Tamara van Donge

Efficacy and safety of amoxicillin in neonates 71 4 validated (internal and external). 6 A large sample size was used (n=187) to develop and validate this model, and the studied population provides an appropriate representation of our target neonatal population. The following covariates were incorporated in the model; GA and PNA as a function of maturation on clearance, weight on volume of distribution and on clearance (by allometric scaling). Additionally, Bayesian TDM tools incorporating post- hoc Bayesian estimation based on opportunistic blood sampling and integrating individual targets could further support personalized dosing regimen selection and adjustment. Conclusion At present, simulations may be used only to identify regimens more or less likely to be appropriate in the context of a specific microbiological epidemiology of neonatal sepsis. A small set of potential dosing regimens emerge as unlikely to be suitable even under very conservative assumptions (low targeted % f T>MIC or low MIC), since acceptable target attainment cannot be expected. The acceptability of all other dosing regimens will strongly be influenced by expected MICs and optimal PKPD targets. The selection of these targets is in turn challenging without clear and robust clinical data linking them to key outcomes. For Switzerland, the presented modelling provided information in selecting a harmonized neonatal intravenous amoxicillin dosing regimen, since reliable information on microbiological epidemiology is available. Implementing demographic patient characteristics in the dosing selection process is necessary but not sufficient. Both the impact of development and maturation (reflected by patient characteristics) and microbiological epidemiology (reflected by targeted pathogens or MIC levels) are needed for optimal antimicrobial dosing in neonates. Therefore, better in vivo characterization of PKPD parameters, preferably using novel randomized trial designs combined with pharmacometric modelling and simulation, could considerably improve beta-lactam use with respect to efficacy and toxicity in this understudied, vulnerable population.