title: Application of patient population-derived pharmacokinetic-pharmacodynamic relationships to tigecycline breakpoint determination for staphylococci and streptococci.
abstract: Correctly determined susceptibility breakpoints are important to both the individual patient and to society at large. A previously derived patient population pharmacokinetic model and Monte Carlo simulation (9999 patients) were used to create a likelihood distribution of tigecycline exposure, as measured by the area under the concentration-time curve at 24 h (AUC(24)). Each resultant AUC(24) value was paired with a clinically relevant fixed MIC value ranging from 0.12 to 2 mg/L. For each AUC(24)-MIC pair, the probability of microbiologic response was calculated using an exposure-response relationship, which was derived from patients with complicated skin and skin structure infections that involved Staphylococcus aureus or streptococci or both. The median probability of microbiologic success was 94% or greater for MIC values up to and including 0.25 mg/L. The median probability of microbiologic success was 66% or less for MIC values of 0.5 mg/L or greater. These data support a susceptibility breakpoint of 0.25 mg/L for S. aureus and streptococci.
authors.affiliation: Institute for Clinical Pharmacodynamics, Ordway Research Institute, Latham, NY 12208, USA. pambrose-icpd@ordwayresearch.org
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
authors.forename: Alison K
authors.initials: AK
authors.lastname: Meagher
authors.forename: Julie A
authors.initials: JA
authors.lastname: Passarell
authors.forename: Scott A
authors.initials: SA
authors.lastname: Van Wart
authors.forename: Brenda B
authors.initials: BB
authors.lastname: Cirincione
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ellis-Grosse
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D003198:Computer Simulation; D006801:Humans; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008954:Models, Biological; D015233:Models, Statistical; D009010:Monte Carlo Method; D012372:ROC Curve; D012044:Regression Analysis; D017192:Skin Diseases, Bacterial / Q000188:drug therapy; D013207:Staphylococcal Skin Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects*; D013290:Streptococcal Infections / Q000188:drug therapy; D013291:Streptococcus / Q000187:drug effects*; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline