A pharmacokinetic-pharmacodynamic model characterizing the emergence of resistant Escherichia coli subpopulations during ertapenem exposure.

Abstract

Resistant subpopulations with reduced expression of outer membrane porins have been observed in ESBL-producing Escherichia coli during exposure to ertapenem. The aim of this work was to develop a pharmacokinetic-pharmacodynamic (PKPD) model to characterize the emergence of resistant E. coli during exposure to ertapenem and to predict bacterial killing following different dosing regimens of ertapenem. Data from in vitro time-kill experiments were used to develop a mechanism-based PKPD model for three E. coli strains: a native strain, an ESBL-producing strain, and an ESBL-producing strain with reduced expression of porins OmpF and OmpC. Each strain was exposed to static ertapenem concentrations (1-512 × MIC) for 24 h using starting inocula of ∼10(6) and 10(8) cfu/mL. The developed PKPD model consisted of three bacterial states: susceptible growing, less susceptible non-growing, and non-susceptible non-growing bacteria. A pre-existing bacterial subpopulation was used to describe the emergence of resistance. The PKPD model adequately characterized the data of the three E. coli strains investigated. Results from predictions suggest that the conventional dosage (1 g intravenously once daily) might result in regrowth of resistant subpopulations when used to treat infection caused by ESBL-producing strains. Resistant subpopulations frequently emerged in E. coli when exposed to ertapenem, supporting that the time course of emergence of resistance should be taken into consideration when selecting dosing regimens.