Bedaquiline: An Insight Into its Clinical Use in Multidrug-Resistant Pulmonary Tuberculosis.

Every year, the World Health Organization reports 500,000 new cases of drug-resistant tuberculosis (TB), which poses a serious global danger. The increased number of XDR-TB and MDR-TB cases reported worldwide necessitates the use of new therapeutic approaches. The main issues with the antitubercular medications now in use for the treatment of multidrug-resistant tuberculosis are their poor side effect profile, reduced efficacy, and antimicrobial resistance. One possible remedy for these problems is bedaquiline. The need for better treatment strategies is highlighted by the strong minimum inhibitory concentrations that bedaquiline (BDQ), a novel anti-TB medicine, exhibits against both drug-resistant and drug-susceptible TB. Bedaquiline may be able to help with these problems. Bedaquiline is a medication that is first in its class and has a distinct and particular mode of action. Bedaquiline is an ATP synthase inhibitor that is specifically directed against Mycobacterium tuberculosis and some nontuberculous mycobacteria. It is metabolized by CYP3A4. Bedaquiline preclinical investigations revealed intralesional drug biodistribution. The precise intralesional and multi-compartment pharmacokinetics of bedaquiline were obtained using PET bioimaging and high-resolution autoradiography investigations. Reduced CFU counts were observed in another investigation after a 12-week course of therapy. Meta-analyses and systematic reviews of phase II trials on bedaquiline's efficacy in treating drug-resistant tuberculosis in patients reported higher rates of cure, better culture conversion, and lower death rates when taken in conjunction with a background regimen. Here is a thorough medication profile for bedaquiline to aid medical professionals in treating individuals with tuberculosis.

Update on drug-resistant pulmonary tuberculosis treatment in hemodialysis patients.

World Health Organization (WHO) issued the latest recommendations regarding the management of drug-resistant Tuberculosis (TB) in 2022, allowing the replacement of ethambutol (6 months) with linezolid (2 months). This recommendation also introduced a new regimen, namely bedaquiline, pretomanide, linezolid, moxifloxacin (BPaLM) for fluoroquinolone-sensitive patients and bedaquiline, pretomanide, linezolid, (BPaL) for patients insensitive to fluoroquinolone (6-9 months). The latest TB regimen introduced by WHO provides a shorter-course treatment, however not much has been discussed about the impact of this new regimen on chronic kidney disease (CKD) patients, particularly on hemodialysis (HD). The condition of CKD can interfere with the pharmacokinetics of TB medication, thus could reduce effectiveness and increase toxicity. The drugs used on this new regimen are mostly safe for renal impairment patients due to the dominant metabolism in the liver. Particular precaution is given to the administration of linezolid due to increased hematology side effects and bedaquiline with the side effect of QTC interval lengthening and increased risk of arrhythmias. Although this regimen research has not been in many studies in renal failure patients, no significant side effects nor kidney damage evidence was found. This remains to be proven by more research on the patient population with renal failure.

In-silico transcriptome analysis of antibiotic-treated Mycobacterium tuberculosis identifies novel antibiotic resistance factors.

The emergence of drug resistant Mycobacterium tuberculosis strains increases the burden on the treatment of tuberculosis. In this study, through in-silico transcriptome analysis of drug-treated M. tuberculosis samples, novel drug targets for the treatment of drug resistance in tuberculosis were identified. Gene expression datasets of tuberculosis patients samples treated with different antibiotics (Isoniazid, Rifampicin, Pyrazinamide, Bedaquiline and Linezolid) were considered in this study. DESeq2 was used to identify the differentially regulated genes. Novel genes which were up-regulated during antibiotic treatment were identified which could be antibiotic resistance factors. Further, to understand the resistance mechanism of the novel genes, we performed gene ontology and gene network analysis for the differentially up-regulated genes. Thus, the in-silico transcriptome analysis paves way for a deeper understanding of the antibiotic resistance in M. tuberculosis.

Treatment outcomes of multidrug resistant tuberculosis (MDR TB) treated with bedaquiline under programmatic management of drug resistant tuberculosis at a tertiary care hospital in Punjab, India.

INTRODUCTION: MDR TB is a serious global concern which is hampering TB elimination goals badly. Standardized MDR TB regimen had high default rates, more side effects and poor treatment outcomes. Bedaquiline is a newer anti-tubercular drug which has made oral regimens possible for MDR TB. We aimed to study the outcomes of MDR TB patients treated with Bdq containing regimens. METHODS: 155 patients of MDR TB on Bdq containing regimen enrolled at GMC, Patiala under NTEP from 2017 to 2020 were enrolled retrospectively. RESULTS: Out of 155 patients enrolled, 82 (52.9 %) were cured, 31 (20 %) completed treatment, 18 (11.6 %) defaulted, 22 (14.2 %) died and 2 (0.12 %) failed treatment. CONCLUSION: Bdq is well tolerated with very less side effects and has better outcomes as compared to standard MDR regimens which were followed earlier.

Impact of bedaquiline regimen on the treatment success rates of multidrug-resistant tuberculosis patients in Egypt.

Bedaquiline (BDQ), an innovative anti-tuberculous (TB) agent, has attracted attention for its potential effectiveness against drug-resistant TB. This study investigated the impact of BDQ-containing regimens on treatment success rates among multi-drug resistant tuberculosis (MDR-TB) patients in Egypt. We conducted a prospective cohort study that included all adult non-pregnant patients treated in MDR-TB centers in Egypt from April 1, 2020, to June 30, 2021, with follow-up extended until December 31, 2022. The study compared patients prescribed BDQ according to national protocols with those receiving conventional treatments for MDR-TB. Treatment success rates, mortality rates, and adverse events were analyzed using descriptive statistics, chi-square tests, logistic regression, and Kaplan-Meier survival curves. Adjustment for potential confounders was conducted using propensity score matching and Cox-hazard regressions. A total of 84 patients were included in this study. The median age of the study participants was 39 years; 22.6% were women, 57.1% were unemployed or housewives, and 1.2% had human immunodeficiency virus (HIV). Regarding the treatment regimen, 67.8% were exposed to BDQ-based treatment. Among the 55 patients (65.5%) with treatment success, a significantly higher success rate was observed in the BDQ group (73.7%) compared to the conventional group (48.1%), P = 0.042. Additionally, the incidence of skin discoloration was significantly higher in the BDQ group compared to the conventional group (38.6% versus 0.0%, P < 0.001). Despite the lower mortality incidence in the BDQ-group (14.0% versus 22.2% in the conventional group), the Kaplan-Meier survival analysis revealed no excess mortality associated with the BDQ-group, with a hazard ratio (HR) of 0.62 (95% CI 0.21-1.78, P = 0.372). Propensity score matching, while considering factors such as lesion site, diabetes mellitus, hepatitis C virus, and smoking, revealed a significant increase in the success rate associated with BDQ inclusion, with an HR of 6.79 (95% CI 1.8-25.8). In conclusion, BDQ is an effective and tolerable medication for treating MDR-TB, associated with lower mortality rates compared to conventional treatment.

Clinical outcomes of multidrug-resistant tracheobronchial tuberculosis receiving anti-tuberculosis regimens containing bedaquiline or delamanid.

The treatment of multidrug-resistant tracheobronchial tuberculosis poses challenges, and research investigating the efficacy of bedaquiline or delamanid as treatment for this condition is limited. This retrospective cohort study was conducted from 2017 to 2021. The study extracted data of patients with multidrug-resistant tracheobronchial tuberculosis from medical records and followed up on prognoses. Participants were divided into three groups: the bedaquiline, delamanid, and control group. Clinical outcomes and the risk factors associated with early culture conversion were analyzed. This study included 101 patients, with 32, 25, and 44 patients in the bedaquiline, delamanid, and control groups respectively. The differences in the treatment success rates among the three groups did not show statistical significance. Both the bedaquiline and delamanid groups had significantly higher culture conversion rates compared to the control after 2 or 6 months of treatment, with significantly shorter median times to culture conversion (bedaquiline group: 2 weeks, delamanid group: 2 weeks, control group: 12 weeks, P < 0.001). Treatment with bedaquiline or delamanid were identified as independent predictors of culture conversion at 2 months (bedaquiline group: aOR = 13.417, 95% CI 4.067-44.260, delamanid group: aOR = 9.333, 95% CI 2.498-34.878) or 6 months (bedaquiline group: aOR = 13.333, 95% CI 3.379-52.610, delamanid group: aOR = 5.000, 95% CI 1.357-18.426) of treatment through multivariable logistic regression analyses. The delamanid group showed better improvement in lumen stenosis compared to bedaquiline. Regimens containing bedaquiline or delamanid may accelerate the culture conversion during the early treatment phase in multidrug-resistant tracheobronchial tuberculosis, and delamanid appears to have the potential to effectively improve airway stenosis.

Comparison of Individual Regimen Containing Bedaquiline with Delamanid and Bedaquiline without Delamanid on Efficacy and Safety in Multidrug-resistant Tuberculosis Patients: Implementation in Dr. Soetomo General Academic Hospital, Indonesia.

BACKGROUND: Bedaquiline is one of the core drugs used to treat multidrug-resistant TB (MDR-TB). Delamanid is one of the companion drugs in group C which is used to complete the treatment regimen when drugs in groups A and B can not be used. This study was conducted to analyze the efficacy and safety between individual regimens containing bedaquiline with delamanid and bedaquiline without delamanid. METHODS: This was an observational analytic study with a retrospective design in MDR-TB patients treated with individual regimens containing bedaquiline with delamanid (bedaquiline-delamanid group) and bedaquiline without delamanid (bedaquiline group). Efficacy was measured according to the time to Acid Fast Bacilli (AFB) conversion and Mycobacterium tuberculosis culture conversion, while safety was measured specifically on QTc interval prolongation. RESULTS: The median (range) time to AFB conversion in bedaquiline-delamanid group was faster than bedaquiline group, although there was no significant difference (1.5 (1-4) months vs. 1 (1-6) months, P=0.429), the median time to culture conversion in bedaquiline-delamanid group also faster than bedaquiline group, although there was no significant difference (1 (1-6) months vs. 2 (1-6) months, P=0.089). The incidence of QTc interval prolongation in bedaquiline-delamanid group was less than bedaquiline group, although there was no significant difference (26.9% vs. 40.3%, P=0.223). CONCLUSIONS: Individual regimens containing bedaquiline with delamanid was proven to provide similar efficacy and safety profiles with individual regimens containing bedaquiline without delamanid. Delamanid should be preferred when selecting drugs to complete the treatment regimen when drugs in groups A and B can not be used.

How much should we still worry about QTc prolongation in rifampicin-resistant tuberculosis? ECG findings from TB-PRACTECAL clinical trial.

Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25-21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT02589782.

Drug Exposure and Treatment Outcomes in Patients With Multidrug-Resistant Tuberculosis and Diabetes Mellitus: A Multicenter Prospective Cohort Study From China.

BACKGROUND: The management of multidrug-resistant tuberculosis (MDR-TB) remains challenging. Treatment outcome is influenced by multiple factors; the specific roles of diabetes and glycemic control remain uncertain. This study aims to assess the impact of glycemic control on drug exposure, to investigate the association between drug exposure and treatment outcomes, and to identify clinically significant thresholds predictive of treatment outcome, among patients with diabetes. METHODS: This multicenter prospective cohort study involved patients with confirmed MDR-TB and diabetes. Drug exposure level was estimated by noncompartmental analysis. The minimum inhibitory concentrations (MICs) were determined for the individual Mycobacterium tuberculosis isolates. The influence of poor glycemic control (glycated hemoglobin ≥7%) on drug exposure and the associations between drug exposure and treatment outcome were evaluated by univariate and multivariate analysis. Classification and regression tree analysis was used to identify the drug exposure/susceptibility thresholds. RESULTS: Among the 131 diabetic participants, 43 (32.8%) exhibited poor glycemic control. Poor glycemic control was independently associated with decreased exposure to moxifloxacin, linezolid, bedaquiline, and cycloserine, but not clofazimine. Additionally, a higher ratio of drug exposure to susceptibility was found to be associated with a favorable MDR-TB treatment outcome. Thresholds predictive of 6-month culture conversion and favorable outcome were bedaquiline area under the concentration-time curve (AUC)/MIC ≥245 and moxifloxacin AUC/MIC ≥67, demonstrating predictive accuracy in patients, regardless of their glycemic control status. CONCLUSIONS: Glycemic control and optimal TB drug exposure are associated with improved treatment outcomes. This dual management strategy should be further validated in randomized controlled trials of patients with MDR-TB and diabetes.

Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

BACKGROUND: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). METHODS AND FINDINGS: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. CONCLUSIONS: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

Sputum culture reversion in longer treatments with bedaquiline, delamanid, and repurposed drugs for drug-resistant tuberculosis.

Sputum culture reversion after conversion is an indicator of tuberculosis (TB) treatment failure. We analyze data from the endTB multi-country prospective observational cohort (NCT03259269) to estimate the frequency (primary endpoint) among individuals receiving a longer (18-to-20 month) regimen for multidrug- or rifampicin-resistant (MDR/RR) TB who experienced culture conversion. We also conduct Cox proportional hazard regression analyses to identify factors associated with reversion, including comorbidities, previous treatment, cavitary disease at conversion, low body mass index (BMI) at conversion, time to conversion, and number of likely-effective drugs. Of 1,286 patients, 54 (4.2%) experienced reversion, a median of 173 days (97-306) after conversion. Cavitary disease, BMI < 18.5, hepatitis C, prior treatment with second-line drugs, and longer time to initial culture conversion were positively associated with reversion. Reversion was uncommon. Those with cavitary disease, low BMI, hepatitis C, prior treatment with second-line drugs, and in whom culture conversion is delayed may benefit from close monitoring following conversion.

Availability of drugs for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis in the World Health Organization European Region, October 2023.

The BPaLM regimen (bedaquiline, pretomanid, linezolid and moxifloxacin) recently recommended by the World Health Organization offers short, safe, and effective treatment for multidrug-resistant/rifampicin-resistant tuberculosis (TB). In a survey with national TB focal points in 18 central and western European countries to explore barriers for the implementation of BPaLM, only three reported full availability of pretomanid, a necessary component of this regimen. Implementation barriers included financing and procurement. Solutions on national and supranational level are needed to guarantee universal access.

Utilization of Truenat chips in defining XDR, pre-XDR and MDR in tuberculous meningitis.

SETTING AND OBJECTIVE: To develop and evaluate newer molecular tests that identify drug resistance according to contemporary definitions in Tuberculous meningitis (TBM), the most severe form of EPTB. DESIGN: 93 cerebrospinal fluid (CSF) specimens [41 culture-positive and 52 culture-negative], were subjected to Truenat MTB Plus assay along with chips for rifampicin, isoniazid, fluoroquinolones and bedaquiline resistance. The performance was compared against phenotypic drug susceptibility testing (pDST), Line probe assay (LPA) and gene sequencing. RESULTS: Against pDST, Truenat chips had a sensitivity and specificity of 100%; 94.47%, 100%; 94.47%, 100%; 97.14% and 100%; 100%, respectively for rifampicin, isoniazid, fluoroquinolones and bedaquiline. Against LPA, all Truenat chips detected resistant isolates with 100% sensitivity; but 2 cases each of false-rifampicin and false-isoniazid resistance and 1 case of false-fluoroquinolone resistance was reported. Truenat drug chips gave indeterminate results in ∼25% cases, which were excluded. All cases reported indeterminate were found to be susceptible by pDST/LPA. CONCLUSION: The strategic drug resistance chips of Truenat Plus assay can contribute greatly to TB elimination by providing rapid and reliable detection of drug resistance pattern in TBM. Cases reported indeterminate require confirmation by other phenotypic and genotypic methods.

Availability of drugs and resistance testing for bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) regimen for rifampicin-resistant tuberculosis in Europe.

OBJECTIVES: Multidrug-resistant/rifampicin-resistant tuberculosis is a major obstacle to successful tuberculosis control. The recommendation by the WHO to use bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) for 6 months, based on results of two trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trials group in 44 of 54 countries of the WHO Europe region documented the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September and November 2023. RESULTS: In total, 24 of 44 (54.5%), 42 of 44 (95.5%), 43 of 44 (97.7%), and 43 of 44 (97.7%) countries had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23 of 44 (52.3%) countries had access to all the drugs composing the BPaL(M) regimen. In total, 21 of 44 (47.7%), 37 of 44 (84.1%), 40 of 44 (90.9%), and 41 of 44 (93.2%) countries had access to DST for pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, DST was available for all medicines composing the BPaL(M) regimen in 21 of 44 (47.7%) countries, including countries where pretomanid DST was available at specialized laboratories. The availability of DST for the drugs the countries had access to, varied from 87.5% to 95.3% (pretomanid 21 of 24 (87.5%), bedaquiline 37 of 42 (88.1%), linezolid 40 of 43 (93.1%) and moxifloxacin 41 of 43 (95.3%)). DISCUSSION: In only about half of the countries participating in the survey, clinicians had access to all the BPaL(M) regimen drugs. A complete DST for the BPaL(M) medicines was possible in less than half of the countries, because of the low accessibility of DST for pretomanid. Equal access to new regimens is urgently needed in Europe and a rapid scale up of DST, especially for pretomanid, is important to prevent unnoticed spread of drug resistance.

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.

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 diarylquinoline TBAJ-587 with GSK2556286 and the DprE1 inhibitor TBA-7371, all of which are currently in early-phase clinical trials. We found the combination of bedaquiline, GSK2556286, and TBA-7371 to be more active than the first-line regimen and nearly as effective as BPaL in terms of bactericidal and sterilizing activity. In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587.