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 microg/ml for all isolates, except for HA-MRSA 56 (MIC, 0.5 microg/ml) and CA-MRSA 156 (MIC, 0.125 microg/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 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% (EI(80)) and 50% (EI(50)) for fAUC/MIC were 5.4 microg/ml (range, 2.8 to 13 microg/ml) and 2.6 microg/ml (range, 0.6 to 5.1 microg/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 microg/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.

• Authors: Jared L Crandon, Mary Anne Banevicius, David P Nicolau
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 53 Issue 3 Pg. 1165-9 (Mar 2009) ISSN: 1098-6596 [Electronic] United States
• PMID: 19114676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Tigecycline
• Minocycline

Topics

• Animals
• Anti-Bacterial Agents (pharmacokinetics, pharmacology, therapeutic use)
• Area Under Curve
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Half-Life
• Humans
• Methicillin-Resistant Staphylococcus aureus
• Mice
• Mice, Inbred ICR
• Microbial Sensitivity Tests
• Minocycline (analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
• Muscle, Skeletal (microbiology)
• Specific Pathogen-Free Organisms
• Staphylococcal Infections (drug therapy, microbiology)
• Staphylococcus aureus (drug effects, isolation & purification)
• Thigh
• Tigecycline