title: In vivo efficacy of 1- and 2-gram human simulated prolonged infusions of doripenem against Pseudomonas aeruginosa.
abstract: Doripenem is a new carbapenem antimicrobial with activity against a range of gram-negative organisms, including Pseudomonas aeruginosa. Previous animal studies have shown efficacy of a 500-mg dose of doripenem given as a 4-h infusion against P. aeruginosa with MICs of < or = 4 microg/ml. The purpose of this study is to evaluate the efficacy of 1- and 2-g-dose prolonged infusions of doripenem against a wide range of P. aeruginosa isolates in the neutropenic murine thigh model. Eighteen clinical P. aeruginosa isolates (MIC range, 2 to 32 microg/ml) were used; 15 of these were multidrug resistant. After infection, groups of mice were administered doripenem doses designed to simulate the free time above the MIC (fT>MIC) observed in humans given 1 or 2 g of doripenem every 8 h as a 4-h infusion. Efficacy correlated well with published fT>MIC bactericidal targets of 40%. After 24 h, 1- and 2-g doses achieved approximately > or = 2 log decreases in CFU against isolates with MICs of < or = 8 and 16 microg/ml, respectively (fT>MIC range, 52.5 to 95%). Results with organisms with higher MICs, where fT>MIC was 0%, were variable, including both increases and decreases in CFU. Compared with 1-g doses, statistically greater efficacy was noted for 2-g doses against three of the eight isolates with MICs of > or =16 microg/ml. While MIC distributions of P. aeruginosa at present necessitate increased exposures for only the most-resistant isolates, the ability of increased doses to achieve pharmacodynamic targets and the efficacy observed when these targets were attained could prove useful when these resistant isolates are encountered.
authors.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT 06102, USA.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.forename: Catharine C
authors.initials: CC
authors.lastname: Bulik
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 / Q000627:therapeutic use*; D015780:Carbapenems / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077726:Doripenem; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D051379:Mice; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem