title: In vivo pharmacodynamic profiling of doripenem against Pseudomonas aeruginosa by 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.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT 06102, USA.
authors.forename: Aryun
authors.initials: A
authors.lastname: Kim
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Banevicius
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D000077726:Doripenem; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem