Use of bedaquiline in children and adolescents with multidrug- and rifampicin-resistant tuberculosis: information note 1Use of bedaquiline in children and adolescents with multidrug- and rifampicin-resistant tuberculosis - Information noteBEDAQUILINEObjectiveTo provide practical guidance on the administration of bedaquiline in children and adolescents in the context of the treatment of multidrug recommendations for bedaquiline in children and adolescentsThe United States Food and Drug Administration granted accelerated approval for bedaquiline in 2012 for the treatment of adults aged 18 years and over with multidrug-resistant pulmonary TB (MDR-TB) for whom an effective treatment regimen could not otherwise be composed (1). This approval was based on phase IIb trial data
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Bedaquiline Resistance and Treatment Outcomes Among Patients With Tuberculosis Previously Exposed to Bedaquiline in India: A Multicentric Retrospective Cohort Study. Bedaquiline (BDQ) resistance presents a critical challenge in the fight against tuberculosis (TB), particularly multidrug-resistant (MDR) strains. The emergence of resistance to BDQ, a key drug in treating MDR-TB, poses significant
In rifampicin-resistant TB, bedaquiline-containing regimens reduced unfavorable status vs. a control regimen at 132 wk. GIM/FP/GP: [Formula: see text] Infectious Disease: [Formula: see text] Pulmonology: [Formula: see text].
Bedaquiline-pretomanid-moxifloxacin-pyrazinamide for drug-sensitive and drug-resistant pulmonary tuberculosis treatment: a phase 2c, open-label, multicentre, partially randomised controlled trial The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months
Bedaquiline Monotherapy for Multibacillary Leprosy. Standard multidrug therapy for leprosy may be associated with severe side effects, which add to the stigma and discrimination that affect persons with the disease. In addition, the threat posed by drug-resistant leprosy shows the need for alternative drug combinations and shorter, safer regimens of multidrug therapy. In this open-label, proof -of-concept study conducted in Brazil, we assigned patients with previously untreated multibacillary leprosy to receive bedaquiline monotherapy for 8 weeks. After completing the 8-week course of bedaquiline, the patients started standard multidrug therapy (as defined by the World Health Organization) for leprosy and were followed for 112 weeks. The primary end point was the change from baseline in the odds
Protocol, rationale and design of BE-PEOPLE (Bedaquiline enhanced exposure prophylaxis for LEprosy in the Comoros): a cluster randomized trial on effectiveness of rifampicin and bedaquiline as post-exposure prophylaxis of leprosy contacts. 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 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
The efficacy of a regimen comprising clarithromycin, clofazimine, and bedaquiline in a mouse model of chronic Mycobacterium avium lung infection. a leading nontuberculous mycobacterium (NTM) pathogen, causes chronic pulmonary infections, particularly in individuals with underlying lung conditions or immunosuppression. Current treatments involve prolonged multidrug regimens with poor outcomes and significant side effects, highlighting the urgent need for improved therapies. Using a BALB/c mouse model of chronic pulmonary disease, we evaluated the efficacy of individual antibiotics-clarithromycin, clofazimine, and rifabutin-and combination regimens including clarithromycin + bedaquiline and clarithromycin + clofazimine + bedaquiline. Clarithromycin demonstrated potent bactericidal activity, reducing
High Prevalence of atpE Mutations in Bedaquiline-Resistant Mycobacterium tuberculosis Isolates, Russia. Bedaquiline is a cornerstone drug for treating drug-resistant tuberculosis. We analyzed 11 isolates from 9 patients who were treated with a bedaquiline-based regimen and remained culture-positive long after treatment start. In 4 of 8 resistant isolates, we found substitutions in AtpE, which encodes subunit c of the Mycobacterium tuberculosis ATP synthase and is rarely identified in clinical isolates. We found Ile66Met and Glu61Asp substitutions in 2 cases each. Additional mutations in mmpL5, mmpL4, and atpB genes could affect the susceptibility to bedaquiline. MmpL5(Asn772Thr) emerged during bedaquiline treatment, whereas AtpB(Val165Leu) was found in 1 case simultaneously with the loss
The Effectiveness and Safety of Bedaquiline, Pretomanid, and Linezolid (BPaL)-Based Regimens for Rifampicin-Resistant Tuberculosis in Non-Trial Settings-A Prospective Cohort Study in Belarus and Uzbekistan. Only 63% of patients initiating multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment in 2020 were treated successfully. 24-Week all-oral bedaquiline, pretomanid
A Bayesian approach to estimate the probability of resistance to bedaquiline in the presence of a genomic variant. Bedaquiline is a core drug for treatment of rifampicin-resistant tuberculosis. Few genomic variants have been statistically associated with bedaquiline resistance. Alternative approaches for determining the genotypic-phenotypic association are needed to guide clinical care. Using published phenotype data for variants in Rv0678, atpE, pepQ and Rv1979c genes in 756 Mycobacterium tuberculosis isolates and survey data of the opinion of 33 experts, we applied Bayesian methods to estimate the posterior probability of bedaquiline resistance and corresponding 95% credible intervals. Experts agreed on the role of Rv0678, and atpE, were uncertain about the role of pepQ and Rv1979c variants
Quabodepistat in combination with delamanid and bedaquiline in participants with drug-susceptible pulmonary tuberculosis: protocol for a multicenter, phase 2b/c, open-label, randomized, dose-finding trial to evaluate safety and efficacy. Delamanid and bedaquiline are two of the most recently developed antituberculosis (TB) drugs that have been extensively studied in patients with multidrug to synthesize key components of its cell wall. The objective of this study is to evaluate the safety, efficacy, and appropriate dosing of a 4-month regimen of QBS in combination with delamanid and bedaquiline in participants with drug-susceptible pulmonary TB in comparison with the 6-month standard treatment (i.e., rifampicin, isoniazid, ethambutol, and pyrazinamide). This phase 2b/c, open-label, randomized
Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis. Drug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains of Mycobacterium tuberculosis (Mtb ) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by off-target resistance-associated variants (RAVs) in the mmpR5 gene (Rv0678), the regulator of an efflux pump, which can also confer cross-resistance to clofazimine, another TB drug. We compiled a dataset of 3682 Mtb genomes, including 180 carrying variants in mmpR5, and its immediate background (i.e. mmpR5 promoter
Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis. The combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We recently found that the addition of GSK2556286 increases the bactericidal and sterilizing activity of BPa-containing regimens in a well-established BALB/c mouse model of tuberculosis. Here, we used this model to evaluate the potential of new regimens combining bedaquiline or the more potent
Bedaquiline Resistance after Effective Treatment of Multidrug-Resistant Tuberculosis, Namibia. Bedaquiline is currently a key drug for treating multidrug-resistant or rifampin-resistant tuberculosis. We report and discuss the unusual development of resistance to bedaquiline in a teenager in Namibia, despite an optimal background regimen and adherence. The report highlights the risk for bedaquiline resistance development and the need for rapid drug-resistance testing.
The exceptions that prove the rule-a historical view of bedaquiline susceptibility. In the accompanying study, Nimmo and colleagues estimated the dates of emergence of mutations in mmpR5 (Rv0678), the most important resistance gene to the anti-tuberculosis drug bedaquiline, in over 3500 geographically diverse Mycobacterium tuberculosis genomes. This provided important insights to improve
A pragmatic randomized controlled trial to evaluate the efficacy and safety of an oral short-course regimen including bedaquiline for the treatment of patients with multidrug-resistant tuberculosis in China: study protocol for PROSPECT. The lack of safe, effective, and simple short-course regimens (SCRs) for multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment has significantly impeded TB control efforts in China. This phase 4, randomized, open-label, controlled, non-inferiority trial aims to assess the efficacy and safety of a 9-month all-oral SCR containing bedaquiline (BDQ) versus an all-oral SCR without BDQ for adult MDR-TB patients (18-65 years) in China. The trial design mainly mirrors that of the "Evaluation of a Standardized Treatment Regimen of Anti
Sub-MIC levels of bedaquiline and clofazimine can select Mycobacterium tuberculosis mutants with increased MIC. Multidrug-resistant tuberculosis (MDR-TB) patients not cured at the time of stopping treatment are exposed to Minimum Inhibitory Concentration (MIC) and sub-MIC levels for many months after discontinuing bedaquiline (BDQ) or clofazimine (CFZ) treatment. cultures treated with BDQ