The pharmacokinetic/pharmacodynamic paradigm for antimicrobial drugs in veterinary medicine: Recent advances and critical appraisal

Abstract

Pharmacokinetic/pharmacodynamic (PK/PD) modelling is the initial step in the semi-mechanistic approach for optimizing dosage regimens for systemically acting antimicrobial drugs (AMDs). Numerical values of PK/PD indices are used to predict dose and dosing interval on a rational basis followed by confirmation in clinical trials. The value of PK/PD indices lies in their universal applicability amongst animal species. Two PK/PD indices are routinely used in veterinary medicine, the ratio of the area under the curve of the free drug plasma concentration to the minimum inhibitory concentration (MIC) (fAUC/MIC) and the time that free plasma concentration exceeds the MIC over the dosing interval (fT > MIC). The basic concepts of PK/PD modelling of AMDs were established some 20 years ago. Earlier studies have been reviewed previously and are not reconsidered in this review. This review describes and provides a critical appraisal of more recent, advanced PK/PD approaches, with particular reference to their application in veterinary medicine. Also discussed are some hypotheses and new areas for future developments. First, a brief overview of PK/PD principles is presented as the basis for then reviewing more advanced mechanistic considerations on the precise nature of selected indices. Then, several new approaches to selecting PK/PD indices and establishing their numerical values are reviewed, including (a) the modelling of time–kill curves and (b) the use of population PK investigations. PK/PD indices can be used for dose determination, and they are required to establish clinical breakpoints for antimicrobial susceptibility testing. A particular consideration is given to the precise nature of MIC, because it is pivotal in establishing PK/PD indices, explaining that it is not a “pharmacodynamic parameter” in the usual sense of this term.