Pharmacokinetic/pharmacodynamic model-based optimization of temocillin dosing strategies for the treatment of systemic infections.

Abstract

Temocillin is increasingly considered as an alternative to carbapenems. However, there is no consensus on optimal dosing strategies and limited data on temocillin efficacy in systemic infections. We compared temocillin dosing strategies using pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation based on plasma exposure and in vitro time-kill data. Temocillin effects on four Escherichia coli strains were evaluated using static time-kill experiments and the hollow-fibre infection model, in which unbound plasma concentrations following intermittent and continuous infusion regimens of 4 and 6 g daily were replicated over 72 h. A PK/PD model was developed to describe the time-kill data. The PK/PD model was coupled to a population PK model of temocillin in critically ill patients to predict bacterial killing and resistance development following various dosing regimens. Amplification of resistant subpopulations was observed within 24 h for all strains. The PK/PD model described the observed bacterial kill kinetics and resistance development from both experimental systems well. Simulations indicated dose-dependent bacterial killing within and beyond the currently used daily dose range, and a superiority of continuous compared with intermittent infusions. However, regrowth of resistant subpopulations was frequently observed. For two strains, bacteriostasis over 72 h was predicted only with doses that are higher than those currently licensed. Continuous infusions and 6 g daily doses of temocillin kill E. coli more effectively than 4 g daily doses and intermittent infusions, and may increase efficacy in the treatment of systemic infections. However, higher daily doses may be required to suppress resistance development.