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Predicting mutant selection in competition experiments with ciprofloxacin-exposed Escherichia coli
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 Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0003-3166-9981
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2018 (English)In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 51, no 3, p. 399-406, article id S0924-8579(17)30392-8Article in journal (Refereed) Published
Abstract [en]

Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E. coli) WT and three well-defined E. coli resistant MTs when exposed to ciprofloxacin. Model predictions for each bacterial strain and ciprofloxacin concentration were made for in vitro static and dynamic time–kill experiments measuring CFU (colony forming units)/mL up to 24 h with concentrations close to or below the minimum inhibitory concentration (MIC), as well as for serial passage experiments with concentrations well below the MIC measuring ratios between the two strains with flow cytometry. The model was found to reasonably well predict the initial bacterial growth and killing of most static and dynamic time–kill competition experiments without need for parameter re-estimation. With parameter re-estimation of growth rates, an adequate fit was also obtained for the 6-day serial passage competition experiments. No bacterial interaction in growth was observed. This study demonstrates the predictive capacity of a PK/PD model and further supports the application of PK/PD modelling for prediction of bacterial kill in different settings, including resistance selection.

Place, publisher, year, edition, pages
2018. Vol. 51, no 3, p. 399-406, article id S0924-8579(17)30392-8
Keywords [en]
Ciprofloxacin, Escherichia coli, PK/PD modelling, PK/PD predictions, Pharmacokinetics/Pharmacodynamics, Time–kill experiments
National Category
Pharmaceutical Sciences Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-343607DOI: 10.1016/j.ijantimicag.2017.10.019ISI: 000427582000016PubMedID: 29127049OAI: oai:DiVA.org:uu-343607DiVA, id: diva2:1186452
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research EU, FP7, Seventh Framework Programme, FP7/2007-2013Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-05-18Bibliographically approved

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Khan, DavidLagerbäck, PernillaMalmberg, ChristerKristoffersson, AndersGullberg, ErikCao, ShaCars, OttoAndersson, Dan I.Hughes, DiarmaidNielsen, Elisabet I.Friberg, Lena E

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Khan, DavidLagerbäck, PernillaMalmberg, ChristerKristoffersson, AndersGullberg, ErikCao, ShaCars, OttoAndersson, Dan I.Hughes, DiarmaidNielsen, Elisabet I.Friberg, Lena E
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Department of Pharmaceutical BiosciencesInfectious DiseasesDepartment of Medical Biochemistry and Microbiology
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