Mechanism-based pharmacokinetic-pharmacodynamic modeling of antimicrobial drug effects

Mathematical modeling of drug effects maximizes the information gained from an experiment, provides further insight into the mechanisms of drug effects, and allows for simulations in order to design studies or even to derive clinical treatment strategies. We reviewed modeling of antimicrobial drug effects and show that most of the published mathematical models can be derived from one common mechanism-based PK-PD model premised on cell growth and cell killing processes. The general sigmoid Emax model applies to cell killing and the various parameters can be related to common pharmacodynamics, which enabled us to synthesize and compare the different parameter estimates for a total of 24 antimicrobial drugs from published literature. Furthermore, the common model allows the parameters of these models to be related to the MIC and to a common set of PK-PD indices. Theoretically, a high Hill coefficient and a low maximum kill rate indicate so-called time-dependent antimicrobial effects, whereas a low Hill coefficient and a high maximum kill rate indicate so-called concentration- dependent effects, as illustrated in the garenoxacin and meropenem examples. Finally, a new equation predicting the time to microorganism eradication after repeated drug doses was derived that is based on the area under the kill-rate curve.