title: A need to revisit clinical breakpoints of tigecycline: effect of atypical non-linear plasma protein binding.
abstract: Tigecycline is highly active against various drug-resistant bacteria. The US Food and Drug Administration (FDA) recently issued a black box warning for tigecycline owing to an associated increase in all-cause mortality. Clinical breakpoints of antibiotics are vital in susceptibility testing of pathogens for the selection of antibiotic therapy; however, no consensus exists between different committees on the clinical breakpoints of tigecycline. Of note, tigecycline exhibits atypical non-linear plasma protein binding (PPB) behaviour, and the pivotal probability of target attainment (PTA) analysis for the determination of clinical breakpoints did not account for the PPB of tigecycline. In this work, the PTA analysis was performed with consideration of atypical non-linear PPB behaviour of tigecycline. A model describing atypical non-linear PPB was developed and validated. Monte Carlo simulations were performed to determine the target ratio of area under the free drug concentration-time curve to minimum inhibitory concentration (fAUC/MIC) for Escherichia coli and, subsequently, PTA analyses were performed. The target fAUC/MIC ratio for E. coli was determined as 2.05, whilst the target AUC/MIC ratio was 6.96. The PTA analyses suggest a lower clinical breakpoint of tigecycline against E. coli. This finding suggests that there is a need to revisit the current clinical breakpoints of tigecycline.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Ravi Shankar Prasad
authors.initials: RSP
authors.lastname: Singh
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Jatinder Kaur
authors.initials: JK
authors.lastname: Mukker
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Stefanie K
authors.initials: SK
authors.lastname: Drescher
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Amelia N
authors.initials: AN
authors.lastname: Deitchman
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA. Electronic address: hartmut@cop.ufl.edu.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism*; D004926:Escherichia coli; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D008962:Models, Theoretical; D009010:Monte Carlo Method; D011485:Protein Binding; D000078304:Tigecycline
chemical_list: D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D000078304:Tigecycline; D008911:Minocycline
keywords: Antibacterial; Atypical non-linear plasma protein binding model; Mortality risk; Pharmacodynamic index; Probability of target attainment