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J Antimicrob Chemother. 2015 Mar;70(3):811-7. doi: 10.1093/jac/dku431. Epub 2014 Oct 25.

Time-kill kinetics of antibiotics active against rapidly growing mycobacteria.

Author information

1
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands beferro@gmail.com.
2
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
3
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.
4
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.

Abstract

OBJECTIVES:

This study was conducted to generate basic pharmacodynamic information on the relationship between antibiotic concentrations and the growth of rapidly growing mycobacteria (RGM), and thereby contribute to a better understanding of current and future drug regimens for diseases caused by RGM.

METHODS:

Type strains of Mycobacterium abscessus and Mycobacterium fortuitum were used; the MICs of cefoxitin, amikacin, moxifloxacin, linezolid and clarithromycin were determined by broth microdilution. Time-kill assays were performed, exposing the bacteria to 2-fold concentrations from 0.25 to 32 times the MIC at 30°C for 120 h. The sigmoid maximum effect (Emax) model was fitted to the time-kill curves data.

RESULTS:

The highest killing of M. abscessus was observed between 24 and 72 h; amikacin had the highest Emax (0.0427 h(-1)), followed by clarithromycin (0.0231 h(-1)) and cefoxitin (0.0142 h(-1)). For M. fortuitum, between 3 and 24 h, amikacin also showed the highest Emax (0.1933 h(-1)). There were no significant differences between the Hill's slopes determined for all the antibiotics tested against M. abscessus or M. fortuitum (P = 0.2213 and P = 0.2696, respectively).

CONCLUSIONS:

The total effect observed for all antibiotics was low and primarily determined by the Emax and not by the Hill's slope. The limited activity detected fits well with the poor outcome of antibiotic treatment for disease caused by RGM, particularly for M. abscessus. An evaluation of drug combinations will be the next step in understanding and improving current treatment standards.

KEYWORDS:

Emax model; Mycobacterium abscessus; kill rate; non-tuberculous mycobacteria; pharmacodynamics

PMID:
25344808
DOI:
10.1093/jac/dku431
[Indexed for MEDLINE]

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