title: Time-kill kinetics of slowly growing mycobacteria common in pulmonary disease.
abstract: OBJECTIVE
  This study aimed to provide basic pharmacodynamic information for key antibiotics used to treat Mycobacterium avium and Mycobacterium xenopi pulmonary disease.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands beferro@gmail.com.
authors.forename: Beatriz E
authors.initials: BE
authors.lastname: Ferro
authors.affiliation: Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jakko
authors.initials: J
authors.lastname: van Ingen
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 Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands National Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment, 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
mesh_terms: D000583:Amikacin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017291:Clarithromycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D008826:Microbial Sensitivity Tests; D009154:Mutation; D059645:Mutation Rate; D009162:Mycobacterium avium / Q000187:drug effects* / Q000235:genetics; D019912:Mycobacterium xenopi / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D000583:Amikacin; D017291:Clarithromycin