Piperacillin pharmacokinetics and pharmacodynamics in paediatric patients who received high frequency intra-operative piperacillin/tazobactam dosing.

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 surgery, including liver transplant. The data supporting the guidelines for intra-operative dosing are sparse and the pharmacokinetics/pharmacodynamics (PK/PD) of q2h dosing has not been studied by simulation or in humans. In this study, PK/PD parameters of high-frequency intra-operative dosing and q6h post-operative dosing were compared in critically ill children. Paediatric patients who received PTZ during complex abdominal surgery or transplant 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. Alternative post-operative dosing strategies were simulated using the patients with the highest and lowest estimated piperacillin clearance. Thirteen patients were included (median age: 3.1 years, 85% liver transplant recipients). PK parameters in the 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, whereas central volume intra-operative values were -40% to 77% of the post-operative values. Intra-operative piperacillin exposure was higher during high-frequency dosing compared with the post-operative period (AUC/h: 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 minimise toxicity and maximise efficacy, indicating a role for individualised dosing in paediatric surgical populations.