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Bedaquiline, a new antituberculosis drug, has already been used in >50 countries. The emergence of bedaquiline resistance is alarming, as it may result in the rapid loss of this new drug. This article aims to review currently identified mechanisms of resistance and the emergence of bedaquiline resistance, and discuss strategies to delay the resistance acquisition. In vitro and clinical studies as well as reports from compassionate use have identified the threat of bedaquiline resistance and cross-resistance with clofazimine, emphasizing the crucial need for the systematic surveillance of resistance. Currently known mechanisms of resistance include mutations within the atpE, Rv0678, and pepQ genes. The development of standardized drug susceptibility testing (DST) for bedaquiline is urgently needed. Understanding any target and non-target-based mechanisms is essential to minimize resistance development and treatment failure and help to develop appropriate DST for bedaquiline and genetic-based resistance screening.

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.

Two new drugs, delamanid and bedaquiline, have recently been approved for treatment of multidrug-resistant and extensively drug-resistant (XDR) tuberculosis. Here, we report a case of clofazimine, bedaquiline, and low-level delamanid resistances acquired during treatment of a patient with XDR tuberculosis.

Nontuberculous mycobacteria can cause disseminated infections in immunocompromised patients and are challenging to treat because of antimicrobial resistance and adverse effects of prolonged multidrug treatment. We report successful treatment with bedaquiline, a novel antimycobacterial drug, as part of combination therapy for 2 patients with disseminated nontuberculous mycobacteria co-infected with HIV.

New classes of antitubercular drugs, diarylquinolines and nitroimidazoles, have been associated with improved outcomes in the treatment of drug-resistant tuberculosis, but that success is threatened by emerging drug resistance. We report a case of bedaquiline and delamanid resistance in a 55-year-old woman in South Africa with extensively drug-resistant tuberculosis and known HIV.

Abstract Background Bedaquiline is used as a substitute for second-line injectable (SLI) intolerance in the treatment of multidrug-resistant (MDR) tuberculosis, but the efficacy and safety of this strategy is unknown. Methods In this retrospective cohort study adults receiving bedaquiline substitution for MDR tuberculosis therapy, plus a matched control group who did not receive bedaquiline, were identified from the electronic tuberculosis register in the Western Cape Province, South Africa. The primary outcome measure was the proportion of patients with death, loss to follow-up, or failure to achieve sustained culture conversion at 12 months of treatment. Results Data from 162 patients who received bedaquiline substitution and 168 controls were analyzed; 70.6% were infected with human immunodeficiency virus. Unfavorable outcomes occurred in 35 of 146 (23.9%) patients in the bedaquiline group versus 51 of 141 (36.2%) in the control group (relative risk, 0.66; 95% confidence interval, .46 –.95). The number of patients with culture reversion was lower in those receiving bedaquiline (1 patient; 0.8%) than in controls (12 patients; 10.3%; P = .001). Delayed initiation of bedaquiline was independently associated with failure to achieve sustained culture conversion (adjusted odds ratio for every 30-day delay, 1.5; 95% confidence interval, 1.1–1.9). Mortality rates were similar at 12 months (11 deaths in each group; P = .97). Conclusions Substituting bedaquiline for SLIs in MDR tuberculosis treatment resulted in improved outcomes at 12 months compared with patients who continued taking SLIs, supporting the use of bedaquiline for MDR tuberculosis treatment in programmatic settings. In this population with a high human immunodeficiency virus coinfection rate, bedaquiline substitution for second-line injectable agents was associated with fewer unfavorable treatment outcomes at 12 months than in a matched control group receiving standard multidrug-resistant tuberculosis treatment.

A 15-year-old patient with cystic fibrosis with a disseminated Mycobacterium abscessus infection was treated with a three-phage cocktail following bilateral lung transplantation. Effective lytic phage derivatives that efficiently kill the infectious M. abscessus strain were developed by genome engineering and forward genetics. Intravenous phage treatment was well tolerated and associated with objective clinical improvement, including sternal wound closure, improved liver function, and substantial resolution of infected skin nodules.Clinical use of engineered bacteriophages for the treatment of disseminated mycobacterial infection.

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-of-function mmpR5 mutation in a susceptible strain. The loss-of-function mutation in the mmpL4 efflux gene was identified in the mixed state, pointing to ongoing selection in a bedaquiline-resistant isolate. Another case of the emergence of the mmpL4 mutation, accompanied by a proportional increase in bedaquiline MIC, was identified by retrospective analysis of genomes from bedaquiline-resistant isolates.

Key Points Tuberculous meningitis (TBM) causes death and disability, with especially high rates of poor outcomes in children and individuals with an HIV-1 co-infection Important risk factors for poor outcome are delayed diagnosis, delayed treatment, advanced disease, and antitubercular drug resistance Intracerebral and spinal pathology in TBM is mediated by a dysregulated inflammatory response that contributes to meningitis, tuberculoma formation, arteritis, obstruction of cerebrospinal fluid (CSF) flow, and vascular complications including stroke Diagnosis of TBM is insensitive and laborious; clinical scoring algorithms are imperfect and few rigorous evaluations of diagnostics have been performed Multidrug antitubercular antibiotic therapy is the mainstay of treatment; however, CSF penetration is probably a major limitation of these therapies, and evidence supporting dosage and treatment combinations is weak The supportive management of TBM complications, which include hyponatraemia, hydrocephalus, hypoxic brain damage and infarction, is poorly understood and researched, but is vital to outcome Tuberculous menigitis (TBM) presents a major health burden around the world, especially in individuals with concomitant HIV infection, in whom mortality is nearly 50%. Here, members of the TBM International Research Consortium summarize our current understanding of TBM pathogenesis, diagnosis and management, and discuss key avenues for future research. Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is tuberculous meningitis (TBM), for which more than 100,000 new cases are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Study of TBM pathogenesis is hampered by a lack of experimental models that recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. Antibiotic regimens for TBM are based on those used to treat pulmonary tuberculosis, which probably results in suboptimal drug levels in the cerebrospinal fluid, owing to poor blood–brain barrier penetrance. The role of adjunctive anti-inflammatory, host-directed therapies — including corticosteroids, aspirin and thalidomide — has not been extensively explored. To address this deficit, two expert meetings were held in 2009 and 2015 to share findings and define research priorities. This Review summarizes historical and current research into TBM and identifies important gaps in our knowledge. We will discuss advances in the understanding of inflammation in TBM and its potential modulation; vascular and hypoxia-mediated tissue injury; the role of intensified antibiotic treatment; and the importance of rapid and accurate diagnostics and supportive care in TBM.

Background 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. Methods 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 I 2 tests.This study is registered with PROSPERO, CRD42024620791. Results 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%. Conclusions 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 .