Abstract
Sepsis plays a fundamental role in the alteration of the pharmacokinetics (PK) of anti-infection agents, responsible in particular for a risk of under or overdose in intensive care patients which can lead to therapeutic failure. Understanding the PK variability of anti-infectives is essential to provide an adequate initial dosing regimens. Furthermore, the development of an animal model of sepsis would improve our understanding of the PK alterations of anti-infection agents induced by septic shock.The aim of this thesis project is to evaluate the capacity of the porcine model of sepsis to predict the PK of anti-infectives in humans. Thus, the study of already known anti-infection agents would enable to confirm its transposition to humans. Echinocandins, which are the first-line treatment for fungal infections, are at the center of this project. Preliminary studies in intensive care patients were first conducted in order to improve our knowledge of their PK in particular situations, such as the use of renal replacement therapy and in the case of secondary peritonitis, where the peritoneal diffusion of echinocandins is decisive to eradicate fungal infections. Finally, the PK of micafungin was studied in a porcine septic model whose physiology is very close to that of humans, in order to compare it with that found in septic patients. These studies were performed using population-based modeling.This work has highlighted the need to increase the dosing regimens of echinocandins in intensive care patients under threat of therapeutic failure. Renal replacement therapy, on the other hand, do not alter the PK of echinocandins. Diffusion into the peritoneal cavity, a frequent infectious site of Candida species, is moderate for these echinocandins but would be sufficient to eradicate fungal infections given the CLSI breakpoints. Finally, the PK of micafungin is similar between the septic pig model and septic patients considering an allometric relationship of the body weight of these species on the central volume of distribution of micafungin. These encouraging results tend to justify the transposability of the pig model to septic patients. If this hypothesis is correct, the porcine septic model would be used to study new anti-infective agents in the preclinical phases, in order to estimate an adequate initial dosing regimens in intensive care patients.