Use of a clinically derived exposure–response relationship to evaluate potential tigecycline-Enterobacteriaceae susceptibility breakpoints

• Published in: Diagnostic microbiology and infectious disease 2009-01, Vol.63 (1), p.38-42
• Main Authors: Ambrose, Paul G, Meagher, Alison K, Passarell, Julie A, Wart, Scott A. Van, Cirincione, Brenda B, Rubino, Chris M, Korth-Bradley, Joan M, Babinchak, Timothy, Ellis-Grosse, Evelyn
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - therapeutic use; Area Under Curve; Bacteriology; Bayes Theorem; Biological and medical sciences; Computer Simulation; Dose-Response Relationship, Drug; Enterobacteriaceae; Enterobacteriaceae - drug effects; Enterobacteriaceae Infections - drug therapy; Female; Fundamental and applied biological sciences. Psychology; Humans; Infectious Disease; Infectious diseases; Internal Medicine; Logistic Models; Male; Medical sciences; Microbial Sensitivity Tests - methods; Microbiology; Minocycline - analogs & derivatives; Minocycline - pharmacokinetics; Minocycline - therapeutic use; Miscellaneous; Models, Biological; Monte Carlo Method; Pharmacokinetic–pharmacodynamic; Skin Diseases, Bacterial - drug therapy; Susceptibility breakpoints; Tigecycline
• ISSN: 0732-8893; 1879-0070
• DOI: 10.1016/j.diagmicrobio.2008.09.014

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 (AUCSS(0-24) ) values for 9999 patients was generated. AUCSS(0-24) values were divided by clinically relevant fixed MIC values to derive AUCSS(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 AUCSS(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.