Unexpected high prevalence of resistance-associated Rv0678 variants in MDR-TB patients without documented prior use of clofazimine or bedaquiline

Resistance-associated variants (RAVs) in Rv0678 , a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are i...

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Bibliographic Details
Published in:Journal of antimicrobial chemotherapy 2017-03, Vol.72 (3), p.684-690
Main Authors: Villellas, Cristina, Coeck, Nele, Meehan, Conor J, Lounis, Nacer, de Jong, Bouke, Rigouts, Leen, Andries, Koen
Format: Article
Language:English
Subjects:
Anti-Inflammatory Agents - pharmacology
Antibiotics, Antitubercular - therapeutic use
Antitubercular Agents - pharmacology
Antitubercular Agents - therapeutic use
Clinical Trials as Topic
Clofazimine - pharmacology
Clofazimine - therapeutic use
Diarylquinolines - pharmacology
Diarylquinolines - therapeutic use
Humans
Microbial Sensitivity Tests
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - genetics
Original Research
Prevalence
Rifampin - therapeutic use
Sequence Analysis, DNA
Tuberculosis, Multidrug-Resistant - epidemiology
Tuberculosis, Multidrug-Resistant - microbiology
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Summary:Resistance-associated variants (RAVs) in Rv0678 , a regulator of the MmpS5-MmpL5 efflux pump, have been shown to lead to increased MICs of bedaquiline (2- to 8- fold) and clofazimine (2- to 4-fold). The prevalence of these Rv0678 RAVs in clinical isolates and their impact on treatment outcomes are important factors to take into account in bedaquiline treatment guidelines. Baseline isolates from two bedaquiline MDR-TB clinical trials were sequenced for Rv0678 RAVs and corresponding bedaquiline MICs were determined on 7H11 agar. Rv0678 RAVs were also investigated in non-MDR-TB sequences of a population-based cohort. Rv0678 RAVs were identified in 23/347 (6.3%) of MDR-TB baseline isolates. Surprisingly, bedaquiline MICs for these isolates were high (> 0.24 mg/L, n  =   8), normal (0.03-0.24 mg/L, n  =   11) or low (
ISSN:0305-7453
1460-2091
DOI:10.1093/jac/dkw502