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Observational Study
. 2017 Feb 23;61(3):e01276-16.
doi: 10.1128/AAC.01276-16. Print 2017 Mar.

Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients

Abdulaziz S Alobaid  1   2 , Steven C Wallis  1 , Paul Jarrett  3 , Therese Starr  3 , Janine Stuart  3 , Melissa Lassig-Smith  3 , Jenny Lisette Ordóñez Mejia  1 , Michael S Roberts  4 , Claire Roger  1   5 , Andrew A Udy  6   7 , Jeffrey Lipman  1   3   8 , Jason A Roberts  9   3   10
Affiliations
Observational Study

Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients

Abdulaziz S Alobaid et al. Antimicrob Agents Chemother. .

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-1 A 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.

Keywords: antibiotics; creatinine clearance; dosing; morbid obesity; pharmacodynamics; pharmacokinetics.

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Figures

FIG 1
FIG 1
Diagnostic plots for the final population pharmacokinetic covariate model. (a) Observed piperacillin concentrations versus population predicted concentration (R2 = 0.653); (b) observed piperacillin concentrations versus individual predicted concentrations (R2 = 0.976); (c) visual predictive check. The median and 5th and 95th percentiles of simulated data with their respective 95% confidence intervals (CI; light gray fields) are shown. Individual points represent observed data. Inter, intercept.
FIG 2
FIG 2
Effect of BMI class on piperacillin clearance.
FIG 3
FIG 3
Effect of BMI class on the piperacillin volume of distribution of the central compartment.
See this image and copyright information in PMC

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