Pharmacokinetics and Pharmacodynamics of High-Dose Piperacillin–Tazobactam in Obese Patients

Background and Objective Standard piperacillin–tazobactam (P-T) dosing may be suboptimal in obesity, but high-dose regimens have not been studied. We prospectively evaluated the pharmacokinetics and pharmacodynamics of standard- and high-dose P-T in obese adult inpatients. Methods Those receiving standard-dose P-T with BMI ≥ 30 kg/m 2 weighing 105–139 kg or ≥ 140 kg were given up to 6.75 g or 9 g every 6 h, respectively. Patients were monitored closely for safety. Elimination phase blood samples were drawn for 28 patients on standard and high doses to calculate the pharmacokinetic values using a one-compartment model. The likelihood of pharmacodynamic target attainment (100% f T > 16/4 mg/L) on various P-T regimens was calculated using each patient’s own pharmacokinetic values. Results Piperacillin and tazobactam half-lives ranged from 0.5–10.6 to 0.9–15.0 h, while volumes of distribution ranged from 13.6–54.8 to 11.5–60.1 L, respectively. Predicted dose requirements for target attainment ranged from 2.25 g every 6 h in hemodialysis patients to a 27 g/24-h continuous infusion in a patient with a short P-T half-life. An amount of 4.5 g every 6 h would have met the target for only 1/12 (8%) patients with creatinine clearance ≥ 80 mL/min and 13/28 (46%) for all enrolled patients. One patient (3%) experienced an adverse event deemed probably related to high-dose P-T. Conclusion Some patients required high P-T doses for target attainment, but dosing requirements were highly variable. Doses up to 6.75 g or 9 g every 6 h may be tolerable; however, studies are needed to see if high dosing, prolonged infusions, or real-time therapeutic drug monitoring improves outcomes in obese patients. Clinical trial registration (clinicaltrials.gov) NCT01923363.