Tamara van Donge

Efficacy and safety of amoxicillin in neonates 63 4 Model-based simulations of amoxicillin exposure We systematically identified population PK models available in the literature developed by a non-linear mixed effect modelling approach, which were applicable to a comparable neonatal population. Amoxicillin exposure was simulated over a timeframe of 7 days in total, for each patient and dosing regimen, following the first intravenous dose to assess amoxicillin exposure at initiation of empiric treatment. Exposure was evaluated after the first dose as adequate early empiric treatment is considered to be crucial for clinical outcomes. It was assumed that PK remains linear across the range of doses simulated. Simulations were performed with NONMEM® (version 7.3.0; ICON Development Solutions, Ellicott City, MD) and R (version 3.5.1; R Development Core Team, Vienna, Austria, http://r-project.org) was used for data analysis and graphics. Non-linear mixed effect models were utilized to perform simulations of amoxicillin exposure, and were characterized in terms of fixed effects and random effects. Fixed effects reflect the population average of the model parameters (e.g. clearance). Random effects relate to the variability effects and allow quantification of inter- and intra- individual variability. Definition of PKPD targets To evaluate the performance of amoxicillin dosing regimens, we considered a variety of antimicrobial outcome parameters informing targeted PKPD indices. First, MICs were based on breakpoints of microorganisms provided by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), and represent various potential target pathogens for amoxicillin in the neonatal population. 13 Pathogens such as Streptococcus agalactiae (GBS), Listeria monocytogenes and enterococci were considered of particular interest because they are important etiologic agents for (early- and late-onset) neonatal sepsis. 14-17 The corresponding target MICs were 0.25 mg/L, 1.0 mg/L and 4.0 mg/L, respectively. In order to provide an extensive profile of the probability of target attainment (PTA) for all potential MICs, we investigated MICs ranging from 0.25 mg/L to 8 mg/L. Second, for the PKPD target of % f T>MIC which is associated with efficacy, five interpretations which are proposed in literature were selected; 30% f T>MIC based on data suggesting to be sufficient to ensure survival in animal models 18 ; 50% f T>MIC as this has been reported as being associated with maximal bactericidal effects in such models 19 ; 70% f T>MIC, 100% f T>MIC and 100% f T>4xMIC as these PKPD indices are being used in beta-lactam therapeutic drug monitoring. 20 Third, the adequacy of each dosing regimen in reaching appropriate exposure in the population of interest was determined by computing the PTA for each dosing regimen (combination of MIC and PKPD target). A PTA ≥90%, meaning that 90% of the neonatal population achieved the PKPD target, was considered adequate, although the acceptable level of PTA is currently still under debate, with values ranging from 90 to 99%. 21