trimethoprim--sulfamethoxazole-drug-combination and Tuberculosis--Multidrug-Resistant

Tuberculosis (TB) is an important cause of illness and death in HIV-positive children living in areas of high TB prevalence. We know that isoniazid prophylaxis prevents TB in HIV-negative children following TB exposure, but there is uncertainty related to its role in TB preventive treatment in HIV-positive children.. To summarise the effects of TB preventive treatment versus placebo in HIV-positive children with no known TB contact on active TB, death, and reported adverse events.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, Embase and two trial registers up to February 2017.. We included trials of HIV-positive children with and without known TB exposure, randomized to receive TB preventive treatment or placebo.. Two review authors independently used the study selection criteria, assessed risk of bias, and extracted data. We assessed effects using risk, incidence rate and hazard ratios and assessed the certainty of evidence using GRADE.. We included three trials, involving 991 participants, below the age of 13 years, from South Africa and Botswana. Children were randomized to isoniazid prophylaxis or placebo, given daily or three times weekly. The median length of follow-up ranged from 5.7 to 34 months; some were on antiretroviral therapy (ART).In HIV-positive children not on ART, isoniazid prophylaxis may reduce the risk of active TB (hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.11 to 0.87; 1 trial, 240 participants, low certainty evidence), and death (HR 0.46, 95% CI 0.22 to 0.95; 1 trial, 240 participants, low certainty evidence). One trial (182 participants) reported number of children with laboratory adverse events, which was similar between the isoniazid prophylaxis and placebo groups. No clinical adverse events were reported.In HIV-positive children on ART, we do not know if isoniazid prophylaxis reduces the risk of active TB (risk ratio (RR) 0.76, 95% CI 0.50 to 1.14; 3 trials, 737 participants, very low certainty evidence) or death (RR 1.45, 95% CI 0.78 to 2.72; 3 trials, 737 participants, very low certainty evidence). Two trials (714 participants) reported number of clinical adverse events and three trials (795 participants) reported number of laboratory adverse events; for both categories, the number of adverse events were similar between the isoniazid prophylaxis and placebo groups.. Isoniazid prophylaxis given to all children diagnosed with HIV may reduce the risk of active TB and death in HIV-positive children not on ART in studies from Africa. For children on ART, no clear benefit was detected. .

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; Child; HIV Infections; Humans; Incidence; Isoniazid; Randomized Controlled Trials as Topic; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tuberculosis (TB) remains a serious public health threat worsened by emerging drug resistance. Mycobacterium tuberculosis has become resistant not only to front-line drugs but also to second-line antimicrobials directed at drug-resistant TB. Renewed efforts are devoted for the development of new antibiotics active against TB. Also, repurposing of other antibiotics is being explored to shorten the time to develop new drugs against M. tuberculosis. As a result, trimethoprim-sulfamethoxazole (SXT) has emerged as a potential new option to treat drug-resistant TB. SXT has been found to be surprisingly active against drug-resistant M. tuberculosis, not only in vitro but also in vivo. The potential role of SXT for the treatment of multidrug resistant/extensively drug resistant TB might be explored in further clinical evaluations.

Topics: Antitubercular Agents; Clinical Trials as Topic; Drug Repositioning; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant

Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of already available drugs. Six drugs with antimicrobial activity (phenothiazine, metronidazole, doxycycline, disulfiram, tigecycline and co-trimoxazole) are not listed in the World Health Organization guidelines on MDR-TB treatment but could be potential candidates for evaluation against Mycobacterium tuberculosis. A systematic review was conducted to evaluate antituberculous activity of these drugs against M. tuberculosis. We searched PubMed, Google Scholar and Embase for English articles published up to December 31, 2012. We reviewed in vitro, in vivo and clinical antituberculous activity of these drugs in addition to pharmacokinetics and side-effects. Of the drugs effective against actively replicating M. tuberculosis, co-trimoxazole seems to be the most promising, because of its consistent pharmacokinetic profile, easy penetration into tissue and safety profile. For the dormant state of TB, thioridazine may play a potential role as an adjuvant for treatment of MDR-TB. A strategy consisting of pharmacokinetic/pharmacodynamic studies, dose finding and phase III studies is needed to explore the role of these drugs in MDR-TB treatment.

Topics: Anti-Infective Agents; Antitubercular Agents; Chemistry, Pharmaceutical; Clinical Trials as Topic; Disulfiram; Doxycycline; Drug Design; Humans; Metronidazole; Minocycline; Mycobacterium tuberculosis; Phenothiazines; Tigecycline; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant

Mortality rates are high in antiretroviral therapy (ART) programmes in sub-Saharan Africa, especially during the first few months of treatment. Tuberculosis (TB) has been identified as a major underlying cause. Under routine programme conditions, between 5 and 40% of adult patients enrolling in ART services have a baseline diagnosis of TB. There is also a high TB incidence during the first few months of ART (much of which is prevalent disease missed by baseline screening) and long-term rates remain several-folds higher than background. We identify three groups of patients entering ART programmes for which different interventions are required to reduce TB-related deaths. First, diagnostic screening is needed in patients who have undiagnosed active TB so that timely anti-TB treatment can be started. This may be greatly facilitated by new diagnostic assays such as the Xpert MTB/RIF assay. Second, patients with a diagnosis of active TB need optimized case management, which includes early initiation of ART (with timing now defined by randomized controlled trials), trimethoprim-sulphamethoxazole prophylaxis and treatment of comorbidity. Third, all remaining patients who are TB-free at enrolment have high ongoing risk of developing TB and require preventive interventions, including optimized immune recovery (with ART ideally started early in the course of HIV infection), isoniazid preventive therapy and infection control to reduce infection risk. Further specific measures are needed to address multidrug-resistant TB (MDR-TB). Finally, scale-up of all these interventions requires nationally and locally tailored models of care that are patient-centred and provide integrated healthcare delivery for TB, HIV and other comorbidities.

Topics: Acquired Immunodeficiency Syndrome; Africa South of the Sahara; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Anti-Infective Agents; CD4 Lymphocyte Count; Delivery of Health Care; Female; HIV Seropositivity; Humans; Incidence; Male; Mass Screening; Risk Factors; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis; Tuberculosis, Multidrug-Resistant

Children with HIV are at increased risk of acquiring tuberculosis (TB), a common cause of acute and chronic respiratory disease and death in HIV-infected children living in areas where prevalence of the disease is high. Children infected with HIV and TB have worse outcomes than HIV-uninfected children who have TB; thus, preventing the infection and disease in HIV-infected children is potentially an important public health intervention. Isoniazid, an anti-tuberculosis medication, has been used effectively to prevent TB in HIV-uninfected children, but currently there are no guidelines on the use of TB preventive therapy in HIV-infected children.. To determine the impact of TB preventive therapy on TB-related incidence and death in HIV-infected children. We searched the Cochrane Controlled Trials Register (CENTRAL/CCTR), Cochrane HIV/AIDS Group Specialized Register, MEDLINE/PubMed, EMBASE, and AIDSearch. In addition, we scanned reference lists, manually searched conference abstracts, and contacted content experts.. We included studies of HIV-infected children randomised to receive TB preventive therapy or placebo, or an alternative TB preventive regimen. Participants could have tuberculin skin test results that were positive or negative.. Two authors independently used the study selection criteria, assessed methodological quality and extracted data. Effects were assessed using hazard ratios.. One trial met the selection criteria for the review. The trial participants were HIV-infected children, most of whom were not taking antiretroviral therapy. Subjects were randomised to isoniazid and cotrimoxazole or placebo and cotrimoxazole, given daily or three times a week. The trial showed a marked reduction in TB incidence and death in the isoniazid group. As yet, however, there are no long-term follow-up data on the durability of the protective effect or on possible long-term adverse events. This trial also was unable to assess the impact of isoniazid prophylaxis on children receiving antiretroviral therapy.. Isoniazid prophylaxis in HIV-infected children has the potential to play a major public health role by reducing TB incidence and death. As yet, however, data are insufficient to guide the duration of prophylaxis and to support its use in children using highly active antiretroviral therapy (HAART) and in those living in areas of low TB prevalence. Further studies are needed to assess whether TB preventive therapy is of benefit in all HIV-infected children, irrespective of use of antiretroviral treatment, the optimal duration of preventive therapy, or long-term adverse events.

Topics: AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; Child; HIV Infections; Humans; Incidence; Isoniazid; Randomized Controlled Trials as Topic; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Tuberculosis is currently an enormous global health problem. In industrialized countries in Western Europe and North America, tuberculosis case rates are low and an increasing proportion of cases now occur in foreign-born individuals and in marginalized populations, including the homeless, prisoners, drug users, and persons with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS). In contrast, the burden of tuberculosis in sub-Saharan Africa continues to grow, largely fueled by the HIV pandemic and poor public health infrastructure. Use of the World Health Organization's (WHO) directly observed therapy, short course (DOTS) strategy has been successful in improving outcomes and preventing the emergence of acquired drug resistance in several African countries; however, case rates are increasing throughout most of the region. It is clear that control of tuberculosis in Africa is closely linked to control of HIV and AIDS. Substantial external donor support and innovative approaches to enhance interactions between HIV/AIDS prevention and treatment efforts and tuberculosis control programs will be needed to improve the current tuberculosis situation in Africa. The purpose of this review is to provide a synopsis of recent developments in these areas and to serve as a reference source for interested readers.

Topics: Adult; Africa South of the Sahara; AIDS-Related Opportunistic Infections; Anti-Infective Agents; Antitubercular Agents; Humans; Incidence; Refugees; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis; Tuberculosis, Multidrug-Resistant; Western World

Worldwide, Drug-resistant Tuberculosis (DR-TB) remains a big problem; the diagnostic capacity has superseded the clinical management capacity thereby causing ethical challenges. In Sub-Saharan Africa, treatment is either inadequate or lacking and some diagnosed patients are on treatment waiting lists. In Uganda, various health system challenges impeded scale-up of DR-TB care in 2012; only three treatment initiation facilities existed, with only 41 of the estimated 1010 RR-TB/MDR-TB cases enrolled on treatment yet 300 were on the waiting list and there was no DR-TB treatment scale-up plan. To scale up care, the National TB and leprosy Program (NTLP) with partners rolled out a DR-TB mixed model of care. In this paper, we share achievements and outcomes resulting from the implementation of this mixed Model of DR-TB care. Routine NTLP DR-TB program data on treatment initiation site, number of patients enrolled, their demographic characteristics, patient category, disease classification (based on disease site and human immunodeficiency virus (HIV) status), on co-trimoxazole preventive therapy (CPT) and antiretroviral therapy (ART) statuses, culture results, smear results and treatment outcomes (6, 12, and 24 months) from 2012 to 2017 RR-TB/MDR-TB cohorts were collected from all the 15 DR-TB treatment initiation sites and descriptive analysis was done using STATA version 14.2. We presented outcomes as the number of patient backlog cleared, DR-TB initiation sites, RR-TB/DR-TB cumulative patients enrolled, percentage of co-infected patients on the six, twelve interim and 24 months treatment outcomes as per the Uganda NTLP 2016 Programmatic Management of drug-resistant Tuberculosis (PMDT) guidelines (NTLP, 2016). Over the period 2013-2015, the RR-TB/MDR-TB Treatment success rate (TSR) was sustained between 70.1% and 74.1%, a performance that is well above the global TSR average rate of 50%. Additionally, the cure rate increased from 48.8% to 66.8% (P = 0.03). The Uganda DR-TB mixed model of care coupled with early application of continuous improvement approaches, enhanced cohort reviews and use of multi-disciplinary teams allowed for rapid DR-TB program expansion, rapid clearance of patient backlog, attainment of high cumulative enrollment and high treatment success rates. Sustainability of these achievements is needed to further reduce the DR-TB burden in the country. We highly recommend this mixed model of care in settings with similar challenges.

Topics: Adolescent; Adult; Aftercare; Anti-Retroviral Agents; Antitubercular Agents; Chemoprevention; Cohort Studies; Coinfection; Delivery of Health Care; Drug Resistance, Multiple, Bacterial; Female; Health Plan Implementation; HIV Infections; Humans; Leprosy; Male; Middle Aged; Models, Organizational; Mycobacterium leprae; Mycobacterium tuberculosis; Patient Care Team; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant; Uganda; Young Adult

A Syrian asylum seeker with multidrug-resistant tuberculosis (TB) developed a bronchopleural fistula after pneumonectomy. Although screening tests were negative on admission, carbapenemase-producing Enterobacteriaceae were cultured after a few months of TB treatment. Prevalence of multidrug-resistant organisms is reported to be increased in asylum seekers compared with the general Dutch population. Arduous conditions during transit and interrupted health care delivery in our patient led to multiple-resistant microorganisms that complicated treatment.

Topics: Adult; Amikacin; Carbapenem-Resistant Enterobacteriaceae; Clofazimine; Drug Monitoring; Humans; Linezolid; Male; Moxifloxacin; Netherlands; Prevalence; Prothionamide; Refugees; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant

Additional drugs are needed for the treatment of multidrug-resistant tuberculosis (TB). Sulfamethoxazole has been shown to have in vitro activity against Mycobacterium tuberculosis; however, there is concern about resistance given the widespread use of trimethoprim-sulfamethoxazole prophylaxis among HIV-infected patients in sub-Saharan Africa. Thirty-eight of 40 Mycobacterium tuberculosis isolates (95%) from pretreatment sputum samples from Ugandan adults with pulmonary TB, including HIV-infected patients taking trimethoprim-sulfamethoxazole prophylaxis, were susceptible with MICs of ≤38.4 μg/ml.

Topics: Adult; Antitubercular Agents; Drug Resistance, Multiple, Bacterial; Female; HIV Infections; Humans; Male; Mycobacterium tuberculosis; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Nigeria is faced with a high burden of Human Immunodeficiency Virus (HIV) infection and multidrug-resistant tuberculosis (MDR-TB). Treatment outcomes among MDR-TB patients registered across the globe have been poor, partly due to high loss-to-follow-up. To address this challenge, MDR-TB patients in Nigeria are hospitalized during the intensive-phase(IP) of treatment (first 6-8 months) and are provided with a package of care including standardized MDR-TB treatment regimen, antiretroviral therapy (ART) and cotrimoxazole prophylaxis (CPT) for HIV-infected patients, nutritional and psychosocial support. In this study, we report the end-IP treatment outcomes among them.. In this retrospective cohort study, we reviewed the patient records of all bacteriologically-confirmed MDR-TB patients admitted for treatment between July 2010 and October 2012.. Of 162 patients, 105(65%) were male, median age was 34 years and 28(17%) were HIV-infected; all 28 received ART and CPT. Overall, 138(85%) were alive and culture negative at the end of IP, 24(15%) died and there was no loss-to-follow-up. Mortality was related to low CD4-counts at baseline among HIV-positive patients. The median increase in body mass index among those documented to be underweight was 2.6 kg/m2 (p<0.01) and CD4-counts improved by a median of 52 cells/microL among the HIV-infected patients (p<0.01).. End-IP treatment outcomes were exceptional compared to previously published data from international cohorts, thus confirming the usefulness of a hospitalized model of care. However, less than five percent of all estimated 3600 MDR-TB patients in Nigeria were initiated on treatment during the study period. Given the expected scale-up of MDR-TB care, the hospitalized model is challenging to sustain and the national TB programme is contemplating to move to ambulatory care. Hence, we recommend using both ambulatory and hospitalized approaches, with the latter being reserved for selected high-risk groups.

Topics: Adult; Anti-HIV Agents; Antitubercular Agents; CD4 Lymphocyte Count; Coinfection; Female; HIV; HIV Infections; Hospitalization; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Nigeria; Retrospective Studies; Survival Analysis; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant

We investigated the activity of trimethoprim-sulfamethoxazole (SXT) against Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB). The MIC distribution of SXT was 0.125/2.4 to 2/38 mg/liter for the 100 isolates tested, including multi- and extensively drug-resistant isolates (MDR/XDR-TB), whereas the intracellular MIC90 of sulfamethoxazole (SMX) for the pansusceptible strain H37Rv was 76 mg/liter. In an exploratory analysis using a ratio of the unbound area under the concentration-time curve from 0 to 24 h over MIC (fAUC0-24/MIC) using ≥ 25 as a potential target, the cumulative fraction response was ≥ 90% at doses of ≥ 2,400 mg of SMX. SXT is a potential treatment option for MDR/XDR-TB.

Topics: Antitubercular Agents; Cell Line; Drug Resistance, Multiple, Bacterial; Gene Expression; Genes, Reporter; Humans; Luciferases; Macrophages; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant

Co-trimoxazole (SXT), a combination of sulfamethoxazole and trimethoprim, has shown in vitro activity against Mycobacterium tuberculosis. However, the pharmacokinetic and pharmacodynamic parameters of SXT in multidrug-resistant (MDR) tuberculosis (TB) are, thus far, lacking. Therefore, we evaluated its pharmacokinetics and drug susceptibility, along with its tolerability during treatment. Based on drug susceptibility testing, MDR-TB patients received SXT as a part of their MDR treatment. The pharmacokinetic parameters of sulfamethoxazole, the effective component of SXT against M. tuberculosis, were evaluated. The ratio of the area under the curve from 0 to 24 h (AUC0-24) to minimum inhibitory concentration (MIC) was used as the best pharmacokinetic/pharmacodynamic parameter to predict the efficacy of sulfamethoxazole. Adverse effects of SXT were also evaluated. 10 patients with MDR-TB (one of whom had extensively drug-resistant TB) received 480 mg of SXT with a median dosage of 6.5 mg·kg(-1) of SXT (range 6.1-6.8 mg·kg(-1)) once daily for a median treatment period of 381 days (range 129-465 days). In two patients, the dose was escalated to 960 mg. The free AUC0-24/MIC of sulfamethoxazole exceeded 25 in only one patient. SXT was safe and well-tolerated, except for one patient who had gastrointestinal side-effects after receiving 960 mg of SXT. Additional studies are needed to find the pharmacokinetic and pharmacodynamic targets, and consequently to set the optimal dose, of SXT for MDR-TB treatment.

Topics: Adult; Antitubercular Agents; Area Under Curve; Extensively Drug-Resistant Tuberculosis; Female; Humans; Male; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant; Young Adult

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Antitubercular Agents; Arthritis, Infectious; Drug Therapy, Combination; Hepatitis C, Chronic; HIV Infections; Humans; Knee Joint; Male; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Pneumocystis carinii; Pneumonia, Pneumocystis; Substance Abuse, Intravenous; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant; Tuberculosis, Osteoarticular

Topics: Anti-Bacterial Agents; Female; Flavobacterium; Gram-Negative Bacterial Infections; Humans; Infant; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant