IN VIVO PHARMACODYNAMIC PROFILING OF DORIPENEM HUMAN SIMULATED EXPOSURES AGAINST PSEUDOMONAS AERUGINOSA

Center for Anti-Infective Research and Development, Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut, USA

^* To whom correspondence should be addressed. Email: dnicola{at}harthosp.org.

	Abstract

Doripenem is a new broad-spectrum carbapenem with activity against a scope of Gram-negative pathogens, including non-fermenting bacteria such as Pseudomonas aeruginosa. The objective of the study was to evaluate human simulated exposures of doripenem using a neutropenic murine thigh infection model against 24 clinical P. aeruginosa isolates with a wide range of MICs. Dosing regimens in mice were designed to approximate the free time above MIC (fT>MIC) observed with doripenem 500 mg every 8 h given as either a 1-h or 4-h intravenous infusion in humans. Maximal antibacterial kill was associated with doripenem exposures 40% fT>MIC; bacteriostatic effects were noted at 20% fT>MIC. The simulated 1-h infusion provided bactericidal effects for isolates with MICs 2 µg/mL, while variable kill was noted with MICs 4-8 µg/mL and regrowth for MIC 16 µg/mL. The 4-h infusion regimen displayed similar kill for MICs 2 µg/mL and enhanced activity for 2 of the 4 isolates with MIC 4 µg/mL. Given that the 4-h regimen yields negligible fT>MIC for MICs 8 µg/mL, regrowth was generally observed. Simulated doses of doripenem 500 mg every 8 h infused over 1 h demonstrated antibacterial kill for P. aeruginosa isolates with MICs 0.125-8 µg/mL. Exposures 40% fT>MIC resulted in the most pronounced bactericidal effects while kill was variable for 20-30% fT>MIC. Doses infused over 4 h enhanced efficacy against selected pseudomonal isolates with MIC 4 µg/mL.