title: Clofazimine Prevents the Regrowth of Mycobacterium abscessus and Mycobacterium avium Type Strains Exposed to Amikacin and Clarithromycin.
abstract: Multidrug therapy is a standard practice when treating infections by nontuberculous mycobacteria (NTM), but few treatment options exist. We conducted this study to define the drug-drug interaction between clofazimine and both amikacin and clarithromycin and its contribution to NTM treatment. Mycobacterium abscessus and Mycobacterium avium type strains were used. Time-kill assays for clofazimine alone and combined with amikacin or clarithromycin were performed at concentrations of 0.25× to 2× MIC. Pharmacodynamic interactions were assessed by response surface model of Bliss independence (RSBI) and isobolographic analysis of Loewe additivity (ISLA), calculating the percentage of statistically significant Bliss interactions and interaction indices (I), respectively. Monte Carlo simulations with predicted human lung concentrations were used to calculate target attainment rates for combination and monotherapy regimens. Clofazimine alone was bacteriostatic for both NTM. Clofazimine-amikacin was synergistic against M. abscessus (I = 0.41; 95% confidence interval [CI], 0.29 to 0.55) and M. avium (I = 0.027; 95% CI, 0.007 to 0.048). Based on RSBI analysis, synergistic interactions of 28.4 to 29.0% and 23.2 to 56.7% were observed at 1× to 2× MIC and 0.25× to 2× MIC for M. abscessus and M. avium, respectively. Clofazimine-clarithromycin was also synergistic against M. abscessus (I = 0.53; 95% CI, 0.35 to 0.72) and M. avium (I = 0.16; 95% CI, 0.04 to 0.35), RSBI analysis showed 23.5% and 23.3 to 53.3% at 2× MIC and 0.25× to 0.5× MIC for M. abscessus and M. avium, respectively. Clofazimine prevented the regrowth observed with amikacin or clarithromycin alone. Target attainment rates of combination regimens were >60% higher than those of monotherapy regimens for M. abscessus and M. avium. The combination of clofazimine with amikacin or clarithromycin was synergistic in vitro. This suggests a potential role for clofazimine in treatment regimens that warrants further evaluation.
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Beatriz E
authors.initials: BE
authors.lastname: Ferro
authors.affiliation: Clinical Microbiology Laboratory, Attikon University General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Joseph
authors.initials: J
authors.lastname: Meletiadis
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wattenberg
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Arjan
authors.initials: A
authors.lastname: de Jong
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands National Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: Mouton
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands vaningen.jakko@gmail.com.
authors.forename: Jakko
authors.initials: J
authors.lastname: van Ingen
mesh_terms: D000583:Amikacin / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017291:Clarithromycin / Q000494:pharmacology*; D002991:Clofazimine / Q000494:pharmacology*; D004347:Drug Interactions; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D009154:Mutation; D009162:Mycobacterium avium / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D009170:Nontuberculous Mycobacteria / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D000583:Amikacin; D002991:Clofazimine; D017291:Clarithromycin