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

John J Veillette, S Alexander Winans, Victoria K Maskiewicz, James Truong, Ronald N Jones, Steven C Forland, John J Veillette, S Alexander Winans, Victoria K Maskiewicz, James Truong, Ronald N Jones, Steven C Forland

Abstract

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/m2 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% fT > 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.

Conflict of interest statement

The authors have no conflicts of interest or financial involvements to disclose.

Figures

Fig. 1
Fig. 1
Predicted free piperacillin steady-state trough concentrations for the same patients on two different dosing regimens: Piperacillin–tazobactam (P-T) 4.5 g every 6 h infused over 30 min (filled circle), and P-T 9 g every 6 h infused over 3 h (open triangle). Creatinine clearance (CrCl) was calculated via the Cockcroft-Gault equation using a lean body weight estimate formula. The three hemodialysis patients were assigned an arbitrary CrCl of 5 mL/min due to inability to calculate an accurate CrCl. MIC minimum inhibitory concentration

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