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.

Evaluating a tylosin dosage regimen for treatment of Staphylococcus delphini infection in mink (Neovison vison): a pharmacokinetic-pharmacodynamic approach

“…We selected the one-log 10 reduction of the initial bacterial concentration as a relevant endpoint of efficacy for the in vivo situation to estimate the PKPD target. This is a univocal efficacy endpoint that is targeted in human medicine [ 37 ]. The estimated f AUC po,0−24 h /MIC for bacteriostatic and bactericidal effects was 48.9 and 98.7 h, respectively.…”

The Role of PK/PD Analysis in the Development and Evaluation of Antimicrobials

“…The organisms should be representative of those most relevant to the intended clinical uses and should exhibit MICs of the test agent that include values at the upper end of the wild-type distribution. The PK/PD model methods fell into three categories: In vitro, ex vivo, and in vivo [20,21], and they must be regarded as complementary. A description of these methods, with the main advantages and disadvantages is included in this section.…”

“…This model consists of perforated cylinder, tubes or spheres, implanted in subcutaneous tissues. After implantation (3 to 4 weeks), the granulation tissue surrounds and partially fills the cage, the remainder being filled with an interstitial fluid which can be inflamed with carrageenan (to produce a sterile exudate), infected (inoculated septic exudate) or not (transudate), allowing antimicrobial action to be monitored as a local, isolated infection [21]. TCs are, actually, test tubes implanted into the animal, enabling ethically accepted sequential sampling.…”

“…The PK/PD approach was firstly applied in veterinary medicine in the 1990s [21,134,135]. Since then, many research studies have been published PK/PD in the veterinary field.…”

“…As with the chemostat, the HFIM allows simulation of a range of drug disposition profiles and bacteria loads. A major advantage over other in vitro methods is that the duration of the experiments is virtually unlimited [26], and durations up to several weeks have been published for Mycobacterium tuberculosis [21,27]. As experiments may last long periods, this method allows evaluating the relationship between drug exposure and resistance development.…”