In Vivo Pharmacodynamic Profiling of Doripenem againstPseudomonas aeruginosaby Simulating Human Exposures

Abstract

Doripenem is a new broad-spectrum carbapenem with activity against a range of gram-negative pathogens, including nonfermenting bacteria such as Pseudomonas aeruginosa. The objective of this study was to evaluate simulated human exposures to 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 500 mg doripenem every 8 h given as either a 1-h or 4-h intravenous infusion in humans. Maximal antibacterial killing was associated with doripenem exposures of > or =40% fT>MIC; bacteriostatic effects were noted at approximately 20% fT>MIC. The simulated 1-h infusion provided bactericidal effects for isolates with MICs of < or =2 microg/ml, while variable killing was noted for isolates with MICs of 4 to 8 microg/ml and regrowth for isolates with an MIC of 16 microg/ml. The 4-h infusion regimen displayed similar killing for isolates with MICs of < or =2 microg/ml and enhanced activity for two of the four isolates with an MIC of 4 microg/ml. Given that the 4-h regimen yields negligible fT>MIC for MICs of > or =8 microg/ml, regrowth was generally observed. Simulated doses of 500 mg doripenem every 8 h infused over 1 h demonstrated antibacterial killing for P. aeruginosa isolates with MICs of 0.125 to 8 microg/ml. Exposures of > or =40% fT>MIC resulted in the most pronounced bactericidal effects, while killing was variable for 20 to 30% fT>MIC. Infusing doses over 4 h enhanced efficacy against selected pseudomonal isolates with an MIC of 4 microg/ml.