In vivo infection models in the pre-clinical pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents
Introduction
The goal of both preclinical and clinical antimicrobial PK/PD investigation is to improve the probability of a positive therapeutic outcome. The premise underlying the PK/PD field of study is that there is an optimal drug exposure for efficacy and safety. Antimicrobial PK/PD traditionally links drug pharmacokinetics and a measure of potency in vitro (the minimum inhibitory concentration or MIC) to efficacy [1, 2•]. Animal infection models have been used to answer two key questions regarding pharmacokinetic optimization. First, which pharmacokinetic index is the strongest driver of efficacy, or simply put, how often do I need to administer the drug? Second, what is the PK/PD target, or how much drug do I need for effect? These PK/PD questions have been addressed using several animal infection models. However, the neutropenic mouse thigh and lung infection models are the traditional ‘work-horse’ models in the PK/PD field. The models represent relatively faithful mimics of soft tissue infection/sepsis and pneumonia, respectively [3]. When immunocompromised via neutropenia, most bacteria are pathogenic in the infection models. Organism burden, measured as number of colony forming units (CFU), at the site of infection provides a relatively reproducible measure of antibiotic effect that has accurately forecasted efficacy in patients. A variety of host, pharmacokinetic, and microorganism factors impact model performance and data interpretation. We discuss these study design variables and output assessment below.
Section snippets
Defining the PK/PD index
PK/PD studies have shown that antibiotics can be divided into two major groups: [1] those that exhibit concentration-dependent killing and prolonged persistent effects (e.g. aminoglycosides, fluoroquinolones), for which the area under the concentration–time curve (AUC) and peak concentration in relation to the MIC of the organism causing the infections (AUC/MIC and Cmax/MIC, respectively) are the PK/PD indices correlating with efficacy; [2•] those antibiotics that exhibit time-dependent killing
Identifying the PK/PD target
The goal of studies designed to discern the PK/PD target is to define the magnitude of PK measure relative to MIC needed for effect. We detail the approach to this question and highlight several experimental factors that can impact the determination of an accurate PK/PD target below.
Human translation and conclusions
The PK/PD index and target can be used in drug development to select treatment regimens for select indications as well as for guidance in preliminary susceptibility breakpoints. The latter can be particularly important for determining the likelihood of treatment success against emerging drug-resistance pathogens that are difficult to study in randomized clinical trials [6•, 27, 28, 29]. As noted above, there are two general categories of caveats to guide successful translation of animal model
Conflicts of interest
DA: Consultant and grant support — Astellas, Melinta, Actelion, Theravance, Zavante, Paratek, Cidara, Scynexis, Amplyx, Meiji, Geom.
AL: None.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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