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Antimicrobial Agents and Chemotherapy, December 2005, p. 5081-5091, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5081-5091.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pharmacodynamic Model To Describe the Concentration-Dependent Selection of Cefotaxime-Resistant Escherichia coli

Sara K. Olofsson,^1, Patricia Geli,^2,3,4, Dan I. Andersson,⁵ and Otto Cars^1*

Antibiotic Research Unit, Department of Medical Sciences, Clinical Bacteriology and Infectious Diseases, Uppsala University, Uppsala, Sweden,¹ Department of Epidemiology, Swedish Institute for Infectious Disease Control (SMI), Solna, Sweden,² Division of Mathematical Statistics, Department of Mathematics, Stockholm University, Stockholm, Sweden,³ Stockholm Group for Epidemic Modeling (S-GEM), Stockholm, Sweden,⁴ Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden⁵

Received 7 January 2005/ Returned for modification 5 May 2005/ Accepted 1 October 2005

Antibiotic dosing regimens may vary in their capacity to select mutants. Our hypothesis was that selection of a more resistant bacterial subpopulation would increase with the time within a selective window (SW), i.e., when drug concentrations fall between the MICs of two strains. An in vitro kinetic model was used to study the selection of two Escherichia coli strains with different susceptibilities to cefotaxime. The bacterial mixtures were exposed to cefotaxime for 24 h and SWs of 1, 2, 4, 8, and 12 h. A mathematical model was developed that described the selection of preexisting and newborn mutants and the post-MIC effect (PME) as functions of pharmacokinetic parameters. Our main conclusions were as follows: (i) the selection between preexisting mutants increased with the time within the SW; (ii) the emergence and selection of newborn mutants increased with the time within the SW (with a short time, only 4% of the preexisting mutants were replaced by newborn mutants, compared to the longest times, where 100% were replaced); and (iii) PME increased with the area under the concentration-time curve (AUC) and was slightly more pronounced with a long elimination half-life (T_1/2) than with a short T_1/2 situation, when AUC is fixed. We showed that, in a dynamic competition between strains with different levels of resistance, the appearance of newborn high-level resistant mutants from the parental strains and the PME can strongly affect the outcome of the selection and that pharmacodynamic models can be used to predict the outcome of resistance development.

Authors contributed equally to the paper.

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