title: Individualization of piperacillin dosing for critically ill patients: dosing software to optimize antimicrobial therapy.
abstract: Piperacillin-tazobactam is frequently used for empirical and targeted therapy of infections in critically ill patients. Considerable pharmacokinetic (PK) variability is observed in critically ill patients. By estimating an individual's PK, dosage optimization Bayesian estimation techniques can be used to calculate the appropriate piperacillin regimen to achieve desired drug exposure targets. The aim of this study was to establish a population PK model for piperacillin in critically ill patients and then analyze the performance of the model in the dose optimization software program BestDose. Linear, with estimated creatinine clearance and weight as covariates, Michaelis-Menten (MM) and parallel linear/MM structural models were fitted to the data from 146 critically ill patients with nosocomial infection. Piperacillin concentrations measured in the first dosing interval, from each of 8 additional individuals, combined with the population model were embedded into the dose optimization software. The impact of the number of observations was assessed. Precision was assessed by (i) the predicted piperacillin dosage and by (ii) linear regression of the observed-versus-predicted piperacillin concentrations from the second 24 h of treatment. We found that a linear clearance model with creatinine clearance and weight as covariates for drug clearance and volume of distribution, respectively, best described the observed data. When there were at least two observed piperacillin concentrations, the dose optimization software predicted a mean piperacillin dosage of 4.02 g in the 8 patients administered piperacillin doses of 4.00 g. Linear regression of the observed-versus-predicted piperacillin concentrations for 8 individuals after 24 h of piperacillin dosing demonstrated an r(2) of >0.89. In conclusion, for most critically ill patients, individualized piperacillin regimens delivering a target serum piperacillin concentration is achievable. Further validation of the dosage optimization software in a clinical trial is required.
authors.affiliation: The University of Manchester, Manchester Academic Health Science Centre, NIHR Clinical Research Facility in Respiratory Medicine, University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: T W
authors.initials: TW
authors.lastname: Felton
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane and Royal Brisbane and Women's Hospital Brisbane, Queensland, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Roberts
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, New York, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Lodise
authors.affiliation: Laboratory of Applied Pharmacokinetics, University of Southern California, School of Medicine, Los Angeles, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: Van Guilder
authors.affiliation: Department of Anaesthesiology and Intensive Care, Édouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.
authors.forename: E
authors.initials: E
authors.lastname: Boselli
authors.affiliation: Laboratory of Applied Pharmacokinetics, University of Southern California, School of Medicine, Los Angeles, California, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Neely
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom william.hope@liverpool.ac.uk.
authors.forename: W W
authors.initials: WW
authors.lastname: Hope
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D001499:Bayes Theorem; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D016638:Critical Illness / Q000628:therapy*; D054796:Drug Dosage Calculations; D004360:Drug Therapy, Computer-Assisted; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077725:Piperacillin, Tazobactam Drug Combination; D057285:Precision Medicine / Q000379:methods*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D003404:Creatinine; D010878:Piperacillin