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Dynamic interaction of colistin and meropenem on a WT and a resistant strain of Pseudomonas aeruginosa as quantified in a PK/PD model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)ORCID iD: 0000-0003-3166-9981
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
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2016 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 5, 1279-1290 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Combination therapy can be a strategy to ensure effective bacterial killing when treating Pseudomonas aeruginosa, a Gram-negative bacterium with high potential for developing resistance. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the in vitro bacterial time-kill curves of colistin and meropenem alone and in combination for one WT and one meropenem-resistant strain of P. aeruginosa.

METHODS: In vitro time-kill curve experiments were conducted with a P. aeruginosa WT (ATCC 27853) (MICs: meropenem 1 mg/L; colistin 1 mg/L) and a meropenem-resistant type (ARU552) (MICs: meropenem 16 mg/L; colistin 1.5 mg/L). PK/PD models characterizing resistance were fitted to the observed bacterial counts in NONMEM. The final model was applied to predict the bacterial killing of ARU552 for different combination dosages of colistin and meropenem.

RESULTS: A model with compartments for growing and resting bacteria, where the bacterial killing by colistin reduced with continued exposure and a small fraction (0.15%) of the start inoculum was resistant to meropenem, characterized the bactericidal effect and resistance development of the two antibiotics. For a typical patient, a loading dose of colistin combined with a high dose of meropenem (2000 mg q8h) was predicted to result in a pronounced kill of the meropenem-resistant strain over 24 h.

CONCLUSIONS: The developed PK/PD model successfully described the time course of bacterial counts following exposures to colistin and meropenem, alone and in combination, for both strains, and identified a dynamic drug interaction. The study illustrates the application of a PK/PD model and supports high-dose combination therapy of colistin and meropenem to overcome meropenem resistance.

Place, publisher, year, edition, pages
2016. Vol. 71, no 5, 1279-1290 p.
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-278022DOI: 10.1093/jac/dkv488ISI: 000376291300021PubMedID: 26850719OAI: oai:DiVA.org:uu-278022DiVA: diva2:906047
Funder
Swedish Foundation for Strategic Research EU, FP7, Seventh Framework Programme
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2018-01-10Bibliographically approved

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Kristoffersson, AndersKarvanen, MattiNielsen, ElisabetCars, OttoFriberg, Lena

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