A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria

Mike Marvin Ruth, Jasper J. N. Sangen, Karlijn Remmers, Lian J. Pennings, Elin Svensson, Rob E. Aarnoutse, Sanne M. H. Zweijpfenning, Wouter Hoefsloot, Saskia Kuipers, Cecile Magis-Escurra, Heiman F. L. Wertheim, Jakko van Ingen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)935-943
JournalJournal of Antimicrobial Chemotherapy
Volume74
Issue number4
DOIs
Publication statusPublished - 2019
Externally publishedYes

Cite this

Ruth, M. M., Sangen, J. J. N., Remmers, K., Pennings, L. J., Svensson, E., Aarnoutse, R. E., ... van Ingen, J. (2019). A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria. Journal of Antimicrobial Chemotherapy, 74(4), 935-943. https://doi.org/10.1093/jac/dky526
Ruth, Mike Marvin ; Sangen, Jasper J. N. ; Remmers, Karlijn ; Pennings, Lian J. ; Svensson, Elin ; Aarnoutse, Rob E. ; Zweijpfenning, Sanne M. H. ; Hoefsloot, Wouter ; Kuipers, Saskia ; Magis-Escurra, Cecile ; Wertheim, Heiman F. L. ; van Ingen, Jakko. / A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria. In: Journal of Antimicrobial Chemotherapy. 2019 ; Vol. 74, No. 4. pp. 935-943.
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title = "A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria",
abstract = "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.",
author = "Ruth, {Mike Marvin} and Sangen, {Jasper J. N.} and Karlijn Remmers and Pennings, {Lian J.} and Elin Svensson and Aarnoutse, {Rob E.} and Zweijpfenning, {Sanne M. H.} and Wouter Hoefsloot and Saskia Kuipers and Cecile Magis-Escurra and Wertheim, {Heiman F. L.} and {van Ingen}, Jakko",
year = "2019",
doi = "10.1093/jac/dky526",
language = "English",
volume = "74",
pages = "935--943",
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Ruth, MM, Sangen, JJN, Remmers, K, Pennings, LJ, Svensson, E, Aarnoutse, RE, Zweijpfenning, SMH, Hoefsloot, W, Kuipers, S, Magis-Escurra, C, Wertheim, HFL & van Ingen, J 2019, 'A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria' Journal of Antimicrobial Chemotherapy, vol. 74, no. 4, pp. 935-943. https://doi.org/10.1093/jac/dky526

A bedaquiline/clofazimine combination regimen might add activity to the treatment of clinically relevant non-tuberculous mycobacteria. / Ruth, Mike Marvin; Sangen, Jasper J. N.; Remmers, Karlijn; Pennings, Lian J.; Svensson, Elin; Aarnoutse, Rob E.; Zweijpfenning, Sanne M. H.; Hoefsloot, Wouter; Kuipers, Saskia; Magis-Escurra, Cecile; Wertheim, Heiman F. L.; van Ingen, Jakko.

In: Journal of Antimicrobial Chemotherapy, Vol. 74, No. 4, 2019, p. 935-943.

Research output: Contribution to journalArticleAcademicpeer-review

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

Y1 - 2019

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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30649327

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