient's score of 6 or more on a Brief Michigan Alcoholism Screening Test (MAST). Based on their statements, 58% of the patients were classified as alcoholic, whereas only 17.9% were thus classified by their MAST scores. Although alcoholics had more abnormal concentrations of aspartate aminotransferase (AST) before and during therapy, there was no significant difference between the alcoholics and non-alcoholics in the incidence of adverse reactions, including hepatotoxic reactions, including hepatotoxic reactions, attributed to the drugs. We concluded that in the absence of clinically significant and persistent pretreatment abnormalities of hepatic function tests, rifampin and isoniazid are not contraindicated in patients categorized as alcoholic by our 2 commonly used methods.

Topics: Alcoholism; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Tuberculosis, Pulmonary

Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Humans; Isoniazid; Rifampin; Time Factors; Tuberculosis; Tuberculosis, Pulmonary

This study compared the efficacy and toxicity of 4 drug regimens containing rifampin, isoniazid, and ethambutol administered both daily and intermittently for a total duration of 6 months (26 wk). There were 411 patients with newly diagnosed, previously untreated, pulmonary tuberculosis admitted to the study. All patients received isoniazid, rifampin, and ethambutol daily in a hospital for the first 8 wk of treatment. One group continued to receive these 3 drugs daily as outpatients for an additional 18 wk; a second group received the same drugs twice weekly, and a third group received the 3 drugs once weekly during the 18-wk "continuation phase." A fourth group of patients received 2 drugs, isoniazid and rifampin, twice weekly during the continuation phase. Drug toxicity was not a major problem; drugs were permanently discontinued in only 1% of the patients. All 4 regimens were highly effective in achieving sputum negativity. By the fifty month, 100% of the patients had become culture negative. However, the relapse rate was found to be relatively high for all regimens (range, 7 to 20%). Patients with extensive disease, large cavities, heavy growth on pretreatment cultures, slow sputum conversion, persistent cavities, heavy use of alcohol, and concomitant diseases were more likely to relapse. In order to achieve relapse rates acceptable in developed countries, regimens containing rifampin and isoniazid must either be given for longer than 6 months or strengthened by the addition of supplemental drugs during the initial phase.

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Poland; Recurrence; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Liver; Rifampin; Tuberculosis, Pulmonary

Two groups of patients suffering from extensive pulmonary tuberculosis treated with daily or twice-weekly regimens of isoniazid (INH) plus rifampicin (RMP) plus ethambutol (EMB) were formed by random selection. The effectiveness of treatment was expressed by the slope of regression line calculated for each patient in terms of quantitative time dependent decrease of mycobacteria isolated by culture per 1 ml of sputum. Chemically serum concentrations of drugs in five time intervals following simultaneous administration were established. It was shown that the rate of decrease of mycobacteria did not significantly vary in the compared groups. Negativity was reached in 48 day on the average. The mean regression line with double standard deviation allocated patients with rapid, normal or slow sputum conversion. Rapid convertors were the youngest, excreted largest amounts of mycobacteria before the start of treatment, and their x-ray showed predominantly changes of exudative character. Slow convertors excreted least amounts of mycobacteria. In the group of slow convetors with daily regimen was significantly higher number of rapid INH inactivators compared with groups of rapid and normal convertors. Analysis of multiple correlation and variance of the ratio of mycobacterial decrease rate and of the parameters of the biological availability of drugs as expressed by the area under the curve of drug serum levels reveal the rate of mycobacterial decrease to be dependent always on the drug out of the combination. In daily regimen the decrease rate was controlled by INH, in the intermittent regimen by RMP. The speed of negativization could therefore be increased in daily regimen by increased doses of INH, chiefly in rapid INH inactivators. The most important share of RMP in the mycobacterial decrease rate during intermittent administration can be judged from dependence of biological availability on the dose of RMP. Under the experimental circumstances of this study the pharmacological means for speeding up negativization were best utilized. Further shortening of time necessary for obtaining negativity would be practicable only when residual factors are involved presumably existing beyond the region of pathogen and drug relationship.

Topics: Adult; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Tuberculosis, Pulmonary

Of 1072 Chinese patients with radiographically active pulmonary tuberculosis and no microscopic evidence of acid-fast bacilli in sputum examinations, only 691 (64%) were sputum-culture negative. All patients were randomly allocated to selective chemotherapy (antituberculosis chemotherapy not being started until the activity of the disease had been confirmed), to daily streptomycin, isoniazid, rifampicin, and pyrazinamide for 2 months or 3 months, or to a standard 12-month control regimen. During the subsequent 12 months, 64% of the patients in the selective chemotherapy series started antituberculosis chemotherapy. Both 2-month and 3-month regimens were inadequate for patients whose pretreatment sputum cultures were positive (relapse-rates 14% and 7%, respectively, in patients with drug-sensitive strains) but in the patients whose first cultures were negative the relapse-rate was only 1% after both short-term regimens.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Sputum; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acid; Antitubercular Agents; Clinical Trials as Topic; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Patient Dropouts; Rifampin; Streptomycin; Thioacetazone; Tuberculosis, Pulmonary

Topics: Blood Bactericidal Activity; Clinical Trials as Topic; Drug Evaluation; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Pulmonary

A total of 822 patients with newly diagnosed pulmonary tuberculosis were assigned randomly to one of 3 daily rifampin-isoniazid (RIF-INH) regimens: 450, 600, or 750 mg of RIF in combination with 300 mg of INH. After an initial 20 weeks of therapy with RIF-INH, patients recieved 300 mg of INH and 15 mg of ethambutol (EMB) per kg of body weight for either 12 or 18 months after their sputum cultures became negative. The rate of bacteriologic conversion of sputum among the 3 RIF-INH regimens was compared for 552 patients who completed the 20 weeks of RIF-INH therapy. Apporximately 60 per cent of these patients also completed their assigned INH-EMB therapy and were examined for relapse for at least one year after therapy was stopped. There was no significant difference in the rate of sputum conversion or rate of relapse between the group of patients who received 600 mg of RIF and those who received 750 mg of RIF. However, the 450-mg RIF regimen was significantly less effective than the other 2 regimens, as manifested by a lower rate of sputum conversion and a higher rate of treatment failures. Further analysis showed that RIF dosages of less than 9 mg per kg of body weight per day may be inadequate for treatment of pulmonary tuberculosis. The acceptability of these regimens was high, and the incidence of adverse reactions requiring discontinuation of RIF-INH therapy was quite low (3.3 per cent). A large proportion of patients (44 per cent) developed increased concentrations of transaminase during therapy with RIF-INH. These abnormalities were usually transient and, in most cases, of no clinical significance. In the relapse analysis, 12 months of chemotherapy after sputum conversion was shown to be as effective as 18 months of therapy after conversion of these RIF-containing regimens.

Topics: Adolescent; Adult; Aged; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Evaluation; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Recurrence; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary; United States; United States Public Health Service

Topics: Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Follow-Up Studies; Humans; Middle Aged; Recurrence; Rifampin; Tuberculosis, Pulmonary

In a study in Singapore, Chinese, Malay, and Indian patients with pulmonary tuberculosis received 2 months of daily treatment with streptomycin, isoniazid, rifampin, and pyrazinamide followed either by daily treatment with isoniazid, rifampin, and pyrazinamide (SHRZ/HRZ regimen) or by daily administration of isoniazid and rifampin (SHRZ/HR regimen) allocated at random. Both regimens were given for either 6 or 4 months by random allocation. All 330 patients with drug-sensitive tubercle bacilli before treatment had a favorable bacteriologic response during chemotherapy. During the first 6 months after the end of chemotherapy, there was only a single bacteriologic relapse among 84 SHRZ/HRZ and 80 SHRZ/HR patients treated for 6 months, but 8 (10 per cent) of 80 SHRZ/HRZ and 4 (5 per cent) of 74 SHRZ/HR patients treated for 4 months relapsed. Of a total of 33 patients with bacilli resistant to isoniazid, streptomycin, or both drugs before treatment, only one had an unfavorable response during chemotherapy, and none of 31 patients relapsed during the first 6 months after stopping chemotherapy. The incidence of adverse reactions was low; 11 (3 per cent) of 397 patients had hepatitis, but not all episodes were attributable to drug toxicity, and one patient had thrombocytopenic purpura.

Topics: Adolescent; Adult; Alanine Transaminase; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

Topics: Adolescent; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Isoniazid; Male; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

In two groups, each of 40 patients, with previously untreated cavernous pulmonary tuberculosis the following treatment schemes were compared in a randomised clinical study: isoniazid, ethambutol, and rifampicin (control group) and isoprodian with rifampicin (study group). Bacteriologic and radiographic parameters showed that in the study group the results were at least as good as in the control group. Symptoms of drug intolerance were equally rare in both groups.

Topics: Dapsone; Drug Combinations; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Prothionamide; Rifampin; Tuberculosis, Pulmonary

Ethambutol is said to be capable of elevating serum urate concentration. This statement was reconsidered in three investigations using strictly supervised administration of ethambutol in a single daily dose of 25 mg. per kg. of body weight: (1) In short term administration 10 healthy subjects received ethambutol for eight days. (2) In a pilot study 13 patients suffering from pulmonary tuberculosis were treated with a triple combination including thambutol for six months. (3) In a controlled trial 23 patients were randomly allocated to one of the following regiments: In the first group patients received ethambutol plus isoniazid plus rifampicin for six months. In the second group patients received streptomycin plus isoniazid plus PAS for three months and thereafter streptomycin plus isoniazid plus ethambutol for another three months. Serum urate concentrations and clearances of uric acid and of creatinine were determined periodically in all subjects. A slight increase in serum urate concentration occurring in long term therapy showed no relation to ethambutol administration, but was obviously dependant on parameters related to the course of the disease in form of increase in body weight and physical activity, or related to the well known syntropy of chronic alcoholism and tuberculosis.

Topics: Alcoholism; Body Weight; Creatinine; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis, Pulmonary; Uric Acid

A comparison was made between 4 regimens of chemotherapy given for 6 or 8 months, with a 6-month period of follow-up thus far. One regimen, which had a 2-month initial intensive phase of streptomycin, isoniazid, rifampin, and pyrazinamide followed by daily administration of thiacetazone and isoniazid, was very effective. Shortening the initial intensive 4-drug phase to 1 month produced a less successful regimen unless the continuation phase was twice-weekly administration of streptomycin, isoniazid, and pyrazinamide. A regimen in which pyrazinamide was omitted from the initial intensive 2-month phase was also less effective. All patients were inpatients for 6 months to ensure that every dose of drug was fully supervised during this period. Increasing the total duration of chemotherapy from 6 months to 8 months was associated with a significant decrease in the early relapse rate in all 4 regimens, although the above differences between the regimen remained. The applicability of the findings is discussed.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Resistance; Drug Therapy, Combination; Female; Humans; Isoniazid; Kenya; Male; Middle Aged; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Tanzania; Thioacetazone; Time Factors; Tuberculosis, Pulmonary; Uganda; Zambia

Five 4-mo regimens of chemotherapy for tuberculosis are compared. The two regimens in which rifampicin was given throughout the 4 mo were associated with bacteriological-relapse rates of 8% in the first 6 mo after stopping chemotherapy, but the three regimens in which rifampicin was given for only the first 2 mo had relapse-rates of 24-32%. There was no evidence that the addition of pyrazinamide in the second 2 mo of chemotherapy reduced the bacteriological-relapse rate. Removal of the streptomycin from the first 2 mo appeared to reduce the bactericidal and sterilising activity of the regimen, although the differences were not statistically significant. The incidence of adverse reactions was very low with all five regimens.

Topics: Adolescent; Adult; Africa, Eastern; Aged; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary; Zambia

Four short-course antituberculosis regimens allocated at random were studied; (1) streptomycin, isoniazid, and rifampin given daily for 6 months; (2) these 3 drugs plus pyrazinamide given daily for 2 months, followed by twice-weekly administration of streptomycin, isoniazid, and pyrazinamide; (3) a regimen that differed from regimen 2 only in that ethambutol replaced pyrazinamide, and (4) streptomycin plus isoniazid plus rifampin plus pyrazinamide given 3 times per week for 4 months, followed by streptomycin plus isoniazid plus pyrazinamide administered twice per week. The last 3 regimens were given for 6 or 8 months at random. All except 1 of 680 patients with tubercle bacilli drug-susceptible before treatment had a favorable bacteriologic response during chemotherapy. The relapse rates during the first 6 months after chemotherapy were low, except in the ethambutol series, in which 19 per cent of the patients relapsed after 6 months of treatment, and 8 per cent relapsed after 8 months. A substantial proportion of the patients with strains initially resistant to either isoniazid or streptomycin had a favorable response to their allocated regimen, but the results were not as good for those patients with strains resistant to both drugs. An important finding is that the incidences of immunologic febrile reactions to rifampin and of rifampin-dependent antibodies were very low during the 3-times-weekly regimen.

Topics: Adolescent; Adult; Antitubercular Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Ethambutol; Humans; Infant, Newborn; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Random Allocation; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

This paper reviews hepatic toxicity during chemoprophylactic treatment with isoniazid alone, and during the treatment or retreatment of active pulmonary tuberculosis with regimens containing one or more of the drugs isoniazid, rifampicin and pyrazinamide. Chemoprophylaxis with isoniazid carries a risk of drug-induced hepatitis, and this risk needs to be weighed against the advantages of preventing tuberculosis morbidity. The risks of hepatitis during standard treatment based on isoniazid are very small, and most patients who develop hepatitis recover. Moreover, it is often doubtful whether hepatitis is in fact drug-induced, and a proportion of patients who develop it already have liver disease at the time treatment is started. The risks are acceptable in the treatment of bacteriologically active disease. There is no consistent evidence that giving rifampicin with isoniazid in the initial treatment of tuberculosis increases the risk of hepatitis; in particular, transient abnormalities in the results of tests of liver function during the early weeks of treatment do not imply serious toxicity; patients who are rapid acetylators of isoniazid are not, as has been suggested, exposed to any special risk, and patients with known liver disease can also be treated without undue risk. Retreatment regimens based on rifampicin plus ethambutol carry a low risk of hepatitis, even though patients who need retreating have often experience toxicity during their initial treatment. Frist-line or second-line regimens containing pyrazinamide in currently accepted dosages, given daily or intermittently, carry a low and acceptable risk of hepatic toxicity. Finally, current studies of daily and intermittent short-course regimens based on isoniazid, rifampicin and pyrazinamide will extend our knowledge of hepatic toxicity. Because such regimens involve small total quantitites of drugs given over short periods they are likely to give rise to less hepatic toxicity than regimens of standard duration.

Topics: Acetylation; Adolescent; Adult; Aged; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Liver Function Tests; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Hong Kong; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Patients with bacteriologically positive pulmonary tuberculosis were treated initially for an average of three and a half months with isoniazid, rifampicin, and ethambutol and then a total of one year's treatment was completed with either rifampicin plus isoniazid (R+I) or with ethambutol plus isoniazid (E+I). 63 patients in each continuation group were followed up for at least one year, and no relapses occurred. Continuation treatment with E+I was as effective and acceptable as that with R+I and was much less costly.

Topics: Drug Therapy, Combination; Ethambutol; Female; Follow-Up Studies; Humans; Isoniazid; Male; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Developing Countries; Drug Therapy, Combination; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

A controlled trial was done in Roumania to compare 2 regimens in patients with culture-positive pulmonary tuberculosis. Both regimens were of twice-weekly doses under supervision for 9 months, a total of 78 doses. Patients were followed up for 15 months after the end of treatment. The regimens were as follows: IR, isoniazid and rifampicin for 3 months followed by isoniazid and either streptomycin or ethambutol for 6 months; ISE, isoniazid, streptomycin and ethambutol for 3 months followed by isoniazid and either streptomycin or ethambutol for 6 months. Of 128 IR cases and 104 ISE cases with sensitive cultures initially all were culture-negative at 6 months. At the end of 9 months there were 1.8% of 112 in the IR group which had had 2 positive cultures in the 6-9 month period and 3.4% of 88 in the ISE group. After 15 months from the end of treatment 5.6% of 89 in the IR group had had a bacteriological relapse and 8.9% of 79 in the ISE group. Cultures from all relapsed cases were still sensitive to the drugs used. All relapses occurred during the first 12 months. In only 5.6% of 232 patients did adverse reactions necessitate change of treatment. The efficacy, cost, tolerance and suitability of the regimens for a national programme are discussed.

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Antibodies; Clinical Trials as Topic; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Singapore; Thrombocytopenia; Tuberculosis, Pulmonary

In this study, pulmonary tuberculosis was treated on an ambulatory basis, with the patients engaging in their usual activities and with a shortened period of chemotherapy. During the first year of the study, patients with pulmonary tuberculosis were randomly included in one of the following two groups: (1) group 1 received isoniazid (5 to 6 mg/kg of body weight), ethambutol (25 mg/kg), and rifampin (rifampicin, 10 mg/kg) daily for a total of six months; and (2) group 2 received the same therapy as group 1, but treatment was continued for a further six months with only isoniazid (5 mg/kg three days per week). At the beginning of the second year of the study, all subsequent patients included in the study were placed into group 1. Of the 163 patients who started the study, 136 patients (99 from group 1 and 37 from group 2) completed the treatment and converted their bacteriologic findings. There was one relapse in group 1. Adverse reactions were observed in six patients, but they did not have to interrupt treatment.

Topics: Adolescent; Adult; Ambulatory Care; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Patient Dropouts; Recurrence; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

A rigimen of rifampicin plus isoniazid, supplemented in the first two months by ethambutol or streptomycin, was given for six, nine, twelve, or eighteen months in a controlled study of 696 patients with culture-positive pulmonary tuberculosis. The results obtained in the thirty-three months since the start of treatment when all the patients in the six-month and nine-month groups had completed at least two years and those in the twelve-month group had completed twenty-one months of post-chemotherapy follow-up revealed no relapses among patients receiving nine months chemotherapy and a 1% relapse-rate in the twelve-month group. The same regimen given for only six months resulted in a relapse-rate of 5% during the subsequent twenty-seven months. There were adverse effects with streptomycin but not with ethambutol. It is concluded that treatment with rifampicin plus isoniazid for nine months, supplemented by ethambutol in a dose of 25 mg/kg for the first two months, is now acceptable as standard chemotherapy for pulmonary tuberculosis in Britain.

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Drug Therapy, Combination; Ethambutol; Follow-Up Studies; Humans; Isoniazid; Middle Aged; Recurrence; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Three hundred and twenty-nine patients with isoniazid-resistant cultures, 66% with radiographically far advanced disease and 86% with cavities, have been treated with rifampicin and ethambutol and followed-up for 2 years after the end of treatment. The drugs were given daily for 12 weeks (600 mg rifampicin and 25 mg/kg ethambutol), thereafter once- or twice-weekly (600 or 1200 mg rifampicin and 50 mg/kg ethambutol) for a total of 12, 18 or 24 months (in the 600 mg group for 12 months only). With both 600 and 1200 mg rifampicin dosage the bacteriological results at the end of a year were similar (5% bacteriologically unfavourable in each group). Prolonging treatment to 18 or 24 months with the 1200 mg rifampicin dose had no effect on the bacteriological results. During the 2 years follow-up period after treatment stopped 6 patients had a bacteriological relapse. Of the 74 with a favourable status after 1 year in the 600 mg rifampicin group 5 (6.7%) relapsed, but only 1 (0.6%) of 168 in the 1200 mg groups treated for 12, 18 or 24 months (the duration of treatment did not appear to be related to relapse). Side-effects were reported more frequently with once-weekly dosage. They were more frequent with 1200 mg rifampicin than with 600 mg and with the former dose more frequent in the groups treated for longer than 1 year. With 12 months treatment with 600 mg rifampicin only 1% of patients had to have the regimen changed; with 1200 mg it was 9% and with this dose for 24 months 20%. With the lower dosage of rifampicin there were fewer failures due to toxicity but more failures due to relapse. Of 82 patients in the 600 mg regimen there were 12% unfavourable results (4 bacteriological failures, 5 relapses and 1 change of treatment for toxicity). Of 78 patients in the 1200 mg regimen there were 13% unfavourable results (3 bacteriological failures, no relapses and 7 changes of treatment for toxicity).

Topics: Age Factors; Clinical Trials as Topic; Ethambutol; Follow-Up Studies; Humans; Mycobacterium tuberculosis; Recurrence; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

In patients with chronic pulmonary tuberculosis the results of chemotherapy between drug regimens containing ethambutol or rifampicin were compared. Patients in both groups were randomized selected. After 4 months of chemotherapy negativization was reached to 100% in the RMP-group compared to 80% of the patients in the EMB-group. In 98 chronics EMB was added to the chemotherapy regimen and resulted in 90% of negativization. In a small subgroup RMP was added to the regimen and 100% negativization could be obtained. Among 220 patients with chronic pulmonary tuberculosis, treated with RMP in 9 hospitals according to our protocoll, in 205 patients (93.2%) the excretion of bacilli was cessated. In 54 new cases treated with EMB and another combination and in 20 new cases treated additionally with RMP the sputum converted to negative in 100% of the patients. But the the negativization was reached 24 days earlier on the average in the group treated with RMP. Antituberculotic drugs are administered in our clinic according to the body weight.

Topics: Chronic Disease; Drug Therapy, Combination; Ethambutol; Humans; Recurrence; Rifampin; Tuberculosis, Pulmonary

The results of short courses of chemotherapy using rifampicin plus isoniazid, supplemented for the first two months by streptomycin or ethambutol, in patients with newly diagnosed pulmonary tuberculosis, have been studied. 174 patients with little or no cavitation received six months chemotherapy. 1 (0.6%) failed to convert to culture negative during treatment and 5 (3%) relapsed in the twelve months after the end of treatment. In 177 patients with similar disease, twelve months chemotherapy was 100% effective in rendering the sputum culture negative and in preventing relapse in the six months after the end of treatment. 151 patients with more extensive cavitation received chemotherapy for nine months; this was 100% effective in sputum conversion and in preventing relapse in the nine months after the end of treatment. In 155 patients with similar disease, the eighteen-month regimen was uniformly successful in sputum conversion. The rifampicin plus isoniazed regimen was well tolerated, producing adverse effects which warranted withdrawal from the study in only 3.6% of patients. Comparison of ethambutol with streptomycin as a third drug given for the first eight weeks showed no significant difference in the rate of sputum conbersion nor in the incidence of relapse. Streptomycin produced significant adverse effects in 8% of patients whilst ethambutol caused none. Chemotherapy with rifampicin plus isoniazed for nine months, supplemented initially by ethambutol, is more acceptable than standard chemotherapy for eighteen months, is highly effective in sputum conversion, and has resulted in no relapses over a nine-month follow-up period. Further follow-up is being continued to confirm that relapse does not occur.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sputum; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Africa, Eastern; Antitubercular Agents; Humans; Isoniazid; Middle Aged; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

A total of 481 adult Chinese, Malays, and Indians in Singapore with newly diagnosed smear-positive pulmonary tuberculosis were allocated at random to four regimens of intermittent rifampicin plus isoniazid. All patients received an initial 2 weeks of daily streptomycin plus isoniazid plus rifampicin. This was followed either by twice-weekly isoniazid 15 mg/kg plus rifampicin 900 mg (HR2 regimen) or 600 mg (LR2 regimen), or by once-weekly isoniazid 15 mg/kg plus rifampicin 900 mg (HR1 regimen) or 600 mg (LR1 regimen). In addition, all patients received a daily capsule containing, at random, either rifampicin 25 mg or a matched placebo to see if the rifampicin supplement would reduce the incidence of adverse reactions to the drug. At 12 months, all the patients on the two twice-weekly regimens (HR2, LR2) had a favourable bacteriological status as had 97% of 102 HR1 and 93% of 112 LR1 patients. The therapeutic response was significantly better on the twice-weekly than on the once-weekly regimens (P = 0-0005), but the dose size of rifampicin did not have a statistically significant effect. Adverse reactions to intermittent rifampicin occurred in 25% of the HR1 patients but on the other three regimens their incidence was low. The incidence of rifampicin-dependent antibodies was higher, ranging from 48% (HR1) to 24% (LR2). The effect of dose size on the incidence of the "flu" syndrome (the commonest reaction) and of antibodies was statistically significant (P less than 0-01 and less than 0-001, respectively). The interval between doses affected the incidence of the "flu" syndrome (P less than 0-001), but not of antibodies (P greater than 0-25). The rifampicin 25 mg supplement had no effect therapeutically or on the incidence of adverse reactions or of antibodies.

Topics: Adolescent; Adult; Clinical Trials as Topic; Culture Techniques; Drug Administration Schedule; Drug Evaluation; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Singapore; Sputum; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Serum-levels of rifampicin were investigated in patients receiving rifampicin alone or with other antituberculosis drugs. 2 g of probenecid given 30 min before 300 mg of rifampicin did not result in raising serum levels to more than half those achieved with the standard 600 mg dose of rifampicin. Hence probenecid should not be used to reduce rifampicin dosage in antituberculosis therapy.

Topics: Administration, Oral; Adult; Drug Therapy, Combination; Humans; Male; Probenecid; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Age Factors; Aged; Antibody Formation; Body Weight; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fever; Humans; Male; Middle Aged; Rifampin; Sex Factors; Tuberculosis, Pulmonary

In a controlled clinical trial in Hong Kong, 575 Chinese adults with smear-positive isoniazid-resistant pulmonary tuberculosis, who had previously been treated with first-line chemotherapy, were allocated at random to regimens of rifampicin plus ethambutol daily (ER7), twice-weekly (ER2), once-weekly (ER1), or daily for 2 months and then once-weekly (ER7ER1), or to a standard retreatment regimen of daily ethionamide plus pyrazinamide plus cycloserine (EtZC). The ER7 patients were allocated to 12 or 18 months of chemotherapy, and the remainder to 18 months. As assessed at 18 months, a favourable response was achieved in 87 per cent of 91 ER7 patients, 79 per cent of 84 ER2, 81 per cent of 53 ER1, 87 per cent of 62 ER7ER1, and in 88 per cent of 68 EtZC patients (93 per cent of 59 EtZC patients if those with ethionamide-resistant strains pretreatment are excluded). As assessed at 18 and 30 months the ER7 regime was as effective as the control EtZC regimen, and 18 months of chemotherapy on the ER7 regimen conferred no benefit over 12 months. No patient on either regimen relapsed after 18 months. Adverse reactions were uncommon on the daily rifampicin regimen but relatively common on the intermittent and control regimens. The commonest reaction to the intermittent regimens was the 'flu' syndrome, which was associated with the presence of circulating rifampicin-dependent antibodies (P less than 0-001).

Topics: Antibody Formation; Body Weight; Clinical Trials as Topic; Cycloserine; Drug Combinations; Drug Resistance; Ethambutol; Ethionamide; Fever; Follow-Up Studies; Humans; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

In a controlled trial in Hong Bong, 575 Chinese patients with pulmonary tuberculosis whose treatment with first-line regimens had failed were allocated at random to the following retreatment regimens of chemotherapy. (1) Rifampicin plus ethambutol daily (ER7). (2) Rifampicin plus ethambutol twice a week (ER2). (3) Rifampicin plus ethambutol once a week (ER1). (4) Rifampicin plus ethambutol daily for 2 months and then once a week (ER7ER1). (5) Ethionamide plus pyrazinamide plus cycloserine daily for 6 months and then ethionamide plus pyrazinamide daily (EtZC), as a control regimen. Answers to a questionnaire on allergic disease, the results of prick tests with standard allergens, ABO blood grouping, size of tuberculin response during chemotherapy, and a rifampicin patch test showed no associations with the occurrence of adverse reactions to daily or intermittent rifampicin. Mantoux testing during chemotherapy provided no evidence of an immunosuppressive effect of rifampicin. Mean platelet counts at 12 months were significantly lower than those at 3 months on the two once-weekly regimens (ER1, ER7ER1) and on the control regimen (EtZC), although still within normal limits. At 3 months, but not at 12 months, mean platelet counts on the two once-weekly regimens were significantly lower 6 hr after a dose of the regimen than they were before the dose.

Topics: ABO Blood-Group System; Blood Cell Count; China; Clinical Trials as Topic; Cycloserine; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Ethionamide; Hematocrit; Hemoglobins; Hong Kong; Humans; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

The present report concerns the results at 1 year of a co-operative controlled clinical study carried out in Poland of the retreatment of patients with active, chronic, polyresistant far-advance pulmonary tuberculosis with an oral regimen of daily followed by intermittent ethambutol and rifampicin. A comparison was made of once- and twice-weekly supervised intermittent regimens of rifampicin 1200 mg plus ethambutol 50 mg/kg body weight under out-patient conditions after an initial inpatient phase of rifampicin 600 mg and ethambutol 25 mg/kg daily for 12 weeks. Patients were allocated at random to the regimens. Of 247 patients admitted to the study, 201 (81 per cent) completed 1 year's treatment as prescribed by the protocol, 46 (19 per cent) patients terminated their treatment prematurely before 1 year. After the daily phase of 12 weeks' treatment, 82 per cent were negative on smear and 85 per cent on culture; in the continuation intermittent phase, 98 per cent of patients in the once-weekly (E1R1) regimen were negative on culture at 28 weeks and 98 per cent in the twice-weekly (E2R2) regimen. The corresponding proportions at 52 weeks were 97 per cent and 97 per cent. At 12 months, 96 per cent of 101 ER/E1R1 and 96 per cent of 100 ER/E2R2 patients who completed 1 years' treatment were culture-negative.

Topics: Adolescent; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Drug Administration Schedule; Drug Hypersensitivity; Drug Resistance, Microbial; Ethambutol; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Purpura; Rifampin; Sputum; Tuberculosis, Pulmonary; Vision Disorders

Topics: Clinical Trials as Topic; Drug Evaluation; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aminosalicylic Acids; Clinical Trials as Topic; Ethambutol; Female; Humans; Male; Middle Aged; Rifampin; Time Factors; Tuberculosis, Pulmonary

Rifampin has been shown to impair both humoral and cell-mediated immune responses in animal models. In order to detect a similar effect in man, 11 patients with active tuberculosis were evaluated before, 2 weeks after, and 12 to 16 weeks after initiating rifampin. Several parameters were serially measured including blood lymphocytes, intradermal response to intermediate strength tuberculin (PPD), and in vitro proliferative responses to phytohemagglutinin (PHA), a nonspecific mitogen, and to the specific antigens, PPD and influenza A. No changes in lymphocyte counts were noted. No changes in response were noted 2 weeks after beginning treatment with rifampin. However, compared with initial and 2-week responses, the PHA response was reduced by 47%, the PPD by 68%, and the influenza by 75%, and 6 of 11 patients showed no induration after tuberculin skin testing at the 12- to 16-week point. These results indicate that in doses employed for the treatment of tuberculosis, rifampin has an immunosuppressive effect in man that develops gradually.

Topics: Adult; Aged; Antibiotics, Antitubercular; Cells, Cultured; Female; Humans; Influenza Vaccines; Lymphocyte Count; Lymphocytes; Male; Middle Aged; Rifampin; Tuberculin; Tuberculin Test; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Africa, Eastern; Clinical Trials as Topic; Drug Combinations; Drug Evaluation; Drug Resistance, Microbial; Drug Therapy, Combination; Follow-Up Studies; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Streptomycin; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Antitubercular Agents; Clinical Trials as Topic; Cycloserine; Drug Evaluation; Drug Therapy, Combination; Ethambutol; Ethionamide; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Tuberculosis, Pulmonary

Topics: Administration, Oral; Adolescent; Adult; Africa; Clinical Trials as Topic; Drug Combinations; Drug Evaluation; Drug Resistance, Microbial; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Sputum; Streptomycin; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Antitubercular Agents; Clinical Trials as Topic; Drug Therapy, Combination; Evaluation Studies as Topic; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Alanine Transaminase; Bacteriological Techniques; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Leukocyte Count; Liver; Male; Middle Aged; Mycobacterium tuberculosis; Radiography; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

Topics: Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Gastrointestinal Diseases; Humans; Isoniazid; Mycobacterium tuberculosis; Phenylthiourea; Pyridoxine; Recurrence; Rifampin; Streptomycin; Thrombocytopenia; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Antibodies; Clinical Trials as Topic; Drug Administration Schedule; Drug Eruptions; Drug Therapy, Combination; Dyspnea; Ethambutol; Female; Humans; Jaundice; Male; Middle Aged; Radiography; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Ethionamide; Female; Heart Failure; Humans; Isoniazid; Kanamycin; Male; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Aminosalicylic Acids; Blood Proteins; Blood Sedimentation; Body Weight; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Isoniazid; Male; Mycobacterium bovis; Radiography; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Adult; Chronic Disease; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary; Yugoslavia

Topics: Chronic Disease; Clinical Trials as Topic; Ethambutol; Humans; Retrospective Studies; Rifampin; Tuberculosis, Pulmonary; Yugoslavia

Topics: Adult; Antitubercular Agents; Brazil; Clinical Trials as Topic; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Evaluation Studies as Topic; Humans; Isoniazid; Male; Pilot Projects; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Therapy, Combination; Humans; Pyrazinamide; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Evaluation Studies as Topic; Humans; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Fever; Gastrointestinal Diseases; Humans; Jaundice; Purpura, Thrombocytopenic; Respiratory Insufficiency; Rifampin; Skin Manifestations; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Clinical Trials as Topic; Cycloserine; Drug Administration Schedule; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Ethionamide; Female; Hong Kong; Humans; Male; Microbial Sensitivity Tests; Pyrazinamide; Radiography; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Alkaline Phosphatase; Aminosalicylic Acids; Aspartate Aminotransferases; Bilirubin; Clinical Trials as Topic; Drug Therapy, Combination; Humans; Isocitrate Dehydrogenase; Isoniazid; Liver; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Clinical Trials as Topic; Drug Administration Schedule; Drug Hypersensitivity; Drug Therapy, Combination; Ethambutol; Female; Hong Kong; Humans; Male; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Alanine Transaminase; Antibodies; Ethambutol; Female; Fever; Humans; Jaundice; Male; Middle Aged; Nausea; Pain; Placebos; Pyrazinamide; Respiratory Tract Diseases; Rifampin; Skin Manifestations; Tuberculosis, Pulmonary

Topics: Adult; Antibiotics, Antitubercular; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Nigeria; Rifampin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Aminosalicylic Acids; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Hypersensitivity; Drug Resistance, Microbial; Ethambutol; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Radiography; Rifampin; Skin Diseases; Sputum; Streptomycin; Time Factors; Tuberculosis, Pulmonary; United Kingdom

Topics: Adolescent; Adult; Clinical Trials as Topic; Contraceptives, Oral; Estriol; Estrogens; Estrone; Ethambutol; Ethinyl Estradiol; Female; Humans; Isoniazid; Menstruation Disturbances; Pregnancy; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adult; Aminosalicylic Acids; Clinical Trials as Topic; Humans; Isoniazid; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Ethambutol; Humans; Rifampin; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Antitubercular Agents; Clinical Trials as Topic; Drug Combinations; Ethambutol; Humans; Isoniazid; Methods; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Alcoholism; Aminosalicylic Acids; Bilirubin; Drug Therapy, Combination; Humans; Isoniazid; Patient Dropouts; Rifampin; Streptomycin; Time Factors; Transaminases; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Therapy, Combination; Female; Fever; Gastrointestinal Diseases; Headache; Humans; Isoniazid; Male; Purpura, Thrombocytopenic; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Antibody Formation; Clinical Trials as Topic; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Kidney Function Tests; Liver Function Tests; Purpura, Thrombocytopenic; Recurrence; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Animals; Antibody Formation; Antigen-Antibody Reactions; Clinical Trials as Topic; Female; Fever; Headache; Humans; Immune Tolerance; Male; Mice; Middle Aged; Purpura, Thrombocytopenic; Rabbits; Rats; Rifampin; Tuberculosis, Pulmonary

Topics: Antibodies, Anti-Idiotypic; Antibody Formation; Blood Cell Count; Blood Platelets; Clinical Trials as Topic; Depression, Chemical; Humans; Immunoglobulin G; Immunoglobulin M; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Antibody Formation; Binding Sites, Antibody; Blood Cell Count; Clinical Trials as Topic; Erythrocytes; Female; Humans; Iproniazid; Isoniazid; Leukocyte Count; Male; Purpura, Thrombocytopenic; Rifampin; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Rifampin; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Therapy, Combination; Humans; Isoniazid; Rifampin; Tuberculosis, Pulmonary

Topics: Administration, Oral; Adolescent; Adult; Antitubercular Agents; Clinical Trials as Topic; Drug Combinations; Drug Resistance, Microbial; Evaluation Studies as Topic; Female; Humans; Injections, Intramuscular; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Pyrazinamide; Radiography; Recurrence; Rifampin; Sputum; Streptomycin; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Antitubercular Agents; Bilirubin; Capreomycin; Clinical Trials as Topic; Ethambutol; Female; Humans; Hypokalemia; Kidney Function Tests; Liver Function Tests; Male; Middle Aged; Mycobacterium tuberculosis; Potassium; Rifampin; Sputum; Tuberculosis, Pulmonary; Vision Disorders; Visual Acuity

This paper reports the nature, incidence, and severity of adverse reactions to regimens of rifampicin and ethambutol given once weekly, twice weekly, or daily and to a standard reserve regimen in a total of 330 Chinese failure patients who completed at least six months' chemotherapy in a therapeutic comparison in Hong Kong.The adverse reactions which occurred on the regimens of intermittent rifampicin were termed cutaneous, abdominal, "flu", and respiratory; in addition, purpura and abnormal liver function tests were encountered. There was an association of adverse reactions with the interval between doses and with the dose size of rifampicin, the highest incidence occurring with once-weekly rifampicin in high dosage. A procedure was developed for managing adverse reactions to intermittent rifampicin. Of 202 patients treated with intermittent rifampicin 60 developed adverse reactions, but in only 7 (3%) was it necessary to terminate the drug, though a further 10 (5%) were changed to daily rifampicin. On daily rifampicin, generalized hypersensitivity, cutaneous reactions, (one with purpura), and impaired liver function were encountered. Adverse reactions on the standard ethionamide, pyrazinamide, and cycloserine regimen were frequent and some were serious.

Topics: Alanine Transaminase; Antitubercular Agents; Bone Diseases; Chemical and Drug Induced Liver Injury; Colic; Drug Eruptions; Dyspnea; Ethambutol; Fever; Hong Kong; Humans; Jaundice; Purpura; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Ethambutol; Humans; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Aged; Aminosalicylic Acids; Clinical Trials as Topic; Drug Combinations; Ethambutol; Female; Humans; Isoniazid; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Pulmonary; Tuberculosis, Renal

Topics: Adult; Clinical Trials as Topic; Humans; Placebos; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Administration, Oral; Adult; Aminosalicylic Acids; Analysis of Variance; Clinical Trials as Topic; Drug Combinations; Ethambutol; Female; Half-Life; Humans; Isoniazid; Kinetics; Male; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Administration, Oral; Adolescent; Adult; Aged; Argentina; Clinical Trials as Topic; Drug Combinations; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Prognosis; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Administration, Oral; Adult; Age Factors; Alanine Transaminase; Clinical Trials as Topic; Drug Combinations; Drug Tolerance; Ethambutol; Evaluation Studies as Topic; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Rifampin; Sex Factors; Time Factors; Tuberculosis, Pulmonary; United States; United States Public Health Service

Topics: Adolescent; Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Body Weight; Ethambutol; Ethionamide; Female; Hemoglobins; Humans; Isoniazid; Liver; Liver Function Tests; Male; Middle Aged; Radiography; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Aminosalicylic Acids; Antitubercular Agents; Clinical Trials as Topic; Ethambutol; Ethionamide; Humans; Isoniazid; Pyrazinamide; Rifampin; Streptomycin; Thioacetazone; Time Factors; Tuberculosis, Pulmonary

Topics: Ethambutol; Humans; Mycobacterium tuberculosis; Radiography; Rifampin; Sputum; Tuberculosis, Pulmonary; Viomycin

Topics: Aminosalicylic Acids; Clinical Trials as Topic; Computers; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Laboratories; Medical Records; Methods; Organization and Administration; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary; United Kingdom

Topics: Clinical Trials as Topic; Drug Combinations; Evaluation Studies as Topic; Humans; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Chronic Disease; Clinical Trials as Topic; Drug Combinations; Drug Resistance, Microbial; Ethambutol; Humans; Isoniazid; Liver; Pilot Projects; Rifampin; Sputum; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Administration, Oral; Adolescent; Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Clinical Trials as Topic; Ethambutol; Female; Hospitalization; Humans; Isoniazid; Leukocyte Count; Liver Function Tests; Male; Middle Aged; Mycobacterium tuberculosis; Pain; Rifampin; Streptomycin; Tuberculosis, Pulmonary; United States; United States Public Health Service; Vertigo

Topics: Alkaline Phosphatase; Aspartate Aminotransferases; Bilirubin; Clinical Trials as Topic; Eosinophilia; Humans; In Vitro Techniques; Intestinal Absorption; Isoniazid; Jaundice; L-Lactate Dehydrogenase; Liver; Liver Function Tests; Mycobacterium; Mycobacterium tuberculosis; Rifampin; Thrombocytopenia; Transaminases; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Combinations; Humans; Isoniazid; Mycobacterium tuberculosis; Preoperative Care; Rifampin; Sputum; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Drug Synergism; Ethambutol; Female; Humans; Isoniazid; Liver Function Tests; Male; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Aminosalicylic Acids; Clinical Trials as Topic; Female; Humans; Isoniazid; Male; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Algeria; Chronic Disease; Clinical Trials as Topic; Drug Synergism; Ethambutol; Humans; Middle Aged; Rifampin; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Body Weight; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Female; Follow-Up Studies; Humans; Leukocyte Count; Male; Radiography; Rifampin; Sputum; Tuberculosis, Pulmonary

Topics: Anti-Bacterial Agents; Clinical Trials as Topic; Cycloserine; Drug Resistance, Microbial; Ethambutol; Ethionamide; Finland; Humans; Rifampin; Sputum; Tuberculosis, Pulmonary; Viomycin

Topics: Adolescent; Adult; Blood Sedimentation; Body Weight; Clinical Trials as Topic; Drug Synergism; Female; Hemoglobins; Humans; Isoniazid; Male; Middle Aged; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Resistance, Microbial; Drug Synergism; Humans; Rifampin; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Body Weight; Clinical Trials as Topic; Drug Synergism; Ethambutol; Humans; Isoniazid; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Ethambutol; Humans; Isoniazid; Middle Aged; Rifampin; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Topics: Clinical Trials as Topic; Drug Synergism; Humans; Isoniazid; Phenylthiourea; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Aged; Aminosalicylic Acids; Anti-Bacterial Agents; Berlin; Clinical Trials as Topic; Cycloserine; Drug Resistance, Microbial; Ethambutol; Humans; Hypocalcemia; Hypokalemia; Kidney Diseases; Middle Aged; Rifampin; Tetracycline; Tuberculosis, Pulmonary; Urea; Vision Disorders

Topics: Adult; Aged; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Hypersensitivity; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Female; Finland; Hearing Disorders; Humans; Kidney Diseases; Male; Middle Aged; Pneumothorax; Rifampin; Tuberculosis, Pulmonary; Vision Disorders

Topics: Adult; Aged; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Hypersensitivity; Eosinophilia; Ethambutol; Female; Gastrointestinal Diseases; Humans; Kidney Diseases; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary; Uric Acid; Vision Disorders

Topics: Adult; Clinical Trials as Topic; Drug Synergism; Female; Humans; Isoniazid; Male; Rifampin; Tuberculosis, Pulmonary

Topics: Adult; Aminosalicylic Acids; Antitubercular Agents; Clinical Trials as Topic; Drug Synergism; Ethambutol; Humans; Isoniazid; Middle Aged; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Drug Resistance, Microbial; Drug Synergism; Ethambutol; Ethionamide; Humans; Phenylthiourea; Rifampin; Tuberculosis, Pulmonary; Viomycin

Topics: Aminosalicylic Acids; Drug Resistance, Microbial; Drug Synergism; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Drug Synergism; Humans; Isoniazid; Male; Radiography; Rifampin; Streptomycin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aminosalicylic Acids; Blood Proteins; Drug Synergism; Ethambutol; Female; Humans; Kidney; Liver; Male; Middle Aged; Rifampin; Transaminases; Tuberculosis, Pulmonary

Since the roll-out of the Xpert MTB/RIF assay, continuous surveillance can provide an estimate of rifampicin-resistant TB (RR-TB) prevalence, provided high drug susceptibility testing (DST) coverage is achieved. We use national data from Rwanda to describe rifampicin DST coverage, estimate the prevalence of RR-TB and assess its predictors.. Routinely collected DST data were entered into an electronic TB case-based surveillance system. DST coverage was calculated among all bacteriologically confirmed pulmonary TB patients notified from 1 July 2019 to 30 June 2020 in Rwanda. The prevalence of RR-TB was estimated among those with DST results. Univariable and multivariable analysis was performed to explore predictors for RR TB.. Among 4066 patients with bacteriologically confirmed pulmonary TB, rifampicin DST coverage was 95.6% (4066/4251). RR-TB was diagnosed in 73 patients. The prevalence of RR-TB was 1.4% (53/3659; 95% CI 1.09 to 1.89%) and 4.9% (20/406; 95% CI 3.03 to 7.51%) in new and previously treated TB cases, respectively. Predictors of RR-TB were: (1) living in Kigali City (adjusted OR [aOR] 1.65, 95% CI 1.03 to 2.65); (2) previous TB treatment (aOR 3.64, 95% CI 2.14 to 6.19); and (3) close contact with a known RR-TB patient (aOR 11.37, 95% CI 4.19 to 30.82).. High rifampicin DST coverage for routine reporting allowed Rwanda to estimate the RR-TB prevalence among new and previously treated patients.

Topics: Antibiotics, Antitubercular; Cross-Sectional Studies; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Rwanda; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome.. Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug's area under the concentration-time curve over 24 hours (AUC0-24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0-24/MIC exposures.. Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21-11.56; P = .022); levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion.. Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs-fluoroquinolones, pyrazinamide, clofazimine-were predictive and should be optimized to improve clinical outcome.. NCT03559582.

Topics: Adult; Antitubercular Agents; Clofazimine; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

Topics: Antibiotics, Antitubercular; Antitubercular Agents; Child; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Pulmonary

Posterior oropharyngeal saliva (POS) is increasingly recognized as an alternative specimen for detecting respiratory pathogens. The accuracy of Xpert® MTB/RIF Ultra (X-Ultra), when performed on POS obtained from patients with paucibacillary pulmonary tuberculosis (TB) is unclear.. We consecutively recruited adults with symptoms suggestive of pulmonary TB who were negative by both smear microscopy and Xpert MTB/RIF (X-Classic). Each participant was required to provide one bronchoalveolar lavage fluid (BALF) and one POS specimen, respectively. Diagnostic performances of X-Ultra and X-Classic on POS were compared against clinical and mycobacterial reference standards.. 686 participants meeting inclusion criteria were consecutively enrolled into the study. The overall diagnostic sensitivities of X-Ultra and X-Classic on POS samples were 78.9% [95% confidence interval (CI): 72.8-83.8] and 56.4% (95% CI: 49.7-62.9), respectively; the specificities were 96.6% (95% CI: 94.3-98.1) for X-Ultra and 97.6 (95CI: 95.5-98.8) for X-Classic in POS specimens. Notably, the sensitivity of X-Ultra on POS was as sensitive as X-Classic on BALF against microbiological reference standard (78.9% VS 73.1%). Against clinical diagnosis as a reference standard, the sensitivities of X-Ultra and X-Classic on POS were 55.9% (95% CI: 50.5-61.2; 193/345) and 40.0% (95% CI: 34.8-45.4; 138/345), respectively. The risk of negative results with POS was dramatically increased with decreasing bacterial loads.. The testing of POS using X-Ultra shows promise as a tool to identify patients with paucibacillary TB. Considering that bronchoscopy is a semi-invasive procedure, POS testing ahead of bronchoscopy, may decrease the need for bronchoscopic procedures, and the cost of care.

Topics: Adult; Antibiotics, Antitubercular; Humans; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary

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

The cure rate of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis in the world is about 60%, and timely surgical intervention can increase the cure rate to more than 85%. The treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis requires multidisciplinary involvement of tuberculosis department, thoracic surgery department, imaging department, laboratory department and other disciplines to significantly reduce its morbidity and mortality. Although the World Health Organization has defined the role and status of surgery in the treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis, there are significant differences in the cognition and diagnosis and treatment methods of domestic clinicians on multidrug-resistant and rifampicin-resistant pulmonary tuberculosis. Therefore, it is urgent to develop expert consensus on surgical treatment of multidrug-resistant and rifampicin-resistant pulmonary tuberculosis for clinicians to learn from in clinical diagnosis and treatment practice. The Chinese Society for Tuberculosis,Chinese Medical Association organized experts in tuberculosis thoracic surgery to write the first draft of consensus based on the expert suggestion on surgical diagnosis and treatment of multidrug-resistant pulmonary tuberculosis written by the European Office of the World Health Organization in 2014 and the 2019 version of China's multidrug-resistant and rifampicin-resistant pulmonary tuberculosis expert consensus, and combined with China's national situation. This consensus systematically elaborated seven aspects, including surgical indications, contraindications to surgery, conditions and timing of surgery, surgical methods and indications of various surgical procedures, preoperative and postoperative chemotherapy, treatment of surgical complications, and perioperative management of patients with multidrug-resistant and rifampin-resistant pulmonary tuberculosis. After discussion and voting by experts, six recommendations were formed, aiming to provide reference for clinicians in the treatment of multidrug-resistant and rifampin-resistant pulmonary tuberculosis and further improve the standardized diagnosis and treatment level of multidrug-resistant and rifampin-resistant pulmonary tuberculosis in China.. 耐多药和利福平耐药肺结核（MDR/RR-PTB）治愈率在60%左右，外科的及时干预可将治愈率提高至85%以上。MDR/RR-PTB的治疗需要结核科、胸外科、影像科、检验科等多学科共同参与，才能明显降低其病死率。世界卫生组织虽已经明确外科手术在MDR/RR-PTB治疗中的作用和地位，但是国内临床医生对其认知和诊疗方法存在较大差异，因此亟须制定MDR/RR-PTB外科治疗专家共识，供临床医师在临床诊治实践中借鉴。中华医学会结核病学分会组织结核胸外科相关专家，基于2014年世界卫生组织欧洲工作处撰写的《耐多药肺结核外科诊疗专家建议》及《中国耐多药和利福平耐药结核病治疗专家共识（2019年版）》，结合我国国情共同撰写了本共识。本共识对MDR/RR-PTB的手术适应证、外科手术禁忌证、手术的条件和时机、手术方式及各种术式适应证、术前术后化疗、手术并发症的处理、患者围手术期管理等7个方面进行了系统的阐述，经专家讨论和投票，共形成6条推荐意见，旨在为临床医生治疗MDR/RR-PTB提供参考，进一步提高我国MDR/RR-PTB规范化诊疗水平。.

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

Hematogenous disseminated tuberculosis predisposes to concurrent tuberculous meningitis (TBM), the most devastating and disabling form of tuberculosis. However, children often have atypical clinical symptoms, difficulty in specimen collection, low specimen content, and an increasing incidence of drug-resistant tuberculosis. Thus, the accurate diagnosis and timely treatment of childhood tuberculosis face monumental challenges.. The 14-year-old female presented to the hospital with intermittent fever, headache, and blurred vision. Her cerebrospinal fluid (CSF) showed a lymphocytic pleocytosis, an elevated protein level, and a decreased chloride level. And her CSF tested positive for TB-RNA. Xpert MTB/RIF detected Mycobacterium tuberculosis in her CSF, but the rifampin resistance test was unknown. Subsequently, her CSF culture was positive for Mycobacterium tuberculosis. The drug sensitivity test (DST) revealed resistance to isoniazid, rifampin, and fluoroquinolones. A computed tomography (CT) of the chest showed diffuse miliary nodules in both lungs. Intracranial enhanced magnetic resonance imaging (MRI) showed "multiple intensified images of the brain parenchyma, cisterns, and part of the meninges." The final diagnosis is miliary pulmonary tuberculosis and pre-extensive drug-resistant TBM. After 19 months of an oral, individualized antituberculosis treatment, she recovered with no significant neurological sequelae.. For patients with miliary pulmonary tuberculosis, especially children, even if there are no typical clinical symptoms, it is necessary to know whether there is TBM and other conditions. Always look for the relevant aetiological basis to clarify whether it is drug-resistant tuberculosis. Only a rapid and accurate diagnosis and timely and effective treatment can improve the prognosis and reduce mortality and disability rates.

Topics: Adolescent; Child; Female; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Meningeal; Tuberculosis, Miliary; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

This study investigated the diagnostic performance of endobronchial ultrasound with Xpert MTB/RIF Ultra (Ultra) for detecting smear-negative pulmonary tuberculosis (TB).. 143 patients suspected of sputum smear-negative pulmonary tuberculosis were enrolled in this study in Shanghai Pulmonary Hospital, China. These patients underwent endobronchial ultrasound with a guide sheath (EBUS-GS) or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) based on their chest CT manifestations. We assessed the sensitivity and specificity of tissue specimens with Ultra in the TB group and non-TB group. Culture and clinical diagnosis were used as gold-standard for TB.. Among these 143 patients, 11 patients were culture-positive TB, 85 patients were diagnosed with culture-negative TB and 47 were with the non-TB diseases. Direct testing with microscopy (Acid-Fast Bacilli smear, AFB), liquid culture, pathology, Xpert MTB/RIF(Xpert) test and Ultra had a sensitivity of 8.3%, 11.5%, 42.7%, 64.6%, and 78.1% individually among all the TB patients. Ultra had a higher sensitivity than Xpert (P = 0.011). But Ultra had a specificity of 59.6% (95% CI 44.3-73.3), lower than that of Xpert (89.4%, 95% CI 76.1-96.0, P = 0.001). Ultra had the same sensitivity on specimens from EBUS-TBNA and EBUS-GS (P = 0.975). Ultra's positive predictive value and negative predictive value were 79.8% and 57.1% respectively.. Tissue specimens from interventional bronchoscopy combined with Ultra provide a sensitive method for diagnosing smear-negative pulmonary tuberculosis, but its specificity was lower than Xpert.

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

The Xpert MTB/rifampicin Ultra (Xpert Ultra) assay improves the early diagnosis of active tuberculosis (TB) in children. Clinical evaluation is paramount for the interpretation of any positive Xpert Ultra test, especially those with low quantities of DNA.. In this study, 391 children with suspected TB who were tested with Xpert Ultra were enrolled. The clinical characteristics and Xpert Ultra results were further analyzed.. The sensitivity and specificity of Xpert Ultra were 45.0% (149/331) and 96.7% (58/60), respectively. Children with higher semiquantitative scales of Xpert Ultra showed higher percentages of a positive MTB culture, positive acid-fast bacilli staining, severe type of disease, fever, cough and expectoration, a higher white blood cell count and higher C-reactive protein concentrations (all P < 0.01). Among 44 children with an Xpert Ultra trace result, there were no differences in clinical characteristics between confirmed cases and unconfirmed TB cases.. The prevalence of trace is relatively high and can be considered positive in paucibacillary children. Clinical presentations are associated with bacterial load quantified by Xpert Ultra. The interpretation of Xpert Ultra trace results based on clinical information is important for the diagnosis of TB.

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

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

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

This study aimed to investigate the significance of miRNA expression levels in peripheral blood lymphocytes of patients clinically diagnosed with pulmonary tuberculosis.. Pulmonary tuberculosis-related datasets in the Gene Expression Omnibus (GEO) database were analyzed, and DE-miRNAs were screened for Gene Ontology (GO) analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment to construct a DE-miRNA-DE-mRNA network. The peripheral blood lymphocytes of 10 patients with pulmonary tuberculosis, 10 patients with rifampicin-resistant tuberculosis and 10 healthy volunteers were selected for validation of RNA expression levels. qRT-PCR was done to verify the expression of DE-miRNA, and western blotting was done to check the expression levels of genes of associated pathways.. Differential expression of miR-660 was found in pulmonary tuberculosis through data analysis and literature mining. The differential expression was also confirmed by qRT-PCR in samples from patients and healthy controls. The expression of miR-660 was significantly upregulated (. The high expression levels of miR-660 may activate the AKT/NF-κB signalling pathway and has the potential to serve as a potential biomarker for the diagnosis of pulmonary tuberculosis.

Topics: Gene Expression Profiling; Humans; Lymphocytes; MicroRNAs; NF-kappa B; Proto-Oncogene Proteins c-akt; Rifampin; Tuberculosis, Pulmonary

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

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

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

Topics: Antibiotics, Antitubercular; Child; Humans; Mozambique; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary

Topics: Bronchoscopy; Female; Humans; Infant; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

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

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

Topics: Antibiotics, Antitubercular; Early Diagnosis; Humans; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Pulmonary

Topics: Adult; Antibiotics, Antitubercular; Bacillus; Firmicutes; Humans; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

Rifampicin is an important agent for tuberculosis treatment; however, it is often discontinued because of adverse reactions. The treatment regimen then can be administered as that for rifampicin-resistant tuberculosis, which can be toxic. We retrospectively reviewed 114 patients with drug-susceptible pulmonary tuberculosis who discontinued rifampicin due to adverse reactions during an 18 year period at a tertiary referral center, of which 92 (80.7%) exhibited favorable response. Hepatotoxicity was the leading cause of intolerance. Patients with a favorable response were younger and less likely to have comorbidities. The majority of patients were administered four medications during the intensive phase and three to four during the consolidative phase. For those with a favorable response, the median duration of treatment was 10.2 months and the most common intensive regimen was a combination of isoniazid, ethambutol, pyrazinamide, and fluoroquinolone (25%). The most common consolidation regimen was a combination of isoniazid, ethambutol, and fluoroquinolone (22.8%). Among the patients with a favorable response, two (2.2%) experienced recurrence after a follow-up of 3.4 (interquartile range 1.8-6.8) years. For patients with drug-susceptible pulmonary tuberculosis who do not tolerate rifampicin owing to its toxicity, a shorter regimen may be a useful alternative.

Topics: Ethambutol; Fluoroquinolones; Humans; Isoniazid; Retrospective Studies; Rifampin; Tuberculosis, Pulmonary

The current study aims to investigate the value of combination of NGS with Xpert MTB/RIF in the diagnosis of early pulmonary tuberculosis (PTB). A total of 85 patients with suspected PTB were analyzed retrospectively. The positive detection rates of PTB by Xpert MTB/RIF, TBseq Ultra, TB-DNA, and TB-RNA were significantly higher than those by acid-fast staining. Xpert MTB/RIF, TBseq Ultra, TB-DNA, and TB-RNA possessed higher sensitivity and accuracy than acid-fast stained smears. Kappa agreement analysis showed good agreement between Xpert MTB/RIF and TBseq Ultra. Combined diagnosis improves the detection sensitivity compared with a single diagnostic method. ROC curve analysis showed that Xpert MTB/RIF combined with TBseq Ultra showed the highest area under the curve (0.886). In conclusion, the combined diagnosis of TBseq Ultra and Xpert MTB/RIF harbors the characteristics of short cycle, high specificity and accuracy, which demonstrated a promising application value in the early diagnosis of PTB.

Topics: Antibiotics, Antitubercular; Early Diagnosis; High-Throughput Nucleotide Sequencing; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

The patient had received five courses of anti-tuberculosis treatment for recurrent tuberculosis. The drug sensitivity test results of the first three courses showed drug-sensitive pulmonary tuberculosis, and the fourth diagnosis was rifampin-resistant tuberculosis (RR-TB), complicated by chronic obstructive pulmonary disease, type Ⅱ respiratory failure, pulmonary heart disease, and heart failure (grade Ⅲ). The patient stopped taking the anti-tuberculosis drugs on his own in the eighth month of receiving the resistant treatment. After admission, the symptoms improved temporarily after receiving oxygen therapy, anti-infection, and anti-tuberculosis treatment. Because of hemoptysis, the patient underwent arterial embolization by catheterization, but a large amount of hemoptysis occurred shortly thereafter. Emergency left total lung resection and gauze packing for hemostasis were performed. After surgery, the patient's vital signs were maintained with mechanical ventilation and vasopressors. Forty-eight hours after surgery, the gauze was removed, and the patient underwent tracheotomy, enteral nutrition, and anti-tuberculosis treatment. After discharge, the patient underwent rehabilitative exercise and anti-resistant tuberculosis therapy. The patient's condition remained stable for more than six months of follow-up.. 本例患者因肺结核经历5次抗结核治疗，前3次药物敏感试验均显示为非耐药肺结核，第4次诊断为利福平耐药结核病（rifampin-resistant tuberculosis，RR-TB），合并慢性阻塞性肺疾病、Ⅱ型呼吸衰竭、肺源性心脏病及心功能不全（Ⅲ级），按照耐药结核病治疗方案8个月后患者自行停药。此次因咳喘、胸闷入院，经吸氧、抗感染、抗结核治疗后症状缓解，因咯血行经导管动脉栓塞术治疗，术后再发大咯血，急诊行胸膜外左全肺切除+胸腔纱布填塞止血术，术后呼吸机、血管活性药物维持生命体征，48 h后拔出纱布并气管切开、鼻饲营养、抗结核等治疗，出院后康复锻炼、口服耐药方案治疗，随访半年余病情平稳。.

Topics: Antitubercular Agents; Hemoptysis; Humans; Lung; Rifampin; Thoracic Diseases; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The Xpert MTB/RIF Ultra (Ultra) is not yet used for the diagnosis of tuberculosis (TB) in China. We compared the performance of the Xpert and Ultra for detecting Mycobacterium tuberculosis and rifampicin resistance in a primary-level clinic in rural China. Sputum samples from suspected pulmonary TB patients were collected and subjected to smear microscopy, liquid culture, Xpert and Ultra tests. We then compared the sensitivity and specificity of Xpert and Ultra for diagnosing TB against liquid culture. Whole-genome sequencing was performed to predict rifampicin resistance and the results were compared with the Xpert and Ultra tests. The sensitivities of Xpert and Ultra were 88.1% and 95.1%, and the specificities were 91.9% and 84.4%, respectively. Among the 61 smear-negative culture-positive patients, the sensitivities of Xpert and Ultra were 80.3% and 91.8%. All Xpert-positive patients were Ultra-positive. Among culture-negative Xpert or Ultra-positive patients, 69.6% were taking anti-TB drugs or had a previous history of TB. Of the samples that Ultra classified as trace, nearly 25% were probably false-positives. Both Xpert and Ultra accurately detected all rifampicin-resistant patients. In conclusion, Ultra was more sensitive than Xpert, especially for smear-negative patients but had decreased specificity with more false-positives, especially with Ultra trace results.

Topics: Antitubercular Agents; China; Humans; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Pulmonary

The incidence of extrapulmonary tuberculosis (EPTB) in low- and middle-income countries, as well as, high-income countries has increased over the last two decades. The acid-fast bacillus (AFB) smear test is easy to perform and cost-effective with a quick turnaround time but the test has low sensitivity. Culture remains the gold standard for detecting TB; however, it has low sensitivity and slow bacterial growth patterns, as it may take up to 6 to 8 weeks to grow. Therefore, a rapid detection tool is crucial for the early initiation of treatment and ensuring an improved therapeutic outcome. Here, the Xpert Ultra system was developed as a nucleic acid amplification technique to accelerate the detection of MTB in paucibacillary clinical samples and endorsed by the World Health Organization. From March 2020 to August 2021, Xpert Ultra was evaluated for its sensitivity and specificity against EPTB and compared with those of the routinely used Xpert, culture, and AFB tests in 845 clinical samples in Saudi Arabia. The results indicate the overall sensitivity and specificity of Xpert Ultra to be 91% and 95%, respectively, compared with the Xpert (82% and 99%, respectively) and AFB smear (18% and 100%, respectively) tests. The results also indicated that despite the low microbial loads that were categorized as trace, very low, or low on Xpert Ultra, yet, complete detection was achieved with some sample types (i.e., 100% detection). Consequently, Xpert Ultra has great potential to replace conventional diagnostic approaches as a standard detection method for EPTB.

Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Saudi Arabia; Sensitivity and Specificity; Sputum; Tuberculosis, Extrapulmonary; Tuberculosis, Pulmonary

To evaluate the application value of nucleotide matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) technology in the rapid diagnosis of pulmonary tuberculosis (PTB) and its drug resistance.. From February 2021 to January 2022, respiratory specimens from 214 suspected PTB patients at the First Hospital of Quanzhou were collected. Nucleotide MALDI-TOF-MS and BACTEC MGIT 960 culture methods were used for the detection of Mycobacterium tuberculosis (MTB) and drug resistance to anti-tuberculosis drugs.. Compared with culture method, nucleotide MALDI-TOF-MS technology had a sensitivity, specificity, and accuracy of 92.2%, 74.1%, and 82.7%, respectively, for the detection of MTB in respiratory specimens. With clinical diagnosis as the reference standard, the sensitivity and accuracy of nucleotide MALDI-TOF-MS were 82.5% and 86.0%, respectively, which were higher than those of the culture method (69.2% and 78.0%, respectively). The specificity of nucleotide MALDI-TOF-MS was 93.0%, which was slightly lower than that of culture method (95.8%). As for drug resistance, the results of nucleotide MALDI-TOF-MS exhibited good consistence with culture methods for rifampin, isoniazid, ethambutol, and streptomycin.. Nucleotide MALDI-TOF-MS detection has a good clinical performance for rapid detection of MTB and drug sensitivity to rifampin, isoniazid, ethambutol, and streptomycin directly on respiratory specimens.

Topics: Drug Resistance; Ethambutol; Humans; Isoniazid; Mycobacterium tuberculosis; Nucleotides; Rifampin; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Streptomycin; Tuberculosis, Pulmonary

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

Topics: Adult; Caffeine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dextromethorphan; Digoxin; Drug Interactions; Humans; Midazolam; Omeprazole; Rifampin; Tolbutamide; Tuberculosis, Pulmonary

Truenat MTB-RIF assay (Truenat), a nucleic acid amplification test (NAAT), is a real-time polymerase chain reaction (RT-PCR) chip-based assay that can detect. Truenat testing data from 1,690 functional Truenat sites under the NTEP from April to June 2021 were analyzed to assess the rates of errors, invalid MTB results, and indeterminate RIF results. Following this analysis, 12 Truenat sites were selected based on site performance in Truenat testing, diversity of climatic conditions, and geographical terrain. These sites were visited to assess the root causes of their high and low rates of inconclusive results using a structured checklist.. A total of 327,649 Truenat tests performed for MTB and RIF testing were analyzed. The rate of invalid MTB results was 5.2% [95% confidence interval (CI): 5.11-5.26;. The main causes affecting Truenat testing performance include suboptimal adherence to standard operating procedures (SOPs), inadequate training, improper storage of testing kits, inadequate sputum quality, lack of quality control, and delays in the rectification of machine issues. Root cause analysis identified that strengthening of training, external quality control, and supervision could improve the rate of inconclusive results. Ensuring hands-on training of technicians for Truenat testing and retesting of samples with inconclusive results are major recommendations while planning for Truenat scale-up. The recommendations from the study were consolidated into technical guidance documents and videos and disseminated to laboratory staff working at the tiered network of TB laboratories under the NTEP in order to improve Truenat MTB-RIF testing performance.

Topics: Humans; India; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis, Pulmonary

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

The MeltPro TB assay (MeltPro) is a molecular rapid diagnostic test designed for detecting resistance to antituberculosis drugs. However, the performance of MeltPro as an initial diagnostic test for simultaneously detecting the presence of Mycobacterium tuberculosis (MTB) and drug resistance has not been evaluated. This study aims to assess the performance of MeltPro as initial diagnostic test for simultaneous detection of MTB and drug resistance in clinical samples from patients with presumptive pulmonary tuberculosis (PTB).. A retrospective analysis was conducted on 1283 patients with presumptive PTB from two clinical centers, out of which 875 were diagnosed with PTB. The diagnostic accuracy of MeltPro, Xpert MTB/RIF (Xpert), and MGIT 960 for PTB detection was evaluated. Rifampicin (RIF), isoniazid (INH), ethambutol (EMB), streptomycin (STR), and fluoroquinolone (FQ) resistance were detected using MeltPro, with Xpert and/or the broth microdilution plate method (MYCOTB) results as references.. For the diagnosis of PTB, MeltPro showed a sensitivity of 69.0%, which was similar to Xpert (72.7%; P > 0.05) and higher than MGIT (58.1%; P < 0.001). The specificity of MeltPro was 97.1%, similar to Xpert (98.0%; P > 0.05). In smear-negative patients, MeltPro's sensitivity was 50.9%, similar to Xpert (56.5%; P > 0.05), and higher than MGIT (33.1%; P < 0.001). Based on Xpert and/or MYCOTB results, MeltPro exhibited a sensitivity and specificity of 98.3% and 99.2%, respectively, for detecting RIF resistance. Based on MYCOTB results, MeltPro's sensitivity for detecting resistance to INH, EMB, STR, and FQ was 96.4%, 89.1%, 97.5%, and 90.3%, respectively, with specificities of 96.0%, 96.0%, 95.2%, and 99.4%, respectively.. The MeltPro TB assay could potentially be an effective alternative as the initial test for rapid diagnosis of PTB with drug-resistance detection in clinical practice.

Topics: Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sputum; Tuberculosis, Pulmonary

Global TB report 2021 mentions 11 % prevalence of pediatric TB, whereas 5.65% of the cases were reported from India in 2020. India features in the list of TB high burden countries, HIV-TB high burden and MDR-TB high burden countries. The diagnosis of pulmonary tuberculosis in children is difficult as they tend to swallow the sputum, invasive techniques of gastric aspirates needs to be followed and the disease itself is paucibacillary. The disease progresses rapidly in young children and hence rapid diagnosis is needed. Obtaining appropriate respiratory samples for diagnosis is difficult especially in primary care settings. Stool sample is easy to obtain and since children swallow sputum, it can be used to diagnose pulmonary tuberculosis. With this background, a pilot study was planned to evaluate the accuracy of the Xpert MTB/RIF assay for the detection of MTB in stool specimens obtained from pediatric pulmonary TB patients confirmed either by gastric lavage(GL) or sputum(SP) Xpert MTB/RIF assay. In addition, the results of microscopy of stool specimen were compared with that of gastric lavage/ sputum (GL/SP) specimen by Ziehl-Neelsen (ZN) and fluorescent light-emitting diode (LED) staining.. A prospective study was carried out on 50 GL/SP Xpert MTB/RIF assay positive children (0-14 years). Stool specimens from these children were processed for Xpert MTB/RIF assay. The GL/SP and stool specimens were processed for ZN and Auramine O fluorescent microscopy as well.. Fluorescent staining detected acid fast bacilli (AFB) in 24 GL/SP and 16 stool specimens as compared to 20 GL/SP and 10 stool specimens by ZN staining. Stool Xpert MTB/ RIF assay was positive in 29 out of 50 children. Rifampicin resistance was detected in 13 of the 50 (26%) GL/SP specimens. Of these 13 children, rifampicin resistance was detected in 7 stool specimens, rifampicin indeterminate resistance was detected in one specimen and in the remaining 5 children, M.tuberculosis was not detected in stool.. Stool is a good non-invasive specimen for the detection of pulmonary TB in children, especially in remote areas, where invasive techniques cannot be performed for sample collection.

Topics: Child; Child, Preschool; Gastric Lavage; Humans; Mycobacterium tuberculosis; Pilot Projects; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

Tuberculosis (TB) remains a serious public health problem and one of the main concern is the emergence of multidrug-resistant and extensively resistant TB. Hyper-reactive patients develop inflammatory necrotic lung lesions that aggravate the pathology and facilitate transmission of mycobacteria. Treatment of severe TB is a major clinical challenge that has few effective solutions and patients face a poor prognosis, years of treatment and different adverse drug reactions. In this work, fifteen novel and thirty-one unusual thiourea derivatives were synthesized and evaluated in vitro for their antimycobacterial and anti-inflammatory potential and, in silico for ADMET parameters and for structure-activity relationship (SAR). Thioureas derivatives 10, 15, 16, 28 and 29 that had shown low cytotoxicity and high activities were selected for further investigation, after SAR study. These five thioureas derivatives inhibited Mtb H37Rv growth in bacterial culture and in infected macrophages, highlighting thiourea derivative 28 (MIC

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antitubercular Agents; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Severity of Illness Index; Structure-Activity Relationship; Thiourea; Tuberculosis, Pulmonary

Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a major health problem worldwide. The treatment for MDR-TB requires medications for a long duration (up to 20-24 months) with second-line drugs resulting in unfavorable outcomes. Nitroimidazoles are promising antimycobacterial agents known to inhibit both aerobic and anaerobic mycobacterial activity. Delamanid and pretomanid are two nitroimidazoles approved by the regulatory agencies for MDR-TB treatment. However, both agents possess unsatisfactory absorption and QTc prolongation. In our search for a safer nitroimidazole, we discovered JBD0131 (2). It exhibited excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo, improved PK and absorption, reduced QT prolongation potential of delamanid. JBD0131 is currently in clinical development in China for pulmonary tuberculosis (CTR20202308).

Topics: Antitubercular Agents; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

A total of 1 328 sputum samples were collected from patients, across 12 clinics in the Shiselweni region, Eswatini. One thousand one hundred and ten (1110; 84%) samples were simultaneously processed on GeneXpert MTB/RIF assay and MGIT culture.. Although detection of tuberculosis using the GeneXpert MTB/RIF assay in sputum samples is not limited to one specific characteristic, sputum volume assessment should be considered as an integral part of routine laboratory diagnosis of tuberculosis especially in high tuberculosis prevalent settings. However, the ability of the GeneXpert MTB/RIF to provide rapid TB diagnosis is not dependent on sputum quality.

Topics: Eswatini; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary

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

There is limited research assessing the utility of the Xpert Mycobacterium tuberculosis/rifampin (MTB/RIF) assay for the analysis of bronchoalveolar lavage fluid (BALF) in Chinese patients with suspected pulmonary tuberculosis (PTB). Thus, our objective was to determine the diagnostic accuracy of the Xpert MTB/RIF assay and evaluate its utility for the determination of rifampicin resistance.. We retrospectively analyzed BALF from 214 patients with suspected PTB between January 2018 and March 2019. Using mycobacterial culture or final clinical diagnosis as the reference standard, the diagnostic accuracy of the smear microscopy (SM), tuberculosis bacillus DNA (TB-DNA), Xpert MTB/RIF assay, and the determination of rifampicin resistance based on the Xpert MTB/RIF assay were compared.. As compared to mycobacterial culture, the sensitivity of the Xpert MTB/RIF assay, SM, and TB-DNA were 85.5% (74.2%-93.1%), 38.7% (26.6%-51.9%), and 67.7% (54.7%-79.1%), respectively. As compared to the final diagnosis, the specificity of the Xpert MTB/RIF assay, SM, and TB-DNA were 100.0% (95.9%-100.0%), 94.3% (87.1%-98.1%), and 98.9% (93.8%-100.0%), respectively. The sensitivity and specificity of the rifampicin resistance detection using the Xpert MTB/RIF assay were 100% and 98.0%, respectively, with liquid culture as the reference.. This study demonstrates that the analysis of BALF with the Xpert MTB/RIF assay provides a rapid and accurate tool for the early diagnosis of PTB. The accuracy of diagnosis was superior compared with the SM and TB-DNA. Moreover, Xpert is a quick and accurate method for the diagnosis of rifampicin-resistant tuberculosis and can also provide more effective guidance for the treatment of PTB or multidrug-resistant tuberculosis (MDR-TB).

Topics: Adult; Antibiotics, Antitubercular; Bronchoalveolar Lavage Fluid; Drug Resistance, Multiple, Bacterial; Female; Humans; Male; Middle Aged; Molecular Typing; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

Rapid diagnosis of tuberculosis (TB) and detection of drug resistance are very important for timely and appropriate management of patients. Xpert MTB/RIF assay is approved for use in TB and rifampicin-resistance diagnosis. However, data are limited on the impact of Xpert MTB/RIF assay under routine clinical settings with a heterogeneous group of patients and sample types in Ethiopia.. A retrospective study was carried out in 2220 presumptive TB cases at Jimma University Medical Center. Data were gathered from the registration logbook using formatted data extraction tools and double entered to epidata version 3.1 and further transported to SPSS version 20 for analysis. Associations were determined using the Chi-square test and P-value <0.05 was considered statistically significant.. Of 2220 cases enrolled, 1665 (75%) were adults and the remaining 555 (25%) were children aged less than 14 years. The majority, 1964 (88.46%), had pulmonary manifestation and 256 (11.54%) had extrapulmonary involvements. The overall, frequency of Mycobacterium tuberculosis (MTB) was 9.3% (206/2220), among this 10.27% (171/1665) and 6.3% (35/555) were adults and children, respectively. M. tuberculosis was detected from 171 (8.75%) of pulmonary patients and 35 (13.28%) of extrapulmonary manifested patients. Out of 206 M. tuberculosis positive cases, 7(3.4%) were rifampicin-resistant: four from pulmonary tuberculosis (PTB) patients and three from EPTB patients. In the Chi-square test, the age group of 15-24 years, previous history of TB, pus/lymph node sample, and being HIV positive were significantly associated with TB positivity by Xpert MTB/RIF (P-value <0.001).. These data suggest that the overall frequency of M. tuberculosis and rifampicin resistance was found to be relatively low compared to the previous reports in Ethiopia. Nevertheless, better diagnostic tools and approaches are still vital to halt the burden of TB and drug-resistant TB in the country.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Drug Resistance, Bacterial; Ethiopia; Female; HIV Seropositivity; HIV-1; Humans; Infant; Infant, Newborn; Male; Middle Aged; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Tuberculosis, Pulmonary

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

On May 5, 2021, CDC's Tuberculosis Trials Consortium and the National Institutes of Health (NIH)-sponsored AIDS Clinical Trials Group (ACTG) published results from a randomized controlled trial indicating that a 4-month regimen containing rifapentine (RPT), moxifloxacin (MOX), isoniazid (INH), and pyrazinamide (PZA) was as effective as the standard 6-month regimen for tuberculosis (TB) treatment (1). On the basis of these findings, CDC recommends the 4-month regimen as a treatment option for U.S. patients aged ≥12 years with drug-susceptible pulmonary TB and provides implementation considerations for this treatment regimen.

Topics: Antitubercular Agents; Centers for Disease Control and Prevention, U.S.; Drug Administration Schedule; Drug Therapy, Combination; Humans; Isoniazid; Moxifloxacin; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Tuberculosis, Pulmonary; United States

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

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

Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modeling bacillary clearance in sputum in adult patients on first-line treatment in Malawi.. Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0-8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (area-under-the-concentration-time-curve [AUC] and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models.. Among 157 participants (58% human immunodeficiency virus [HIV] coinfected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavorable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified.. Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes.

Topics: Adult; Antitubercular Agents; Bacillus; Ethambutol; Humans; Isoniazid; Pyrazinamide; Rifampin; Sputum; Tuberculosis, Pulmonary

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

This study investigated the potential use of the String Test (ST) for the diagnosis of pulmonary tuberculosis (PTB) in children and adolescents. This is a case series of patients aged 4-15 years presenting with clinically presumed PTB and submitted to ST in three pediatric TB referral centers in Brazil, between November 2017 and July 2020. The ST was performed in the morning, after 4-12 h of fasting, followed by ingestion of the capsule by the patient, which was attached to the patient's malar region. The material was collected for simultaneous smear microscopy (acid-fast bacilli - AFB), culture and the molecular investigation by the GeneXpert MTB/RIF®. Thirty-three patients with presumed PTB were included and ST was performed in 26 (78.8%) of them and 7 (21.2%) patients could not swallow the cord. The diagnosis of PTB was established in 11 (42.3%) of the 26 patients who underwent the ST. The diagnosis of PTB was confirmed (by culture or GeneXpert MTB/RIF®) in 5 patients, 4 of whom were also positive by the ST. Two of them showed positivity by the GeneXpert MTB/RIF® only in the ST sample. Two other patients had a positive ST following the induced sputum test (AFB, GeneXpert MTB/RIF®, and positive culture in both specimens). Thus, ST was positive in 36.4% of the patients in whom PTB was diagnosed. ST could be a useful test for diagnosing PTB in children and adolescents.

Topics: Adolescent; Brazil; Child; Child, Preschool; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

Prompt and accurate diagnosis of gastrointestinal tuberculosis (GITB) along with simultaneous detection of drug resistance is inevitable for tuberculosis elimination. Truenat MTB Plus (TruPlus), a chip-based real-time polymerase chain reaction assay, was evaluated for the first time for diagnosing GITB and detecting rifampicin resistance.. Fifty ileocecal biopsy specimens (5 microbiologically confirmed GITB [culture-positive], 25 clinically confirmed GITB [culture-negative], and 20 control patients) processed in the Department of Microbiology between 2011 and 2021 were subjected to TruPlus assay, Xpert MTB RIF assay multiplex polymerase chain reaction. Their performance was evaluated against both culture and composite reference standard.. The overall sensitivity and specificity of TruPlus in diagnosing GITB was 70% (21/30) and 100%, respectively. The sensitivity was 60% (3/5) for microbiologically confirmed cases and 72% (18/25) for clinically confirmed cases. Performance of TruPlus was superior to Xpert (sensitivity = 30%; P = 0.001) and comparable with MPCR (sensitivity = 83.33%; P = 0.13). Both TruPlus and MPCR had moderate agreement with reference standards, and MPCR detected additional three cases. Both TruPlus and Xpert correctly reported Rifampicin resistance in three cases.. TruPlus, with its greater portability and higher sensitivity than Xpert, could serve as an important tool for diagnosing GITB and rifampicin resistance at outreach endemic areas.

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

Multidrug-resistant Mycobacterium tuberculosis (MDR-TB) is one of the leading causes of death in the world. The resource constraints make it difficult to diagnose and monitor the cases of MDR-TB. GeneXpert is a recognized tool used to diagnose the patients of pulmonary tuberculosis in clinical settings across the globe.. The present one-year cross-sectional study was conducted to estimate the occurrence of MDR-TB in patients with pulmonary TB. A total of 1000 patients suspected of pulmonary tuberculosis were included in this study. A random convenient sampling technique was done to collect the sputum samples (twice) from the patients. Samples were processed for the detection of Mycobacterium tuberculosis using conventional detection methods like the Ziehl Nelson staining method and fluorescent microscopy. Additionally, Cepheid GeneXpert was used for molecular detection of MDR-TB in smear-positive samples of pulmonary tuberculosis by amplifying the rifampicin resistance determining region (RRDR; rpoB gene). All the tests were performed in the biosafety level III lab of District Headquarters Hospital Nankana Sahib.. It was observed that 103 (10.3%) individuals were diagnosed as positive for tuberculosis among 1000 patients. Among these 103 TB positive cases, there were 11 (10.7%) patients diagnosed with rifampicin resistance gene (RR-Gene) of Mycobacterium tuberculosis.. Overall findings of the study showed that MDR-TB is prevalent in pulmonary TB patients and GeneXpert is the most sensitive technique for early diagnosis of the disease, which may be very helpful in the treatment and control of this public health menace in low and middle-income countries.

Topics: Antitubercular Agents; Cross-Sectional Studies; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis, Lymph Node; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

Topics: Humans; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Tuberculosis; Tuberculosis, Pulmonary

A national drug resistance survey (DRS) was implemented for the first time in Timor-Leste (TL) in 2019. The primary objective of the survey was to assess the prevalence of drug resistance among new and previously treated pulmonary TB patients in the country.. This nation-wide cross-sectional survey was conducted in 2019 targeting all new and previously treated sputum smear-positive pulmonary TB patients. Sputum samples were submitted to the National TB Reference Laboratory for confirmation of TB and to determine resistance to rifampicin by Xpert MTB/RIF. Culture was performed on solid media, and culture isolates of confirmed TB cases were shipped to the WHO Supranational TB Reference Laboratory in Chennai, India for whole genome sequencing (WGS). Survey summary statistics, data cross-tabulations and analysis of potential risk factors of rifampicin-resistant TB (RR-TB) were conducted using R statistical software (version 3.5.2).. A total of 953 sputum-smear positive patients were enrolled, of which 917 were confirmed as positive for TB by either Xpert MTB/RIF or culture. An electronic web-based system was used for entry and storage of the data. Rifampicin resistance was detected among 0.6% (95% CI 0.2-1.3) of new cases and 2.7% (95% CI 0.5- 8.2) of previously treated cases. WGS was conducted for validation purposes on 65 randomly selected isolates (29% of RR-TB (2/7) and 7% of RS-TB (63/910) by Xpert MTB/RIF or pDST). The original test results agreed with the WGS validation results for 62/64 isolates (97%).. The prevalence of RR-TB in Timor-Leste is relatively low compared to the estimated proportions of RR-TB in the WHO South-East Asia Region (2.5% [95% CI 1.9-3.3] among new cases and 14% [95% CI 7.7-21] among previously treated cases). The rapid sputum collection and transportation mechanism implemented in the survey demonstrates its feasibility in low resource settings and should be replicated for routinely transporting TB specimens from microscopy labs to GeneXpert sites. Establishment of in-country capacity for rapid molecular diagnostics for both first- and second-line DST is an immediate need for achieving universal drug susceptibility testing (DST) to guide appropriate patient management.

Topics: Antibiotics, Antitubercular; Cross-Sectional Studies; Drug Resistance, Bacterial; Humans; India; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Timor-Leste; Tuberculosis, Pulmonary

We aimed to investigate the use of core needle biopsy (CNB) in epididymal tuberculosis (TB) diagnosis.. We analyzed 41 samples collected between January 1, 2018, and January 31, 2021, from patients who underwent CNB for suspected epididymal TB. All specimens were examined using histopathological examination and the Xpert Mycobacterium tuberculosis bacilli/rifampicin (MTB/RIF) assay. We analyzed the examination results to determine the application value of CNB in epididymal TB diagnosis and evaluate its safety.. According to the comprehensive reference standard established in this study, 37 of the 41 patients had epididymal TB and four patients had chronic epididymitis. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve of histopathological examination were 86.49% (71.23-95.46%), 100.00% (39.76-100.00%), 100.00% (89.11-100.00%), 44.44% (13.70-78.80%), and 0.93 (0.81-0.99), respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the curve of the Xpert MTB/RIF assay were 62.16% (44.76-77.54%), 100.00% (39.76-100.00%), 100.00% (85.18-100.00%), 22.22% (6.41-47.76%), and 0.81 (0.66-0.92), respectively. No postoperative complication attained a Clavien-Dindo classification grade of >2.. CNB was useful in diagnosing epididymal TB. Therefore, we recommend using CNB as a sample collection tool for diagnosing epididymal TB.

Topics: Biopsy, Large-Core Needle; Humans; Male; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary

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

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

Topics: DNA; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The aim of this study was to assess the role of nanopore sequencing using respiratory specimens in the early diagnosis of pulmonary tuberculosis (PTB) and simultaneously compare it head-to-head with Mycobacterium tuberculosis (MTB) culture, and Xpert MTB/rifampin (RIF).. The clinical data of 164 patients with suspected PTB were retrospectively reviewed to determine the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of the acid-fast bacilli (AFB) smear, MTB culture, Xpert MTB/RIF, and nanopore sequencing and assess their diagnostic accuracy compared with culture combined with clinical diagnosis.. The overall sensitivity, specificity, PPV, NPV, and AUC of the AFB smear were 27.6%, 87.5%, 84.2%, 33.3%, and 0.58, respectively; for MTB culture, these values were 57.8%, 100.0%, 100.0%, 49.5%, and 0.79, respectively; for Xpert MTB/RIF, these values were 62.9%, 97.9%, 98.7%, 52.2%, and 0.80, respectively; and for nanopore sequencing, these values were 94.8%, 97.9%, 99.1%, 88.7%, and 0.96, respectively.. The diagnostic accuracy of nanopore sequencing was excellent in terms of PTB diagnosis and was considerably better than that of the Xpert MTB/RIF and MTB culture. Nanopore sequencing could be an effective alternative to Xpert MTB/RIF for the initial detection of PTB to improve the accuracy of PTB diagnosis.

Topics: Antibiotics, Antitubercular; Humans; Mycobacterium tuberculosis; Nanopore Sequencing; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

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

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

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

Smear-negative pulmonary TB (PTB) is difficult to diagnose. Current diagnosis and treatment monitoring methods have inherent limitations. Droplet digital PCR (ddPCR) is a new technique with high sensitivity. This study presents a novel ddPCR for rapid and sensitive identification of Mycobacterium tuberculosis (MTB).. MTB DNA was detected in respiratory specimens from suspected PTB cases using ddPCR assay, which was directed at two different locations within IS6110. We, for the first time, evaluated the clinical diagnostic ability of this ddPCR for paucibacillary smear-negative PTB.. A total of 605 PTB suspects were recruited, including 263 patients with confirmed PTB (84.03% from smear-negative PTB) and 342 without PTB. The sensitivity and specificity of IS6110 ddPCR were 61.22% (95% confidence interval (CI) 55.00-67.10%) and 95.03% (95% CI 92.20-97.10%) for total PTB and 57.92% (95% CI 51.10-64.50%) and 94.57% (95% CI 91.20-96.90%) for smear-negative PTB. ddPCR assay outperformed Xpert MTB/RIF (53.08% vs 28.46%, P = 0.020) in smear-negative PTB detection. Furthermore, effective anti-TB treatment was linked to significantly lower IS6110 copies detected by ddPCR.. Herein, we developed and validated a highly sensitive and robust ddPCR assay for MTB quantification in respiratory specimens, which improves diagnosis and therapeutic effect evaluation of smear-negative PTB.

Topics: Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

GeneXpert MTB/RIF is a reliable molecular diagnostic tool capable of detecting Mycobacterium tuberculosis (MTB) and identifying genetic determinants of rifampicin (RIF) resistance. This study aimed to assess physicians' diagnostic decision-making processes for TB based on GeneXpert MTB/RIF results and how this affected the initiation of multidrug resistance (MDR) treatment. This study employed a mixed method: data were collected retrospectively from the medical records of TB patients and in-depth interviews were conducted with healthcare workers in areas with a high TB burden in Thailand. A total of 2,030 complete TB records from 2 patient groups were reviewed, including 1443 suspected cases with negative smear results and 587 with high risk of MDR-TB. GeneXpert MTB/RIF was routinely used to assist the physicians in their decision-making for the diagnosis of pulmonary tuberculosis (PTB) and the initiation of MDR-TB treatment. The physicians used it as a "rule-in test" for all patients with negative chest X-rays (CXR) and smear results, to ensure timely treatment. Approximately one-fourth of the patients with negative CXR/smear and GeneXpert MTB/RIF results were diagnosed with PTB by the physicians, who based their decisions on other evidence, such as clinical symptoms, and did not use GeneXpert MTB/RIF as a "rule-out test." GeneXpert MTB/RIF proved effective in early detection within a day, thereby radically shortening the time required to initiate second-line drug treatment. Despite its high sensitivity for detecting PTB and MDR-TB, GeneXpert MTB/RIF had contradictory results (false positive and/or false negative) for 21.8% of cases among patients with negative smear results and 41.1% of cases among patients with high risk of MDR-TB. Therefore, physicians still used the results of other conventional tests in their decision-making process. It is recommended that GeneXpert MTB/RIF should be established at all points of care and be used as the initial test for PTB and MDR-TB diagnosis.

Topics: Humans; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Thailand; Tuberculosis, Lymph Node; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Humans; Male; Recurrence; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

Refractory rifampicin-resistant/multidrug resistant/extensively-drug resistant tuberculosis (RR/MDR/XDR-TB) were defined as patients infected with Mycobacterium tuberculosis (MTB) resistant to rifampicin(RR-TB), or at least resistant to rifampicin and isoniazid (MDR-TB) or added resistant to fluoroquinolones (FQs) and one of second line injectable agents (XDR-TB), a patient for whom an effective regimen (fewer than 4 effective agents due to adverse events (AEs) or multiple drug resistances) cannot be developed. To compare the effectiveness and safety of bedaquiline (BDQ)-containing and BDQ-free regimens for treatment of patients with refractory RR/MDR/XDR-TB.. Patients with refractory RR/MDR/XDR-TB receiving BDQ-containing regimens (BDQ group, n = 102) and BDQ-free regimens (non-BDQ group, n = 100) satisfied with included criteria were strictly included in this retrospective historical control study across East China. Culture conversion, treatment outcome, cavity closing rate, and AEs were compared between two groups.. The baseline characteristics involved all possible aspects of patients were well balanced between two groups (p > 0.05). Culture conversion rates in the BDQ group at month 3 (89.2% vs. 66.0%), month 6 (90.2% vs 72.0%), month 9 (91.2% vs. 66.0%), and month 12 (94.1% vs 65.0%) were all significantly higher than those in non-BDQ group (p < 0.001). Similar results were observed in the cavity closing rate at month 9 (19.6% vs 8.0%, p = 0.0) and month 12 (39.2% vs 15.0%, p < 0.001). Patients receiving BDQ-containing regimens had more treatment success than those receiving BDQ-free regimens (p < 0.001; cure rate, 69.6% vs. 45.0%; complete the treatment, 22.5% vs. 18.0%; treatment success, 92.2% vs. 63.0%); the use of BDQ and combined with Linezolid or Clofazimine or Cycloserine were identified as independent predictors of treatment success and no culture reversion (P < 0.05). AEs were similarly reported in 26.5% of patients in the BDQ group and 19.0% in the non-BDQ group (p = 0.2).. BDQ-containing regimens resulted in better treatment outcomes and similar safety relative to BDQ-free regimens for patients with refractory pulmonary RR/MDR/XDR-TB.

Topics: Antitubercular Agents; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Humans; Retrospective Studies; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Globally, the emergence of multidrug-resistant strains of Mycobacterium tuberculosis is an increasing problem that adversely affects patient care and public health. This cross sectional descriptive study was carried out in the Department of Microbiology, Mymensingh Medical College from January 2010 to December 2010 to isolate M. tuberculosis from smear-positive sputum samples by Lowenstein-Jensen (L-J) media and investigate the drug resistance pattern. Among 101 smear-positive cases 80(79.20%) yielded growth of Mycobacteria, 5(4.95%) were contaminated and 16(15.84%) showed no growth. Among 80 isolates 76(95.0%) were M. tuberculosis and the remaining 4(5.0%) were Non-tuberculous Mycobacteria (NTM). Out of 76 M. tuberculosis 27(35.52%) were resistant to at least one drug, 4(5.26%) to Isoniazid (INH), 1(1.32%) to Rifampicin (RMP), 8(10.53%) to Streptomycin (SM) and 0(0.0%) to Ethambutol (EMB) and multi-drug resistant tuberculosis (MDR-TB) was 9(11.84%). The present study creates the impression that fairly high rate of anti-tuberculosis drug resistance among the tuberculosis cases and also high MDR-TB (Resistant to both Rifampicin and Isoniazide). The emergence of MDR-TB poses significant trouble to TB control activities throughout the world. The complexity of MDR-TB operation makes it essential to produce new skills to design, plan, application and monitor interventions for the management of MDR-TB. More surveillance and immediate remedial interventions should be performed to combat the trouble of MDR-TB to the general population.

Topics: Antitubercular Agents; Bangladesh; Cross-Sectional Studies; Drug Resistance; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

We determined the prevalence of rifampicin resistance in pulmonary tuberculosis patients in Enugu Nigeria.. A prospective hospital-based study involving 1300 presumptive multidrug-resistant tuberculosis patients was conducted in Enugu between April 2017 and 31st March, 2019.Participants age ranged from 15 years and older and each submitted one sputum specimens Sputum specimens were analyzed using the Gene Xpert MTB/RIF assay to detect resistance to rifampicin according to manufacturer's protocol.. The prevalence of rifampicin resistant tuberculosis was 6.8% (95% CI: 5.5- 8.3). Rifampicin resistance was significantly higher in males (9.0%) than females (4.2%) (P = 0.036< 0.05). Most of the cases were seen in the age group 35-44 years (28.4%). Prevalence of rifampicin resistant tuberculosis was 2.7% in treatment naive (new) patients and 4.1% in patients on anti-tuberculosis therapy (previously treated).. The prevalence of rifampicin resistant tuberculosis in Enugu was high. Rifampicin resistance in treatment naive (new) patients was also high. This study therefore highlights that active transmission of Multidrug-resistant tuberculosis among young males could be on-going.

Topics: Adolescent; Adult; Drug Resistance, Bacterial; Female; Humans; Male; Mycobacterium tuberculosis; Nigeria; Prevalence; Prospective Studies; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Pulmonary tuberculosis is a chronic infectious disease of the respiratory system. It is still one of the leading causes of death from a single infectious disease, but it has been stuck in the study of a single pathogen. Recent studies have shown that many diseases are associated with disruption of the native microbiota. In this study we investigated the occurrence of tuberculosis and the correlation between drug resistance and respiratory flora. High-throughput 16 S rRNA gene sequencing was used to characterize the respiratory microbiota composition of 30 tuberculosis (TB) affected patients and compared with 30 healthy (H) controls. According to their Gene Xpert results, 30 pulmonary tuberculosis patients were divided into 12 persons in the drug-sensitive group (DS0) and 18 persons in the drug-resistant group (DR0). The microbial flora of the two were compared with the H group.. The data generated by sequencing showed that Firmicutes, Proteus, Bacteroides, Actinomyces and Fusobacterium were the five main bacterial phyla detected, and they constituted more than 96% of the microbial community. The relative abundances of Fusobacterium, Haemophilus, Porphyromonas, Neisseria, TM7, Spirochetes, SR1, and Tenericutes in the TB group was lower than that of the H group, and Granulicatella was higher than the H group. The PcoA diagrams of the two groups had obvious clustering differences. The Alpha diversity of the TB group was lower than that of the H group, and the Beta diversity was higher than that of the H group (P < 0.05). The relative abundance of Streptococcus in the DS0 group was significantly higher than that in the DR0 group (P < 0.05).. Pulmonary tuberculosis can cause disorders of the respiratory tract microbial flora, in which the relative abundance of Streptococcus was significantly different between rifampicin-sensitive and rifampicin-resistant patients.

Topics: Fusobacterium; Humans; Microbiota; Respiratory System; Rifampin; Tuberculosis, Pulmonary

Topics: Chromatography, Liquid; Humans; Isoniazid; Latent Infection; Prognosis; Rifampin; Tandem Mass Spectrometry; Tuberculosis, Pulmonary

Tuberculosis is a major health problem contributing to significant morbidity and mortality. Early diagnosis and treatment is the key for TB control. Sputum microscopy is a rapid and inexpensive test but due to low and variable sensitivity, many cases can be missed. Culture is considered to be the gold standard but is time consuming. Gene Xpert is a novel and rapid cartridge based nucleic acid amplification test (CBNAAT) that can be used for prompt diagnosis.. To compare the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of Gene Xpert with culture in diagnosing tuberculosis in sputum smear negative patients.. The study is a prospective observational study conducted from December 2017 to January 2019 on 189 patients, who were sputum smear negative but had signs and symptoms suggestive of tuberculosis. Their respiratory samples were taken (either sputum or bronchoalveolar lavage) and sent for Gene Xpert. The results were compared with culture, which was taken as the gold standard, and diagnostic accuracy was assessed.. A total of 189 patients were included in the study. In 25 patients sputum was taken and in 164 patients BAL was taken (which included 22 patients in whom sputum Gene Xpert was negative but there was high clinical suspicion of tuberculosis). The sensitivity, specificity, PPV and NPV of Gene Xpert in diagnosing smear negative pulmonary tuberculosis was found to be 96.3%, 81.3%, 87.5% and 94.2% respectively.. Gene Xpert can be used as a rapid diagnostic tool in patients who are sputum smear negative but have clinical features highly suggestive of tuberculosis. It additionally helps in detecting rifampicin resistance. But every Gene Xpert positive case does not necessarily mean an active disease, therefore, past history of tuberculosis along with radiological signs of disease activity are to be considered. In case of negative Gene Xpert but high clinico-radiological suspicion of TB, patients should be followed up on regular intervals, while awaiting their culture.

Topics: Humans; Microscopy; Radiology; Rifampin; Sputum; Tuberculosis, Pulmonary

Drug resistant tuberculosis (DR-TB), particularly multidrug resistance (MDR-TB) and extensive drug resistance (XDR-TB) pose a serious threat to public health. This study aimed to identify drug resistance in pulmonary tuberculosis patients and to see their association with diabetes, human immunodeficiency virus (HIV), previous history of tuberculosis (TB) and family history of TB.. Sputum specimens obtained from 11,874 pulmonary tuberculosis patients were subjected to smear microscopy, cartridge based nucleic acid amplification test (CBNAAT) and liquid culture (LC). Smear positive isolates were subjected to first line Line probe assay (FL-LPA) for isoniazid and rifampicin resistance. FL- LPA positive isolates were subjected to second line Line probe assay (SL-LPA) for fluoroquinolones and second line injectable drug resistance.. Out of 11,874 microbiologically confirmed cases of pulmonary tuberculosis, 976 (8.2%) had a drug resistant tuberculosis. Five patterns of drug resistance were identified monoisoniazid; 394 (3.32%), rifampicin; 461 (3.88%) (monorifampicin; 383 (3.22%)), multidrug; 73 (0.61), extensivedrug; 11 (0.09) and others; 37 (0.31). Previous history of tuberculosis was significantly associated with rifampicin resistance and MDR-TB. Family history of tuberculosis contact was strongly associated with rifampicin resistance, MDR-TB and XDR-TB.. There has been an increasing trend in drug resistance in the recent years, particularly in retreatment cases. This study highlights the pattern of drug resistance and need to detect resistance among all tuberculosis cases, in order to interrupt transmission and control this emerging epidemic.

Topics: Drug Resistance; Extensively Drug-Resistant Tuberculosis; Humans; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

According to reports, between 30 and 40 percent of extrapulmonary tuberculosis (EPTB) cases are caused by urinary tract tuberculosis (UTB). It is critical to identify UTB quickly since it frequently precedes delayed medical attention, which can have detrimental effects. This study examined the use of Xpert MTB/RIF, a PCR test that can detect MTB as well as resistance to an important drug, rifampicin (RIF), in UTB particularly, for the early identification of UTB.. 180 participants with clinically presumptive UTB whose urine samples were chosen for urine sediment smear, culture, Xpert MTB/RIF, and TB-DNA testing at Henan Chest Hospital between January 2019 and July 2022. Evaluation of test performance using Composite Reference Standards (CRSs). We studied and compared the positivity rate for various tests using the t-test. The effectiveness of smear, culture, Xpert MTB/RIF, and TB-DNA was assessed using McNemar test.. In this subject, a total of 108 participants were diagnosed with UTB, and the positivity rate was 67.1%. Compared with CRS, the positivity rate of Xpert MTB/RIF, smear, culture, and TB-DNA was 29.69% (19/64, P < 0.001), 7.56% (9/119, P < 0.1), 12.12% (4/33, P > 0.05), and 18.75% (6/32, P < 0.1), respectively. The sensitivity of Xpert MTB/RIF assay was significantly better than that of smear and culture tests (78.9% vs. 77.8%, P < 0.05; 78.9% vs. 75%, P < 0.05). Under CRS, the positivity rate for Xpert, culture, and TB-DNA was 31.6% (6/19, P < 0.1), 6.2% (1/16, P > 0.05), and 26.7% (4/15, P > 0.05) for TB-DNA, respectively, compared to smear negative. Xpert MTB/RIF assay specificity was significant for culture and TB-DNA (53.6% vs. 25%, P < 0.01; 53.6% vs. 38.9%, P < 0.05), and Xpert MTB/RIF assay FPV was significant for culture and TB-DNA (53.6% vs. 0%, P < 0.001; 53.6% vs. 0%, P < 0.001).. Xpert MTB/RIF outperforms smear, cultures, and TB-DNA in detecting UTB, plus Xpert MTB/RIF is better suited for early diagnosis in smear-negative UTB.

Topics: Drug Resistance, Bacterial; Early Diagnosis; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

Globally, TB is the leading cause of infectious disease morbidity and mortality with many diagnostic uncertainties. Access to affordable and rapid diagnostics remained a major challenge for many developing countries which bear the greatest burden of TB delaying the initiation time to treatment.. This study aimed to assess the GeneXpert MTBRIF assay probe utility for the detection of pulmonary TB and Rifampicin-resistant TB cases in Addis Ababa, Ethiopia.. A cross-sectional study was performed from October 2019 to July 2020 in Saint Peter TB Specialized Hospital in Addis Ababa metropolitan area, Ethiopia. This study enrolled 216 clinically suspected new presumptive pulmonary TB cases confirmed by GeneXpert MTB/RIF Assay. Sociodemographic and clinical characteristics were captured using a structured tool. Data were entered in Microsoft Excel 2019, checked for inconsistency, cleaned promptly, and exported to IBM SPSS Statistics for Windows, Version 26.0. Armonk, N.Y: IBM Corp, the USA for analysis. Descriptive analysis and binary and multivariate logistics regression were performed and all statistical significance was determined at a 95% confidence level.. The majority of the study participants, 55.1% [119/216] were males aged 6-80 years. The prevalence of RR MTB was 11.11% [24/216]. A higher proportion of RR TB was found in female patients [54.2%, 13/24], in patients in the age group of 30-50 years [45.8%, 11/24], in married individuals [62.5%, 15/24], in persons whose residence is urban [79.2%, 19/24], in persons who had a previous history of TB symptoms [100%, 24/24], in persons who had a history of contact with active and LTBI [33.3%, 8/24], and in persons who had a history of HIV and IDUs [41.7%, 10/24]. Occupation (AOR 22.868, 95% CI 1.655-316.022, p = 0.019), history of previous PTB+ (AOR 4.222, 95% CI 1.020-17.47, p = 0.047), and history of HIV and IDUs (AOR 4.733, 95% CI 1.416-15.819, p = 0.012) were independent predictors associated with RR-TB emergence. The commonest mutation 62.5% [15/24] was found in probe E (codons 529-533) region. There was no mutation associated with probe A (codons 507-511), probe B (codons 511-518), and probe C (codons 518-523) regions, as well as no combination of missed probes, was revealed. However, 12.5% [3/24] of RR TB patients were found without unidentified missed probe types detected outside of the RRDR. The delta Ct max was >4.0 and the highest proportion of 35.6% [77/216] RR TB was detected in samples of medium DNA load.. The proportion of RR-TB we observed in this study was high. Similarly, a higher proportion of RR TB was detected outside of the RRDR. Moreover, a significant number of the GeneXpert MTB/RIF Assay probes were identified as unhybridized and this critical observation would mean that most of the probes had no or minimal utility in this geographical region. This calls for further studies to uncover mutation in the rpoB gene conferring RR and reshape TB triage and definite diagnostic algorithm in Ethiopia.

Topics: Adult; Codon; Cross-Sectional Studies; Ethiopia; Female; HIV Infections; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

Diagnosis of. To determine TDG in Xpert negative samples, or in samples in which Xpert could not be performed, in a low-incidence area for MTB.. Retrospective analysis (2015-2020) of a database including all cultures for mycobacteria in a University Hospital covering approximately 500'000 inhabitants. Analysis was restricted to culture positive (C+) samples for MTB for which 1/Xpert was negative or could not be performed because of limited sample volume, and 2/collected from subjects treated less than 24 hours. TDG was analyzed according to microscopy, origin of sample (pulmonary or not) and presence of cavitation.. Among 837 C+ samples for MTB, 236 samples (80% of respiratory origin) from 147 patients fulfilled study criteria; 78 samples (49 patients, 33%) were acid-fast bacilli (AFB) positive. Median (IQR) TDG was 25 (17; 40) days for all samples. TDG exceeded 28 days in 43% of samples and was significantly shorter in AFB+. In Xpert negative samples, or samples for which Xpert could not be performed, TDG exceeded 4 weeks in 43% of samples. AFB+ and samples from cavitary lung disease had a significantly shorter TDG.

Topics: Humans; Incidence; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

Effective treatment reduces a tuberculosis patient's ability to infect others even before they test negative in sputum or culture. Currently, the basis of reduced infectiousness of the Mycobacterium tuberculosis (Mtb) with effective treatment is unclear. We evaluated changes in aerosolized bacteria expelled by patients through a transcriptomic approach before and after treatment initiation (up to 14 days) by RNA sequencing. A distinct change in the overall transcriptional profile was seen post-treatment initiation compared to pretreatment, only when patients received effective treatment. This also led to the downregulation of genes associated with cellular activities, cell wall assembly, virulence factors indicating loss of pathogenicity, and a diminished ability to infect and survive in new host cells. Based on this, we identified genes whose expression levels changed with effective treatment. The observations of the study open up avenues for further evaluating the changes in bacterial gene expression during the early phase of treatment as biomarkers for monitoring response to tuberculosis treatment regimens and provide means of identifying better correlates of Mtb transmission.

Topics: Adult; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Transcriptome; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

Similar to global trends, the incidence rate of tuberculosis (TB) in China declined from 2000 to 2018. In this study, we aimed to evaluate TB trends in northern Guizhou Province and identify risk factors associated with rifampicin-resistant (RR) and concurrent extrapulmonary TB (EPTB). We analyzed data of TB patients hospitalized in Affiliated Hospital of Zunyi Medical University from 2011 to 2018, and assessed correlations between demographic characteristics of patients and RR-TB as well as concurrent EPTB. Our results showed that numbers of new, retreated, RR-TB and concurrent EPTB cases increased gradually from 2011 to 2018. Retreated patients had the highest odds of RR-TB but a lower likelihood of concurrent EPTB compared to new patients. Patients between 21 and 40 years of age had a higher likelihood of RR-TB compared to those 20 years and younger. Female patients and patients from Bijie city as well as the Miao ethnic minority had higher odds of concurrent EPTB. In summary, our data demonstrate upward trends in new, rifampicin-resistant and concurrent extrapulmonary TB cases in northern Guizhou Province of China, which should not be overlooked especially during and post the COVID-19 pandemic because TB is a greater long-term global health threat than COVID-19.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Child; China; Drug Resistance, Multiple, Bacterial; Expert Systems; Female; Humans; Incidence; Male; Middle Aged; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Risk Factors; Tuberculosis, Pulmonary; Young Adult

To evaluate five examination techniques in the diagnosis and treatment of osteoarticular tuberculosis (TB).. Microbiological samples were collected from a total of 284 patients during the period August 2017 to December 2019 in Wuhan Pulmonary Hospital. The specimens were examined by acid-fast bacillus (AFB) smear microscopy, mycobacterial culture, PCR, T-SPOT.TB, and X-pert MTB/RIF rapid molecular detection.. The diagnostic sensitivity of the Xpert technology was 96.8% (116/120), specificity was 96.8% (58/60), the Youden index was 0.936, and the area under the receiver operating characteristic (ROC) curve was 0.967. The sensitivity and specificity of PCR were 84.2% (104/128) and 95.2% (76/80), respectively; the area under the ROC curve was 0.881. T-SPOT.TB had a detection sensitivity of 75.0% (12/16) and specificity of 85.0% (17/20). AFB smear microscopy had a sensitivity of 60.0% (75/125) and specificity of 95.8% (152/159). TB culture sensitivity was 58.1% (72/124) and specificity was 96.2% (73/76). The sensitivity and specificity of Xpert MTB/RIF for detecting rifampicin resistance were 100% (2/2) and 97.3% (73/75), respectively.. The Xpert MTB/RIF technique was found to have a good diagnostic value. With an additional diagnosis of Rifampicin resistance, it was also useful in tuberculosis therapy.

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

Despite the exalted status of sputum mycobacterial load for gauging pulmonary tuberculosis treatment and progress, Chest X-rays supplement valuable information for taking instantaneous therapeutic decisions, especially during the COVID-19 pandemic. Even though literature on individual parameters is overwhelming, few studies have explored the interaction between radiographic parameters denoting severity with mycobacterial burden signifying infectivity. By using a sophisticated approach of integrating Chest X-ray parameters with sputum mycobacterial characteristics, evaluated at all the three crucial time points of TB treatment namely pre-treatment, end of intensive phase and completion of treatment, utilizing the interactive Cox Proportional Hazards model, we aimed to precisely deduce predictors of unfavorable response to TB treatment.. We extracted de-identified data from well characterized clinical trial cohorts that recruited rifampicin-sensitive Pulmonary TB patients without any comorbidities, taking their first spell of anti-tuberculosis therapy under supervision and meticulous follow up for 24 months post treatment completion, to accurately predict TB outcomes. Radiographic data independently obtained, interpreted by two experienced pulmonologists was collated with demographic details and, sputum smear and culture grades of participants by an independent statistician and analyzed using the Cox Proportional Hazards model, to not only adjust for confounding factors including treatment effect, but also explore the interaction between radiological and bacteriological parameters for better therapeutic application.. Of 667 TB patients with data available, cavitation, extent of involvement, lower zone involvement, smear and culture grade at baseline were significant parameters predisposing to an unfavorable TB treatment outcome in the univariate analysis. Reduction in radiological lesions in Chest X-ray by at least 50% at 2 months and 75% at the end of treatment helped in averting unfavorable responses. Smear and Culture conversion at the end of 2 months was highly significant as a predictor (p<0.001). In the multivariate analysis, the adjusted hazards ratios (HR) for an unfavorable response to TB therapy for extent of involvement, baseline cavitation and persistence (post treatment) were 1.21 (95% CI: 1.01-1.44), 1.73 (95% CI: 1.05-2.84) and 2.68 (95% CI: 1.4-5.12) respectively. A 3+ smear had an HR of 1.94 (95% CI: 0.81-4.64). Further probing into the interaction, among patients with 3+ and 2+ smears, HRs for cavitation were 3.26 (95% CI: 1.33-8.00) and 1.92 (95% CI: 0.80-4.60) while for >2 zones, were 3.05 (95% CI: 1.12-8.23) and 1.92 (95% CI: 0.72-5.08) respectively. Patients without cavitation, zonal involvement <2, and a smear grade less than 2+ had a better prognosis and constituted minimal disease.. Baseline Cavitation, Opacities occupying >2 zones and 3+ smear grade individually and independently forecasted a poorer TB outcome. The interaction model revealed that Zonal involvement confined to 2 zones, without a cavity and smear grade up to 2+, constituting "minimal disease", had a better prognosis. Radiological clearance >50% along with smear conversion at the end of intensive phase of treatment, observed to be a reasonable alternative to culture conversion in predicting a successful outcome. These parameters may potentially take up key positions as stratification factors for future trials contemplating on shorter TB regimens.

Topics: Adult; Female; Humans; Kaplan-Meier Estimate; Male; Multivariate Analysis; Mycobacterium tuberculosis; Proportional Hazards Models; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

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

Tuberculosis (TB) is one of the top 10 causes of death worldwide and is the leading infectious cause of death. The incidence of TB, especially active TB, is increased in pregnant and postpartum women. Newborns can be infected with TB from their mothers through several routes. Diagnosis of TB in pregnant women and infants is difficult. Here, we report the simultaneous postdelivery diagnosis of TB in a mother and infant pair.. A 28-year-old woman presented with a sudden onset of convulsions, loss of consciousness, coughing, fever, and breathing difficulty. Her 18-day-old infant daughter developed cough and wheezing.. The mother's chest computed tomography showed diffuse interstitial changes and both lungs' exudation. Enhanced cranial magnetic resonance imaging showed scattered nodular intracranial lesions. A tuberculin skin test and an interferon-gamma release assay were negative. Xpert MTB/RIF (Xpert) testing and acid-fast bacilli smear of bronchoalveolar lavage (BAL) fluid of the mother were negative. Loop-mediated isothermal amplification of BAL fluid was positive for Mycobacterium tuberculosis, and next-generation sequencing confirmed the diagnosis of TB. A biopsy specimen also showed characteristic TB findings. The mother was diagnosed with TB and TB encephalitis. The infant's BAL fluid was positive for acid-fast bacilli and Xpert and, therefore, was diagnosed with TB.. The mother was treated with rifampicin and isoniazid for 9 months, ethambutol and pyrazinamide for 3 months, and prednisolone acetate for 8 weeks. The infant received ventilator-assisted ventilation for 10 days and anti-tuberculous therapy for 11 months.. After anti-tuberculous therapy, the mother and infant both gradually recovered. The mother's chest computed tomography showed significant recovery 9 months after discharge. The infant developed normally during the 11-month follow-up.. This mother-child case pair highlights the value of loop-mediated isothermal amplification and next-generation sequencing as new diagnostic technologies for diagnosing TB in patients with multiple negative tests.

Topics: Adult; Antibiotics, Antitubercular; Female; High-Throughput Nucleotide Sequencing; Humans; Infant, Newborn; Isoniazid; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Rifampin; Tuberculosis, Pulmonary

Tuberculosis (TB) is the global health problem with the second highest number of deaths from a communicable disease after COVID-19. Although TB is curable, poor health infrastructure, long and grueling TB treatments have led to the spread of TB pandemic with alarmingly increasing multidrug-resistant (MDR)-TB prevalence. Alternative host modulating therapies can be employed to improve TB drug efficacies or dampen the exaggerated inflammatory responses to improve lung function. Here, we investigated the adjunct therapy of natural immune-modulatory compound berberine in C57BL/6 mouse model of pulmonary TB. Berberine treatment did not affect

Topics: Animals; Antitubercular Agents; Berberine; Cytokines; Dendritic Cells; Drug Therapy, Combination; Female; Humans; Immunologic Factors; Isoniazid; Lung; Macrophages; Male; Mice, Inbred C3H; Mice, Inbred C57BL; Mycobacterium tuberculosis; Neutrophils; Rifampin; Spleen; Tuberculosis, Pulmonary

Conventionally gastric aspirates are neutralized with sodium bicarbonate to improve the culture yield of MTB. However, only limited data is there to support this practice. The aim of this study was to compare the contamination rate, culture yield and time to detection of Mycobacterium tuberculosis (MTB) in neutralized and non-neutralized gastric aspirate samples and report the drug resistance.. A total of 336 neutralized and non-neutralized gastric aspirate samples were simultaneously cultured by both LJ culture and MGIT 960 to compare the difference in isolation rate, time to detection and contamination rate. First line drug susceptibility testing was performed using MGIT 960 SIRE kit.. MTB was isolated from 8.6% (29/336) of GA samples by one or more of the culture methods. The isolation rate of MTB from neutralized and non-neutralized GA samples by combined LJ and MGIT 960 culture was 7.1% (24/336) and 6.8% (23/336), respectively. Both of them detected 18 MTB isolates in common. However, the neutralized and non-neutralized GA samples detected additional 6 and 5 MTB isolates, respectively. The mean time to detection of MTB were similar. In MGIT 960 culture, contamination rate of non-neutralized samples (17%) was significantly lower when compared to neutralized samples (21.1%) (P = 0.044). Drug susceptibility testing of MTB isolates revealed that, out of 26 isolates, 2 were resistant to ethambutol, one each was resistant to isoniazid and rifampicin.. The findings of this study suggest that non-neutralized samples should be routinely processed in addition to the neutralized samples for optimum isolation of MTB from gastric aspirate samples.

Topics: Child; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary

A laboratory validation study was conducted to assess the equivalence of Xpert MTB/RIF Ultra testing on the GeneXpert System and the GeneXpert Omni System ('Omni') for tuberculosis and rifampicin resistance. High concordance of the two devices was demonstrated for well-characterized clinical samples as well as control materials, with controls tested on Omni at normal and challenging environmental conditions (i.e. 35°C, 90% relative humidity). Equivalence of the Cts for all probes was also shown. Equivalence was demonstrated for the Omni and GeneXpert devices for tuberculosis and rifampicin resistance detection for a diverse range of clinical specimens and environmental conditions.

Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Point-of-Care Testing; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tuberculosis (TB) and COVID-19 pandemics are both diseases of public health threat globally. Both diseases are caused by pathogens that infect mainly the respiratory system, and are involved in airborne transmission; they also share some clinical signs and symptoms. We, therefore, took advantage of collected sputum samples at the early stage of COVID-19 outbreak in Ghana to conduct differential diagnoses of long-standing endemic respiratory illness, particularly tuberculosis.. Sputum samples collected through the enhanced national surveys from suspected COVID-19 patients and contact tracing cases were analyzed for TB. The sputum samples were processed using Cepheid's GeneXpert MTB/RIF assay in pools of 4 samples to determine the presence of Mycobacterium tuberculosis complex. Positive pools were then decoupled and analyzed individually. Details of positive TB samples were forwarded to the NTP for appropriate case management.. Seven-hundred and seventy-four sputum samples were analyzed for Mycobacterium tuberculosis in both suspected COVID-19 cases (679/774, 87.7%) and their contacts (95/774, 12.3%). A total of 111 (14.3%) were diagnosed with SARS CoV-2 infection and six (0.8%) out of the 774 individuals tested positive for pulmonary tuberculosis: five (83.3%) males and one female (16.7%). Drug susceptibility analysis identified 1 (16.7%) rifampicin-resistant tuberculosis case. Out of the six TB positive cases, 2 (33.3%) tested positive for COVID-19 indicating a coinfection. Stratifying by demography, three out of the six (50%) were from the Ayawaso West District. All positive cases received appropriate treatment at the respective sub-district according to the national guidelines.. Our findings highlight the need for differential diagnosis among COVID-19 suspected cases and regular active TB surveillance in TB endemic settings.

Topics: Antibiotics, Antitubercular; Coinfection; COVID-19; Diagnosis, Differential; Drug Resistance, Bacterial; Female; Ghana; Humans; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pandemics; Rifampin; SARS-CoV-2; Sputum; Tuberculosis, Pulmonary

The World Health Organization recommends the Xpert MTB/RIF Ultra assay for diagnosing pulmonary tuberculosis (PTB) in children. Though stool is a potential alternative to respiratory specimens among children, the diagnostic performance of Xpert Ultra on stool is unknown. Thus, we assessed the diagnostic performance of Xpert Ultra on stool to diagnose PTB in children.. We conducted a cross-sectional study among consecutively recruited children (< 15 years of age) with presumptive PTB admitted in 4 tertiary care hospitals in Dhaka, Bangladesh, between January 2018 and April 2019. Single induced sputum and stool specimens were subjected to culture, Xpert, and Xpert Ultra. We considered children as bacteriologically confirmed on induced sputum if any test performed on induced sputum was positive for Mycobacterium tuberculosis and bacteriologically confirmed if M. tuberculosis was detected on either induced sputum or stool.. Of 447 children, 29 (6.5%) were bacteriologically confirmed on induced sputum and 72 (16.1%) were bacteriologically confirmed. With "bacteriologically confirmed on induced sputum" as a reference, the sensitivity and specificity of Xpert Ultra on stool were 58.6% and 88.1%, respectively. Xpert on stool had sensitivity and specificity of 37.9% and 100.0%, respectively. Among bacteriologically confirmed children, Xpert Ultra on stool was positive in 60 (83.3%), of whom 48 (80.0%) had "trace call.". In children, Xpert Ultra on stool has better sensitivity but lesser specificity than Xpert. A high proportion of Xpert Ultra assays positive on stool had trace call. Future longitudinal studies on clinical evolution are required to provide insight on the management of children with trace call.

Topics: Antibiotics, Antitubercular; Bangladesh; Child; Cross-Sectional Studies; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

To determine the prevalence and risk factors associated with rifampicin (RIF)-resistant tuberculosis using GeneXpert technology.. A cross-sectional study was conducted from April 2018 to November 2019 among tuberculosis (TB)-infected Cameroonian patients in the Littoral Region using records from patients presenting with clinically suspected or documented TB. The patients were screened for TB using GeneXpert MDR/RIF ultra. Data were documented with an ad hoc survey form and analysed with SPSS version 22.. 153 patients were included in the study. 64.1% were males; mean age was 37.9 ± 14.7 years and median age 37 years (range: 2-82). Most patients were new cases (76.4%). Relapses accounted for 8.5% and recurrences for 2.6%. Pulmonary TB was diagnosed among 98.7% patients using mostly sputum samples (85%). The prevalence of RIF resistance was 6.7% (95% CI: 3.4%-12.7%). This prevalence was significantly higher in samples of mucus and mucopurulent aspect (P-value = 0.04). RIF-resistant M. tuberculosis strains were significantly more frequent among relapses than new cases (23.1% vs. 2.3% P-value < 0.0001). A statistically significant association was found between GeneXpert-based quantification results and type and aspect of samples.. This study confirms the circulation of RIF-resistant M. tuberculosis strains in the Littoral region. There is a need for extensive studies in other parts of the country.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Cameroon; Child; Child, Preschool; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; Hospitals; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Recurrence; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Sputum; Tuberculosis, Pulmonary; Young Adult

To assess the prevalence and risk factors of drug-resistant tuberculosis (TB), the fifth national anti-TB drug resistance survey was conducted in Thailand.. A cross-sectional study was conducted by stratified cluster sampling with probability proportional to size of TB cases from public health facilities in 100 clusters throughout Thailand from August 2017 to August 2018. Susceptibility testing of TB isolates to first- and second-line anti-TB drugs was performed on Löwenstein-Jensen medium using the indirect proportion method. Multiple imputation was done for handling missing data using Stata 16. The proportion of TB cases with drug resistance was determined. The odds ratio was used to evaluate risk factors associated with drug-resistant TB.. Among 1501 new TB and 69 previously treated TB cases, 14.0% [95% confidence interval (CI): 12.1-16.1] and 33.4% (95% CI: 23.6-44.8), respectively, had resistance to any anti-TB drug. Multidrug-resistant TB accounted for 0.8% (95% CI: 0.5-1.4) of new TB cases and 13.0% (95% CI: 6.5-24.4) of previously treated TB cases. Drug-resistant TB was associated with prior TB treatment [odds ratio (OR), 2.9; 95% CI: 1.6-5.0], age at 45-54 years (OR, 1.6; 95% CI: 1.0-2.4), male (OR, 1.5; 95% CI: 1.0-2.1) and human immunodeficiency virus (HIV) infection (OR, 1.6; 95% CI: 1.0-2.4).. The burden of drug-resistant TB remains high in Thailand. Intensified prevention and control measures should be implemented to reduce the risks of drug-resistant TB in high-risk groups previously treated, especially individuals of late middle age, males and those with coinfection of TB and HIV.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Coinfection; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Prevalence; Rifampin; Risk Factors; Sputum; Thailand; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

The Xpert MTB/RIF Ultra is a recent advancement in molecular diagnostics of tuberculosis (TB) with higher sensitivity compared to its predecessor, the Xpert MTB/RIF assay. Prospective studies evaluating the performance of Xpert MTB/RIF Ultra in children with suspected TB are lacking. In this study, we evaluated the Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis in samples from 156 children, of which one was excluded from the analysis. Of the remaining 155 samples, 6·5% (10/155), 21·3% (33/155), 20% (31/155) and 21·9% (34/155) were positive by smear examination, MGIT culture, Xpert MTB/RIF and Xpert MTB/RIF Ultra, respectively. The Xpert MTB/RIF and Xpert MTB/RIF Ultra had a similar overall sensitivity of 81·8% (95% CI: 64·5-93) and 84·8% (95% CI: 68·1-94·9), respectively. In suspected pediatric TB patients, the Xpert MTB/RIF Ultra had higher sensitivity compared to the Xpert MTB/RIF (72·7 vs 63·6). The AUC (area under the curve) of 0·905 for the Xpert MTB/RIF and 0·893 for the Xpert MTB/RIF Ultra indicate similar and good overall performance. Both Xpert assays were found to be equally efficient, however Xpert MTB/RIF Ultra showed better detection rate in suspected TB cases.

Topics: Antibiotics, Antitubercular; Child; Diagnostic Tests, Routine; Drug Resistance, Bacterial; Female; Humans; Male; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Prospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary

The resistance to first-line drugs can increase the risk of treatment failure and development of resistance to other anti-TB drugs. In TB endemic settings, a considerable rate of recurrence cases exhibited each, year which adds significant burden to the prevalence of disease worldwide.. A total of 562 sputum samples were collected from presumptive positive clinical cases of MDR tuberculosis. Treatment history and demographic data of the patients were obtained after informed consent. Xpert MTB/RIF assay was performed for simultaneous detection of MTB and rifampicin resistance. The mutation patterns of isoniazid and rifampicin were observed after multiplex PCR and reverse hybridization by Genotype® MTBDRplus version 2.0 assay.. A total of 73 of 97 cases (75.2%) of treatment failure were found positive for MDR-TB, whereas 79.6% newly diagnosed and 72.9% default cases were MDR in our isolates. The mutation of rpoB S531L was slightly higher in new treatment cases (89.3%) as compared to the default (80.4%) and failure cases (84.8%), whereas rpoB D516V mutation was more prevalent in default cases (19.6%) with complete absence of rpoB 526 mutation, which was observed in the other two types of cases. The mutation pattern of katG resistance differed among drug naïve and recurrence cases. The resistance in newly diagnosed cases was mostly conferred by katG 315 (49.1%) whereas in default (70.8%) and failure cases (63.3%) isoniazid resistance was commonly associated with katG S315T1 mutation. Mutations in inhA promoter region occurred at nucleotide position -8 and -15. In new cases the rate of mutation of C-15T was 3.7% and T-8A was 1.5% while in treatment failure cases the frequency for C-15T and T-8C was 2.5 and 3.8% respectively. However, no inhA promoter region mediated mutations were detected in default treatment cases.. Retreated cases are at more risk of developing hot spot mutations. An unusual difference in mutation pattern was determined in naïve and recurrence cases. Some mutations were exclusively associated with the retreatment of 35anti-TB drugs which suggest the increased risk of resistance with poor treatment outcome.

Topics: Adult; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Female; Humans; Isoniazid; Male; Middle Aged; Mutation; Mycobacterium tuberculosis; Reinfection; Rifampin; Treatment Failure; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

This study described the population structure of M. tuberculosis complex (MTBc) strains among patients with pulmonary or lymph node tuberculosis (TB) in Northwest Ethiopia and tested the performance of culture isolation and MPT64-based speciation for Lineage 7 (L7).. Patients were recruited between April 2017 and June 2019 in North Gondar, Ethiopia. The MPT64 assay was used to confirm MTBc, and spoligotyping was used to characterize mycobacterial lineages. Line probe assay (LPA) was used to detect resistance to rifampicin and isoniazid.. Among 274 MTBc genotyped isolates, there were five MTBc lineages: L1-L4 and L7 were identified, with predominant East-African-Indian (L3) (53.6%) and Euro-American (L4) (40.1%) strains, and low prevalence (2.6%) of Ethiopia L7. The genotypes were similarly distributed between pulmonary and lymph node TB, and all lineages were equally isolated by culture and recognized as MTBc by the MPT64 assay. Additionally, LPA showed that 259 (94.5%) MTBc were susceptible to both rifampicin and isoniazid, and one (0.4%) was multi-drug resistant (resistant to both rifampicin and isoniazid).. These findings show that TB in North Gondar, Ethiopia, is mainly caused by L3 and L4 strains, with low rates of L7, confirmed as MTBc by MPT64 assay and with limited resistance to rifampicin and isoniazid.

Topics: Adult; Africa, Eastern; Americas; Animals; Drug Resistance, Bacterial; Ethiopia; Female; Genetic Variation; Genotype; Humans; India; Isoniazid; Jupiter; Male; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Lymph Node; Tuberculosis, Pulmonary; Young Adult

To evaluate the diagnostic efficacy of stool-based Xpert MTB/RIF Ultra assay versus other assays for the detection of paediatric pulmonary tuberculosis (PTB).. A prospective head-to-head comparative study was conducted from Dec 2017 to May 2019 in Shanghai Public Health Clinical Centre. Samples were collected from children (< 15 years) with abnormal chest imaging (X-ray or CT scan) results for the following tests: Ultra on stool sample (Ultra-Stool), Ultra on respiratory tract sample (Ultra-RTS), Xpert MTB/RIF assay (Xpert) on RTS (Xpert-RTS), acid-fast bacilli smear on RTS (AFB-RTS), and Mycobacterium tuberculosis (Mtb) culture on RTS (Culture-RTS). The results were compared with a composite reference standard.. A total of 126 cases with paired results were analysed. Against a composite reference standard, Ultra-RTS demonstrated the highest sensitivity (52%) and specificity (100%). Ultra-Stool showed 84.1% concordance with Ultra-RTS, demonstrating 45.5% sensitivity and 94.7% specificity (kappa = 0.65, 95% CI= 0.51-0.79). The sensitivity of Ultra-Stool was similar to Mtb culture (45.5%, p = 1.000) and higher than AFB-RTS (27.3%, p < 0.05). Assay positivity was associated with age and infiltration range in chest imaging.. When RTS is difficult to obtain, stool sample-based Ultra is a comparable alternative.

Topics: Antibiotics, Antitubercular; Child; China; Humans; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

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

Topics: Diagnostic Tests, Routine; HIV Infections; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

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

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

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

Rifampicin is one of the key drugs used to treat tuberculosis and is currently used orally. The use of higher oral doses of rifampicin is desired for better therapeutic efficacy, but this is accompanied by increased risk of systemic toxicity thus limiting its recommended oral dose to 10 mg/kg per day. Inhaled delivery of rifampicin is a potential alternative mode of delivery, to achieve high drug concentrations in both the lung and potentially the systemic circulation. In addition, rifampicin exists either as amorphous or crystalline particles, which may show different pharmacokinetic behaviour. However, disposition behaviour of amorphous and crystalline rifampicin formulations after inhaled high-dose delivery is unknown. In this study, rifampicin pharmacokinetics after intra-tracheal administration of carrier-free, amorphous and crystalline powder formulations to Sprague Dawley rats were evaluated. The formulations were administered once daily for seven days by oral, intra-tracheal and oral plus intra-tracheal delivery, and the pharmacokinetics were studied on day 0 and day 6. Intra-tracheal administration of the amorphous formulation resulted in a higher area under the plasma concentration curve (AUC) compared to the crystalline formulation. For both formulations, the intra-tracheal delivery led to significantly higher AUC compared to the oral delivery at the same dose suggesting higher rifampicin bioavailability from the inhaled route. Increasing the intra-tracheal dose resulted in a more than dose proportional AUC suggesting non-linear pharmacokinetics of rifampicin from the inhaled route. Upon repeated administration for seven days, no significant decrease in the AUCs were observed suggesting the absence of rifampicin induced enzyme auto-induction in this study. The present study suggests an advantage of inhaled delivery of rifampicin in achieving higher drug bioavailability compared to the oral route.

Topics: Administration, Inhalation; Administration, Oral; Animals; Antibiotics, Antitubercular; Area Under Curve; Biological Availability; Dry Powder Inhalers; Extensively Drug-Resistant Tuberculosis; Humans; Male; Models, Animal; Powders; Rats; Rats, Sprague-Dawley; Rifampin; Tuberculosis, Pulmonary

Regardless of a plethora of advanced diagnostics, TB and drug resistance remains a principal killer. We proposed gold nanoparticles (AuNPs) attached with probes to enhance the efficiency of GeneXpert MTB/RIF assay instead of conventional dye probes for molecular detection. A total of 15,000 samples were collected from TB suspects and subjected to Xpert MTB/RIF assay, where 6800 (45.3%) were detected as MTB positive, 280 (4.3%) were detected to harbor mutations in the RRDR, while invalid /errors were found in 690 (4.6%) cases. The mutations were detected by probe E, 199 (71.1%), while probes B and D, 30 and 26 (10% and 9%), respectively. In the Xpert MTB/RIF Assay were found mutations picked by probes E and B codons 529-533 (71%) and 512-518 (10%), respectively. The fast-rising works of TB nano-diagnostics, of Xpert probes, may improve by the applications of gold nanoparticle probes.

Topics: Antibiotics, Antitubercular; Codon; Drug Resistance, Multiple, Bacterial; Gold; Humans; Metal Nanoparticles; Molecular Probes; Mutation; Mycobacterium tuberculosis; Pakistan; Rifampin; Sensitivity and Specificity; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tuberculosis is a chronic disease that displays several features commonly associated with biofilm-associated infections: immune system evasion, antibiotic treatment failures, and recurrence of infection. However, although Mycobacterium tuberculosis (Mtb) can form cellulose-containing biofilms in vitro, it remains unclear whether biofilms are formed during infection in vivo. Here, we demonstrate the formation of Mtb biofilms in animal models of infection and in patients, and that biofilm formation can contribute to drug tolerance. First, we show that cellulose is also a structural component of the extracellular matrix of in vitro biofilms of fast and slow-growing nontuberculous mycobacteria. Then, we use cellulose as a biomarker to detect Mtb biofilms in the lungs of experimentally infected mice and non-human primates, as well as in lung tissue sections obtained from patients with tuberculosis. Mtb strains defective in biofilm formation are attenuated for survival in mice, suggesting that biofilms protect bacilli from the host immune system. Furthermore, the administration of nebulized cellulase enhances the antimycobacterial activity of isoniazid and rifampicin in infected mice, supporting a role for biofilms in phenotypic drug tolerance. Our findings thus indicate that Mtb biofilms are relevant to human tuberculosis.

Topics: Animals; Biofilms; Cellulase; Cellulose; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Isoniazid; Mice; Mice, Inbred C57BL; Mycobacterium abscessus; Mycobacterium avium; Mycobacterium fortuitum; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Pulmonary

Data on active TB case finding activities among artisanal gold mining communities (AMC) is limited. The study assessed the yield of TB cases from the TB screening activities among AMC in Ghana, the factors associated with TB in these communities and the correlation between the screening methods and a diagnosis of TB.. We conducted secondary data analyses of NTP program data collected from TB case finding activities using symptom screening and mobile X-ray implemented in hard to reach AMC. Yield of TB cases, number needed to screen (NNS) and the number needed to test (NNT) to detect a TB case were assessed and logistic regression were conducted to assess factors associated with TB. The performance of screening methods chest X-ray and symptoms in the detection of TB cases was also evaluated.. In total 10,441 people from 78 communities in 24 districts were screened, 55% were female and 60% (6,296) were in the aged 25 to 54 years. Ninety-five TB cases were identified, 910 TB cases per 100,000 population screened; 5.6% of the TB cases were rifampicin resistant. Being male (aOR 5.96, 95% CI 3.25-10.92, P < 0.001), a miner (aOR 2.70, 95% CI 1.47-4.96, P = 0.001) and age group 35 to 54 years (aOR 2.27, 95% CI 1.35-3.84, P = 0.002) were risk factors for TB. NNS and NNT were 110 and 24 respectively.; Cough of any duration had the strongest association with X-ray suggestive of TB with a correlation coefficient of 0.48. Cough was most sensitive for a diagnosis of TB; sensitivity of 86.3% (95% CI 79.4-93.2) followed by X-ray, sensitivity 81.1% (95% CI 71.7-88.4). The specificities of the symptoms and X-rays ranged from 80.2% (cough) to 97.3% (sputum).. The high risk of TB in the artisanal mining communities and in miners in this study reinforces the need to target these populations with outreach programs particularly in hard to reach areas. The diagnostic value of cough highlights the usefulness of symptom screening in this population that may be harnessed even in the absence of X-ray to identify those suspected to have TB for further evaluation.

Topics: Adult; Cough; Cross-Sectional Studies; DNA, Bacterial; Drug Resistance, Bacterial; Feasibility Studies; Female; Ghana; Gold; Humans; Male; Mass Screening; Microbial Sensitivity Tests; Middle Aged; Mining; Mycobacterium tuberculosis; Occupational Exposure; Prevalence; Rifampin; Risk Factors; Sputum; Tuberculosis, Pulmonary

In this study, we aimed to assess the performance of the Xpert MTB/RIF assay for the detection of pulmonary tuberculosis compared to the acid-fast bacilli (AFB) smear and culture analysis, and the incidence of rifampin resistance using the drug susceptibility test. The specimens referred for AFB smear and culture analysis and Xpert MTB/RIF assay from April 2015 to March 2018 were retrospectively reviewed. The sensitivity, specificity, and mean cycle threshold (Ct) values obtained in Xpert MTB/RIF assay and for rifampin resistance were analyzed. The results of Xpert MTB/RIF assay for pulmonary tuberculosis were evaluated based on the AFB smear grade. Among 3,840 specimens, 491 were positive in Xpert MTB/RIF assay and 626 in culture analysis. The sensitivity and specificity of Xpert MTB/RIF assay were 75.6% and 99.4%, respectively. The sensitivity of Xpert MTB/RIF assay for smear-positive/culture-positive specimens was 98.6% and that of smear-negative and -trace/culture-positive specimens was 63.1%. The positivity of Xpert MTB/RIF assay for culture-positive specimens was 89.9%, 98.6%, 95.7%, 100.0%, and 100.0% for the smear grades trace, 1+, 2+, 3+, 4+, respectively. The Ct values of 491 specimens significantly decreased as the AFB smear grade increased (P < 0.0001). The Ct values of smear-positive, -trace, and -negative specimens were 21.7 ± 4.2, 26.5 ± 3.9, and 27.4 ± 3.6, respectively. Rifampin resistance evaluated using Xpert MTB/RIF assay and culture analysis exhibited a correlation of 98.3%. The region covered by probe E was the most frequently mutated region (50.0%). Xpert MTB/RIF assay demonstrated reliable performance in detecting pulmonary tuberculosis from smear-positive and culture-positive specimens; however, further improvements are still required to detect smear-negative and culture-positive specimens.

Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Humans; Incidence; Mycobacterium tuberculosis; Polymerase Chain Reaction; Republic of Korea; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Sputum; Tertiary Care Centers; Tuberculosis, Pulmonary

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

The prevalence of drug-resistant

Topics: Adolescent; Adult; Aged; Antitubercular Agents; DNA, Bacterial; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Microbiota; Middle Aged; Mycobacterium tuberculosis; Rifampin; RNA, Ribosomal, 16S; Sensitivity and Specificity; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Novel tuberculosis (TB) prevention and control strategies are urgently required. Utilising specimens from the Improving Retreatment Success (NCT02114684) trial we assessed the associations between inflammatory markers, measured during active TB, with treatment response and disease severity in HIV-infected and uninfected individuals. Multiplex immunoassays and ELISA were used to measure plasma expression of 24 cytokines/chemokines. Cytokines were log transformed to adjust for skewness. We conducted a nested, un-matched, case (n= 31) - control (n=101) study with cases defined as those participants who failed to sputum culture convert within 8-weeks of TB treatment initiation. Additionally, we examined the association between the measured cytokines and time to culture conversion and presence of lung cavitation using cox proportional hazards and logistic regression models, respectively. Multivariable analyses adjusted for a wide range of baseline clinical and demographic variables. IP-10 expression during active TB was associated with increased odds of sputum culture conversion by 8-weeks overall (aOR 4.255, 95% CI 1.025 - 17.544, p=0.046)) and among HIV-infected individuals (OR 10.204, 95% CI 1.247 - 83.333, p=0.030). Increased MCP-3 (aHR 1.723, 95% CI 1.040 - 2.855, p=0.035) and IL-6 (aHR 1.409, 95% CI 1.045 - 1.899, p=0.024) expression was associated with a shorter time to culture conversion in the total cohort. Higher plasma expression of IL-6 (aHR 1.783, 95% CI 1.128 - 2.820, p=0.013), IL-1RA (aHR 2.595, 95% CI 1.136 - 5.926, p=0.024), IP-10 (aHR 2.068, 95% CI 1.034 - 4.137, p=0.040) and IL-1α (aHR 2.008, 95% CI 1.053 - 3.831, p=0.035) were significantly associated with shorter time to culture conversion among HIV-infected individuals. Increased IL-6 and IL-1RA expression was significantly associated with the presence of lung cavitation during active TB in the total cohort (OR 2.543, 95% CI 1.254 - 5.160, p=0.010), (OR 4.639, 95% CI 1.203 - 21.031, p=0.047) and in HIV-infected individuals (OR 2.644, 95% CI 1.062 - 6.585, p=0.037), (OR 7.795, 95% CI 1.177 - 51.611, p=0.033) respectively. Our results indicate that inflammatory cytokines/chemokines play an important role in TB disease outcome. Importantly, the observed associations were stronger in multivariable models highlighting the impact of behavioural and clinical variables on the expression of immune markers as well as their potential effects on TB outcome.

Topics: Adult; Antibiotics, Antitubercular; Biomarkers; Case-Control Studies; Coinfection; Cytokines; Female; HIV Infections; Humans; Inflammation; Male; Rifampin; South Africa; Tuberculosis, Pulmonary

Whole-genome sequencing has shown that the Mycobacterium tuberculosis infection process can be more heterogeneous than previously thought. Compartmentalized infections, exogenous reinfections, and microevolution are manifestations of this clonal complexity. The analysis of the mechanisms causing the microevolution -the genetic variability of M. tuberculosis at short time scales- of a parental strain into clonal variants with a patient is a relevant issue that has not been yet completely addressed. To our knowledge, a whole genome sequence microevolution analysis in a single patient with inadequate adherence to treatment has not been previously reported.. In this work, we applied whole genome sequencing analysis for a more in-depth analysis of the microevolution of a parental Mycobacterium tuberculosis strain into clonal variants within a patient with poor treatment compliance in Argentina. We analyzed the whole-genome sequence of 8 consecutive Mycobacterium tuberculosis isolates obtained from a patient within 57-months of intermittent therapy. Nineteen mutations (9 short-term, 10 fixed variants) emerged, most of them associated with drug resistance. The first isolate was already resistant to isoniazid, rifampicin, and streptomycin, thereafter the strain developed resistance to fluoroquinolones and pyrazinamide. Surprisingly, isolates remained susceptible to the pro-drug ethionamide after acquiring a frameshift mutation in ethA, a gene required for its activation. We also found a novel variant, (T-54G), in the 5' untranslated region of whiB7 (T-54G), a region allegedly related to kanamycin resistance. Notably, discrepancies between canonical and phage-based susceptibility testing to kanamycin were previously found for the isolate harboring this mutation. In our patient, microevolution was mainly driven by drug selective pressure. Rare short-term mutations fixed together with resistance-conferring mutations during therapy.. This report highlights the relevance of whole-genome sequencing analysis in the clinic for characterization of pre-XDR and MDR resistance profile, particularly in patients with incomplete and/or intermittent treatment.

Topics: Adult; Antitubercular Agents; Argentina; Drug Resistance, Multiple, Bacterial; Female; Humans; Isoniazid; Medication Adherence; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Phylogeny; Pyrazinamide; Rifampin; Streptomycin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Whole Genome Sequencing

Retropharyngeal abscess (RPA) is an acute or chronic deep neck tissue infection. Tuberculous RPA is chronic and extremely rare in adults. A 20-year-old female patient visited the local hospital due to cough and sputum. The sputum smear was positive for acid-fast staining, and lung computed tomography (CT) indicated pulmonary tuberculosis (TB). The patient received the standard regimen of isoniazid+rifampicin+pyrazinamide+ethambutol (HRZE) for 6 months. After HRZE, pulmonary symptoms improved, but some pharyngeal discomfort remained. In another case, a 25-year-old male patient was admitted to our hospital because of a mass on the left side of his neck. Lymph node TB was considered after a puncture biopsy. Lung CT showed no obvious abnormality. After HRZE for 5 months, the mass had progressively enlarged. Both patients underwent B-ultrasonography-guided puncture, and Xpert® MTB/RIF of the abscess was positive and rifampin-sensitive. Tuberculous RPA was diagnosed and treated with isoniazid+rifampicin (HR) for 12 months. After combination anti-TB therapy and surgical drainage, both patients fully recovered. Tuberculous RPA is rare in adults; because of pharyngeal symptoms or progressive enlargement of a neck mass with anti-TB treatment, clinicians need to suspect tuberculous RPA in adults, which is treated with anti-TB therapy and surgery.

Topics: Adult; Female; Humans; Male; Mycobacterium tuberculosis; Pyrazinamide; Retropharyngeal Abscess; Rifampin; Tuberculosis, Pulmonary; Young Adult

Tuberculosis (T.B) is one of the major infectious diseases in the developing countries. The diagnosis of extrapulmonary T.B (EPTB) remains problematic and emergence of resistant strains poses a significant threat. Improved diagnosis of tuberculosis is a global priority for proper control. The study aimed to assess the diagnostic accuracy of GeneXpert MTB/RIF assay for diagnosis of pulmonary TB (PTB) and EPTB and to evaluate the performance of GeneXpert system for demonstrating rifampicin resistance among the studied patients.. A total of 582 clinical samples (449 pulmonary; 430 sputum and 19 bronchoalveolar lavage (BAL) and 133 extra-pulmonary origins; 26 pleural fluid, 62 CSF, 19 ascetic fluid, 12 pus and 14 urine) were collected from patients under clinical and radiological assessment of either PTB or EPTB who were admitted to Menoufia Chest Hospital over a period of three years. Clinical samples were processed and investigated for detection of Mycobacterium tuberculosis (MTB) by both Xpert assay and the conventional methods including Ziehl-Neelsen (ZN)/acid-fast bacillus (AFB) smear microscopy and Lowenstein-Jensen (LJ) culture. Patients' demographic, clinical characteristics and risk factors for acquiring rifampicin resistance were analyzed.. The sensitivity, specificity, false- negative rate and total accuracy of AFB smear microscopy respectively were 72.1 %, 81.3 %, 27.9 and 78.8 % for PTB. However for EPTB, they were 63.2 %, 70.5 %, 36.8 and 68.4 % respectively in relation to LJ culture as the gold standard. GeneXpert MTB/RIF revealed better performance for PTB than EPTB. For PTB, it showed 90.2 % sensitivity, 86.9 % specificity, and 9.8 % false- negative rate. For EPTB, the assay showed a sensitivity of 81.6 %, specificity of 78.9 % and false- negative rate of 18.5 %. Multivariate regression analysis showed that presence of EPTB and contacts with known TB cases were independent risk factors for developing rifampicin resistance.. GeneXpert MTB/RIF assay is a rapid and highly sensitive technique for diagnosis of PTB or EPTB. Its simplicity and accuracy make this new method a very impressive tool for diagnosis of MTB and rifampicin resistance.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Proteins; Child; Child, Preschool; Cross-Sectional Studies; DNA-Directed RNA Polymerases; Female; Humans; Infant; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis, Pulmonary; Young Adult

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

The incidence of pulmonary tuberculosis (PTB) can be reduced by preventing transmission with rapid and precise case detection and early treatment. The Gene-Xpert MTB/RIF assay is a useful tool for detecting Mycobacterium tuberculosis (MTB) with rifampicin resistance within approximately two hours by using a nucleic acid amplification technique. This study was designed to reduce the underdiagnosis of smear-negative pulmonary TB and to assess the clinical and radiological characteristics of PTB patients. This cross-sectional study included 235 participants who went to the Luyang primary health care clinic from September 2016 to June 2017. The demographic data were analyzed to investigate the association of patient gender, age group, and ethnicity by chi-square test. To assess the efficacy of the diagnostic test, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. The area under the curve for sputum for both AFB and gene-Xpert was analyzed to compare their accuracy in diagnosing TB. In this study, TB was more common in males than in females. The majority (50.71%) of the cases belonged to the 25-44-year-old age group and the Bajau ethnicity (57.74%). Out of 50 pulmonary TB cases (smear-positive with AFB staining), 49 samples were positive according to the Gene-Xpert MTB/RIF assay and was confirmed by MTB culture. However, out of 185 smear-negative presumptive cases, 21 cases were positive by Gene-Xpert MTB/RIF assay in that a sample showed drug resistance, and these results were confirmed by MTB culture, showing resistance to isoniazid. In comparison to sputum for AFB, Gene-Xpert showed more sensitivity and specificity with almost complete accuracy. The additional 21 PTB cases detection from the presumptive cases by GeneXpert had significant impact compared to initial observation by the routine tests which overcame the diagnostic challenges and ambiguities.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Predictive Value of Tests; Rifampin; Sputum; Tuberculosis, Pulmonary; Young Adult

in Cameroon patients with multidrug/rifampicin resistant pulmonary tuberculosis (MDR/RR-PTB) are treated with a 9-11 month standardised shorter treatment regimen. Despite its effectiveness, factors associated with the occurrence of an unfavourable treatment outcome in this group of patients are not known. Determine the incidence and identify factors associated with an unfavourable treatment outcome among patients with rifampicin resistant pulmonary tuberculosis (RR-PTB) in Yaoundé.. we conducted a retrospective record review of all consecutive patients with bacteriologically confirmed RR-PTB followed up at the specialised MDR/RR-TB treatment centre of the Jamot Hospital in Yaoundé (JHY) from January 2013 to November 2019. A patient was classified as having an unfavourable outcome if he/she had treatment failure, died or was lost to follow-up during the course of treatment.. a total of 242 RR-PTB patients with a mean age of 35.59 ± 12.02 years including 144 (59.5%) males were registered. Forty-nine (49) of the 242 patients had an unfavourable treatment outcome giving a cumulative incidence of 20.20% (95% confidence interval (95% CI): 15.40-25.90%). Multivariable analysis revealed that patients with an unfavourable outcome were more likely to be males (odds ratio (OR): 2.94; 95% CI: 1.24-7.00, p= 0.015), HIV infected (OR: 2.67; 95% CI: 1.17-6.06, p = 0.019), and have a baseline haemoglobin level ≤ 10g/dl (OR: 2.87; 95% CI: 1.25-6.58, p = 0.013).. the rate of an unfavourable treatment outcome among patients with RR-PTB at the specialised MDR/RR-TB treatment centre of the JHY is relatively high. The male sex, HIV infection and moderate to severe anaemia are independent factors associated with an unfavourable treatment outcome.

Topics: Adult; Anemia; Antitubercular Agents; Cameroon; Female; HIV Infections; Humans; Incidence; Male; Middle Aged; Retrospective Studies; Rifampin; Risk Factors; Sex Factors; Treatment Failure; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

In this study, we aimed to investigate the molecular epidemiology and drug-resistance profiles of tuberculosis (TB) in Luodian, an area with highest TB incidence and limited healthcare resources in Guizhou, China. The passive case finding strategy was used to identify suspected pulmonary TB with symptoms, and individuals with positive Mycobacterium tuberculosis (MTB) culture were enrolled from May 22, 2018 to April 21, 2019. All the 107 cases except three came from nine towns, including 55.1% from Longping and Bianyang. The phylogeny tree showed that 53.3% of strains were Lineage 2 (Beijing genotype), while 46.7% were Lineage 4 (Euro-American genotype). Among Lineage 2 strains, 66.7% were of "modern" Beijing type. Seven clusters with genomic distance within 12 SNPs were identified. The clusters included 14 strains, accounting for a clustering rate of 13.1%. The distance separating the clustered cases was between 2.1 and 71.0 km (Km), with an average paired distance of 21.8 Km (interquartile range, 2.8-38.0 Km). Based on the gene mutations associated with drug-resistance, we predicted that 4.8% of strains were resistant to isoniazid, 3.7% to rifampicin, and 3.7% to streptomycin; only one strain (0.9%) had multidrug resistance (MDR). This study found low drug-resistance rates in Luodian, and the sub-lineage of the "modern" Beijing branch has recent expansion in Luodian. This work may also serve as a genomic baseline to assess the evolution and spread of MTB in Guizhou.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; China; Drug Resistance, Bacterial; Female; Humans; Incidence; Isoniazid; Male; Middle Aged; Molecular Epidemiology; Phylogeny; Prevalence; Rifampin; Streptomycin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Whole Genome Sequencing; Young Adult

Xpert MTB/RIF is recommended by the World Health Organization (WHO) for a rapid and simultaneous detection of Mycobacterium tuberculosis (Mtb) and rifampicin resistance specific to patients who have symptoms and signs.. The aim of this study was to evaluate the diagnostic significance possessed by various assays specific to the detection of Mtb. This study included 345 suspected TB patients who received treatment at the Shandong Public Health Clinical Center during May 2019 and August 2019. Related data included demographics, gender, age, past medical history (PMH), country of birth, country of residence, clinical information and laboratory test outcomes. The smear method was performed three times, the BD960 method was conducted two times and the MTB/ RIF and Xpert Ultra (phlegm precipitation) assays were performed once. All methods were completed simultaneously.. The Xpert Ultra MTB (phlegm precipitation) method exhibited the highest consistency and sensitivity, followed by the Xpert MTB, Mtb culture, and smear methods, respectively. The Xpert Ultra MTB method also exhibited a significantly higher detection rate relative to the smear method (X2 = 13.411, p < 0.001).. Xpert MTB/RIF along with Xpert Ultra (phlegm precipitation) exhibited higher sensitivity specific for the diagnosis of TB and rifampicin-resistance. The combined effects of these four methods showed outstanding sensitivity compared with single methods alone.

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

The present study was planned to assess the distribution of tuberculosis in children and evaluate the antimycobacterial sensitivity pattern of Mycobacterium tuberculosis (MTB) isolates from pediatric patients. A total number of 1718 pediatric patients suspected of Mycobacterium tuberculosis were enrolled in the Institute of Child Health and Children's Hospital, Lahore during 2016-17. Out of 1718, only 710 different types of samples were tested for MTB. The samples were processed using bacteriology and GeneXpert along with the chest X-ray and clinical picture of the patients. The sensitivity pattern of Streptomycin, Isoniazid, Rifampicin and Ethambutol (SIRE) was determined using BACTEC MGIT 960. Total patients were divided into four groups including group A (birth to 12 months), B (1 to 5 years), C (6 to 10 years), and D (11 to 15 years). Out of 710, 106 (55 females and 51 males) were declared positive and 604 negative for tuberculosis. Out of 106 positive cases, 89 (83.96%) were sensitive to Rifampicin and 17 (16.04%) were resistant. Only, 04 (3.77%) were resistant to both Rifampicin and Isoniazid and declared as multidrug-resistant (MDR). It was concluded that children of age 11 to 15 years were more prone to MTB and a minimum percentage of MDR isolates was recorded in age group A (birth to 12 months).

Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Ethambutol; Humans; Infant; Infant, Newborn; Isoniazid; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pakistan; Rifampin; Streptomycin; Tertiary Care Centers; Tuberculosis, Pulmonary

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

Tuberculosis (TB) continues to be a significant health burden, most commonly affecting the lungs and referred to as pulmonary TB (PTB). Diagnostic techniques of PTB primarily rely on expectorated sputum samples. However, the diagnostic yields are often hindered due to insufficient volume and quality of the sputum specimens. Moreover, some individuals are unable to provide sputum samples due to scanty sputum production or difficulty in coughing up and require an invasive procedure to obtain a respiratory sample, such as bronchoscopic or gastric aspiration. Thus, challenges in the acquisition of respiratory specimens warrant an alternate specimen. Therefore, this systematic review aims to evaluate the diagnostic accuracy of a stool specimen for the diagnosis of PTB in adults.. We will search MEDLINE (Ovid), Embase (Ovid), Web of Science and Cochrane database from inception to April 2021 using a comprehensive search strategy. Two reviewers will independently perform screening, data extraction and quality assessment. The risk of bias assessment and applicability of results of eligible studies will be performed using the Quality of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects models will be performed to calculate pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio and diagnostic odds ratio along with 95% CI of stool specimen for each reported diagnostic method against any of the reference standard test (ie, mycobacterial culture or smear microscopy or Xpert assay using respiratory specimens). Heterogeneity between studies will be assessed by I. The results will be disseminated through publishing in a peer-reviewed medical journal and public presentations in relevant national and international conferences. As this is a systematic review of publicly available data, ethics approval is not required.. CRD42021245203.

Topics: Adult; Antibiotics, Antitubercular; Humans; Meta-Analysis as Topic; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Systematic Reviews as Topic; Tuberculosis, Pulmonary

Early access to diagnosis is crucial for effective management of any disease including tuberculosis (TB). We investigated the barriers and opportunities to maximise uptake and utilisation of molecular diagnostics in routine healthcare settings.. Health officers representing 190 districts/counties participated in the survey across Kenya, Tanzania and Uganda. The survey findings were corroborated by 145 healthcare facility (HCF) audits and 11 policy-maker engagement workshops. Xpert MTB/RIF coverage was 66%, falling behind microscopy and clinical diagnosis by 33% and 1%, respectively. Stratified by HCF type, Xpert MTB/RIF implementation was 56%, 96% and 95% at district, regional and national referral hospital levels. LPA coverage was 4%, 3% below culture across the three countries. Out of 111 HCFs with Xpert MTB/RIF, 37 (33%) used it to full capacity, performing ≥8 tests per day of which 51% of these were level five (zonal consultant and national referral) HCFs. Likewise, 75% of LPA was available at level five HCFs. Underutilisation of Xpert MTB/RIF and LPA was mainly attributed to inadequate-utilities, 26% and human resource, 22%. Underfinancing was the main reason underlying failure to acquire molecular diagnostics. Second to underfinancing was lack of awareness with 33% healthcare administrators and 49% practitioners were unaware of LPA as TB diagnostic. Creation of a national health tax and decentralising its management was proposed by policy-makers as a booster of domestic financing needed to increase access to diagnostics.. Our findings suggest higher uptake and utilisation of molecular diagnostics at tertiary level HCFs contrary to the WHO recommendation. Country-led solutions are crucial for unlocking barriers to increase access to diagnostics.

Topics: Humans; Mycobacterium tuberculosis; Pathology, Molecular; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary

The 2018 World Health Organization (WHO) treatment guidelines for multidrug-/rifampicin-resistant tuberculosis (MDR/RR-TB) give preference to all-oral long regimens lasting for 18-20 months. The guidelines strongly recommend combining bedaquiline, levofloxacin (or moxifloxacin) and linezolid, supplemented by cycloserine and/or clofazimine. The effectiveness of this combination in a long regimen has not been tested in any study to date, with corresponding uncertainty. The guidelines indicate that, ideally, all MDR-TB patients should have - as a minimum - the isolate tested for fluoroquinolones, bedaquiline and linezolid susceptibility before the start of treatment. Unfortunately, the capacity for drug susceptibility testing is insufficient in resource-limited settings. The risk of acquired bedaquiline resistance cannot be ignored, especially in patients with undetected resistance to fluoroquinolones. Both linezolid and cycloserine are known for their high frequency of serious adverse events. The combination of bedaquiline, moxifloxacin and clofazimine in the same regimen may excessively increase the QT interval. These expected adverse effects are difficult to monitor and manage in resource-limited settings, and may result in frequent modifications and a less effective regimen. The final STREAM results have confirmed the non-inferiority of the short regimen compared with the long regimen. Before evidence on the all-oral long and modified all-oral short treatment regimens is available, the WHO-recommended short MDR-TB regimens, with monitoring for ototoxicity, remain a better treatment option for the management of MDR/RR-TB patients who are eligible for short regimens in low- and middle-income countries. National tuberculosis programmes should also strengthen their capacity in the detection and management of fluoroquinolone-resistant MDR-TB following the WHO guidelines.

Topics: Antitubercular Agents; Clofazimine; Diarylquinolines; Humans; Linezolid; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Pulmonary

Weight change may inform tuberculosis treatment response, but its predictive power may be confounded by human immunodeficiency virus (HIV).. We prospectively followed up adults with culture-confirmed, drug-susceptible, pulmonary tuberculosis receiving standard 4-drug therapy (isoniazid, rifampin, pyrazinamide, and ethambutol) in Brazil. We examined median weight change 2 months after treatment initiation by HIV status, using quantile regression, and unsuccessful tuberculosis treatment outcome (treatment failure, tuberculosis recurrence, or death) by HIV and weight change status, using Cox regression.. Among 547 participants, 102 (19%) were HIV positive, and 35 (6%) had an unsuccessful outcome. After adjustment for confounders, persons living with HIV (PLWH) gained a median of 1.3 kg (95% confidence interval [CI], -2.8 to .1) less than HIV-negative individuals during the first 2 months of tuberculosis treatment. PLWH were at increased risk of an unsuccessful outcome (adjusted hazard ratio, 4.8; 95% CI, 2.1-10.9). Weight change was independently associated with outcome, with risk of unsuccessful outcome decreasing by 12% (95% CI, .81%-.95%) per 1-kg increase.. PLWH gained less weight during the first 2 months of tuberculosis treatment, and lack of weight gain and HIV independently predicted unsuccessful tuberculosis treatment outcomes. Weight, an easily collected biomarker, may identify patients who would benefit from alternative treatment strategies.

Topics: Adult; Antitubercular Agents; Brazil; Ethambutol; Female; HIV Seropositivity; Humans; Isoniazid; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary; Weight Gain

Patients with suspected pulmonary tuberculosis (PTB) are usually placed in respiratory isolation awaiting three sputum smear microscopy results for acid-fast bacilli (3AFB). GeneXpert MTB/RIF (Xpert) on a pooled sample from two sputa may allow for more rapid de-isolation.. To compare the sensitivity and negative predictive value (NPV) of Xpert performed on a single pooled sputum sample ('pooled Xpert') to 3AFB, in order to exclude PTB in patients placed in respiratory isolation.. Hospital inpatients in respiratory isolation for possible PTB were enrolled prospectively. Three expectorated sputum samples were obtained for smear microscopy. Two of the same samples had 0.5 ml removed from each and pooled for pooled Xpert. The diagnostic accuracy of pooled Xpert and 3AFB were assessed and compared to liquid culture at 8 weeks as the reference standard.. Of 56 participants, nine (16.1%) were diagnosed with PTB. Compared to liquid culture, pooled Xpert had a sensitivity of 88.9% (95% confidence interval (CI) 57-99%) and NPV of 97.9% (95% CI 89-99%). 3AFB had a sensitivity of 66.7% (95% CI 35-88%) and NPV of 93.5% (95% CI 83-98%).. A single pooled Xpert was non-inferior to 3AFB, with a strong trend towards greater sensitivity and better NPV. These findings support the use of a single pooled Xpert as an effective rapid screening approach for ruling out PTB in low incidence settings. Its value in high incidence settings and optimal combination with smear microscopy and culture warrant further evaluation.

Topics: Adult; Aged; Antibiotics, Antitubercular; Female; Humans; Inpatients; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

International policy for treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR TB) relies largely on individual patient data (IPD) from observational studies of patients treated under routine conditions. We prepared guidance on which data to collect and what measures could improve consistency and utility for future evidence-based recommendations. We highlight critical stages in data collection at which improvements to uniformity, accuracy, and completeness could add value to IPD quality. Through a repetitive development process, we suggest essential patient- and treatment-related characteristics that should be collected by prospective contributors of observational IPD in MDR/RR TB.

Topics: Antitubercular Agents; Humans; Mycobacterium tuberculosis; Observational Studies as Topic; Quality Improvement; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rapid and correct determination of Mycobacterium tuberculosis (MTB) drug susceptibility is a challenge for tuberculosis (TB) management. Phenotypic drug susceptibility testing (DST) remains the reference method but is time consuming. In this study, genotypic prediction of the first-line drug susceptibility profile obtained by whole-genome sequencing (WGS) was compared with that obtained by phenotypic DST and the line probe assay (LPA). All MTB strains isolated from patients during routine practice at the mycobacteria laboratory of Lyon University Hospital, France, between November 2016 and July 2019 were included (n = 274). Isolates were tested for the first-line drugs using phenotypic DST (Mycobacteria Growth Indicator Tube) and for genotypic prediction of the susceptibility profile with LPA and WGS. Considering phenotypic DST as the reference, WGS predicted resistance to rifampicin, isoniazid, ethambutol and pyrazinamide with sensitivities of 100%, 100%, 100% and 93.8%, respectively, and susceptibility to these drugs with specificities of 99.6%, 100%, 98.5% and 100%, respectively. Performance of the LPA was poorer, with sensitivity of 83.3% for rifampicin and 85.7% for isoniazid resistance. Five isolates were classified as susceptible according to phenotypic DST (1 for rifampicin, 4 for ethambutol) while WGS detected resistance mutations in rpoB and embB genes. WGS, used under appropriate quality-control conditions, has good performance to predict the resistance profile for the four first-line drugs and can correct phenotypic DST results. This study highlights the need for future guidelines recommending WGS as the initial tool in routine practice in areas where the prevalences of TB and drug-resistant MTB are low.

Topics: Antitubercular Agents; Bacterial Proteins; DNA-Directed RNA Polymerases; Drug Resistance, Multiple, Bacterial; Ethambutol; France; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pentosyltransferases; Pyrazinamide; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Whole Genome Sequencing

Topics: Antitubercular Agents; Diagnosis, Differential; Drug Eruptions; Humans; Male; Middle Aged; Rifampin; Tuberculosis, Pulmonary

The Lesotho guidelines for the management of drug-resistant tuberculosis (TB) recommend initiation of patients diagnosed with rifampicin resistant (RR)-TB on a standardized drug resistant regimen while awaiting confirmation of rifampicin resistant TB (RR-TB) and complete drug susceptibility test results. Review of diagnostic records between 2014 and 2016 identified 518 patients with RR-TB. Only 314 (60.6%) patients could be linked to treatment records at the Lesotho MDR hospital. The median delay in treatment initiation from the availability of Xpert MTB/RIF assay result was 12 days (IQR 7-19). Only 32% (101) of patients had a documented first-line drug resistant test. MDR-TB was detected in 56.4% of patients while 33.7% of patients had rifampicin mono-resistance. Only 7.4% of patients assessed for second-line resistance had a positive result (resistance to fluoroquinolone). Treatment success was 69.8%, death rate was 28.8%, loss to follow up was 1.0%, and 0.4% failed treatment. Death was associated with positive or unavailable sputum smear at the end of first month of treatment (Fisher exact p < 0.001) and older age (p = 0.007). Urgent attention needs to be given to link patients with RR-TB to care worldwide. The association of death rate with positive sputum smear at the end of the first month of treatment should trigger early individualization of treatment.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; Fluoroquinolones; Follow-Up Studies; Humans; Lesotho; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Practice Guidelines as Topic; Retrospective Studies; Rifampin; Sputum; Time-to-Treatment; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Rapid tests to diagnose tuberculosis relies on molecular detection of the M. tuberculosis. GeneXpert MTB/RIF test identifies M. tuberculosis and rifampicin resistance. We present a case of simultaneous coinfection with M. tuberculosis and M. avium. M. tuberculosis was detected in the sputum by PCR GeneXpert method. Unrecognized coexistence of M. tuberculosis and M. avium modified the results of drug susceptibility tests making the primary identification of M. tuberculosis as multi-drug resistant strain. We performed in vitro experiments to investigate the effect of the coexistence of M. avium with M. tuberculosis on the results of GeneXpert method, and drug susceptibility test.

Topics: Antibiotics, Antitubercular; Coinfection; Drug Resistance, Bacterial; Female; Humans; Microbial Sensitivity Tests; Middle Aged; Mycobacterium avium; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sputum; Tuberculosis, Pulmonary

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

Xpert MTB/RIF (Xpert) is an automated molecular test recommended by World Health Organization (WHO) for diagnosis of tuberculosis (TB). This study evaluated the effect of Xpert implementation on the detection of pulmonary TB (PTB) and rifampicin-resistant TB (RR-TB) cases in Shanghai, China.. Xpert was routinely implemented in 2018 for all presumptive PTB patients. All PTB patients above 15 years-old identified within the Provincial TB Control Program during the first half of each of 2017 and 2018, were enrolled to compare the difference in proportions of bacteriological confirmation, patients with drug susceptibility test (DST) results for rifampicin (ie, DST coverage) and RR-TB detection before and after Xpert's implementation.. A total of 6047 PTB patients were included in the analysis with 1691 tested by Xpert in 2018. Percentages of bacteriological confirmation, DST coverage and RR-TB detection in 2017 and 2018 were 50% vs. 59%, 36% vs. 49% and 2% vs. 3%, respectively (all p-values < 0.05). Among 1103 PTB patients who completed sputum smear, culture and Xpert testing in 2018, Xpert detected an additional 121 (11%) PTB patients who were negative by smear and culture, but missed 248 (23%) smear and/or culture positive patients. Besides, it accounted for an increase of 9% in DST coverage and 1% in RR-TB detection. The median time from first visit to a TB hospital to RR-TB detection was 62 days (interquartile range -IQR 48-84.2) in 2017 vs. 9 days (IQR 2-45.7) in 2018 (p-value < 0.001). In the multivariate model, using Xpert was associated with decreased time to RR-TB detection (adjusted hazard ratio = 4.62, 95% confidence interval: 3.18-6.71).. Integrating Xpert with smear, culture and culture-based DST in a routine setting significantly increased bacteriological confirmation, DST coverage and RR-TB detection with a dramatic reduction in the time to RR-TB diagnosis in Shanghai, China. Our findings can be useful for other regions that attempt to integrate Xpert into routine PTB and RR-TB case-finding cascade. Further study should focus on the identification and elimination of operational level challenges to fully utilize the benefit of rapid diagnosis by Xpert.

Topics: Adult; Antitubercular Agents; Bacteriological Techniques; China; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

In children requiring lopinavir coformulated with ritonavir in a 4:1 ratio (lopinavir-ritonavir-4:1) and rifampin, adding ritonavir to achieve a 4:4 ratio with lopinavir (LPV/r-4:4) overcomes the drug-drug interaction. Possible drug-drug interactions within this regimen may affect abacavir concentrations, but this has never been studied. Children weighing <15 kg needing rifampin and LPV/r-4:4 were enrolled in a pharmacokinetic study and underwent intensive pharmacokinetic sampling on 3 visits: (i) during the intensive and (ii) continuation phases of antituberculosis treatment with LPV/r-4:4 and (iii) 1 month after antituberculosis treatment completion on LPV/r-4:1. Pharmacometric modeling and simulation were used to compare exposures across weight bands with adult target exposures. Eighty-seven children with a median (interquartile range) age and weight of 19 (4 to 64) months and 8.7 (3.9 to 14.9) kg, respectively, were included in the abacavir analysis. Abacavir pharmacokinetics were best described by a two-compartment model with first-order elimination and transit compartment absorption. After allometric scaling adjusted for the effect of body size, maturation could be identified: clearance was predicted to be fully mature at about 2 years of age and to reach half of this mature value at about 2 months of age. Abacavir bioavailability decreased 36% during treatment with rifampin and LPV/r-4:4 but remained within the median adult recommended exposure, except for children in the 3- to 4.9-kg weight band, in which the exposures were higher. The observed predose morning trough concentrations were higher than the evening values. Though abacavir exposure significantly decreased during concomitant administration of rifampin and LPV/r-4:4, it remained within acceptable ranges. (This study is registered in ClinicalTrials.gov under identifier NCT02348177.).

Topics: Anti-HIV Agents; Antitubercular Agents; Biological Availability; Child; Child, Preschool; Dideoxynucleosides; Drug Combinations; Drug Interactions; HIV Infections; Humans; Lopinavir; Prospective Studies; Rifampin; Ritonavir; Tuberculosis, Pulmonary

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

Lack of blood pressure control is often seen in hypertensive patients concomitantly taking antituberculosis medications due to the complex drug-drug interactions between rifampin and antihypertensive drugs. Therefore, it is of clinical importance to understand the underlying mechanisms of these interactions to help formulate recommendations on the use of antihypertensive drugs in patients taking these medications concomitantly. Our objective was to assess the reliability of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to predict potential interactions between rifampin and antihypertensive drugs and thus provide recommendations on the choice of antihypertensive drugs in patients receiving rifampin.. Evidence-based in vitro and in vivo predictions of drug-drug interactions.. We systematically evaluated interactions between rifampin and antihypertensive drugs using the theory of the BDDCS, taking into consideration the role of drug transporters and metabolic enzymes involved in these interactions. We provide recommendations on the selection of antihypertensive drugs for patients with tuberculosis. Antihypertensive drugs approved by the U.S. Food and Drug Administration and the China National Medical Products Administration were included in this study. The drugs were classified into four categories under the BDDCS classification. Detailed information on cytochrome P450 (CYP) enzymes and drug transporters for each antihypertensive drug was searched in PubMed and other electronic databases. This information was combined with the effects of rifampin on CYP enzymes and drug transporters, and the direction and relative extent of the potential interactions between rifampin and antihypertensive drugs were predicted. Recommendations were then made using the theory of BDDCS. A thorough systematic literature review was performed, and data from all published human studies and case reports were summarized for the validation of our predictions. Interventional and observational studies published in PubMed and two Chinese databases (CNKI and WanFang) through December 16, 2019, were included, and data were extracted for validation of the predictions. Using the BDDCS theory, class 3 active drugs were predicted to exhibit minimal interactions with rifampin. On reviewing case reports and pre-post studies, the predictions we made were found to be reliable. When antituberculosis medications that include rifampin are started in patients with hypertension, it is recommended that the use of calcium channel blockers and classes 1 and 2 β-blockers be avoided. Angiotensin-converting enzyme inhibitors, olmesartan, class 3 β-blockers, spironolactone, and hydrochlorothiazide would be preferable because clinically relevant interactions would not be expected.. Application of the BDDCS to predict interactions between rifampin and antihypertensive drugs for patients with both tuberculosis and hypertension was found to be reliable. It should be noted, however, that based on the CYP enzyme and drug transporter information we reviewed, the mechanisms of all of the interactions could not be elucidated, and the predictions are only based on theory. The real effects of rifampin on antihypertensive drugs need to be further observed. More studies in both animals and humans are needed in the future.

Topics: Antihypertensive Agents; Antitubercular Agents; Biopharmaceutics; Drug Interactions; Humans; Hypertension; Rifampin; Tuberculosis, Pulmonary

Prolonged therapy, drug toxicity, noncompliance, immune suppression, and alarming emergence of drug resistance necessitate the search for therapeutic vaccine strategies for tuberculosis (TB). Such strategies ought to elicit not only IFN-γ, but polyfunctional response including TNF-α, which is essential for protective granuloma formation. Here, we investigated the impact of PD-1 inhibition in facilitating protective polyfunctional T cells (PFTs), bacillary clearance, and disease resolution. We have observed PD-1 inhibition preferentially rescued the suppressed PFTs in active tuberculosis patients. In addition, polyfunctional cytokine milieu favored apoptosis of infected MDMs over necrosis with markedly reduced bacillary growth (≪CFU) in our in vitro monocyte-derived macrophages (MDMs) infection model. Furthermore, the animal study revealed a significant decline in the bacterial burden in the lungs and spleen of infected mice after in vivo administration of α-PD-1 along with antitubercular treatment. Our findings suggest that rescuing polyfunctional immune response by PD-1 inhibition works synergistically with antituberculosis chemotherapy to confer improved control over bacillary growth and dissemination. In summary, our data strongly indicate the therapeutic potential of α-PD-1 as adjunct immunotherapy that can rejuvenate suppressed host immunity and enhance the efficacy of candidate therapeutic vaccine(s).

Topics: Adolescent; Adult; Animals; Antibodies; Antitubercular Agents; Bacterial Load; CD4-Positive T-Lymphocytes; Combined Modality Therapy; Female; Humans; Interferon-gamma; Isoniazid; Lung; Macrophages; Male; Mice; Mice, Inbred BALB C; Middle Aged; Mycobacterium tuberculosis; Primary Cell Culture; Programmed Cell Death 1 Receptor; Rifampin; Spleen; Treatment Outcome; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

Tuberculosis (TB) is a chronic disease that mostly affects low-income countries. TB is transmitted through droplet aerosolization from a person with active pulmonary TB. Afghanistan is one of the 22 high TB burden countries where 39,445 people develop this disease and 7840 people die each year. Treatment outcome is one of the best measurements that explain how the current regimen works.. This was a retrospective cohort study, conducted in Kandahar Province, to find out the treatment outcome of anti-TB drugs regimens in TB patients. Data of pulmonary and extra-pulmonary TB patients, who fulfilled the eligible criteria of the study and were treated from 2005 to 2015, was retrieved from their medical record forms.. Among 1000 TB patients, 599 (59.9%) were females and 401 (40.1%) males; most of the patients (678/1000 [67.8%]) were from Kandahar city while 322/1000 (32.2%) were from the other districts of Kandahar. Mean age of the patients were 36.1 years with SD of 19.3 years. Main signs and symptoms of fever, cough, and weight loss were present in 949/1000 (94.9%), 880/1000 (88%), and 544/1000 (54.4%) of the patients, respectively. On first visit 459/1000 (45.9%) patients were sputum AFB (acid fast bacilli) positive. Majority (247/459 [53.8%]) of these patients were AFB 2+. After 2 months of intensive anti-TB treatment, 9/459 (1.9%) patients were still AFB positive (1+). Treatment outcome of these 1000 patients showed that 479 (47.9%) completed the treatment, 298 (29.8%) were cured, 35 (3.5%) failed the anti-TB treatment, while 5 (0.5%) patients died.. This clearly shows that TB is still one of the major threats to the people of Kandahar Province. There are cases of TB who do not respond to the first line regimens of anti-TB drugs advised by WHO and Afghan Ministry of Public Health (MoPH).

Topics: Adolescent; Adult; Afghanistan; Antitubercular Agents; Cohort Studies; Cough; Drug Therapy, Combination; Duration of Therapy; Ethambutol; Female; Fever; Humans; Isoniazid; Male; Middle Aged; Mortality; Prognosis; Pyrazinamide; Retreatment; Retrospective Studies; Rifampin; Sex Distribution; Sputum; Treatment Failure; Treatment Outcome; Tuberculosis, Pulmonary; Weight Loss; Young Adult

In Japan, tuberculosis has been recognized as one of the major infections requiring urgent measures because of its high morbidity rate even now especially in elderly people suffering from tuberculosis during the past epidemic and its reactivation. Hence, many Japanese clinicians have made efforts to suppress the onset of tuberculosis and treat it effectively. The objectives of this study are to (1) identify covariate(s) that may explain the variation of rifampicin, which is the key antitubercular agent, under the steady-state by evaluating its population pharmacokinetics and (2) to propose an appropriate dosing method of rifampicin to Japanese patients. For this purpose, serum concentration-time data were obtained from 138 patients receiving rifampicin (300-450 mg) and isoniazid (300-400 mg) every day over 14 days, and analyzed using nonlinear mixed effects model. Thereby, population pharmacokinetic parameters were estimated followed by elucidating relations between the parameters and statistical factors. The analysis adopted one-compartment model including Lag-time by assuming that the absorption process is 0+1st order. The analyses demonstrate that meal affected the bioavailability, primary absorption rate constant, and zero order absorption time in the constructed model. A body weight calculated from the power model was selected as the covariate by the Stepwise Covariate Model method and found to highly affect the clearance in the range from -31.6% to 47.4%. We conclude that the dose in Japanese tuberculous patients can be well estimated by the power model formula and should be taken into consideration when rifampicin is administered.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Biological Availability; Biological Variation, Population; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Food-Drug Interactions; Gastrointestinal Absorption; Humans; Japan; Male; Middle Aged; Models, Biological; Retrospective Studies; Rifampin; Solubility; Tuberculosis, Pulmonary; Young Adult

The larynx is the second most commonly affected site in the head and neck region in patients with extrapulmonary tuberculosis (TB). Despite this, the prevalence of laryngeal TB is largely unknown, particularly in areas with a high TB burden. The laboratory diagnosis of TB includes microscopy, culture and molecular testing. The aims of this study were to determine the prevalence of laryngeal TB in patients presenting with laryngeal pathology in a region with a high TB burden and to determine the optimal diagnostic methods for the diagnosis of laryngeal TB.. This was a prospective descriptive study of 80 adult patients undergoing direct laryngoscopy and biopsy for laryngeal pathology in the Department of Otorhinolaryngology, Universitas Academic Hospital, Bloemfontein, South Africa over a 1 year period. Histopathological and microbiological investigations (microscopy, Xpert MTB/RIF, and TB culture) were performed on all laryngeal biopsies.. Five (6.25%) out of 80 patients were diagnosed with laryngeal TB. In one patient, the Xpert MTB/RIF assay was positive on the laryngeal tissue and histology showed granulomas. Two patients had granulomas on histology although the microbiological tests on the tissue were negative. Two patients had only positive tissue cultures for Mycobacterium tuberculosis. None of the biopsies had positive Ziehl-Neelsen stains.. The results suggest that the diagnosis of laryngeal TB required a combination of histopathology, culture and PCR and that the Xpert MTB/RIF assay is not a sensitive test for the diagnosis of laryngeal TB.

Topics: Adult; Antibiotics, Antitubercular; Humans; Prospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis, Laryngeal; Tuberculosis, Pulmonary

Tuberculosis (TB) can manifest prolonged fever or fever of unknown origin, especially when it is located extrapulmonary. We report a case of disseminated TB complicated by iliac bone osteolysis and a gluteal abscess in a 75-year-old female patient with fever and bone marrow dysplasia. Diagnosis of TB was made despite transient false-positive high-titer agglutination tests and ELISA antibodies to Brucella. The case presented shows that in a highly suggestive case of TB, positive agglutination tests or ELISA antibodies to Brucella should be interpreted with caution, and repeated testing should be performed to assess their persistence and fluctuation over time.

Topics: Aged; Anti-Bacterial Agents; Brucella; Brucellosis; Diagnosis, Differential; Doxycycline; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Fever; Humans; Rifampin; Tuberculosis, Pulmonary

Studying within-host genetic diversity of Mycobacterium tuberculosis (Mtb) in patients during treatment may identify adaptations to antibiotic and immune pressure. Understanding the significance of genetic heteroresistance, and more specifically heterozygous resistance-associated variants (RAVs), is clinically important given increasing use of rapid molecular tests and whole genome sequencing (WGS).. We analyse data from six studies in KwaZulu-Natal, South Africa. Most patients (>75%) had baseline rifampicin resistance. Sputum was collected for culture at baseline and at between two and nine intervals until month six. Positive cultures underwent WGS. Mixed infections and reinfections were excluded from analysis.. Baseline Mtb overall genetic diversity (at treatment initiation or major change to regimen) was associated with cavitary disease, not taking antiretroviral therapy if HIV infected, infection with lineage 2 strains and absence of second-line drug resistance on univariate analyses. Baseline genetic diversity was not associated with six-month outcome. Genetic diversity increased from baseline to weeks one and two before returning to previous levels. Baseline genetic heteroresistance was most common for bedaquiline (6/10 [60%] of isolates with RAVs) and fluoroquinolones (9/62 [13%]). Most patients with heterozygous RAVs on WGS with sequential isolates available demonstrated RAV persistence or fixation (17/20, 85%). New RAVs emerged in 9/286 (3%) patients during treatment. We could detect low-frequency RAVs preceding emergent resistance in only one case, although validation of deep sequencing to detect rare variants is required.. In this study of single-strain Mtb infections, baseline within-host bacterial genetic diversity did not predict outcome but may reveal adaptations to host and drug pressures. Predicting emergent resistance from low-frequency RAVs requires further work to separate transient from consequential mutations.. Wellcome Trust, NIH/NIAID.

Topics: Adult; Antitubercular Agents; Cohort Studies; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Female; Fluoroquinolones; Gene Expression Regulation, Bacterial; Genes, Bacterial; Genetic Variation; Host-Pathogen Interactions; Humans; Male; Metabolic Networks and Pathways; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; South Africa; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The MDR/MTB ELITe MGB® Kit on the ELITe InGenius® platform (ELITechGroup SpA, Italy) is the first system for simultaneous detection of the Mycobacterium tuberculosis complex (MTBc) genome and the main mutations responsible for resistance to Isoniazid (inhA, katG) and Rifampicin (rpoB), from decontaminated and heat inactivated samples. In this study we compared the performance of the MDR/MTB ELITe MGB® Kit (ELITe) with culture in 100 pulmonary and 160 extra-pulmonary samples. The sensitivity and specificity of ELITe compared to culture for pulmonary samples were 98.0% and 98.0% respectively; for extra-pulmonary samples the overall sensitivity was 86.3% (80% for urine, 85% for biopsy and gastric aspirate and 95% for cavitary fluid) and specificity was 100%. Genotypic Isoniazid and Rifampicin susceptibility typing was feasible in 96% of sputum MTBc-positive samples and 43% of extra-pulmonary samples; all samples were found to be drug susceptible by phenotypic and ELITe (100% agreement). Detection of mutations in the rpoB, kat G or inhA genes was evaluated on 300 spiked samples (60 per biological matrix) and all resistance profiles were correctly identified by ELITe. Molecular agreement between ELITe and Xpert was 98.0% and 93.3% for pulmonary and extra-pulmonary samples, respectively. In conclusion, our results provide evidence to support the use of MDR/MTB ELITe MGB® Kit in combination with ELITe InGenius® for the diagnosis of MTBc and the detection of Rifampicin and Isoniazid resistance-related mutations in both pulmonary and extra-pulmonary samples. This system simplifies the laboratory workflow, shortens report time and is an aid in choosing appropriate therapeutic treatment and patient management.

Topics: Antibiotics, Antitubercular; Biopsy; Drug Resistance, Bacterial; Genotype; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Reagent Kits, Diagnostic; Reproducibility of Results; Retrospective Studies; Rifampin; ROC Curve; Sensitivity and Specificity; Temperature; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The Xpert MTB/RIF assay is an automated molecular test that is designed to simultaneously detect Mycobacterium tuberculosis (MTB) complex and rifampin resistance. However, there are relatively few studies on this method in China. Xpert has been routinely used at Peking University People's Hospital (PKUPH) since November 2016. Thus, the aim of this study was to evaluate the performance of Xpert, and provide a reference and guidance for the detection and diagnosis of TB in non-TB specialized hospitals.. The medical records of inpatients simultaneously tested with Xpert, acid-fast bacilli (AFB) smear microscopy, and interferon-gamma release assay (IGRA, by T-SPOT®.TB) at PKUPH from November 2016 to October 2018 were reviewed. Active TB cases were considered according to a composite reference standard (CRS). Then, the three methods were evaluated and compared.. In total, 787 patients simultaneously tested with Xpert, AFB, and IGRA were enrolled; among them 11.3% (89/787) were diagnosed and confirmed active pulmonary TB (PTB, 52 cases), extrapulmonary TB (EPTB, 17 cases), and tuberculous pleurisy (TP, 20 cases). The sensitivity of Xpert in detecting PTB, EPTB, and TP was 88.5, 76.5, and 15.0%, respectively, which was slightly lower than IGRA (96.2, 82.4, and 95.0%, respectively), but higher than AFB (36.5, 11.8, and 0%, respectively); IGRA showed the highest sensitivity, but its specificity (55.9, 67.1, and 45.2%, respectively) was significantly lower than Xpert (99.6, 99.4, and 100%, respectively) and AFB (99.0, 99.4, and 100%, respectively) (P < 0.001). The sensitivity of Xpert in detecting lung tissue, cerebrospinal fluid, lymph nodes, and joint fluid was 100%, followed by sputum (88.5%), alveolar lavage (85.7%), and bronchoscopy secretion (81.2%); the pleural fluid sensitivity was the lowest, only 15.0%. For AFB negative patients, the sensitivity of Xpert in detecting PTB, EPTB, and TP was 84.9, 73.3, and 15.0%, respectively.. Xpert showed both high sensitivity and high specificity, and suggested its high value in TB diagnosis; however, the application of pleural fluid is still limited, and should be improved. Owing to the high sensitivity of IGRA, it is recommended for use as a supplementary test, especially for assisting in the diagnosis of TP and EPTB.

Topics: Adolescent; Adult; Aged; China; Drug Resistance, Bacterial; Female; Hospitals, Teaching; Humans; Interferon-gamma Release Tests; Male; Microscopy; Middle Aged; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis, Pleural; Tuberculosis, Pulmonary; Young Adult

Proper characterization of drug effects on Mycobacterium tuberculosis relies on the characterization of phenotypically resistant bacteria to correctly establish exposure-response relationships. The aim of this work was to evaluate the potential difference in phenotypic resistance in in vitro compared to murine in vivo models using CFU data alone or CFU together with most probable number (MPN) data following resuscitation with culture supernatant. Predictions of in vitro and in vivo phenotypic resistance i.e. persisters, using the Multistate Tuberculosis Pharmacometric (MTP) model framework was evaluated based on bacterial cultures grown with and without drug exposure using CFU alone or CFU plus MPN data. Phenotypic resistance and total bacterial number in in vitro natural growth observations, i.e. without drug, was well predicted by the MTP model using only CFU data. Capturing the murine in vivo total bacterial number and persisters during natural growth did however require re-estimation of model parameter using both the CFU and MPN observations implying that the ratio of persisters to total bacterial burden is different in vitro compared to murine in vivo. The evaluation of the in vitro rifampicin drug effect revealed that higher resolution in the persister drug effect was seen using CFU and MPN compared to CFU alone although drug effects on the other bacterial populations were well predicted using only CFU data. The ratio of persistent bacteria to total bacteria was predicted to be different between in vitro and murine in vivo. This difference could have implications for subsequent translational efforts in tuberculosis drug development.

Topics: Animals; Antitubercular Agents; Colony Count, Microbial; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Humans; Lung; Mice; Microbial Sensitivity Tests; Models, Biological; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Pulmonary

To reach WHO End tuberculosis (TB) targets, countries need a quality-assured laboratory network equipped with rapid diagnostics for tuberculosis diagnosis and drug susceptibility testing. Diagnostic network analysis aims to inform instrument placement, sample referral, staffing, geographical prioritization, integration of testing enabling targeted investments and programming to meet priority needs.. Supply chain modelling and optimization software was used to map Lesotho's TB diagnostic network using available data sources, including laboratory and programme reports and health and demographic surveys. Various scenarios were analysed, including current network configuration and inclusion of additional GeneXpert and/or point of care instruments. Different levels of estimated demand for testing services were modelled (current [30,000 tests/year], intermediate [41,000 tests/year] and total demand needed to find all TB cases [88,000 tests/year]).. Lesotho's GeneXpert capacity is largely well-located but under-utilized (19/24 sites use under 50% capacity). The network has sufficient capacity to meet current and near-future demand and 70% of estimated total demand. Relocation of 13 existing instruments would deliver equivalent access to services, maintain turnaround time and reduce costs compared with planned procurement of 7 more instruments. Gaps exist in linking people with positive symptom screens to testing; closing this gap would require extra 11,000 tests per year and result in 1000 additional TB patients being treated. Closing the gap in linking diagnosed patients to treatment would result in a further 629 patients being treated. Scale up of capacity to meet total demand will be best achieved using a point-of-care platform in addition to the existing GeneXpert footprint.. Analysis of TB diagnostic networks highlighted key gaps and opportunities to optimize services. Network mapping and optimization should be considered an integral part of strategic planning. By building efficient and patient-centred diagnostic networks, countries will be better equipped to meet End TB targets.

Topics: Antibiotics, Antitubercular; Clinical Laboratory Services; Community Networks; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Lesotho; Microbial Sensitivity Tests; Models, Theoretical; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Point-of-Care Systems; Rifampin; Software; Tuberculosis, Pulmonary

Tuberculosis (TB) diagnosis in children still remains a challenge in developing countries. We analyze the performance of Xpert MTB/RIF assay for the diagnosis of pediatric TB under programmatic conditions. We retrospectively analyzed the performance of Xpert MTB/RIF assay from February 2016 to March 2018. A total 2678 samples from TB suspects below 14 years were received in the laboratory and were frontline tested by Xpert MTB/RIF assay according to the manufacturer's instructions. If sample was sufficient, the smear microscopy and culture were performed as per standard World Health Organization's guidelines. The smears and cultures were performed in 2178 and 588 samples, respectively. Among 2678 samples, 68 were rejected, Xpert MTB/RIF assay was positive in 357/2610 (13.6%) cases, while the smear was positive in 81/2178 (3.3%) cases. The sensitivity of smear and Xpert MTB/RIF when compared with culture was 24.6% (14.1-37.8%) and 81% (68.6-90.1%), respectively. The diagnostic accuracy of Xpert MTB/RIF and smear was 97.1% and 92.2%, respectively. Thirty samples (8.5%) were detected as rifampicin resistance by Xpert MTB/RIF assay. The Xpert MTB/RIF increased the detection rate up to fourfold when compared with smear microscopy. Xpert MTB/RIF assay is the most rapid, sensitive, and specific method for microbiological confirmation and rifampicin resistance detection in pediatric tuberculosis.

Topics: Child; Drug Resistance, Bacterial; Humans; India; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary

Topics: Adolescent; Antitubercular Agents; Conjunctivitis; Diagnosis, Differential; Ethambutol; Glucocorticoids; Humans; Isoniazid; Male; Prednisolone; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

GeneXpert (GX) is a novel, integrated, cartridge-based, nucleic acid amplification test with an established role for rapid diagnosis of Mycobacterium tuberculosis and detection of rifampicin resistance.. To evaluate the role of GX in pulmonary and extrapulmonary tuberculosis (TB) cases.. A prospective study was conducted in the pulmonary medicine department of a tertiary care hospital after the Ethics Comittee permission. Data of 257 presumptive TB patients was retrieved for GX, acid fast bacilli smear and cul-ture (AFB smear and culture) and drug susceptibility test (DST). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of GX in diagnosis and determination of rifampicin resistance in pulmonary and extrapulmonary TB cases were calculated and compared with culture and DST results.. Our study included 132 pulmonary and 125 extrapulmonary cases. On the basis of clinicoradiological and microbiological correlation, diagnosis of TB was confirmed in 104 pulmonary and 103 extrapulmonary cases. Out of a total of 104 pulmonary TB cases, 73 were rifampicin-sensitive and 31 were rifampicin-resistant cases. 103 extrapulmonary TB patients included 66 rifampicin-sensitive and 37 rifampicin-resistant cases. The sensitivity, specificity, PPV, NPV of GX in diagnosis and detection of rifampicin resistance in pulmonary TB was 95%, 93%, 98%, 84% and 96%, 100%, 100%, 96%, respectively. The sensitivity, specificity, PPV, NPV of GX in diagnosis and detection of rifampicin resistance in extrapulmonary TB cases was 79%, 86%, 96%, 47% and 97%, 95%, 97%, 95%, respectively.. GX results are superior to smear microscopy and comparable to culture with shorter turnaround time.We recom-mend using it in routine TB diagnosis as this will expedite the management of patients with presumptive TB.

Topics: Adult; Antibiotics, Antitubercular; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sputum; Tuberculosis, Pulmonary

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

Tuberculosis (TB) is among the top 10 causes of mortality and the first killer among infectious diseases worldwide. One of the factors fuelling the TB epidemic is the global rise of multidrug resistant TB (MDR-TB). The aim of this study was to determine the magnitude and factors associated with MDR-TB in the Tigray Region, Ethiopia.. This study employed a facility-based cross-sectional study design, which was conducted between July 2018 and August 2019. The inclusion criteria for the study participants were GeneXpert-positive who were not under treatment for TB, PTB patients' ≥15 years of age and who provided written informed consent. A total of 300 participants were enrolled in the study, with a structured questionnaire used to collect data on clinical, sociodemographic and behavioral factors. Sputum samples were collected and processed for acid-fast bacilli staining, culture and drug susceptibility testing. Drug susceptibility testing was performed using a line probe assay. Logistic regression was used to analyze associations between outcome and predictor variables.. The overall proportion of MDR-TB was 16.7% (11.6% and 32.7% for new and previously treated patients, respectively). Of the total MDR-TB isolates, 5.3% were pre-XDR-TB. The proportion of MDR-TB/HIV co-infection was 21.1%. A previous history of TB treatment AOR 3.75; 95% CI (0.7-2.24), cigarette smoking AOR 6.09; CI (1.65-2.50) and patients who had an intermittent fever (AOR = 2.54, 95% CI = 1.21-5.4) were strongly associated with MDR-TB development.. The magnitude of MDR-TB observed among new and previously treated patients is very alarming, which calls for an urgent need for intervention. The high proportion of MDR-TB among newly diagnosed cases indicates ongoing transmission, which suggests the need for enhanced TB control program performance to interrupt transmission. The increased proportion of MDR-TB among previously treated cases indicates a need for better patient management to prevent the evolution of drug resistance. Assessing the TB control program performance gaps and an optimal implementation of the WHO recommended priority actions for the management of drug-resistant TB, is imperative to help reduce the current high MDR-TB burden in the study region.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Cross-Sectional Studies; Ethiopia; Female; HIV Infections; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Risk Factors; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Topics: Adenosine Monophosphate; Alanine; Antitubercular Agents; Antiviral Agents; Betacoronavirus; Coinfection; Comorbidity; Coronavirus Infections; COVID-19; Drug Interactions; HIV Infections; HIV-1; Humans; Mycobacterium tuberculosis; Pandemics; Pneumonia, Viral; Prevalence; Rifampin; SARS-CoV-2; Survival Analysis; Tuberculosis, Pulmonary; United States

Rapid and accurate notification of childhood pulmonary tuberculosis (PTB) is a worldwide challenge. Although the Xpert MTB/RIF assay (Xpert) has been endorsed as the initial test for suspected PTB in many countries, limited studies have reported the performance of Xpert in childhood PTB. The aim of this study is to evaluate the real-world performance of Xpert for the detection of childhood PTB among HIV negative children in China.. We consecutively extracted the data of all patients ≤14 years with pulmonary disease through the electronic medical record (EMR) systems of Shanghai Public Health Clinical Center from January 2014 to December 2017. The clinical profile, the decision-making tests including AFB smear, solid/liquid culture, pathological examination and Xpert result were matched and assessed. The real diagnostic accuracy and the all-factors case notification rate for childhood PTB with the implementation of Xpert were evaluated.. 519 HIV negative cases ≤14 years with pulmonary disease were extracted from the data base. Of these, 145 had matched results, there were 374 non-matched cases including 346 with incomplete or unavailable data and 28 with NTM, BCG or an unidentified strain. For matched data, the overall sensitivity and specificity of the Xpert assay were 66.7% (32/48, 95%CI 0.52-0.80) and 87.6% (85/97, 95%CI 0.87-0.98) respectively against the gold standard; 34.6% (44/127, 95%CI 26.6-43.7) and 100% against the composite clinical reference standard (CCRS). The all-factors case notification rate by Xpert was 29%.. Xpert/MTB RIF assay has acceptable sensitivity and excellent specificity for rapid diagnosis of children with pulmonary TB as well as for the detection of RIF resistance in China. However, implementation of Xpert for the initial diagnosis of childhood PTB is inadequate to meet the urgent requirement for rapid and accurate detection of childhood PTB.

Topics: Adolescent; Child; Child, Preschool; China; Female; HIV Infections; Humans; Male; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

Phenotypic testing for drug susceptibility of

Topics: Antitubercular Agents; Drug Resistance, Bacterial; Humans; Luciferases; Luminescent Measurements; Microbial Sensitivity Tests; Mycobacteriophages; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

A 67-year-old mental institute resident was treated for smear-positive pulmonary tuberculosis. His background history included chronic essential hypertension which was well-controlled with amlodipine 10mg daily. However, his blood pressure became suboptimal one week into antitubercular treatment, necessitating escalation of antihypertensive therapy up to six medications. Following completion of antitubercular treatment, his blood pressure improved markedly. The number of antihypertensives was able to be reduced to only two after a month. We postulate that rifampicin has attenuated the therapeutic effect of amlodipine via potent induction of hepatic CYP3A4 but the failure to control the blood pressure even with medications unrelated to cytochrome P450 pathways raises the spectre of an additional interaction.

Topics: Aged; Amlodipine; Antibiotics, Antitubercular; Antihypertensive Agents; Drug Interactions; Drug Therapy, Combination; Humans; Hypertension; Male; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

The potential of genetic testing for rapid and accurate diagnosis of drug-resistant Mycobacterium tuberculosis strains is vital for efficient treatment and reduction in dissemination. MTBDR plus assays rapidly detect mutations related to drug resistance and wild type sequences allied with susceptibility. Although these methods are promising, the examination of molecular level performance is essential for improved assay result interpretation and continued diagnostic development. Therefore this study aimed to determine novel mutations that were inhibiting wild type probe hybridization in the Line probe assay by DNA sequencing. Using data collected from Line Probe assay (GenoType MTBDRplus assay) the contribution of absent wild type probe hybridization to the detection of rifampicin resistance was assessed via comparison to a reference standard method i.e. DNA sequencing.. Sequence analysis of the rpoB gene of 47 MTB resistant strains from clinical specimens showed that 37 had a single mutation, 9 had double mutations and one had triple mutations in the ropB gene.. The absence of wild type probe hybridization without mutation probe hybridization was mainly the result of the failure of mutation probe hybridization and the result of the novel or rare mutations. Additional probes are necessary to be included in the Line probe assay to improve the detection of rifampicin-resistant Mycobacterium tuberculosis strains.

Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA Mutational Analysis; DNA Probes; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Humans; In Situ Hybridization; Mutation; Mycobacterium tuberculosis; Rifampin; Sequence Analysis, DNA; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Aged; Anti-Bacterial Agents; Antitubercular Agents; Bronchoalveolar Lavage Fluid; Bronchoscopy; Clarithromycin; Ethambutol; Glucocorticoids; Humans; Immunocompromised Host; Immunosuppressive Agents; Male; Methotrexate; Mycobacterium; Mycobacterium Infections, Nontuberculous; Nucleic Acid Amplification Techniques; Polymyalgia Rheumatica; Polyps; Prednisolone; Pulmonary Atelectasis; Rifampin; Tomography, X-Ray Computed; Treatment Outcome; Tuberculosis, Pulmonary

We aimed to investigate the effect of interval between food intake and drug administration at fasting condition on the plasma concentrations of first-line anti- tuberculosis (TB) drugs in Chinese population. Newly diagnosed TB patients administered the anti-TB drugs under fasting conditions orally, and then had prepared breakfast at 30 minutes and 120 min after dosing, respectively. Blood sampling was also performed 120  minutes after dosing for the detection of Cmax purpose. Overall, twenty-five participants were included in our analysis. The Cmaxs of 30  minutes interval and 120  minutes interval were 21.8 ± 2.0 and 19.2 ± 2.0 μg/mL for rifampin, 1.6 ± 0.2 and 2.1 ± 0.2 μg/mL for isoniazid (INH), 1.5 ± 0.1and 1.5 ± 0.2 μg/mL for ethambutol (EMB), and 49.2 ± 3.7 and 41.5 ± 3.9 μg/mL for pyrazinamide, respectively. Statistical analysis revealed that there was no statistical difference between 2 groups. Additionally, 88.0% and 72.0% of the 25 participants at 2-hour interval group had peak concentrations less than the lower limit of the reference range for INH and EMB, respectively. The Cmaxs of INH were 0.9 ± 0.4 μg/ml for rapid acetylator, which was significantly lower than those of intermediate (1.4 ± 1.0 μg/mL), and slow acetylator (2.5 ± 1.0 μg/mL), respectively (P < .01). In conclusion, our data demonstrate that early food intake at 30 minutes after drug administration had no significant influence on the plasma concentrations. In addition, a high proportion of patients receiving first-line anti-TB regimen fail to achieve the expected plasma drug ranges of INH and EMB (P > .05).

Topics: Administration, Oral; Adult; Antitubercular Agents; China; Drug Administration Schedule; Eating; Ethambutol; Fasting; Female; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Tuberculosis prevalence surveys have demonstrated the benefit of screening with chest x-ray (CXR) and sensitive diagnostic tests compared to symptoms and smear microscopy. However, in programmatic practice there is little evidence on the yield of different algorithms. We implemented contact tracing in Chennai, India for adult sputum-positive TB patients registered from January 2015 to March 2016. Patients with symptoms or abnormal X-ray findings further underwent testing using Xpert MTB/RIF (Xpert) and smear microscopy. A retrospective cohort study was done to summarize the key findings. We verbally screened 5553 contacts for symptoms, CXR through private sector collaboration, Xpert, and smear microscopy. Overall, 1312 (23.6%) contacts screened positive. CXR alone identified 531 (40.5%) of them, 679 (51.8%) were symptom-positive only, while 102 (7.8%) were positive on both the symptom and CXR screen. Overall, 35 bacteriologically positive cases were identified (0.7%). A standard approach of symptoms screening followed by microscopy identified only 9 (25.7%) of the total number of bacteriologically positive cases, whereas the combination of a CRX screening followed by microscopy identified 13 (37.1%) of the cases. The algorithm of symptoms screening followed by Xpert testing, detected 20 cases, whereas the combination of symptoms and CXR followed by Xpert increased this number to 35 (75% increase compared to symptoms and Xpert). Optimal use of more sensitive screening tests, better diagnostic tests, and novel private sector engagement can improve diagnostic yield in a programmatic setting.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Contact Tracing; Drug Resistance, Bacterial; Female; Humans; India; Male; Mass Screening; Microscopy; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Radiography; Reagent Kits, Diagnostic; Retrospective Studies; Rifampin; Sputum; Tuberculosis, Pulmonary; Young Adult

it is unclear what the optimal treatment regimen for previously treated patients with rifampicin-susceptible isoniazid resistant tuberculosis should be. Conflicting evidence exists as to the effectiveness of the WHO standardized category II regimen in these patients. The objectives were to compare treatment outcomes between previously treated rifampicin-susceptible pulmonary tuberculosis patients with and without isoniazid resistance using the category II regimen and determine factors associated with an unfavourable outcome in those with isoniazid resistance in four regions of Cameroon.. we conducted a retrospective review of all bacteriologically confirmed previously treated rifampicin-susceptible patients with and without isoniazid resistance registered in four regions of Cameroon from January 2012 to March 2015.. a total of 753 patients with a mean age of 38 ± 12 years including 498(66%) males were registered. Forty seven of the 753 had isoniazid-resistant TB, giving a prevalence of 6.2% (95% CI: 4.7-8.2). Treatment outcomes could only be ascertained for 733 patients as 20 (2.7%) were transferred out to other regions. Twenty-nine percent of patients with isoniazid resistance as against 21% of isoniazid susceptible patients had an unfavourable outcome (p = 0.32). In a multivariate logistic regression analysis, only HIV infection was significantly associated with an unfavourable outcome in isoniazid-resistant patients (p = 0.02).. treatment outcomes using WHO category II regimen in previously treated rifampicin -susceptible pulmonary tuberculosis patients with and without isoniazid resistance in four regions of Cameroon are similar. HIV infection is an independent risk factor for an unfavourable outcome in patients with rifampicin-susceptible isoniazid-resistant disease treated with this regimen.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Cameroon; Child; Child, Preschool; Female; HIV Infections; Humans; Isoniazid; Male; Middle Aged; Retrospective Studies; Rifampin; Risk Factors; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Introduction: The Xpert MTB/RIF™ is a rapid molecular test that diagnoses tuberculosis and rifampin resistance. Since 2010, it is recommended by the World Health Organization (WHO) and although it was introduced in Colombia since 2012, the results of its implementation are unknown.\ Objective: To describe the coverage and fidelity in the implementation of the Xpert MTB/RIF™ in patients with pulmonary tuberculosis in a city with a high burden for the disease in Colombia.\ Materials and methods: We conducted a retrospective, descriptive study of cases from a tuberculosis program in Cali between 2013 and 2019. We estimated the coverage as the total number of tests used compared to the cases registered in the program and the fidelity based on international Xpert MTB/RIF™ implementation protocols. We performed a multivariate analysis of multiple correspondences between the test and the sociodemographic variables.\ Results: We included 6,328 patients with pulmonary tuberculosis of whom 181 were drugresistant. The Xpert MTB/RIF™ coverage was 10,3% (n=655) with an annual variation between 0.2% and 23%. Loyalty among the highest risk groups of MDR-TB was 46.8%. The use of the test was related to being an Afro-Colombian man between 41 and 60 years of age.\ Conclusions: The coverage of the Xpert MTB/RIF in Cali is low and its use does not follow the recommended prioritization for its implementation. Implementation strategies are required for its proper use to contribute to the goal of ending tuberculosis.. Introducción. La prueba Xpert MTB/RIF™ es una prueba molecular rápida para el diagnóstico de la tuberculosis y la resistencia a la rifampicina. Desde el 2010 es la recomendada por la Organización Mundial de la Salud (OMS) y, aunque fue introducida en Colombia en el 2012, se desconocen los resultados de su uso. Objetivo. Describir la cobertura y la fidelidad en el uso de la prueba Xpert MTB/RIF™ en pacientes con tuberculosis pulmonar en una ciudad con alta carga de la enfermedad en Colombia. Materiales y métodos. Se hizo un estudio retrospectivo descriptivo de casos del programa de tuberculosis en Cali entre el 2013 y el 2019. La cobertura se estimó como el total de pruebas empleadas en los casos registrados en el programa. La fidelidad se midió con base en los protocolos internacionales de uso de la Xpert MTB/RIF™. Además, se hizo un análisis de correspondencias múltiples entre la prueba y las variables sociodemográficas. Resultados. Se incluyeron 6.328 pacientes con tuberculosis pulmonar, de los cuales 181 eran resistentes a los fármacos. La cobertura total de la Xpert MTB/RIF™ durante el periodo de estudio fue de 10,3 % (n=655), con una variación anual entre 0,2 y 23 %. La fidelidad fue de 46,8 % para los grupos de mayor riesgo de tuberculosis multirresistente (TB-MDR). El uso de la prueba se relacionó con la condición de ser hombre, afrocolombiano, y tener entre 41 y 60 años de edad. Conclusiones. La cobertura de la prueba Xpert MTB/RIF™ en Cali es baja y su uso no responde a la priorización recomendada para su implementación. Se requieren estrategias para promover su uso adecuado, de manera que contribuya a la meta de poner fin a la tuberculosis.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Child; Child, Preschool; Colombia; Drug Resistance, Bacterial; Female; Humans; Infant; Infant, Newborn; Insurance Coverage; Male; Microbial Sensitivity Tests; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Retrospective Studies; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Infection with the new coronavirus has been declared an international health emergency. Its curative treatment is unknown and is the subject of several clinical trials. In addition, the concomitant association of COVID-19 with tuberculosis and the human immunodeficiency virus, hitherto never described, is potentially fatal. We report the illustrative case of a 32-year-old patient who presented this trifecta of infections and who did well under treatment with chloroquine and anti-mycobacterial drugs. This patient arrived at the ER with respiratory discomfort that had been evolving over a month with symptoms of flu and deterioration of her general condition. A chest CT scan revealed an aspect of lung miliary tuberculosis with isolation of Koch's bacilli in the sputum. A polymerization chain reaction (PCR) was positive for COVID-19 on a nasopharyngeal swab. HIV serology was positive. The course was marked by a spectacular clinical improvement and two negative COVID-19 PCR controls at the end of treatment (at days 9 and 10). Anti-tubercular drugs (especially, rifampin) are powerful enzyme inducers that can reduce the effectiveness of chloroquine in our patient. This therapeutic success may be linked to the effect of anti-tubercular drugs against SARS ncov-2, especially rifampin, inhibiting the formation of messenger RNAs of SARS ncov-2 or to the synergistic effect of chloroquine and rifampin. Researchers should explore the effect of these drugs on SARS ncov-2.

Topics: Adult; Antimalarials; Antiviral Agents; Chloroquine; COVID-19; COVID-19 Drug Treatment; Diagnosis, Differential; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Rifampin; SARS-CoV-2; Tomography, X-Ray Computed; Tuberculosis, Pulmonary

There are few data on the on the care experiences of pregnant women with rifampicin-resistant TB.. To describe the treatment journeys of pregnant women with RR-TB-including how their care experiences shape their identities-and identify areas in which tailored interventions are needed.. In this qualitative study in-depth interviews were conducted among a convenience sample from a population of pregnant women receiving treatment for RR-TB. This paper follows COREQ guidelines. A thematic network analysis using an inductive approach was performed to analyze the interview transcripts and notes. The analysis was iterative and a coding system developed which focused on the care experiences of the women and how these experiences affected their perceptions of themselves, their children, and the health care system in which treatment was received.. Seventeen women were interviewed. The women described multiple challenges in their treatment journeys which required them to demonstrate sustained resilience (i.e. to "be brave"). Care experiences required them to negotiate seemingly contradictory identities as both new mothers-"givers of life"-and RR-TB patients facing a complicated and potentially deadly disease. In terms of their "pregnancy identity" and "RR-TB patient identity" that emerged as part of their care experiences, four key themes were identified that appeared to have elements that were contradictory to one another (contradictory areas). These included: 1) the experience of physical symptoms or changes; 2) the experience of the "mothering" and "patient" roles; 3) the experience of the care they received for their pregnancy and their RR-TB; and 4) the experience of community engagement. There were also three areas that overlapped with both roles and during which identity was negotiated/reinforced and they included: 1) faith; 2) socioeconomic issues; and 3) long-term concerns over the child's health. At times, the health care system exacerbated these challenges as the women were not given the support they needed by health care providers who were ill-informed or angry and treated the women in a discriminatory fashion. Left to negotiate this confusing time period, the women turned to faith, their own mothers, and the fathers of their unborn children.. The care experiences of the women who participated in this study highlight several gaps in the current health care system that must be better addressed in both TB and perinatal services in order to improve the therapeutic journeys for pregnant women with RR-TB and their children. Suggestions for optimizing care include the provision of integrated services, including specialized counseling as well as training for health care providers; engagement of peer support networks; provision of socioeconomic support; long-term medical care/follow-up for children born to women who were treated for RR-TB; and inclusion of faith-based services in the provision of care.

Topics: Adult; Antitubercular Agents; Courage; Female; Humans; Infant; Mothers; Mycobacterium tuberculosis; Patient Satisfaction; Pregnancy; Pregnant Women; Qualitative Research; Rifampin; Social Identification; Social Support; South Africa; Surveys and Questionnaires; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rifampicin is a key first-line antimycobacterial agent employed for the treatment of pulmonary tuberculosis (PTB). This study sought to obtain prevalence data on rifampicin-resistant Mycobacterium tuberculosis among smear-positive PTB patients in the Klang District of Malaysia.. A total of 103 patients from the Chest Clinic of Hospital Tengku Ampuan Rahimah with sputum smears positive for acid-fast bacilli were included in this cross-sectional study. All sputa were tested using Xpert MTB/RIF to confirm the presence of M. tuberculosis complex and detect rifampicin resistance. Sputa were also sent to a respiratory medicine institute for mycobacterial culture. Positive cultures were then submitted to a reference laboratory, where isolates identified as M. tuberculosis complex underwent drug susceptibility testing (DST).. A total of 58 (56.3%) patients were newly diagnosed and 45 (43.7%) patients were previously treated. Xpert MTB/RIF was able to detect rifampicin resistance with a sensitivity and specificity of 87.5% and 98.9%, respectively. Assuming that a single resistant result from Xpert MTB/RIF or any DST method was sufficient to denote resistance, a total of 8/103 patients had rifampicinresistant M. tuberculosis. All eight patients were previously treated for PTB (p<0.05). The overall prevalence of rifampicin resistance among smear-positive PTB patients was 7.8%, although it was 17.8% among the previously treated ones.. The local prevalence of rifampicin-resistant M. tuberculosis was particularly high among previously treated patients. Xpert MTB/RIF can be employed in urban district health facilities not only to diagnose PTB in smear-positive patients, but also to detect rifampicin resistance with good sensitivity and specificity.

Topics: Adult; Aged; Antibiotics, Antitubercular; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; Humans; Malaysia; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Prevalence; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary; Urban Health Services

There is a need for an affordable, easy, high-sensitivity test usable at the peripheral health facility for diagnosis of drug-resistant (DR) tuberculosis (TB) to interrupt disease transmission. Nucleic acid amplification tests (NAATs) for early detection of DR-TB are ideal to bring testing near to the patient. Truenat. Consecutive patients aged 18-65 yr, with symptoms suggestive of TB and with a history of previous treatment, reporting to the National TB Elimination Programme (NTEP) clinics under four national institutes, namely AIIMS (All India Institute of Medical Sciences, New Delhi), NITRD (National Institute of Tuberculosis and Respiratory Diseases, New Delhi), NIRT (National Institute for Research in Tuberculosis, Chennai) and ICMR-National JALMA Institute for Leprosy and other Mycobacterial Diseases, Agra, were included in the study. Two sputum samples (one spot and one morning) were collected from each patient, after obtaining informed written consent. The samples were subjected to smear, GeneXpert and MGIT 960 culture (and drug susceptibility testing to RIF) (surrogate for MDR-TB) to serve as reference tests. The samples were coded to ensure blinding and subjected to Truenat MTB-RIF. Truenat MTB-RIF Version 1.5 was used for testing 1084 samples for RIF resistance, while Version 2.0 was used to test another 1201 samples.. Truenat MTB-RIF Version 1.5 in comparison with comprehensive laboratory reference standards yielded sensitivity and specificity of 76.2 and 94.7 per cent, respectively for the detection of RIF resistance in 1084 samples, collected across four sites. Based on the analysis of discordant samples, Version 2.0 of Truenat was developed by the manufacturer and this was further tested on additional 1201 samples, yielding a sensitivity of 87.5 per cent and specificity of 99.5 per cent.. Multicentric trial of Truenat

Topics: Adolescent; Adult; Aged; Humans; India; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Heteroresistant Mycobacterium tuberculosis (MTB) is defined as a group of drug-susceptible and resistant bacteria in a single clinical specimen from tuberculosis (TB) patients. Heteroresistance of MTB is considered a preliminary stage to full resistance. The present study aimed to determine the heteroresistance in Mycobacterium tuberculosis in Tabuk province, in the north of the Kingdom of Saudi Arabia.. GenoType MTBDRplus assay was used to determine mutations associated with isoniazid and rifampicin resistance.. A total number of 46 confirmed M. tuberculosis positive sputum samples were scanned for heteroresistance. The present study revealed 3 (6.5%) heteroresistant mutations to either rpoB gene alone, 2 (4.4%) to rpoB and 1 (2.2%) to inhA genes.. The detection of heteroresistant mutations could guide the initiation of an appropriate regimen of treatment.

Topics: Antitubercular Agents; Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Genotype; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Rifampin; Saudi Arabia; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

A population pharmacokinetic (PopPK) model for pretomanid was developed using data from 14 studies in the pretomanid development program: six phase 1 studies, six phase 2 studies, and two phase 3 studies. The final analysis data set contained 17,725 observations from 1,054 subjects, including healthy subjects and subjects with drug-sensitive, multidrug-resistant, or extensively drug-resistant pulmonary tuberculosis dosed pretomanid in monotherapy or combination therapy for up to 6 months. Pretomanid pharmacokinetic behavior was described by a one-compartment model that at a given dose was linear in its absorption and clearance processes but where the rate of absorption and extent of bioavailability changed with dose. Clearance and volume of distribution scaled allometrically with weight. Apparent clearance in females was 18% less than in males. Among HIV-positive subjects, absent the effect of CYP3A4-inducing antiretrovirals, apparent clearance was 6% higher. Some effects of total bilirubin and albumin were found, but the impacts on exposure were small. Bioavailability in the fasted condition was about half that in the fed condition. Relative bioavailability decreased with increasing dose in the fasted condition, but not for doses of ≤200 mg in the fed condition. HIV-positive subjects taking efavirenz and lopinavir/ritonavir had exposures that were reduced by 46 and 17%, respectively. There was little evidence for noteworthy effects of regimen partners on pretomanid. Standard diagnostics indicated that the model described the voluminous, diverse data well, so that the model could be used to generate exposure metrics for exposure/response analyses to be reported elsewhere.

Topics: Antitubercular Agents; Biological Availability; Clinical Trials as Topic; Extensively Drug-Resistant Tuberculosis; Female; HIV Infections; Humans; Lopinavir; Male; Nitroimidazoles; Rifampin; Ritonavir; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Drug Resistance, Microbial; Drug Therapy, Combination; Ethambutol; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Precision Medicine; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Multi-drug-resistant TB (MDR-TB) has become a significant public health problem and an obstacle to effective TB control. Rapid diagnostic tests for anti tubercular drugs sensitivity have significantly reduced total time in initiation of treatment. Still there is a significant gap between MDR diagnosis and start of category IV treatment. Delay in establishing the diagnosis may cause disease progression, transmission, lost to follow up and death. This study was planned to assess the actual delay from day one of sputum examination to the day of initiation of category IV in operational settings.. MDR-TB suspected patients attending the Respiratory medicine department, JLNMC, Ajmer from June-15 to July-16 were followed from sputum examination to sample deposition for drug sensitivity testing (LPA/CBNAAT) to MDR detection to category IV initiation, for assessment of procedural delay at various steps.. LPA group (371 patients): Sputum smear to LPA deposition mean duration was 8.02 days, LPA deposition to LPA result upload mean duration was 3.78 days, LPA deposition to patients received LPA reports mean duration was 21.73 days and reports received to PMDT site admission (if drug resistant) mean duration was 3.61 days. Total time duration in category IV initiation was 32.63 days. CBNAAT group (50 patients): Sputum smear to CBNAAT deposition mean duration was 6.70 days, CBNAAT deposition to CBNAAT result upload mean duration was 1.13 days, CBNAAT deposition to patients received CBNAAT reports mean duration was 6.53 days and reports received to PMDT site admission (if R-resistant) mean duration was 3.8 days. Total time duration in category IV initiation was 12.4 days.. Major delay seen on part of receiving sensitivity reports indicates the need to stress upon field staff motivation, appropriate training, sensitisation and expert counselling.

Topics: Antitubercular Agents; Benchmarking; Delayed Diagnosis; Drug Administration Schedule; Humans; India; Mycobacterium tuberculosis; National Health Programs; Rifampin; Sputum; Tertiary Care Centers; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

To investigate the prevalence and factors associated with the prevalence of multidrug/rifampicin-resistant tuberculosis among suspected drug resistant tuberculosis patients in Botswana.. A retrospective review of medical records of suspected drug resistant tuberculosis patients receiving care at public health facilities in Botswana was conducted from January, 2013 and December, 2014. Patient characteristics and drug susceptibility data were abstracted from 2568 medical records on to a pre-tested checklist form. The prevalence of multidrug/rifampicin resistance was computed. Bivariate and multivariate logistic regression was carried out to determine the factors associated with the prevalence of multidrug/rifampicin in the study population.. Overall, multidrug/ rifampicin - resistance among suspected drug resistant tuberculosis patients in Botswana were found in 139 (5.4%) cases with 1.3% among new cases and 7.7% among previously treated tuberculosis patients. Being a previously treated tuberculosis patient and having a positive smear were found to be factors associated with the prevalence of multidrug/rifampicin-resistant tuberculosis (p < 0.05). However, age, sex, living in urban area and HIV status were not associated with this disease (p > 0.05).. This study highlights a low burden of multidrug/rifampicin resistant tuberculosis among suspected drug resistant tuberculosis patients receiving care at public health facilities in Botswana. Strategies in controlling MDR/RR-TB should emphasize on effective implementation of Directly Observation Treatment - short course strategy, continuous surveillance of drug resistance cases, prevention of the development of new cases of MDR/RR-TB and to treat existing patients. Further interventions should focus on strengthening TB infection control activities.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Botswana; Child; Child, Preschool; Drug Resistance, Multiple, Bacterial; Female; Humans; Infant; Male; Middle Aged; Mycobacterium tuberculosis; Prevalence; Retrospective Studies; Rifampin; Risk Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

To demonstrate how phenotypic cell viability data can provide insight into antimycobacterial effects for the isoniazid/rifampicin treatment backbone.. Data from a Mycobacterium komossense hollow-fibre infection model comprising a growth control group, rifampicin at three different exposures (Cmax = 0.14, 0.4 and 1.47 mg/L with t½ = 1.57 h and τ = 8 h) and rifampicin plus isoniazid (Cmax rifampicin = 0.4 mg/L and Cmax isoniazid = 1.2 mg/L with t½ = 1.57 h and τ = 8 h) were used for this investigation. A non-linear mixed-effects modelling approach was used to fit conventional cfu data, quantified using solid-agar plating. Phenotypic proportions of respiring (alive), respiring but with damaged cell membrane (injured) and 'not respiring' (dead) cells data were quantified using flow cytometry and Sytox Green™ (Sigma-Aldrich, UK) and resazurin sodium salt staining and fitted using a multinomial logistic regression model.. Isoniazid/rifampicin combination therapy displayed a decreasing overall antimicrobial effect with time (θTime1/2 = 438 h) on cfu data, in contrast to rifampicin monotherapy where this trend was absent. In the presence of isoniazid a phenotype associated with cell injury was displayed, whereas with rifampicin monotherapy a pattern of phenotypic cell death was observed. Bacterial killing onset time on cfu data correlated negatively (θTime50 = 28.9 h, θLAGRIF50 = 0.132 mg/L) with rifampicin concentration up to 0.165 mg/L and this coincided with a positive relationship between rifampicin concentration and the probability of phenotypic cell death.. Cell viability data provide structured information on the pharmacodynamic interaction between isoniazid and rifampicin that complements the understanding of the antibacillary effects of this mycobacterial treatment backbone.

Topics: Antitubercular Agents; Isoniazid; Logistic Models; Microbial Viability; Models, Theoretical; Mycobacteriaceae; Phenotype; Rifampin; Tuberculosis, Pulmonary

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

Diabetes mellitus (DM) is associated with poor TB treatment outcome. Previous studies examining the effect of DM on TB drug concentrations yielded conflicting results. No studies have been conducted to date in an African population.. To compare exposure to TB drugs in Tanzanian TB patients with and without DM.. A prospective pharmacokinetic study was performed among 20 diabetic and 20 non-diabetic Tanzanian TB patients during the intensive phase of TB treatment. Plasma pharmacokinetic parameters of isoniazid, rifampicin, pyrazinamide and ethambutol were compared using an independent-sample t-test on log-transformed data. Multiple linear regression analysis was performed to assess the effects of DM, gender, age, weight, HIV status and acetylator status on exposure to TB drugs.. A trend was shown for 25% lower total exposure (AUC0-24) to rifampicin among diabetics versus non-diabetics (29.9 versus 39.9 mg·h/L, P=0.052). The AUC0-24 and peak concentration (Cmax) of isoniazid were also lower in diabetic TB patients (5.4 versus 10.6 mg·h/L, P=0.015 and 1.6 versus 2.8 mg/L, P=0.013). Pyrazinamide AUC0-24 and Cmax values were non-significantly lower among diabetics (P=0.08 and 0.09). In multivariate analyses, DM remained an independent predictor of exposure to isoniazid and rifampicin, next to acetylator status for isoniazid.. There is a need for individualized dosing of isoniazid and rifampicin based on plasma concentration measurements (therapeutic drug monitoring) and for clinical trials on higher doses of these TB drugs in patients with TB and DM.

Topics: Adult; Aged; Aged, 80 and over; Antitubercular Agents; Diabetes Complications; Diabetes Mellitus; Female; Humans; Isoniazid; Male; Middle Aged; Plasma; Prospective Studies; Pyrazinamide; Rifampin; Tanzania; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

Pulmonary tuberculosis (TB) with detectable Mycobacterium tuberculosis in the sputum is a major source of transmission. In resource limited TB endemic settings, cure is declared through sputum smear examination for acid fast bacilli without performing culture. This may lead to erroneous treatment outcomes as viable bacteria may be missed due to the low sensitivity of direct smear method. The aim of this study was to investigate if sterilizing cure is achieved among the new pulmonary TB cases declared cured by sputum smear conversion and to evaluate the impact of addition of ethambutol in the continuation phase in achieving it.. New sputum smear-positive pulmonary TB patients registered at a tertiary care hospital in Pakistan from November 2013 to March 2014 were followed under standard Directly Observed Treatment Short Course strategy for 6 months. Half of these patients received ethambutol in addition to isoniazid and rifampicin in the continuation phase. Sputum specimens were examined on microscopy at 2 months and at the end of treatment. Sputa of patients with negative direct smear examination at the end of treatment were cultured.. Among 5746 TB suspects, 1595 were new sputum smear positive pulmonary TB cases, and 533 were registered at our hospital. Among these, 504 converted sputum negative at 2 months and 348 converted at the end of 6 months of treatment and were declared cured. Sputa of 204/348 patients were cultured, and 12/204 (6%) were culture-positive. Culture positivity at 6 months was not associated with bacterial load, smoking, diabetes, presence of cavities, history of contact with TB patients, age, sex, socioeconomic status, or addition of ethambutol in the continuation phase.. Viable cultivable bacilli were detected in 6% of cured patients, which would have significant impact on the control of TB. This highlights the need for an inexpensive and accurate surrogate marker for culture as it is not feasible to perform culture in routine for monitoring treatment response in the low-resource settings. The treatment outcome did not improve by addition of ethambutol emphasizing the need to find the optimal duration of treatment for individual or carefully selected groups of patients.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Bacterial Load; Diagnostic Tests, Routine; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Pakistan; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

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

WHO endorsed Xpert MTB/RIF assay has proven to be rapid with results obtained within 2h. The evidence base regarding the use of Xpert MTB/RIF in pulmonary TB is strong. Relatively few performance data have been published to date on detection of Mycobacterium tuberculosis in aspirated pus specimens from abscesses.. The aim of the study was to determine the sensitivity and specificity of Xpert MTB/RIF assay for the detection of M. tuberculosis and rifampicin resistance in aspirated pus specimens using culture on Lowenstein Jensen (LJ) medium and economic variant of proportion method (PM) for drug susceptibility testing (DST) as the reference standard.. Xpert MTB/RIF assay in comparison to conventional reference method showed sensitivity and specificity of 76.19% and 68.75% for detection of M. tuberculosis and 71.4% and 100% for detection of rifampicin resistance respectively.. The simplicity, sensitivity, speed and automation makes this assay a very promising diagnostic test for detection of M. tuberculosis and rifampicin resistance in aspirated pus specimens.

Topics: Abscess; Antibiotics, Antitubercular; Diagnostic Tests, Routine; Humans; India; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Suppuration; Tuberculosis, Pulmonary

In most developing countries, smear-negative pulmonary TB (SNPT) often gets missed from the diagnosis of consideration, though it accounts 30-65% of total PTB cases, due to deficient or inaccessible molecular diagnostic modalities.. The cross-sectional study enrolled 360 patients with clinical-radiological suspicion of SNPT in Tribhuvan University Teaching Hospital (TUTH). The patient selection was done as per the algorithm of Nepal's National Tuberculosis Program (NTP) for Xpert MTB/RIF testing. Participants' demographic and clinical information were collected using a pre-tested questionnaire. The specimens were collected, processed directly for Xpert MTB/RIF test according to the manufacturer's protocol. The same samples were stained using the Ziehl-Neelsen technique then observed microscopically. Both findings were interpreted; rifampicin-resistant, if obtained, on Xpert testing was confirmed with a Line Probe Assay.. Of 360 smear-negative sputum samples analyzed, 85(23.61%) found positive while 3(0.8%) of them were rifampicin resistance. The infection was higher in males, i.e. 60(25.3%) compared to female 25(20.3%). The age group, > 45(nearly 33%) with median age 42 ± 21.5, were prone to the infection. During the study period, 4.6% (515/11048) sputum samples were reported as smear-positive in TUTH. Consequently, with Xpert MTB/RIF assay, the additional case 16.5% (n = 85/515) from smear-negative presumptive TB cases were detected. Among the most occurring clinical presentations, cough and chest pain were positively associated with SNPT. While upper lobe infiltrates (36.4%) and pleural effusion (40.4%) were the most peculiar radiological impression noted in PTB patient. 94 multi-drug resistant(MDR) suspected cases were enrolled; of total suspects, 29(30.8%) samples were rifampicin sensitive, 1(1.06%) indeterminate, 3(3.19%) rifampicin-resistant while remaining of them were negative. 2(2.2%) MDR cases were recovered from the patient with a previous history of ATT, of total 89 previously treated cases enrolled However, a single rifampicin-resistant from the new suspects.. With an application of the assay, the additional cases, missed with smear microscopy, could be sought and exact incidence of the diseases could be revealed.

Topics: Adolescent; Adult; Algorithms; Biological Assay; Chest Pain; Cough; Cross-Sectional Studies; Developing Countries; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Female; Hospitals, University; Humans; Male; Microscopy; Middle Aged; Mycobacterium tuberculosis; Nepal; Pleural Effusion; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary; Young Adult

Ethiopia stood third in drug-resistant tuberculosis (TB) in Africa, and more than 5,000 MDR-TB patients are reported each year. Greater than 90% of rifampicin (RIF) resistant strains are resistant to isoniazid (INH) and hence the objective of this study was to determine the prevalence and risk factors of RIF resistant MTB among presumptive TB cases at Dubti General Hospital, Afar, Ethiopia.. In this cross-sectional study, 384 presumptive TB cases were recruited and a structured questionnaire was used to collect socio-demographic and clinical data. Sputum samples were collected and examined using X-pertMTB/RIF assay. Bivariate, multivariate logistic regressions, and fishers' exact analysis were done to assess the associations between the prevalence of TB and MDR-TB with different socio-demographic and clinical variables.. In the present study, the overall prevalence of pulmonary TB was 24.5% (94/384), of this 4 (4.3%) isolates were resistant to RIF. History of anti-TB treatment (AOR = 2.4, 95% CI: 1.3-4.4 and TB contact (AOR = 3.6, 95% CI: 2.1-6.2 were significantly associated with gene X-pert MTB/RIF positive TB. Moreover, resistance to rifampicin was statistically associated with the history of TB contact with multi-drug resistant TB (P = 0.027) and khat chewer cases (P = 0.04).. The overall prevalence of TB and its drug-resistant were relatively higher than that of in the general population in Ethiopia. History of anti-TB treatment and TB contact were significantly associated with X-pert MTB/RIF positive MDR-TB.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Bacteriological Techniques; Child; Cross-Sectional Studies; Drug Resistance, Bacterial; Ethiopia; Female; Genotyping Techniques; Hospitals; Humans; Male; Middle Aged; Prevalence; Rifampin; Risk Factors; Sputum; Surveys and Questionnaires; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

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

Topics: Antibiotics, Antitubercular; Drug Resistance, Bacterial; Genotype; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Phenotype; Rifampin; Tuberculosis, Pulmonary

A 30-year-old man experienced subacute peripheral visual field loss with preserved central vision in his right eye. He was diagnosed with optic perineuritis due to tuberculosis. Optic perineuritis is an uncommon disorder and, at times, can be difficult to distinguish from optic neuritis. The differentiation can have significant impact on diagnostic testing and patient management.

Topics: Adult; Antitubercular Agents; Bronchoscopy; Drug Therapy, Combination; Humans; Isoniazid; Magnetic Resonance Imaging; Male; Optic Neuritis; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Vision Disorders; Visual Acuity; Visual Fields

Poor response to TB therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic parameters can be affected by comorbidities or the interaction of drugs with food.. This study aimed to determine the effect of food intake upon pharmacokinetics of rifampicin and isoniazid in a Peruvian population with TB.. Rifampicin and isoniazid levels were analysed at 2, 4 and 6 h after drug intake in both fasting and non-fasting states using LC-MS methods.. Sixty patients participated in the study. The median rifampicin Cmax and AUC0-6 were higher during fasting than non-fasting: 7.02 versus 6.59 mg/L (P = 0.054) and 28.64 versus 24.31 mg·h/L (P = 0.002). There was a statistically significant delay overall of non-fasting Tmax compared with the fasting state Tmax (P = 0.005). In the multivariate analysis, besides the effect of fasting, Cmax for females was 20% higher than for males (P = 0.03). Concerning isoniazid, there were significant differences in the Cmax during non-fasting (median = 3.51 mg/L) compared with fasting (4.54 mg/L). The isoniazid dose received had an effect upon the isoniazid levels (1.26, P = 0.038). In the multivariate analysis, isoniazid exposure during fasting was found to be 14% higher than during non-fasting (CI = 1.02-1.28, P < 0.001). Neither radiological extent of the disease nor consumption of food with drug intake nor pharmacokinetics of rifampicin or isoniazid was associated with a poorer treatment outcome.. Rifampicin in particular and isoniazid pharmacokinetics were significantly affected by the intake of the drug with food between and within individuals.

Topics: Adult; Antitubercular Agents; Biological Variation, Individual; Eating; Fasting; Female; Food-Drug Interactions; Humans; Isoniazid; Male; Middle Aged; Multivariate Analysis; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

Xpert MTB/RIF is recommended for the simultaneous detection of tuberculosis (TB) and rifampicin resistance directly from sputum specimens. Since young children cannot always expectorate, we assessed urine as a possible specimen source to diagnose TB in children using Xpert MTB/RIF.. During a field study to enhance childhood TB identification, spot urine samples were prospectively collected from consecutive ambulatory children aged 0 to 14 years presenting with presumptive pulmonary TB in community health centers. Urine Xpert MTB/RIF was performed by blinded technicians in 182 samples using 2ml of unprocessed urine.. The mean age of presumptive TB cases was 5.9 years (median 5.4, range 0.1 to 14.7) with more males (113, 62%) compared to females. All urine samples tested negative for Xpert MTB/RIF, regardless of whether concentration was performed or not. Out of these 182 presumptive TB cases, 50 (28%) were clinically diagnosed and 5 (3%) were bacteriologically diagnosed to have TB disease using either sputum or nasopharyngeal aspirate specimens.. In this community-based study, urine Xpert MTB/RIF does not appear to contribute to the diagnosis of childhood TB.

Topics: Adolescent; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Humans; Infant; Infant, Newborn; Male; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Pulmonary; Urine

Topics: Bacteriological Techniques; Humans; Microbial Sensitivity Tests; Microscopy; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

We report a 46-year-old woman presenting with leprosy, HIV and active pulmonary tuberculosis (TB). It is advisable to screen for each one of TB, HIV and leprosy patients, especially when an extra feature emerges. Particularly in a leprosy case, if TB remains undiagnosed, the development of rifampicin resistance secondary to monotherapy in leprosy is a major concern.

Topics: Antiretroviral Therapy, Highly Active; Drug Resistance, Bacterial; Female; HIV Infections; Humans; Leprostatic Agents; Leprosy; Middle Aged; Rifampin; Tuberculosis, Pulmonary

The GeneXpert MTB/RIF Assay (Xpert®) is known to be a feasible, effective and a hopeful tool for rapid tuberculosis (TB) diagnosis and treatment. However, little is known about the time delay caused by initial negative sputum smear microscopy (NSSM), but consecutive positive Xpert TB test (PXTBt) and its association with TB mortality in resource-constrained settings. We aimed to estimate the median time delay between initial NSSM but consecutive PXTBt and TB treatment initiation and its association with TB mortality among TB/HIV co-infected patients in Beira, Mozambique.. we used data from a retrospective cohort study of TB/HIV co-infected patients in six TB services in Beira city. The study included all patients that tested NSSM, followed by a PXTBt in the six health centers with TB services during the year 2015. Data were extracted from the laboratory and TB treatment registers. To assess the difference in median time delays between groups, Mann-Whitney and Kruskal-Wallis tests were computed. To analyze the associations between the time delays and TB mortality, logistic regression model was used.. Among the 283 patients included in the study, median (IQR) age was 31 (17) years, 59.0% were males, 57.6% in the WHO clinical fourth stage of HIV. The median (IQR) values for diagnostic delay, treatment delay and total time delay was 10 (9) days, 13 (12) days and 28 (20) days, respectively. For TB/HIV co-infected patients who tested negative for smear microscopy initially, a total time delay of one month or longer was associated with high mortality (aOR = 12.40, 95% CI: 5.70-22.10).. Our study indicates that delays in TB diagnosis and treatment resulting from initial NSSM, but consecutive PXTBt are common in Beira city and are one of the main factors associated with TB mortality among TB/HIV co-infected patients. Applying GeneXpert assay as gold standard for HIV-positive patients with suspected pulmonary TB or replacing the sputum smear microscopy by Xpert assay and its availability within 24 h is urgently needed to ensure early diagnosis and treatment, and to maximize the impact of the few resources available in the country.

Topics: Adolescent; Adult; Cohort Studies; Coinfection; Delayed Diagnosis; Female; HIV Infections; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mozambique; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sputum; Time-to-Treatment; Tuberculosis, Pulmonary; Young Adult

To analyse the diagnostic performance of MTB/RIF assay for the diagnosis of pulmonary tuberculosis and detection of rifampicin resistance using sputum samples.. Observational cross-sectional study.. Provincial TB Reference Laboratory (PTRL), Hayatabad Medical Complex, Peshawar, Pakistan, from January to October 2015.. A total of 268 participants were consecutively enrolled in the study after meeting the inclusion criteria. Their sputum samples were collected and processed by N-acetyl-L-cysteine-sodium hydroxide (NALC-NaOH) method and GeneXpert MTB/RIF assay.. This study determined the overall sensitivity and specificity of MTB/RIF assay, it was 92.4% (86/93) and 97.1% (138/142), respectively. The sensitivity was 98.4% (60/61) in culture proven smear positive samples, whilst sensitivity in culture proven smear negative samples was 93.7% (30/32), using culture as reference standard.. GeneXpert MTB/RIF assay could greatly improve early diagnosis of PTB in smear negative cases as well as multidrug resistant tuberculosis.

Topics: Antibiotics, Antitubercular; Bacteriological Techniques; Cross-Sectional Studies; Female; Humans; Male; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Humans; Rifampin; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Humans; Rifampin; Tuberculosis, Pulmonary

To present results of the first national anti-tuberculosis (TB) drug resistance survey conducted in Lao PDR between May 2016 and August 2017 to determine the prevalence of resistance to first-line anti-TB drugs among new and previously treated pulmonary TB cases in the country.. Patients with sputum smear-positive pulmonary TB were enrolled from 42 TB laboratories distributed in 40 clusters throughout the country. Survey sites were selected using probability-proportional-to-size sampling among all diagnostic centres in the country. In addition to smear microscopy, all patients underwent Xpert MTB/RIF testing and those found positive to Mycobacterium tuberculosis underwent sputum culture and drug susceptibility testing using the proportion method on solid Löwenstein-Jensen medium.. Among 1006 eligible patients, 946 sputum smear-positive and Xpert MTB/RIF positive (Mycobacterium tuberculosis detected) patients were included in the survey, comprising 897 new and 49 previously treated TB cases. The prevalence of rifampicin-resistant TB was 1.2% (95% CI: 0.5-2.0%, n = 11/897) among new cases and 4.1% (95% CI: 0-9.6%, n = 2/49) among previously treated cases. Among the 946 TB cases confirmed by Xpert MTB/RIF, phenotypic drug sensitivity testing was available for 820 (776 new and 44 previously treated). The prevalence of multidrug-resistant TB (MDR-TB) was 0.5% (95% CI: 0-1.0%, n = 4/776) among new cases and 2.3% (95% CI: 0-6.7%, n = 1/44) among previously treated cases. No resistance to second-line injectable agents nor to fluoroquinolones was detected among MDR-TB patients.. The first national anti-TB drug resistance survey in Lao PDR demonstrated an encouragingly low prevalence of MDR-TB. The results appear lower than previous WHO estimates, and in line with the routine surveillance based on Xpert MTB/RIF testing (conducted among 50% of presumptive TB patients in 2017). The country should continue to expand its Xpert MTB/RIF network and strive to achieve universal drug susceptibility testing.. Présenter les résultats de la première surveillance nationale de la résistance aux médicaments antituberculeux, menée en République Démocratique Populaire (RDP) Lao entre mai 2016 et août 2017 afin de déterminer la prévalence de la résistance aux médicaments antituberculeux de première intention chez les nouveaux cas et les cas déjà traités de tuberculose (TB) pulmonaire dans le pays. MÉTHODES: Les patients atteints de TB pulmonaire à frottis d'expectoration positif ont été recrutés dans 42 laboratoires TB répartis dans 40 groupes à travers tout le pays. Les sites de surveillance ont été sélectionnés sur la base d'un échantillon probabiliste proportionnel à la taille parmi tous les centres de diagnostic du pays. Outre l'examen microscopique des frottis, tous les patients ont subi un test Xpert MTB/RIF et ceux trouvés positifs pour Mycobacterium tuberculosis ont subi une culture d'expectorations et un test de sensibilité aux médicaments en utilisant la méthode des proportions sur un milieu solide de Löwenstein-Jensen. RÉSULTATS: Parmi les 1.006 patients éligibles, 946 patients à frottis positif et Xpert MTB/RIF positif (Mycobacterium tuberculosis détecté) ont été inclus dans la surveillance, comprenant 897 nouveaux cas et 49 cas de TB déjà traités. La prévalence de la TB résistante à la rifampicine était de 1,2% (IC95%: 0,5-2,0%, n = 11/897) chez les nouveaux cas et de 4,1% (IC95%: 0-9,6%, n = 2/49) chez les cas traités. Parmi les 946 cas de TB confirmés par Xpert MTB/RIF, des tests de sensibilité phénotypique aux médicaments étaient disponibles pour 820 (776 nouveaux cas et 44 cas traités antérieurement). La prévalence de la TB multirésistante (TB-MDR) était de 0,5% (IC95%: 0-1,0%, n = 4/776) chez les nouveaux cas et de 2,3% (IC95%: 0 à 6,7%, n = 1/44) parmi les cas précédemment traités. Aucune résistance aux agents injectables de deuxième intention ni aux fluoroquinolones n'a été détectée chez les patients atteints de TB-MDR.. La première surveillance nationale de la résistance aux médicaments antituberculeux menée en RDP Lao a révélé une prévalence rassurante de la TB-MDR. Les résultats apparaissent inférieurs aux estimations précédentes de l’OMS et conformes à la surveillance de routine basée sur le test Xpert MTB/RIF (menée auprès de 50% des patients atteints de TB présumée en 2017). Le pays devrait continuer à élargir son réseau Xpert MTB/RIF et s'efforcer d'atteindre des tests universels de sensibilité aux médicaments.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Humans; Infant; Infant, Newborn; Laos; Male; Mass Screening; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Prevalence; Rifampin; Sputum; Surveys and Questionnaires; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Tuberculosis (TB) is a worldwide public health concern, including in high-resource countries with a low prevalence of TB. Xpert MTB/RIF assay was developed to improve TB and rifampicin (RIF) resistance detection, but sensitivity remains poor on smear-negative sputum. Xpert MTB/RIF Ultra assay was designed to enhance the sensitivity of TB detection in clinical samples. Herein, we evaluated retrospectively the performance of this test on smear-negative respiratory samples. Respiratory specimens with smear-negative and a Mycobacterium tuberculosis (MTB) complex-positive culture were retrospectively selected from those taken from patients during routine care, and analysed in the Mycobacteria Laboratory of the Lyon University hospital, France. Specimens were stored at - 20 °C before testing by Xpert MTB/RIF Ultra. For each sample, growth delay and date of anti-TB treatment initiation were recorded. Forty-six samples-29 sputum, 8 bronchial aspirates, 6 broncho-alveolar lavages, and 3 gastric aspirates-were selected. Among samples collected before treatment initiation (n = 33), sensitivity was 81.8% (95% CI [64.5; 93.0]) and there was a significant correlation between the quantitative measurements (Ct) of Xpert MTB/RIF Ultra assay and the time to growth detection in culture. Among samples collected after treatment initiation (n = 12), sensitivity was 100%, without correlation with time to growth detection due to presence of afterglow DNA in samples. In high-resource settings, the Xpert MTB/RIF Ultra test represents a useful tool for pulmonary TB diagnosis, notably for the paucibacillary forms. Moreover, quantitative measurement of Xpert MTB/RIF Ultra could help to predict time to MTB culture positivity and be used as a quality indicator of MTB culture process.

Topics: Antibiotics, Antitubercular; Diagnostic Tests, Routine; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Rifamycins are a group of antibiotics mainly used in the treatment of tuberculosis (TB), however they interact with antiretroviral therapy (ART). Rifabutin allows more regimens options for concomitant imunodeficiency virus (HIV) treatment compared to rifampicin.. Compare the outcomes of TB-HIV co-infected patients who used rifampicin or rifabutin.. We analysed data from a prospective cohort study at National Institute of Infectious Diseases Evandro Chagas, Rio de Janeiro (RJ), Brazil. Patients who were treated for TB and HIV with rifampicin or rifabutin, from February 2011 to September 2016 were included.. There were 130 TB-HIV patients, of whom 102 were treated with rifampicin and 28 with rifabutin. All patients in the rifabutin-treated group and 55% of the rifampicin-treated group patients were ART-experienced. Patients treated with rifampicin had similar abandon and cure rates, interruptions in treatment due to adverse reactions, immune reconstitution inflammatory syndrome and a similar mortality rate as those treated with rifabutin. However, rifampicin-treated patients had higher CD4 counts and more frequently undetectable HIV viral load by the end of treatment (67% versus 18%, p < 0.001) compared to rifabutin-treated patients, even when only ART-experienced patients were evaluated (66,6% versus 36,3%, p = 0.039).. Patients who used rifabutin had worst immune and virological control. This group had more ART-experienced patients. New and simpler regimens are needed for patients who do not respond to previous antiretroviral therapies.

Topics: Adult; Anti-HIV Agents; Antibiotics, Antitubercular; Cohort Studies; Drug Interactions; Female; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Rifabutin; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Multidrug-resistant tuberculosis (MDR-TB) jeopardizes global TB control. The prevalence and predictors of Rifampicin-resistant (RR) TB, a proxy for MDR-TB, and the treatment outcomes with standard and shortened regimens have not been assessed in post-conflict regions, such as the South Kivu province in the eastern Democratic Republic of the Congo (DRC). We aimed to fill this knowledge gap and to inform the DRC National TB Program.. of adults and children evaluated for pulmonary TB by sputum smear microscopy and Xpert MTB/RIF (Xpert) from February 2012 to June 2017. Multivariable logistic regression, Kaplan-Meier estimates, and multivariable Cox regression were used to assess independent predictors of RR-TB and treatment failure/death.. Of 1535 patients Xpert-positive for TB, 11% had RR-TB. Independent predictors of RR-TB were a positive sputum smear (adjusted odds ratio [aOR] 2.42, 95% confidence interval [CI] 1.63-3.59), retreatment of TB (aOR 4.92, 95% CI 2.31-10.45), and one or more prior TB episodes (aOR 1.77 per episode, 95% CI 1.01-3.10). Over 45% of RR-TB patients had no prior TB history or treatment. The median time from Xpert diagnosis to RR-TB treatment initiation was 12 days (interquartile range 3-60.2). Cures were achieved in 30/36 (83%) and 84/114 (74%) of patients on 9- vs 20/24-month MDR-TB regimens, respectively (P = .06). Predictors of treatment failure/death were the absence of directly observed therapy (DOT; adjusted hazard ratio [aHR] 2.77, 95% CI 1.2-6.66) and any serious adverse drug event (aHR 4.28, 95% CI 1.88-9.71).. Favorable RR-TB cure rates are achievable in this post-conflict setting with a high RR-TB prevalence. An expanded Xpert scale-up; the prompt initiation of shorter, safer, highly effective MDR-TB regimens; and treatment adherence support are critically needed to optimize outcomes.

Topics: Adult; Antibiotics, Antitubercular; Child; Cohort Studies; Democratic Republic of the Congo; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Prevalence; Retrospective Studies; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The objective of this study is to evaluate the performance of the GeneXpert MTB/RIF system in Mycobacterium tuberculosis (MTB) diagnosis and the detection of rifampicin resistance in pulmonary and extrapulmonary clinical samples.. A total of 849 samples (611 pulmonary and 238 extrapulmonary), which were sent to the laboratory of our hospital on suspicion of MTB, were included in the study. The samples cultured on Lowenstein Jensen medium and Mycobacteria Growth Indicator Tubes. All samples were also tested with the GeneXpert MTB/RIF test. The drug susceptibility test was determined using the Bactec MGIT 960 system.. MTB grew in the culture in 84 (9.8%) of all samples, and 78 (9.1%) were found to be positive by the GeneXpert MTB/RIF test, while acid-fast bacillus (AFB), MTB/RIF test, and culture positivity were 41 (6.7%), 74 (12.1%), and 75 (12.3%), respectively, in pulmonary samples, and these values were found to be 2 (0.8%), 4 (1.7%), and 9 (3.8%), respectively, in extrapulmonary samples. In the automated culture and susceptibility system, rifampicin resistance was detected in only one of 84 (2.6%) isolated strains. This resistant strain was also identified by the GeneXpert MTB/RIF test. According to the culture results of all samples examined, the sensitivity of the GeneXpert MTB/RIF test was calculated as 83.3%, specificity as 98.9%, PPV as 89.7%, and NPV as 98.1%.. The GeneXpert MTB/RIF test used in the study was found to be highly successful, very quick, and requiring low workload in pulmonary samples and extrapulmonary samples in terms of sensitivity and specificity. It was observed that it can be used safely due to its high sensitivity, especially in AFB-positive samples.

Topics: Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

Current treatments for tuberculosis (TB) are effective in controlling Mycobacterium tuberculosis (Mtb) growth, yet have significant side effects and do not prevent reinfection. Therefore, it is critical to understand why our host defense system is unable to generate permanent immunity to Mtb despite prolonged anti-tuberculosis therapy (ATT). Here, we demonstrate that treatment of mice with the most widely used anti-TB drugs, rifampicin (RIF) or isoniazid (INH) and pyrazinamide (PYZ), significantly altered the composition of the gut microbiota. Unexpectedly, treatment of mice with the pro-Mtb drugs INH and PYZ, but not RIF, prior to Mtb infection resulted in an increased bacterial burden, an effect that was reversible by fecal transplantation from untreated animals. Mechanistically, susceptibility of INH/PYZ-treated mice was associated with impaired metabolism of alveolar macrophages and defective bactericidal activity. Collectively, these data indicate that dysbiosis induced by ATT administered to millions of individuals worldwide may have adverse effects on the anti-Mtb response of alveolar macrophages.

Topics: Animals; Antibiotics, Antitubercular; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Dysbiosis; Gastrointestinal Microbiome; Host-Pathogen Interactions; Humans; Immunity, Innate; Immunomodulation; Isoniazid; Macrophages, Alveolar; Mice; Mice, Inbred C57BL; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

We present a case of pulmonary tuberculosis treated with a rifampicin (RMP) containing regimen, which led to marked haemolysis and acute kidney injury. The patient was shown to have RMP-induced haemolysis on detailed immunological testing. RMP is described as a rare cause of drug-induced haemolysis in the literature. However, it is a widely used drug and this complication may be severe. RMP-induced haemolysis precludes further treatment with the drug. Clinicians should consider this possibility and seek advice if patients on RMP develop haemolysis.

Topics: Acute Kidney Injury; Adolescent; Antitubercular Agents; Hemolysis; Humans; Male; Rifampin; Tuberculosis, Pulmonary

Tuberculosis continues to be a major public health problem worldwide. The aim of the present study was to evaluate the accuracy of the Xpert MTB/RIF rapid molecular test for tuberculosis, using pulmonary samples obtained from patients treated at the Júlia Kubitschek Hospital, which is operated by the Hospital Foundation of the State of Minas Gerais, in the city of Belo Horizonte, Brazil. This was a retrospective study comparing the Xpert MTB/RIF test results with those of standard culture for Mycobacterium tuberculosis and phenotypic susceptibility tests. Although the Xpert MTB/RIF test showed high accuracy for the detection of M. tuberculosis and its resistance to rifampin, attention must be given to the clinical status of the patient, in relation to the test results, as well as to the limitations of molecular tests.

Topics: Antibiotics, Antitubercular; Bronchoalveolar Lavage Fluid; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Reproducibility of Results; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tertiary Care Centers; Trachea; Tuberculosis, Pulmonary

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

Mycobacteriophages express various peptides/proteins to infect

Topics: Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Drug Synergism; Humans; Macrophages; Mice; Mice, Inbred BALB C; Mycobacteriophages; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Pulmonary; Viral Proteins

Tuberculosis (TB), an ancient scourge of humanity known for several thousands of years, is still a significant public health challenge in many countries today even though some progress has been made in recent years in controlling the disease. The study's aim was to determine the prevalence of mutations responsible for drug resistance in Mycobacterium tuberculosis among patients visiting selected health centers in Nairobi, Kenya.. The cross-sectional study involved 132 TB positive patients visiting Mbagathi and Chandaria hospitals between September 2015 and August 2016. Sputum samples were collected from the participants and handled in a biosafety level 3 laboratory at the Kenya Medical Research Institute (KEMRI). Samples were decontaminated using N-Acetyl-L-Cysteine (NALC) - Sodium Hydroxide (NALC-NaOH), stained using Zeihl-Neelsen (ZN), and cultured in Mycobacterium Growth Indicator Tube (MGIT). DNA extracted from cultured isolates using Genolyse™ technique was subjected to Multiplex PCR amplification and reverse hybridization for detection of drug resistance mutations on rpoB, katG, inhA, gyrA, gyrB, rrs and eis genes using Hain Genotype MTBDRplus and MTBDRsl.. All 132 (100%) patients included in the study were culture positive for M. tuberculosis. Among them, 72 (54%) were male while the remaining 60 (46%) were female. The mean age of the patients was 26.4 ± 19.4 (SD) with a range of 18 to 60 years. Overall, the prevalence of the resistance to first and second-line TB drugs was 1.5% (2/132). Resistance to isoniazid (INH) was observed in 1 of 132 patients (0.8%), as was multi-drug resistant tuberculosis (MDR-TB), also at 0.8%. No resistance to fluoroquinolones (FQ) or kanamycin (KAN) was observed. The INH resistant strain had the katG mutations S315 T, while mutations detected for the MDR-TB were katG S513 T for INH, rpoB S531 L for rifampicin (RIF) and rrs G1484 T for cross-resistance to aminoglycosides/capreomycin (AG/CP).. Molecular analysis confirms transmission of the drug-resistant M. tuberculosis strains. The data suggested that there is homogeneity when it comes to the type of drug resistance and mutation that occurs in the region. This calls for intensified drug resistance surveillance and drug adherence among patients infected with TB.

Topics: Adolescent; Adult; Antitubercular Agents; Capreomycin; Cross-Sectional Studies; Drug Resistance, Bacterial; Female; Gene Frequency; Genotype; Humans; Isoniazid; Kanamycin; Kenya; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Human-immunodeficiency virus (HIV) infection is increasing worldwide and nontuberculous mycobacteria (NTM) is an established microbiologic cause of pulmonary disease, lymphadenitis, and disseminated disease in cases of advanced immune suppression. Data on patients coinfected with HIV and NTM are limited. Thus, this study aimed to analyze the clinical characteristics, drug resistance, and pathogen spectrum of patients coinfected with both HIV and NTM in the Chengdu area of China.. Data of 59 patients coinfected with both HIV and NTM collected from the Public Health Clinical Center of Chengdu, between January 2014 and December 2018, were analyzed. NTM drug sensitivity testing was performed using the microporous plate ratio method. Data were analyzed using SPSS 19.0, and the change in drug resistance rate was analyzed using the chi-square (χ) test.. Seven species/complex of NTM were identified from patients coinfected with HIV and NTM in this study, with Mycobacterium avium-intracellulare complex (52.5%) and M. kansasii (27.1%) as the predominant species. Male patients were more affected 50/59 (84.7%); the mean age of the 59 cases was 45 years. The clinical characteristics mainly included anemia (86.4%), cough and expectoration (79.7%). The baseline CD4 count was <50 cells/μL (84.7%). Patients were mainly in advanced acquired immunodeficiency syndrome (AIDS) stage. Chest imaging mainly showed patchy shadows (42.4%) and nodules (32.2%), with various degrees of AIDS-defining diseases. The drug resistance of NTM was severe, and the rate of isoniazid resistance (100.0%) was the highest, followed by rifampicin (94.9%), streptomycin (94.9%), ofloxacin (93.2%), and others. Ethambutol (52.5%) and clarithromycin (33.9%) were relatively low. No significant difference was found in the drug resistance rate of NTM strain against nine antituberculosis drugs in 5 years (P > 0.05).. The immune level of patients coinfected with HIV and NTM is low in advanced AIDS stage; more male are affected in patients who are mainly infected with MAC and M. kansasii and with serious drug resistance. The drug resistance rate of ethambutol and clarithromycin is relatively low.

Topics: Acquired Immunodeficiency Syndrome; Adult; Aged; Aged, 80 and over; Antitubercular Agents; China; Clarithromycin; Ethambutol; Female; HIV Infections; HIV-1; Humans; Isoniazid; Male; Middle Aged; Mycobacterium avium Complex; Nontuberculous Mycobacteria; Retrospective Studies; Rifampin; Streptomycin; Tuberculosis, Pulmonary; Young Adult

The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization.. A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts.. Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/.

Topics: Adult; Antitubercular Agents; Decision Support Techniques; Disease Progression; Drug Administration Schedule; Drug Dosage Calculations; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Humans; Isoniazid; Kanamycin; Linezolid; Lung; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Tissue Distribution; Treatment Failure; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Topics: Humans; Minors; Mycobacterium tuberculosis; Rifampin; Sweden; Tuberculosis, Pulmonary

Most studies assessing drug resistant tuberculosis (DRTB) in human immunodeficiency virus (HIV) co-infected patients in India have used conventional culture- based systems to diagnose DRTB that have a longer turnaround time leading to risk of amplification of resistance to an empirical regimen. We determined the prevalence of DRTB amongst people living with HIV (PLHIV) using the line probe assay and determined risk factors associated with the presence of multi drug resistant tuberculosis (MDRTB).. A Cross-sectional study was undertaken at Poona Hospital and Research Center (PHRC) and the Institute of Infectious Diseases, two tertiary level private care centers in Pune, India. Consenting PLHIV with confirmed Pulmonary TB (PTB) and/or extra-pulmonary TB (EPTB) diagnosed based on detection of Mycobacterium TB by line probe assay (Geno Type MTBDRplus version 2) on clinical specimens were included. Those with documented past history of DRTB were excluded. Resistance against anti-TB drugs was determined by the same assay. The prevalence of any form of drug resistant TB (DRTB), MDRTB, Rifampicin resistant TB (RRTB) and Isoniazid (INH) mono-resistant TB were determined as the proportion of these amongst all included PLHIV-TB. A multivariate analysis was conducted to determine risk factors that were statistically associated with MDRTB, DRTB, RRTB and INH mono-resistant TB.. Two hundred PLHIV were recruited. The prevalence (95% CI) of MDRTB, INH mono- resistance and RR resistance was 12.5% (7.9-17.1%), 9% (6.9-11.2%) and 2.5% (1.4-3.6%), respectively. The prevalence (95% CI) of MDRTB among new and relapsed patients was 8.8% (6.5-11.1%) and 23.1% (17.2-28.9%), respectively. Tuberculosis relapse was the only factor significantly associated with MDRTB, DRTB and INH mono-resistant TB.. We document a high prevalence of drug resistance to anti-TB drugs including MDRTB among PLHIV in our setting using Geno Type MTBDRplus directly on clinical specimens. This validates the WHO recommendation of performing routine rapid molecular resistance testing prior to initiating anti-TB treatment among all PLHIV with presumptive TB. Using rapid molecular testing especially Geno Type MTBDRplus (that detects resistance to INH and Rifampicin simultaneously) reduces the turn-around time helping in optimizing treatment.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Antitubercular Agents; Child; Cross-Sectional Studies; Female; HIV Infections; Humans; India; Isoniazid; Male; Middle Aged; Prevalence; Rifampin; Risk Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

This case report has tried to highlight the ease and benefit of Gene-Xpert testing in difficult to diagnose patient with sputum smear negative pulmonary tuberculosis. Early treatment of tuberculosis is usually delayed by lack of rapid and accurate diagnostic modalities, especially in resource-limited settings like ours. Gene-Xpert is a rapid test based on real time PCR assay and molecular technology for the detection of Mycobacterium tuberculosis. It is highly sensitive tool and enables simultaneous detection of rifampicin resistance within short period of time i,e. <2hrs. It has distinct advantage of providing same-day diagnosis which could potentially limit loss to follow up during diagnostic evaluation of smear negative tuberculosis patients. Keywords: Gene-Xpert; pulmonary tuberculosis; sputum microscopy.

Topics: Antitubercular Agents; False Negative Reactions; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Radiography, Thoracic; Rifampin; Sputum; Tomography, X-Ray Computed; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antibiotics, Antitubercular; Bacteriological Techniques; Humans; Microbial Viability; Mycobacterium tuberculosis; Phenotype; Predictive Value of Tests; Rifampin; Sputum; Tuberculosis, Pulmonary

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

Sarcoidosis and tuberculosis are chronic diseases that rarely occur concomitantly. We present the case of a 39-year-old woman with microbiological confirmation of pulmonary tuberculosis and concomitant sarcoidosis. Four weeks after corticosteroid therapy for sarcoidosis was introduced we had positive findings of mycobacterium culture from bronchial aspirate. Based on these results, corticosteroid therapy was discontinued and the patient received anti-tuberculosis therapy for six months as required by the national guidelines. During this period, new nodes on face, nose, and ear appeared and the patient was diagnosed with skin sarcoidosis. The patient received colchicine and corticosteroids as per the national guidelines.. In cases of diagnostic uncertainty between sarcoidosis and tuberculosis we should administer corticosteroid therapy until we have microbiological confirmation of mycobacterium culture.

Topics: Adult; Antitubercular Agents; Deprescriptions; Ethambutol; Female; Glucocorticoids; Humans; Isoniazid; Prednisolone; Pyrazinamide; Radiography, Thoracic; Rifampin; Romania; Sarcoidosis, Pulmonary; Tomography, X-Ray Computed; Tuberculosis, Pulmonary; Vitamin B 6; Vitamin B Complex

The diagnoses of active smear negative PTB, remains difficult. As a result, treatment is often carried out empirically relaying on clinical criteria. The distribution and magnitude of smear negative PTB, smear negative MDR-TB and associated factors in the same day diagnosis strategy are not clearly known in the study area. Therefore, this study aimed to determine the prevalence of TB, MDR-TB and associated risk factors among presumptive smear negative pulmonary tuberculosis patients in Addis Ababa, Ethiopia.. Analytic cross sectional study design was used. A total of 418 smear negative presumptive pulmonary TB patients were enrolled from selected health facilities since August 01, 2017 to January 5, 2018. Sputum samples were examined by Ziehl Neelsen microscopy, Xpert MTB/RIF assay and Culture. Drug susceptibility testing was performed by line probe assay and BACTEC MGIT 960 system. These laboratory tests were performed in Ethiopian Public Health Institute, National TB Reference Laboratory. Data was analyzed by SPSS Ver.20.. From the total of 418 enrolled patients, 27 (6.5%) were Xpert MTB/ RIF and 26 (6.4%) were culture confirmed smear negative PTB patients. The positivity rate among male and female was 10.2 and 3.5% (p = 0.005) respectively. From 26 culture positive isolates 3 (11.54%) were MDR TB; from MDR-TB confirmed isolates 2/23 (8.7%) were among new and 1/3 (33.3%) was among retreatment smear negative presumptive pulmonary TB patients. All Rifampicin resistant smear negative pulmonary TB isolates by Xpert MTB/ RIF assay were found to be MDR TB and 7/26 (26.9%) isolates were INH mono resistant. History of migration found to be a potential factor for developing smear negative pulmonary TB.. In this study a significant proportion of smear negative pulmonary TB was diagnosed. Furthermore, a high smear negative multi drug resistant (MDR) TB and other mono drug resistant TB prevalence was confirmed. Due to the limitations of smear microscopy which is used as a primary diagnostic tool, these TB strains are missed to be diagnosed and transmission continues in the community.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Comorbidity; Cross-Sectional Studies; Ethiopia; Female; Humans; Infant; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Prevalence; Rifampin; Risk Factors; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The molecular bacterial load (MBL) assay is a new tuberculosis biomarker which provides results in ∼4 hours. The relationship between MBL and time-to-positivity (TTP) has not been thoroughly studied, and predictive models do not exist. We aimed to develop a model for MBL and identify the MBL-TTP relationship in patients. The model was developed on data from 105 tuberculosis patients from Malawi, Mozambique, and Tanzania with joint MBL and TTP observations quantified from patient sputum collected for 12 weeks. MBL was quantified using PCR of mycobacterial RNA and TTP using the mycobacterial growth indicator tube (MGIT) 960 system. Treatment consisted of isoniazid, pyrazinamide, and ethambutol in standard doses together with rifampin 10 or 35 mg/kg of body weight. The developed MBL-TTP model included several linked submodels, a component describing decline of bacterial load in sputum, another component describing growth in liquid culture, and a hazard model translating bacterial growth into a TTP signal. Additional components for contaminated and negative TTP samples were included. Visual predictive checks performed using the developed model gave good description of the observed data. The model predicted greater total sample loss for TTP than MBL due to contamination and negative samples. The model detected an increase in bacterial killing for 35 versus 10 mg/kg rifampin (

Topics: Antitubercular Agents; Bacterial Load; Biological Assay; Biomarkers, Pharmacological; Computer Simulation; DNA, Bacterial; Drug Dosage Calculations; Drug Monitoring; Ethambutol; Female; Humans; Isoniazid; Malawi; Male; Models, Statistical; Mozambique; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Sputum; Tanzania; Time Factors; Tuberculosis, Pulmonary

The Gene Xpert MTB/ RIF assay (Xpert) is used for rapid, simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin resistance. This study examined the accuracy of Xpert in children with suspected pulmonary tuberculosis (PTB).. Children admitted to Port Moresby General Hospital with suspected PTB were prospectively enrolled between September 2014 and March 2015. They were classified into probable, possible and TB-unlikely groups. Sputum or gastric aspirates were tested by Xpert and smear microscopy; mycobacterial culture was undertaken on a subset. Children were diagnosed with TB on the basis of standard criteria which were used as the primary reference standard. Xpert, smear for acid-fast bacilli (AFB) and the Edwards TB score were compared with the primary reference standard.. A total of 93 children ≤14 years with suspected PTB were enrolled; 67 (72%) were classified as probable, 21 (22%) possible and 5 (5.4%) TB-unlikely. Eighty were treated for TB based on the primary reference standard. Xpert was positive in 26/93 (28%) MTB cases overall, including 22/67 (33%) with probable TB and 4/21 (19%) with possible TB. Three (13%) samples identified rifampicin resistance. Xpert confirmed more cases of TB than AFB smear (26 vs 13, p = 0.019). The sensitivity of Xpert, AFB smear and an Edwards TB score of ≥7 was 31% (25/80), 16% (13/80) and 90% (72/80), respectively, and the specificity was 92% (12/13), 100% (13/13) and 31% (4/13), respectively, when compared with the primary reference standard.. Xpert sensitivity is sub-optimal and cannot be relied upon for diagnosing TB, although a positive result is confirmatory. A detailed history and examination, standardised clinical criteria, radiographs and available tests remain the most appropriate way of diagnosing TB in children in resource-limited countries. Xpert helps confirm PTB better than AFB smear, and identifies rifampicin resistance. Practical guidelines should be used to identify children who will benefit from an Xpert assay.

Topics: Adolescent; Antitubercular Agents; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Gastric Juice; Humans; Infant; Infant, Newborn; Male; Microscopy; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Papua New Guinea; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

Accumulating evidence suggests that increasing doses of rifampicin may shorten tuberculosis treatment. The PanACEA HIGHRIF1 trial assessed safety, pharmacokinetics, and antimycobacterial activity of rifampicin at doses up to 40 mg/kg. Eighty-three pulmonary tuberculosis patients received 10, 20, 25, 30, 35, or 40 mg/kg rifampicin daily over 2 weeks, supplemented with standard doses of isoniazid, pyrazinamide, and ethambutol in the second week. This study aimed at characterizing rifampicin pharmacokinetics observed in HIGHRIF1 using nonlinear mixed effects modeling. The final population pharmacokinetic model included an enzyme turnover model accounting for time-dependent elimination due to autoinduction, concentration-dependent clearance, and dose-dependent bioavailability. The relationship between clearance and concentration was characterized by a Michaelis-Menten relationship. The relationship between bioavailability and dose was described using an E

Topics: Adult; Antibiotics, Antitubercular; Area Under Curve; Biological Availability; Dose-Response Relationship, Drug; Drug Dosage Calculations; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Male; Models, Biological; Rifampin; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Antitubercular Agents; Choroid Diseases; Drug Combinations; Ethambutol; Female; Granuloma; Humans; Immunocompetence; Isoniazid; Magnetic Resonance Imaging; Male; Pyrazinamide; Rifampin; Tomography, X-Ray Computed; Tuberculosis, Ocular; Tuberculosis, Pulmonary; Ultrasonography

The Xpert MTB/RIF test (Cepheid, Sunnyvale, CA) can simultaneously detect the Mycobacterium tuberculosis (MTB) complex DNA and rifampicin (RFP) resistance and can rapidly determine RFP resistance and predict multidrug-resistant tuberculosis (MDR-TB). In this study, we analyzed clinical examination results of a hospital specializing in TB treatment in Wuhan, Hubei, China, and examined the use of traditional culture and drug-sensitive test (DST) results as a gold standard to assess the diagnosis value of the Xpert MTB/RIF test in RFP resistance and MDR-TB.. A total of 2,910 specimens were received in the Mycobacteriology Laboratory, Wuhan Pulmonary Hospital, for Xpert MTB/RIF testing between December 2013 and December 2014. After the results were reviewed by exclusion criteria, 1,066 Xpert test results were eligible for our study. We then compared the Xpert test results with sputum acid-fast bacilli staining, cultures, and DST results.. In total, Xpert correctly identified 96.71% (147/152) RFP-resistant TB and 98.25% (898/914) RFP-sensitive TB specimens. Of the 147 RFP-resistant TB specimens detected by Xpert, 122 MDR-TB (82.99%) were identified by traditional culture and DST techniques.. Xpert can simultaneously detect MTB and RFP resistance with high sensitivity and specificity. Thus, Xpert testing aids in saving a considerable amount of time in the diagnosis and treatment of MDR-TB.

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; China; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Lopinavir-ritonavir forms the backbone of current first-line antiretroviral regimens in young HIV-infected children. As multidrug-resistant (MDR) tuberculosis (TB) frequently occurs in young children in high-burden TB settings, it is important to identify potential interactions between MDR-TB treatment and lopinavir-ritonavir. We describe the pharmacokinetics of and potential drug-drug interactions between lopinavir-ritonavir and drugs routinely used for MDR-TB treatment in HIV-infected children. A combined population pharmacokinetic model was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir in 32 HIV-infected children (16 with MDR-TB receiving treatment with combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a fluoroquinolone, and amikacin and 16 without TB) who were established on a lopinavir-ritonavir-containing antiretroviral regimen. One-compartment models with first-order absorption and elimination for both lopinavir and ritonavir were combined into an integrated model. The dynamic inhibitory effect of the ritonavir concentration on lopinavir clearance was described using a maximum inhibition model. Even after adjustment for the effect of body weight with allometric scaling, a large variability in lopinavir and ritonavir exposure, together with strong correlations between the pharmacokinetic parameters of lopinavir and ritonavir, was detected. MDR-TB treatment did not have a significant effect on the bioavailability, clearance, or absorption rate constants of lopinavir or ritonavir. Most children (81% of children with MDR-TB, 88% of controls) achieved therapeutic lopinavir trough concentrations (>1 mg/liter). The coadministration of lopinavir-ritonavir with drugs routinely used for the treatment of MDR-TB was found to have no significant effect on the key pharmacokinetic parameters of lopinavir or ritonavir. These findings should be considered in the context of the large interpatient variability found in the present study and the study's modest sample size.

Topics: Anti-HIV Agents; Antitubercular Agents; Child; Drug Administration Schedule; Drug Combinations; Drug Interactions; Ethambutol; Female; HIV; HIV Infections; Humans; Isoniazid; Lopinavir; Male; Models, Statistical; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Ritonavir; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Humans; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The Xpert MTB/RIF assay is an automated molecular test that has improved the detection of tuberculosis and rifampicin resistance, but its sensitivity is inadequate in patients with paucibacillary disease or HIV. Xpert MTB/RIF Ultra (Xpert Ultra) was developed to overcome this limitation. We compared the diagnostic performance of Xpert Ultra with that of Xpert for detection of tuberculosis and rifampicin resistance.. In this prospective, multicentre, diagnostic accuracy study, we recruited adults with pulmonary tuberculosis symptoms presenting at primary health-care centres and hospitals in eight countries (South Africa, Uganda, Kenya, India, China, Georgia, Belarus, and Brazil). Participants were allocated to the case detection group if no drugs had been taken for tuberculosis in the past 6 months or to the multidrug-resistance risk group if drugs for tuberculosis had been taken in the past 6 months, but drug resistance was suspected. Demographic information, medical history, chest imaging results, and HIV test results were recorded at enrolment, and each participant gave at least three sputum specimen on 2 separate days. Xpert and Xpert Ultra diagnostic performance in the same sputum specimen was compared with culture tests and drug susceptibility testing as reference standards. The primary objectives were to estimate and compare the sensitivity of Xpert Ultra test with that of Xpert for detection of smear-negative tuberculosis and rifampicin resistance and to estimate and compare Xpert Ultra and Xpert specificities for detection of rifampicin resistance. Study participants in the case detection group were included in all analyses, whereas participants in the multidrug-resistance risk group were only included in analyses of rifampicin-resistance detection.. Between Feb 18, and Dec 24, 2016, we enrolled 2368 participants for sputum sampling. 248 participants were excluded from the analysis, and 1753 participants were distributed to the case detection group (n=1439) and the multidrug-resistance risk group (n=314). Sensitivities of Xpert Ultra and Xpert were 63% and 46%, respectively, for the 137 participants with smear-negative and culture-positive sputum (difference of 17%, 95% CI 10 to 24); 90% and 77%, respectively, for the 115 HIV-positive participants with culture-positive sputum (13%, 6·4 to 21); and 88% and 83%, respectively, across all 462 participants with culture-positive sputum (5·4%, 3·3 to 8·0). Specificities of Xpert Ultra and Xpert for case detection were 96% and 98% (-2·7%, -3·9 to -1·7) overall, and 93% and 98% for patients with a history of tuberculosis. Xpert Ultra and Xpert performed similarly in detecting rifampicin resistance.. For tuberculosis case detection, sensitivity of Xpert Ultra was superior to that of Xpert in patients with paucibacillary disease and in patients with HIV. However, this increase in sensitivity came at the expense of a decrease in specificity.. Government of Netherlands, Government of Australia, Bill & Melinda Gates Foundation, Government of the UK, and the National Institute of Allergy and Infectious Diseases.

Topics: Adult; Africa; Antibiotics, Antitubercular; Asia; Bacteriological Techniques; Brazil; Drug Resistance, Bacterial; Europe; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Alcoholism; Antitubercular Agents; Conjunctival Diseases; Ethambutol; Eye Pain; Glucocorticoids; Humans; Hyperemia; Interferon-gamma; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Scleritis; Tobacco Use Disorder; Tuberculosis, Pulmonary

In 2010, the World Health Organization (WHO) revised the paediatric dosages of anti-tuberculosis drugs, increasing rifampicin to 15 mg/kg, isoniazid to 10 mg/kg and pyrazinamide to 35 mg/kg. We assessed treatment outcomes, safety and adherence among children treated with the new recommended dosages.. Prospective cohort of children started on anti-tuberculosis treatment in Uganda with 12 months of follow-up, including alanine aminotransferase (ALT) monitoring. Treatment intake was observed.. Of 144 treated children, 81 were male (56.3%), 106 (73.6%) were aged <5 years, 30 (22%) had moderate to severe malnutrition and 48 (33.3%) had human immunodeficiency virus infection. Treatment outcomes were as follows: 117 (81.3%) successes, 3 (2.1%) failures, 4 (2.8%) lost to follow-up, 19 (13.2%) deaths and 1 (0.7%) transferred out. There was no relapse. Severe malnutrition (adjusted hazard ratio 8.76, 95% confidence interval [CI] 1.59-48.25) was the only predictor of death. Two serious adverse events were attributed to treatment: one case of increased ALT and one with peripheral neuropathy. Median ALT values at baseline and at weeks 2, 4 and 8 were respectively 24 (interquartile range [IQR] 16-39), 26 (IQR 18-38), 28 (IQR 21-40) and 27 (IQR 19-38) international units/l. Treatment adherence was above 85% on all visits.. We confirm the good tolerability of and adherence to the new treatment recommendations. The increased risk of fatal outcome among severely malnourished children requires attention.

Topics: Antitubercular Agents; Child, Preschool; Cohort Studies; Female; HIV Infections; Humans; Infant; Infant, Newborn; Isoniazid; Male; Malnutrition; Patient Compliance; Practice Guidelines as Topic; Prospective Studies; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary; Uganda; World Health Organization

Topics: Animals; Antibiotics, Antitubercular; ATP-Binding Cassette Transporters; Cells, Cultured; Drug Resistance, Bacterial; Gene Expression Regulation; Gene Transfer Techniques; Genes, Reporter; Host-Pathogen Interactions; Humans; Ketoconazole; Lung; Macrophages; Male; Mice, Inbred C57BL; Microbial Viability; Mycobacterium tuberculosis; Pregnane X Receptor; Recombinant Proteins; Rifampin; RNA Interference; Tuberculosis, Pulmonary

To evaluate the feasibility of the implementation of a commercial rapid molecular diagnostic test (Xpert MTB/RIF) for the routine diagnosis of smear-negative or extrapulmonary tuberculosis (TB) and its diagnostic accuracy, and to assess HIV prevalence in a real-life setting in Madagascar. This study was set in a tertiary care hospital in Madagascar.. A prospective cohort study was conducted of all consecutive cases with suspected smear-negative and/or extrapulmonary TB over a 2-year period. Cases were classified as proven, probable, or possible TB cases, or as having an alternative diagnosis.. Of the 363 patients included, 183 (50.4%) had suspected smear-negative pulmonary TB and 180 (49.6%) had suspected extrapulmonary TB. For proven cases, the sensitivity, specificity, positive and negative predictive values of Xpert MTB/RIF were 82.4%, 98.8%, 98.3%, and 86.6%, respectively; for proven and probable cases grouped together, these values were 65%, 98.8%, 98.5%, and 64%, respectively. The diagnostic accuracy was slightly lower for extrapulmonary TB compared to smear-negative pulmonary TB. The prevalence of HIV infection was 12.1%, but almost half of these cases did not have TB (alternative diagnosis group).. The implementation of a rapid diagnosis programme for TB in a resource-poor setting is feasible. The performance of the Xpert-MTB/RIF was remarkable in this difficult-to-diagnose population. HIV prevalence in this study was much higher than the prevalence reported in the general population in Madagascar, in patients with TB and patients with conditions other than TB.

Topics: Adult; Antitubercular Agents; Feasibility Studies; Female; Humans; Madagascar; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Prevalence; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary

Topics: Aged; Antitubercular Agents; Celiac Disease; Diarrhea; Diet, Gluten-Free; Drug Compounding; Drug Substitution; Drug Therapy, Combination; Ethambutol; Glutens; Hemoptysis; Humans; Isoniazid; Male; Metronidazole; Moxifloxacin; Pyrazinamide; Rifampin; Smoking; Tomography, X-Ray Computed; Tuberculosis, Pulmonary

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

Tuberculosis (TB) is caused by M. tuberculosis complex and remains a major global public health problem. The epidemic remains a threat to sub-Saharan Africa, including Ethiopia, with further emergence of drug resistant TB. We investigated the drug sensitivity pattern and molecular epidemiology of mycobacterial strains isolated from pulmonary TB patients in and around Ambo town in Oromia Region, Central Ethiopia.. A cross-sectional study was conducted involving 105 consecutive new smear positive pulmonary TB patients diagnosed at Ambo Hospital and surrounding Health Centers between May 2014 and March 2015 upon informed consent. Sputum samples were cultured on Löwenstein-Jensen (LJ) media using standard techniques to isolate mycobacteria. Region of difference 9 (RD9)-based polymerase chain reaction (PCR) and spoligotyping was employed for the identification of the isolates at species and strain levels. The spoligotype patterns were entered into the SITVIT database to determine Octal and SIT (Spoligotyping International Typing) numbers for each strain. The sensitivity of the isolates to isoniazid (INH), rifampicin (RIF), ethambutol (ETB) and streptomycin (STM) was evaluated on LJ-medium with the indirect proportion method.. Cultures were positive in 86/105 (82%) of newly diagnosed smear positive pulmonary TB cases. All of the 86 isolates were confirmed as M. tuberculosis. The majority (76.7%) of them were clustered into seven groups while the rest (23.3%) appeared unique. The most predominant Spoligotypes were SIT53 and SIT149, consisting of 24.4% and 20.9% of the isolates, respectively. Assigning of the isolates to family using SPOTCLUST software revealed that 45.3% of the isolates belonged to T1, 23.3% to T3 and 13% to CAS family. The majority (76.7%) of the M. tuberculosis isolates were susceptible to all the four drugs. Any resistance to any one of the four drugs was detected in 23.3% of the isolates. The highest proportion of any resistance was observed against isoniazid (9.3%) and ethambutol (7%). There was only a single case (1.2%) of multidrug resistant/rifampicin resistant (MDR/RR) TB.. The majority of the isolates were clustered suggesting on-going active transmission in the study area. Mono resistance is relatively prevalent while the magnitude of MDR/RR-TB was found to be lower than in previous studies.

Topics: Adolescent; Adult; Cross-Sectional Studies; Ethambutol; Ethiopia; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Epidemiology; Mycobacterium tuberculosis; Rifampin; RNA, Viral; Streptomycin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

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

Drug resistant tuberculosis (TB) is increasing in prevalence worldwide. Treatment failure and relapse is known to be high for patients with isoniazid resistant TB treated with standard first line regimens. However, risk factors for unfavourable outcomes and the optimal treatment regimen for isoniazid resistant TB are unknown. This cohort study was conducted when Vietnam used the eight month first line treatment regimen and examined risk factors for failure/relapse among patients with isoniazid resistant TB.. Between December 2008 and June 2011 2090 consecutive HIV-negative adults (≥18 years of age) with new smear positive pulmonary TB presenting at participating district TB units in Ho Chi Minh City were recruited. Participants with isoniazid resistant TB identified by Microscopic Observation Drug Susceptibility (MODS) had extended follow-up for 2 years with mycobacterial culture to test for relapse. MGIT drug susceptibility testing confirmed 239 participants with isoniazid resistant, rifampicin susceptible TB. Bacterial and demographic factors were analysed for association with treatment failure and relapse.. Using only routine programmatic sputum smear microscopy for assessment, (months 2, 5 and 8) 30/239 (12.6%) had an unfavourable outcome by WHO criteria. Thirty-nine patients were additionally detected with unfavourable outcomes during 2 year follow up, giving a total of 69/239 (28.9%) of isoniazid (INH) resistant cases with unfavourable outcome by 2 years of follow-up. Beijing lineage was the only factor significantly associated with unfavourable outcome among INH-resistant TB cases during 2 years of follow-up. (adjusted OR = 3.16 [1.54-6.47], P = 0.002).. One third of isoniazid resistant TB cases suffered failure/relapse within 2 years under the old eight month regimen. Over half of these cases were not identified by standard WHO recommended treatment monitoring. Intensified research on early identification and optimal regimens for isoniazid resistant TB is needed. Infection with Beijing genotype of TB is a significant risk factor for bacterial persistence on treatment resulting in failure/relapse within 2 years. The underlying mechanism of increased tolerance for standard drug regimens in Beijing genotype strains remains unknown.

Topics: Adolescent; Adult; Antitubercular Agents; Cohort Studies; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Recurrence; Rifampin; Risk Factors; Sputum; Treatment Failure; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Vietnam; Young Adult

BACKGROUNDHospitalized patients with suspected tuberculosis (TB) are placed in airborne isolation until 3 sputum smear samples are negative for acid-fast bacilli (AFB). The Xpert MTB/RIF assay ("Xpert") nucleic acid amplification test (NAAT) to identify Mycobacterium tuberculosis DNA and resistance to rifampicin is superior to AFB sputum smear microscopy for the diagnosis of TB.OBJECTIVETo compare the performance of a single Xpert to AFB smear microscopy for time to airborne infection isolation (AII) discontinuation.METHODSConsecutive patients over 17 years of age in AII for suspected pulmonary TB between October 1, 2014, and March 31, 2016, with leftover respiratory AFB samples were enrolled in this study. A single Xpert was performed on the first available sample. Demographic, clinical, and microbiological data were recorded for each patient. We compared the duration of AII using a single Xpert to AFB smear microscopy under multiple theoretical scenarios using Kaplan-Meier cumulative incidence curves and the log-rank test.RESULTSIn total, 131 samples were included in our performance analysis of the Xpert, and 114 samples were included in our AII analysis. Overall, 81 patients (65%) were immunosuppressed, of whom 46 (37%) were positive for human immunodeficiency virus (HIV). The sensitivity and specificity of Xpert for diagnosis of M. tuberculosis infection were 67% and 100%, respectively. Xpert was negative in all cases of nontuberculous mycobacteria. Use of a single Xpert reduced AII duration from a median of 67 hours per patient to 42 hours with usual reporting, to 26 hours with direct communication, and to 12 hours with immediate testing.CONCLUSIONSA single negative Xpert result can reduce AII duration compared to the AFB smear microscopy technique under multiple theoretical scenarios.Infect Control Hosp Epidemiol 2018;39:590-595.

Topics: Air Microbiology; Antibiotics, Antitubercular; Baltimore; Drug Resistance, Bacterial; Female; HIV Infections; Hospitals, University; Humans; Infection Control; Male; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Patient Isolation; Rifampin; Sensitivity and Specificity; Sputum; Survival Analysis; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Drug Therapy, Combination; Humans; Isoniazid; Mycobacterium tuberculosis; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tuberculosis continues to be a major health problem worldwide. Multidrug resistant tuberculosis (MDR-TB) infection that occurs in childhood is caused by adult MDR-TB agents which are in circulation and resistant to primary drugs. In this case report a 17-month-old child with MDR-TB who was cured after a 24-month therapy regimen was presented. Physical examination of a 17-month-old girl admitted to the hospital with the cause of recurrent pneumonia revealed a rubbery lymphadenopathy less than 2 cm in the right upper cervical region. Crepitant rales were detected in the right basal on auscultation of the lung. Interferon gamma release assay (IGRA) and tuberculin skin (TST) tests were negative. Computed tomography (CT) scan of the chest showed mediastinal conglomerate pathologic lymphadenopathy and air bronchograms were detected near the lower lobe of the left lung. Treatment of isoniazid, rifampicin, pyrazinamide with the diagnosis of epituberculosis was started by taking a sample of gastric aspirate culture sample. In the sixth month of the treatment patient was admitted to our clinic with enlarged cervical rubbery lymphadenopathy. It was determined that microbiological test of gastric aspirate culture specimen was positive for M.tuberculosis complex resistant to isoniazid, rifampin, ethambutol, streptomycin, ethionamide and rifabutin. Control CT showed residual peribronchial infiltrations and hilar calcific lymph nodes. Hearing test, vision control and, thyroid function tests were performed and treatment of moxifloxacin, amikacin, para-amino salicylic acid, protionamide and pyrazinamide was started based on minor drug susceptibility results of M.tuberculosis isolate which was still growing in gastric aspirate culture. Gastric aspirate culture for M.tuberculosis was still positive after 3 months of treatment and the current treatment was continued. Amikacin was stopped after 6 months. Therapy regimen was stopped after 24-months. Over the course of a follow-up period of more than 3 years, the clinical and radiological resultsof the patient has improved significantly. The clinical presentation of TB in children is often nonspecific and differs from the patterns seen in adults. MDR-TB cases can be seen in this age group since tuberculosis in children is mainly caused by transmission of drug-resistant strains from adults. This situation is particularly problematic due to the long-term treatment and the lack of specific drug formulations for children.

Topics: Adult; Antitubercular Agents; Female; Humans; Infant; Isoniazid; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Amino Acid Sequence; Amino Acid Substitution; DNA-Directed RNA Polymerases; Drug Resistance, Multiple, Bacterial; Genetic Fitness; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Peptide Chain Elongation, Translational; Peptide Chain Termination, Translational; Protein Domains; Rifampin; Rifamycins; Tuberculosis, Pulmonary

Tuberculosis (TB) remains one of the most deadly infections with approximately a quarter of cases not being identified and/or treated mainly due to a lack of resources. Rapid detection of TB or drug-resistant TB enables timely adequate treatment and is a cornerstone of effective TB management. We evaluated the analytical performance of a single-tube assay for multidrug-resistant TB (MDR-TB) on an experimental platform utilising RT-PCR and melting curve analysis that could potentially be operated as a point-of-care (PoC) test in resource-constrained settings with a high burden of TB. Firstly, we developed and evaluated the prototype MDR-TB assay using specimens extracted from well-characterised TB isolates with a variety of distinct rifampicin and isoniazid resistance conferring mutations and nontuberculous Mycobacteria (NTM) strains. Secondly, we validated the experimental platform using 98 clinical sputum samples from pulmonary TB patients collected in high MDR-TB settings. The sensitivity of the platform for TB detection in clinical specimens was 75% for smear-negative and 92.6% for smear-positive sputum samples. The sensitivity of detection for rifampicin and isoniazid resistance was 88.9 and 96.0% and specificity was 87.5 and 100%, respectively. Observed limitations in sensitivity and specificity could be resolved by adjusting the sample preparation methodology and melting curve recognition algorithm. Overall technology could be considered a promising PoC methodology especially in resource-constrained settings based on its combined accuracy, convenience, simplicity, speed, and cost characteristics.

Topics: Antitubercular Agents; Base Sequence; Drug Resistance, Multiple, Bacterial; Humans; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Nucleic Acid Denaturation; Point-of-Care Systems; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Delayed diagnosis and treatment of tuberculosis (TB) contribute to poor outcomes, especially for endobronchial TB (EBTB), which typically leads to tracheobronchial stenosis. Finding rapid and accurate diagnostic tools for EBTB is crucial. GeneXpert Mycobacterium tuberculosis (MTB)/rifampin (RIF) was recommended by the World Health Organization (WHO) as a standard molecular biological diagnostic technique for MTB. The aim of this study was to evaluate the efficacy of GeneXpert MTB/RIF for diagnosing EBTB and for evaluating RIF resistance.. Biopsy tissue and bronchial brushings from EBTB patients were prospectively assessed with GeneXpert MTB/RIF. The diagnostic yields of auramine O-stained sputum smears and bronchial brush smears were obtained, and the results were compared with the cultures of sputum and biopsy tissues for MTB.. In 61 confirmed cases of EBTB, the sensitivities of sputum smear, bronchial brush smear, sputum culture and tissue culture to diagnose EBTB were 13.1%, 32.8%, 36.1% and 68.9%, respectively. For bronchial brushings and biopsies, our data showed sensitivities of 57.4% and 63.9%, respectively, and a specificity of 100% for GeneXpert MTB/RIF, and these results were superior to those of sputum smears, bronchial brush smears and sputum culture. GeneXpert MTB/RIF for bronchial brushings and biopsies showed complementarity in its diagnostic performance. Resistance to RIF was identified in 17.4% (8/46) of GeneXpert MTB-positive cases.. GeneXpert MTB/RIF may enable more rapid EBTB diagnosis and determination of RIF resistance, which are crucial for timely treatment.

Topics: Adult; Antibiotics, Antitubercular; Biopsy; Bronchi; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary; Young Adult

Topics: Animals; Antibiotics, Antitubercular; Bacterial Load; Clinical Trials, Phase II as Topic; Computer Simulation; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Mice; Microbial Sensitivity Tests; Models, Biological; Mycobacterium tuberculosis; Rifampin; Translational Research, Biomedical; Treatment Outcome; Tuberculosis, Pulmonary

Experience with delamanid (Dlm) is limited, particularly among HIV-positive individuals. We describe early efficacy and safety data from a programmatic setting in South Africa.This was a retrospective cohort study of patients receiving Dlm-containing treatment regimens between November 2015 and August 2017. We report 12-month interim outcomes, sputum culture conversion (SCC) by months 2 and 6, serious adverse events (SAEs) and QT intervals corrected using the Frederica formula (QTcF).Overall, 103 patients were initiated on Dlm; 79 (77%) were HIV positive. The main indication for Dlm was intolerance to second-line anti-tuberculosis (TB) drugs (n=58, 56%). There were 12 months of follow-up for 46 patients; 28 (61%) had a favourable outcome (cure, treatment completion or culture negativity). Positive cultures were found for 57 patients at Dlm initiation; 16 out of 31 (52%) had SCC within 2 months and 25 out of 31 (81%) within 6 months. There were 67 SAEs reported in 29 patients (28%). There were four instances of QTcF prolongation >500 ms in two patients (2%), leading to permanent discontinuation in one case; however, no cardiac arrhythmias occurred.This large cohort of difficult-to-treat patients receiving Dlm for rifampicin-resistant TB treatment in a programmatic setting with high HIV prevalence had favourable early treatment response and tolerated treatment well. Dlm should remain available, particularly for those who cannot be treated with conventional regimens or with limited treatment options.

Topics: Adult; Antitubercular Agents; Female; Humans; Logistic Models; Male; Nitroimidazoles; Oxazoles; Retrospective Studies; Rifampin; South Africa; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

To evaluate prevalence and patterns of drug resistance among pulmonary tuberculosis (TB) patients in Hangzhou City, China.. Sputum samples of smear positive TB patients enrolled in 2011 and 2015 were collected and tested for drug susceptibility, and demographic and medical record data were extracted from the electronic database of China Information System for Disease Control and Prevention. Chi-square test was used to compare drug resistance prevalence between new and treated patients and between male and female patients, and Chi-square test for trend was used to compare the prevalence over calendar years 2011 and 2015.. Of 1326 patients enrolled in 2015, 22.3% had resistance to any first-line anti-TB drugs and 8.0% had multi-drug resistance (MDR); drug resistance rates among previously treated cases were significantly higher than among new cases. Significant declines of resistance to isoniazid, rifampin, ethambutol and streptomycin, and MDR from 2011 to 2015 were observed among previously treated patients, while a significant decline of resistance to rifampin was observed among new cases.. While the prevalence of acquired drug resistance decreased due to due to implementation of DOTS-Plus program, the prevalence of primary drug resistance due to transmission remained high. Greater efforts should be made to screen drug resistance for case finding and to reduce transmission through improving the treatment and management of drug-resistant patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Child; China; Drug Resistance, Multiple, Bacterial; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Rifampin; Streptomycin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Unilateral hypoplasia of the lung is a rare congenital condition, the mechanism of which is poorly understood. Primary pulmonary hypoplasia occurring in an adult is extremely rare and we present what is probably the first case of a link to a tuberculous pleural effusion in a young woman after childbirth.. Herein, we describe a 31-year-old woman with left lung hypoplasia, and she not only survived to adulthood without problems, but was able to deliver a baby in natural labor.. Left lung hypoplasia, right tuberculous pleural effusion.. We initiated an anti-tuberculosis treatment for this patient with dose adjustments to her weight of isoniazid (0.3 g/day), rifampicin (0.45 g/day), pyrazinamide (1.5 g/day), and ethambutol (0.75 g/day) for 2 months then isoniazid and rifampicin for another 4 months.. Ten days later after beginning therapy, she became afebrile and the pleural effusion resolved. No recurrence was observed during a 6-month follow-up period.. In clinical practice, if one sees a chest x-ray revealing complete or incomplete opacification of a hemithorax with volume loss and history of repeated respiratory infections, one should consider the possibility of unilateral pulmonary hypoplasia. In such cases, regular close follow-up is important to minimize infections and to prevent development of cor pulmonale or respiratory failure.

Topics: Abnormalities, Multiple; Adult; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Lung; Lung Diseases; Mycobacterium tuberculosis; Parturition; Pleural Effusion; Pregnancy; Pulmonary Heart Disease; Respiratory Insufficiency; Rifampin; Tomography, X-Ray Computed; Treatment Outcome; Tuberculosis, Pleural; Tuberculosis, Pulmonary

Topics: Anaerobiosis; Antitubercular Agents; Benzodiazepines; Cell Line; Humans; Isoniazid; Mycobacterium tuberculosis; Nylons; Pyrroles; Rifampin; Tuberculosis, Pulmonary

Ulcerative skin tuberculosis (TB) is a rare form of extrapulmonary TB.. We present a case of a 65-year-old patient with perianal ulcer, which had been present for 1 year. Anamnesis revealed he had been persistently coughing for the same period of time. Histological examination of perianal skin showed necrotizing granulomatous lesions, acid-fast staining in sputum samples was ++++, TB antibody in the blood was positive, TB DNA test was positive, and chest scan that showed secondary pulmonary TB accompanied by possible pulmonary cavity formation in the 2 upper lungs.. Anti-TB therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide for 6 months. The skin ulcer completely healed after 6 months.. TB should be suspected for nonhealing ulcers. Pertinent studies should be done early during the lesion; finally, TB treatment should be initiated immediately after diagnosis is made.

Topics: Aged; Antitubercular Agents; Ethambutol; Fissure in Ano; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Sputum; Tomography, X-Ray Computed; Treatment Outcome; Tuberculosis, Cutaneous; Tuberculosis, Pulmonary

Host directed immunomodulation represents potential new adjuvant therapies in infectious diseases such as tuberculosis. Major cytokines like TNFα exert a multifold role in host control of mycobacterial infections. GM-CSF and its receptor are over-expressed during acute M. tuberculosis infection and we asked how GM-CSF neutralization might affect host response, both in immunocompetent and in immunocompromised TNFα-deficient mice. GM-CSF neutralizing antibodies, at a dose effectively preventing acute lung inflammation, did not affect M. tuberculosis bacterial burden, but increased the number of granuloma in wild-type mice. We next assessed whether GM-CSF neutralization might affect the control of M. tuberculosis by isoniazid/rifampicin chemotherapy. GM-CSF neutralization compromised the bacterial control under sub-optimal isoniazid/rifampicin treatment in TNFα-deficient mice, leading to exacerbated lung inflammation with necrotic granulomatous structures and high numbers of intracellular M. tuberculosis bacilli. In vitro, GM-CSF neutralization promoted M2 anti-inflammatory phenotype in M. bovis BCG infected macrophages, with reduced mycobactericidal NO production and higher intracellular M. bovis BCG burden. Thus, GM-CSF pathway overexpression during acute M. tuberculosis infection contributes to an efficient M1 response, and interfering with GM-CSF pathway in the course of infection may impair the host inflammatory response against M. tuberculosis.

Topics: Animals; Antibodies, Neutralizing; Antitubercular Agents; Cattle; Disease Models, Animal; Granulocyte-Macrophage Colony-Stimulating Factor; Immunologic Factors; Immunomodulation; Isoniazid; Macrophages; Mice; Mycobacterium bovis; Mycobacterium tuberculosis; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

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

Tuberculosis remains a huge public health problem and the prolonged treatment duration obstructs effective tuberculosis control. Higher rifampicin doses have been associated with better bactericidal activity, but optimal dosing is uncertain. This analysis aimed to characterize the relationship between rifampicin plasma exposure and treatment response over 6 months in a recent study investigating the potential for treatment shortening with high-dose rifampicin.. Data were analyzed from 336 patients with pulmonary tuberculosis (97 with pharmacokinetic data) treated with rifampicin doses of 10, 20, or 35 mg/kg. The response measure was time to stable sputum culture conversion (TSCC). We derived individual exposure metrics with a previously developed population pharmacokinetic model of rifampicin. TSCC was modeled using a parametric time-to-event approach, and a sequential exposure-response analysis was performed.. Higher rifampicin exposures increased the probability of early culture conversion. No maximal limit of the effect was detected within the observed range. The expected proportion of patients with stable culture conversion on liquid medium at week 8 was predicted to increase from 39% (95% confidence interval, 37%-41%) to 55% (49%-61%), with the rifampicin area under the curve increasing from 20 to 175 mg/L·h (representative for 10 and 35 mg/kg, respectively). Other predictors of TSCC were baseline bacterial load, proportion of culture results unavailable, and substitution of ethambutol for either moxifloxacin or SQ109.. Increasing rifampicin exposure shortened TSCC, and the effect did not plateau, indicating that doses >35 mg/kg could be yet more effective. Optimizing rifampicin dosage while preventing toxicity is a clinical priority.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Rifampin; South Africa; Tanzania; Time Factors; Tuberculosis, Pulmonary; Young Adult

India has the world's highest estimated burden of multi-drug-resistant tuberculosis (MDR-TB). While prevalence of MDR-TB is known to be 2-3% among new TB patients and 12-17% in previously treated patients, programmatic information on the extent of transmission of TB and MDR-TB among household contacts of known MDR-TB patients is scarce. Systematic screening of household contacts of all MDR-TB patients on treatment was implemented as an intervention in the states of Andhra Pradesh and Telangana states of India. We undertook this prospective interventional study to measure the extent of TB symptoms developed among the household contacts of the known MDR-TB patients treated under Revised National TB Control Programme (RNTCP). The extent of rifampicin sensitive or resistance TB, bacteriologically confirmed using Xpert MTB-RIF, was examined among the symptomatic household contacts.. All MDR-TB patients registered and on treatment under RNTCP between July 2011 and Sep 2013 in Andhra Pradesh and Telangana States were selected for the study. They were contacted through home visit by the trained RNTCP teams during 11th Dec 2013 and 7th Jan 2014. All household contacts of MDR-TB patients were screened once for TB symptoms such as cough, fever, weight loss, night sweats, and haemoptysis and extra pulmonary site specific symptoms if any. If found symptomatic, two sputum specimen were collected (spot-morning) from each of the contact and transported for testing on Xpert MTB-RIF for detection of pulmonary TB with or without RR-TB.. A total of 1750 MDR-TB patients were registered between July 2011 and Sep 2013. Of these, 1602 (91.5%) MDR-TB patients were included in the study. A total of 4858 household contacts of these 1602 patients were identified with an average of 3 contacts per MDR-TB patient. Of these, after excluding 87 (1.8%) contacts with past history of diagnosis and/or treatment for TB, 4771 (98.2%) contacts were screened for current signs and symptoms suggestive of TB. Their mean age was 28.5 years and 2151 (45%) were females. Of the 4771 contacts screened, 793 (16.6%) had at least one of the symptoms suggestive of TB of whom 781 (98.5%) had two sputum specimen transported and tested on Xpert MTB-Rif. Specimen could not be collected during the study period in 12 symptomatic patients including 4 with symptoms of extra pulmonary TB. Among 781 symptomatic contacts examined, 34 (4.4%) were bacteriologically confirmed with TB and 15 (44%) also had Rif resistance (RR).. High extent of TB, particularly RR-TB was observed among household contacts of known MDR-TB patients with symptom screening and early diagnosis using Xpert-MTB-Rif. Regular systematic active screening for TB and MDR-TB among this highly vulnerable group using Xpert-MTB-Rif is useful in India for early diagnosis among close contacts of known MDR-TB patients.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Child; Child, Preschool; Contact Tracing; Drug Resistance, Bacterial; Family Characteristics; Female; Humans; India; Male; Mass Screening; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Curable disease tuberculosis is becoming incurable or difficult to treat due to drug resistance. Multi drug resistance tuberculosis is a major health problem for less developed countries. Development of drug resistance is mainly as result of man related factors and poor lifestyle. Identifying predictors of drug resistance and working on them is the important way of reducing the expansion in high burden countries. Ethiopia is one of TB, TB/HIV, and multi-drug resistant tuberculosis (MDR-TB) high burden country globally. This study was aimed to assess predictor of MDR-TB in southwest part of Ethiopia.. Unmatched case control study was conducted in case to control ratio of 1:1.2 in southwest part of Ethiopia. The cases were recruited from confirmed MDR-TB patient enrolled on second line treatment in Shenen Gibe Hospital (MDR-TB treatment center of the prefecture) and the controls were recruited from previously TB patients who cured or patient with smear negative at the end of treatment month during the study period in the same area. The data was collected by structured questionnaire by interview and logistic regression analyses were used to identify predictors of MDR-TB. Odds ratios with 95% CI were computed to determine the predictors.. From the total 132 participants about 45% of them were cases. None disclosed tuberculosis infected to relatives [AOR = 3.4, 95% CI (1.2-9.8)], insufficient instruction on how to take anti-TB drug [AOR = 4.7, 95% CI (1.4-14.6)], contact history with MDR-TB [AOR = 8.5, 95% CI (2.9-25.5)], interruption of first-line anti-TB treatment for at list 1 day [AOR = 7.9, 95% CI (2.5-24.9)], and having alcohol drinking habits [AOR = 5.1, 95% CI (1.4-18.7)] were identified predictors for MDR-TB infection in study area.. TB infection disclosure status, insufficient instruction on drug usage, contact history with MDR-TB, interruption of first-line anti-TB drugs, and alcohol drinking habits were identified predictor of MDR-TB case. Therefore, early detection and proper treatment of drug susceptible TB, strengthening directly observed treatment, short-course on daily bases, community involvement, and supporting the patient to intervene identified factors is paramount.

Topics: Adolescent; Adult; Antitubercular Agents; Case-Control Studies; Child; Drug Resistance, Multiple, Bacterial; Early Diagnosis; Ethiopia; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Rifampin; Surveys and Questionnaires; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Mutations in the rpoB gene of Mycobacterium tuberculosis can result in resistance to rifampin. Among various mutations in the rpoB gene, some known as disputed rpoB mutations can cause low-level rifampin resistance. It has been suggested that a high-dose rifampin (20 mg/kg)-based regimen might be effective in treating tuberculosis (TB) caused by M. tuberculosis with disputed rpoB mutations exhibiting low-level resistance. We herein report the first two cases of pulmonary TB caused by M. tuberculosis with a disputed rpoB mutation (CTG511CCG) that showed successful treatment outcomes with a high-dose rifampin-based regimen.

Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; Dose-Response Relationship, Drug; Humans; Male; Middle Aged; Mutation; Mycobacterium tuberculosis; Radiography, Thoracic; Rifampin; Tuberculosis, Pulmonary

Cape Town, South Africa.. To model the diagnosis of rifampicin-resistant tuberculosis (RR-TB) and laboratory costs of smear/culture and Xpert-based algorithms and the effect of varying adherence and human immunodeficiency virus (HIV) testing in the Xpert-based algorithm.. We used a validated operational model (100 000 population) and published laboratory cost data. We estimated the number and cost of RR-TB cases identified using the smear/culture- and Xpert-based algorithms. We modelled varying adherence and different levels of known HIV status against the Xpert-based algorithm.. The number of RR-TB cases identified increased from 603 with smear/culture to 1178 with the Xpert-based algorithm (100% adherence; 60% knew their HIV status). The overall laboratory cost increased from US$1 073 858 to US$2 430 050 and the cost per RR-TB case identified increased from US$1781 to US$2063 in the respective algorithms. When adherence to the Xpert-based algorithm was increased from 50% to 100% (60% knew their HIV status), the number of RR-TB cases identified increased from 721 to 1178.. The Xpert-based algorithm is efficient in identifying RR-TB, as the increase in costs is offset by the increase in the number of cases identified. Adherence to the Xpert-based algorithm is important to ensure that all presumptive TB cases receive the benefit of simultaneous TB and RR-TB testing.

Topics: Algorithms; Antibiotics, Antitubercular; Costs and Cost Analysis; Diagnostic Techniques and Procedures; HIV Infections; Humans; Models, Economic; Rifampin; South Africa; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antibiotics, Antitubercular; Humans; Rifampin; Tuberculosis, Pulmonary

Timely diagnosis of drug-resistant tuberculosis (DR-TB) is beneficial for case treatment and management. We implemented an algorithm to improve molecular diagnostic utilization to intensify DR-TB case findings. The GeneXpert MTB/RIF (Xpert) test was used for initial diagnosis. Samples with Mycobacterium tuberculosis complex (MTBC)-positive and rifampicin resistance (RR) results were subsequently and simultaneously tested using the GenoType MTBDRplus (DRplus) and MTBDRsl (DRsl) tests. This prospective cohort study enrolled 2957 high-risk DR-TB cases. We tested sputum specimens using conventional mycobacteriological and molecular tests. Gene sequencing was performed to resolve discordant results. According to the Xpert test, 33.6% of specimens were MTBC-positive and 5.1% were RR. RR specimens were further analyzed in the DRplus and DRsl tests. We identified 1 extensively drug-resistant (XDR), 8 pre-XDR, 18 simple multidrug-resistant (MDR), 22 mono-RR, and 2 RR cases with concurrent second-line injection DR-TB. Of these, 25 (49%) were relapses, 13 (25.5%) were treatment failures, 10 (19.6%) were from MDR-TB high-incidence areas/countries, 1 was from MDR-TB contact and 2 were unknown. Among culture-positive TB cases, the sensitivities, specificities, and positive predictive values (PPVs) of the Xpert test and RR cases were 73.6% and 100.0%, 85.7% and 98.6%, and 73.5% and 80.0%, respectively. Gene sequencing of discordant results revealed 7 disputed rpoB mutations and 2 silent mutations for RIF, 1 ahpC mutation for isoniazid and 1 gyrA mutation for fluoroquinolone. The algorithm effectively identified approximately 23% of annual MDR-/XDR-TB and 37.5% of RR-TB cases that were enrolled in our DR-TB treatment and management program within 3 days.

Topics: Adult; Aged; Algorithms; Antitubercular Agents; Communicable Disease Control; Drug Resistance, Bacterial; Female; Fluoroquinolones; Genotype; Humans; Incidence; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Predictive Value of Tests; Prospective Studies; Rifampin; Sequence Analysis, DNA; Taiwan; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Measurement of rifampin levels is not part of routine practice. However, low levels are associated with failure of tuberculosis treatment. The clinical relevance of serum levels in daily practice is unclear. The objective was to evaluate rifampin serum concentrations and factors associated with insufficient concentrations.. Patients with at least one rifampin concentration drawn 3 hours after intake (C3) between 2005 and 2014 were included. Data on demographic and clinical characteristics were collected, including side effects and dose adjustments. Two different criteria were used to define adequate concentrations (criterion 1: C3 a nd C 6 ≥ 3 mg/l; criterion 2: C3 or C6 ≥ 5 mg/l).. Of 63 patients, 66% and 76% had a sufficient level according to criterion 1 or 2, respectively. C3 exceeded C6 in most patients, while a late maximum was significantly associated with diabetes mellitus (p = 0.003). A dose adjustment was made in 19% of cases, more frequently in patients with insufficient levels (p = 0.02) or with ≥ 2 side effects (p = 0.03).. Rifampin levels varied but were mostly adequate and a single measurement at 3 hours after intake provided the required information in most cases, indicating that full AUC0-24 measurements could be limited to specific situations.

Topics: Adolescent; Adult; Aged; Antibiotics, Antitubercular; Child; Child, Preschool; Drug Monitoring; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Retrospective Studies; Rifampin; Time Factors; Tuberculosis, Pulmonary; Young Adult

Multidrug resistant TB (MDR-TB), defined as resistance to at least rifampicin and isoniazid together, has been rapidly spreading in recent years. In new pulmonary tuberculosis patients, rapid spread of MDR-TB and XDR-TB challenging the effectiveness of national TB control programs especially in many low-income countries. This study was aimed to determine the resistance pattern of Mycobacterium tuberculosis among new cases, cured, failure, relapse, defaulted, treatment completed, treatment not evaluated and suspect to be resistant to first line antitubercular drugs of pulmonary tuberculosis (PTB).. The study was conducted during 2013-2016 in which 148 patients were enrolled infected with pulmonary TB. Three sputum samples were consecutively collected and transported for drug analysis to the Provincial Reference Laboratory (PRL) at Hayatabad Medical complex Peshawar (HMCP) TB laboratory, within three days of collection at +4°C in a cold box. Using the standard proportion method, drug susceptibility test was performed on 132 (89.2%) sputum samples for rifampicin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E), and streptomycin (S).. Prevalence of resistance to one drug was 5 (3.4%). The highest proportion of mono-drug resistance was observed against E, 3 (2%), followed by H, 1 (0.7%), and R, 1 (0.7%). Pattern of resistant to two drugs was 14 (9.5%). The proportion of poly resistant was 3 (2%). 112 (93.33%) diagnose patients were MDR-TB.. To formulate an effective regimen, it is important to know drug resistant pattern because drug resistant pattern varies from different period of time also from one place to another.

Topics: Adult; Antitubercular Agents; Ethambutol; Female; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Pakistan; Prevalence; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The Xpert® MTB/RIF assay detects Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance. RIF-resistant (RIF-R) MTB cases detected using Xpert on sputum specimens at three private-sector TB screening centres in Dhaka, Bangladesh, were subjected to consecutive confirmatory Xpert testing, the results of which were MTB-positive/RIF-susceptible, MTB-positive/RIF-indeterminate or MTB-negative.. To assess the possible causes of discordant MTB and RIF-R results.. Discordant confirmatory Xpert test results were subjected to further investigations using the GenoType® MTBDRplus assay, culture and rpoB gene sequencing.. The confirmatory Xpert test was performed on a remnant or a second specimen collected from individuals with an initial RIF-R result (n = 69); 22 (32%) results were discordant, 20 of which had an 'MTB detected-very low' result. Further investigations were mostly concordant with the confirmatory Xpert test. Average variability in paired cycle threshold (Ct) values were higher in 'MTB detected-very low' results vs. specimens with low, medium or high detected MTB results (P < 0.05); discordant results were mostly observed in specimens with 'MTB detected-very low' (20/22).. Repeating the Xpert test and comparing with other available tests should be considered in case of 'MTB detected-very low, RIF resistance detected' results on Xpert.

Topics: Antibiotics, Antitubercular; Bacterial Load; Bangladesh; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sequence Analysis, DNA; Tuberculosis, Pulmonary

The diagnosis of tuberculosis and its treatment is challenging in resource - limited settings. The growth and speed of multi drug - resistant tuberculosis (MDR-TB) in high burden countries like Nigeria is a growing concern. This study is aimed at determining the prevalence of rifampicin resistance in sputum specimens of patients with pulmonary tuberculosis in Yenagoa, Nigeria.. A descriptive survey of all consecutive sputum specimens of adults greater than 15 years of age that presented to the Tuberculosis Referral Hospital Laboratory were subjected to the automated Genexpert test between January and December 2016.. All 446 specimens were tested using the Genexpert automated system. 102 (22.9%) of the sputum specimens were positive for Mycobacterium tuberculosis, with 15 (14.7%) showing rifampicin resistance.. There was significantly high prevalence of MDR-TB much higher than the World Health Organisation (WHO) prediction of 3.2 -5.4% for Nigeria.Pan African Medical Journal - ISSN: 1937- 8688 (www.panafrican-med-journal.com)Published in partnership with the African Field Epidemiology Network (AFENET). (www.afenet.net)Pan African Medical Journal - ISSN: 1937- 8688 (www.panafrican-med-journal.com)Published in partnership with the African Field Epidemiology Network (AFENET). (www.afenet.net).

Topics: Adolescent; Adult; Antitubercular Agents; Humans; Mycobacterium tuberculosis; Nigeria; Nucleic Acid Amplification Techniques; Prevalence; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

In Cameroon, tuberculosis (TB) cases are diagnosed and treated within a nationwide network of 248 diagnostic and treatment centres. In 2016, the centers notified a total of 175 multidrug-resistant (MDR-)TB cases, most of them retreatment cases. According to the WHO, the expected number of MDR-TB cases was estimated to be 1200 (1000-2200) corresponding to a rate of 6.8 (4.3-9.4) per 100,000 population. This indicates a notification gap of more than 80%. The objective of this study was to estimate the prevalence of MDR-TB in new bacteriologically confirmed pulmonary TB cases. We undertook a nationwide cross sectional survey during 6 weeks.. During the study period, the NTP notified 1478 new bacteriologically confirmed pulmonary TB cases. Among them, 1029 (70%) had a valid Xpert result and 16 were identified with rifampicin resistant (RR-TB), a tracer of MDR-TB. This gives a prevalence of 1.6% (95% CI 0.8-2.3) among incident cases. The rate of RR-TB in the regions varied between 0 and 3.3%. If the results of this study are confirmed, the incidence rate given by WHO (2.8%, 95% CI 2.1-3.4) might be an over-estimation.

Topics: Adolescent; Antitubercular Agents; Cameroon; Cross-Sectional Studies; Female; Humans; Male; Mycobacterium tuberculosis; Rifampin; Surveys and Questionnaires; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-TB drugs remains poorly characterized. Newly diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (predose and 0.5, 2, and 6 h postdose) during the intensive and continuation phases of treatment. The effect of DM and HbA1c values on the maximum concentration (

Topics: Adult; Antitubercular Agents; Diabetes Mellitus; Female; Glycated Hemoglobin; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Rifampin; Sputum; Tuberculosis, Pulmonary; Young Adult

Tuberculosis is a major public health problem and extrapulmonary tuberculosis (EPTB) accounts for a significant proportion of tuberculosis cases worldwide.. To determine the magnitude of EPTB, associated risk factors, and agreement of diagnostic techniques at Dessie Referral Hospital.. A cross-sectional study was conducted on consecutive presumptive EPTB cases from March 1 to June 30, 2017. Sociodemographic characteristics and other variables were collected using a structured questionnaire. Clinical specimens were collected and processed using fluorescent microscopy and Gene Xpert assay. Data was analyzed using SPSS version 20. Chi-square test and logistic regression were done and a P value of ≤0.05 was taken as statistically significant.. From a total of 353 presumptive EPTB cases the overall prevalence of Gene Xpert assay and smear confirmed patients was 8.8% and 2.5%, respectively. Tuberculosis lymphadenitis was the predominant (33.3%) type followed by pleural (11.9%) and peritoneal (6.7%) tuberculosis. Previous history of pulmonary tuberculosis was significantly associated with extrapulmonary infection (AOR:2.8; 95%CI: 1.05-7.54; p=0.04); however, other variables such as age, residence, sex, marital status, occupation, level of education, and monthly income did not show any association.. High proportions (71%) of Gene Xpert assay confirmed EPTB patients were smear-negative. Sensitivity of microscopy should be enhanced in resource limited countries like Ethiopia where Gene Xpert machine is not easily accessible.

Topics: Adolescent; Adult; Cross-Sectional Studies; Ethiopia; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Referral and Consultation; Rifampin; Risk Factors; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary; Young Adult

Tuberculosis (TB) treatment is often carried out empirically, based on clinical and radiological findings. Chest X-ray (CXR) has good sensitivity but poor specificity in TB diagnosis. Xpert MTB/RIF (Mycobacterium tuberculosis/Rifampicin) is increasingly used in many countries as the initial diagnostic test for TB. The aim of the present study was to evaluate the association of radiological findings with the Xpert MTB/RIF test in patients with suspected pulmonary TB.. Cross-sectional study in an outpatient TB clinic. Sputum AFB smear, culture, Xpert MTB/RIF, and CXR were collected in patients with suspected pulmonary TB.. During the study period, 312 patients met the inclusion criteria and were included in the analysis. Among Xpert MTB/RIF-positive cases, the radiographic patterns were classified as typical of TB, compatible of TB, and normal in 78 (70.3%), 31 (27.9%), and 2 (1.8%) patients, respectively. CXRs were classified as typical of TB, compatible of TB, and normal in 20 (10.0%), 25 (12.4%), and 152 (75.6%) patients, respectively, in Xpert MTB/RIF-negative cases.. We found an association between radiographic patterns and Xpert MTB/RIF results in patients with suspected pulmonary TB. These results confirm the current recommended diagnosis algorithm.

Topics: Adult; Aged; Antibiotics, Antitubercular; Cross-Sectional Studies; DNA, Bacterial; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Predictive Value of Tests; Radiography, Thoracic; Rifampin; Sputum; Tuberculosis, Pulmonary

The Xpert MTB/RIF (Xpert) assay technology allows rapid and sensitive diagnosis of pulmonary tuberculosis (PTB) from sputum specimens. However, diagnosis of PTB is difficult for patients who cannot produce sputum. The objective of this study was to investigate the use of Xpert assay for successful detection of PTB using stool samples from adult subjects.. Both stool and sputum samples from known smear and Xpert positive PTB patients were collected from a TB hospital in Dhaka. Stool samples were collected from healthy individuals without TB symptoms from a slum area of Dhaka. Stool and sputum samples were decontaminated and concentrated using NALC-NaOH-Na-citrate solution and the resultant sediment was used for Xpert, acid-fast bacilli (AFB) microscopy and culture.. A total of 102 stool samples were collected from PTB patients and another 50 stool samples from healthy individuals without TB. The sensitivity of the Xpert assay for detection of M. tuberculosis in stool samples of PTB patients was 90.2% (95% CI, 82.9-95.0). All 50 stool samples from healthy individuals were negative by the assay (Specificity 100%; 95% CI, 92.9-100). Compared with the sputum culture positive results the sensitivity of the stool Xpert assay was 94.8% (95% CI, 88.5-97.8). Moreover, stool Xpert demonstrated full concordant results with the sputum culture for detection of rifampicin susceptibility. The cycle threshold values of rpoB probes obtained from Xpert assay correlated significantly with the bacilli load in the corresponding stool (Spearman correlation = -0.40, P < 0.01) and sputum (Spearman correlation = -0.77, P < 0.01) samples as determined by microscopy.. Stool Xpert can be applied as a potential alternative of sputum testing for detection of M. tuberculosis and accurate determination of RIF susceptibility in adult PTB patients. The assay would be beneficial for rapid diagnosis of PTB for those adult patients who cannot expectorate sputum.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Bacteriological Techniques; Feces; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Specimen Handling; Sputum; Tuberculosis, Pulmonary; Young Adult

Topics: Adult; Antitubercular Agents; Belgium; Biopsy; Child, Preschool; Diagnosis, Differential; Drug Therapy, Combination; Female; Humans; Interferon-gamma Release Tests; Isoniazid; Male; Rifampin; Tuberculin Test; Tuberculosis, Ocular; Tuberculosis, Pulmonary

New therapeutic strategies are needed to treat drug resistant tuberculosis (TB) and to improve treatment for drug sensitive TB. Pyrazinamide (PZA) is a critical component of current first-line TB therapy. However, the rise in PZA-resistant TB cases jeopardizes the future utility of PZA. To address this problem, we used the guinea pig model of TB and tested the efficacy of an inhaled dry powder combination, referred to as Pyrazinoic acid/ester Dry Powder (PDP), which is comprised of pyrazinoic acid (POA), the active moiety of PZA, and pyrazinoic acid ester (PAE), which is a PZA analog. Both POA and PAE have the advantage of being able to act on PZA-resistant Mycobacterium tuberculosis. When used in combination with oral rifampicin (R), inhaled PDP had striking effects on tissue pathology. Effects were observed in lungs, the site of delivery, but also in the spleen and liver indicating both local and systemic effects of inhaled PDP. Tissue granulomas that harbor M. tuberculosis in a persistent state are a hallmark of TB and they pose a challenge for therapy. Compared to other treatments, which preferentially cleared non-necrotic granulomas, R+PDP reduced necrotic granulomas more effectively. The increased ability of R+PDP to act on more recalcitrant necrotic granulomas suggests a novel mechanism of action. The results presented in this report reveal the potential for developing therapies involving POA that are optimized to target necrotic as well as non-necrotic granulomas as a means of achieving more complete sterilization of M. tuberculosis bacilli and preventing disease relapse when therapy ends.

Topics: Aerosols; Animals; Antitubercular Agents; Bacterial Load; Disease Models, Animal; Drug Therapy, Combination; Dry Powder Inhalers; Granuloma, Respiratory Tract; Guinea Pigs; Male; Mycobacterium tuberculosis; Necrosis; Pyrazinamide; Respiratory Tract Absorption; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Recent reports indicate that the sputum of 80% or more of treatment-naive subjects with tuberculosis recruited in England or South Africa contained more viable

Topics: Adult; Antitubercular Agents; Colony Count, Microbial; Drug Therapy, Combination; Female; Haiti; Humans; Isoniazid; Male; Microbiological Techniques; Mycobacterium tuberculosis; Pyrazinamide; Randomized Controlled Trials as Topic; Rifampin; Sputum; Tuberculosis, Pulmonary; Young Adult

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

Topics: Antitubercular Agents; DNA, Bacterial; Drug Resistance, Bacterial; Fatty Acid Synthesis Inhibitors; Genotyping Techniques; Humans; Isoniazid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Transition Temperature; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Automation, Laboratory; China; Cross-Sectional Studies; Culture Media; Drug Resistance, Bacterial; Female; Hospitals; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Predictive Value of Tests; Quality Control; Reagent Kits, Diagnostic; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Rifampin; Sputum; Tuberculosis, Pulmonary

Current treatment therapeutic approach for tuberculosis is the administration of first line drugs in the form of tablets and capsules for 4-6 months. However, this approach leads to severe adverse effects. Therefore, present study was designed to achieving local and sustained targeting of anti-tubercular drugs in order to reduce dose and frequency. The nanoparticle based dry powder formulation of rifampicin was developed and analyzed with respect to its direct targeting potential of lungs. Rifampicin loaded nanoparticles were formulated by ionic gelation probe sonication method, and characterized with respect to particle size, zeta potential, entrapment and drug loading efficiency. The range of size and entrapment efficiency of prepared nanoparticles was estimated from 124.1±0.2 to 402.3±2.8nm and 72.00±0.1%, respectively. The freeze-dried powder of nanoparticle formulation was used to carry out in vitro lung deposition studies through Andersen cascade impactor. The cumulative in vitro drug release studies with developed nanoparticle formulation showed sustained release up to 24h. Our in vitro sustained drug release results were corroborated by the extended residence and slow clearance of rifampicin from the lungs. Furthermore, our results suggest the minimum lung distribution of drug in treated rats which confirms the negligible toxicity rendered by nanoparticle dry powder formulation. Moreover, pharmacokinetic and toxicity studies carried out with prepared NPs dry powder inhalation (DPI) formulations and compared with conventional DPI.

Topics: Administration, Inhalation; Animals; Antitubercular Agents; Cell Line; Chitosan; Delayed-Action Preparations; Drug Liberation; Dry Powder Inhalers; Freeze Drying; Half-Life; Lung; Macrophages, Alveolar; Male; Mice; Nanoparticles; Particle Size; Powders; Rats; Rats, Wistar; Rifampin; Tuberculosis, Pulmonary

Antituberculosis drug-induced hepatotoxicity (ATDH) remains a common and severe challenge in tuberculosis (TB) chemotherapy. A growing number of studies have revealed that genetic polymorphisms affect an individual's susceptibility to ATDH. The aim of this study was to explore the role of cytochrome P450 family 2 subfamily B member 6 (CYP2B6) gene polymorphisms in the development of ATDH in Chinese TB patients.. CYP2B6*6 genotypes were determined in TB patients with and without ATDH. Association between polymorphisms and risk of ATDH was estimated by multiple logistic regression analysis.. A total of 343 eligible TB patients (166 with ATDH; 177 without ATDH) were included in this study. Analysis of all subjects revealed no statistical differences in genotype distribution between the two groups. However, the CYP2B6 *6/*6 genotype was significantly associated with decreased risk of ATDH in the male subgroup (P=0.039, OR=0.097, 95% CI: 0.011-0.885). Furthermore, in male patients, the presence of the CYP2B6*6 allele was significantly higher in the non-ATDH group compared with the ATDH group (26.2% vs. 15.5%, P=0.020, OR=0.522, 95% CI: 0.301-0.903).. This study is the first to demonstrate an association between CYP2B6 polymorphisms and the risk of ATDH in the Chinese population. We have shown that males who have the CYP2B6 *6/*6 genotype may be less susceptible to the development of ATDH. Further studies are required to confirm this genetic association result.

Topics: Adult; Alleles; Antitubercular Agents; Asian People; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP2B6; Ethambutol; Female; Gene Expression; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Polymorphism, Single Nucleotide; Prospective Studies; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

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

In this study, we aimed to design controlled-release microspheres for the treatment of cavitary pulmonary tuberculosis (TB) for solving the issues of poor drug delivery and short duration maintained at effective drug concentration during bronchoscopic interventional therapy. We fabricated rifapentine-linezolid-loaded poly(lactic acid-co-glycolic acid) microspheres (RLPMs) using the oil-in-water emulsion solvent evaporation method and assessed their in vitro release as well as the bronchial mucosal retention characteristics. The microspheres are spherical in shape with a circular concave on the surface. The particle size of RLPMs was 27.38±1.28 μm. The drug loading of rifapentine and linezolid was 18.51±0.26 and 8.42%±0.24%, respectively, while the encapsulation efficiencies were 55.53±0.78 and 16.87%±0.47%, respectively (n=3). During the burst release phase of the in vitro release test, 21.37%±0.68% rifapentine was released in 3 days and 43.56%±2.54% linezolid was released in 1 day. Then, both the drugs entered the sustained release phase. Finally, the cumulative percentage release of rifapentine and linezolid in 14 days was 27.61±1.52 and 51.01%±3.31%, respectively (n=3). Bronchoscopic observation revealed that the controlled-release microspheres could slowly release the drugs and retain them on the surface of bronchial mucosa of canines for 20 days. These results indicated that the fabricated microspheres exhibited a significant sustained release effect and could effectively retain the drugs on the surface of bronchial mucosa. Therefore, this study provides a theoretical and practical foundation for the development of fabricated microspheres loaded with multiple anti-TB drugs in the bronchoscopic interventional therapy of cavity pulmonary TB.

Topics: Animals; Bronchoscopy; Dogs; Female; Lactic Acid; Linezolid; Microspheres; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rifampin; Surface Properties; Tuberculosis, Pulmonary

Tuberculosis (TB) is a serious public health problem in developing countries such as Pakistan. Rapid diagnosis of TB and detection of drug resistance are very important for timely and appropriate management of multidrug-resistant TB (MDR-TB).. The purpose of this study was to determine the diagnostic efficacy of the Xpert MTB/RIF assay for rapid diagnosis of TB and detection of rifampicin (RIF) resistance in extrapulmonary and smear-negative pulmonary TB suspects.. A total of 98 bronchoalveolar lavage fluid (BALF) and 168 extrapulmonary specimens were processed by Xpert MTB/RIF. Culture results are considered as the gold standard for diagnosis of TB, and drug susceptibility testing for detection of RIF resistance. Diagnostic efficacy was measured in terms of sensitivity, specificity and positive and negative predictive values.. The Xpert MTB/RIF assay detected 40 (40.8 %) of 98 BALF of presumptive pulmonary TB and 60 (35.7 %) of 168 extrapulmonary specimens. Sensitivity and specificity of the Xpert MTB/RIF assay for detection of TB was 86 and 88.4 %, respectively. The positive predictive value was 71.5 % while negative predictive value was 95.1 %.. The Xpert MTB/RIF assay is a rapid and simple technique with high sensitivity and specificity for diagnosing TB and detecting drug resistance in extrapulmonary and smear-negative TB cases.

Topics: Bronchoalveolar Lavage Fluid; Drug Resistance, Multiple, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pakistan; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Simultaneous use of genotypic and phenotypic diagnostic tools for detection of rifampicin (RIF) susceptibility may yield discrepant results.. To measure the discordance between the RIF-susceptibility results by Xpert MTB/RIF and Mycobacterium Growth Indicator Tube (MGIT), to evaluate if application of both tests to the same sample affects the discrepancy, and to evaluate treatment outcome in patients with the discordant strains.. Sputa from patients with tuberculosis managed in the penitentiary system of Azerbaijan during 2011-2015 were examined for RIF susceptibility using Xpert MTB/RIF and MGIT. Strains with discrepant results were sequenced.. Of 532 patients included, 6.2% had discordant RIF-susceptibility results. No significant association of the discordant RIF-susceptibility results with application of both tests on one sample versus sequential samples was found. L511P mutation accounted significantly (p = 0.006) for the discrepancy among those RIF resistant on Xpert MTB/RIF, but sensitive on MGIT. No significant association was identified between the outcomes of treatment with the first- or second-line drugs and the presence of any mutation.. The Xpert MTB/RIF and MGIT testing may be used in sequential sputum samples without increase in the RIF-susceptibility discordance rate. L511P mutation significantly accounts for discordant RIF-susceptibility results, but its clinical relevance may be low.

Topics: Anti-Bacterial Agents; Azerbaijan; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the

Topics: Adult; Antibiotics, Antitubercular; Antitubercular Agents; Carboxylic Ester Hydrolases; Genotype; Humans; Liver-Specific Organic Anion Transporter 1; Malawi; Polymorphism, Single Nucleotide; Rifampin; South Africa; Tuberculosis, Pulmonary; Uganda

Rifampicin is the key drug responsible for sterilizing activities in the first-line TB treatment regimen. Damage to the gut during acute and chronic HIV infection may inhibit drug absorptive capacity. We sought to test the hypothesis that markers of intestinal damage, bacterial translocation and systemic immune activation would relate to rifampicin bioavailability among HIV/TB patients.. We conducted a prospective cohort study of rifampicin pharmacokinetics in HIV/TB patients in Gaborone, Botswana. We performed two intensively sampled pharmacokinetic visits, before and after ART initiation. Non-linear mixed-effects modelling was performed to determine whether variability in markers of gut damage, microbial translocation or systemic immune activation contributed to variability in rifampicin bioavailability before and after the initiation of ART.. We enrolled 40 HIV/TB patients in the first pharmacokinetic visit and 24 patients returned for the second pharmacokinetic visit after initiating ART. Low rifampicin exposure, as defined by the maximum serum concentration, was observed in 40% of patients prior to initiating ART and 46% of patients after initiating ART. In the non-linear mixed-effects model, we did not observe significant covariate effects of markers of gut damage, microbial translocation or immune activation on rifampicin bioavailability before and after ART initiation.. Markers of intestinal damage, microbial translocation and systemic immune activation did not explain variability in rifampicin bioavailability. The a priori identification of HIV/TB patients at risk for low rifampicin concentrations remains a challenge, supporting a role for therapeutic drug monitoring during HIV/TB therapy.

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Bacterial Translocation; Biological Availability; Biomarkers; Cohort Studies; Female; Gastrointestinal Tract; HIV Infections; Humans; Male; Middle Aged; Prospective Studies; Rifampin; Tuberculosis, Pulmonary

Delayed diagnosis of tuberculosis (TB) and drug-resistant TB are major challenges of TB control in Thailand. This study assessed the practicality of the Xpert MTB/RIF assay in a real-life setting with high prevalence of human immunodeficiency virus (HIV) infection and pulmonary tuberculosis (PTB).. This prospective study was conducted at 3 large tertiary care hospitals. Patients who had suspected PTB were enrolled into the study. Expectorated sputum samples were sent for staining, mycobacterial culture, and Xpert MTB/RIF.. Four hundred ninety-four patients were enrolled. From 355 cases with final diagnosis of PTB, 263 (71.8%) had definite diagnosis and 92 cases had probable diagnosis. Among TB culture-positive cases, Xpert MTB/RIF had 100% and 81% sensitivity in sputum smear-positive and smear-negative groups, respectively. The specificity was 95.7%. The sensitivity and positive predictive value of Xpert MTB/RIF in culture-negative but clinically diagnosed PTB was 37.8% and 83.8%, respectively. Centrifugation was required in 59% cases with scanty sputum. Five cases were false-positive by Xpert MTB/RIF in patients with nontuberculous mycobacteria, old PTB scar, and immune reconstitution syndrome. Discordant rifampicin susceptibility results of Xpert MTB/RIF and mycobacteria growth indicator tube (MGIT) were confirmed by using rpoB gene sequencing, which raised the sensitivity of Xpert MTB/RIF in detecting rifampicin resistance to 93.8%.. Xpert MTB/RIF is an effective tool in diagnosing PTB but will be more cost-effective for sputum-negative patients and in settings with high prevalence of rifampicin resistance. Early diagnosis of TB results in early treatment and implementation of strategies to limit spreading of TB. Sputum centrifugation may increase the yield of Xpert MTB/RIF.

Topics: Adult; Bacterial Proteins; Coinfection; Delayed Diagnosis; DNA-Directed RNA Polymerases; Female; HIV Infections; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Prevalence; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tertiary Care Centers; Thailand; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Drug-resistant tuberculosis (TB) is an emerging health problem. Rifampicin (RIF) is the major first-line drug against TB. RIF resistance can be used as a marker for the detection of multidrug-resistant TB (MDR-TB). The purpose of this study was to determine the RIF resistance pattern of Mycobacterium tuberculosis complex isolates among treated and untreated patients in Khyber Pakhtunkhwa, Pakistan.. A total of 349 drug-treated and untreated TB-diagnosed patients were enrolled in this study. RIF resistance was detected using a GeneXpert. The overall prevalence of RIF resistance was 5.2% (18/349). Among 49 untreated TB patients, 3 samples (6.1%) were found resistant to RIF. Among 235 patients with a category 1 treatment regimen, 10 samples (4.3%) were resistant to RIF, whilst among 65 patients with a category 2 (Cat-2) treatment regimen, 5 samples (7.7%) were resistant to RIF. A comparison based on patient sex revealed high RIF resistance among male compared with female patients. RIF resistance was highest (4/21; 19.0%) in the 21-40 years age group among Cat-2 patients.. The overall prevalence of RIF resistance was high among treated and untreated TB patients. These findings will be helpful for better monitoring and management of RIF resistance in TB patients from Khyber Pakhtunkhwa, Pakistan.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Genotyping Techniques; Humans; Infant; Infant, Newborn; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pakistan; Prevalence; Rifampin; RNA Polymerase II; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

The delivery of antitubercular drugs through direct lung targeting can lead to reduction in the dose as well as side effects of the drug. In the present investigation, carrier (lactose)-based dry-powder inhaler of rifampicin was prepared to achieve direct targeting of the drug into the lungs.. The dry powder inhaler formulation was prepared by simply mixing micronized rifampicin with coarse and fine lactose preblend. Preliminary blends of the drug were prepared with various lactose grades (Inhalac. Based on preliminary trials, Inhalac 230 and Inhalac 400 were selected as coarse and fine lactose grades, respectively. Rotahaler. The carrier-mediated dry-powder inhaler of rifampicin could serve as an improved and efficient system for local targeting of drugs into the lungs.

Topics: Administration, Inhalation; Animals; Antibiotics, Antitubercular; Cell Line; Cell Survival; Chemistry, Pharmaceutical; Drug Delivery Systems; Dry Powder Inhalers; Lactose; Lung; Macrophages; Macrophages, Alveolar; Male; Mice; Rats; Rats, Wistar; Rifampin; Time Factors; Tissue Distribution; Tuberculosis, Pulmonary

Preliminary preclinical and observational studies suggest the potential utility of metformin as an adjunctive, host-directed agent for treatment of tuberculosis (TB). In this study, we sought to investigate the bactericidal and sterilizing activities of human-like exposures of metformin when given in combination with the first-line regimen against chronic tuberculosis in BALB/c mice. Mice receiving metformin adjunctive therapy had similar lung bacillary burdens with control mice during treatment, and the proportion of mice with microbiological relapse was similar between the two groups.

Topics: Animals; Antitubercular Agents; Bacterial Load; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Isoniazid; Lung; Metformin; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Rifampin; Tuberculosis, Pulmonary

Drug-resistant tuberculosis, especially multidrug-resistant tuberculosis (MDR-TB), is a major public health problem. Effective management of MDR-TB relies on accurate and rapid diagnosis. In this study, we assessed the diagnostic accuracy of the Genotype MTBDRplus assay in diagnosing MDR-TB in Cameroon, and then discuss on its utility within the diagnostic algorithm for MDR-TB.. In this cross-sectional study, 225 isolates of Mycobacterium tuberculosis cultured from sputum samples collected from new and previously treated pulmonary tuberculosis patients in Cameroon were used to determine the accuracy of the Genotype MTBDRplus assay. We compared the results of the Genotype MTBDRplus assay with those from the automated liquid culture BACTEC MGIT 960 SIRE system for sensitivity, specificity, and degree of agreement. The pattern of mutations associated with resistance to RIF and INH were also analyzed.. The Genotype MTBDRplus assay correctly identified Rifampicin (RIF) resistance in 48/49 isolates (sensitivity, 98% [CI, 89%-100%]), Isoniazid (INH) resistance in 55/60 isolates (sensitivity 92% [CI, 82%-96%]), and MDR-TB in 46/49 (sensitivity, 94% [CI, 83%-98%]). The specificity for the detection of RIF-resistant and MDR-TB cases was 100% (CI, 98%-100%), while that of INH resistance was 99% (CI, 97%-100%). The agreement between the two tests for the detection of MDR-TB was very good (Kappa = 0.96 [CI, 0.92-1.00]). Among the 3 missed MDR-TB cases, the Genotype MTBDRplus assay classified two samples as RIF-monoresistant and one as INH monoresistant. The most frequent mutations detected by the Genotype MTBDRplus assay was the rpoB S531 L MUT3 41/49 (84%) in RIF-resistant isolates, and the KatG S315 T1 (MUT1) 35/55 (64%) and inhA C15T (MUT1) 20/55 (36%) mutations in INH-resistant isolates.. The Genotype MTBDRplus assay had good accuracy and could be used for the diagnosis of MDR-TB in Cameroon. For routine MDR-TB diagnosis, this assay could be used for Mycobacterium tuberculosis cultures containing contaminants, to complement culture-based drug susceptibility testing or to determine drug resistant mutations.

Topics: Adult; Antitubercular Agents; Bacterial Proteins; Cameroon; Cross-Sectional Studies; Female; Genotype; Genotyping Techniques; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Molecular Diagnostic Techniques; Mutation; Mutation Rate; Mycobacterium tuberculosis; Oxidoreductases; Rifampin; Sensitivity and Specificity; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Poncet's disease is a rare reactive polyarthritis associated with active tuberculosis and no evidence of Mycobacterium tuberculosis in the affected joint.. We report a case of a 35 year old Human Immunodeficiency Virus positive Kenyan male of Kikuyu ethnicity from Kiambu County who presented to hospital with a 6 day history of bilateral knee pain and swelling, bilateral ankle pain with right ankle swelling. The patient reported 6 months history of cough and weight loss. Chest radiograph had features consistent with pulmonary tuberculosis and sputum smear was positive for acid fast bacilli. Analysis of fluid from knee effusion showed no evidence of tuberculosis. Resolution of joint swelling was seen after 3 weeks of tuberculosis chemotherapy suggesting that this was reactive arthritis following pulmonary tuberculosis in a patient infected with human immunodeficiency virus.. This case represents a rare manifestation of tuberculosis presenting as a reactive arthritis. There are very few cases of Poncet's disease reported in literature and the diagnosis of Poncet's disease in Human Immunodeficiency Virus/tuberculosis coinfected patient is extremely uncommon. This case report has been presented to raise awareness of this unusual tuberculosis complication and review its diagnosis and treatment.

Topics: Adult; Antibiotics, Antitubercular; Antiretroviral Therapy, Highly Active; Arthritis, Reactive; Ethambutol; HIV Infections; Humans; Isoniazid; Male; Pyrazinamide; Rifampin; Tomography, X-Ray Computed; Tuberculosis, Pulmonary

Pyrazinamide is used in the treatment of tuberculosis (TB) because its sterilizing effect against tubercle bacilli allows the shortening of treatment. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). Pyrazinamide pharmacokinetic (PK) data from 61 HIV/TB-coinfected patients in South Africa were used in the analysis. The patients were administered weight-adjusted doses of pyrazinamide, rifampin, isoniazid, and ethambutol in fixed-dose combination tablets according to WHO guidelines and underwent intensive PK sampling on days 1, 8, 15, and 29. The data were interpreted using nonlinear mixed-effects modeling. PK profiles were best described using a one-compartment model with first-order elimination. Allometric scaling was applied to disposition parameters using fat-free mass. Clearance increased by 14% from the 1st day to the 29th day of treatment. More than 50% of patients with weight less than 55 kg achieved lower pyrazinamide exposures at steady state than the targeted area under the concentration-time curve from 0 to 24 h of 363 mg · h/liter. Among patients with drug-susceptible TB, adding 400 mg to the dose for those weighing 30 to 54 kg improved exposure. Average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1,500 mg, 1,750 mg, and 2,000 mg to patients in the 33- to 50-kg, 51- to 70-kg, and greater than 70-kg weight bands, respectively.

Topics: Adolescent; Adult; Antitubercular Agents; Coinfection; Drug Combinations; Ethambutol; HIV Infections; Humans; Isoniazid; Male; Metabolic Clearance Rate; Middle Aged; Pyrazinamide; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

The aim of the study is to compare counting of colony forming units (CFU), the time to positivity (TTP) assay and the molecular bacterial load (MBL) assay, and explore whether the last assays can detect a subpopulation which is unable to grown on solid media. CFU counting, TTP and the MBL assay were used to determine the mycobacterial load in matched lung samples of a murine tuberculosis model. Mice were treated for 24 weeks with 4 treatment arms: isoniazid (H) - rifampicin (R) - pyrazinamide (Z), HRZ-Streptomycin (S), HRZ - ethambutol (E) or ZES. Inverse relationships were observed when comparing TPP with CFU or MBL. Positive associations were observed when comparing CFU with MBL. Description of the net elimination of bacteria was performed for CFU vs. time, MBL vs. time and 1/TTP vs. time and fitted by nonlinear regression. CFU vs. time and 1/TTP vs. time showed bi-phasic declines with the exception of HRZE. A similar rank order, based on the alpha slope, was found comparing CFU vs. time and TTP vs. time, respectively HRZE, HRZ, HRZS and ZES. In contrast, MBL vs. time showed a mono-phasic decline with a flat gradient of elimination and a different rank order respectively, ZES, HRZ, HRZE and HRZS. The correlations found between methods reflects the ability of each to discern the general mycobacterial load. Based on the description of net elimination, we conclude that the MBL assay can detect a subpopulation of Mycobacterium tuberculosis which is not detected by the CFU or TTP assays.

Topics: Animals; Antitubercular Agents; Bacterial Load; Colony Count, Microbial; Disease Models, Animal; DNA, Bacterial; Ethambutol; Female; Isoniazid; Lung; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nonlinear Dynamics; Predictive Value of Tests; Pyrazinamide; Ribotyping; Rifampin; RNA, Ribosomal, 16S; Streptomycin; Time Factors; Tuberculosis, Pulmonary

Shortening the standard 6-month treatment for drug-susceptible pulmonary tuberculosis (DS-PTB) would be a major improvement for TB case management and disease control.. We are conducting a randomized, open-label, controlled, non-inferiority trial involving patients with smear-positive, newly diagnosed DS-PTB cases nationwide to assess the efficacy and safety of two 4.5- month regimens in comparison to the standard 6-month WHO recommended regimen. The regimen used in one experiment group is a 4.5-month fluoroquinolone-containing regimen, which consists of full course of levofloxacin, isoniazid (H), rifampin (R), parazinamid (Z) and ethambutol (E). Regimen used in the second experiment group includes 4.5-month full course of H, R, Z, E with levofloxacin removed. Patients in the control group, receive H, R, Z and E for 2 months, followed by 4 months of H and R. The primary endpoint is treatment failure or relapse within 24 month after treatment completion.. Results from this trial along with other studies will contribute to the science of constructing a shorter, effective and safe regiment for TB patients.. The protocol has been registered on ClinicalTrials.gov on 2 September,2016 with identifier NCT02901288 .

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Levofloxacin; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Effective treatment of Mycobacterium tuberculosis (Mtb) infection requires at least 6 months of daily therapy with multiple orally administered antibiotics. Although this drug regimen is administered annually to millions worldwide, the impact of such intensive antimicrobial treatment on the host microbiome has never been formally investigated. Here, we characterized the longitudinal outcome of conventional isoniazid-rifampin-pyrazinamide (HRZ) TB drug administration on the diversity and composition of the intestinal microbiota in Mtb-infected mice by means of 16S rRNA sequencing. We also investigated the effects of each of the individual antibiotics alone and in different combinations.. While inducing only a transient decrease in microbial diversity, HRZ treatment triggered a marked, immediate and reproducible alteration in community structure that persisted for the entire course of therapy and for at least 3 months following its cessation. Members of order Clostridiales were among the taxa that decreased in relative frequencies during treatment and family Porphyromonadaceae significantly increased post treatment. Experiments comparing monotherapy and different combination therapies identified rifampin as the major driver of the observed alterations induced by the HRZ cocktail but also revealed unexpected effects of isoniazid and pyrazinamide in certain drug pairings.. This report provides the first detailed analysis of the longitudinal changes in the intestinal microbiota due to anti-tuberculosis therapy. Importantly, many of the affected taxa have been previously shown in other systems to be associated with modifications in immunologic function. Together, our findings reveal that the antibiotics used in conventional TB treatment induce a distinct and long lasting dysbiosis. In addition, they establish a murine model for studying the potential impact of this dysbiosis on host resistance and physiology.

Topics: Animals; Antitubercular Agents; Clostridiales; Drug Combinations; Dysbiosis; Gastrointestinal Microbiome; Intestines; Isoniazid; Mice; Mycobacterium tuberculosis; Porphyromonas; Pyrazinamide; Rifampin; RNA, Ribosomal, 16S; Tuberculosis, Pulmonary

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

Upon diagnosis, Pulmonary Tuberculosis patients are treated for TB for a period of 6-9 months. At present, there exists very little indication of the efficacy of the particular treatment. A few previous studies have shown that soluble urokinase plasminogen activator receptor (SuPAR) may be used as treatment efficacy marker. SuPAR is a cellular receptor for serine protease urokinase plasminogen activator (uPA). Bacterial endotoxins and cytokines of the innate immune system stimulate the secretion of uPA in monocytes & neutrophils. Serum SuPAR levels are elevated when TB is active and decrease when the patient responds positively to therapy.. To investigate if SuPAR levels decline upon treatment and whether serum SuPAR levels may be used as a biomarker to monitor Tuberculosis treatment efficacy.. The study was conducted in the department of Biochemistry at VIMS, Ballari, Karnataka. The study subjects were randomly selected from RNTCP centre of VIMS.. Twelve tuberculin skin test positive healthy controls from the community.. A total of 60 cases were enrolled for the study and were divided into 3 groups with 20 in each, based on the duration of TB treatment. Group I (n=20): Newly diagnosed pulmonary TB patients before initiation of DOTS. Group II (n=20): TB patients, 2-3 months after initiation of DOTS. Group III (n=20): TB patients who had completed 6 months of DOTS.. Hb%, TC, DC(P)%, DC(L)% & ESR were measured by standard procedures. Serum suPAR was measured by the quantitative sandwich enzyme immunoassay technique using the R & D systems Human uPAR Quantikine ELISA Kit.. The suPAR levels were elevated before treatment (3.27+2.08ng/ml) and dropped significantly in groups after 2 months of initiation of therapy (2.18+1.17ng/ml) and after completion of 6 months of treatment (1.50+0.93ng/ml).. The decrease in suPAR levels in PTB patients with treatment is a manifestation of treatment efficacy. Hence suPAR levels can be used to guide clinical decisions in TB management.

Topics: Adult; Aged; Antitubercular Agents; Biomarkers; Drug Monitoring; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Receptors, Urokinase Plasminogen Activator; Rifampin; Tuberculosis, Pulmonary; Young Adult

The GenoType MTBDRplus, a commercial Line Probe Assay (LPA) kit from Hain Lifescience, Germany, is endorsed by India's RNTCP Program for diagnosis of DRTB cases among smear-positive sputum samples. Although the LPA has been studied in several laboratories, there is a wide variation in existing M. tuberculosis strains across the globe, and false results can occur due to the presence of unique genetic mutations in different settings.. An attempt was made to carry out band pattern analysis using LPA and also to observe uncommon mutations in MDR strains.. Sputum samples were collected from MDR suspects and transported to intermediate reference laboratory (IRL) at New Delhi Tuberculosis Centre in Delhi. Sputum decontamination, DNA extraction, amplification, hybridization, and band pattern analysis of Line Probe assay strips was performed as per manufacturer's instructions.. Among the 3000 samples with interpretable LPA strips, rifampicin drug resistance with or without isoniazid was observed in 600 samples. The most common mutation detected by LPA in the rpoB gene was Ser516Leu (29.0%). Novel mutations reported in this study include mutation from CAG (Gin) to CAT (His) at codon 517, AGC (Ser)-AGG (Arg) at codon 512, ACA (Thr) to GCA (Ala) at codon 526, TTG (Leu)-CTG (Leu). High frequencies of uncommon mutations in rpoB gene by LPA were observed, highlighting possibility of those in-silico detected mutations that may not impart phenotypic resistance further.

Topics: Antibiotics, Antitubercular; Bacterial Proteins; DNA-Directed RNA Polymerases; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Ethambutol; Humans; India; Isoniazid; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Rifampin; Sputum; Streptomycin; Tuberculosis, Pulmonary

Resistance to second-line tuberculosis drugs is common, but slow to diagnose with phenotypic drug sensitivity testing. Rapid molecular tests speed up diagnosis, but can only detect limited mutations. Whole genome sequencing (WGS) of culture isolates can generate a complete genetic drug resistance profile, but is delayed by the initial culture step. In the case presented here, successful WGS directly from sputum was achieved using targeted enrichment.. A 29-year-old Nigerian woman was diagnosed with tuberculosis. Xpert MTB/RIF and Hain line probe assays identified rpoB and inhA mutations consistent with rifampicin and intermediate isoniazid resistance, and a further possible mutation conferring fluoroquinolone resistance. WGS directly from sputum identified a further inhA mutation consistent with high-level isoniazid resistance and confirmed the absence of fluoroquinolone resistance. Isoniazid was stopped, and the patient has completed 18 months of a fluoroquinolone-based regimen without relapse.. Compared to rapid molecular tests (which can only examine a limited number of mutations) and WGS of culture isolates (which requires a culture step), WGS directly from sputum can quickly generate a complete genetic drug resistance profile. In this case, WGS altered the clinical management of drug-resistant tuberculosis and demonstrated potential for guiding individualized drug treatment where second-line drug resistance is common.

Topics: Adult; Antitubercular Agents; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis, Pulmonary; Whole Genome Sequencing

Topics: Antitubercular Agents; Cohort Studies; Communicable Disease Control; Drug Resistance, Bacterial; Genotype; Humans; India; Infectious Disease Medicine; Linezolid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Predictive Value of Tests; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Animals; Antitubercular Agents; Disease Models, Animal; Drug Therapy, Combination; Ethambutol; Female; Isoniazid; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Streptomycin; Treatment Outcome; Tuberculosis, Pulmonary

The study aimed at assessing the Tuberculosis (TB) medication adherence level and the efficacy of smear microscopy in the diagnosing pulmonary TB at month 2.. A prospective study was conducted at the four sites located in the Northern-western Tanzania. New smear positive, pulmonary TB patients were followed up and their adherence to TB medication assessed after 2 months of the treatment. In addition, the acid fast bacilli (AFB) smear microscopy was performed after 2 and 5 months of the treatment. All smear positive samples were subjected to geneXpert (MTB/RIF) assay and culture on the Lowenstein Jensen (LJ) media.. A total of 331 smear positive, newly diagnosed patients with pulmonary TB were enrolled. The median age was 36 [Interquartile range (IQR): 28-45] years and males formed the slightly majority, 187 (56.5%) of the participants. A total of 105 (31.7%) patients were infected with HIV. Out of 331 patients, 36 (10.9%) were still AFB smear positive at the end of two month. Of these 19 (52.8%) were positive on GeneXpert MTB RIF and none was Rifampicin resistant. Of note, only 13 (31.1%) were culture positive (viable). None of the patients was positive at month 5. Poor adherence to TB medications in the first 2 months of treatment was observed in 56/331 (16.9%) [95% CI=12.9-21.0] of the patients.. Over two thirds of smear positive patients are wrongly put in one month extension of the intensive phase treatment; this may cause increased costs and drug toxicity. Culture should be advocated to confirm smear positivity after 2 months of medications. TB treatment drug adherence in our setting is good and is associated with successful cure. No multidrug resistant tuberculosis (MDR-TB) was observed. Continued surveillance and emphasizing of TB drug adherence should be kept upbeat in order to control tuberculosis in developing countries.

Topics: Adult; Drug Resistance, Multiple, Bacterial; Female; Humans; Male; Medication Adherence; Microscopy; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Rifampin; Tanzania; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; World Health Organization

GeneXpert MTB/RIF (Xpert) assay, a rapid and automated system based on real-time PCR and molecular beacon technology, proved to be a sensitive and specific tool capable of detecting Mycobacterium tuberculosis and rifampin resistance in clinical specimens. In this study we provide a Xpert-dedicated successful protocol for processing paraffin-embedded tissue and assess the feasibility of the Xpert assay-based tuberculosis (TB) diagnosis on these specimens, thus proving the Xpert assay as a valuable TB diagnostic tool in supporting conventional histopathological methods.

Topics: Antibiotics, Antitubercular; Automation, Laboratory; Bacteriological Techniques; Biopsy; Case-Control Studies; DNA, Bacterial; Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Paraffin Embedding; Predictive Value of Tests; Real-Time Polymerase Chain Reaction; Rifampin; Tuberculosis, Lymph Node; Tuberculosis, Pleural; Tuberculosis, Pulmonary

During active TB in humans a spectrum of pulmonary granulomas with central necrosis and hypoxia exists. BALB/c mice, predominantly used in TB drug development, do not reproduce this complex pathology thereby inaccurately predicting clinical outcome. We found that Nos2

Topics: Animals; Antitubercular Agents; Disease Models, Animal; Fibrosis; Foam Cells; Humans; Hypoxia; Isoniazid; Mice; Mice, Knockout; Necrosis; Nitric Oxide Synthase Type II; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

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

Lung transplantation remains an important potential therapeutic option for end-stage lung disease. It can improve quality of life and in some cases be a life-lengthening therapy. Despite the possible benefits, there are also many potential complications following transplantation. Here we describe a novel presentation of nontuberculous mycobacterium manifesting as an endobronchial mass developing 4 years after lung transplantation.. A 66-year-old African-American woman presented with progressive dyspnea, cough, and persistent wheezing of 2 months' duration. She had a distant history of breast cancer and received bilateral lung transplantation due to end-stage pulmonary fibrosis 4 years prior to her current presentation. She denied fevers, but did endorse night sweats. She had diffuse expiratory wheezing on auscultation. Chest computed tomography imaging showed an endobronchial soft tissue lesion nearly occluding the left mainstem bronchus, which was concerning for endobronchial carcinoma. Rigid bronchoscopy demonstrated a fibrinous mass protruding into the left mainstem proximal to the anastomosis. A pathology report noted fragments of partially necrotic granulation tissue in addition to scant fragments of focally ulcerated bronchial mucosa. Both the tissue culture and bronchial wash stained positively for acid-fast bacilli and grew Mycobacterium avium complex.. Nontuberculous mycobacterium pulmonary disease is common post lung transplant and risk factors are related to immunosuppression and history of structural lung disease. Mycobacterium avium complex presenting as an endobronchial lesion in a patient post lung transplant is a novel presentation.

Topics: Aged; Antitubercular Agents; Ethambutol; Female; Fluoroquinolones; Graft Rejection; Humans; Immunosuppressive Agents; Lung; Lung Transplantation; Moxifloxacin; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Prednisone; Pulmonary Fibrosis; Rifampin; Tacrolimus; Tomography, X-Ray Computed; Tuberculosis, Pulmonary

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a health problem worldwide. Patients with pulmonary TB show a neuro-immune-endocrine imbalance characterized by an impaired cellular immunity together with increased plasma levels of cortisol, pro- and anti-inflammatory cytokines and markedly decreased dehydroepiandrosterone (DHEA) levels. Extending these findings, we now investigated the immune-endocrine profile of TB patients undergoing specific treatment. Patients (n = 24) were bled at diagnosis (T0), 2, 4, 6 months after treatment initiation and 3 months following its completion. At T0, TB patients showed increased plasma levels of interleukin-6 (IL-6), C reactive protein, interferon-gamma (IFN-γ) and transforming growth factor beta (TGF-β). These mediators decreased during treatment, reaching levels similar to those from healthy controls (n = 26). Specific treatment led to an increased lymphoproliferative response along with clinical improvement. Newly diagnosed patients had low levels of DHEA, with increased cortisol amounts and cortisol/DHEA ratio, which normalized upon specific treatment. As regards glucocorticoid receptors (GR), TB patients at diagnosis presented a reduced mRNA GRα/GRβ ratio in their peripheral blood mononuclear cells. Furthermore, multivariate analysis showed that cortisol/DHEA ratio was positively associated with inflammatory mediators for which this ratio may constitute a disease biomarker. Anti-mycobacterial treatment results in a better immune-endocrine scenario for the control of physiopathological processes accompanying disease development and hence implied in clinical recovery.

Topics: Adult; Antitubercular Agents; C-Reactive Protein; Case-Control Studies; Dehydroepiandrosterone; Ethambutol; Female; Gene Expression Regulation; Humans; Hydrocortisone; Interferon-gamma; Interleukin-6; Isoniazid; Leukocytes, Mononuclear; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Receptors, Glucocorticoid; Rifampin; Transforming Growth Factor beta; Treatment Outcome; Tuberculosis, Pulmonary

The relatively simple and cheaper light-emitting diode fluorescent microscopy (LED-FM) was recommended by the World Health Organization (WHO) to replace the conventional tuberculosis (TB) microscopy in both high- and low-volume laboratories. More recently the WHO also endorsed one more technique, Xpert MTB/RIF® assay (Xpert), for improved TB diagnosis particularly among human immunodeficiency virus (HIV)-infected cases. However, the relative performance of both of these tools differs from setting to setting in reference to the conventional TB diagnostics. This study thus aimed to evaluate these tools for TB detection in individuals visiting Ambo Hospital, west-central Ethiopia.. Cross-sectional early-morning sputum samples were collected from presumptive TB patients between January and August 2015. Socio-demographic data were captured using a structured questionnaire. Clinical information was gathered from patients' medical records. The sputum samples were diagnosed using LED-FM, Xpert, concentrated Ziehl-Neelsen (cZN) staining and Lowenstein-Jensen (LJ) culture as the gold standard. Drug sensitivity test (DST) was also conducted.. Out of 362 sputum samples collected and processed, 36(9.9%) were positive by LED-FM, 42(11.6%) by cZN and 50(13.8%) by Xpert. But, only 340 samples could be declared culture positive or negative for mycobacteria. Of these 340, eight were non-tubercle mycobacteria (NTM). Out of the remaining 332 samples, 45(13.6%) had culture-confirmed TB with 11(24.4%) being HIV co-infected. LED-FM, Xpert and culture detected 54.5% (6/11), 90.9% (10/11) and 100% (11/11) mycobacteria in HIV-positive individuals and 81.3% (26/32), 73.7% (28/38), 78.8% (26/33) and 73.2% (30/41), in HIV negatives respectively. Two samples were rifampicin resistant by both Xpert and DST. The overall sensitivity, specificity, positive and negative predictive values of LED-FM and Xpert were 77.8, 100, 100 and 96; and 93.3, 98, 97.5 and 98.9% respectively.. The data demonstrated the high diagnostic yield of Xpert. LED-FM sensitivity is higher compared to results quoted by recent systematic reviews although it appears to be lower than what was cited in the WHO policy statement (83.6%) during the recommendation of the technology. The high specificity of LED-FM in the study area is encouraging and is expected to boost its reliability and uptake.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; AIDS-Related Opportunistic Infections; Biological Assay; Child; Child, Preschool; Coinfection; Cross-Sectional Studies; Drug Resistance, Bacterial; Ethiopia; Female; HIV Infections; Hospitals; Humans; Male; Microscopy, Fluorescence; Middle Aged; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary; Young Adult

Tuberculosis (TB) is a leading cause of death among people living with HIV in sub-Saharan Africa. Several factors influence the efficacy of TB treatment by leading to suboptimal drug concentrations and subsequently affecting treatment outcome. The aim of this cohort is to determine the association between anti-TB drug concentrations and TB treatment outcomes.. Patients diagnosed with new pulmonary TB at the integrated TB-HIV outpatient clinic in Kampala, Uganda, were enrolled into the study and started on first-line anti-TB treatment.. Between April 2013 and April 2015, the cohort enrolled 268 patients coinfected with TB/HIV ; 57.8% are male with a median age of 34 years (IQR 29-40). The median time between the diagnosis of HIV and the diagnosis of TB is 2 months (IQR 0-22.5). The majority of the patients are antiretroviral therapy naive (75.4%). Our population is severely immunosuppressed with a median CD4 cell count at enrolment of 163 cells/µL (IQR 46-298). Ninety-nine per cent of the patients had a diagnosis of pulmonary TB confirmed by sputum microscopy, Xpert/RIF or culture and 203 (75.7%) have completed TB treatment with 5099 aliquots of blood collected for pharmacokinetic analysis.. This cohort provides a large database of well-characterised patients coinfected with TB/HIV which will facilitate the description of the association between serum drug concentrations and TB treatment outcomes as well as provide a research platform for future substudies including evaluation of virological outcomes.. NCT01782950; Pre-results.

Topics: Adult; Anti-Retroviral Agents; Antitubercular Agents; Biomedical Research; CD4 Lymphocyte Count; Cohort Studies; Coinfection; Drug Combinations; Ethambutol; Female; HIV Infections; Humans; Isoniazid; Male; Pyrazinamide; Research Design; Rifampin; Tuberculosis, Pulmonary; Uganda

We estimated the incidence of acquired isoniazid and rifampicin resistance in rifampicin-susceptible tuberculosis in a setting of high human immunodeficiency virus type 1 (HIV-1) infection and tuberculosis coprevalence.. GeneXpert MTB/RIF-confirmed patients with rifampicin-susceptible tuberculosis were recruited at antituberculosis treatment initiation in Khayelitsha, South Africa. Liquid culture and adherence assessment were performed at 2 and 5-6 months. MTBDRplus was performed on mycobacteria-positive cultures to ascertain acquired drug resistance (ADR). Spoligotyping and whole-genome sequencing were performed to ascertain homogeneity between baseline isolates and isolates with ADR. Baseline isolates were retrospectively tested for isoniazid monoresistance. An electronic database review was performed to ascertain tuberculosis recurrences.. A total of 306 participants (62% with HIV-1 coinfection, of whom 71% received antiretroviral therapy) were recruited. Ascertainment of outcomes was complete for 284 participants. Five acquired a resistant Mycobacterium tuberculosis strain during or subsequent to treatment. One strain was confirmed to have ADR, 2 were confirmed as causing exogenous reinfection, and 2 were unrecoverable for genotyping. Incident ADR was estimated to have ranged from 0.3% (95% confidence interval [CI], .1%-1.9%; 1 of 284 participants) to 1% (95% CI, .2%-3%; 3 of 284 participants). Seventeen of 279 baseline isolates (6.1%; 95% CI, 3.6%-9.6%) had isoniazid monoresistance (13 of 17 had an inhA promoter mutation), but 0 of 17 had amplified resistance.. Treatment with standardized antituberculosis regimens dosed daily throughout, high uptake of antiretroviral therapy, and low prevalence of isoniazid monoresistance were associated with a low frequency of ADR.

Topics: Adult; Anti-Retroviral Agents; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Female; HIV Infections; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Mycobacterium tuberculosis; Prevalence; Prospective Studies; Retrospective Studies; Rifampin; South Africa; Treatment Outcome; Tuberculosis, Pulmonary

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

A tertiary referral hospital in Bangkok, Thailand.. To evaluate the efficacy of a bronchoalveolar lavage fluid (BALF) tuberculosis (TB) polymerase chain reaction (PCR) assay for the diagnosis of sputum smear-negative pulmonary TB (PTB) and the usefulness of a drug-resistant (DR) TB-PCR assay compared with standard drug susceptibility testing (DST).. BALF samples from 918 patients with acid-fast bacilli (AFB) negative sputum smears who underwent bronchoscopy for diagnostic evaluations of pulmonary diseases were prospectively determined for specific genetic elements of TB using the AnyplexTM MTB/NTM Real-Time Detection kit. Positive TB-PCR samples were subsequently evaluated for DR-TB using the Anyplex II MTB/MDR Detection kit.. A total of 224 patients were finally diagnosed with PTB. The sensitivity, specificity, positive predictive value and negative predictive value of the TB-PCR assay were respectively 38.8%, 100%, 100%, and 83.5%. The TB-PCR assay was more sensitive than culture (30.4%) and smear (6.7%). Of the 68 TB-positive culture samples, three cases with either isoniazid (INH) or rifampicin (RMP) resistance were detected by DST. The Anyplex II MTB/MDR assay provided similar results.. The BALF TB-PCR assay is a useful tool in the diagnosis of sputum smear-negative PTB. It can also provide INH and RMP susceptibility patterns similar to those of standard DST.

Topics: Adult; Aged; Antitubercular Agents; Bronchoalveolar Lavage Fluid; Drug Resistance, Bacterial; Female; Humans; Isoniazid; Male; Microbial Sensitivity Tests; Middle Aged; Polymerase Chain Reaction; Predictive Value of Tests; Prospective Studies; Rifampin; Sensitivity and Specificity; Sputum; Tertiary Care Centers; Thailand; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Performance of the Xpert MTB/RIF assay, designed to simultaneously detect Mycobacterium tuberculosis complex (MTBC) and rifampin (RIF) resistance, has been well documented in low-resource settings with high TB-incidence. However, few studies have assessed its accuracy in low TB incidence settings. We evaluated the performance of Xpert MTB/RIF using clinical sputum specimens routinely collected from suspect pulmonary TB patients over a 4-year time period in San Diego County, California. Xpert MTB/RIF results were compared to acid-fast bacilli (AFB) smear microscopy, mycobacterial culture, and phenotypic drug susceptibility testing (DST). Of 751 sputum specimens, 134 (17.8%) were MTBC culture-positive and 2 (1.5%) were multidrug-resistant (MDR). For the detection of MTBC, Xpert MTB/RIF sensitivity was 89.6% (97.7% and 74.5% in smear-positive and -negative sputa, respectively) and specificity was 97.2%; while AFB smear sensitivity and specificity were 64.9% and 77.8%, respectively. Xpert MTB/RIF detected 35 of 47 smear-negative culture-positive specimens, and excluded 124 of 137 smear-positive culture-negative specimens. Xpert MTB/RIF also correctly excluded 99.2% (121/122) of nontuberculous mycobacteria (NTM) specimens, including all 33 NTM false-positives by smear microscopy. For the detection of RIF resistance, Xpert MTB/RIF sensitivity and specificity were 100% and 98.3%, respectively. Our findings demonstrate that Xpert MTB/RIF is able to accurately detect MTBC and RIF resistance in routinely collected respiratory specimens in a low TB-incidence setting, with comparable performance to that achieved in high-incidence settings; and suggest that under these conditions the assay has particular utility in detecting smear-negative TB cases, excluding smear-positive patients without MTBC disease, and differentiating MTBC from NTM.

Topics: Biological Assay; California; Drug Resistance, Microbial; Humans; Mycobacterium tuberculosis; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

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

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

Tuberculosis (TB) is considered as one of the most important infectious diseases in the world, and recent rise and spread of multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains, have made the matter worsened. Due to the importance of TB prevalence in Iran, this study was designed to investigate the genetic diversity among MDR strains of MTB by MIRU-VNTR typing scheme. A total of 88 drug resistant M. tuberculosis isolates belong to pulmonary TB cases were collected from several TB reference centers of Iran. Drug susceptibility testing for Isoniazid and Rifampin was performed using the agar proportion method and MDR isolates were underwent genotyping by using 12-locus- based MIRU-VNTR typing. On performing proportion method, 22 isolates were identified as MDR. By typing of MDR isolates using 12-loci MIRU-VNTR technique, high diversity were demonstrated in MDR strains and these were classified into 20 distinct MIRU-VNTR genotypes. MIRU loci 10 and 26 were the most discriminatory loci with 8 and 7 alleles respectively; while MIRU loci 2, 20, 24 and 39 were found to be the least discriminatory with 1-2 alleles each. We noticed a mixed infection in isolate 53, as this isolate comprised simultaneous two alleles in MIRU loci 40, 10, 16 and 39. In conclusion, this result represents MIRU-VNTR typing as a useful tool for studying genetic diversity of MDR-MTB in regional settings, and will help the health sectors to construct a preventive program for MDR-TB. Additionally, it can detect mixed infection which can facilitate management of treatment.

Topics: Alleles; Antitubercular Agents; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Genetic Loci; Humans; Iran; Isoniazid; Microbial Sensitivity Tests; Minisatellite Repeats; Multilocus Sequence Typing; Mycobacterium tuberculosis; Polymorphism, Genetic; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

BACKGROUND Oxycodone is a semisynthetic opioid receptor agonist, and is frequently used for pain control in patients with cancer. Most oxycodone is metabolized by N-demethylation to noroxycodone by CYP3A. Rifampin is a strong inducer of several drug-metabolizing enzymes, including CYP3A. Hence, rifampin-induced CYP3A activity may decrease the effect of oxycodone. CASE REPORT Osteosarcoma is a highly aggressive primary bone tumor of childhood and adolescence. Here, we report a 30-year-old male with osteosarcoma of the femur with lung metastases in the upper lobe. The lung also contained small, scattered nodular lesions that were identified as tuberculosis. Multi-drug therapy, including rifampin, was administered. The upper-lobe metastatic lesion extended to the brachial plexus and caused severe pain. Over 1000 mg per day of oxycodone was ineffective for pain control. However, morphine was able to control his pain at about one-third the equivalent dose. CONCLUSIONS Our patient demonstrated oxycodone resistance due to rifampin. Chemotherapy may have compromised the patient's immune system, thus theoretically increasing the risk of tuberculosis. Recognition of the interactions between rifampin and oxycodone is important in this and other cancers. Notably, for patients using high doses of oxycodone to manage severe pain, stopping rifampin may lead to oxycodone overdose.

Topics: Adult; Analgesics, Opioid; Antibiotics, Antitubercular; Bone Neoplasms; Cancer Pain; Drug Resistance; Humans; Lung Neoplasms; Male; Osteosarcoma; Oxycodone; Rifampin; Tuberculosis, Pulmonary

China has a high burden of drug-resistant tuberculosis (TB). As irrational use and inadequate dosing of anti-TB drugs may contribute to the epidemic of drug-resistant TB, we assessed the drug types and dosages prescribed in the treatment of TB cases in a representative sample of health care facilities in Yunnan.. We applied multistage cluster sampling using probability proportion to size to select 28 counties in Yunnan. Consecutive pulmonary TB patients were enrolled from either the TB centers of Yunnan Center of Disease Control or designated TB hospitals. Outcomes of interest included the regimen used in the treatment of new and retreatment TB patients; and the proportion of patients treated with adequate dosing of anti-TB drugs. Furthermore, we assess whether there has been reduction in the use of fluoroquinolone and second line injectables in Tuberculosis Clinical Centre (TCC) after the training activity in late 2012.. Of 2390 TB patients enrolled, 582 (24.4%) were prescribed second line anti-TB drugs (18.0% in new cases and 60.9% in retreatment cases); 363(15.2%) prescribed a fluoroquinolone. General hospitals (adjusted odds ratio (adjOR) 1.97, 95% confidence interval (CI) 1.47-2.66), retreatment TB cases (adjOR 4.75, 95% CI 3.59-6.27), smear positive cases (adjOR 1.69, 95% CI 1.22-2.33), and extrapulmonary TB (adjOR 2.59, 95% CI 1.66-4.03) were significantly associated with the use of fluoroquinolones. The proportion of patients treated with fluoroquinolones decreased from 41.4% before 2013 to 13.5% after 2013 (adjOR 0.19, 95% CI 0.12-0.28) in TCC. The proportion of patients with correct, under and over dosages of isoniazid was 88.2%, 1.5%, and 10.4%, respectively; of rifampicin was 50.2%, 46.8%, and 2.9%; of pyrazinamide was 67.6%, 31.7% and 0.7%; and of ethambutol was 41.4%, 57.5%, and 1.0%.. The prescribing practice of anti-TB drugs was not standardized, findings with significant programmatic implication.

Topics: Adult; Aged; Antitubercular Agents; Asian People; China; Clinical Audit; Ethambutol; Female; Fluoroquinolones; Humans; Isoniazid; Male; Middle Aged; Outcome Assessment, Health Care; Prescriptions; Pyrazinamide; Retreatment; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Besides inclusion in 1st line regimens against tuberculosis (TB), pyrazinamide (PZA) is used in 2nd line anti-TB regimens, including in the short regimen for multidrug-resistant TB (MDR-TB) patients. Guidelines and expert opinions are contradictory about inclusion of PZA in case of resistance. Moreover, drug susceptibility testing (DST) for PZA is not often applied in routine testing, and the prevalence of resistance is unknown in several regions, including in most African countries.. Six hundred and twenty-three culture isolates from rifampicin-resistant (RR) patients were collected in twelve Sub-Saharan African countries. Among those isolates, 71% were from patients included in the study on the Union short-course regimen for MDR-TB in Benin, Burkina Faso, Burundi, Cameroon, Central Africa Republic, the Democratic Republic of the Congo, Ivory Coast, Niger, and Rwanda PZA resistance, and the rest (29%) were consecutive isolates systematically stored from 2014-2015 in Mali, Rwanda, Senegal, and Togo. Besides national guidelines, the isolates were tested for PZA resistance through pncA gene sequencing.. Over half of these RR-TB isolates (54%) showed a mutation in the pncA gene, with a significant heterogeneity between countries. Isolates with fluoroquinolone resistance (but not with injectable resistance or XDR) were more likely to have concurrent PZA resistance. The pattern of mutations in the pncA gene was quite diverse, although some isolates with an identical pattern of mutations in pncA and other drug-related genes were isolated from the same reference center, suggesting possible transmission of these strains.. Similar to findings in other regions, more than half of the patients having RR-TB in West and Central Africa present concomitant resistance to PZA. Further investigations are needed to understand the relation between resistance to PZA and resistance to fluoroquinolones, and whether continued use of PZA in the face of PZA resistance provides clinical benefit to the patients.

Topics: Adolescent; Adult; Africa South of the Sahara; Aged; Aged, 80 and over; Amidohydrolases; Antitubercular Agents; Child; Drug Resistance, Multiple, Bacterial; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary; Young Adult

Mycobacterium tuberculosis (MTB) is one of the most significant causes of mortality and morbidity. Early diagnose is important especially in multiple drug resistant tuberculosis to avoid transmission. Traditional techniques requires at least one to three weeks for diagnosis of tuberculosis. Diagnostic delays with multiple drug resistant tuberculosis are associated with worse clinical outcomes and increased transmission The Xpert MTB/RIF assay is one of the new diagnostic device for the diagnosis of tuberculosis and rapid detection of rifampicin resistance.. We assessed the performance of Xpert MTB/RIF assay for detecting rifampicin resistance using phenotypic drug susceptibility tests as automated BD MGIT 960.. Total of 2136 specimens were included in the study. Xpert MTB/RIF testing was performed on samples, using version 4 cartridges, according to the manufacturer's recommendations. The MTBC culture and first-line phenotypic DST were performed in automated BD MGIT 960 (Becton & Dickinson, USA) according to the recommendations of the manufacturer. Agar proportion was used in the case of inconsistency for rifampicin resistance.. Thirty-four samples (19 respiratory and 15 nonrespiratory samples) were determined as positive for M. tuberculosis complex by Xpert MTB/RIF (Cepheid GeneXpert® System, USA). Xpert MTB/RIF assay detected 4/34 (11.7%) specimens as rifampicin resistant. One of the rifampicin resistant isolates was determined susceptible in MGIT 960 automated system. This isolate was also tested with agar proportion method and found susceptible to rifampicin.. The Xpert MTB/RIF assay can be used as first-line assay for the detection of M. tuberculosis. However, microbiologists must be aware of the limitations of the assay.

Topics: Antibiotics, Antitubercular; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenotype; Reproducibility of Results; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Multidrug resistant (MDR) and extensively drug resistant tuberculosis (TB) are a threat to the TB control programs in developing countries, and the situation is worsened by the human immunodeficiency virus (HIV) pandemic. This study was performed to correlate treatment outcome with the resistance patterns in HIV-seropositive patients coinfected with pulmonary TB. Sputum specimens were collected from 1643 HIV-seropositive patients and subjected to microscopy and liquid culture for TB. The smear- and culture-positive Mycobacterium tuberculosis isolates were subjected to Genotype MTBDRplus assay version 2.0. The M. tuberculosis culture-positivity rate was 39.44% (648/1643) among the 1643 HIV-seropositive patients and the overall MDR-TB rate was 5.6% (36/648). There were 421 newly diagnosed and 227 previously treated patients, among whom, MDR-TB was associated with 2.9% and 10.57% cases, respectively. The rate of rifampicin monoresistant TB among the cases of MDR-TB was 2.31% (15/648) and the rate of combined rifampicin and isoniazid resistance was 3.24% (21/648). The cure and death rates among the 20 registered cases were 30% (6/20) and 35% (7/20), respectively. Five cases were on treatment and two cases were defaulters among the 20 registered cases. High death rate (13, 36.1%, 95% confidence interval 20.8-53.8) was observed in this study among the patients who had mutations at the 530-533 codons. The present study emphasized the prerequisite to monitor the trend of drug-resistant TB in various mutant populations in order to timely implement appropriate interventions to curb the threat of MDR-TB.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Child; Child, Preschool; Female; HIV Infections; Humans; Infant; Infant, Newborn; Male; Middle Aged; Mycobacterium tuberculosis; Prevalence; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

This work aims to develop a mannosylated nanostructured lipid carrier (NLC) loaded with rifampicin to improve tuberculosis treatment.. An active targeting strategy was used and the nanoparticles were characterized. Effects on cell viability and the antimycobacterial activity of the nanoformulations were evaluated.. The nanoparticles developed exhibited a size of about 315 nm and polydispersity <0.2. The drug encapsulation efficiency was higher than 90% and its release was sensitive to pH. The mannosylated NLCs showed efficient uptake by bone marrow derived macrophages. Further, rifampicin-loaded mannosylated NLCs were more efficient in inducing a decrease of intracellular growth of mycobacteria.. The NLCs developed can be used as a promising carrier for safer and efficient management of tuberculosis.

Topics: Animals; Antibiotics, Antitubercular; Biological Transport; Cell Survival; Drug Carriers; Drug Liberation; Female; Humans; Hydrogen-Ion Concentration; Lipids; Macrophages; Mannose; Mice, Inbred C57BL; Mycobacterium avium; Nanoparticles; Particle Size; Rifampin; Surface Properties; Tuberculosis, Pulmonary

The aim of the present study was to compare the efficacy of the commercial Xpert Mycobacterium tuberculosis/rifampin (MTB/RIF) test for evaluating different types of spinal tuberculosis (TB) tissue specimens.. Pus, granulation tissue, and caseous necrotic tissue specimens from 223 patients who were diagnosed with spinal TB and who underwent curettage were collected for bacterial culture and the Xpert MTB/RIF assay to calculate the positive rate. Bacterial culture and phenotypic drug sensitivity testing (pDST) were adopted as the gold standards to calculate the sensitivity and specificity of the Xpert bacterial detection and drug resistance (DR) test.. The positive rate (68.61% ± 7.35%) from the Xpert MTB/RIF assays of spinal TB patients' tissue specimens was higher compared with bacterial culture (44.39% ± 6.51%, Z = 5.1642, p < 0.01), and the positive rates from Xpert MTB/RIF assays on the three types of specimens were all higher than those of bacterial culture, with statistically significant results for pus and granulation tissue specimens. The positive rates for pus using the two bacteriological tests were higher than those for granulation tissue but were not statistically significant. However, the positive rates obtained from granulation tissue were statistically significantly higher than those obtained from caseous necrotic tissue. With bacterial culture and pDST as the gold standards, the sensitivity of Xpert MTB/RIF assays for MTB was 96.97%, while the sensitivity and specificity of the DR test also remained relatively high.. For efficient and accurate diagnosis of spinal TB and DR and timely provision of effective treatment, multiple specimens, especially the pus of spinal TB patients, should be collected for Xpert MTB/RIF assays.

Topics: China; Drug Resistance, Bacterial; Female; Humans; Male; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis, Pulmonary; Tuberculosis, Spinal

The discrepancy rates of drug susceptibility testing (DST) results between solid and liquid media have been reported to range from 2.4 to 7.4% for isoniazid. Most isolate with isoniazid DST discrepancies between solid and liquid media test as susceptible on solid medium and resistant in liquid medium, however, the optimal management of patients with discordant testing is unknown. This study was conducted to evaluate the effect of treatment regimen on treatment outcomes when patients with rifampicin-susceptible pulmonary tuberculosis have isoniazid resistance (INH-R) in liquid medium but isoniazid susceptibility (INH-S) on solid medium.. This study was retrospectively conducted by reviewing patient medical records on the liquid compared to solid culture based phenotypic testing at Samsung Medical Center between January 2009 and December 2015. The study population which have INH-R in liquid medium and INH-S on solid medium was divided into two groups: group A (n = 30), which included patients treated for INH-S tuberculosis by discontinuing pyrazinamide (and ethambutol), and group B (n = 56), which included patients treated for INH-R tuberculosis by continuing pyrazinamide and/or adding fluoroquinolone. Unfavorable outcomes included treatment failure and relapse.. There were no statistically significant differences between the two groups including demographic data, comorbidities, radiologic data, and treatment duration. However, baseline smear positive rates were more frequent in group A (19/30, 63.3%) than in group B (22/56, 39.3%; P = 0.033). Only three patients had unfavorable outcomes; one was bacteriologically proven treatment failure and the other two were clinically judged as unfavorable outcomes. All of them were in the group A (3/30, 10%); no unfavorable outcomes occurred in the group B (0/56, 0%; P = 0.040).. Unfavorable outcomes were less frequent in the group B than in the group A, indicating that treatment regimen modification according to DST results on liquid medium could improve treatment outcomes in patients with rifampicin-susceptible pulmonary tuberculosis. Further studies are required to confirm these findings to overcome the small number of unfavorable outcomes.

Topics: Aged; Antitubercular Agents; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Female; Fluoroquinolones; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Nucleic Acid Synthesis Inhibitors; Pyrazinamide; Republic of Korea; Retrospective Studies; Rifampin; Treatment Failure; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

In sub-Saharan Africa, diagnostic methods for tuberculosis are inadequate and are essentially based on microscopy. They constitute a real obstacle to the control of tuberculosis. This study aimed to evaluate the performance of GeneXpert MTB/RIF test compared to classical Ziehl-Neelsen staining at the the general referral provincial hospital of Bukavu, in the east of the Democratic Republic of the Congo after 10 months of use.. The results of Ziehl-Neelsen staining and GeneXpert MTB/RIF molecular biology test performed in 452 patients with suspected tuberculosis were collected. This study compares the validity of these different diagnostic tests in the detection of tuberculosis.. In the entire group, the frequency of the pulmonary tuberculosis was 16.3%. The positivity rate was significantly higher in GeneXpert MTB/RIF test than in Ziehl-Neelsen staining in the entire group (15.9% vs 9.3%, p = 0.03) and in HIV seropositive patients (52.0% vs 24.0%; p = 0.007). However, the sensitivity of GeneXpert MTB/RIF test compared to that in Ziehl-Neelsen staining wasn't maximum (95.2%). Finally, GeneXpert MTB/RIF test detected rifampicin resistance in 20.8%.. This study confirms the superiority of GeneXpert MTB/RIF test compared to Ziehl-Neelsen staining in the detection of tuberculosis and in the prediction of multi-resistance. Its systematic use coupled with Ziehl-Neelsen staining would better control tuberculosis in sub-Saharan Africa.

Topics: Adult; Antitubercular Agents; Democratic Republic of the Congo; Drug Resistance, Multiple, Bacterial; Female; HIV Seropositivity; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Retrospective Studies; Rifampin; Sensitivity and Specificity; Staining and Labeling; Tuberculosis, Pulmonary; Young Adult

Information on tuberculosis (TB) treatment outcomes would be useful for the improvement of the TB control program. The aim of the present study was to evaluate treatment outcomes of TB and identify associated factors in TB patients at the Jinka General Hospital (JGH), remote Zone of Ethiopia.. The result showed that 13.1% (154/1172) of the cases were cured, 60.9% treatment completed, 10.2% died and 9.1% were lost to follow-up. Thus, the overall treatment success rate was 74%. Male patients [AOR = 0.70 (0.52-0.93)] and HIV co-infected patients [AOR = 0.67 (0.45-0.98)] were associated with unsuccessful treatment outcomes.

Topics: Adolescent; Adult; Antitubercular Agents; Coinfection; Drug Combinations; Ethambutol; Ethiopia; Female; HIV Infections; Hospitals, General; Humans; Isoniazid; Male; Middle Aged; Pyrazinamide; Retrospective Studies; Rifampin; Sex Factors; Streptomycin; Survival Analysis; Treatment Outcome; Tuberculosis, Pulmonary

Among infectious agents, Mycobacterium tuberculosis remains one of\ the most significant causes of death worldwide. Rapid and accurate diagnosis\ of pulmonary tuberculosis (TB) remains a great challenge. GeneXpert MTB/RIF\ assay is a novel integrated diagnostic system for rapid diagnosis of TB and particularly\ of rifampicin-resistant strains. A study was conducted between January\ 2010 and December 2014 to compare the performance of the sputum GeneXpert\ MTB/RIF assay with the conventional sputum AFB smear for diagnosis of active\ pulmonary TB in Thailand, a country with a high burden of this disease. Of the\ 125 patients who had cough and/or prolonged fever together with abnormal chest\ radiograph, 63 were diagnosed as having pulmonary TB by mycobacterium culture\ assay, while the remaining subjects were considered of having TB-like conditions,\ viz non-tuberculous mycobacterium infection (NTM), bacterial pneumonia or\ bronchogenic carcinoma. Two-thirds of the patients had underlying diseases, eg,\ diabetes mellitus (19 patients), autoimmune diseases (14), and HIV (6). Among\ patients with positive diagnosis of M. tuberculosis infection, 30 were AFB smear\ positive and 53 by sputum GeneXpert MTB/RIF method; among patients negative\ for M. tuberculosis infection, 4 were AFB smear positive and 5 by GeneXpert MTB/\ RIF assay. Sensitivity and specificity of the sputum AFB smear and GeneXpertMTB/\ RIF assay test were 48% (95% CI: 35-61) and 84% (95% CI: 73-92), and 94% (95%\ CI: 84-98) and 92% (95% CI: 82-97), respectively. Diagnostic performance of the\ GeneXpert MTB/RIF assay among AFB smear positive patients was higher than\ among AFB smear negative patients (adjusted OR 6.7; 95% CI: 2.3-19.9). Earlier\ diagnosis of pulmonary TB using GeneXpert MTB/RIF assay will lead to earlier\ appropriate treatment and provide opportunities to interrupt TB transmission.

Topics: Adult; Aged; Cross-Sectional Studies; Diagnostic Tests, Routine; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Sputum; Thailand; Tuberculosis, Pulmonary

The primary role of any tuberculosis (TB) control program is to ensure the prompt identification and effective treatment of active disease. The host immune system often succeeds in containing the initial (or primary) infection with Mycobacterium tuberculosis (Mtb), but may fail to eliminate the pathogen. The persistence of viable organisms explains the potential for the development of active disease years or even decades after infection. This is known as latent tuberculosis infection (LTBI) although, rather than a distinct entity, this probably represents part of a dynamic spectrum. Individuals with LTBI are asymptomatic and it is therefore clinically undetectable. The World Health Organization (WHO) estimates that one-third of the global population has been infected with Mtb, with highest prevalence of LTBI in countries/regions with the highest prevalence of active disease. In 2013, 88% of 1322 notifications in Australia were in the overseas-born population (incidence 19.5 per 100,000 v. 1.0 per 100,000), with this proportion rising over the course of the last decade. Combined with epidemiological evidence of low local transmission, this strongly implies that the vast majority resulted from reactivation of latent infection acquired prior to immigration. Contrasting trends in TB incidence in other developed countries probably reflect differences in policy regarding LTBI.. The diagnosis and treatment of LTBI represents an important opportunity for intervention by jurisdictional TB control programs.

Topics: Antitubercular Agents; Australia; Chemoprevention; Communicable Disease Control; Disease Notification; Drug Combinations; Emigration and Immigration; Humans; Interferon-gamma Release Tests; Isoniazid; Latent Tuberculosis; Mycobacterium tuberculosis; Prevalence; Rifampin; Transients and Migrants; Tuberculin Test; Tuberculosis, Pulmonary

Rifampicin can induce hypothyroidism. We report a case of pulmonary tuberculosis and tuberculous pleurisy that was complicated by rifampicin-induced hypothyroidism. The patient received rifampicin-based tuberculosis treatment and experienced persistent appetite loss, which led us to pro- vide concomitant hypothyroidism treatment. An 85-year-old woman with no underlying thyroid-related disease presented to her local hospital with a 3-month history of appetite and weight loss. A chest radiograph revealed pleural effusions and infiltrative shadows in the lower fields of both lungs, and we also detected high levels of lympho- cytes and adenosine deaminase levels (49.6 IU/1) in the pleu- ral effusion, with positive results from a polymerase chain reaction assay of a sputum sample. Thus, we diagnosed the patient with pulmonary tuberculosis and tuberculous pleurisy, and initiated treatment using isoniazid, rifampicin, etham- butol, and pyrazinamide. Her clinical course was good and her anorexia was improved. However, she subsequently experienced recurrent appetite loss, malaise, and bilateral lower-leg edema. Follow-up laboratory testing revealed that she had developed hypothyroidism. We started treatment using levothyroxine without interrupting the tuberculosis treatment. The loss of appetite and other thyroid-related symptoms were improved. The patient's thyroid function had been normal at her admission, and there were no findings of Hashimoto's thyroiditis or other thyroid conditions. Based on the clinical course, we conclude that the rifampicin induced the hypothyroidism. Therefore, rifampicin-induced hypothyroidism should be considered in cases with persistent appetite loss, even if the patient appears to be experiencing anorexia as an adverse drug reaction.

Topics: Aged, 80 and over; Antibiotics, Antitubercular; Female; Humans; Hypothyroidism; Rifampin; Treatment Outcome; Tuberculosis, Pleural; Tuberculosis, Pulmonary

Pulmonary infection due to Mycobacterium malmoense can be difficult to diagnose. These difficulties can be responsible for a delay in the implementation of optimal treatment. Moreover, the treatment is not standardized.. We report the case of a 56-year-old patient who developed a Mycobacterium malmoense pulmonary infection whose diagnosis was delayed due to initial suspicion of pulmonary Mycobacterium tuberculosis infection. Once the diagnosis was confirmed, the patient was treated empirically with rifampicin, ethambutol, and clarithromycin for 12 months after culture conversion, giving a total of 15 months. The clinical and radiological outcomes were favorable.. This clinical case highlights the difficulties of diagnosing pulmonary atypical mycobacterial infection according to the American Thoracic Society criteria, particularly Mycobacterium malmoense, a non-tuberculous mycobacterium (NTM) quite uncommon in France. Currently, there are new diagnostic techniques such as GenoType Mycobacteria Direct. A more systematic reporting strategy could allow cohort studies and therefore provide us with data on the most efficient drugs in the treatment of the rarest NTM infections.

Topics: Clarithromycin; Diagnosis, Differential; Ethambutol; Humans; Lung Diseases; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Respiratory Tract Infections; Rifampin; Tuberculosis, Pulmonary

The diagnosis of smear-negative pulmonary tuberculosis (PTB) is particularly challenging, and automated liquid culture and molecular line probe assays (LPA) may prove particularly useful. The objective of our study was to evaluate the diagnostic potential of automated liquid culture (ALC) technology and commercial LPA in sputum smear-negative PTB suspects. Spot sputum samples were collected from 145 chest-symptomatic smear-negative patients and subjected to ALC, direct drug susceptibility test (DST) testing and LPA, as per manufacturers' instructions. A diagnostic yield of 26.2% was observed among sputum smear-negative TB suspects with 47.4% of the culture isolates being either INH- and/or rifampicin-resistant. Complete agreement was observed between the results of ALC assay and LPA except for two isolates which demonstrated sensitivity to INH and rifampicin at direct DST but were rifampicin-resistant in LPA. Two novel mutations were also detected among the multidrug isolates by LPA. In view of the diagnostic challenges associated with the diagnosis of TB in sputum smear-negative patients, our study demonstrates the applicability of ALC and LPA in establishing diagnostic evidence of TB.

Topics: Adult; Bacteriological Techniques; Bronchoalveolar Lavage Fluid; Drug Resistance, Multiple; Female; Humans; Male; Middle Aged; Molecular Probe Techniques; Mutation; Mycobacterium tuberculosis; Pleura; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Pneumatosis intestinalis (PI), defined as intestinal intra- and extramural gas accumulation, is a rare radiographic finding in conditions of intestinal wall damage of varied etiology. Here, we report on a 56-year-old female with multiple myeloma who presented with undulating fever, fluctuating abdominal symptoms, and a distended abdomen 5 months after allogeneic hematopoietic stem cell transplantation (HSCT). Abdominal X-ray and CT scan documented PI with gas accumulation both in the intestinal and colonic bowel walls. Concurrently, thoracic CT revealed mediastinal and bihilar lymphadenopathy associated with bilateral pleural effusions. Microscopy of bronchoalveolar lavage fluid (BALF) revealed acid-fast bacilli, which were identified as Mycobacterium tuberculosis. Tuberculostatic treatment resulted in timely clinical improvement, a complete clearance of the radiological and clinical findings of PI, and the control of the tuberculosis (Tbc), determined by multiple negative BALF results. Taken together, PI occurred as the initial symptom of Tbc in an allogeneic stem cell recipient, achieving complete recovery by tuberculostatic treatment only.

Topics: Antineoplastic Combined Chemotherapy Protocols; Antitubercular Agents; Bronchoalveolar Lavage Fluid; Female; Hematopoietic Stem Cell Transplantation; Humans; Isoniazid; Middle Aged; Multiple Myeloma; Mycobacterium tuberculosis; Pleural Effusion; Pneumatosis Cystoides Intestinalis; Rifampin; Tomography, X-Ray Computed; Treatment Outcome; Tuberculosis, Pulmonary

Several infectious diseases of global importance-e.g., HIV infection and tuberculosis (TB)-require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against the

Topics: Antitubercular Agents; Bayes Theorem; Biological Availability; Computer Simulation; Drug Administration Schedule; Drug Resistance, Multiple, Bacterial; Extensively Drug-Resistant Tuberculosis; Fluoroquinolones; Humans; Microbial Sensitivity Tests; Models, Statistical; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis, Pulmonary

Since 1967, Rifampin (RMP, a Rifamycin) has been used as a first line antibiotic treatment for tuberculosis (TB), and it remains the cornerstone of current short-term TB treatment. Increased occurrence of Rifamycin-resistant (RIF

Topics: Antibiotics, Antitubercular; Bacterial Proteins; Binding Sites; Crystallography, X-Ray; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Escherichia coli; Humans; Mutation; Mycobacterium tuberculosis; Protein Conformation; Rifampin; RNA, Bacterial; Tuberculosis, Pulmonary

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

Globally 3.9% of new and 21% of re-treatment tuberculosis (TB) cases are multidrug-resistant or rifampicin-resistant (MDR/RR), which is often interpreted as evidence that drug resistance results mainly from poor treatment adherence. This study aims to assess the respective contributions of the different causal pathways leading to MDR/RR-TB at re-treatment.. We use a simple mathematical model to simulate progression between the different stages of disease and treatment for patients diagnosed with TB. The model is parameterised using region and country-specific TB disease burden data reported by the World Health Organization (WHO). The contributions of four separate causal pathways to MDR/RR-TB among re-treatment cases are estimated: I) initial drug-susceptible TB with resistance amplification during treatment; II) initial MDR/RR-TB inappropriately treated as drug-susceptible TB; III) MDR/RR-TB relapse despite appropriate treatment; and IV) re-infection with MDR/RR-TB.. At the global level, Pathways I, II, III and IV contribute 38% (28-49, 95% Simulation Interval), 44% (36-52, 95% SI), 6% (5-7, 95% SI) and 12% (7-19, 95% SI) respectively to the burden of MDR/RR-TB among re-treatment cases. Pathway II is dominant in the Western Pacific (74%; 67-80 95% SI), Eastern Mediterranean (68%; 60-74 95% SI) and European (53%; 48-59 95% SI) regions, while Pathway I makes the greatest contribution in the American (53%; 40-66 95% SI), African (43%; 28-61 95% SI) and South-East Asian (50%; 40-59 95% SI) regions.. Globally, failure to diagnose MDR/RR-TB at first presentation is the leading cause of the high proportion of MDR/RR-TB among re-treatment cases. These findings highlight the need for contextualised solutions to limit the impact and spread of MDR/RR-TB.

Topics: Antitubercular Agents; Humans; Models, Statistical; Retreatment; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; World Health Organization

Tuberculosis (TB) kills approximately two million people and infects around nine million worldwide annually. Its proper management, especially in resource-limited settings, has been hindered by the lack of rapid and easy-to-use diagnostic tests. Sputum smear microscopy remains the cheapest, readily available diagnostic method but it only identifies less than half of the patients with a HIV/TB co-infection because the bacilli would have disseminated from the lungs to other areas of the body. The fully automated Xpert® MTB/RIF assay is a promising innovation for diagnosing TB and detecting resistance to rifampicin. This study aimed to evaluate the use of Xpert® MTB/RIF assay and microscopy in the diagnosis of Mycobacterium tuberculosis in Namibia, by determining the disease's epidemiology and calculating the proportion of cases infected just with TB and those with a resistance to rifampicin among the total suspected cases of TB in the country.. This retrospective study analysed TB cases that were diagnosed using both the Xpert® MTB/RIF assay and microscopy. Data were collected from patient records from the Meditech laboratory information system of the Namibia Institute of Pathology for the time period of July 2012-April 2013. Data from 13 regions were collected.. The total number of specimens collected from patients with symptoms of pulmonary TB was 1 842. Of these, 594 (32.20%) were found to be positive for MTB by Xpert® MTB/RIF assay, out of which 443 (24.05%) were also found to be positive by microscopy. The remainder was negative. The male patients were more resistant to rifampicin when compared to the female patients.. Tuberculosis is widely distributed throughout Namibia, with slightly more males infected than females. Most TB patients are also co-infected with HIV. Both microscopy and Xpert® MTB/RIF assay are crucial for the diagnosis of TB in the country. Screening diagnostic efforts should focus on the sexually active HIV positive male population who could be the source of more RIF-resistant TB than females to prevent its spread.

Topics: Antibiotics, Antitubercular; Coinfection; Diagnostic Tests, Routine; Drug Resistance, Bacterial; HIV; HIV Infections; Humans; Mycobacterium tuberculosis; Namibia; Retrospective Studies; Rifampin; Sensitivity and Specificity; Tuberculosis, Pulmonary

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

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

Tuberculosis (TB) remains one of the world's deadliest communicable diseases. In Ethiopia, tuberculosis patients have different pattern of health care seeking behavior. They usually adopt other approaches like traditional healers and spiritual holy water sites before consulting public health facilities. This study was aimed to assess the prevalence of smear positive pulmonary tuberculosis and associated risk factors among tuberculosis suspects attending spiritual holy water sites.. A cross-sectional study was conducted from February 01, 2015 to March 30, 2015 in seven selected holy water sites in Northwest Ethiopia. During the study period, a total of 1384 adult holy water users were screened for PTB symptoms. A total of 382 pulmonary tuberculosis suspects participated in the study. Socio-demographic data were collected using a semi-structured questionnaire. Spot-morning-spot sputum specimens were collected and examined for acid fast bacilli using Auramine O fluorescence staining technique. Smear positive sputum samples were tested by GeneXpert MTB/RIF assay for rifampicin resistance. Descriptive statistics, binary and multivariate logistic regression analysis were employed using SPSS-16 software.. The prevalence of smear positive pulmonary tuberculosis was 2.9% with point prevalence of 795/100, 000 holy water users. History of contact with tuberculosis patient (AOR = 9.174, 95% C.I = 2.195-38.34) and the number of family members > 5 per household (AOR = 9.258, 95% C.I = 1.14-74.97) were significantly associated with smear positive pulmonary tuberculosis. Rifampicin resistance was not detected from all smear positives by GeneXpert MTB/RIF assay.. The prevalence of smear positive pulmonary tuberculosis in spiritual holy water sites was 7.4 fold higher than the general population. History of contact with active tuberculosis patients and increased family size were significantly associated with smear positive pulmonary TB. The national tuberculosis program should consider spiritual holy water sites as potential foci for TB transmission and plan regular survey and health education in holy water sites for effective TB prevention and control in the country.

Topics: Adolescent; Adult; Antitubercular Agents; Cross-Sectional Studies; Ethiopia; Family Characteristics; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Prevalence; Religion; Rifampin; Risk Factors; Sputum; Travel; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Tuberculosis is considered the second most common cause of death due to infectious agent. The currently preferred regimen for treatment of pulmonary tuberculosis (PTB) is isoniazid, rifampin, pyrazinamide, and ethambutol, which has been used either as separate tablets (ST) or as fixed-dose combination (FDC). To date, no studies have compared both regimens in Qatar. We aim to evaluate the safety and effectiveness of FDC and ST regimen for treating PTB, in addition to comparing safety and efficacy of FDC and ST regimens in patients with diabetes treated for TB.. A retrospective observational study was conducted in two general hospitals in Qatar. Patients diagnosed with PTB received anti-tuberculosis medications (either as FDC or ST) administered by the nurse. Sputum smears were tested weekly. We assessed the time to negative sputum smear and incidence of adverse events among FDC and ST groups.. The study included 148 patients. FDC was used in 90 patients (61%). Effectiveness was not different between FDC and ST regimens as shown by mean time to sputum conversion (29.9 ± 18.3 vs. 35.6 ± 23 days, p = 0.12). Similarly, there was no difference in the incidence of adverse events, except for visual one that was higher in ST group. Among the 33 diabetic patients, 19 received the FDC and had faster sputum conversion compared to those who received ST (31 ± 12 vs. 49.4 ± 30.9 days, p = 0.05). Overall, diabetic patients needed longer time for sputum conversion and had more hepatotoxic and gastric adverse events compared to non-diabetics.. ST group had higher visual side effects compared to FDC. FDC may be more effective in diabetic patients; however, further studies are required to confirm such finding.

Topics: Adult; Antitubercular Agents; Diabetes Complications; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Ethambutol; Female; Hospitals, General; Humans; Isoniazid; Male; Pyrazinamide; Qatar; Retrospective Studies; Rifampin; Sputum; Tablets; Treatment Outcome; Tuberculosis, Pulmonary

Treatment of HIV-infected patients coinfected with

Topics: Antirheumatic Agents; Antitubercular Agents; Cells, Cultured; Cobicistat; Darunavir; Drug Interactions; Drug Therapy, Combination; Hepatocytes; HIV Infections; HIV-1; Humans; Metabolic Clearance Rate; Mycobacterium tuberculosis; Rifampin; Ritonavir; Tuberculosis, Pulmonary

There is scant evidence to support target drug exposures for optimal tuberculosis outcomes. We therefore assessed whether pharmacokinetic/pharmacodynamic (PK/PD) parameters could predict 2-month culture conversion.. One hundred patients with pulmonary tuberculosis (65% human immunodeficiency virus coinfected) were intensively sampled to determine rifampicin, isoniazid, and pyrazinamide plasma concentrations after 7-8 weeks of therapy, and PK parameters determined using nonlinear mixed-effects models. Detailed clinical data and sputum for culture were collected at baseline, 2 months, and 5-6 months. Minimum inhibitory concentrations (MICs) were determined on baseline isolates. Multivariate logistic regression and the assumption-free multivariate adaptive regression splines (MARS) were used to identify clinical and PK/PD predictors of 2-month culture conversion. Potential PK/PD predictors included 0- to 24-hour area under the curve (AUC0-24), maximum concentration (Cmax), AUC0-24/MIC, Cmax/MIC, and percentage of time that concentrations persisted above the MIC (%TMIC).. Twenty-six percent of patients had Cmax of rifampicin <8 mg/L, pyrazinamide <35 mg/L, and isoniazid <3 mg/L. No relationship was found between PK exposures and 2-month culture conversion using multivariate logistic regression after adjusting for MIC. However, MARS identified negative interactions between isoniazid Cmax and rifampicin Cmax/MIC ratio on 2-month culture conversion. If isoniazid Cmax was <4.6 mg/L and rifampicin Cmax/MIC <28, the isoniazid concentration had an antagonistic effect on culture conversion. For patients with isoniazid Cmax >4.6 mg/L, higher isoniazid exposures were associated with improved rates of culture conversion.. PK/PD analyses using MARS identified isoniazid Cmax and rifampicin Cmax/MIC thresholds below which there is concentration-dependent antagonism that reduces 2-month sputum culture conversion.

Topics: Adult; Antitubercular Agents; Coinfection; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; Humans; Isoniazid; Logistic Models; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Sputum; Treatment Outcome; Tuberculosis, Pulmonary

Disseminated intravascular coagulation (DIC) induced by daily rifampicin therapy is rare, especially the patient is absent of malignancy, severe infection, and prior exposure to rifampicin.. We report a case of DIC induced by daily rifampicin treatment for pulmonary tuberculosis. A 22-year-old, previously healthy man received an anti-tuberculosis therapy consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide on the daily dose recommended by the World Health Organization tuberculosis guidelines after a diagnosis of pulmonary tuberculosis. Two weeks later, he was transferred to the West China Hospital with nasal hemorrhage for 1 week, hematochezia, hematuria, and petechiae for 5 days.. Laboratory data and symptoms on admission indicated DIC.. The anti-tuberculosis drugs were discontinued after admission and he was initiated with targeted treatment for DIC, omeprazole and polyene hosphatidylcholine infusion, as well as nutrition supportive treatment. Five days after admission, ethambutol, moxifloxacin, and amikacin were added to the patient without further active hemorrhage. Eight days after admission, the platelet count had risen gradually. Isoniazid was administered on 24 days after admission, while his liver function tests and platelet counts returned to normal. No recurrence of DIC occurred. The diagnosis of rifampicin-induced DIC was confirmed.. The patient recovered and left hospital with isoniazid, ethambutol, levofloxacin, and streptomycin after 4 weeks of hospitalization. There was no recurrence of DIC or hemorrhage during the 8 months of follow-up. The literature review revealed that there were 10 other cases of rifampicin-induced DIC. Only 4 cases received rifampicin on a daily basis for pulmonary tuberculosis treatment and the others were on intermittent dosing schedule for pulmonary tuberculosis or leprosy treatment.. As a rare adverse effect, DIC induced by rifampicin occurs irregularly and unpredictably, which is reported to be more associated with the intermittent usage of rifampicin, but can occur with rifampicin daily administration. Identification of early symptoms, drug discontinuation, supportive management, and regular monitoring are the key points to correct this adverse effect, which may contribute to severe even fetal results in patients and deserves more attention.

Topics: Antitubercular Agents; China; Disseminated Intravascular Coagulation; Gastrointestinal Hemorrhage; Hematuria; Humans; Male; Purpura; Rifampin; Tuberculosis, Pulmonary; Young Adult

Topics: Antibiotics, Antitubercular; Clinical Trials as Topic; Humans; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The Indian Revised National Tuberculosis (TB) Control Programme uses thrice-weekly treatment with standard drug dosages. The role of plasma drug levels and other factors in determining TB treatment outcomes is not well understood. We aimed to determine the factors influencing the concentrations of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) at 2 h postdosing in adult TB patients and to study the factors impacting TB treatment outcome. We recruited 1,912 adult TB patients (newly treated and retreated patients) with pulmonary/extrapulmonary TB receiving antitubercular treatment (ATT) in the RNTCP in Chennai, India. At steady state, the concentrations of RMP, INH, and PZA were determined at 2 h postdosing after supervised drug administration. A total of 1,648 patients had a favorable outcome, while 264 (14%) had an unfavorable outcome. A total of 91%, 16%, and 17% of the patients had suboptimal concentrations of RMP (<8 μg/ml), INH (<3 μg/ml), and PZA (<20 μg/ml), respectively. Factors associated with treatment outcome were low RMP concentrations (adjusted odds ratio [aOR], 0.94; 95% confidence interval [CI], 0.89 to 0.99;

Topics: Adult; Antitubercular Agents; Arylamine N-Acetyltransferase; Drug Dosage Calculations; Drug Therapy, Combination; Female; Humans; India; Isoniazid; Male; Middle Aged; Prospective Studies; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Child; Humans; Isoniazid; Middle Aged; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary; Young Adult

Topics: Antibiotics, Antitubercular; Bacteriological Techniques; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Rifampin; Sensitivity and Specificity; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

More than 25% of the world population has been infected with tuberculosis (TB), however only 10% of those infected will ever develop active disease. Clinically significant disease occurs through progression of primary infection or through later reactivation of latent TB infection (LTBI); this is most likely to occur in the first few years following infection, although late reactivation can occur several decades later, particularly in individuals who become immunosuppressed. Risk of TB acquisition is increased in people who have come to the UK from high incidence countries or who are born in the UK but come from high-risk ethnic minority groups. In 2015, 73% of those diagnosed with active TB were born outside the UK. Other risk groups include those who are homeless, in prison or who misuse drugs or alcohol. Once infected people who are immunosuppressed are at greater risk of progression to active disease. Infants below the age of 12 months can develop rapidly progressive and potentially fatal infection. Initial clinical assessment with chest radiography and the collection of three deep respiratory samples for smear microscopy and culture remain the standard of care. The management of active TB has not changed significantly over many years. The most significant changes in the 2016 NICE guidance relate to screening for LTBI in individuals who are contacts of a patient with active TB, or who are recent entrants to the UK from a high incidence country. NICE recommends that only contacts of patients with active pulmonary or laryngeal TB be screened.

Topics: Antitubercular Agents; Contact Tracing; Humans; Isoniazid; Latent Tuberculosis; Mass Screening; Practice Guidelines as Topic; Radiography, Thoracic; Rifampin; Tuberculosis, Pulmonary

We report the case of a 28-year-old resident doctor with no past history of having taken rifampicin, who presented with thrombocytoapaenic purpura occurring after the initiation of anti-tuberculosis therapy (isoniazid, rifampicin, pyrazinamide and ethambutol) for tubercular lymphadenopathy.

Topics: Adult; Antibiotics, Antitubercular; Humans; Lymph Nodes; Male; Mediastinum; Purpura, Thrombocytopenic; Radiography, Thoracic; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary; Withholding Treatment

The aim of this study was to prepare and characterize spray dried inhalable chitosan nanoparticles (CNPs) for sustained delivery of anti-tubercular drugs, isoniazid (INH) and rifampicin (RIF), to the lungs. CNPs were prepared by ionic gelation technique followed spray drying. Results showed that the CNPs obtained had a smooth spherical shape with an average size of 230 ± 4.5 nm, with a poly dispersity index of 0.180 ± 0.021. Both drugs, were detected in various organs (lungs, liver, spleen and kidney) until 24 h post nebulization. The chemotherapeutic efficacy of a single dose of drug-loaded CNPs suggested that they are more effective against the mycobacterium than free drugs.

Topics: Administration, Inhalation; Animals; Antibiotics, Antitubercular; Chitosan; Disease Models, Animal; Drug Carriers; Female; Humans; Isoniazid; Mice; Mice, Inbred BALB C; Nanoparticles; Rifampin; Tuberculosis, Pulmonary

Rifampicin (RIF) induces cytochrome P450, which in turn catalyzes drug metabolism; however, pharmacokinetic studies on this phenomenon in the Chinese population, especially in the context of disease, are limited. Therefore, we sought to establish population-based pharmacokinetic models of RIF in a Chinese population with pulmonary tuberculosis (TB). Clinical data were retrospectively collected from 54 patients with pulmonary TB and analyzed alongside RIF blood levels from 95 samples collected prior to RIF administration and between 2 and 12 hours after treatment. HPLC was used to measure serum RIF concentrations. A nonlinear mixed model used to characterize RIF pharmacokinetics and the data generated from the present study were validated using a bootstrap method. Covariates, including demographics, as well as hematological and biological indicators were analyzed. We observed a 1-compartment model with first-order absorption. Typical population values of apparent clearance (CL/F) and apparent volume of distribution (VD /F) were 4.02 L/h and 57.8 L, respectively. No covariate significantly changed the parameters of CL/F and VD . The present study may serve as a foundation for individualized therapy and offer a basis for pharmacokinetic-pharmacodynamic (PK-PD) analysis.

Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antitubercular; Asian People; Female; Humans; Male; Middle Aged; Models, Biological; Rifampin; Tuberculosis, Pulmonary; Young Adult

Therapeutic drug monitoring in tuberculosis remains controversial. We evaluated the relationship between antituberculosis drug levels in blood and clinical outcome. Serum concentrations of first-line antituberculosis drugs were measured in tuberculosis patients between March 2006 and April 2013. Venous blood was drawn 2 h after drug ingestion and was analyzed using high-performance liquid chromatography-tandem mass spectrometry. We retrospectively reviewed the data and determined the association of serum drug levels with clinical outcome. Among 413 patients, the prevalences of low serum concentrations of isoniazid (INH), rifampin (RMP), ethambutol (EMB), and pyrazinamide (PZA) were 59.9%, 27.8%, 12.8%, and 8.7%, respectively. The low INH group had a greater percentage of patients with a history of tuberculosis treatment (19.2% versus 11.0%; P = 0.026) and was more likely to present with drug-resistant strains (17.6% versus 8.8%; P = 0.049) than the normal INH group; however, low levels of INH, RMP, EMB, and PZA were not related to treatment outcome. Low INH level had a tendency to be associated with 2-month culture positivity, but it was not statistically significant (P = 0.072) in multivariate analysis. Seventeen (4.1%) patients experienced a recurrence. However, the recurrence rate was not statistically different between the low and normal INH groups. Low serum INH may play a role in recurrence and in acquired drug resistance. However, the serum level of INH was not directly related to either treatment response or recurrence rate. The role and usefulness of therapeutic drug monitoring should be evaluated in further prospective studies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antitubercular Agents; Chromatography, Liquid; Drug Monitoring; Ethambutol; Female; Humans; Isoniazid; Male; Mass Spectrometry; Middle Aged; Multivariate Analysis; Mycobacterium tuberculosis; Pyrazinamide; Recurrence; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

Rifampin is a key sterilizing drug in the treatment of tuberculosis (TB). It induces its own metabolism, but neither the onset nor the extent of autoinduction has been adequately described. Currently, the World Health Organization recommends a rifampin dose of 8 to 12 mg/kg of body weight, which is believed to be suboptimal, and higher doses may potentially improve treatment outcomes. However, a nonlinear increase in exposure may be observed because of saturation of hepatic extraction and hence this should be taken into consideration when a dose increase is implemented. Intensive pharmacokinetic (PK) data from 61 HIV-TB-coinfected patients in South Africa were collected at four visits, on days 1, 8, 15, and 29, after initiation of treatment. Data were analyzed by population nonlinear mixed-effects modeling. Rifampin PKs were best described by using a transit compartment absorption and a well-stirred liver model with saturation of hepatic extraction, including a first-pass effect. Autoinduction was characterized by using an exponential-maturation model: hepatic clearance almost doubled from the baseline to steady state, with a half-life of around 4.5 days. The model predicts that increases in the dose of rifampin result in more-than-linear drug exposure increases as measured by the 24-h area under the concentration-time curve. Simulations with doses of up to 35 mg/kg produced results closely in line with those of clinical trials.

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; Area Under Curve; Biological Availability; Biotransformation; Body Weight; Clinical Trials as Topic; Cohort Studies; Coinfection; Computer Simulation; Ethambutol; Female; Half-Life; HIV Infections; Humans; Isoniazid; Liver; Male; Middle Aged; Models, Statistical; Rifampin; Tuberculosis, Pulmonary

Topics: Adolescent; Antitubercular Agents; Drug Eruptions; Drug Therapy, Combination; Humans; Isoniazid; Male; Rifampin; Tuberculosis, Pulmonary

Pyrazinamide (PZA) is a key sterilizing drug in first-line tuberculosis (TB) regimens and exerts its activity entirely during the first 2 months in human infections. We recently described the reduced activity of PZA in C3HeB/FeJ mice with large caseous tubercles due to neutral pH. Here, we aimed to determine the contribution of PZA to the sterilizing activity of the first-line TB regimen in C3HeB/FeJ and BALB/c mice. Three regimens were compared (in combinations: R, rifampin; H, isoniazid; E, ethambutol; Z, pyrazinamide; with numbers indicating the treatment duration, in months): 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ. Lung CFU counts were assessed after 0 and 2 months of treatment, and relapse rates were assessed 3 months after 3, 4.5, and 6 months of treatment. The relapse rates after 3 months of treatment were 53% and 95% in C3HeB/FeJ mice receiving 2RHEZ/1RH and 2RHE/1RH, respectively, and 67%, 100%, and 80% in BALB/c receiving 2RHEZ/1RH, 2RHE/1RH, and 2RHEZ/1RHZ, respectively. The relapse rates after 4.5 months of treatment were 32%, 20%, and 0% in C3HeB/FeJ mice receiving 2RHEZ/2.5RH, 2RHE/2.5RH, and 2RHEZ/2.5RHZ, respectively, and 0% and 67% in BALB/c receiving 2RHEZ/2.5RH and 2RHE/2.5RH, respectively. The month-6 relapse rates were 0%, 13%, and 0% in C3HeB/FeJ mice given 2RHEZ/4RH, 2RHE/4RH, and 2RHEZ/4RHZ, respectively, and 7% in BALB/c mice receiving 2RHE/4RH. The addition of PZA shortens the duration of treatment needed to prevent relapse in both mouse strains. However, while its contribution is limited to the first 2 months of treatment in BALB/c mice, continuing PZA beyond the first 2 months is beneficial in C3HeB/FeJ mice by preventing relapse among those with the highest disease burden.

Topics: Animals; Antitubercular Agents; Disease Models, Animal; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Female; Isoniazid; Mice, Inbred BALB C; Mice, Inbred C3H; Mutation; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Treatment Outcome; Tuberculosis, Pulmonary

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

This case study examines the ethical dimensions of isolation for patients diagnosed with tuberculosis (TB) in Australia. It seeks to explore the issues of resource allocation, liberty, and public safety for wider consideration and discussion.

Topics: Adult; Antitubercular Agents; Australia; Ethics, Institutional; Family; Humans; Isoniazid; Male; Mycobacterium tuberculosis; Patient Isolation; Rifampin; Sputum; Transients and Migrants; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Emergency Service, Hospital; Ethambutol; Female; Humans; Isoniazid; Mycobacterium tuberculosis; Parents; Pyrazinamide; Recurrence; Rifampin; Risk Assessment; Risk Factors; Siblings; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

The Xpert MTB/RIF (Xpert) assay is a rapid nucleic acid amplification test widely used in settings of high tuberculosis prevalence to detect tuberculosis as well asrpoBmutations associated with rifampin resistance. Data are needed on the diagnostic performance of Xpert in lower-prevalence settings to inform appropriate use for both tuberculosis detection and the need for respiratory isolation.. Xpert was compared to 2 sputum samples, each evaluated with acid-fast bacilli (AFB) smear and mycobacterial culture using liquid and solid culture media, from participants with suspected pulmonary tuberculosis from the United States, Brazil, and South Africa.. Of 992 participants enrolled with evaluable results, 22% had culture-confirmed tuberculosis. In 638 (64%) US participants, 1 Xpert result demonstrated sensitivity of 85.2% (96.7% in participants with AFB smear-positive [AFB(+)] sputum, 59.3% with AFB smear-negative [AFB(-)] sputum), specificity of 99.2%, negative predictive value (NPV) of 97.6%, and positive predictive value of 94.9%. Results did not differ between higher- and low-prevalence settings. A second Xpert assay increased overall sensitivity to 91.1% (100% if AFB(+), 71.4% if AFB(-)), with specificity of 98.9%. In US participants, a single negative Xpert result predicted the absence of AFB(+)/culture-positive tuberculosis with an NPV of 99.7%; NPV of 2 Xpert assays was 100%, suggesting a role in removing patients from airborne infection isolation. Xpert detected tuberculosis DNA and mutations associated with rifampin resistance in 5 of 7 participants with rifampin-resistant, culture-positive tuberculosis. Specificity for rifampin resistance was 99.5% and NPV was 98.9%.. In the United States, Xpert testing performed comparably to 2 higher-tuberculosis-prevalence settings. These data support the use of Xpert in the initial evaluation of tuberculosis suspects and in algorithms assessing need for respiratory isolation.

Topics: Adult; Antibiotics, Antitubercular; Brazil; DNA, Bacterial; Drug Resistance, Bacterial; Female; Humans; Male; Middle Aged; Mutation; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Prevalence; Rifampin; Sensitivity and Specificity; South Africa; Sputum; Tuberculosis, Pulmonary; United States

The failure of current Standard Short-Course Chemotherapy (SCC) in new and previously treated cases with tuberculosis (TB) was mainly due to drug resistance development. But little is known on the characteristics of acquired drug resistant TB during SCC and its correlation with SCC failure. The objective of the study is to explore the traits of acquired drug resistant TB emergence and evaluate their impacts on treatment outcomes.. A prospective observational study was performed on newly admitted smear positive pulmonary TB (PTB) cases without drug resistance pretreatment treated with SCC under China's National TB Control Program (NTP) condition from 2008 to 2010. Enrolled cases were followed up through sputum smear, culture and drug susceptibility testing (DST) at the end of 1, 2, and 5 months after treatment initiation. The effect factors of early or late emergence of acquired drug resistant TB , such as acquired drug resistance patterns, the number of acquired resistant drugs and previous treatment history were investigated by multivariate logistic regression; and the impact of acquired drug resistant TB emergence on treatment failure were further evaluated.. Among 1671 enrolled new and previously treated cases with SCC, 62 (3.7%) acquired different patterns of drug resistant TB at early period within 2 months or later around 3-5 months of treatment. Previously treated cases were more likely to develop acquired multi-drug resistant TB (MDR-TB) (OR, 3.8; 95%CI, 1.4-10.4; P = 0.015). Additionally, acquired MDR-TB cases were more likely to emerge at later period around 3-5 months after treatment starting than that of non-MDR-TB mainly appeared within 2 months (OR, 8.3; 95%CI, 1.7-39.9; P = 0.008). Treatment failure was associated with late acquired drug resistant TB emergence (OR, 25.7; 95%CI, 4.3-153.4; P < 0.001) with the reference of early acquired drug resistant TB emergence.. This study demonstrates that later development of acquired drug resistant TB during SCC is liable to suffer treatment failure and acquired MDR-TB pattern may be one of the possible causes.

Topics: Adolescent; Adult; Antitubercular Agents; China; Cohort Studies; Drug Resistance, Bacterial; Drug Therapy, Combination; Ethambutol; Female; Humans; Isoniazid; Male; Middle Aged; Mycobacterium tuberculosis; Prospective Studies; Pyrazinamide; Rifampin; Streptomycin; Treatment Failure; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

The extent to which the Xpert MTB/RIF (Gene Xpert) contributes to tuberculosis (TB) diagnosis in samples other than sputum and cerebrospinal fluid remains uncertain. We aimed to assess the role of Xpert MTB/RIF for detecting M. tuberculosis in post-mortem tissues. We conducted a study among 30 complete diagnostic autopsies (CDA) performed at the Maputo Central Hospital (Mozambique). Lung tissues were screened for TB in all cases. In addition other tissues were tested when compatible lesions were identified in the histological exam. We used in-house real time PCR and LAMP assays to confirm the presence of M. tuberculosis DNA. The diagnosis of tuberculosis at death was established based on microbiological and histopathological results. Eight out of 30 cases (26.7%) were diagnosed of tuberculosis. Xpert had a sensitivity to detect TB in lung tissue of 87.5% (95% CI 47.3-99.7) and a specificity of 95.7% (95% CI: 78.1-99.9). In-house DNA amplification methods and Xpert showed 93.6% concordance for lung tissue and 100% concordance for brain and liver tissues. The final cause of death was attributable to tuberculosis in four cases. Xpert MTB/RIF may represent a valuable, easy-to perform technique for post-mortem TB diagnosis.

Topics: Adolescent; Adult; Aged; Brain; Cause of Death; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Female; Humans; Liver; Lung; Male; Middle Aged; Mycobacterium tuberculosis; Nucleic Acid Amplification Techniques; Reagent Kits, Diagnostic; Rifampin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Topics: Child; Drug Resistance, Bacterial; Humans; Molecular Diagnostic Techniques; Mycobacterium tuberculosis; Rifampin; Sensitivity and Specificity; Sputum; Tuberculosis; Tuberculosis, Pulmonary

We report investigation of 22 TB cases with positive Xpert MTB/RIF result for resistance to Rifampin and "Very Low" MTB detection level. Twelve cases were false positive without rpoB mutations, 2 were false-positives with a silent mutation in rpoB codon T508, and only 10 were true positives.

Topics: Bacterial Load; Humans; Microbial Sensitivity Tests; Mutation; Mycobacterium tuberculosis; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Rifampin; Sputum; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary