title: 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.affiliation: Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut 06102, USA.
authors.forename: Jared L
authors.initials: JL
authors.lastname: Crandon
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Banevicius
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D019540:Area Under Curve; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D018482:Muscle, Skeletal / Q000382:microbiology; D013047:Specific Pathogen-Free Organisms; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000302:isolation & purification; D013848:Thigh; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline