title: Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients.
abstract: The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma samples were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean ± standard deviation age, weight, and BMI were 50 ± 15 years, 104 ± 35 kg, and 38.0 ± 15.0 kg/m2, respectively. The concentration-time data were best described by a two-compartment linear model. The mean ± SD parameter estimates for the final covariate model were a clearance of 14.0 ± 7.1 liters/h, a volume of distribution of the central compartment of 49.0 ± 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 ± 0.6 liters · h-1, and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 ± 2.8 liters · h-1A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations.
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.|Department of Pharmacy, King Saud Medical City, Riyadh, Saudi Arabia.
authors.forename: Abdulaziz S
authors.initials: AS
authors.lastname: Alobaid
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Jarrett
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Therese
authors.initials: T
authors.lastname: Starr
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Janine
authors.initials: J
authors.lastname: Stuart
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lassig-Smith
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Jenny Lisette Ordóñez
authors.initials: JL
authors.lastname: Mejia
authors.affiliation: Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Roberts
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.|Department of Anesthesiology, Critical Care Pain, and Emergency Medicine, Nimes University Hospital, Nimes, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Roger
authors.affiliation: Department of Intensive Care and Hyperbaric Medicine, The Alfred, Prahran, Melbourne, Victoria, Australia.|Department of Epidemiology and Preventive Medicine, The Alfred, Monash University, Prahran, Melbourne, Victoria, Australia.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Udy
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.|Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.|Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia j.roberts2@uq.edu.au.|Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.|Centre for Translational Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D001682:Biological Availability; D015992:Body Mass Index; D003404:Creatinine / Q000097:blood; D016638:Critical Illness; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D009767:Obesity, Morbid / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D010878:Piperacillin / Q000097:blood / Q000493:pharmacokinetics*; D000077725:Piperacillin, Tazobactam Drug Combination
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D003404:Creatinine; D010878:Piperacillin
keywords: antibiotics; creatinine clearance; dosing; morbid obesity; pharmacodynamics; pharmacokinetics