Beatriz E Ferro1, Jakko van Ingen2, Melanie Wattenberg2, Dick van Soolingen3, Johan W Mouton4. 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.
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.
Authors: Beatriz E Ferro; Shashikant Srivastava; Devyani Deshpande; Jotam G Pasipanodya; Dick van Soolingen; Johan W Mouton; Jakko van Ingen; Tawanda Gumbo Journal: Antimicrob Agents Chemother Date: 2016-05-23 Impact factor: 5.191
Authors: Beatriz E Ferro; Shashikant Srivastava; Devyani Deshpande; Carleton M Sherman; Jotam G Pasipanodya; Dick van Soolingen; Johan W Mouton; Jakko van Ingen; Tawanda Gumbo Journal: Antimicrob Agents Chemother Date: 2015-12-07 Impact factor: 5.191
Authors: Beatriz E Ferro; Joseph Meletiadis; Melanie Wattenberg; Arjan de Jong; Dick van Soolingen; Johan W Mouton; Jakko van Ingen Journal: Antimicrob Agents Chemother Date: 2015-12-07 Impact factor: 5.191
Authors: Hannelore I Bax; Irma A J M Bakker-Woudenberg; Marian T Ten Kate; Annelies Verbon; Jurriaan E M de Steenwinkel Journal: Antimicrob Agents Chemother Date: 2016-03-25 Impact factor: 5.191
Authors: Mike M Ruth; Jasper J N Sangen; Lian J Pennings; Jodie A Schildkraut; Wouter Hoefsloot; Cecile Magis-Escurra; Heiman F L Wertheim; Jakko van Ingen Journal: Antimicrob Agents Chemother Date: 2018-09-24 Impact factor: 5.191