title: Use of a clinically derived exposure-response relationship to evaluate potential tigecycline-Enterobacteriaceae susceptibility breakpoints.
abstract: Potential tigecycline-Enterobacteriaceae susceptibility breakpoints were evaluated using 2 approaches, which differed in the nature of the probabilities assessed by MIC value. Using a previously derived tigecycline population pharmacokinetic model and Monte Carlo simulation, a probability density function of steady-state area under the concentration-time curve for 24 h (AUC(SS(0-24))) values for 9999 patients was generated. AUC(SS(0-24)) values were divided by clinically relevant fixed MIC values to derive AUC(SS(0-24))/MIC ratios, which were used to calculate the clinical response expectation by MIC value based upon a logistic regression model for efficacy (1st approach). For the 2nd approach, the probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment was calculated as the proportion of patients with AUC(SS(0-24))/MIC ratios greater than the threshold value of 6.96, the PK-PD target associated with optimal clinical response. Probabilities of clinical response and PK-PD target attainment were poorly correlated at MIC values >0.25 mg/L. For instance, the median probability of clinical success was 0.76, whereas the probability of PK-PD target attainment was 0.27 at an MIC value of 1 mg/L, suggesting that the probability of PK-PD target attainment metrics underestimates the clinical performance of tigecycline at higher MIC values.
authors.affiliation: Institute for Clinical Pharmacodynamics, Ordway Research, Latham, NY, 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: Chris M
authors.initials: CM
authors.lastname: Rubino
authors.forename: Joan M
authors.initials: JM
authors.lastname: Korth-Bradley
authors.forename: Timothy
authors.initials: T
authors.lastname: Babinchak
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; D001499:Bayes Theorem; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004755:Enterobacteriaceae / Q000187:drug effects*; D004756:Enterobacteriaceae Infections / Q000188:drug therapy; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D008911:Minocycline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008954:Models, Biological; D009010:Monte Carlo Method; D017192:Skin Diseases, Bacterial / Q000188:drug therapy; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline