In vivo efficacy of 1- and 2-gram human simulated prolonged infusions of doripenem against Pseudomonas aeruginosa.
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.
Crandon
Jared L
JL
Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT 06102, USA.
Bulik
Catharine C
CC
Nicolau
David P
DP
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
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem