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Antimicrobial Agents and Chemotherapy, March 2009, p. 1165-1169, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.00647-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Pharmacodynamics of Tigecycline against Phenotypically Diverse Staphylococcus aureus Isolates in a Murine Thigh Model {triangledown}

Jared L. Crandon,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 16 May 2008/ Returned for modification 23 June 2008/ Accepted 20 December 2008

Tigecycline is a currently marketed antimicrobial agent with activity against resistant gram-positive cocci, including methicillin-resistant Staphylococcus aureus (MRSA). Despite the proven efficacy of tigecycline in the treatment of infections caused by these pathogens, questions remain as to the exposure-response relationship best associated with its efficacy. The purpose of this study was to define this relationship against seven distinct S. aureus isolates by using a neutropenic murine thigh model. Single-dose pharmacokinetics were evaluated, and free drug exposures were calculated after determination of protein binding. Doses of 1.56 to 400 mg/kg of body weight divided 1 to 8 times daily were administered against two methicillin-susceptible S. aureus isolates, two hospital-associated MRSA (HA-MRSA) isolates, and three community-associated (CA-MRSA) isolates. Tigecycline pharmacokinetics were best described by a two-compartment model, with a mean half-life of 9.9 h. Protein binding was dose dependent (range, 92.9 to 81.2%). MICs were 0.25 µg/ml for all isolates, except for HA-MRSA 56 (MIC, 0.5 µg/ml) and CA-MRSA 156 (MIC, 0.125 µg/ml). Tigecycline displayed efficacy against all isolates, producing maximum decreases in log10 numbers of CFU/ml of 1.8 to 2.3 from 0-h controls. Mean correlation coefficients for free-drug (f) concentration exposures derived from the parameters fT>MIC (the percentage of time during which the concentration of f remains above the MIC), fCmax/MIC (the ratio of the maximum concentration of f to the MIC), and fAUC/MIC (the ratio of the area under the concentration-time curve of f to the MIC) were 0.622, 0.812, and 0.958, respectively. Values for the mean effective exposure index at 80% (EI80) and 50% (EI50) for fAUC/MIC were 5.4 µg/ml (range, 2.8 to 13 µg/ml) and 2.6 µg/ml (range, 0.6 to 5.1 µg/ml), respectively. Experiments with nonneutropenic mice infected with CA-MRSA 156 resulted in maximum kill at all fAUC/MIC exposures tested (1.8 to 8.8 µg/ml). The fAUC/MIC ratio is the pharmacodynamic parameter most predictive of tigecycline efficacy. Furthermore, the presence of a functioning immune system markedly reduces the required exposure.

* 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 29 December 2008.

Antimicrobial Agents and Chemotherapy, March 2009, p. 1165-1169, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.00647-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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