A mechanism-based pharmacokinetic/pharmacodynamic model allows prediction of antibiotic killing from MIC values for WT and mutants

The Journal of Antimicrobial Chemotherapy
David D KhanLena E Friberg

Abstract

In silico pharmacokinetic/pharmacodynamic (PK/PD) models can be developed based on data from in vitro time-kill experiments and can provide valuable information to guide dosing of antibiotics. The aim was to develop a mechanism-based in silico model that can describe in vitro time-kill experiments of Escherichia coli MG1655 WT and six isogenic mutants exposed to ciprofloxacin and to identify relationships that may be used to simplify future characterizations in a similar setting. In this study, we developed a mechanism-based PK/PD model describing killing kinetics for E. coli following exposure to ciprofloxacin. WT and six well-characterized mutants, with one to four clinically relevant resistance mutations each, were exposed to a wide range of static ciprofloxacin concentrations. The developed model includes susceptible growing bacteria, less susceptible (pre-existing resistant) growing bacteria, non-susceptible non-growing bacteria and non-colony-forming non-growing bacteria. The non-colony-forming state was likely due to formation of filaments and was needed to describe data close to the MIC. A common model structure with different potency for bacterial killing (EC50) for each strain successfully characterized the time-kill ...Continue Reading

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Citations

Jun 23, 2016·The Journal of Antimicrobial Chemotherapy·Wanchana UngphakornElisabet I Nielsen
Dec 26, 2015·The Journal of Antimicrobial Chemotherapy·Oskar CleweUlrika S H Simonsson
Nov 12, 2016·Journal of Microbiological Methods·Wanchana UngphakornThomas Tängdén
Jun 15, 2016·CPT: Pharmacometrics & Systems Pharmacology·R J Svensson, Ush Simonsson
Feb 8, 2018·The Journal of Antimicrobial Chemotherapy·Sherwin K B SyHartmut Derendorf
Oct 26, 2018·The Journal of Antimicrobial Chemotherapy·Boas C L van der PuttenConstance Schultsz
Apr 11, 2020·PLoS Computational Biology·Loïc Marrec, Anne-Florence Bitbol
Apr 24, 2020·Drugs·Lu ChenRoger J M Brüggemann
Nov 25, 2020·Drug Discovery Today·Carlos Victor Montefusco-PereiraClaus-Michael Lehr
Feb 2, 2021·Clinical Pharmacology and Therapeutics·Lena E Friberg
Feb 9, 2021·Clinical Pharmacology and Therapeutics·Craig R RaynerKaren Rowland-Yeo

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