Do the redefined EUCAST susceptibility categories warrant adjustment of paediatric antibiotic dosages? Pragmatic physiologically based pharmacokinetic modelling of four commonly used agents

TL;DR

This study uses pharmacokinetic modeling to determine if pediatric antibiotic doses should be increased based on new EUCAST guidelines.

Contribution

The study evaluates the need for pediatric dose adjustments using PBPK modeling for four antibiotics under new EUCAST susceptibility categories.

Findings

Current pediatric doses result in higher antibiotic exposure than adult EUCAST 'I' doses.

Pediatric PTA varies by drug-microorganism combination and age.

No need to increase recommended pediatric doses for the tested antibiotics.

Abstract

With the redefinition of the EUCAST ‘I’ susceptibility category, from ‘intermediate’ to ‘susceptible, increased exposure’, the focus is now to use higher doses to treat infections of this category. These higher dosages in adults provided by EUCAST are fixed, yet it is uncertain whether a similar increase should apply to paediatric doses. We aimed to compare antibiotic exposure in adults and children, using pragmatic physiologically based pharmacokinetic (PBPK) modelling and simulation to evaluate the need for dose increases in children for the ‘I’ susceptibility category micro-organisms.

For amoxicillin, ceftazidime, cefuroxime and ciprofloxacin, we used existing PBPK models and verified them with published adult and paediatric pharmacokinetic data. Then, the adult EUCAST category ‘I’ doses and a wide paediatric dosage range was simulated. We compared AUC values as a surrogate for antibiotic exposure. In addition, simulations were performed to assess the PTA of the adult and paediatric doses for specific drug–micro-organism combinations.

Model verification proved successful for all antibiotics. Simulations showed that antibiotic plasma exposure increases with decreasing age using current paediatric doses. Simulating doses for neonates and infants resulted in substantially higher AUCs compared with adults receiving the EUCAST ‘I’ dose. Simulations showed that PTA is highly variable with age and can be poor in case of less susceptible micro-organisms.

In contrast to adults, there is no need to increase the currently recommended paediatric dosages for the tested antibiotics. At the same time, further simulations showed that the PTA varies by drug-micro-organism combination and age, providing a potential opportunity to tailor doses to individual patients.

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