Tamara van Donge

Efficacy and safety of amoxicillin in neonates 61 4 Introduction Neonatal sepsis, including possible serious bacterial infection, is a significant driver of antibiotic use. Globally around 3 million cases of and up to 600’000 deaths due to neonatal sepsis are estimated to occur every year. 1 A penicillin combined with gentamicin is the first-line treatment for neonatal sepsis recommended by the World Health Organization (WHO), and the combination of benzylpenicillin or an aminopenicillin with gentamicin accounts for 29% and 15% of all regimens used in high income and low/middle income countries, respectively. 2,3 In countries such as Switzerland and France, ampicillin is not available and amoxicillin is used instead to treat suspected or proven neonatal sepsis. Despite the longstanding use of amoxicillin for the treatment of neonates, data supporting optimized dosing are limited. In vitro amoxicillin efficacy is time- dependent and the key pharmacokinetic/pharmacodynamic (PKPD) index is the fraction of time during which the antibiotic concentration remains above the minimal inhibitory concentration of the targeted pathogen (% f T>MIC). 4 Most studies have not investigated amoxicillin pharmacokinetics (PK) across the entire age and disease spectrum of premature and term infants cared for in neonatal units. 4-9 This limits the identification of optimal dosing approaches in a population that is subject to short- term maturational changes in drug clearance during the postnatal period. Therefore, intravenous amoxicillin dosing recommendations show a large variation with a range from 40 mg/kg per day to 120 mg/kg per day administered in one, two, three or four doses with or without dose stratification according to gestational or post-conceptional age. PK modelling and simulation can support antibiotic dose optimization to identify regimens with suboptimal performance under a range of assumptions. 10,11 The main objective of this study was to investigate how the variability of currently used neonatal amoxicillin dosing regimens may impact (i) efficacy, given a range of different equally valid assumptions for MICs, PKPD targets, and (ii) safety, given drug concentration associated with potential neurotoxicity in neonates. Materials and methods Individual amoxicillin exposures based on international and Swiss neonatal dosing recommendations were assessed by a population PK model, which is informed by data from an international cohort.