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JAC Advance Access published online on April 19, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl135
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received July 19, 2005
Accepted March 21, 2006

Original article

Selection of ciprofloxacin resistance in Escherichia coli in an in vitro kinetic model: relation between drug exposure and mutant prevention concentration

Sara K. Olofsson 1, Linda L. Marcusson 2, Patricia Komp Lindgren 2, Diarmaid Hughes 2, and Otto Cars 1 *

1 Antibiotic Research Unit, Department of Medical Sciences, Clinical Bacteriology and Infectious Diseases, Uppsala University, S-751 22 Uppsala, Sweden
2 Microbiology Programme, Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, S-751 24 Uppsala, Sweden

* To whom correspondence should be addressed.
Otto Cars, E-mail: otto.cars{at}smi.ki.se


  Abstract

Objectives: To evaluate the mutant prevention concentrations (MPCs) of ciprofloxacin for two susceptible and one first-step gyrA resistant mutant Escherichia coli strains in an in vitro kinetic model and to identify the pharmacodynamic index that best predicts prevention of resistance emergence.

Methods: An in vitro kinetic model was used to measure MPC with static antibiotic concentrations and to test different dosing profiles to study pharmacokinetics/pharmacodynamics indices important to prevent the growth of resistant mutants. In one set of kinetic experiments the starting concentration was equal to the MPC and the T > MPC was varied before antibiotic dilution was begun. In a second set of kinetic experiments Cmax was varied and dilution of the antibiotic was started at time zero.

Results: From the static experiments we calculated MPC values of 0.128 mg/L for both the susceptible strains (16x MIC) and 0.188 mg/L (4x MIC) for the first-step resistant (gyrA) strain. The kinetic experiments showed that the T > MPC needed to prevent the growth of resistant bacteria was shorter with an increased Cmax. When resistance was selected, several subpopulations with different levels of susceptibility to ciprofloxacin emerged.

Conclusions: Neither T > MPC nor Cmax proved to be single correlates for preventing resistance development. For the two investigated wild-type strains, an AUC/MPC ratio of ≥22 was the single pharmacodynamic index that predicted prevention of resistant mutant development.

Keywords: antibiotic resistance; MPC; PK/PD; E. coli.
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