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Antimicrobial Agents and Chemotherapy, October 2009, p. 4352-4356, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00282-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

In Vivo Efficacy of 1- and 2-Gram Human Simulated Prolonged Infusions of Doripenem against Pseudomonas aeruginosa{triangledown}

Jared L. Crandon,1 Catharine C. Bulik,1 and David P. Nicolau1,2*

Center for Anti-Infective Research and Development,1 Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut2

Received 2 March 2009/ Returned for modification 18 May 2009/ Accepted 14 June 2009

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 µg/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 µg/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 µg/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 µg/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.

* Corresponding author. Mailing address: Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102. Phone: (860) 545-3941. Fax: (860) 545-3992. E-mail: dnicola{at}harthosp.org

{triangledown} Published ahead of print on 21 September 2009.

Antimicrobial Agents and Chemotherapy, October 2009, p. 4352-4356, Vol. 53, No. 10
0066-4804/09/$08.00+0     doi:10.1128/AAC.00282-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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