Time-kill kinetics of slowly growing mycobacteria common in pulmonary disease

• Published in: Journal of antimicrobial chemotherapy 2015-10, Vol.70 (10), p.2838-2843
• Main Authors: Ferro, Beatriz E, van Ingen, Jakko, Wattenberg, Melanie, van Soolingen, Dick, Mouton, Johan W
• Format: Article
• Language: English
• Subjects: Amikacin - pharmacology; Anti-Bacterial Agents - pharmacology; Antibiotics; Bioassays; Biological activity; Chronic obstructive pulmonary disease; Clarithromycin - pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Kinetics; Microbial Sensitivity Tests; Microbiology; Mutation; Mutation Rate; Mycobacterium avium; Mycobacterium avium - drug effects; Mycobacterium avium - genetics; Mycobacterium xenopi; Mycobacterium xenopi - drug effects; Time Factors
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkv180

This study aimed to provide basic pharmacodynamic information for key antibiotics used to treat Mycobacterium avium and Mycobacterium xenopi pulmonary disease. M. avium subspecies hominissuis IWGMT49 and M. xenopi ATCC 19250 type strains were used; the MICs of clarithromycin, amikacin and moxifloxacin were determined by broth microdilution. Time-kill assays were performed, exposing bacteria to 2-fold concentrations from 0.062× to 32× the MIC at 37°C for 240 h for M. avium or 42 days for M. xenopi. The sigmoid maximum effect (Emax) model was fitted to the time-kill curve data. Maximum killing of M. avium by amikacin was obtained between 24 and 120 h (0.0180 h(-1)) and was faster and higher than with clarithromycin (0.0109 h(-1)); however, regrowth and amikacin-resistant mutants were observed. Killing rates for M. xenopi were higher, 0.1533 h(-1) for clarithromycin and 0.1385 h(-1) for moxifloxacin, yet required 42 days. There were no significant differences between the Hill's slopes determined for all of the antibiotics tested against M. avium or M. xenopi (P = 0.9663 and P = 0.0844, respectively). The killing effect of amikacin and clarithromycin on M. avium subspecies hominissuis was low, although amikacin activity was higher than that of clarithromycin, supporting its role in a combined therapy. Clarithromycin and moxifloxacin may have similar activity within treatment regimens for M. xenopi disease. Future studies of in vitro and in vivo pharmacokinetic/pharmacodynamic interactions are needed to improve the current regimens to treat these two important slowly growing mycobacteria in pulmonary disease.