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

Background and objective 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. Methods 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. Results 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. Conclusions 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-microorganism combination and age, providing a potential opportunity to tailor doses to individual patients.