TY - JOUR
T1 - A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria
AU - Ruth, Mike Marvin
AU - Sangen, Jasper J. N.
AU - Remmers, Karlijn
AU - Pennings, Lian J.
AU - Svensson, Elin
AU - Aarnoutse, Rob E.
AU - Zweijpfenning, Sanne M. H.
AU - Hoefsloot, Wouter
AU - Kuipers, Saskia
AU - Magis-Escurra, Cecile
AU - Wertheim, Heiman F. L.
AU - van Ingen, Jakko
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Background: Non-tuberculous mycobacteria (NTM) infections are hard to treat. New antimicrobial drugs and smarter combination regimens are needed. Objectives: Our aimwas to determine the in vitro activity of bedaquiline against NTM and assess its synergy with established antimycobacterials. Methods: We determined MICs of bedaquiline for clinically relevant NTM species and Mycobacterium tuberculosis by brothmicrodilution for 30 isolates. Synergy testingwas performed using the chequerboardmethod for 22 reference strains and clinical isolates of Mycobacterium abscessus (MAB) and Mycobacterium avium complex (MAC). Time-kill kinetics (TK) assayswith resistancemonitoring of bedaquiline alone and combinedwith clofaziminewere 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. Results: Bedaquiline had modest activity against tested NTM, with MICs between <0.007 and 1mg/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. Conclusions: Following 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.
AB - Background: Non-tuberculous mycobacteria (NTM) infections are hard to treat. New antimicrobial drugs and smarter combination regimens are needed. Objectives: Our aimwas to determine the in vitro activity of bedaquiline against NTM and assess its synergy with established antimycobacterials. Methods: We determined MICs of bedaquiline for clinically relevant NTM species and Mycobacterium tuberculosis by brothmicrodilution for 30 isolates. Synergy testingwas performed using the chequerboardmethod for 22 reference strains and clinical isolates of Mycobacterium abscessus (MAB) and Mycobacterium avium complex (MAC). Time-kill kinetics (TK) assayswith resistancemonitoring of bedaquiline alone and combinedwith clofaziminewere 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. Results: Bedaquiline had modest activity against tested NTM, with MICs between <0.007 and 1mg/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. Conclusions: Following 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85062949076&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30649327
U2 - 10.1093/jac/dky526
DO - 10.1093/jac/dky526
M3 - Article
C2 - 30649327
SN - 0305-7453
VL - 74
SP - 935
EP - 943
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
IS - 4
ER -