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BackgroundNon-tuberculous mycobacteria (NTM) infections are hard to treat. New antimicrobial drugs and smarter combination regimens are needed.ObjectivesOur aim was to determine the in vitro activity of bedaquiline against NTM and assess its synergy with established antimycobacterials.MethodsWe determined MICs of bedaquiline for clinically relevant NTM species and Mycobacterium tuberculosis by broth microdilution for 30 isolates. Synergy testing was performed using the chequerboard method for 22 reference strains and clinical isolates of Mycobacterium abscessus (MAB) and Mycobacterium avium complex (MAC). Time-kill kinetics (TK) assays with resistance monitoring of bedaquiline alone and combined with clofazimine were performed for MAB CIP 104536 and M. avium ATCC 700898; bedaquiline/clarithromycin combinations were evaluated against M. avium ATCC 700898. Interactions were assessed for TK experiments based on Bliss independence.ResultsBedaquiline had modest activity against tested NTM, with MICs between <0.007 and 1 mg/L. Bedaquiline showed no interaction with tested drugs against MAB or MAC. Lowest mean fractional inhibitory concentration index (FICI) values were 0.79 with clofazimine for MAB and 0.97 with clofazimine and 0.82 with clarithromycin for MAC. In TK assays, bedaquiline showed a bacteriostatic effect. Clofazimine extended the bacteriostatic activity of bedaquiline against MAB and yielded a slight bactericidal effect against M. avium. The bedaquiline/clofazimine combination slowed emergence of bedaquiline resistance for M. avium but promoted it for MAB. Relative to Bliss independence, bedaquiline/clofazimine showed synergistic interaction over time for MAB and no interaction for M. avium and bedaquiline/clarithromycin showed antagonistic interaction for M. avium.ConclusionsFollowing these in vitro data, a bedaquiline/clofazimine combination might add activity to MAB and MAC treatment. The bedaquiline/clarithromycin combination might have lower activity compared with bedaquiline alone for MAC treatment.

Original publication

DOI

10.1093/jac/dky526

Type

Journal

The Journal of antimicrobial chemotherapy

Publication Date

04/2019

Volume

74

Pages

935 - 943

Addresses

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

Keywords

Mycobacterium avium Complex, Mycobacterium tuberculosis, Clofazimine, Antitubercular Agents, Microbial Sensitivity Tests, Drug Synergism, Microbial Viability, Diarylquinolines, Mycobacterium abscessus