Population Pharmacokinetics of Piperacillin-Tazobactam in Children’s Plasma and Cerebrospinal Fluid Across a Wide Spectrum of Childhood Ages

Introduction: Piperacillin-tazobactam is a combined β-lactam and β-lactamase inhibitor with broad spectrum and time-dependent antibacterial activity commonly prescribed in children. Despite there were several paediatric population pharmacokinetic (PPK) studies, PPK studies on cerebrospinal fluid (CSF) are still in absence. As a time-dependent β-lactam antibacterial agent, if prolonged infusions improve the target attainments also need further exploration.

Aims: To 1) develop a population pharmacokinetic model to describe the time-course of piperacillin and tazobactam in both plasma and CSF of children; 2) evaluate the antibacterial effect in CSF; 3) to define an optimised dosing regimen for children.

Methods: Retrospective piperacillin-tazobactam therapeutic drug monitoring data from Royal Children’s Hospital was analysed using NONMEM. Population pharmacokinetic parameter and data approach was applied. Monte Carlo simulations were performed to assess the target attainments with various dosing regimens, including intermittent and extended infusions.

Results: 113 plasma samples and 7 CSF samples were collected from 105 children with a median (range) age of 6.4 years (0.01-17.3). A two-compartment model with first-order elimination could jointly describe the concentration of piperacillin and tazobactam in plasma and CSF. A maturation function was used to describe the maturation of renal function [1]. Serum creatinine (SCR) and weight were significant covariates of clearance (CL). The concentration of piperacillin in CSF is 3.3% of the free concentration in plasma. When the target was 75% fT > MIC, the PK/PD cutoff of intermittent infusion was less than 1 mg/L while that of extended infusion was 4 mg/L.

Conclusions: Piperacillin-tazobactam may not exert the antibacterial effect in CSF. Extended infusion could improve the target attainment significantly.


[1] Lonsdale DO, Kipper K, Baker EH, et al. β-Lactam antimicrobial pharmacokinetics and target attainment in critically ill patients aged 1 day to 90 years: the ABDose study. J Antimicrob Chemother. 2020;75(12):3625-3634.