Tamara van Donge

Chapter 4 64 In addition to efficacy targets, we evaluated the maximum exposure expected for each neonate in the model population for the different dosing scenarios. We were interested in the proportion of neonates experiencing a maximal concentration Cmax >140 mg/L at steady-state (i.e. exposure at day 7 after one week of treatment) as this has been described as representing a potentially neurotoxic aminopenicillin exposure in this population. 22 Results Identification of dosing recommendations Six international guidelines and all surveyed Swiss NICUs provided recommendations for intravenous amoxicillin dosing. Fifteen unique dosing regimens were identified and investigated. Dosing regimens ranged from 10 mg/kg every 12 hours to 50 mg/kg every 4 hours. Total daily doses of amoxicillin in use in Swiss NICUs (50-200 mg/kg/day) were higher than those recommended in international guidelines (20-200 mg/kg/day) with one exception (Shann; suggesting a maximum total daily dose of 300 mg/kg). Model-based simulations of amoxicillin Two different population PK models were retrieved from literature. 5,6 One model was excluded as it studied exclusively term neonates undergoing therapeutic hypothermia. 5 Therefore, one population PK model fulfilled the pre-specified criteria and was selected to simulate neonatal amoxicillin exposure. 6 Data from this analysis originated from a prospective, multi-centre, PK study with a sample size of 187 preterm and term infants. 6 Three covariates for amoxicillin clearance in neonates were identified, namely weight, GA, and PNA. A two-compartment model with first-order elimination kinetics was identified to describe PK amoxicillin data accurately. 6 Amoxicillin exposure under different dosing recommendations None of the dosing regimens achieved the PKPD targets of 100% f T>MIC or 100% f T>4xMIC at any of the relevant MICs based on a desired PTA of ≥90% (Table 2). All dosing regimens achieved 30% f T>MIC with an adequate PTA of ≥90% for all relevant MICs (0.25 – 4.0 mg/L), with the exception of amoxicillin administered at 10-20 mg/kg every 12 hours (Lexicomp and Harriet Lane). Focusing on targeted MICs of predefined organisms of interest, the majority of regimens achieved a PTA ≥90% for GBS (MIC 0.25 mg/L) and L. monocytogenes (MIC 1 mg/L) when targeting 70% f T>MIC or less, with the exception of 10-20 mg/kg every 12 hours, achieving a PTA <75% (Table 2). In contrast, none of the regimens resulted in a PTA ≥90% targeting