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 <= 4 mu g/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 mu g/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 >= 2 log decreases in CFU against isolates with MICs of <= 8 and 16 mu g/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 >= 16 mu g/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.