A pharmacokinetic-pharmacodynamic model characterizing the emergence of resistant Escherichia coli subpopulations during ertapenem exposure
Wanchana Ungphakorn (1), Thomas Tängdén (2), Linus Sandegren (3), Elisabet I. Nielsen (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Sweden; (2) Department of Medical Sciences, Uppsala University, Sweden; (3) Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden
Objectives: Antimicrobial resistance in Escherichia coli related to the production of extended-spectrum β-lactamases (ESBLs) is increasing worldwide. Further, resistant subpopulations with reduced expression of outer membrane porins have been observed in ESBL-producing E. coli exposed to ertapenem antibiotic [1]. However, to date, there is limited information on how ertapenem exposures influence the emergence of resistance. 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 in adult patients.
Methods: In vitro time-kill curve experiments were performed with three E. coli strains; native strain, ESBL-producing strain and ESBL-producing strain with reduced porin expression (ompR mutant). Each strain was exposed to static ertapenem concentrations ranging from 1 to 512 times the MIC for 24 h using both standard and high starting inocula. Mechanism-based PKPD models were developed using NONMEM 7.3. Bactericidal activity of ertapenem and the emergence of resistance were predicted following different dosing strategies using a previously reported population PK model [2] and the developed PKPD model.
Results: Bacterial regrowth and increased MICs were detected for all three strains when exposed to intermediate ertapenem concentrations. The final PKPD model consisted of susceptible growing, less-susceptible non-growing and insusceptible non-growing bacteria. A pre-existing bacterial subpopulation explained the emergence of resistance. Results from dose predictions supported the effectiveness of commonly used ertapenem dosage regimens for the native strain, while regrowth of resistant subpopulations for the ESBL-producing and the ESBL-producing ompR strains was predicted. No clear advantages of extended infusions, or fractionated doses were found, questioning time above MIC as PD driver.
Conclusions: The developed PKPD model adequately characterized the emergence of resistance for the three E. coli strains investigated. This study supports that the time-course of emergence of resistance should be taken into consideration when selecting dosing regimens.
References:
[1] Tängdén T, Adler M, Cars O, Sandegren L, Löwdin E. 2013. Frequent emergence of porin-deficient subpopulations with reduced carbapenem susceptibility in ESBL-producing Escherichia coli during exposure to ertapenem in an in vitro pharmacokinetic model. J. Antimicrob. Chemother. 68:1319–26.
[2] Wiskirchen DE, Housman ST, Quintiliani R, Nicolau DP, Kuti JL. 2013. Comparative pharmacokinetics, pharmacodynamics, and tolerability of ertapenem 1 gram/day administered as a rapid 5-minute infusion versus the standard 30-minute infusion in healthy adult volunteers. Pharmacotherapy 33:266–74.