rifampin and bedaquiline

The emergence of drug resistance continues to afflict TB control where drug resistant strains have become a global health concern. Contrary to drug-sensitive TB, the treatment of MDR/XDR-TB is more complicated requiring the administration of second-line drugs that are inefficient than the first line drugs and are associated with greater side effects. The emergence of drug resistant Mtb strains had coincided with an innovation void in the field of drug discovery of anti-mycobacterials. However, the approval of bedaquiline and delamanid recently for use in MDR/XDR-TB has given an impetus to the TB drug discovery. The review discusses the drug discovery efforts in the field of tuberculosis with a focus on the strategies adopted and challenges confronted by TB research community. Here, we discuss the diverse clinical candidates in the current TB drug discovery pipeline. There is an urgent need to combat the current TB menace through multidisciplinary approaches and strategies making use of the recent advances in understanding the molecular biology and pathogenesis of Mtb. The review highlights the recent advances in drug discovery, with the host directed therapeutics and nanoparticles-drug delivery coming up as important tools to fight tuberculosis in the future.

Topics: Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Ethambutol; Extensively Drug-Resistant Tuberculosis; Humans; Isoniazid; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Pyrazinamide; Rifampin

Tuberculosis (TB) being the leading infectious killer in the domain wherein globally, almost 20% of all TB strains are resistant to at least 1 major TB drug and there's a growing incidence of multi-drug resistance tuberculosis (MDR-TB). Looking at the current scenario and challenges the existing strategies fall back in terms of treatment of TB. So, to overcome this new, stronger, improved TB drug pipeline and a new standard for the development of novel anti-TB drugs are required in order to make more drug-resistant and efficient drug which also lower the duration period of the treatment of the TB. This review article aims to highlight the recent developments in the anti-tuberculosis agents, those are currently in the clinical development stage.

Topics: Adamantane; Antitubercular Agents; Diarylquinolines; Drug Development; Drug Therapy, Combination; Duration of Therapy; Ethambutol; Ethylenediamines; Humans; Isoniazid; Macrolides; Medication Adherence; Nitroimidazoles; Oxazolidinones; Pyrazinamide; Rifampin; Tuberculosis, Multidrug-Resistant

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

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

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

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

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

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

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

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

The STREAM stage 2 trial assessed two bedaquiline-containing regimens for rifampicin-resistant tuberculosis: a 9-month all-oral regimen and a 6-month regimen containing an injectable drug for the first 2 months. We did a within-trial economic evaluation of these regimens.. STREAM stage 2 was an international, phase 3, non-inferiority randomised trial in which participants with rifampicin-resistant tuberculosis were randomly assigned (1:2:2:2) to the 2011 WHO regimen (terminated early), a 9-month injectable-containing regimen (control regimen), a 9-month all-oral regimen with bedaquiline (oral regimen), or a 6-month regimen with bedaquiline and an injectable for the first 2 months (6-month regimen). We prospectively collected direct and indirect costs and health-related quality of life data from trial participants until week 76 of follow-up. Cost-effectiveness of the oral and 6-month regimens versus control was estimated in four countries (oral regimen) and two countries (6-month regimen), using health-related quality of life for cost-utility analysis and trial efficacy for cost-effectiveness analysis. This trial is registered with ISRCTN, ISRCTN18148631.. 300 participants were included in the economic analyses (Ethiopia, 61; India, 142; Moldova, 51; Uganda, 46). In the cost-utility analysis, the oral regimen was not cost-effective in Ethiopia, India, Moldova, and Uganda from either a provider or societal perspective. In Moldova, the oral regimen was dominant from a societal perspective. In the cost-effectiveness analysis, the oral regimen was likely to be cost-effective from a provider perspective at willingness-to-pay thresholds per additional favourable outcome of more than US$4500 in Ethiopia, $1900 in India, $3950 in Moldova, and $7900 in Uganda, and from a societal perspective at thresholds of more than $15 900 in Ethiopia, $3150 in India, and $4350 in Uganda, while in Moldova the oral regimen was dominant. In Ethiopia and India, the 6-month regimen would cost tuberculosis programmes and participants less than the control regimen and was highly likely to be cost-effective in both cost-utility analysis and cost-effectiveness analysis. Reducing the bedaquiline price from $1·81 to $1·00 per tablet made the oral regimen cost-effective in the provider-perspective cost-utility analysis in India and Moldova and dominate over the control regimen in the provider-perspective cost-effectiveness analysis in India.. At current costs, the oral bedaquiline-containing regimen for rifampicin-resistant tuberculosis is unlikely to be cost-effective in many low-income and middle-income countries. The 6-month regimen represents a cost-effective alternative if injectable use for 2 months is acceptable.. USAID and Janssen Research & Development.

Topics: Antitubercular Agents; Cost-Benefit Analysis; Humans; Quality of Life; Rifampin; Tuberculosis, Multidrug-Resistant

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

Leprosy is an ancient infectious disease with an annual global incidence of around 200,000 over the past decade. Since 2018, the World Health Organization (WHO) recommends single-dose rifampicin as post-exposure prophylaxis (SDR-PEP) for contacts of leprosy patients. The Post ExpOsure Prophylaxis for Leprosy (PEOPLE) trial evaluated PEP with a double dose of rifampicin in Comoros and Madagascar. Preliminary results of this trial show some reduction in leprosy incidence in intervention villages but a stronger regimen may be beneficial. The objective of the current Bedaquiline Enhanced ExpOsure Prophylaxis for LEprosy trial (BE-PEOPLE) is to explore effectiveness of a combination of bedaquiline and rifampicin as PEP.. BE-PEOPLE is a cluster-randomized trial in which 44 clusters in Comoros will be randomized to two study arms. Door-to-door screening will be conducted annually during four years, leprosy patients identified will be offered standard of care treatment. Based on study arm, contacts aged five years and above and living within a 100-meter radius of an index case will either receive bedaquiline (400-800 mg) and rifampicin (150-600 mg) or only rifampicin (150-600 mg). Contacts aged two to four years will receive rifampicin only. Household contacts randomized to the bedaquiline plus rifampicin arm will receive a second dose four weeks later. Incidence rate ratios of leprosy comparing contacts who received either of the PEP regimens will be the primary outcome. We will monitor resistance to rifampicin and/or bedaquiline through molecular surveillance in all incident tuberculosis and leprosy patients nationwide. At the end of the study, we will assess anti-M. leprae PGL-I IgM seropositivity as a proxy for the population burden of M. leprae infection in 8 villages (17,000 individuals) that were surveyed earlier as part of the PEOPLE trial.. The COLEP trial on PEP in Bangladesh documented a reduction of 57% in incidence of leprosy among contacts treated with SDR-PEP after two years, which led to the WHO recommendation of SDR-PEP. Preliminary results of the PEOPLE trial show a lesser reduction in incidence. The BE-PEOPLE trial will explore whether reinforcing SDR-PEP with bedaquiline increases effectiveness and more rapidly reduces the incidence of leprosy, compared to SDR-PEP alone.. NCT05597280. Protocol version 5.0 on 28 October 2022.

Topics: Antibodies; Comoros; Humans; Leprosy; Mycobacterium leprae; Post-Exposure Prophylaxis; Randomized Controlled Trials as Topic; Rifampin

Globally rifampicin-resistant tuberculosis disease affects around 460,000 people each year. Currently recommended regimens are 9-24 months duration, have poor efficacy and carry significant toxicity. A shorter, less toxic and more efficacious regimen would improve outcomes for people with rifampicin-resistant tuberculosis.. TB-PRACTECAL is an open-label, randomised, controlled, phase II/III non-inferiority trial evaluating the safety and efficacy of 24-week regimens containing bedaquiline and pretomanid to treat rifampicin-resistant tuberculosis. Conducted in Uzbekistan, South Africa and Belarus, patients aged 15 and above with rifampicin-resistant pulmonary tuberculosis and requiring a new course of therapy were eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients were randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also included moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment was administered under direct observation for 24 weeks in investigational arms and 36 to 96 weeks in the standard of care arm. The second stage of the study was equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome was the percentage of unfavourable outcomes at 72 weeks post-randomisation. This was a composite of early treatment discontinuation, treatment failure, recurrence, lost-to-follow-up and death. The study is being conducted in accordance with ICH-GCP and full ethical approval was obtained from Médecins sans Frontières ethical review board, London School of Hygiene and Tropical Medicine ethical review board as well as ERBs and regulatory authorities at each site.. TB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel treatments that are effective and safe to patients quicker. The trial took a patient-centred approach, adapting to best practice guidelines throughout recruitment. The implementation faced significant challenges from the COVID-19 pandemic. The trial was terminated early for efficacy on the advice of the DSMB and will report on data collected up to the end of recruitment and, additionally, the planned final analysis at 72 weeks after the end of recruitment.. Clinicaltrials.gov NCT02589782. Registered on 28 October 2015.

Topics: Adolescent; Adult; Antibiotics, Antitubercular; Antitubercular Agents; Diarylquinolines; Humans; Linezolid; Pandemics; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Young Adult

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

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

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

Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established. Our aim was to characterise the effects of bedaquiline, delamanid, or both on the QTc interval, longitudinally over 6 months of multidrug treatment, among patients with multidrug-resistant or rifampicin-resistant tuberculosis taking multidrug background therapy.. ACTG A5343 is a phase 2, open-label, randomised, controlled trial in which adults with multidrug-resistant or rifampicin-resistant tuberculosis receiving multidrug background treatment were randomly assigned 1:1:1 by centrally, computer-generated randomisation, by means of permuted blocks to receive bedaquiline, delamanid, or both for 24 weeks. Participants were enrolled at TASK in Cape Town and the South African Tuberculosis Vaccine Initiative in Worcester, both in South Africa, and Hospital Maria Auxiliadora in Peru. Individuals with QTc greater than 450 ms were excluded. HIV-positive participants received dolutegravir-based antiretroviral therapy. Clofazimine was disallowed, and levofloxacin replaced moxifloxacin. ECG in triplicate and sputum cultures were done fortnightly. The primary endpoint was mean QTcF change from baseline (averaged over weeks 8-24); cumulative culture conversation at week 8-24 was an exploratory endpoint. Analyses included all participants who initiated study tuberculosis treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT02583048 and is ongoing.. Between Aug 26, 2016 and July 13, 2018, of 174 screened, 84 participants (28 in each treatment group, and 31 in total with HIV) were enrolled. Two participants did not initiate study treatment (one in the delamanid group withdrew consent and one in the bedaquiline plus delamanid group) did not meet the eligibility criterion). Mean change in QTc from baseline was 12·3 ms (95% CI 7·8-16·7; bedaquiline), 8·6 ms (4·0-13·1; delamanid), and 20·7 ms (16·1-25·3) (bedaquiline plus delamanid). There were no grade 3 or 4 adverse QTc prolongation events and no deaths during study treatment. Cumulative culture conversion by week 8 was 21 (88%) of 24 (95% CI 71-97; bedaquiline), 20 (83%) of 24 (65-95; delamanid), and 19 (95%) of 20 (79-100; bedaquiline plus delamanid) and was 92% (77-99) for bedaquiline, 91% (76-99), for delamanid, and 95% (79-100) for bedaquiline plus delamanid at 24 weeks.. Combining bedaquiline and delamanid has a modest, no more than additive, effect on the QTc interval, and initial microbiology data are encouraging. This study provides supportive evidence for use of these agents together in patients with multidrug-resistant or rifampicin-resistant tuberculosis with normal baseline QTc values.. Division of AIDS, National Institutes of Health.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Electrocardiography; Female; Humans; Male; Nitroimidazoles; Oxazoles; Peru; Rifampin; South Africa; Treatment Outcome; Tuberculosis, Multidrug-Resistant

A December 2019 WHO rapid communication recommended the use of 9-month all-oral regimens for treating multidrug-resistant tuberculosis (MDR-TB). Besides the clinical benefits, they are thought to be less costly than the injectable-containing regimens, for both the patient and the health system. STREAM is the first randomised controlled trial with an economical evaluation to compare all-oral and injectable-containing 9-11-month MDR-TB treatment regimens.. Health system costs of delivering a 9-month injectable-containing regimen and a 9-month all-oral bedaquiline-containing regimen will be collected in Ethiopia, India, Moldova and Uganda, using 'bottom-up' and 'top-down' costing approaches. Patient costs will be collected using questionnaires that have been developed based on the STOP-TB questionnaire. The primary objective of the study is to estimate the cost utility of the two regimens, from a health system perspective. Secondary objectives include estimating the cost utility from a societal perspective as well as evaluating the cost-effectiveness of the regimens, using both health system and societal perspectives. The effect measure for the cost-utility analysis will be the quality-adjusted life years (QALY), while the effect measure for the cost-effectiveness analysis will be the efficacy outcome from the clinical trial.. The study has been evaluated and approved by the Ethics Advisory Group of the. ISRCTN18148631.

Topics: Antitubercular Agents; Cost-Benefit Analysis; Diarylquinolines; Ethiopia; Humans; India; Moldova; Myocardial Infarction; Rifampin; Tuberculosis, Multidrug-Resistant; Uganda

New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in the first 8 weeks of treatment of pulmonary tuberculosis.. In this multicentre, open-label, partially randomised, phase 2b trial, we prospectively recruited patients with drug-susceptible or rifampicin-resistant pulmonary tuberculosis from seven sites in South Africa, two in Tanzania, and one in Uganda. Patients aged 18 years or older with sputum smear grade 1+ or higher were eligible for enrolment, and a molecular assay (GeneXpert or MTBDRplus) was used to confirm the diagnosis of tuberculosis and to distinguish between drug-susceptible and rifampicin-resistant tuberculosis. Patients who were HIV positive with a baseline CD4 cell count of less than 100 cells per uL were excluded. Patients with drug-susceptible tuberculosis were randomly assigned (1:1:1) using numbered treatment packs with sequential allocation by the pharmacist to receive 56 days of treatment with standard tuberculosis therapy (oral isoniazid, rifampicin, pyrazinamide, and ethambutol; HRZE), or pretomanid (oral 200 mg daily) and pyrazinamide (oral 1500 mg daily) with either oral bedaquiline 400 mg daily on days 1-14 then 200 mg three times per week (B. Between Oct 24, 2014, and Dec 15, 2015, we enrolled 180 patients with drug-susceptible tuberculosis (59 were randomly assigned to B. B. TB Alliance, UK Department for International Development, Bill & Melinda Gates Foundation, US Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and the Federal Ministry for Education and Research of Germany.

Topics: Antitubercular Agents; Diarylquinolines; Drug Administration Schedule; Drug Therapy, Combination; Humans; Moxifloxacin; Nitroimidazoles; Pyrazinamide; Rifampin; South Africa; Sputum; Tanzania; Treatment Outcome; Tuberculosis, Multidrug-Resistant; Uganda

Bedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture.. Subjects were randomly assigned to receive two single 400 mg doses of bedaquiline, alone, and, after a 4 week washout period, in combination with steady-state daily dosing of either rifabutin 300 mg or rifampin 600 mg. Blood samples were collected prior to dosing and at multiple time points subsequently, to measure plasma drug concentrations and bactericidal activity in ex vivo M tuberculosis-infected whole blood cultures (WBA).. Single oral doses of bedaquiline produced readily detectable WBA ex vivo, reaching a maximal effect of -0.28 log/day, with negative values indicating bacterial killing. Plasma concentrations of 355 ng/ml were sufficient for intracellular mycobacteriostasis. Combined dosing with rifampin or rifabutin produced maximal effects of -0.91 and -0.79 log/d, respectively. However, the activity of the rifabutin combination was sustained throughout the dosing interval, thereby producing a greater cumulative or total effect. At low drug concentrations, rifabutin plus bedaquiline yielded greater mycobactericidal activity than the sum of their separate effects. Neither drug metabolites nor cellular drug accumulation could account for this observation.. The combination of rifabutin plus bedaquiline produces sustained intracellular mycobactericidal activity that is greater than the sum of their individual effects. Further studies of the treatment-shortening potential of this combination are warranted.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Drug Therapy, Combination; Humans; Mycobacterium tuberculosis; Rifabutin; Rifampin

This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.).

Topics: Adult; Diarylquinolines; Female; Healthy Volunteers; Humans; Male; Middle Aged; Rifampin; Young Adult

Bedaquiline is the first drug of a new class approved for the treatment of TB in decades. Bedaquiline is metabolized by cytochrome P450 (CYP) 3A4 to a less-active M2 metabolite. Its terminal half-life is extremely long (5-6 months), complicating evaluations of drug-drug interactions. Rifampicin and rifapentine, two anti-TB drugs now being optimized to shorten TB treatment duration, are potent inducers of CYP3A4. This analysis aimed to predict the effect of repeated doses of rifampicin or rifapentine on the steady-state pharmacokinetics of bedaquiline and its M2 metabolite from single-dose data using a model-based approach.. Pharmacokinetic data for bedaquiline and M2 were obtained from a Phase I study involving 32 individuals each receiving two doses of bedaquiline, alone or together with multiple-dose rifampicin or rifapentine. Sampling was performed over 14 days following each bedaquiline dose. Pharmacokinetic analyses were performed using non-linear mixed-effects modelling. Models were used to simulate potential dose adjustments.. Rifamycin co-administration increased bedaquiline clearance substantially: 4.78-fold [relative standard error (RSE) 9.10%] with rifampicin and 3.96-fold (RSE 5.00%) with rifapentine. Induction of M2 clearance was equally strong. Average steady-state concentrations of bedaquiline and M2 are predicted to decrease by 79% and 75% when given with rifampicin or rifapentine, respectively. Simulations indicated that increasing the bedaquiline dosage to mitigate the interaction would yield elevated M2 concentrations during the first treatment weeks.. Rifamycin antibiotics reduce bedaquiline concentrations substantially. In line with current treatment guidelines for drug-susceptible TB, concomitant use is not recommended, even with dose adjustment.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Drug Interactions; Female; Humans; Male; Middle Aged; Rifampin; 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

The incidence of tuberculosis has been increasing substantially on a worldwide basis over the past decade, but no tuberculosis-specific drugs have been discovered in 40 years. We identified a diarylquinoline, R207910, that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro (minimum inhibitory concentration 0.06 mug/ml). In mice, R207910 exceeded the bactericidal activities of isoniazid and rifampin by at least 1 log unit. Substitution of drugs included in the World Health Organization's first-line tuberculosis treatment regimen (rifampin, isoniazid, and pyrazinamide) with R207910 accelerated bactericidal activity, leading to complete culture conversion after 2 months of treatment in some combinations. A single dose of R207910 inhibited mycobacterial growth for 1 week. Plasma levels associated with efficacy in mice were well tolerated in healthy human volunteers. Mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.

Topics: Amino Acid Sequence; Animals; Antitubercular Agents; Bacterial Proton-Translocating ATPases; Diarylquinolines; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance, Bacterial; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Male; Mice; Microbial Sensitivity Tests; Molecular Sequence Data; Mycobacterium smegmatis; Mycobacterium tuberculosis; Point Mutation; Protein Subunits; Quinolines; Tuberculosis; Tuberculosis, Multidrug-Resistant

World Health Organization recommends a 7-drug 9-11-month rifampicin-resistant tuberculosis (RR-TB) short treatment regimen (STR). To reduce the pill burden, we assessed the safety and effectiveness of a 5-drug 9-11-month modified STR (mSTR).. Prospective cohort study of an all-oral mSTR (comprising bedaquiline, levofloxacin, linezolid [LZD], clofazimine, and/or pyrazinamide) for patients with RR-TB without confirmed fluoroquinolone resistance, enrolled in Vietnam between 2020-2021.. A total of 108 patients were enrolled in this study. Overall, 63 of 74 (85%) achieved culture conversion at 2 months. Of 106 evaluated, 95 (90%) were successfully treated, six (6%) were lost-to-follow-up, one (1%) died, and four (4%) had treatment failure, including three with permanent regimen change owing to adverse events (AE) and one with culture reversion. Of 108, 32 (30%) patients encountered at least one AE. Of 45 AEs recorded, 13 (29%) were serious (hospitalization, life threatening, or death). The median time to AE was 3 months (IQR: 2-5). A total of 26 AEs led to regimen adaptation: either dose reduction (N = 1), drug temporary interruption (N = 19), or drug permanent discontinuation (N = 6, 4 attributed to LZD).. The high treatment success of 5-drug mSTR might replace the 7-drug regimen in routine care. AEs were frequent, but manageable in most patients. Active AEs monitoring is essential, particularly when using LZD throughout.

Topics: Antitubercular Agents; Diarylquinolines; Humans; Linezolid; Prospective Studies; Rifampin; Tuberculosis, Multidrug-Resistant; Vietnam

Rifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons start treatment, and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, 6-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200-mg linezolid. After US Food and Drug Administration approval in 2019, some US clinicians rapidly implemented BPaL using an initial 600-mg linezolid dose adjusted by serum drug concentrations and clinical monitoring.. Data from US patients treated with BPaL between 14 October 2019 and 30 April 2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider driven, and most patients had linezolid adjusted by therapeutic drug monitoring.. Of 70 patients starting BPaL, 2 changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and 2 of the 68 (2.9%) experienced relapse after completion. Using an initial 600-mg linezolid dose daily adjusted by therapeutic drug monitoring and careful clinical and laboratory monitoring for adverse effects, supportive care, and expert consultation throughout BPaL treatment, 3 patients (4.4%) with hematologic toxicity and 4 (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months.. BPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in 2019 US guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the United States is feasible.

Topics: Antitubercular Agents; Diarylquinolines; Humans; Linezolid; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; United States

Topics: Antitubercular Agents; Diarylquinolines; HIV Infections; HIV Seropositivity; Humans; Linezolid; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant; World Health Organization

Meropenem in combination with β-lactamase inhibitors (BLIs) and other drugs was tested to identify alternative treatment regimens for multidrug-resistant tuberculosis (MDR-TB).. The following were performed: (1) MIC experiments; (2) static time-kill studies (STKs) with different BLIs; and (3) a hollow fibre model system of TB (HFS-TB) studies with meropenem-vaborbactam combined with human equivalent daily doses of 20 mg/kg or 35 mg/kg rifampin, or moxifloxacin 400 mg, or linezolid 600 mg vs. bedaquiline-pretonamid-linezolid (BPaL) for MDR-TB. The studies were performed using Mycobacterium tuberculosis (M. tuberculosis) H37Rv and an MDR-TB clinical strain (named M. tuberculosis 16D) that underwent whole genome sequencing. Exponential decline models were used to calculate the kill rate constant (K) of different HFS-TB regimens.. Adding meropenem-vaborbactam could potentially restore the efficacy of isoniazid and rifampin against MDR-TB. The meropenem-vaborbactam-moxifloxacin backbone regimen has implications for creating a new effective MDR-TB regimen.

Topics: Antitubercular Agents; beta-Lactamase Inhibitors; Humans; Isoniazid; Linezolid; Meropenem; Moxifloxacin; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant

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

Translational efforts in the evaluation of novel anti-tubercular drugs demand better integration of pharmacokinetic-pharmacodynamic data arising from preclinical protocols. However, parametric approaches that discriminate drug effect from the underlying bacterial growth dynamics have not been fully explored, making it difficult to translate and/or extrapolate preclinical findings to humans. This analysis aims to develop a drug-disease model that allows distinction between drug- and system-specific properties.. Given their clinical relevance, rifampicin and bedaquiline were used as test compounds. A two-state model was used to describe bacterial growth dynamics. The approach assumes the existence of fast- and slow-growing bacterial populations. Drug effect on the growth dynamics of each subpopulation was characterised in terms of potency (EC. The doubling time of the fast- and slow-growing population was estimated to be 25 h and 42 days, respectively. Rifampicin was more potent against the fast-growing (EC. Model parameter estimates suggest that nearly maximum killing rate is achieved against fast-growing, but not against slow-growing populations at the tested doses. Evidence of differences in drug potency for each subpopulation may facilitate the translation of preclinical findings and improve the dose rationale for anti-tubercular drugs in humans.

Topics: Animals; Bacteria; Diarylquinolines; Mice; Mice, Inbred BALB C; Rifampin

Bedaquiline improves outcomes of patients with rifampicin-resistant and multidrug-resistant (MDR) tuberculosis; however, emerging resistance threatens this success. We did a cross-sectional and longitudinal analysis evaluating the epidemiology, genetic basis, and treatment outcomes associated with bedaquiline resistance, using data from South Africa (2015-19).. Patients with drug-resistant tuberculosis starting bedaquiline-based treatment had surveillance samples submitted at baseline, month 2, and month 6, along with demographic information. Culture-positive baseline and post-baseline isolates had phenotypic resistance determined. Eligible patients were aged 12 years or older with a positive culture sample at baseline or, if the sample was invalid or negative, a sample within 30 days of the baseline sample submitted for bedaquiline drug susceptibility testing. For the longitudinal study, the first surveillance sample had to be phenotypically susceptible to bedaquiline for inclusion. Whole-genome sequencing was done on bedaquiline-resistant isolates and a subset of bedaquiline-susceptible isolates. The National Institute for Communicable Diseases tuberculosis reference laboratory, and national tuberculosis surveillance databases were matched to the Electronic Drug-Resistant Tuberculosis Register. We assessed baseline resistance prevalence, mutations, transmission, cumulative resistance incidence, and odds ratios (ORs) associating risk factors for resistance with patient outcomes.. Between Jan 1, 2015, and July 31, 2019, 8041 patients had surveillance samples submitted, of whom 2023 were included in the cross-sectional analysis and 695 in the longitudinal analysis. Baseline bedaquiline resistance prevalence was 3·8% (76 of 2023 patients; 95% CI 2·9-4·6), and it was associated with previous exposure to bedaquiline or clofazimine (OR 7·1, 95% CI 2·3-21·9) and with rifampicin-resistant or MDR tuberculosis with additional resistance to either fluoroquinolones or injectable drugs (pre-extensively-drug resistant [XDR] tuberculosis: 4·2, 1·7-10·5) or to both (XDR tuberculosis: 4·8, 2·0-11·7). Rv0678 mutations were the sole genetic basis of phenotypic resistance. Baseline resistance could be attributed to previous bedaquiline or clofazimine exposure in four (5·3%) of 76 patients and to primary transmission in six (7·9%). Odds of successful treatment outcomes were lower in patients with baseline bedaquiline resistance (0·5, 0·3-1). Resistance during treatment developed in 16 (2·3%) of 695 patients, at a median of 90 days (IQR 62-195), with 12 of these 16 having pre-XDR or XDR.. Bedaquiline resistance was associated with poorer treatment outcomes. Rapid assessment of bedaquiline resistance, especially when patients were previously exposed to bedaquiline or clofazimine, should be prioritised at baseline or if patients remain culture-positive after 2 months of treatment. Preventing resistance by use of novel combination therapies, current treatment optimisation, and patient support is essential.. National Institute for Communicable Diseases of South Africa.

Topics: Antitubercular Agents; Clofazimine; Cross-Sectional Studies; Diarylquinolines; Humans; Longitudinal Studies; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant

Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs.. We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented.. Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 patients (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died, and 7.2% experienced treatment failure.. Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.

Topics: Antitubercular Agents; Clofazimine; Cohort Studies; Diarylquinolines; Electrolytes; Fluoroquinolones; Humans; Linezolid; Nitroimidazoles; Oxazoles; Prospective Studies; Rifampin; Tuberculosis, Multidrug-Resistant

Pharmacokinetic data for bedaquiline in children are limited. We described the pharmacokinetics and safety of bedaquiline in South African children and adolescents receiving treatment for multidrug/rifampicin-resistant tuberculosis (MDR/RR-TB) in routine care.. In this observational cohort study, children aged 6-17 years receiving bedaquiline at recommended doses as part of MDR/RR-TB treatment underwent semi-intensive pharmacokinetic sampling. Bedaquiline and the M2 metabolite plasma concentrations were quantified, and nonlinear mixed-effects modeling performed. Pediatric data were described using a pre-established model of bedaquiline pharmacokinetics in adults. The exposure reference was 187 µg ⋅ h/mL, the median weekly area under the curve (AUC) of adults at week 24 of treatment with bedaquiline. Safety was assessed through monthly clinical, blood and electrocardiogram monitoring, and treatment outcomes described.. Fifteen children (3 human immunodeficiency virus [HIV]-positive) with median age 13.3 years (range 6.5-16.3) were included. A bedaquiline pharmacokinetic model was adapted to be allometrically scaled in clearance and volume, centered in the median child population weight. Bedaquiline bioavailability was 57% of that in adults. Overall bedaquiline exposures were below target, and AUC reference attainment was achieved in only 3 (20%) children. Ten children experienced 27 adverse events at least possibly related to bedaquiline; no adverse events led to bedaquiline withdrawal. Two adverse events (arthritis and arthralgia) were considered severe, and 2 children had mild QT interval corrected for heart rate using Fridericia's formula (QT) prolongation.. The evaluated doses of bedaquiline in children ≥ 6 years of age were safe but achieved slightly lower plasma concentrations compared to adults receiving the recommended dose, possibly due to delayed food intake relative to bedaquiline administration.

Topics: Adolescent; Adult; Antitubercular Agents; Child; Diarylquinolines; HIV; HIV Infections; HIV Seropositivity; Humans; Rifampin; Tuberculosis, Multidrug-Resistant

There is a need for short and safe all-oral treatment of rifampicin-resistant tuberculosis. We compared outcomes up to 24 months after treatment initiation for patients with rifampicin-resistant tuberculosis in South Africa treated with a short, all-oral bedaquiline-containing regimen (bedaquiline group), or a short, injectable-containing regimen (injectable group).. Patients with rifampicin-resistant tuberculosis, aged 18 years or older, eligible for a short regimen starting treatment between Jan 1 and Dec 31, 2017, with a bedaquiline-containing or WHO recommended injectable-containing treatment regimen of 9-12 months, registered in the drug-resistant tuberculosis database (EDRWeb), and with known age, sex, HIV status, and national identification number were eligible for study inclusion; patients receiving linezolid, carbapenems, terizidone or cycloserine, delamanid, or para-aminosalicylic acid were excluded. Bedaquiline was given at a dose of 400 mg once daily for two weeks followed by 200 mg three times a week for 22 weeks. To compare regimens, patients were exactly matched on HIV and ART status, previous tuberculosis treatment history, and baseline acid-fast bacilli smear and culture result, while propensity score matched on age, sex, province of treatment, and isoniazid-susceptibility status. We did binomial linear regression to estimate adjusted risk differences (aRD) and 95% CIs for 24-month outcomes, which included: treatment success (ie, cure or treatment completion without evidence of recurrence) versus all other outcomes, survival versus death, disease free survival versus survival with treatment failure or recurrence, and loss to follow-up versus all other outcomes.. Overall, 1387 (14%) of 10152 patients with rifampicin-resistant tuberculosis treated during 2017 met inclusion criteria; 688 in the bedaquiline group and 699 in the injectable group. Four patients (1%) had treatment failure or recurrence, 44 (6%) were lost to follow-up, and 162 (24%) died in the bedaquiline group, compared with 17 (2%), 87 (12%), and 199 (28%), respectively, in the injectable group. In adjusted analyses, treatment success was 14% (95% CI 8-20) higher in the bedaquiline group than in the injectable group (70% vs 57%); loss to follow-up was 4% (1-8) lower in the bedaquiline group (6% vs 12%); and disease-free survival was 2% (0-5) higher in the bedaquiline group (99% vs 97%). The bedaquiline group had 8% (4-11) lower risk of mortality during treatment (17·0% vs 22·4%), but there was no difference in mortality post-treatment.. Patients in the bedaquiline group experienced significantly higher rates of treatment success at 24 months. This finding supports the use of short bedaquiline-containing regimens in eligible patients.. WHO Global TB Programme.. For the French translation of the abstract see Supplementary Materials section.

Topics: Antitubercular Agents; Diarylquinolines; HIV Infections; Humans; Retrospective Studies; Rifampin; South Africa; Treatment Outcome; Tuberculosis, Multidrug-Resistant

We aimed to explore the effect of pregnancy on bedaquiline pharmacokinetics (PK) and describe bedaquiline exposure in the breast milk of mothers treated for rifampicin-resistant tuberculosis (TB), where there are no human data available.. We performed a longitudinal PK study in pregnant women treated for rifampicin-resistant TB to explore the effect of pregnancy on bedaquiline exposure. Pharmacokinetic sampling was performed at 4 time-points over 6 hours in the third trimester, and again at approximately 6 weeks postpartum. We obtained serial breast milk samples from breastfeeding mothers, and a single plasma sample taken from breastfed and nonbreastfed infants to assess bedaquiline exposure. We used liquid chromatography-tandem mass spectrometry to perform the breast milk and plasma bedaquiline assays, and population PK modelling to interpret the bedaquiline concentrations.. We recruited 13 women, 6 of whom completed the ante- and postpartum PK sampling. All participants were HIV-positive on antiretroviral therapy. We observed lower ante- and postpartum bedaquiline exposures than reported in nonpregnant controls. Bedaquiline concentrations in breast milk were higher than maternal plasma (milk to maternal plasma ratio: 14:1). A single random plasma bedaquiline and M2 concentration was available in 4 infants (median age: 6.5 wk): concentrations in the 1 breastfed infant were similar to maternal plasma concentrations; concentrations in the 3 nonbreastfed infants were detectable but lower than maternal plasma concentrations.. We report low exposure of bedaquiline in pregnant women treated for rifampicin-resistant TB. Bedaquiline significantly accumulates in breast milk; breastfed infants receive mg/kg doses of bedaquiline equivalent to maternal doses.

Topics: Breast Feeding; Child; Diarylquinolines; Female; Humans; Infant; Milk, Human; Pregnancy; Rifampin; Tuberculosis, Multidrug-Resistant

Uganda remains one of the countries with the highest burden of TB/HIV. Drug-resistant TB remains a substantial challenge to TB control globally and requires new strategic effective control approaches. Drug resistance usually develops due to inadequate management of TB patients including improper treatment regimens and failure to complete the treatment course which may be due to an unstable supply or a lack of access to treatment, as well as patient noncompliance.. Two sputa samples were collected from Xpert MTB/RIF® assay-diagnosed multi-drug resistant tuberculosis (MDR-TB) patient at Lira regional referral hospital in northern Uganda between 2020 and 2021 for comprehensive routine mycobacterial species identification and drug susceptibility testing using culture-based methods. Detection of drug resistance-conferring genes was subsequently performed using whole-genome sequencing with Illumina MiSeq platform at the TB Supranational Reference Laboratory in Uganda.. In both isolates, extensively drug-resistant TB (XDR-TB) was identified including resistance to Isoniazid (katG p.Ser315Thr), Rifampicin (rpoB p.Ser450Leu), Moxifloxacin (gyrA p.Asp94Gly), Bedaquiline (Rv0678 Glu49fs), Clofazimine (Rv0678 Glu49fs), Linezolid (rplC Cys154Arg), and Ethionamide (ethA c.477del). Further analysis of these two high quality genomes revealed that this 32 years-old patient was infected with the Latin American Mediterranean TB strain (LAM).. This is the first identification of extensively drug-resistant Mycobacterium tuberculosis clinical isolates with bedaquiline, linezolid and clofazimine resistance from Uganda. These acquired resistances were because of non-adherence as seen in the patient's clinical history. Our study also strongly highlights the importance of combating DR-TB in Africa through implementing next generation sequencing that can test resistance to all drugs while providing a faster turnaround time. This can facilitate timely clinical decisions in managing MDR-TB patients with non-adherence or lost to follow-up.

Topics: Adult; Antitubercular Agents; Clofazimine; Diarylquinolines; Extensively Drug-Resistant Tuberculosis; Humans; Linezolid; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Rifampin; Tuberculosis, Multidrug-Resistant; Uganda

TBI-166, derived from riminophenazine analogues, shows more potent anti-TB activity than clofazimine and is being assessed against tuberculosis (TB) in a phase IIa clinical trial in China. Preclinical regimen studies containing TBI-166 will support the phase IIb clinical trials of TBI-166. In the present study, we compared the efficacy in three murine TB models of an all-oral drug-resistant TB drug regimen of TBI-166 with bedaquiline (BDQ) and pyrazinamide (PZA) with the first-line regimen of isoniazid (INH) with rifampin (RFP) and PZA (HRZ regimen), the most effective reported TBI-166-containing regimen of TBI-166 with BDQ and linezolid (LZD), and the Nix-TB clinical trial regimen of BDQ with pretomanid and LZD (BPaL regimen). In the C3HeB/FeJ murine TB model, for the TBI-166+BDQ+PZA regimen, the lungs of mice were culture negative at 4 weeks, and there were no relapses at 8 weeks of treatment. The reduction in bacterial burden and relapse rate were greater than those of the HRZ regimen and the TBI-166+BDQ+LZD regimen. Compared with the BPaL regimen, the TBI-166+BDQ+PZA regimen had similar or stronger early bactericidal activity, bactericidal activity, and sterilizing activity in the BALB/c murine TB model. The bacterial burden in the TBI-166+BDQ+PZA regimen group decreased significantly more than that in the BPaL regimen group and was almost or totally relapse free (<13.33% after 8 weeks). In conclusion, oral short-course three-drug regimens, including TBI-166 with high efficacy, were identified. The TBI-166+BDQ+PZA regimen is recommended for further study in a TBI-166 phase IIb clinical trial.

Topics: Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Isoniazid; Linezolid; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Pyrazinamide; Rifampin; Tuberculosis; Tuberculosis, Multidrug-Resistant

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

Bedaquiline (BDQ) is a core drug for rifampicin-resistant tuberculosis (RR-TB) treatment. Accurate prediction of a BDQ-resistant phenotype from genomic data is not yet possible. A Bayesian method to predict BDQ resistance probability from next-generation sequencing data has been proposed as an alternative.. We performed a qualitative study to investigate the decision-making of physicians when facing different levels of BDQ resistance probability. Fourteen semi-structured interviews were conducted with physicians experienced in treating RR-TB, sampled purposefully from eight countries with varying income levels and burden of RR-TB. Five simulated patient scenarios were used as a trigger for discussion. Factors influencing the decision of physicians to prescribe BDQ at macro-, meso- and micro levels were explored using thematic analysis.. The perception and interpretation of BDQ resistance probability values varied widely between physicians. The limited availability of other RR-TB drugs and the high cost of BDQ hindered physicians from altering the BDQ-containing regimen and incorporating BDQ resistance probability in their decision-making. The little experience with BDQ susceptibility testing and whole-genome sequencing results, and the discordance between phenotypic susceptibility and resistance probability were other barriers for physicians to interpret the resistance probability estimates. Especially for BDQ resistance probabilities between 25% and 70%, physicians interpreted the resistance probability value dynamically, and other factors such as clinical and bacteriological treatment response, history of exposure to BDQ, and resistance profile were often considered more important than the BDQ probability value for the decision to continue or stop BDQ. In this grey zone, some physicians opted to continue BDQ but added other drugs to strengthen the regimen.. This study highlights the complexity of physicians' decision-making regarding the use of BDQ in RR-TB regimens for different levels of BDQ resistance probability.. Ensuring sufficient access to BDQ and companion drugs, improving knowledge of the genotype-phenotype association for BDQ resistance, availability of a rapid molecular test, building next-generation sequencing capacity, and developing a clinical decision support system incorporating BDQ resistance probability will all be essential to facilitate the implementation of BDQ resistance probability in personalizing treatment for patients with RR-TB.

Topics: Antitubercular Agents; Bayes Theorem; Decision Making; Humans; Rifampin; Tuberculosis, Multidrug-Resistant

To evaluate the 24-week interim outcomes of bedaquiline-containing regimens in the treatment of adolescents with rifampicin-resistant tuberculosis (RR-TB) in China.. Adolescents with RR-TB from two hospitals were included in this retrospective study. All patients received the longer regimen containing bedaquiline. Sputum culture, chest computed tomography, blood tests and electrocardiography were performed regularly, and the outcomes after 24 weeks of treatment were reported.. Four male and six female adolescents aged 11 to 17 years old were included. Among them, four (40.0%), four (40.0%) and two (20.0%) were confirmed to have RR-TB, multidrug-resistant TB and extensively drug-resistant TB, respectively. The most common companion drugs included linezolid (100.0%), cycloserine (90.0%), pyrazinamide (80.0%), moxifloxacin (50.0%) and levofloxacin (40.0%). Culture conversion rates of 80.0%, 100.0% and 100.0% were observed at weeks 2, 4 and 24, respectively. The mean maximum drug concentration of bedaquiline at weeks 2, 12 and 24 was 3.29 ± 0.66, 1.78 ± 0.81 and 1.93 ± 0.74 μg/mL, respectively. Six adverse events including leukopenia (50.0%), Fridericia-corrected QT (QTcF) interval prolongation (16.7%), anaemia (16.7%) and peripheral neuropathy (16.7%) were observed in five (50.0%) patients. No patient discontinued bedaquiline owing to QTcF interval prolongation. Meanwhile, no deaths, reversions or serious adverse events were reported during 24 weeks of treatment.. A longer regimen containing bedaquiline was effective and well tolerated in Chinese adolescents with RR-TB. The combination of bedaquiline and linezolid may be a favourable choice for this population.

Topics: Adolescent; Antitubercular Agents; Child; Diarylquinolines; Female; Humans; Male; Retrospective Studies; Rifampin; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Topics: Diarylquinolines; Female; Humans; Infant; Pregnancy; Pregnant Women; Rifampin; South Africa; Tuberculosis, Multidrug-Resistant

At the end of 2018, South Africa updated its all-oral regimen, to include bedaquiline (BDQ) and 2 months of linezolid (LZD) for all patients initiating the shorter 9-12 months regimen for rifampicin-resistant tuberculosis (RR-TB). We assessed a group of patients in rural KwaZulu-Natal for safety and effectiveness of this treatment regimen under programmatic conditions.. We conducted a retrospective cohort analysis on RR-TB patients treated with a standardized all-oral short regimen between 1 July 2018 and 30 April 2019 in 3 facilities in King Cetshwayo District. An electronic register (EDR web) and facility-based clinical charts were used to collect variables, which were entered into an Epi-Info database.. Our cohort included 117 patients; 68.4% (95% confidence interval [CI]: 59.3-76.3) tested positive for human immunodeficiency virus (HIV). The median time to culture conversion was 56 days (95% CI: 50-57). Treatment success was achieved in 75.2% (95% CI: 66.5-82.3) of patients. Mortality within the cohort was 12.8% (95% CI: 7.8-20.3). Anemia was the most frequent severe adverse event (AE). The median time to develop severe anemia was 7.1 weeks (interquartile range [IQR] 4.0-12.9) after treatment initiation. LZD was interrupted in 25.2% (95% CI: 17.8-34.5) of participants.. An all-oral shorter regimen, including BDQ and LZD as core drugs for the treatment of RR-TB, shows good outcomes, in a high HIV burden rural setting. AEs are common, especially for LZD, but could be managed in the program setting. Support is needed when introducing new regimens to train staff in the monitoring, management, and reporting of AEs.

Topics: Antitubercular Agents; Cohort Studies; Diarylquinolines; HIV; HIV Infections; Humans; Retrospective Studies; Rifampin; South Africa; Tuberculosis, Multidrug-Resistant

The mycomembrane layer of the mycobacterial cell envelope is a barrier to environmental, immune, and antibiotic insults. There is considerable evidence of mycomembrane plasticity during infection and in response to host-mimicking stresses. Since mycobacteria are resource and energy limited under these conditions, it is likely that remodeling has distinct requirements from those of the well-characterized biosynthetic program that operates during unrestricted growth. Unexpectedly, we found that mycomembrane remodeling in nutrient-starved, nonreplicating mycobacteria includes synthesis in addition to turnover. Mycomembrane synthesis under these conditions occurs along the cell periphery, in contrast to the polar assembly of actively growing cells, and both liberates and relies on the nonmammalian disaccharide trehalose. In the absence of trehalose recycling,

Topics: Adenosine Triphosphate; Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Bacterial Proteins; Cell Membrane; Cell Wall; Cord Factors; Diarylquinolines; Energy Metabolism; Galactans; Gene Expression; Glucose; Maltose; Membrane Transport Proteins; Mycobacterium smegmatis; Mycobacterium tuberculosis; Mycolic Acids; Rifampin; Trehalose

Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2, and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used noncompartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 to 2,540 ng/ml in plasma and 16.2 to 5,478 ng/ml in PBMCs, and concentrations of M2 over the 6-month treatment period ranged from 34.3 to 496 ng/ml in plasma and 109.2 to 16,764 ng/ml in PBMCs. Plasma concentrations of bedaquiline were higher than those of M2, but intracellular concentrations of M2 were considerably higher than those of bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratios 1 and 2 months after start of treatment were 0.61 (95% confidence interval [CI]: 0.42 to 0.92) and 1.10 (95% CI: 0.74 to 1.63) for bedaquiline and 12.4 (95% CI: 8.8 to 17.8) and 22.2 (95% CI: 15.6 to 32.3) for M2. The intracellular-plasma ratios for both bedaquiline and M2 were decreased by 54% (95% CI: 24 to 72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting

Topics: Antitubercular Agents; Chromatography, Liquid; Diarylquinolines; Humans; Leukocytes, Mononuclear; Rifampin; Tandem Mass Spectrometry; Tuberculosis

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

Pyrazinamide still may be a useful drug for treatment of rifampin-resistant (RR-TB) or multidrug-resistant tuberculosis (MDR-TB) in China while awaiting scale up of new drugs and regimens including bedaquiline and linezolid. The level of pyrazinamide resistance among MDR-TB patients in China is not well established. Therefore, we assessed pyrazinamide resistance in a representative sample and explored determinants and patterns of pncA mutations.. MDR-TB isolates from the 2007 national drug resistance survey of China were sub-cultured and examined for pyrazinamide susceptibility by BACTEC MGIT 960 method. pncA mutations were identified by sequencing. Characteristics associated with pyrazinamide resistance were analyzed using univariable and multivariable log-binominal regression.. Of 401 MDR-TB isolates, 324 were successfully sub-cultured and underwent drug susceptibility testing. Pyrazinamide resistance was prevalent in 40.7% of samples, similarly among new and previously treated MDR-TB patients. Pyrazinamide resistance in MDR-TB patients was associated with lower age (adjusted OR 0.54; 95% CI, 0.34-0.87 for those aged ≧60 years compared to < 40 years). Pyrazinamide resistance was not associated with gender, residential area, previous treatment history and Beijing genotype. Of 132 patients with pyrazinamide resistant MDR-TB, 97 (73.5%) had a mutation in the pncA gene; with 61 different point mutations causing amino acid change, and 11 frameshifts in the pncA gene. The mutations were scattered throughout the whole pncA gene and no hot spot region was identified.. Pyrazinamide resistance among MDR-TB patients in China is common, although less so in elderly patients. Therefore, pyrazinamide should only be used for treatment of RR/MDR-TB in China if susceptibility is confirmed. Molecular testing for detection of pyrazinamide resistance only based on pncA mutations has certain value for the rapid detection of pyrazinamide resistance in MDR-TB strains but other gene mutations conferring to pyrazinamide resistance still need to be explored to increase its predictive ability .

Topics: Adult; Age Factors; Amidohydrolases; Antitubercular Agents; Base Sequence; China; Diarylquinolines; Genes, Bacterial; Genotype; Humans; Linezolid; Male; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Point Mutation; Polymorphism, Single Nucleotide; Prevalence; Pyrazinamide; Rifampin; Risk Factors; Tuberculosis, Multidrug-Resistant

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

Buruli ulcer (BU), caused by Mycobacterium ulcerans, is currently treated with a daily combination of rifampin and either injectable streptomycin or oral clarithromycin. An intermittent oral regimen would facilitate treatment supervision. We first evaluated the bactericidal activity of newer antimicrobials against M. ulcerans using a BU animal model. The imidazopyridine amine telacebec (Q203) exhibited high bactericidal activity whereas tedizolid (an oxazolidinone closely related to linezolid), selamectin and ivermectin (two avermectine compounds) and the benzothiazinone PBTZ169 were not active. Consequently, telacebec was evaluated for its bactericidal and sterilizing activities in combined intermittent regimens. Telacebec given twice a week in combination with a long-half-life compound, either rifapentine or bedaquiline, sterilized mouse footpads in 8 weeks, i.e. after a total of only 16 doses, and prevented relapse during a period of 20 weeks after the end of treatment. These results are very promising for future intermittent oral regimens which would greatly simplify BU treatment in the field.

Topics: Animals; Antitubercular Agents; Buruli Ulcer; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Imidazoles; Mice; Mice, Inbred BALB C; Mycobacterium ulcerans; Oxazolidinones; Piperidines; Pyridines; Rifampin; Tetrazoles

Regimens that could treat both rifampin-resistant (RR) and rifampin-susceptible tuberculosis (TB) while shortening the treatment duration have reached late-stage clinical trials. Decisions about whether and how to implement such regimens will require an understanding of their likely clinical impact and how this impact depends on local epidemiology and implementation strategy.. A Markov state-transition model of 100,000 representative South African adults with TB was used to simulate implementation of the regimen BPaMZ (bedaquiline, pretomanid, moxifloxacin, and pyrazinamide), either for RR-TB only or universally for all patients. Patient outcomes, including cure rates, time with active TB, and time on treatment, were compared to outcomes under current care. Sensitivity analyses varied the drug-resistance epidemiology, rifampin susceptibility testing practices, and regimen efficacy.. Using BPaMZ exclusively for RR-TB increased the proportion of all RR-TB that was cured by initial treatment from 60 ± 1% to 67 ± 1%. Expanding use of BPaMZ to all patients increased cure of RR-TB to 89 ± 1% and cure of all TB from 87.3 ± 0.1% to 89.5 ± 0.1%, while shortening treatment by 1.9 months/person. In sensitivity analyses, reducing the coverage of rifampin susceptibility testing resulted in lower projected proportions of patients cured under all regimen scenarios (current care, RR-only BPaMZ, and universal BPaMZ), compared to the proportions projected using South Africa's high coverage; however, this reduced coverage resulted in greater expected incremental benefits of universal BPaMZ implementation, both when compared to RR-only BPaMZ implementation and when compared to to current care under the same low rifampin susceptibility testing coverage. In settings with higher RR-TB prevalence, the benefits of BPaMZ were magnified both for RR-specific and universal BPaMZ implementation.. Novel regimens such as BPaMZ could improve RR-TB outcomes and shorten treatment for all patients, particularly with universal use. Decision-makers weighing early options for implementing such regimens at scale will want to consider the expected impact on patient outcomes and on the burden of treatment in their local context.

Topics: Adult; Antitubercular Agents; Diarylquinolines; Humans; Markov Chains; Nitroimidazoles; Prevalence; Pyrazinamide; Rifampin; South Africa; Treatment Outcome; Tuberculosis; Tuberculosis, Multidrug-Resistant

South Africa led the world with guidelines on bedaquiline (BDQ) use as a single drug substitution to manage rifampin resistant tuberculosis regimen toxicity. We examined reasons for giving BDQ in a retrospective cohort: >75% of patients were switched to BDQ for toxicity (ototoxicity or renal dysfunction) rather than drug resistance.

Topics: Adult; Antitubercular Agents; Coinfection; Diarylquinolines; Drug Substitution; Drug Therapy, Combination; Female; HIV Infections; Humans; Male; Middle Aged; Mycobacterium tuberculosis; Retreatment; Retrospective Studies; Rifampin; South Africa; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Nearly 20,000 people were diagnosed with multi-drug and rifampicin-resistant tuberculosis (MDR/RR-TB) in South Africa in 2015, yet only one-half of the patients who start treatment are expected to have a successful outcome. There is increasing evidence of the effectiveness and safety of new drug regimens containing bedaquiline for MDR/RR-TB; however, whether they are affordable for high-burden, limited-resource settings is uncertain.. Our objective was to determine the incremental cost effectiveness of a bedaquiline-based regimen for MDR/RR-TB treatment in South Africa compared with the standard kanamycin-based regimen.. We established a Markov model for ambulatory treatment of MDR/RR-TB in a high-HIV prevalence setting, parameterized using clinical outcomes from the South African National TB Programme (SA NTP) before (2012-2014) and after (2015-2016) bedaquiline roll-out. The effectiveness of treatment was evaluated in disability-adjusted life-years (DALYs). Ingredient costs from the provider's perspective were collected in 2016 South African Rand and converted to $US, including bedaquiline at $US675.23 per 6-month treatment course. Culture conversion rates were derived from the phase IIb trial of bedaquiline, and disability adjustments were adapted from published literature. Costs and effectiveness were discounted at 3%.. For non-bedaquiline regimens, the total expected cost over the 10-year time horizon for a patient with MDR/RR-TB was $US4439 with disability-adjusted survival of 5.1 years. Replacing capreomycin with bedaquiline in patients who failed MDR/RR-TB treatment and required treatment for extensively drug-resistant (XDR-TB) resulted in cost savings ($US4356; 1.8% less) and similar effectiveness (0.02 DALYs averted). As a result, the standard regimen (no bedaquiline) was dominated. Replacing kanamycin with bedaquiline to provide all patients with MDR/RR-TB access to bedaquiline cost $US4647 (4.3% more) and averted 0.17 DALYs compared with the no bedaquiline regimen. The incremental cost-effectiveness ratio was $US1242/DALY averted.. Markov modelling indicates providing bedaquiline for all patients with MDR/RR-TB could increase the 24-month treatment success rate in South Africa from 56.3% using the current regimen to 60.6%, at a cost $US2.6 million over a 10-year horizon, less than 1% of the estimated $US425 million SA NTP annual budget.

Topics: Antitubercular Agents; Coinfection; Cost-Benefit Analysis; Diarylquinolines; Drug Costs; Health Care Costs; HIV Infections; Humans; Markov Chains; Rifampin; South Africa; Time Factors; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Topics: Antitubercular Agents; Communicable Disease Control; Databases, Factual; Diarylquinolines; Humans; Infectious Disease Medicine; Isoniazid; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Patient Safety; Public Health; Rifampin; Tuberculosis, Multidrug-Resistant; World Health Organization

Adverse drug reactions (ADRs) are common during standard, long-course treatment for multidrug-resistant and rifampicin-resistant tuberculosis (MDR-/RR-TB). In particular, second-line injectables (SLIs) are associated with permanent hearing loss, acute renal injury and electrolyte imbalance. We adapted an established Markov model for ambulatory treatment to estimate the impact of the toxicity profile on the incremental cost-effectiveness ratio (ICER) for a proposed MDR-/RR-TB regimen replacing the SLI with bedaquiline (BDQ).. Treatment effectiveness was evaluated in disability-adjusted life-years (DALYs). Clinical outcomes and ingredient costs from a provider perspective were derived from the South African public-sector treatment program or extracted from the literature. Costs and effectiveness were discounted at 3% per year over 10 years.. A BDQ-based MDR-/RR-TB regimen compared with the SLI regimen had a mean ICER of US$516 per DALY averted using the standard Markov model. Costs for both regimens increased and effectiveness decreased for the SLI regimen once adjusted for toxicity. The resulting ICER for the BDQ-based regimen was cost saving (US$96/patient) and more effective (0.96 DALYs averted) after adjusting for ADRs.. Decision-analysis models of treatment for MDR-/RR-TB, including new drug regimens, should consider the costs of managing ADRs and their sequelae.

Topics: Antitubercular Agents; Cost-Benefit Analysis; Diarylquinolines; Drug Costs; Health Care Costs; Humans; Markov Chains; Quality-Adjusted Life Years; Rifampin; South Africa; Treatment Outcome; Tuberculosis, Multidrug-Resistant

Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues.. niazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI).. PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cut-off or minimum inhibitory concentration for the dosing interval.. The PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001-0.0025 h-1 and 0.0015-0.0025 h-1, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing.. We identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed.

Topics: Adolescent; Adult; Antitubercular Agents; Diarylquinolines; Drug Administration Schedule; Drug Liberation; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Isoniazid; Latent Tuberculosis; Male; Middle Aged; Nitroimidazoles; Oxazoles; Proof of Concept Study; Rifampin; Treatment Outcome; Young Adult

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) complex remains a deadly infectious disease worldwide. Mtb is an intracellular pathogen, and autophagy is an essential component of the immune response leading to TB clearance. Anti-TB treatment is based on classical isoniazid (INH) and rifampicin (RIF), but also new drugs, such as linezolid (LNZ) and bedaquiline (BDQ). However, little is known about these antibiotics' impact on Mtb intra-macrophagic behavior independent of their impact on host cells. We explored the effect of mycobacterial pre-treatment with these four antibiotics on the intra-macrophagic Mtb survival and trafficking, thanks to bacterial counts and microscopy confocal imaging. Our results showed that INH and BDQ impaired Mtb phagosome escape, RIF increased autolysosome formation, and LNZ and BDQ improved autophagy activation and efficacy. These data suggest that antibiotics favoring autophagy activation (LNZ and BDQ) may allowed better Mtb clearance by macrophages and could provide basis for future anti-TB strategies.

Topics: Antitubercular Agents; Autophagy; Diarylquinolines; Host-Pathogen Interactions; Humans; Isoniazid; Linezolid; Macrophages; Mycobacterium tuberculosis; Phagosomes; Rifampin; Tuberculosis; U937 Cells

Tuberculosis (TB) continues to be one of the most common bacterial infectious diseases and is the leading cause of death in many parts of the world. A major limitation of TB therapy is slow killing of the infecting organism, increasing the risk for the development of a tolerance phenotype and drug resistance. Studies indicate that

Topics: Antitubercular Agents; Diarylquinolines; Fluoroquinolones; Isoniazid; Mefloquine; Moxifloxacin; Mycobacterium tuberculosis; Proteome; Proteomics; Rifampin

Topics: Antitubercular Agents; Diarylquinolines; Drug Resistance, Bacterial; Humans; Mycobacterium tuberculosis; Nitroimidazoles; Oxazoles; Rifampin; Tuberculosis, Multidrug-Resistant

Resistance-associated variants (RAVs) in Rv0678 , a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines.. Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort.. Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24 mg/L, n  =   8), normal (0.03-0.24 mg/L, n  =   11) or low (< 0.03 mg/L, n  =   4). A variant at position -11 in the intergenic region mmpS5 - Rv0678 was identified in 39 isolates (11.3%) and appeared to increase the susceptibility to bedaquiline. In non-MDR-TB isolates, the frequency of Rv0678 RAVs was lower (6/852 or 0.7%). Competition experiments suggested that rifampicin was not the drug selecting for Rv0678 RAVs.. RAVs in Rv0678 occur more frequently in MDR-TB patients than previously anticipated, are not associated with prior use of bedaquiline or clofazimine, and in the majority of cases do not lead to bedaquiline MICs above the provisional breakpoint (0.24 mg/L). Their origin remains unknown. Given the variety of RAVs in Rv0678 and their variable effects on the MIC, only phenotypic drug-susceptibility methods can currently be used to assess bedaquiline susceptibility.

Topics: Anti-Inflammatory Agents; Antibiotics, Antitubercular; Antitubercular Agents; Clinical Trials as Topic; Clofazimine; Diarylquinolines; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prevalence; Rifampin; Sequence Analysis, DNA; Tuberculosis, Multidrug-Resistant

A number of inhibitors of the essential

Topics: Antitubercular Agents; beta-Lactams; Clofazimine; Diarylquinolines; Drug Synergism; Membrane Transport Proteins; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Mycolic Acids; Rifampin

The treatment of Buruli ulcer (BU) that is caused by Mycobacterium ulcerans, is currently based on a daily administration of rifampin and streptomycin (RIF-STR). A fully oral intermittent regimen would greatly simplify its treatment on the field.. The objective of this study was to assess the bactericidal and sterilizing activities of intermittent oral regimens in a murine model of established M. ulcerans infection. Regimens combining rifapentine (RFP 20 mg/kg) with either moxifloxacin (MXF 200 mg/kg), clarithromycin (CLR 100 mg/kg) or bedaquiline (BDQ 25 mg/kg) were administrated twice (2/7) or three (only for RFP-CLR 3/7) times weekly during 8 weeks. The bactericidal but also the sterilizing activities of these four intermittent oral regimens were at least as good as those obtained with control weekdays regimens, i.e. RFP-CLR 5/7 or RIF-STR 5/7. A single mouse from the RFP-MFX 2/7 group had culture-positive relapse at the end of the 28 weeks following treatment completion among the 157 mice treated with one of the four intermittent regimens (40 RFP-CLR 2/7, 39 RFP-CLR 3/7, 39 RFP-MXF 2/7, 39 RFP-BDQ 2/7).. These results open the door for a fully intermittent oral drug regimen for BU treatment avoiding intramuscular injections and facilitating supervision by health care workers.

Topics: Animals; Anti-Bacterial Agents; Buruli Ulcer; Clarithromycin; Diarylquinolines; Drug Therapy, Combination; Female; Fluoroquinolones; Humans; Mice; Mice, Inbred BALB C; Moxifloxacin; Mycobacterium ulcerans; Rifampin

The recent approval of new tuberculosis (TB) drugs raises hope for new and more effective anti-tuberculosis treatment regimens. The Global Alliance for TB Drug Development (TB Alliance) is committed to ensuring that new anti-tuberculosis drugs fulfill the needs of patients, their families and the local health services that serve the communities. Here we present highlights of the TB Alliance's pipeline of regimen development, with novel regimens for patients with drug-susceptible, multidrug-resistant and extensively drug-resistant TB. The ongoing clinical trials (STAND, NC-005, Nix-TB and LIN-CL001) are outlined and their rationale and goals presented.

Topics: Antitubercular Agents; Clinical Protocols; Diarylquinolines; Dose-Response Relationship, Drug; Ethambutol; Extensively Drug-Resistant Tuberculosis; Fluoroquinolones; Humans; Isoniazid; Linezolid; Moxifloxacin; Nitroimidazoles; Pyrazinamide; Randomized Controlled Trials as Topic; Research Design; Rifampin; Tuberculosis, Multidrug-Resistant

Mycobacterium tuberculosis 18b, a streptomycin (STR)-dependent mutant that enters a viable but nonreplicating state in the absence of STR, has been developed as a simple model for drug testing against dormant bacilli. Here, we further evaluated the STR-starved 18b (SS18b) model both in vitro and in vivo by comparing the behavior of 22 approved and experimental tuberculosis drugs. Using the resazurin reduction microplate assay (REMA), rifampin (RIF), rifapentine (RPT), TMC207, clofazimine (CFM), and linezolid (LIN) were found to be active against SS18b in vitro, and their bactericidal activity was confirmed by determining the number of CFU. A latent 18b infection was established in mice, and some of the above-mentioned drugs were used for treatment, either alone or in combination with RIF. RIF, RPT, TMC207, CFM, and pyrazinamide (PZA) were all active in vivo, while cell wall inhibitors were not. A comparative kinetic study of rifamycin efficacy was then undertaken, and the results indicated that RPT clears latent 18b infection in mice faster than RIF. Intrigued by the opposing responses of live and dormant 18b cells to cell wall inhibitors, we conducted a systematic analysis of 14 such inhibitors using REMA. This uncovered an SS18b signature (CWPRED) that accurately predicted the activities of cell wall inhibitors and performed well in a blind study. CWPRED will be useful for establishing the mode of action of compounds with unknown targets, while the SS18b system should facilitate the discovery of drugs for treating latent tuberculosis.

Topics: Acetamides; Amino Acid Sequence; Animals; Antitubercular Agents; Clofazimine; Diarylquinolines; Disease Models, Animal; Drug Discovery; Drugs, Investigational; Female; Genetic Engineering; Latent Tuberculosis; Linezolid; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Molecular Sequence Data; Mycobacterium tuberculosis; Oxazines; Oxazolidinones; Quinolines; Rifampin; Streptomycin; Structure-Activity Relationship; Xanthenes

Benzothiazinones (BTZ) are a new class of drug candidates to combat tuberculosis that inhibit decaprenyl-phosphoribose epimerase (DprE1), an essential enzyme involved in arabinan biosynthesis. Using the checkerboard method and cell viability assays, we have studied the interaction profiles of BTZ043, the current lead compound, with several antituberculosis drugs or drug candidates against Mycobacterium tuberculosis strain H37Rv, namely, rifampin, isoniazid, ethambutol, TMC207, PA-824, moxifloxacin, meropenem with or without clavulanate, and SQ-109. No antagonism was found between BTZ043 and the tested compounds, and most of the interactions were purely additive. Data from two different approaches clearly indicate that BTZ043 acts synergistically with TMC207, with a fractional inhibitory concentration index of 0.5. TMC207 at a quarter of the MIC (20 ng/ml) used in combination with BTZ043 (1/4 MIC, 0.375 ng/ml) had a stronger bactericidal effect on M. tuberculosis than TMC207 alone at a concentration of 80 ng/ml. This synergy was not observed when the combination was tested on a BTZ-resistant M. tuberculosis mutant, suggesting that DprE1 inhibition is the basis for the interaction. This finding excludes the possibility of synergy occurring through an off-target mechanism. We therefore hypothesize that sub-MICs of BTZ043 weaken the bacterial cell wall and allow improved penetration of TMC207 to its target. Synergy between two new antimycobacterial compounds, such as TMC207 and BTZ043, with novel targets, offers an attractive foundation for a new tuberculosis regimen.

Topics: Adamantane; Antitubercular Agents; Aza Compounds; Diarylquinolines; Drug Combinations; Drug Synergism; Ethambutol; Ethylenediamines; Fluoroquinolones; Isoniazid; Meropenem; Microbial Sensitivity Tests; Microbial Viability; Moxifloxacin; Mycobacterium tuberculosis; Nitroimidazoles; Quinolines; Rifampin; Spiro Compounds; Thiazines; Thienamycins

The experimental compound TMC207 is showing promise against infections caused by Mycobacterium tuberculosis both in a variety of animal studies and in the field. In this study, we used the guinea pig model, a species that shows several similarities to human tuberculosis, including the hallmark of primary granuloma necrosis, to determine the efficacy of a combination regimen combining TMC207 with rifampin and pyrazinamide. This drug regimen rapidly reduced the bacterial load in the lungs to undetectable levels by 8 weeks of treatment. This reduction was associated with a substantial improvement in lung pathology, but despite this effect areas of residual necrosis still remained. In the draining lymph nodes, however, tissue damage was rapid and not significantly reversed by the drug treatment. Approximately 10 to 11 months after the treatment had ended, the animals began to trigger a Karnovsky scale indicating bacterial regrowth and potential relapse, an event confirmed by the new development of both pulmonary and extrapulmonary granulomatous lesions. Interestingly, a similar rate of relapse was also seen in animals receiving 24 weeks of rifampin, pyrazinamide, and isoniazid standard chemotherapy. These data indicate that TMC207 could be a useful addition to current treatment regimens for tuberculosis.

Topics: Animals; Antitubercular Agents; Diarylquinolines; Female; Flow Cytometry; Guinea Pigs; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Tuberculosis

Multidrug-resistant and extensively drug-resistant tuberculosis (MDR/XDR-TB) is an emerging global health threat. Proper management of close contacts of infectious patients is increasingly important. However, no evidence-based recommendations for treating latent TB infection (LTBI) after MDR/XDR-TB exposure (DR-LTBI) exist. An ultrashort regimen for LTBI caused by drug-susceptible strains (DS-LTBI) is also desirable. TMC207 has bactericidal and sterilizing activity in animal models of TB and improves the activity of current MDR-TB therapy in patients.. The objective of this study was to determine whether TMC207 might enable short-course treatment of DR-LTBI and ultrashort treatment of DS-LTBI.. Using an established experimental model of LTBI chemotherapy in which mice are aerosol-immunized with a recombinant bacillus Calmette-Guérin vaccine before low-dose aerosol infection with Mycobacterium tuberculosis, the efficacy of TMC207 alone and in combination with rifapentine was compared with currently recommended control regimens as well as once-weekly rifapentine + isoniazid and daily rifapentine ± isoniazid.. Outcomes included monthly lung colony-forming unit counts and relapse rates.. Lung colony-forming unit counts were stable at about 3.75 log(10) for up to 7.5 months postinfection in untreated mice. Rifamycin-containing regimens were superior to isoniazid monotherapy. TMC207 exhibited sterilizing activity at least as strong as that of rifampin alone and similar to that of rifampin + isoniazid, but daily rifapentine +/- isoniazid was superior to TMC207. Addition of TMC207 to rifapentine did not improve the sterilizing activity of rifapentine in this model.. TMC207 has substantial sterilizing activity and may enable treatment of DR-LTBI in 3-4 months.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Diarylquinolines; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Extensively Drug-Resistant Tuberculosis; Female; Latent Tuberculosis; Lung; Mice; Mice, Inbred BALB C; Mycobacterium tuberculosis; Quinolines; Rifampin; Stem Cells; Treatment Outcome

The in vitro interactions of two new antitubercular drugs, SQ109 and TMC207, with each other and with rifampin (RIF) were evaluated. The combination of SQ109 with TMC207 (i) improved an already excellent TMC207 MIC for M. tuberculosis H37Rv by 4- to 8-fold, (ii) improved the rate of killing of bacteria over the rate of killing by each single drug, and (iii) enhanced the drug postantibiotic effect by 4 h. In no instance did we observe antagonistic activities with the combination of SQ109 and TMC207. Rifampin activates cytochrome P450 genes to reduce the area under the curve (AUC) for TMC207 in humans. The presence of RIF in three-drug combinations did not affect the synergistic activities of SQ109 and TMC207, and SQ109 also dramatically decreased the MIC of RIF. SQ109 was active by itself, and both its activity was improved by and it improved the in vitro activities of both RIF and TMC207.

Topics: Adamantane; Antitubercular Agents; Diarylquinolines; Drug Interactions; Ethylenediamines; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Quinolines; Rifampin

TMC207, rifapentine, and moxifloxacin are in clinical testing for the treatment of tuberculosis. Five experimental regimens with various combinations of TMC207, rifapentine, moxifloxacin, and pyrazinamide were tested for their bactericidal and sterilizing potencies in Swiss mice intravenously inoculated with Mycobacterium tuberculosis bacilli. TMC207 had the strongest bactericidal efficacy, while rifapentine was the strongest contributor to sterilizing efficacy. The rank order of sterilizing potencies was different from the rank order of bactericidal potencies, underlining the importance of prioritizing new regimens designed to shorten the treatment duration by their sterilizing potencies rather than by their bactericidal potencies. Both 3 months of treatment with a regimen combining TMC207, pyrazinamide, and rifapentine and 5 months of treatment with a regimen combining TMC207, pyrazinamide, and moxifloxacin resulted in relapse rates similar to the rate obtained by 6 months of treatment with rifampin-isoniazid-pyrazinamide.

Topics: Animals; Antibiotics, Antitubercular; Aza Compounds; Diarylquinolines; Disease Models, Animal; Female; Fluoroquinolones; Mice; Moxifloxacin; Mycobacterium tuberculosis; Pyrazinamide; Quinolines; Rifampin; Tuberculosis

R207910 (TMC207 or J) is a member of the diarylquinolines, a new family of antituberculous drugs with high bactericidal activity when given daily in the murine model of tuberculosis. R207910 exhibits a long half-life and thus is a good candidate for once-weekly therapy of tuberculosis.. To study the activity of once-weekly R207910 monotherapy and combinations of R207910 with other antituberculous agents (isoniazid, rifapentine, moxifloxacin, and pyrazinamide).. The established infection model of murine tuberculosis was used. Colony counts were determined in the lungs.. Eight weeks of monotherapy reduced the bacillary load by 3 to 4 log(10) for rifapentine and by 5 to 6 log(10) for R207910 (P < 0.05). The addition of rifapentine and isoniazid or moxifloxacin did not improve the bactericidal activity of R207910 monotherapy. In contrast, the triple combination of R207910 plus rifapentine plus pyrazinamide given once weekly for 2 months (i.e., a total of only eight administrations), was significantly (P < 0.05) more active than R207910 monotherapy or other R207910 combinations, and led to lung culture negativity in 9 of 10 mice, whereas all lungs were culture positive in the groups treated with other drug combinations. Moreover, R207910 plus rifapentine plus pyrazinamide given once weekly was more active than the current standard regimen of rifampin plus isoniazid plus pyrazinamide given five times per week.. The unprecedented activity of the triple combination of R207910 plus rifapentine plus pyrazinamide suggests that it may be feasible to develop a fully intermittent once-weekly regimen.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Drug Therapy, Combination; Female; Lung; Mice; Pyrazinamide; Quinolines; Rifampin; Tuberculosis

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

The diarylquinoline R207910 (TMC207) is a promising candidate in clinical development for the treatment of tuberculosis. Though R207910-resistant mycobacteria bear mutations in ATP synthase, the compound's precise target is not known. Here we establish by genetic, biochemical and binding assays that the oligomeric subunit c (AtpE) of ATP synthase is the target of R207910. Thus targeting energy metabolism is a new, promising approach for antibacterial drug discovery.

Topics: Antitubercular Agents; ATP Synthetase Complexes; Bacterial Proteins; Bacterial Proton-Translocating ATPases; Binding Sites; Diarylquinolines; Electrophoresis, Gel, Two-Dimensional; Kinetics; Mycobacterium smegmatis; Protein Subunits; Quinolines

The lengthy chemotherapy of tuberculosis reflects the ability of a small subpopulation of Mycobacterium tuberculosis bacteria to persist in infected individuals. To date, the exact location of these persisting bacteria is not known. Lung lesions in guinea pigs infected with M. tuberculosis have striking similarities, such as necrosis, mineralization, and hypoxia, to natural infections in humans. Guinea pigs develop necrotic primary lesions after aerosol infection that differ in their morphology compared to secondary lesions resulting from hematogenous dissemination. In infected guinea pigs conventional therapy for tuberculosis during 6 weeks reduced the bacterial load by 1.7 logs in the lungs and, although this completely reversed lung inflammation associated with secondary lesions, the primary granulomas remained largely unaffected. Treatment of animals with the experimental drug R207910 (TMC207) for 6 weeks was highly effective with almost complete eradication of the bacteria throughout both the primary and the secondary lesions. Most importantly, the few remnants of acid-fast bacilli remaining after R207910 treatment were to be found extracellular, in a microenvironment of residual primary lesion necrosis with incomplete dystrophic calcification. This zone of the primary granuloma is hypoxic and is morphologically similar to what has been described for human lung lesions. These results show that this acellular rim may, therefore, be a primary location of persisting bacilli withstanding drug treatment.

Topics: Animals; Antibiotics, Antitubercular; Antitubercular Agents; Colony Count, Microbial; Diarylquinolines; Female; Granuloma; Guinea Pigs; Hypoxia; Isoniazid; Lung; Mycobacterium tuberculosis; Nitroimidazoles; Pyrazinamide; Quinolines; Radiation-Sensitizing Agents; Rifampin; Spleen; Tuberculosis

Seven antimicrobials were tested in vitro against 29 clinical isolates of Mycobacterium ulcerans. R207910 demonstrated the lowest MIC(50) and MIC(90), followed by moxifloxacin (MXF), streptomycin (STR), rifampin (RIF), amikacin (AMK), linezolid (LZD), and PA-824. All but PA-824 demonstrated an MIC(90) significantly less than the clinically achievable peak serum level. Administered as monotherapy to mice, RIF, STR, AMK, MXF, R207910, and LZD demonstrated some degree of bactericidal activity, whereas PA-824 failed to prevent mortality and to reduce the mean number of CFU in the footpads. Because 4 or 8 weeks of treatment by the combinations RIF-MXF, RIF-R207910, and RIF-LZD displayed bactericidal effects similar to those of RIF-STR and RIF-AMK, these three combinations might be considered as orally administered combined regimens for treatment of Buruli ulcer. Taking into account the cost, potential toxicity, and availability, the combination RIF-MXF appears more feasible for application in the field; additional experiments with mice are warranted to define further its activity against M. ulcerans. In addition, a pilot clinical trial is proposed to test the efficacy of RIF-MXF for treatment of Buruli ulcer.

Topics: Acetamides; Amikacin; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Aza Compounds; Colony Count, Microbial; Diarylquinolines; Dose-Response Relationship, Drug; Female; Fluoroquinolones; Foot; In Vitro Techniques; Linezolid; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Moxifloxacin; Mycobacterium Infections, Nontuberculous; Mycobacterium ulcerans; Nitroimidazoles; Oxazolidinones; Quinolines; Rifampin; Streptomycin; Survival Analysis; Time Factors

The objective of the present study was to identify the optimal R207910-containing regimen to administer to patients who cannot receive rifampin (RIF) and isoniazid (INH) because of multidrug-resistant tuberculosis (MDR-TB), concomitant use of antiretroviral drugs, or toxicity. Mice were infected intravenously with 5 x 10(6) CFU of the H37Rv strain and treated five times per week with R207910 alone or various combinations of R207910 with the second-line drugs amikacin (AMK), pyrazinamide (PZA), moxifloxacin (MXF), and ethionamide (ETH). All R207910-containing regimens were significantly more active than the non-R207910-containing regimens after 1 month of therapy. When given for 2 months, R207910 alone was more active than the WHO standard first-line regimen RIF-INH-PZA. When R207910 was combined with second-line drugs, the combinations were more active than the currently recommended regimen of MDR-TB AMK-ETH-MXF-PZA, and culture negativity of both the lungs and spleen was reached after 2 months of treatment in almost every case.

Topics: Animals; Anti-Bacterial Agents; Antitubercular Agents; Aza Compounds; Colony Count, Microbial; Diarylquinolines; Drug Combinations; Drug Resistance, Multiple, Bacterial; Ethionamide; Fluoroquinolones; Lung; Mice; Moxifloxacin; Mycobacterium tuberculosis; Organ Size; Pyrazinamide; Quinolines; Rifampin; Spleen; Survival Analysis; Tuberculosis