bedaquiline and Tuberculosis--Pulmonary

Treatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens.. We did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug.. 58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed.. Fluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis.. Canadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

Topics: Adult; Aminosalicylic Acid; Antitubercular Agents; Canada; Clofazimine; Diarylquinolines; Drug-Related Side Effects and Adverse Reactions; Female; Fluoroquinolones; Humans; Incidence; Linezolid; Male; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

TB is a global disease and the leading cause of death among infectious diseases worldwide. TB was considered incurable till the mid 19th century. The major landmark in the treatment was the discovery of Rifampicin which has led to shorter courses of therapy as compared to the previous regimens which also consisted of injectables. Although, treatment for TB is evolving expeditiously today but a lot needs to be done as far as drug resistant TB (DRTB) is concerned. Non-standard regimens in private sector, lack of access to drug susceptibility testing, delay in the treatment, poor follow up and default in the treatment has led to emergence DRTB. Addition of newer drugs like bedaquiline and delamanid has made oral regimen possible in DRTB as well. Encouraging results of BPaL regimen for extensively drug resistant TB (XDR-TB) may prove to be a game changer. The target of TB elimination by 2025 is onerous considering the huge population, rising DRTB patients and private sector non engagement in the programme despite implementation of second largest national programme of the world.

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Humans; Microbial Sensitivity Tests; Nitroimidazoles; Oxazoles; Tuberculosis, Pulmonary

Multidrug-resistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR)-TB epidemics are key obstacles towards TB control and elimination.. Diagnosis of MDR/XDR-TB is difficult and requires several weeks. New diagnostic tools are being tested and proposed allowing for shorter time to diagnosis and reduced delays in starting an adequate treatment regimen. MDR/XDR-TB treatment strategies are currently on an evolving stage. New shortened treatments based on the recommended 'Bangladesh regimen' or on the newer anti-TB drugs, delamanid and bedaquiline may represent part of the future scenario. In addition, more information on safety and efficacy of delamanid and bedaquiline has been published, allowing to better position these drugs. Recent information on treatment regimens for the paediatric age, with or without delamanid or bedaquiline, has become available. This is of great help in designing safer and more efficacious regimens for the treatment of MDR/XDR-TB in children and adolescents.. The accessibility, sustainability and scale-up of new diagnostic technologies are lagging behind and more efforts are needed. In addition, we need high-quality information on safety and efficacy of various combinations of drugs to obtain the best possible regimens to treat the largest possible proportion of patients.

Topics: Adolescent; Antitubercular Agents; Child; Diarylquinolines; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis.. In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration.. Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I. Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition.. American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Topics: Amikacin; Antitubercular Agents; Capreomycin; Carbapenems; Clofazimine; Diarylquinolines; Drug Therapy, Combination; Fluoroquinolones; Humans; Kanamycin; Levofloxacin; Linezolid; Moxifloxacin; Recurrence; Treatment Failure; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Few innovative anti-microbial products have been brought to market in recent years to combat the global multidrug resistant-tuberculosis (MDR-TB) epidemic. Bedaquiline, a novel oral diarylquinoline, was approved by the US FDA as a part of combination therapy in adults with pulmonary MDR-TB based on phase II trials.. Pubmed searches were conducted using search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included World Health Organization, Clinicaltrial.gov, US Food and Drug Administration. Bedaquiline is an ATP synthase inhibitor specific for M. tuberculosis and some nontuberculous mycobacteria. It is metabolized by CYP3A4 and it's drug exposure can be influenced by inducers and inhibitors of this enzyme. Phase II studies showed promising results on efficacy of bedaquiline when being used in combination with a background regimen for MDR-TB. Main safety concerns include QTc prolongation and hepatotoxicity. Phase III trials are ongoing to confirm efficacy findings from phase II studies and provide additional evidence of safety and efficacy. Expert commentary: Critical data for long-term efficacy and safety are incomplete and scarce, supporting the cautious use of bedaquiline.

Topics: Administration, Oral; Adult; Animals; Antitubercular Agents; Cytochrome P-450 CYP3A; Diarylquinolines; Drug Interactions; Drug Therapy, Combination; Humans; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Child; Diarylquinolines; Drug Evaluation; Drug Resistance, Multiple, Bacterial; Humans; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

In recent years, a pressing need to develop new, effective and safe drugs against tuberculosis (TB) has continued. Poor adherence to a long therapeutic regimen against TB, intermittent drug use, errors in medical prescriptions, low quality of old TB drugs and ineffective TB control have led to the emergence of resistant TB.. Two new drugs have gained importance and seem promising against resistant TB: bedaquiline and delamanid. This review summarizes the main characteristics of these two drugs and their role in TB management.. Bedaquiline and delamanid appear to be promising new anti-TB drugs. Due to a mechanism of action that is different from that of other available drugs, their efficacy has appeared optimal in cases of adults with resistant pulmonary TB. Although their pharmacokinetic and pharmacodynamic profiles seem optimal, potential cardiologic side effects such as QT-interval prolongation have been associated with their use. However, specific studies performed in the pediatric population are needed to confirm these results. This seems particularly important considering the long duration of TB treatment required for resistant TB as well as the potential interactions with other drugs included in anti-TB regimens or administered for an underlying comorbidity.

Topics: Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Interactions; Drug Resistance, Bacterial; Humans; Nitroimidazoles; Oxazoles; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Treatment of multidrug-resistant tuberculosis (MDR-TB) is hindered by limited efficacy and significant toxicity of second-line drugs. The need for new therapeutic options is critical to combat the global MDR-TB epidemic. Bedaquiline is a novel oral diarylquinoline approved by Food and Drug administration (FDA) for the treatment of adults with pulmonary MDR-TB on the basis of Phase IIb trial data under the provisions of the accelerated approval regulations for serious or life-threatening conditions. The FDA advisory committee members voted unanimously on efficacy data based on surrogate measures, however they were split on the issues of safety of bedaquiline. Main safety concerns include QT interval prolongation, hepatic related adverse events, and excess mortality in bedaquiline treated patients. While bedaquiline approval is a story of many firsts and certainly a welcome addition to the existing arsenal of anti-TB agents, a cautiously optimistic approach is required to assess the risk benefit profile of the drug. Acceleration of further Phase III trials and clinical studies is imperative, as is timely analysis of emerging data on the real world use of the drug. This mini review outlines the clinical pharmacology of bedaquiline highlighting the potential promises and challenges that implicate the risk benefit profile of drug.

Topics: Antitubercular Agents; Diarylquinolines; Humans; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

TB still represents a serious public health problem. The latest reports estimate an incidence of 8.7 million cases in 2011 and 1.4 million deaths. Drug resistance contributed an estimated 630,000 cases of multidrug-resistant TB, making control of the disease harder. Recent reports show cases of TB that were almost resistant to all available antibiotics. Therefore, there is an urgent need to develop new anti-TB drugs with the potential of reducing the current length of treatment. Bedaquiline, formerly TMC207, is a new diarylquinoline antibiotic with specific activity against Mycobacterium tuberculosis and several nontuberculous mycobacteria. It acts by inhibiting ATP synthase, interfering with the energy generation needed by the bacterial cell. Based on clinical evaluations for safety, tolerability and efficacy, bedaquiline has recently received accelerated approval for the treatment of pulmonary multidrug-resistant TB in adults. This article will review the main aspects related to the chemistry, microbiology, pharmacology, efficacy and tolerability of bedaquiline.

Topics: Adenosine Triphosphate; Antitubercular Agents; Diarylquinolines; Drug Approval; Drug-Related Side Effects and Adverse Reactions; Energy Metabolism; Humans; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Although treatment of drug-susceptible tuberculosis (TB) under ideal conditions may be successful in >or=95% of cases, cure rates in the field are often significantly lower due to the logistical challenges of administering and properly supervising the intake of combination chemotherapy for 6-9 months. Success rates are far worse for multidrug-resistant and extensively drug-resistant TB cases. There is general agreement that new anti-TB drugs are needed to shorten or otherwise simplify treatment for drug-susceptible and multidrug-resistant/extensively drug-resistant-TB, including TB associated with HIV infection. For the first time in over 40 years, a nascent pipeline of new anti-TB drug candidates has been assembled. Eleven candidates from seven classes are currently being evaluated in clinical trials. They include novel chemical entities belonging to entirely new classes of antibacterials, agents approved for use against infections other than TB, and an agent already approved for limited use against TB. In this article, we review the current state of TB treatment and its limitations and provide updates on the status of new drugs in clinical trials. In the conclusion, we briefly highlight ongoing efforts to discover new compounds and recent advances in alternative drug delivery systems.

Topics: Adamantane; Animals; Antitubercular Agents; Carbapenems; Clinical Trials as Topic; Diarylquinolines; Drug Delivery Systems; Ethylenediamines; Fluoroquinolones; Humans; Isonicotinic Acids; Mice; Mycobacterium tuberculosis; Nitroimidazoles; Oxazolidinones; Patient Compliance; Pyrroles; Quinolines; Rifamycins; Tuberculosis, Pulmonary

Tools for effective TB control have been available for years. Case finding, active medications, case management and directly observed therapy are the foundations for the management of TB. The current TB epidemic, centered in resource-limited settings is fueled by the HIV-1 epidemic. Lack of ability to diagnose and treat drug-resistant TB has led to development of more extensive patterns of resistance. Among the currently available drugs, there is reason to hope that rifamycins paired with fluoroquinolones will lead to shorter treatment regimens for drug-susceptible TB. As the result of novel public-private collaborations and investments of resources, new drugs are being developed. These include TMC207, already shown to have activity early in the treatment of multidrug-resistant TB and others that are likely to be active against persistor organisms, and have the prospect to dramatically shorten treatment courses for active and latent TB. Given that these drugs have novel mechanisms of action, combinations have the prospect to be highly active even against multidrug-resistant organisms.

Topics: Animals; Antitubercular Agents; Clinical Protocols; Diarylquinolines; Directly Observed Therapy; Drug Resistance, Bacterial; Fluoroquinolones; Humans; Mice; Mycobacterium tuberculosis; Quinolines; Rifamycins; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

It is estimated that a third of the world's population is currently infected with tuberculosis, leading to 1.6 million deaths annually. The current drug regimen is 40 years old and takes 6-9 months to administer. In addition, the emergence of drug resistant strains and HIV co-infection mean that there is an urgent need for new anti-tuberculosis drugs. The twenty-first century has seen a revival in research and development activity in this area, with several new drug candidates entering clinical trials. This review considers new potential first-line anti-tuberculosis drug candidates, in particular those with novel mechanisms of action, as these are most likely to prove effective against resistant strains. A brief overview of current first-line and recent drugs (such as fluoroquinolones, rifampicin and isoniazid analogues) is initially presented. This is followed by a description of structure-activity relationships, in vitro and in vivo activity, pharmacokinetics, mechanism of action, combination regimens and clinical trials of the new drug candidates SQ109, PA-824, OPC-67683, TMC207 and others.

Topics: Adamantane; Animals; Antitubercular Agents; Diarylquinolines; Drug Design; Drug Resistance, Multiple, Bacterial; Ethylenediamines; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Quinolines; Structure-Activity Relationship; 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

Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin.. Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course.. DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages.. DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

Topics: Adult; Antitubercular Agents; Drug Therapy, Combination; Humans; Linezolid; Moxifloxacin; Oxazolidinones; Treatment Outcome; Tuberculosis, Pulmonary

Drug-resistant tuberculosis (DR-TB) is a global public health problem. Patients suffer for months if undiagnosed or treated inadequately, transmitting DR-TB in the community before succumbing to the disease. Early diagnosis, prompt treatment initiation and completion play a significant role in treatment success. However, extended regimens with injectable result in poor treatment adherence and outcomes. Our objective is to evaluate the effectiveness, safety and tolerability of various doses and duration of linezolid (LZD) in combination with bedaquiline (BDQ) and pretomanid (Pa) after 26 weeks of treatment in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary TB.. A multicentric, randomised pragmatic clinical trial in India will enrol participants in one of the three arms-control arm (arm 1): BDQ, Pa and LZD 600 mg daily for 26 weeks or intervention arms (arm 2): BDQ, Pa and LZD 600 mg for 9 weeks followed by 300 mg for 17 weeks or arm 3: BDQ, Pa and LZD 600 mg for 13 weeks followed by 300 mg for 13 weeks. The primary endpoint is the proportion of patients with favourable outcomes as sustained cure and treatment completion. The secondary endpoint is unfavourable outcomes, including deaths, treatment failure, toxicity/adverse events and lost to follow-up till 48 weeks post-treatment.. The study has been approved by the ethics committees of participating institutes and the National Institute for Research in TB. The trial results will help establish evidence towards a safe and effective dose of LZD that can be used in a fully, all-oral short course regimen for highly DR-TB patients. The results of this study will be shared with the National TB Elimination Programme of the country and the WHO guidelines development group through publications and dissemination meetings.. NCT05040126.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Humans; Linezolid; Nitroimidazoles; Randomized Controlled Trials as Topic; 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

Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes.. In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated.. A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid.. The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).

Topics: Administration, Oral; Adolescent; Adult; Antitubercular Agents; Bacterial Load; Diarylquinolines; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Humans; Intention to Treat Analysis; Linezolid; Male; Middle Aged; Mycobacterium tuberculosis; Nitroimidazoles; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Bedaquiline, a diarylquinoline with a novel mode of action that specifically inhibits mycobacterial adenosine 5׳-triphosphate (ATP) synthase, has been approved in over 50 countries including the USA and EU for the treatment of pulmonary multidrug-resistant tuberculosis (pMDR-TB) in adults.. This study was conducted to evaluate the safety, efficacy, and pharmacokinetics of bedaquiline in adult Japanese patients with pMDR-TB. In this study, patients received bedaquiline for 24 weeks or more (maximum 48 weeks) with an individualized background regimen (BR). Efficacy was assessed as the time to sputum culture conversion after the initiation of bedaquiline treatment.. No new safety signals in patients, including those receiving bedaquiline with BR beyond 24 weeks, and the faster culture conversion time indicate that the administration of bedaquiline as part of a multi-drug regimen for at least 24 weeks is a suitable treatment for adult Japanese patients with pMDR-TB.

Topics: Adult; Aged; Antitubercular Agents; Asian People; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Female; Humans; Male; Middle Aged; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Bedaquiline is a novel agent for the treatment of pulmonary multidrug-resistant Mycobacterium tuberculosis infections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminal t1/2 was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, and Vc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Biological Availability; Diarylquinolines; Female; Half-Life; Humans; Male; Middle Aged; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Young Adult

Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies.

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Quinolines; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development.. In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851.. The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol.. PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens.. The Global Alliance for TB Drug Development (TB Alliance).

Topics: Adult; Antitubercular Agents; Aza Compounds; Colony Count, Microbial; Diarylquinolines; Double-Blind Method; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Male; Microbial Viability; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Prospective Studies; Pyrazinamide; Quinolines; Sputum; Tuberculosis, Pulmonary; Young Adult

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

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

In decentralized sites, with fewer resources and a high prevalence of advanced HIV, the effectiveness of the new short-course, bedaquiline-based regimen for rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) is not well-described.. Adults with pulmonary RR/MDR-TB initiating the short-course regimen in KwaZulu-Natal, South Africa were prospectively enrolled at a decentralized program that integrated person-centered TB care.. In addition to standard of care monitoring, study visits occurred at enrollment and months 1, 2, 4, 6, and 9. Favorable RR/MDR-TB outcome was defined as cure or treatment completion without loss to follow-up, death, or failure by treatment. In patients with HIV, we assessed antiretroviral therapy (ART) uptake, virologic and immunologic outcomes.. Among 57 patients, HIV was present in 73.7% (95% CI: 60.3-84.5), with a median CD4 count of 170 cells/mm 3 (intraquartile range 49-314). A favorable RR/MDR-TB outcome was achieved in 78.9% (CI: 67.1-87.9). Three deaths occurred, all in the setting of baseline advanced HIV and elevated viral load. Overall, 21.1% (95% CI: 12.1-32.9) experienced a severe or life-threatening adverse event, the most common of which was anemia. Among patients with HIV, enrollment resulted in increased ART uptake by 24% (95% CI: 12.1%-39.4%), a significant improvement from baseline ( P = 0.004); virologic suppression during concomitant treatment was observed in 71.4% (n = 30, 95% CI: 55.4-84.3).. Decentralized, person-centered care for RR/MDR-TB in patients with HIV using the short-course, bedaquiline-based regimen is effective and safe. In patients with HIV, enrollment led to improved ART use and reassuring virologic outcomes.

Topics: Adult; Antitubercular Agents; HIV Infections; Humans; South Africa; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Diarylquinolines; Humans; Long QT Syndrome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

With current treatment options most patients with CNS TB develop severe disability or die. Drug-resistant tuberculous meningitis is nearly uniformly fatal. Novel treatment strategies are needed. Bedaquiline, a potent anti-TB drug, has been reported to be absent from CSF in a single report.. To explore the pharmacokinetics of bedaquiline and its M2 metabolite in the CSF of patients with pulmonary TB.. Individuals with rifampicin-resistant pulmonary TB established on a 24 week course of treatment with bedaquiline underwent a lumbar puncture along with multiple blood sample collections over 24 h for CSF and plasma pharmacokinetic assessment, respectively. To capture the expected low bedaquiline and M2 concentrations (due to high protein binding in plasma) we optimized CSF collection and storage methods in vitro before concentrations were quantified via liquid chromatography with tandem MS.. Seven male participants were enrolled, two with HIV coinfection. Using LoBind® tubes lined with a 5% BSA solution, bedaquiline and M2 could be accurately measured in CSF. Bedaquiline and M2 were present in all patients at all timepoints at concentrations similar to the estimated unbound fractions in plasma.. Bedaquiline and M2 penetrate freely into the CSF of pulmonary TB patients with a presumably intact blood-brain barrier. Clinical studies are urgently needed to determine whether bedaquiline can contribute meaningfully to the treatment of CNS TB.

Topics: Antitubercular Agents; Diarylquinolines; Humans; Male; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Drug-resistant tuberculosis remains a major public health concern in many countries. We compared the efficacy and safety of bedaquiline plus optimized background regimen (Bdq+OBR) with high dose moxifloxacin and optimized background regimen (Mfx(h)+OBR) for the treatment of patients with multidrug-resistant tuberculosis with additional resistance to fluoroquinolones. In this prospective observational study, newly diagnosed cases of multidrug-resistant tuberculosis with additional resistance to fluoroquinolone were enrolled. They received either Bdq+OBR or Mfx(h)+OBR and were followed up for six months. The sputum culture conversion rate at the end of six months and the time to culture conversion in each group were studied. The safety profile of both regimens was also studied. The sputum culture conversion was achieved in 41 patients (100%) in the Bdq+OBR group and 36 patients (87.8%) in the Mfx(h)+OBR group at the end of 6 months. The mean time to culture conversion was found to be 3.10±0.8 months in the Bdq+OBR group and 3.32±0.9 months in the Mfx(h)+OBR group. Mortality was 6.8% in the Bdq+OBR group and 10.8 % in the Mfx(h)+OBR group at 6 months. Raised serum lipase and dark discolouration of skin were significantly more common in the Bdq+OBR group while vomiting and ototoxicity were more common in the Mfx(h)+OBR group. Bdq+OBR was associated with higher success of sputum culture conversion at 6 months and faster sputum culture conversion rate as compared to the Mfx(h)+OBR.

Topics: Antitubercular Agents; Fluoroquinolones; Humans; Moxifloxacin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Bedaquiline is a new ATP synthesis inhibitor developed as an anti-tuberculosis agent. It has resistance-associated variants (RAV), regardless of preceding bedaquiline exposure. Herein, we describe the case of a patient with multidrug-resistant tuberculosis (MDR-TB) who had no history of bedaquiline therapy but presented a relatively high minimum inhibitory concentration (MIC) of bedaquiline (1 μg/mL). Whole genome sequencing revealed a mutation in the resistance-associated gene Rv0678. The patient was first treated with a five-drug regimen (bedaquiline, delamanid, levofloxacin, cycloserine, and amikacin), which induced negative sputum culture conversion. Despite the successful treatment outcome, several questions remain regarding the efficacy of bedaquiline in this patient. Bedaquiline is an indispensable drug for MDR-TB treatment, but its clinical efficiency in the presence of Rv0678 mutations remains unclear. Therefore, evaluating the MIC of bedaquiline even in patients without a history of bedaquiline use is important for therapeutic regimen selection and may emphasize the importance of therapeutic drug monitoring in cases of bedaquiline RAV.

Topics: Antitubercular Agents; Diarylquinolines; Humans; Microbial Sensitivity Tests; Mycobacterium 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

A critical barrier to codevelopment of tuberculosis (TB) regimens is a limited ability to identify optimal drug and dose combinations in early-phase clinical testing. While pharmacokinetic-pharmacodynamic (PKPD) target attainment is the primary tool for exposure-response optimization of TB drugs, the PD target is a static index that does not distinguish individual drug contributions to the efficacy of a multidrug combination. A PKPD model of bedaquiline-pretomanid-pyrazinamide (BPaZ) for the treatment of pulmonary TB was developed as part of a dynamic exposure-response approach to regimen development. The model describes a time course relationship between the drug concentrations in plasma and their individual as well as their combined effect on sputum bacillary load assessed by solid culture CFU counts and liquid culture time to positivity (TTP). The model parameters were estimated using data from the phase 2A studies NC-001-(J-M-Pa-Z) and NC-003-(C-J-Pa-Z). The results included a characterization of BPaZ activity as the most and least sensitive to changes in pyrazinamide and bedaquiline exposures, respectively, with antagonistic activity of BPa compensated by synergistic activity of BZ and PaZ. Simulations of the NC-003 study population with once-daily bedaquiline at 200 mg, pretomanid at 200 mg, and pyrazinamide at 1,500 mg showed BPaZ would require 3 months to attain liquid culture negativity in 90% of participants. These results for BPaZ were intended to be an example application with the general approach aimed at entirely novel drug combinations from a growing pipeline of new and repurposed TB drugs.

Topics: Antitubercular Agents; Diarylquinolines; Humans; Nitroimidazoles; Pyrazinamide; Tuberculosis; Tuberculosis, Multidrug-Resistant; 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

Topics: Diarylquinolines; Humans; Moxifloxacin; Nitroimidazoles; Pyrazinamide; Tuberculosis; 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 Korea Centers for Disease Control & Prevention has implemented a review process for the approval of new drugs used to treat patients with multidrug-resistant tuberculosis (MDR-TB) since September 2016. Therefore, this study aimed to evaluate the efficacy and safety of these new drugs bedaquiline (Bdq) and delamanid (Dlm).. A total of 318 patients with MDR-TB were reviewed by the committee from September 2016 to February 2018; 282 (88.7%) of them were treated with the new drugs (Bdq, 107 patients; Dlm, 108 patients; and both concurrently or sequentially, 67 patients) and retrospectively evaluated. Culture conversion rates, interim treatment outcomes at 12 months, and predictors of unfavorable outcomes were analyzed. Treatment efficacy was also compared between Bdq and Dlm.. The mean age of the patients was 49.3 years, and 197 (69.9%) were male. Three patients were HIV seropositive and 151 (53.5%) were quinolone resistant. The culture conversion rates at 2 and 6 months were 57.4% (81/141) and 89.4% (126/141), respectively. A favorable outcome at 12 months was achieved in 84.8% of patients (239/282). Differences in the culture conversion rate or interim treatment outcomes were not statistically significant among the drug susceptibility test patterns or new drugs used. Multivariable analysis showed that age >60 years and body mass index of <18.5 kg/m. The use of new drugs resulted in satisfactory interim treatment results, without significant differences between them.

Topics: Age Factors; Aged; Body Mass Index; Diarylquinolines; Drug Resistance, Bacterial; Drug Resistance, Multiple; Drug Therapy, Combination; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Nitroimidazoles; Oxazoles; Republic of Korea; Retrospective Studies; Risk Factors; Safety; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

Bedaquiline (BDQ) has been recently approved for drug resistant tuberculosis with active drug safety monitoring under programmatic condition. The present study was conducted to evaluate safety, tolerability and efficacy of bedaquiline plus optimised background regimen.. A prospective study was conducted on cohort of pre-extensively drug resistant (XDR) and XDR pulmonary TB patients. Eligible patients were closely monitored for cardiac safety, adverse events (AEs), clinical and microbiological improvement during BDQ (6 months) and post BDQ phase for twelve months.. Of 127 patients enrolled, a significant increase in mean QTc interval was observed on 13th day and 3rd week as compared to baseline (p < 0.0001). Mean maximum increase of QTc was 37.92ms (95% CI, 14.1-61.74ms). Concomitant anti-TB medications, age, gender, low body mass index (BMI) had significant effect on QTc prolongation (p < 0.0001, p < 0.05). However, none of the patient required discontinuation of BDQ. Majority of AEs (86.3%) were non-serious and not preventable 108 (87.1%). The median time for sputum-culture conversion was 40.89 ± 3.5 days (95% CI, 34-48 days) and the treatment outcome was successful in 102 (80.3%) patients with negative sputum culture conversion.. Bedaquiline containing regimen achieved favourable outcome. Although, bedaquiline along with concomitant anti-TB medications has the potential to prolong QTc interval, the benefit certainly outweighs the risk. This calls for a through pre-treatment cardiovascular and biochemical evaluation as a preventive measure and appropriate selection of patients for safe use of BDQ and successful outcome.

Topics: Adult; Antitubercular Agents; Culture Techniques; Diarrhea; Diarylquinolines; Drug Eruptions; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Humans; Long QT Syndrome; Male; Pigmentation Disorders; Skin Pigmentation; Sputum; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Vomiting

Drug-resistant tuberculosis is an increasing healthcare challenge. Drug regimen building demands the use of different therapeutic groups, many of which harbor neurotoxicity as a side-effect, whether central or peripheral. Peripheral neuropathy is a major concern as it tends to be severe and usually irreversible. Anti-tubercular drugs that may contribute to peripheral neuropathy include INH, ethambutol, linezolid, cycloserine and para-amino salicylic acid. This potential adverse effect must be balanced against the intrinsically grave prognosis that drug resistant tuberculosis harbors. We present such a clinically challenging case of a 25 years-old female with extremely drug resistant tuberculosis whose treatment necessitated the use of several neurotoxic anti-tubercular drugs, leading to severe sensory peripheral neuropathy who did not improve despite the withdrawal of culprit drugs. She developed positive and negative sensory symptoms in both lower limbs. Nerve conduction studies were suggestive of sensory neuropathy affecting both lower limbs. Alternate causes of peripheral neuropathy including HIV, vasculitis, B12 deficiency and diabetes were ruled out. Despite drug withdrawal, the patient did not improve significantly. This case emphasizes the irreversibility of anti-tubercular therapy-induced peripheral neuropathy, demanding more rigorous clinical screening for the same while managing such patients.

Topics: Adult; Aminosalicylic Acid; Antitubercular Agents; Clofazimine; Cycloserine; Deprescriptions; Diarylquinolines; Ethionamide; Extensively Drug-Resistant Tuberculosis; Female; Humans; Kanamycin; Linezolid; Neural Conduction; Neurotoxicity Syndromes; Peripheral Nervous System Diseases; Pyrazinamide; Pyridoxine; Tuberculosis, Pulmonary

Topics: Diarylquinolines; Humans; Moxifloxacin; Nitroimidazoles; Pyrazinamide; Tuberculosis; Tuberculosis, Pulmonary

In the regions where bedaquiline (BDQ) is introduced into the regimen, analysis of MIC and screening for preexisting resistance mutations could be crucial. The high prevalence of isolates with high BDQ MICs without prior exposure to BDQ was worrisome. It was also concluded that efflux pumps play a pivotal role in intrinsic BDQ resistance; therefore, the potential of verapamil as an adjunctive therapy to combat BDQ resistance should be investigated.

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Bacterial; Humans; Iran; Membrane Transport Proteins; Mycobacterium tuberculosis; Retrospective Studies; Tuberculosis, Pulmonary; Verapamil

NTP was pilot tested in Anantapur district of Andhra Pradesh during 1961 and thereafter the programme was launched throughout the country. In 1992, the Government of India together with the World Health Organization (WHO) and Swedish International Development Agency (SIDA) reviewed the National TB Programme and concluded that it suffered from managerial weakness, inadequate funding, over-reliance on x-ray, non-standard treatment regimens, low rates of treatment completion and lack of systematic information on treatment outcomes. Programme review showed that only 30% of patients were diagnosed and only 30% of those treated successfully. Based on the findings and recommendations of the review in 1992, the GOI evolved a revised strategy and launched the Revised National TB Control Programme (RNTCP).

Topics: Antitubercular Agents; Diarylquinolines; Directly Observed Therapy; Goals; History, 20th Century; History, 21st Century; Humans; India; National Health Programs; Nitroimidazoles; Oxazoles; Practice Guidelines as Topic; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Bedaquiline (BDQ) was approved for treatment of drug resistant TB (DR-TB) under Conditional Access Programme (CAP) of Revised National Tuberculosis Control Programme (RNTCP) and was also implemented in the National Institute of TB and Respiratory Diseases (NITRD). We present early efficacy and safety of BDQ containing regimens for DR-TB.. To ascertain the early efficacy and safety of Bedaquline containing regimens in treatment of DR-TB.. BDQ containing regimens along with other drugs were designed as per WHO recommendations for DR-TB patients. They were followed up for sputum smear and culture conversion, adverse events during the treatment.. A cohort of 290 DR-TB patients (Median age-29.77) were initiated on BDQ containing regimens. Of the available Sputum results, smear conversion was seen in 51% and 91% patients at the end of 1st week and 3rd month respectively. Similarly, 93% and 98% patients had culture conversion at the end of 3rd and 6th month respectively. 201 adverse events (AE) including 47 deaths were reported among 109 patients. QTc prolongation was seen in 29% patients but only 4 required discontinuation of BDQ. Lost to follow up of treatment was about 6%.. Bedaquiline along with an optimized background regimen has shown early sputum conversion in larger number of difficult to treat patients having additional resistance of second line drugs along with INH and Rifampicin. The regimen is feasible in programmatic conditions and is relatively safe.

Topics: Adult; Antitubercular Agents; Cardiotoxicity; Clofazimine; Cycloserine; Diarylquinolines; Drug Therapy, Combination; Electrocardiography; Ethionamide; Female; Humans; India; Linezolid; Male; Moxifloxacin; National Health Programs; Sputum; Time Factors; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

This study aimed to provide information that bedaquilline is significantly effective for treatment of totally drug resistant (TDR) Mycobacterium tuberculosis that shows resistant to all first- and second-line drugs-using an innovative disc agarose channel (DAC) system. Time-lapse images of single bacterial cells under culture conditions with different concentrations of bedaquiline were analysed by image processing software to determine minimum inhibitory concentrations (MICs). Bedaquiline inhibited the growth of TDR M. tuberculosis strains, with MIC values ranging from 0.125 to 0.5 mg/L. The results of the present study demonstrate that bedaquiline, newly approved by the United States Food and Drug Administration (FDA), may offer therapeutic solutions for TDR-TB.

Topics: Antitubercular Agents; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Time-Lapse Imaging; Tuberculosis, Pulmonary

New regimens based on 2 or more novel agents are sought to shorten or to simplify treatment of tuberculosis (TB), including drug-resistant forms. Prior studies showed that the novel combinations of bedaquiline (BDQ) plus pretomanid (PMD) plus pyrazinamide (PZA) and PMD plus moxifloxacin (MXF) plus PZA shortened the treatment duration necessary to prevent relapse by 2 to 3 months and 1 to 2 months, respectively, compared with the current first-line regimen, in a murine TB model. These 3-drug combinations are now being studied in clinical trials. Here, the 4-drug combination of BDQ+PMD+MXF+PZA was compared to its 3-drug component regimens and different treatment durations of PZA and MXF were explored, to identify the optimal regimens and treatment times and to estimate the likelihood of success against drug-resistant strains. BDQ+PMD+MXF+PZA rendered all mice relapse-free after 2 months of treatment. PZA administration could be discontinued after the first month of treatment without worsening outcomes, whereas the absence of MXF, PZA, or BDQ administration from the beginning necessitated approximately 0.5, 1, or 2 months, respectively, of additional treatment to attain the same outcome.

Topics: Animals; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Female; Fluoroquinolones; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Pyrazinamide; Tuberculosis, Pulmonary

Topics: Adolescent; Antitubercular Agents; Compassionate Use Trials; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Female; Humans; India; Jurisprudence; Mycobacterium tuberculosis; Tuberculosis, Pulmonary

We report the experiences of 5 patients taking bedaquiline with delamanid in combination: 1 patient was cured; 3 culture converted, with 2 continuing and 1 changing therapy; and 1 died from respiratory insufficiency. For 2 patients, QT-interval prolongation but no arrhythmias occurred. Use of this therapy is justified for patients with limited options.

Topics: Adolescent; Adult; Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Humans; Male; Nitroimidazoles; Oxazoles; Tuberculosis, Pulmonary; Young Adult

A woman with extremely drug-resistant tuberculosis treated with a drug regimen including linezolid and bedaquiline during her last 3 weeks of pregnancy gave birth to a child without abnormalities. No fetal toxicities were noted by 2 years after delivery. This drug combination might be safe during the late third trimester of pregnancy.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Humans; Linezolid; Mycobacterium tuberculosis; Pregnancy; Pregnancy Complications, Infectious; Tuberculosis, Pulmonary

Novel therapies for multidrug-resistant tuberculosis (MDR-TB) are likely to be expensive. The cost of novel drugs (e.g., bedaquiline, delamanid) may be so prohibitively high that a traditional cost-effectiveness analysis (CEA) would rate regimens containing these drugs as not cost-effective. Traditional CEA may not appropriately account for considerations of social justice, and may put the most disadvantaged populations at greater risk. Using the example of novel drug regimens for MDR-TB, we propose a novel methodology, 'justice-enhanced CEA', and demonstrate how such an approach can simultaneously assess social justice impacts alongside traditional cost-effectiveness ratios. Justice-enhanced CEA, as we envision it, is performed in three steps: 1) systematic data collection about patients' lived experiences, 2) use of empirical findings to inform social justice assessments, and 3) incorporation of data-informed social justice assessments into a decision analytic framework that includes traditional CEA. These components are organized around a core framework of social justice developed by Bailey et al. to compare impacts on disadvantage not otherwise captured by CEA. Formal social justice assessments can produce three composite levels: 'expected not to worsen…', 'may worsen…', and 'expected to worsen clustering of disadvantage'. Levels of social justice impact would be assessed for each major type of outcome under each policy scenario compared. Social justice assessments are then overlaid side-by-side with cost-effectiveness assessments corresponding to each branch pathway on the decision tree. In conclusion, we present a 'justice-enhanced' framework that enables the incorporation of social justice concerns into traditional CEA for the evaluation of new regimens for MDR-TB.

Topics: Antitubercular Agents; Cost-Benefit Analysis; Decision Trees; Diarylquinolines; Humans; Models, Theoretical; Nitroimidazoles; Oxazoles; Social Justice; Social Stigma; South Africa; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Bedaquiline (BDQ), a diarylquinoline antibiotic that targets ATP synthase, is effective for the treatment of Mycobacterium tuberculosis infections that no longer respond to conventional drugs. While investigating the off-label use of BDQ as salvage therapy, seven of 13 patients with Mycobacterium intracellulare lung disease had an initial microbiological response and then relapsed. Whole-genome comparison of pretreatment and relapse isolates of M. intracellulare uncovered mutations in a previously uncharacterized locus, mmpT5 Preliminary analysis suggested similarities between mmpT5 and the mmpR5 locus, which is associated with low-level BDQ resistance in M. tuberculosis Both genes encode transcriptional regulators and are adjacent to orthologs of the mmpS5-mmpL5 drug efflux operon. However, MmpT5 belongs to the TetR superfamily, whereas MmpR5 is a MarR family protein. Targeted sequencing uncovered nonsynonymous mmpT5 mutations in isolates from all seven relapse cases, including two pretreatment isolates. In contrast, only two relapse patient isolates had nonsynonymous changes in ATP synthase subunit c (atpE), the primary target of BDQ. Susceptibility testing indicated that mmpT5 mutations are associated with modest 2- to 8-fold increases in MICs for BDQ and clofazimine, whereas one atpE mutant exhibited a 50-fold increase in MIC for BDQ. Bedaquiline shows potential for the treatment of M. intracellulare lung disease, but optimization of treatment regimens is required to prevent the emergence of mmpT5 variants and microbiological relapse.

Topics: Aged; Antitubercular Agents; Diarylquinolines; Drug Resistance, Bacterial; Female; Genome, Bacterial; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mutation, Missense; Mycobacterium avium Complex; Recurrence; Sequence Analysis, DNA; Transcription Factors; Tuberculosis, Pulmonary

Topics: Adolescent; Antitubercular Agents; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Female; Health Policy; Health Services Accessibility; Humans; India; Tuberculosis, Pulmonary

Treatment of multidrug-resistant tuberculosis (MDR-TB) is complex, lengthy, and involves a minimum of four drugs termed a background regimen (BR), that have not previously been prescribed or that have proven susceptible to patient sputum culture isolates. In recent years, promising new treatment options have emerged as add-on therapies to a BR. The aim of this study was to evaluate the long-term costs and effectiveness of adding the novel or group 5 interventions bedaquiline, delamanid, and linezolid to a background regimen (BR) of drugs for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis (MDR-TB), within their marketing authorisations, from a German healthcare cost-effectiveness perspective.. A cohort-based Markov model was developed to simulate the incremental cost-effectiveness ratio of bedaquiline plus BR, delamanid plus BR, or linezolid plus BR versus BR alone in the treatment of MDR-TB, over a 10-year time horizon. Effectiveness of treatment was evaluated in Quality-Adjusted Life-Years (QALYs) and Life-Years Gained (LYG), using inputs from clinical trials for bedaquiline and delamanid and from a German observational study for linezolid. Cost data were obtained from German Drug Directory costs (€/2015), published literature, and expert opinion. A 3% yearly discount rate was applied. Probabilistic and deterministic sensitivity analyses were conducted.. The total discounted costs per-patient were €85,575 for bedaquiline plus BR, €81,079 for delamanid plus BR, and €80,460 for linezolid plus BR, compared with a cost of €60,962 for BR alone. The total discounted QALYs per-patient were 5.95 for bedaquiline plus BR, 5.36 for delamanid plus BR, and 3.91 for linezolid plus BR, compared with 3.68 for BR alone. All interventions were therefore associated with higher QALYs and higher costs than BR alone, with incremental costs per QALY gained of €22,238 for bedaquiline, €38,703 for delamanid, and €87,484 for linezolid, versus BR alone. In a fully incremental analysis, bedaquiline plus BR was the most cost-effective treatment option at thresholds greater than €22,000 per QALY gained. In probabilistic analyses, the probability that bedaquiline plus BR was the most cost-effective treatment strategy at a willingness-to-pay threshold of €30,000 was 54.5%, compared with 22.9% for BR alone, 18.2% for delamanid plus BR, and 4.4% for linezolid.. In Germany, the addition of bedaquiline, delamanid, or linezolid to a BR would result in QALY gains over BR alone. Based on this analysis, bedaquiline is likely to be the most cost-effective intervention for the treatment of MDR-TB, when added to a BR regimen at thresholds greater than €22,000 per QALY.

Topics: Adult; Antitubercular Agents; Clinical Protocols; Clinical Trials as Topic; Cost-Benefit Analysis; Diarylquinolines; Drug Costs; Drug Therapy, Combination; Female; Germany; Humans; Linezolid; Male; Nitroimidazoles; Observational Studies as Topic; Oxazoles; Quality-Adjusted Life Years; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

New regimens based on two or more novel agents are sought to shorten or simplify treatment of tuberculosis (TB). Pretomanid (PMD) is a nitroimidazole in phase 3 trials that has significant bactericidal activity alone and in combination with bedaquiline (BDQ) and/or pyrazinamide (PZA). We previously showed that the novel combination of BDQ+PMD plus the oxazolidinone sutezolid (SZD) had sterilizing activity superior to that of the first-line regimen in a murine model of TB. The present experiments compared the activity of different oxazolidinones in combination with BDQ+PMD with or without PZA in the same model. The 3-drug regimen of BDQ+PMD plus linezolid (LZD) had sterilizing activity approaching that of BDQ+PMD+SZD and superior to that of the first-line regimen. The addition of PZA further enhanced activity. Reducing the duration of LZD to 1 month did not significantly affect the activity of the regimen. Halving the LZD dose or replacing LZD with RWJ-416457 modestly reduced activity over the first month but not after 2 months. AZD5847 and tedizolid also increased the bactericidal activity of BDQ+PMD, but they were less effective than the other oxazolidinones. These results provide optimism for safe, short-course oral regimens for drug-resistant TB that may also be superior to the current first-line regimen for drug-susceptible TB.

Topics: Animals; Antitubercular Agents; Bacterial Load; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Female; Linezolid; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nitroimidazoles; Organophosphates; Oxazoles; Oxazolidinones; Pyrazinamide; Time Factors; Treatment Outcome; Tuberculosis, Pulmonary

This paper explores the notion of reciprocity in the context of active pulmonary and laryngeal tuberculosis (TB) treatment and related control policies and practices. We seek to do three things: First, we sketch the background to contemporary global TB care and suggest that poverty is a key feature when considering the treatment of TB patients. We use two examples from TB care to explore the role of reciprocity: isolation and the use of novel TB drugs. Second, we explore alternative means of justifying the use of reciprocity through appeal to different moral and political theoretical traditions (i.e., virtue ethics, deontology, and consequentialism). We suggest that each theory can be used to provide reasons to take reciprocity seriously as an independent moral concept, despite any other differences. Third, we explore general meanings and uses of the concept of reciprocity, with the primary intention of demonstrating that it cannot be simply reduced to other more frequently invoked moral concepts such as beneficence or justice. We argue that reciprocity can function as a mid-level principle in public health, and generally, captures a core social obligation arising once an individual or group is burdened as a result of acting for the benefit of others (even if they derive a benefit themselves). We conclude that while more needs to be explored in relation to the theoretical justification and application of reciprocity, sufficient arguments can be made for it to be taken more seriously as a key principle within public health ethics and bioethics more generally.

Topics: Antitubercular Agents; Beneficence; Communicable Disease Control; Congresses as Topic; Diarylquinolines; Directly Observed Therapy; Ethical Analysis; Ethical Theory; Global Health; Humans; Moral Obligations; Nitroimidazoles; Oxazoles; Patient Isolation; Personal Autonomy; Pharmacovigilance; Poverty; Public Health; Social Justice; Social Responsibility; Tuberculosis, Laryngeal; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Virtues

Bedaquiline is a newly approved drug for the treatment of multidrug-resistant tuberculosis, but there are concerns about its safety in humans. We found that the coadministration of verapamil with subinhibitory doses of bedaquiline gave the same bactericidal effect in mice as did the full human bioequivalent bedaquiline dosing. Adding verapamil to bedaquiline monotherapy also protected against the development of resistant mutants in vivo. The adjunctive use of verapamil may permit use of lower doses of bedaquiline to be used and thereby reduce its dose-related toxicities in tuberculosis patients.

Topics: Animals; Antitubercular Agents; Calcium Channel Blockers; Diarylquinolines; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Tuberculosis, Pulmonary; Verapamil

Bedaquiline is an oral antimycobacterial agent belonging to a new class of drugs called diarylquinolines. It has low equivalent minimal inhibitory concentrations for Mycobacterium tuberculosis and nontuberculous mycobacterial (NTM) lung disease, especially Mycobacterium avium complex (MAC) and Mycobacterium abscessus (Mab). Bedaquiline appears to be effective for the treatment of multidrug-resistant TB but has not been tested clinically for NTM disease.. We describe a case series of off-label use of bedaquiline for treatment failure lung disease caused by MAC or Mab. Only patients whose insurance would pay for the drug were included. Fifteen adult patients were selected, but only 10 (six MAC, four Mab) could obtain bedaquiline. The 10 patients had been treated for 1 to 8 years, and all were on treatment at the start of bedaquiline therapy. Eighty percent had macrolide-resistant isolates (eight of 10). The patients were treated with the same bedaquiline dosage as that used in TB trials and received the best available companion drugs (mean, 5.0 drugs). All patients completed 6 months of therapy and remain on bedaquiline.. Common side effects included nausea (60%), arthralgias (40%), and anorexia and subjective fever (30%). No abnormal ECG findings were observed with a mean corrected QT interval lengthening of 2.4 milliseconds at 6 months. After 6 months of therapy, 60% of patients (six of 10) had a microbiologic response, with 50% (five of 10) having one or more negative cultures.. This small preliminary report demonstrates potential clinical and microbiologic activity of bedaquiline in patients with advanced MAC or Mab lung disease but the findings require confirmation with larger studies.

Topics: Adult; Aged; Anorexia; Antitubercular Agents; Arthralgia; Cohort Studies; Diarylquinolines; Female; Fever; Humans; Male; Middle Aged; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections, Nontuberculous; Nausea; Salvage Therapy; Treatment Outcome; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; ATP Synthetase Complexes; Clinical Trials, Phase II as Topic; Diarylquinolines; Drug Resistance, Multiple, Bacterial; Humans; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Adult; Antitubercular Agents; Compassionate Use Trials; Diarylquinolines; Drug Substitution; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Humans; Male; Tomography, X-Ray Computed; Treatment Outcome; Tuberculosis, Pulmonary

Active tuberculosis is a serious, sometimes fatal, bacterial infection. Multidrug-resistant strains are associated with higher mortality. Bedaquiline, a diarylquinoline antibiotic, has been authorised in the EU, in combination with other antibiotics, for patients with multidrug-resistant pulmonary tuberculosis. Clinical evaluation of bedaquiline in multidrug-resistant tuberculosis is based on a double-blind, randomised, placebo-controlled trial including 160 patients. During follow-up, there were 10 deaths in the bedaquiline group (including 5 deaths from disease progression) and 2 deaths (both due to tuberculosis) in the placebo group. An analysis of data on 133 patients showed that it took a median of 83 days for sputum cultures to become negative in the bedaquiline group, versus 125 days in the placebo group (p = 0.0004). QT prolongation and hepatic and pancreatic disorders were more frequent with bedaquiline than with placebo. The most frequently reported adverse effects were headache, nausea, arthralgia and pulmonary infections. In practice, bedaquiline reduced the number of contagious patients with multidrug-resistant pulmonary tuberculosis, but mortality was higher than in the placebo group. Its harm-benefit balance is unclear, especially in patients with extensively drug-resistant tuberculosis, for whom there are very few active antibiotics available.

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Humans; Mycobacterium tuberculosis; Patient Selection; Risk Assessment; Risk Factors; Sputum; Time Factors; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Compassionate Use Trials; Diarylquinolines; Drug Monitoring; Helping Behavior; Humans; Infectious Disease Transmission, Patient-to-Professional; Patient Participation; Physicians; Quinolines; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Diarylquinolines; Humans; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

TMC207 is a first-in-class diarylquinoline with a new mode of action against mycobacteria targeting the ATP synthase. It is metabolized to an active derivative, N-desmethyl TMC207, and both compounds are eliminated with long terminal half-lives (50 to 60 h in mice) reflecting slow release from tissues such as lung and spleen. In vitro, TMC207 is 5-fold more potent against Mycobacterium tuberculosis than N-desmethyl TMC207, and the effects of the two compounds are additive. The pharmacokinetic and pharmacodynamic (PK-PD) response was investigated in the murine model of tuberculosis (TB) infection following oral administration of different doses of TMC207 or N-desmethyl TMC207 at 5 days per week for 4 weeks starting the day after intravenous infection with M. tuberculosis and following administration of different doses of TMC207 at various dosing frequencies for 6 weeks starting 2 weeks after infection. Upon administration of N-desmethyl TMC207, maximum plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to 168 h postdose (AUC(168h)), and minimum plasma concentration (C(min)) were approximately dose proportional between 8 and 64 mg/kg, and the lung CFU counts were strongly correlated with these pharmacokinetic parameters using an inhibitory sigmoid maximum effect (E(max)) model. Administration of the highest dose (64 mg/kg) produced a 4.0-log(10) reduction of the bacillary load at an average exposure (average concentration [C(avg)] or AUC(168h) divided by 168) of 2.7 μg/ml. Upon administration of the highest dose of TMC207 (50 mg/kg) 5 days per week for 4 weeks, the total reduction of the bacillary load was 4.7 log(10). TMC207 was estimated to contribute to a 1.8-log(10) reduction and its corresponding exposure (C(avg)) was 0.5 μg/ml. Optimal bactericidal activity with N-desmethyl TMC207 was reached at a high exposure compared to that achieved in humans, suggesting a minor contribution of the metabolite to the overall bactericidal activity in TB-infected patients treated with TMC207. Following administration of TMC207 at a total weekly dose of 15, 30, or 60 mg/kg fractionated for either 5 days per week, twice weekly, or once weekly, the bactericidal activity was correlated to the total weekly dose and was not influenced by the frequency of administration. Exposures (AUC(168h)) to TMC207 and N-desmethyl TMC207 mirrored this dose response, indicating that the bactericidal activity of TMC207 is concentration dependent a

Topics: Animals; Antitubercular Agents; Area Under Curve; ATP Synthetase Complexes; Bacterial Proteins; Biotransformation; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Drug Administration Routes; Drug Administration Schedule; Drug Dosage Calculations; Female; Half-Life; Humans; Lung; Male; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Quinolines; Tuberculosis, Pulmonary

To truly transform the landscape of tuberculosis treatment, novel regimens containing at least 2 new drugs are needed to simplify the treatment of both drug-susceptible and drug-resistant forms of tuberculosis. As part of an ongoing effort to evaluate novel drug combinations for treatment-shortening potential in a murine model, we performed two long-term, relapse-based experiments. In the first experiment, TMC207 plus pyrazinamide, alone or in combination with any third drug, proved superior to the first-line regimen including rifampin, pyrazinamide, and isoniazid. On the basis of CFU counts at 1 month, clofazimine proved to be the best third drug combined with TMC207 and pyrazinamide, whereas the addition of PA-824 was modestly antagonistic. Relapse results were inconclusive due to the low rate of relapse in all test groups. In the second experiment evaluating 3-drug combinations composed of TMC207, pyrazinamide, PA-824, moxifloxacin, and rifapentine, TMC207 plus pyrazinamide plus either rifapentine or moxifloxacin was the most effective, curing 100% and 67% of the mice treated, respectively, in 2 months of treatment. Four months of the first-line regimen did not cure any mice, whereas the combination of TMC207, PA-824, and moxifloxacin cured 50% of the mice treated. The results reveal new building blocks for novel regimens with the potential to shorten the duration of treatment for both drug-susceptible and drug-resistant tuberculosis, including the combination of TMC207, pyrazinamide, PA-824, and a potent fluoroquinolone.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Nitroimidazoles; Quinolines; Secondary Prevention; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary

The bactericidal activities of the diarylquinoline TMC207 in a liquid culture medium started with a bacteriostatic phase lasting about 7 days and then continued with a dose-related bactericidal phase. In comparison, its intra-cellular activity in primary mouse peritoneal macrophages (PM) and in the J774 macrophage-like cell line had little or no static phase so that the bactericidal kill was evident by 5-7 days presumably due to low bacterial ATP levels. Bactericidal activities in the three systems were compared by estimating the rate of bacterial killing (K) during exposure to 0.12-1.0 μg/ml TMC207 which were similar at, -0.35 in the J774 cells and -0.27 in mouse PM (p = 0.6) with each lower than -0.11 in extra-cellular cultures (p < 0.001) and [2] the TMC207 concentration at the intersection between the curve relating cfu count to TMC207 concentration and the cfu count at day-0, defined as the static concentration. Static concentrations were 0.22 μg/ml for extra-cellular cultures, 0.17 μg/ml for mouse PM and 0.06 μg/ml for J774 cells, significantly lower than the extra-cellular value (p < 0.001). Thus, the intra-cellular activity of TMC207 is clearly greater than its extra-cellular activity mainly because the preliminary static phase was a shorter or absent.

Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Cell Line; Diarylquinolines; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Quinolines; Tuberculosis, Pulmonary

Topics: Antitubercular Agents; Diarylquinolines; Half-Life; Humans; Quinolines; Rifampin; Tuberculosis, Pulmonary

The diarylquinoline R207910 (TMC207) has potent bactericidal activity in a murine model of tuberculosis (TB), but its sterilizing activity has not been determined.. To evaluate the sterilizing activity of R207910-containing combinations in the murine model of TB.. Swiss mice were intravenously inoculated with 6 log(10) of Mycobacterium tuberculosis strain H37Rv, treated with R207910-containing regimens, and followed for 3 months to determine relapse rates (modified Cornell model).. Quantitative lung and spleen colony-forming unit counts and bacteriological relapse rates 3 months after the end of therapy were compared for the following regimens: 2, 3, or 4 months of R207910 (J) and pyrazinamide (Z) combined with rifampin (R) or isoniazid (H) or both and 3 or 4 months of a moxifloxacin (M)-containing regimen and 6 months of the standard WHO regimen RHZ. All J-treated mice were culture negative after 4 months of therapy. The relapse rate in the group treated with 4 months of JHRZ was similar to that of mice treated for 6 months with the RHZ regimen (6 vs. 17%; P = 0.54) and lower than that of RMZ (6 vs. 42%; P = 0,03), a moxifloxacin-containing regimen that was the most active in mice on once-daily basis.. Four months of treatment with some J-containing regimens was as effective as the 6-month standard regimen and more effective than 4 months of treatment with M-containing regimens. Supplementation of standard regimen (RHZ) with J or substitution of J for H may shorten the treatment duration needed to cure TB in patients.

Topics: Animals; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Hydrolases; Isoniazid; Mice; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Splenic

New drugs are needed to shorten the duration of tuberculosis treatment. R207910, a diarylquinoline, is very active against Mycobacterium tuberculosis both in vitro and in mice. In healthy volunteers, the coadministration of R207910 and rifampin induced the increased metabolism of R207910, resulting in a 50% reduction in the level of R207910 exposure. We assessed the impact of reducing the dose of R207910 on its efficacy when R207910 was combined with a background regimen of isoniazid, rifampin, and pyrazinamide. Addition of 25 mg/kg of body weight or 12.5 mg/kg R207910 to the background regimen resulted in faster bacterial clearance and culture negativity. The difference in efficacy between the two doses was not statistically significant. The minimal bactericidal dose of R207910 when it was tested as part of the combination was identical to that when it was tested as monotherapy. Because of the drug-drug interaction in humans, the activity of R207910 in humans could be less than that expected from studies with mice. Our data from the mouse model demonstrate that R207910 has significant activity, even when its exposure is reduced by 50% and when it is added to a strong background regimen of isoniazid, rifampin, and pyrazinamide. In killing kinetic studies, the bactericidal effect of R207910 in mice was modest during the first week of treatment, but it increased in the following 3 weeks, while the bactericidal activity of isoniazid was limited to the first week of treatment.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Drug Interactions; Female; Humans; Isoniazid; Lung; Mice; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Spleen; Tuberculosis, Pulmonary

In previous studies, the diarylquinoline R207910 (also known as TMC207) was demonstrated to have high bactericidal activity when combined with first- or second-line antituberculous drugs. Here we extend the evaluation of R207910 in the curative model of murine tuberculosis by assessing the activities of one-, two-, and three-drug combinations containing R207910 and isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), or moxifloxacin (MXF) in the setting of a high initial bacillary load (7.2 log(10) CFU). Two months of treatment with the combinations R207910-PZA, R207910-PZA-INH, R207910-PZA-RIF, or R207910-PZA-MXF resulted in culture-negative lung homogenates in 70 to 100% of the mice, while mice treated with INH-RIF-PZA (the reference regimen) or RIF-MXF-PZA remained culture positive. Combinations including R207910 but not PZA (e.g., R207910-INH-RIF and R207910-MXF-RIF) were less active than R207910-PZA-containing regimens administered either alone or with the addition of INH, RIF, or MXF. These results reveal a synergistic interaction between R207910 and PZA. Three-drug combinations containing these two drugs and INH, RIF, or MXF have the potential to significantly shorten the treatment duration in patients, provided that these results can be confirmed in long-term experiments including periods of relapse.

Topics: Animals; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Drug Synergism; Female; Lung; Mice; Organ Size; Pyrazinamide; Quinolines; Spleen; Survival Analysis; Tuberculosis, Pulmonary

Topics: Animals; Antitubercular Agents; Clinical Trials as Topic; Diarylquinolines; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Quinolines; Tuberculosis, Pulmonary