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

Abstract

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 log ₁₀ 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), fC _max /MIC (the ratio of the maximum concentration of f to the MIC), and f AUC/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% (EI ₈₀ ) and 50% (EI ₅₀ ) for f AUC/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 f AUC/MIC exposures tested (1.8 to 8.8 μg/ml). The f AUC/MIC ratio is the pharmacodynamic parameter most predictive of tigecycline efficacy. Furthermore, the presence of a functioning immune system markedly reduces the required exposure.