Study rationale

In infectious diseases, treatment targets are often linked to laboratory standards set by EUCAST (the European Committee on Antimicrobial Susceptibility Testing). EUCAST defines breakpoints that classify bacteria and antibiotics into three categories, . Based on newly adopted clinical breakpoints, EUCAST has redefined one of these categories, the “intermediate susceptibility” category (denoted as “I”) to “susceptible with increased exposure”, indicating that certain microorganisms need higher antibiotic dosages. Consequently, adult dosing recommendations for certain drug-pathogen combinations have been doubled or even tripled. However, this raised an important clinical question: Should paediatric doses also be increased?

The role of PBPK modelling in supporting clinical decision-making

Since there is limited clinical research to guide paediatric dose adjustments, physiologically-based pharmacokinetic (PBPK) modelling can be a valuable tool. In this study, PBPK models were used to simulate paediatric drug exposure for four antibiotics: amoxicillin, ceftazidime, cefuroxime, and ciprofloxacin.

At first, drug exposure was compared between adults and several paediatric age groups, typically quantified as the area under the concentration-time curve (AUC). The currently recommended doses from the Dutch Paediatric Formulary were simulated and the exposure levels were assessed for similarity to adult exposure at the higher doses recommended by EUCAST.

Secondly, the desired therapeutic effect was assessed. To address this, the authors also assessed drug exposure to the likelihood of achieving microbiological efficacy. This method is called probability of target attainment (PTA) and represents the probability that the drug concentration at the site of infection will be high enough to achieve the pharmacodynamic target for bacterial suppression or killing.

Evaluation of paediatric dosing

The findings led to the conclusion that the current paediatric dosing recommendations for these four antibiotics are adequate. The PTA analysis highlighted that there are age-dependent differences in the probability of achieving therapeutic efficacy, particularly for infections caused by more resistant pathogens.

PBPK modelling in this study provides valuable insights by simulating paediatric drug exposure and comparing it to adult exposure, ensuring that current paediatric dosing regimens achieve adequate exposure. Additionally, it links predicted exposure to pharmacodynamic targets, providing valuable insights in case the selected antimicrobial therapy proves ineffective.

The full paper can be accessed here.