The pharmacokinetic–pharmacodynamic modelling framework as a tool to predict drug resistance evolution

Abstract

Pharmacokinetic–pharmacodynamic (PKPD) models, which describe how drug concentrations change over time and how that affects pathogen growth, have proven highly valuable in designing optimal drug treatments aimed at bacterial eradi-cation. However, the fast rise of antimicrobial resistance calls for increased focus on an additional treatment optimization criterion: avoidance of resistance evolution. We demonstrate here how coupling PKPD and population genetics models can be used to determine treatment regimens that minimize the potential for antimicrobial resistance evolution. Importantly, the resulting modelling framework enables the assessment of resistance evolution in response to dynamic selection pressures, including changes in antimicrobial concentration and the emergence of adaptive phenotypes. Using antibiotics and antimicrobial peptides as an example, we discuss the empirical evidence and intuition behind individual model parameters. We further suggest several extensions of this framework that allow a more comprehensive and realistic prediction of bacterial escape from antimicrobials through various phenotypic and genetic mechanisms.