Abstract
Pharmacokinetic/pharmacodynamic (PK/PD) analysis has proved to be very useful to establish rational dosage regimens of antimicrobial agents in human and veterinary medicine. Actually, PK/PD studies are included in the European Medicines Agency (EMA) guidelines for the evaluation of medicinal products. The PK/PD approach implies the use of in vitro, ex vivo, and in vivo models, as well as mathematical models to describe the relationship between the kinetics and the dynamic to determine the optimal dosing regimens of antimicrobials, but also to establish susceptibility breakpoints, and prevention of resistance. The final goal is to optimize therapy in order to maximize efficacy and minimize side effects and emergence of resistance. In this review, we revise the PK/PD principles and the models to investigate the relationship between the PK and the PD of antibiotics. Additionally, we highlight the outstanding role of the PK/PD analysis at different levels, from the development and evaluation of new antibiotics to the optimization of the dosage regimens of currently available drugs, both for human and animal use.
Highlights
We present an overview of the PK/PD principles and the models to evaluate the relationship between the PK and the PD of antibiotics, including breakpoints establishment, susceptibility surveillance, therapeutic drug monitoring, and prediction of resistances
In a previous study using a tissue cage (TC) model in calves, the authors unexpectedly did not detect the effect of trimethoprim on E. coli, since the high levels of thymidine were enough to antagonize the antibacterial effect of the antimicrobial [33]
This review outlines the current state of the art of the PK/PD analysis in the development and evaluation of antimicrobials
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Different models, including in vitro, ex vivo, and in vivo, have been developed to establish the relationship between the PK and the PD of antimicrobials, and one of the main applications is to design dosing strategies to enhance the probability of success of the antibiotic therapy, as well as minimize the side effects and the emergence of resistances [9]. To assure the quality of drugs, the European Medicines Agency (EMA) and its Committee for Medicinal Products for Human Use (CHMP) provide guidelines for the evaluation of medicinal products, which in the area of antibacterial agents include microbiological research, studies in animals, PK/PD investigations, and clinical trials [17,18]. Preclinical models require robust indicators for antibacterial activity in humans, and their results are very useful to optimize dose regimens for efficacy and prevention of resistance [5]. A description of these methods, with the main advantages and disadvantages is included
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