Abstract

AIMS: Beta-lactam dose optimisation in critical care is a current priority. We aimed to review the PK of three commonly used beta-lactams (amoxicillin+/-clavulanate, piperacillin-tazobactam and meropenem) to compare PK parameters reported in critically and non-critically ill neonates, children and adults, and to investigate whether allometric and maturation scaling principles could be applied to describe changes in PK parameters through life. METHODS: A systematic review of PK studies of the three drugs was undertaken using MEDLINE and EMBASE. Pharmacokinetic parameters and summary statistics were extracted and scaled using allometric principles to 70 kg individual for comparison. Pooled data was used to model clearance maturation and decline using a sigmoidal (Hill) function. RESULTS: A total of 130 papers were identified. Age ranged from 29 weeks-82 years and weight from 0.9-200 kg. PK parameters from critically ill populations were reported with wider confidence intervals than those in healthy volunteers, indicating greater PK variability in critical illness. The standard allometric size and sigmoidal maturation model adequately described increasing clearance in neonates and a sigmoidal model was also used to describe decline in older age. Adult weight-adjusted clearance was achieved at approximately 2 years post menstrual age. Changes in volume of distribution were well described by the standard allometric model, although amoxicillin data suggested a relatively higher volume of distribution in neonates. CONCLUSIONS: Critical illness is associated with greater PK variability than in healthy volunteers. The maturation models presented will be useful for optimising beta-lactam dosing, although a prospective, age-inclusive study is warranted for external validation.