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A pharmacokinetic-pharmacodynamic model characterizing the emergence of resistant Escherichia coli subpopulations during ertapenem exposure
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2016 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 9, 2521-2533 p.Article in journal (Refereed) Published
Abstract [en]

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 (1-512aEuroSxaEuroSMIC) for 24 h using starting inocula of similar to 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.

Place, publisher, year, edition, pages
2016. Vol. 71, no 9, 2521-2533 p.
National Category
Infectious Medicine Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-306278DOI: 10.1093/jac/dkw205ISI: 000383911600022PubMedID: 27330073OAI: oai:DiVA.org:uu-306278DiVA: diva2:1040169
Funder
Swedish Foundation for Strategic Research
Available from: 2016-10-26 Created: 2016-10-26 Last updated: 2016-10-26Bibliographically approved

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Ungphakorn, WanchanaTängdén, ThomasSandegren, LinusNielsen, Elisabet I.
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Department of Pharmaceutical BiosciencesInfectious DiseasesDepartment of Medical Biochemistry and Microbiology
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