Selection of ciprofloxacin resistance in Escherichia coli in an in vitro kinetic model: relation between drug exposure and mutant prevention concentration.
OBJECTIVE
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 C(max) 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 C(max). When resistance was selected, several subpopulations with different levels of susceptibility to ciprofloxacin emerged.


CONCLUSIONS
Neither T > MPC nor C(max) proved to be single correlates for preventing resistance development. For the two investigated wild-type strains, an AUC/MPC ratio of > or =22 was the single pharmacodynamic index that predicted prevention of resistant mutant development.
Olofsson
Sara K
SK
Antibiotic Research Unit, Department of Medical Sciences, Clinical Bacteriology and Infectious Diseases, Uppsala University, S-751 22 Uppsala, Sweden.
Marcusson
Linda L
LL
Komp Lindgren
Patricia
P
Hughes
Diarmaid
D
Cars
Otto
O
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D002939:Ciprofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D015169:Colony Count, Microbial; D027081:DNA Gyrase / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D004927:Escherichia coli Infections / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009154:Mutation; D012641:Selection, Genetic; D014552:Urinary Tract Infections / Q000382:microbiology
D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D027081:DNA Gyrase