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

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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 (16× MIC) and 0.188 mg/L (4× 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.

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