Amoxicillin Dosing Regimens for the Treatment of Neonatal Sepsis: Balancing Efficacy and Neurotoxicity

Abstract

<b><i>Introduction:</i></b> Large variability in neonatal amoxicillin dosing recommendations may reflect uncertainty about appropriate efficacy and toxicity targets. <b><i>Objective:</i></b> The aim of this study was to model efficacious and safe exposure for current neonatal amoxicillin dosing regimens, given a range of assumptions for minimal inhibitory concentration (MIC), targeted %<i>f</i>T &#x3e; MIC, and potential for aminopenicillin-related neurotoxicity. <b><i>Methods:</i></b> Individual intravenous amoxicillin exposures based on 6 international and 9 Swiss neonatal dosing recommendations, reflecting the range of current dosing approaches, were assessed by a previously developed population pharmacokinetic model informed by neonatal data from an international cohort. Exposure was simulated by attributing each dosing regimen to each patient cohort. End points of interest were %<i>f</i>T &#x3e; MIC and potential neurotoxicity using <i>C</i>_max &#x3e; 140 mg/L as threshold. <b><i>Results:</i></b> None of the dosing regimens achieved targets of ≥100%<i>f</i>T &#x3e; MIC at any of the relevant MICs for a desired probability of target attainment (PTA) of ≥90%. All regimens achieved a PTA ≥90% for <i>Streptococcus agalactiae</i> (MIC 0.25 mg/L) and <i>Listeria monocytogenes</i> (MIC 1 mg/L) when targeting ≤70%<i>f</i>T &#x3e; MIC. In contrast, none of the regimens resulted in a PTA ≥90% targeting ≥70%<i>f</i>T &#x3e; MIC for enterococci (MIC 4 mg/L). The maximum amoxicillin concentration associated with potential neurotoxicity was exceeded using 4 dosing regimens (100 mg/kg q12, 60/30 mg/kg q12/8, 50 mg/kg q12/8/6, and 50 mg/kg q12/8/4) for ≥10% of neonates. <b><i>Conclusions:</i></b> The acceptability of regimens is highly influenced by efficacy and toxicity targets, the selection of which is challenging. Novel randomized trial designs combined with pharmacometric modeling and simulation could assist in selecting optimal dosing regimens in this understudied population.