The dissertation entitled
In vitro and in vivo pharmacokinetic/pharmacodynamic evaluation of
Will be presented on September 21, 2018 in partial fulfillment
of the requirements for the Degree of Doctor of Philosophy of the University of Poitiers
Committee : Pr. William COUET (Thesis Supervisor), Dr. Nicolas GREGOIRE,
Pr. France MENTRE, Pr. Peggy GANDIA, Dr. Marylore CHENEL,
Dr. Shampa DAS, Dr. Bruno FRANÇOIS, Pr. Sandrine MARCHAND
This PhD project was part of IMI – COMBACT-CARE
The rapid increase in antibiotic resistance during the last decades and the few numbers of recently approved new antibiotics lead to a significant interest to drug combinations. Among these combinations, the β-lactam-β-lactamase inhibitor combination, such as aztreonam-avibactam (ATM-AVI), is one strategy that aims to overcome the resistance due to β-lactamases production, one of the most relevant mechanisms of resistance in Gram-negative bacteria. However, drug interactions can be complex. To better understand the PK/PD of ATM-AVI, two issues have been addressed in this thesis:
- ATM-AVI PK at the infection site. A microdialysis study performed in rats with or without peritonitis showed that ATM and AVI distribution in intraperitoneal fluid was rapid and that concentrations at the target site could be predicted from blood concentrations.
- PD interaction between ATM and AVI. Checkerboard experiments analyzed with an Emax model have been used to characterize AVI effect on ATM MIC in terms of efficacy and potency in the presence of various multi-drug resistant strains. A PK/PD model was developed based on in vitro data to describe the time-course of ATM-AVI combined effect and to investigate the individual contribution of each of the AVI effects to the combined activity. According to the modeling results, the combined bactericidal activity was mainly explained by AVI enhancing effect, even though AVI demonstrated high efficiency to prevent ATM hydrolysis.