Dose optimization of piperacillin/tazobactam in critically ill children

作者：De Cock Pieter A J G; van Dijkman Sven C; de Jaeger Annick; Willems Jef; Carlier Mieke; Verstraete Alain G; Delanghe Joris R; Robays Hugo; Vande Walle Johan; Della Pasqua Oscar E; De Paepe Peter

来源：Journal of Antimicrobial Chemotherapy, 2017, 72(7): 2002-2011.

DOI：10.1093/jac/dkx093

Objectives: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen.
Patients and methods: This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling.
Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% fT(> MIC) > 16 mg/L).
Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children > 2 months of age.

• 出版日期2017-7