Bedaquiline 100mg tablets

Drug-resistant tuberculosis (TB) remains a major global public health challenge. While bedaquiline (BDQ) offers improved treatment outcomes for patients with multi-drug resistant TB (MDR-TB), its widespread use has led to the emergence of BDQ resistance. This systematic review evaluated the prevalence of BDQ resistance among adult patients through searches of PubMed, Web of Science, and Embase databases. Sensitivity and subgroup analyses were performed to explore sources of heterogeneity and compare prevalence estimates across groups. The Joanna Briggs Institute’s quality assessment checklist was used to evaluate the methodological quality of the included studies. Heterogeneity between studies was evaluated using Cochran’s Q and I2 tests.This study is registered with PROSPERO, CRD42024620791. The weighted average prevalence of BDQ resistance was 5.7% (95% CI: 3.6–8.3), with acquired resistance reported at 5.4%. Geographic differences were observed, with South Africa showing a higher prevalence (10.4%) compared to China (2.4%).High-quality studies reported a prevalence of 5.2%, while fair-quality studies reported 7.7%. Mutations in the Rv0678 gene represented a significant proportion, reaching as high as 65.6%. Our findings highlight an increasing trend in acquired resistance to BDQ, offering critical insights for managing MDR-TB. The application of whole-genome sequencing shows promise for advancing understanding of drug resistance mechanisms in Mycobacterium tuberculosis.

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BACKGROUND: Clinical bedaquiline resistance predominantly involves mutations in mmpR5 (Rv0678). However, mmpR5 resistance-associated variants (RAVs) have a variable relationship with phenotypic Mycobacterium tuberculosis resistance. We did a systematic review to assess the maximal sensitivity of sequencing bedaquiline resistance-associated genes and evaluate the association between RAVs and phenotypic resistance, using traditional and machine-based learning techniques. METHODS: We screened public databases for articles published from database inception until Oct 31, 2022. Eligible studies performed sequencing of at least mmpR5 and atpE on clinically sourced M tuberculosis isolates and measured bedaquiline minimum inhibitory concentrations (MICs). A bias risk scoring tool was used to identify bias. Individual genetic mutations and corresponding MICs were aggregated, and odds ratios calculated to determine association of mutations with resistance. Machine-based learning methods were used to define test characteristics of parsimonious sets of diagnostic RAVs, and mmpR5 mutations were mapped to the protein structure to highlight mechanisms of resistance. This study was registered in the PROSPERO database (CRD42022346547). FINDINGS: 18 eligible studies were identified, comprising 975 M tuberculosis isolates containing at least one potential RAV (mutation in mmpR5, atpE, atpB, or pepQ), with 201 (20·6%) showing phenotypic bedaquiline resistance. 84 (29·5%) of 285 resistant isolates had no candidate gene mutation. Sensitivity and positive predictive value of taking an any mutation approach was 69% and 14%, respectively. 13 mutations, all in mmpR5, had a significant association with a resistant MIC (adjusted p<0·05). Gradient-boosted machine classifier models for predicting intermediate or resistant and resistant phenotypes both had receiver operator characteristic c statistic of 0·73 (95% CI 0·70-0·76). Frameshift mutations clustered in the α1 helix DNA-binding domain, and substitutions in the α2 and α3 helix hinge region and in the α4 helix-binding domain. INTERPRETATION: Sequencing candidate genes is insufficiently sensitive to diagnose clinical bedaquiline resistance, but where identified, some mutations should be assumed to be associated with resistance. Genomic tools are most likely to be effective in combination with rapid phenotypic diagnostics. This study was limited by selective sampling in contributing studies and only considering single genetic loci as causative of resistance. FUNDING: Francis Crick Institute and National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

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

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<h2>Summary</h2><h3>Background</h3> Pre-extensively drug-resistant (pre-XDR) tuberculosis (ie, multidrug-resistant or rifampicin-resistant with additional resistance to any fluoroquinolone) is difficult to treat. endTB-Q aimed to evaluate the efficacy and safety of bedaquiline, delamanid, linezolid, and clofazimine (BDLC) compared with the standard of care for patients with pre-XDR tuberculosis. <h3>Methods</h3> This open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial was conducted in ten hospitals in India, Kazakhstan, Lesotho, Pakistan, Peru, and Viet Nam. Participants aged 15 years or older who had pulmonary tuberculosis with resistance to rifampicin and fluoroquinolones were included. Participants were randomly assigned (2:1) to the BDLC group (all-oral bedaquiline 400 mg once per day for 2 weeks followed by 200 mg three times per week, delamanid 100 mg twice per day, linezolid 600 mg once per day for 16 weeks and then either 300 mg once per day or 600 mg three times per week, and clofazimine 100 mg once per day) or the control group (individualised WHO-recommended longer standard of care). Randomisation was stratified by country and baseline disease extent. BDLC was administered for 39 weeks (9-month regimen) for extensive disease and 24 weeks (6-month regimen) for limited disease and extended to 9 months for those with a positive culture at 8 weeks or later or a missing 8-week culture result. Site staff and participants were not masked, whereas investigators and laboratory staff were masked to treatment assignment. The primary endpoint was favourable outcome (two consecutive, negative cultures including one between weeks 65 and 73; or favourable bacteriological, radiological, and clinical evolution) at week 73 after randomisation in the modified intention-to-treat (mITT) and per-protocol populations. We report the risk differences adjusted for stratification variables, with a non-inferiority margin of –12%. This trial is registered with ClinicalTrials.gov, NCT03896685. <h3>Findings</h3> Between April 4, 2020, and March 28, 2023, 1030 individuals were screened and 324 (31%) were randomly assigned (219 to the BDLC group and 105 to the control group). 114 (46%) participants were female and 133 (54%) were male. Median age was 30·5 years (IQR 21·6–43·0). 157 (64%) participants had extensive disease at baseline. In the BDLC group, 47 (29%) of 163 were assigned to receive the 6-month regimen and 116 (71%) the 9-month regimen. The core regimen of BDLC plus one or more other drugs was used for 76 (91%) of 84 participants in the control group. At week 73, favourable outcome was reached by 141 (87%) participants in the BDLC group versus 75 (89%) in the control group in the mITT population (adjusted risk difference 0·2% [95% CI –9·1 to 9·5]; p_{non-inferiority}=0·0051) and by 138 (88%) of 157 versus 71 (93%) of 76 in the per-protocol population (adjusted risk difference –3·5% [–12·8 to 5·9]; p_{non-inferiority}=0·037). Overall non-inferiority was not shown. 145 (68%) of 213 participants in the BDLC group and 77 (73%) of 105 in the control group had at least one grade 3 or higher adverse event, with eight (4%) and two (2%) all-cause deaths by week 73, respectively. <h3>Interpretation</h3> The shortened BDLC strategy was not non-inferior to the control. Accumulating evidence suggests that this patient population might require longer, reinforced regimens. <h3>Funding</h3> Unitaid, Médecins Sans Frontières, Partners In Health, Interactive Research and Development, Ramón Areces Foundation, the Jung Foundation for Science and Research, Research Foundation-Flanders. <h3>Translations</h3> For the Hindi, Marathi, Spanish, Vietnamese, Russian, Urdu and French translations of the abstract see Supplementary Materials section.

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BACKGROUND: Linezolid is a key component globally in first-line therapy for drug-resistant tuberculosis but has considerable toxicity. New and safer alternative oxazolidinones are needed. Sutezolid is one such promising alternative. We aimed to evaluate preliminary efficacy and safety of sutezolid and to identify an optimal dose. METHODS: PanACEA-SUDOCU-01 was a prospective, open-label, randomised, phase 2b dose-finding study in four tuberculosis trial sites in Tanzania and South Africa. Adults aged 18-65 years with newly diagnosed, drug-sensitive, smear-positive tuberculosis were enrolled and randomly assigned (1:1:1:1:1) by a probabilistic minimisation algorithm using a web-based interface, stratified by site, sex, and HIV status, to receive no sutezolid (U0), sutezolid 600 mg once daily (U600), sutezolid 1200 mg once daily (U1200), sutezolid 600 mg twice daily (U600BD), or sutezolid 800 mg twice daily (U800BD), all administered orally for 12 weeks followed by standard therapy for 6 months. All participants received oral bedaquiline (400 mg once daily for 14 days followed by 200 mg thrice weekly), oral delamanid (100 mg twice daily), and oral moxifloxacin (400 mg once daily). For the primary endpoint, measured in the modified intention-to-treat population, sputum samples were taken weekly to measure the change in bacterial load measured by time to positivity using the mycobacterial growth indicator tube system. Safety was assessed through weekly electrocardiography, safety blood tests, vision testing, and physical and neurological examinations. Intensive pharmacokinetic measurements were done on day 14 to determine exposure to sutezolid, bedaquiline, delamanid, and moxifloxacin. This trial is registered with ClinicalTrials.gov (NCT03959566). FINDINGS: Between May 20, 2021, and Feb 17, 2022, 186 individuals were screened for eligibility, 75 of whom were enrolled and randomly assigned to U0 (n=16), U600 (n=15), U1200 (n=14), U600BD (n=15), or U800BD (n=15). 56 (75%) participants were male and 19 (25%) were female. The final pharmacokinetic-pharmacodynamic model showed a benefit of sutezolid, with an increase in time to positivity slope steepness of 16·7% (95% CI 0·7-35·0) at the maximum concentration typical for the 1200 mg dose, compared with no sutezolid exposure. A maximum effect of sutezolid exposure was not observed within the investigated dose range. Six (8%) participants (one in the U600 group, two in the U600BD group, one in the U800BD group, and two retrospectively identified in the U600 group) had an increase in a QT interval using Fridericia correction greater than 60 ms from baseline. Two (3%) participants in the U600BD group had grade 4 adverse events, one each of neutropenia and hepatotoxicity, but they were not deemed associated with the use of sutezolid by the investigators. No neuropathy was reported. INTERPRETATION: Sutezolid, combined with bedaquiline, delamanid, and moxifloxacin, was shown to be efficacious and added activity to the background drug combination, although we cannot make a final dose recommendation yet. This study provides valuable information for the selection of sutezolid doses for future studies, and described no oxazolidinone class toxicities at the doses used. FUNDING: EDCTP2 programme funded by the EU; German Ministry for Education and Research; German Center for Infection Research; and Nederlandse Organisatie voor Wetenschappelijk Onderzoek.

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Background Linezolid plays a crucial role in the first-line treatment of drug-resistant tuberculosis globally.Its prolonged use can lead to neurological and haematological toxicity, highlighting the need for safer oxazolidinones.Delpazolid, a novel oxazolidinone, might be safer.We aimed to evaluate the safety and efficacy of delpazolid and identify an optimal dose.Methods PanACEA-DECODE-01 was a prospective, randomised, open-label, phase 2b, multicentre, dose-finding trial done in five tuberculosis trial sites in Tanzania and South Africa.Adults aged 18-65 years, who weighed 40-90 kg, and had newly diagnosed, smear positive pulmonary tuberculosis were randomly assigned (1:1:1:1:1) through centralised allocation, using a probabilistic minimisation algorithm to receive no delpazolid (D0), delpazolid 400 mg once daily (D400), delpazolid 800 mg once daily (D800), delpazolid 1200 mg once daily (D1200), or delpazolid 800 mg twice daily (D800BD), all administered orally for 16 weeks with follow-up to week 52.All participants received bedaquiline (400 mg orally once daily for the first 14 days, then 200 mg orally thrice weekly), delamanid (100 mg orally twice daily), and moxifloxacin (400 mg orally once daily).Randomisation was stratified based on bacterial load in sputum as measured by GeneXpert cycle threshold (<16 vs 16), site, and HIV status.The primary efficacy objective was to establish an exposure-response model with the primary endpoint, measured in the modified intention-to-treat population, of change in mycobacterial load measured by time to positivity using the liquid culture mycobacterial growth indicator tube system.A secondary outcome was the time on treatment to sustained conversion to negative sputum culture in liquid media.The primary safety outcome was the occurrence of oxazolidinone class toxicities defined as peripheral or optical neuropathy, incident leukopenia, anaemia or thrombocytopenia, or adverse events in line with tyramine pressor response, all of grade 2 or higher, possibly, probably or definitely related to delpazolid.This study was registered with ClinicalTrials.gov,NCT04550832.Findings Between Oct 28, 2021, and Aug 31, 2022, 156 individuals were screened for eligibility, 76 of whom were enrolled and randomly assigned to D0 (n=15), D400 (n=15), D800 (n=15), D1200 (n=16), or D800BD (n=15).60 (79%) of 76 participants were male and 16 (21%) were female.Population pharmacokinetic-pharmacodynamic modelling suggests maximal microbiological activity at a daily total exposure of delpazolid (area under the concentration curve from 0 h to 24 h [AUC 0-24 ]) of 50 mg/L per h; close to the median exposure observed after a 1200 mg dose.This maximal effect was estimated at a 38% (95% CI 4-83; p=0025) faster decline in bacterial load compared with no delpazolid.In the secondary time-to-event analysis, there was no significant difference in time to culture conversion between treatment arms or exposure tertile.When all delpazolid-containing groups were combined, the hazard ratio for the time to sustained culture conversion to negative, comparing all delpazolidcontaining groups with the group without delpazolid was 153 (95% CI 084-276).Two drug-related serious adverse events (one gastritis and one anaemia) occurred in the D800BD group, with high individual AUC 0-24 .Apart from the anaemia and one event of brief, moderate neutropenia observed at only one visit in the D800 group not in line with the characteristics of oxazolidinone class toxicity, no oxazolidinone class toxicities occurred.Interpretation The pharmacokinetic-pharmacodynamic modelling results suggest that delpazolid adds efficacy on top of bedaquiline, delamanid, and moxifloxacin; and that a dose of 1200 mg once daily would result in exposures with maximum efficacy.That dose was shown to be safe, raising hope that linezolid toxicities could be averted in long-term treatment.Delpazolid is a promising drug for future tuberculosis treatment regimens and could be widely usable if safety and efficacy are confirmed in larger trials.

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BACKGROUND: Quabodepistat (formerly OPC-167832) showed potent activity in preclinical studies and in the first stage of an early bactericidal activity study in adults with smear-positive, drug-susceptible pulmonary tuberculosis. Stage 2 of this study was designed to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both versus rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy for 14 days. METHODS: and the ability to produce an adequate volume of sputum (≥10 mL overnight) and were excluded if they had drug-resistant tuberculosis or previous treatment for Mycobacterium tuberculosis within the past 3 years. Participants were centrally randomly assigned via interactive web response technology system, with no stratification, into four treatment groups in a ratio of 14:14:14:4 (quabodepistat 30 mg plus delamanid 300 mg, quabodepistat 30 mg plus bedaquiline 400 mg, or quabodepistat 30 mg plus delamanid 300 mg plus bedaquiline 400 mg orally once daily for 14 days, or rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy [control] according to local standard of care for 20 days). The primary outcomes were safety and tolerability during and after 14 days of treatment in all participants who received any study medication and pharmacokinetics at day 1 and day 14 in participants in the quabodepistat groups with adequate data for deriving pharmacokinetics parameters. The main secondary outcome was bactericidal activity from baseline to day 14 in all eligible participants who were quantitatively culture-positive at baseline. The study was not powered for formal statistical hypothesis testing; therefore, data were summarised by treatment group with descriptive statistics. This study is registered with ClinicalTrials.gov (NCT03678688) and is closed to new participants. FINDINGS: colony-forming units per mL were -2·73 (SD 1·51) for quabodepistat plus delamanid plus bedaquiline (n=12) and -2·71 (SD 0·92) for control (n=19); mean change was -2·17 (SD 1·83) in the quabodepistat plus delamanid cohort (n=11) and -1·97 (SD 1·29) in the quabodepistat plus bedaquiline cohort (n=11). INTERPRETATION: In this 14-day trial, quabodepistat plus delamanid plus bedaquiline, a novel three-drug combination, appeared to be safe, well tolerated, and provided robust early bactericidal activity in adults with drug-susceptible pulmonary tuberculosis. Further evaluation is warranted. FUNDING: Otsuka Pharmaceutical Development & Commercialization and the Bill & Melinda Gates Foundation.

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