Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis

Pym, Alexander S.; Diacon, Andreas H.; Tang, Shenjie; Conradie, Francesca; Danilovitš, Manfred; Chuchottaworn, Charoen; Vasilyeva, Irina; Andries, Koen; Bakare, Nyasha; Marez, Tine De; Haxaire-Theeuwes, Myriam; Lounis, Nacer; Meyvisch, Paul; Baelen, B. Van; Heeswijk, Rolf P. G. van; Dannemann, Brian

doi:10.1183/13993003.00724-2015

Cited by 275 publications

(254 citation statements)

References 27 publications

(37 reference statements)

Supporting

Mentioning

236

Contrasting

Unclassified

Order By: Relevance

“…In mice, Rv0678 resistant mutants may be selected with 8 weeks of bedaquiline monotherapy (D. Almeida, unpublished observation) but emerge only late in the course of combination therapy and are eventually cleared, presumably by the action of companion agents (6). Clinically, these mutants emerged almost entirely among patients with pre-XDR-and XDR-TB (6), but their isolation has not clearly been associated with poorer clinical outcomes among patients receiving bedaquiline with more effective companion agents (28). These results underscore the importance of appropriate combination therapy and adherence and the risk of premature discontinuation of therapy.…”

Section: Discussionmentioning

confidence: 99%

Mutations in pepQ Confer Low-Level Resistance to Bedaquiline and Clofazimine in Mycobacterium tuberculosis

Almeida

Ioerger

Tyagi

et al. 2016

Antimicrob Agents Chemother

Self Cite

181

142

View full text Add to dashboard Cite

fThe novel ATP synthase inhibitor bedaquiline recently received accelerated approval for treatment of multidrug-resistant tuberculosis and is currently being studied as a component of novel treatment-shortening regimens for drug-susceptible and multidrug-resistant tuberculosis. In a limited number of bedaquiline-treated patients reported to date, >4-fold upward shifts in bedaquiline MIC during treatment have been attributed to non-target-based mutations in Rv0678 that putatively increase bedaquiline efflux through the MmpS5-MmpL5 pump. These mutations also confer low-level clofazimine resistance, presumably by a similar mechanism. Here, we describe a new non-target-based determinant of low-level bedaquiline and clofazimine cross-resistance in Mycobacterium tuberculosis: loss-of-function mutations in pepQ (Rv2535c), which corresponds to a putative Xaa-Pro aminopeptidase. pepQ mutants were selected in mice by treatment with clinically relevant doses of bedaquiline, with or without clofazimine, and were shown to have bedaquiline and clofazimine MICs 4 times higher than those for the parental H37Rv strain. Coincubation with efflux inhibitors verapamil and reserpine lowered bedaquiline MICs against both mutant and parent strains to a level below the MIC against H37Rv in the absence of efflux pump inhibitors. However, quantitative PCR (qPCR) revealed no significant differences in expression of Rv0678, mmpS5, or mmpL5 between mutant and parent strains. Complementation of a pepQ mutant with the wild-type gene restored susceptibility, indicating that loss of PepQ function is sufficient for reduced susceptibility both in vitro and in mice. Although the mechanism by which mutations in pepQ confer bedaquiline and clofazimine cross-resistance remains unclear, these results may have clinical implications and warrant further evaluation of clinical isolates with reduced susceptibility to either drug for mutations in this gene. Multidrug-resistant tuberculosis (MDR-TB) is a major threat to global control of tuberculosis (TB). When multidrug resistance is not diagnosed, patients respond poorly to standardized first-line regimens and additional resistance may develop. When MDR-TB is diagnosed, current second-line regimens require prolonged treatment durations and are less effective, more toxic, and far more expensive than first-line therapy (1).The diarylquinoline drug bedaquiline (B) received accelerated approval from the U.S. Food and Drug Administration as part of combination therapy for MDR-TB when other alternatives are not available (2). It is now being studied as a component of novel short-course regimens for MDR as well as drug-susceptible TB (ClinicalTrials.gov identifiers NCT02333799, NCT02193776, NCT02589782, NCT02409290, and NCT02454205 [https://clinicaltrials.gov/]). For new drugs such as bedaquiline, it is essential to define and catalog the mechanisms conferring bacterial resistance in order to design appropriate diagnostic tests (including rapid molecular tests), to better manage the treatment of patients who fail ...

show abstract

Section: Discussionmentioning

confidence: 99%

Mutations in pepQ Confer Low-Level Resistance to Bedaquiline and Clofazimine in Mycobacterium tuberculosis

Almeida

Ioerger

Tyagi

et al. 2016

Antimicrob Agents Chemother

Self Cite

181

142

View full text Add to dashboard Cite

show abstract

“…Although encouraging initial observations have been made of faster culture conversion in early bactericidal activity and phase 2 studies of bedaquiline, 365,366 and high rates of culture conversion in French 367 and South African patients with XDR tuberculosis (100% in the French cohort and 85% in the South African cohort), 324 another analysis 368 indicated that the 120-week culture conversion rate was 70% in patients with pre-XDR tuberculosis and 62% in XDR tuberculosis when bedaquiline was used with companion drugs and an optimised background regimen. Thus, even with newer drugs such as bedaquiline, treatment failure will be common in patients with XDR tuberculosis or those with resistance beyond XDR tuberculosis, for which no effective therapy is available and so it remains programmatically incurable.…”

Section: Bedaquilinementioning

confidence: 99%

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

Dheda

Gumbo

Maartens

et al. 2017

The Lancet Respiratory Medicine

533

493

View full text Add to dashboard Cite

“…Preliminary DST methodology for bedaquiline was previously piloted and then used in two phase II clinical studies (3)(4)(5)(6). In these studies, bedaquiline DST was performed by 7H11 agar dilution and 7H9 broth microdilution methods using the resazurin microtiter assay (REMA) (11,12).…”

mentioning

confidence: 99%

“…Bedaquiline, a diarylquinoline antimycobacterial (2), has received accelerated/conditional approval for use based on phase II trials in the United States (2012), the European Union (2014), and 7 countries with high MDR-TB burden (3)(4)(5)(6)(7)(8). Interim policy guidance for the use of bedaquiline as part of combination therapy for adults who have pulmonary MDR-TB has been issued by the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) (9,10).…”

mentioning

confidence: 99%

A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testing

et al. 2016

Self Cite

View full text Add to dashboard Cite

jThe aim of this study was to establish standardized drug susceptibility testing (DST) methodologies and reference MIC quality control (QC) ranges for bedaquiline, a diarylquinoline antimycobacterial, used in the treatment of adults with multidrug-resistant tuberculosis. Two tier-2 QC reproducibility studies of bedaquiline DST were conducted in eight laboratories using Clinical Laboratory and Standards Institute (CLSI) guidelines. Agar dilution and broth microdilution methods were evaluated. Mycobacterium tuberculosis H37Rv was used as the QC reference strain. Bedaquiline MIC frequency, mode, and geometric mean were calculated. When resulting data occurred outside predefined CLSI criteria, the entire laboratory data set was excluded. N ewer drugs are being developed to counter the growing problem of multidrug-resistant (MDR) strains of Mycobacterium tuberculosis. Of the 9.6 million estimated new M. tuberculosis cases occurring globally in 2014, 3.3% were MDR, in addition to 20% of previously treated tuberculosis (TB) cases estimated to have MDR; this equates to an overall estimate of 480,000 people with MDR-TB annually. Furthermore, current treatment outcome data for patients started on MDR-TB treatment in 2015 suggest a success rate of only 50% (1). The approval of new antimycobacterials effective against MDR-TB strains has highlighted the need for validated and standardized drug susceptibility testing (DST) methods to enhance patient care and for facilitating drug resistance surveillance.Bedaquiline, a diarylquinoline antimycobacterial (2), has received accelerated/conditional approval for use based on phase II trials in the United States (2012), the European Union (2014), and 7 countries with high MDR-TB burden (3-8). Interim policy guidance for the use of bedaquiline as part of combination therapy for adults who have pulmonary MDR-TB has been issued by the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) (9, 10).Preliminary DST methodology for bedaquiline was previously piloted and then used in two phase II clinical studies (3-6). In these studies, bedaquiline DST was performed by 7H11 agar dilution and 7H9 broth microdilution methods using the resazurin microtiter assay (REMA) (11,12). For bedaquiline DST, the standard quality control (QC) strain M. tuberculosis H37Rv should be used under the same conditions as the clinical M. tuberculosis isolates to ensure that the bedaquiline MIC of the reference falls within a predefined QC range. For QC purposes when testing clinical isolates prior to the present study, the provisional bedaquiline MIC ranges against strain H37Rv were 0.03 to 0.12 g/ml for 7H11 agar and 0.03 to 0.12 g/ml for REMA (7H9

show abstract

Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis

Cited by 275 publications

References 27 publications

Mutations in pepQ Confer Low-Level Resistance to Bedaquiline and Clofazimine in Mycobacterium tuberculosis

Mutations in pepQ Confer Low-Level Resistance to Bedaquiline and Clofazimine in Mycobacterium tuberculosis

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

A Multilaboratory, Multicountry Study To Determine Bedaquiline MIC Quality Control Ranges for Phenotypic Drug Susceptibility Testing

Contact Info

Product

Resources

About