Piperacillin Pharmacokinetics and Pharmacodynamics in Paediatric Patients Who Received High Frequency Piperacillin/Tazobactam Dosing Intra-Operatively.

Piperacillin/tazobactam (PTZ) is a broad-spectrum antibiotic, typically dosed every six hours (q6h). Guidelines recommend dosing PTZ every 2 hours (q2h) intra-operatively for complex abdominal surgeries, including liver transplant. The data supporting the guidelines for intra-operative dosing are sparse and the pharmacokinetics/pharmacodynamics (PK/PD) of q2h dosing has never been studied by simulation or in humans. We compared PK/PD parameters of high-frequency intra-operative dosing and q6h post-operative dosing in critically ill children. Paediatric patients who received PTZ during complex abdominal surgery or transplants and who had intra-operative and post-operative opportunistic samples were included. Using a published PK model and observed concentrations, individual piperacillin PK/PD parameters were estimated using Bayesian estimation. We simulated alternative postoperative dosing strategies using the patients with the highest and lowest estimated piperacillin clearance. Thirteen patients were included (median age: 3.1 years, 85% liver transplant). PK parameters between intra-operative and post-operative phases were not significantly different (clearance: 15.8 +/- 7.2 vs. 12.6 +/- 6.3 L/h/70 kg, p =0.070; central volume: 13.4 [13.1, 13.8] vs 15.2 [12.2, 16.0] L/70 kg, p=0.22). At an individual level, intra-operative clearance values were -35% to 139% of the post-operative values, while central volume intra-operative values were -40% to 77% of the post-operative values. Intra-operative piperacillin exposures were higher during high-frequency dosing compared to the post-operative period (AUC/hour: 109 [93.4, 127] vs. 62.8 [41.6, 78.3] mg/L, p=0.002). Simulations showed great variation in optimal dosing strategies that would minimize toxicity and maximize efficacy, demonstrating a role for individualized dosing in paediatric surgical populations.