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

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.

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients.

Our objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n = 6) and morbidly obese (n = 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m2, respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment (Vc) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of >30 kg/m2 A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.