Population pharmacokinetics of intravenous cefotaxime indicates that higher doses are required for critically ill children

Abstract

Background

Cefotaxime is frequently used in critically ill children, however pharmacokinetic (PK) studies to support adequate dosing in this patient population are limited.

Objectives

To characterize cefotaxime PK in critically ill children and evaluate exposures achieved by current and alternative dosing regimens.

Methods

Children (0–18 years) admitted to the paediatric ICU, receiving intravenous cefotaxime (100–150 mg/kg/day, interval 6–8 h) were included (Clinicaltrials.gov NCT03248349). Total plasma cefotaxime concentrations were measured on multiple study days. Population-PK analysis was performed using nonlinear mixed effects modelling (NONMEM™). Dose evaluations were performed using typical patients across the paediatric age range and target attainment was determined for MICs of 0.5, 2 and 4 mg/L.

Results

479 cefotaxime plasma concentrations from 52 children (median age 1.6, range 0.03–17.7 years) were used to describe cefotaxime PK. We describe a two-compartment structural model with interindividual variability, including bodyweight as covariate for volume of distribution and clearance. Model predicted exposure for 150 mg/kg/day (current dose) showed trough concentrations <0.5 mg/L in patients >4 years of age. The maximum cefotaxime doses (200 mg/kg/day, interval 6 h) proved adequate for MICs ≤0.5 mg/L across the whole age range. Similar daily doses with increased frequency (interval 4 h) covered MICs up to 2 mg/L, while a loading dose followed by continuous infusion regimens are needed to adequately treat MICs of 4 mg/L.

Conclusions

Higher cefotaxime doses are required for adequate exposure for most pathogens in critically ill children. A higher dose frequency or continuous infusion is advisable to improve target attainment for intermediately susceptible pathogens.