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Antimicrobial Agents and Chemotherapy, July 2008, p. 2497-2502, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.01252-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vivo Pharmacodynamic Profiling of Doripenem against Pseudomonas aeruginosa by Simulating Human Exposures{triangledown}

Aryun Kim,1 Mary Anne Banevicius,1 and David P. Nicolau1,2*

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

Received 25 September 2007/ Returned for modification 17 December 2007/ Accepted 30 April 2008

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 ≥40% fT>MIC; bacteriostatic effects were noted at {approx}20% fT>MIC. The simulated 1-h infusion provided bactericidal effects for isolates with MICs of ≤2 µg/ml, while variable killing was noted for isolates with MICs of 4 to 8 µg/ml and regrowth for isolates with an MIC of 16 µg/ml. The 4-h infusion regimen displayed similar killing for isolates with MICs of ≤2 µg/ml and enhanced activity for two of the four isolates with an MIC of 4 µg/ml. Given that the 4-h regimen yields negligible fT>MIC for MICs of ≥8 µg/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 µg/ml. Exposures of ≥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 µg/ml.

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

{triangledown} Published ahead of print on 5 May 2008.

Antimicrobial Agents and Chemotherapy, July 2008, p. 2497-2502, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.01252-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Crandon, J. L., Bulik, C. C., Nicolau, D. P. (2009). In Vivo Efficacy of 1- and 2-Gram Human Simulated Prolonged Infusions of Doripenem against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 53: 4352-4356 [Abstract] [Full Text]  
  • Cirillo, I., Vaccaro, N., Turner, K., Solanki, B., Natarajan, J., Redman, R. (2009). Pharmacokinetics, Safety, and Tolerability of Doripenem After 0.5-, 1-, and 4-Hour Infusions in Healthy Volunteers. J Clin Pharmacol 49: 798-806 [Abstract] [Full Text]  
  • Wagenlehner, F. M. E., Wagenlehner, C., Redman, R., Weidner, W., Naber, K. G. (2009). Urinary Bactericidal Activity of Doripenem versus That of Levofloxacin in Patients with Complicated Urinary Tract Infections or Pyelonephritis. Antimicrob. Agents Chemother. 53: 1567-1573 [Abstract] [Full Text]  


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