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 as susceptible or resistant and, for certain infections, indicates when increased drug exposure may be required for successful treatment. Based on newly adopted clinical breakpoints, EUCAST has redefined the “intermediate susceptibility” category (denoted as “I”) to “susceptible with increased exposure”. This means selected microorganisms are only susceptible at higher drug exposure, necessitating a higher dose for treatment. Consequently, adult dosing recommendations for certain drug-pathogen combinations have been increased. 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. The study used two methods to evaluate the appropriateness of paediatric dosing: exposure matching and probability of target attainment (PTA).

Exposure matching is a method used to compare the drug exposure (typically quantified as the area under the concentration-time curve, AUC) between different populations. In this study, the objective was to assess whether currently recommended doses by the Dutch Paediatric Formulary provided exposure levels similar to,  or greater than, those achieved by adults receiving the EUCAST-recommended higher doses.

While exposure matching compares drug exposure levels between populations, it does not directly assess whether these levels are sufficient to achieve the desired therapeutic effect. To address this, the authors also used probability of target attainment (PTA), a method that links drug exposure to the likelihood of achieving microbiological efficacy. PTA represents the probability that the drug concentration at the site of infection will exceed the minimum inhibitory concentration (MIC) of the pathogen for a sufficient amount of time to effectively treat the infection. In other words, it evaluates whether the simulated drug exposure is high enough to achieve the pharmacodynamic target for bacterial suppression or killing.

Evaluation of paediatric dosing

The findings from both exposure matching and PTA analysis led to the conclusion that the current paediatric dosing recommendations for many antibiotics are adequate. The PTA analysis highlighted that there are age-dependent differences in the probability of achieving therapeutic efficacy, particularly for certain drug-pathogen combinations.

PBPK modelling in this study provides valuable insights by simulating paediatric drug exposure and comparing it to adult doses, ensuring that current paediatric dosing regimens achieve adequate exposure. Additionally, it links predicted exposure to pharmacodynamic targets, helping identify when individualized dosing or therapeutic drug monitoring may be needed to optimise efficacy, especially for infections caused by more resistant pathogens.