SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

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

van Donge, T; Fuchs, A; Leroux, S; Pfister, M; Rodieux, F; Atkinson, A; Giannoni, E; van den Anker, J; Bielicki, J (2021) Amoxicillin Dosing Regimens for the Treatment of Neonatal Sepsis: Balancing Efficacy and Neurotoxicity. Neonatology, 117 (5). pp. 619-627. ISSN 1661-7819 https://doi.org/10.1159/000509751
SGUL Authors: Bielicki, Julia Anna

[img]
Preview
PDF Published Version
Available under License Creative Commons Attribution Non-commercial.

Download (521kB) | Preview

Abstract

INTRODUCTION: Large variability in neonatal amoxicillin dosing recommendations may reflect uncertainty about appropriate efficacy and toxicity targets. OBJECTIVE: 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 %fT > MIC, and potential for aminopenicillin-related neurotoxicity. METHODS: 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 %fT > MIC and potential neurotoxicity using Cmax > 140 mg/L as threshold. RESULTS: None of the dosing regimens achieved targets of ≥100%fT > MIC at any of the relevant MICs for a desired probability of target attainment (PTA) of ≥90%. All regimens achieved a PTA ≥90% for Streptococcus agalactiae (MIC 0.25 mg/L) and Listeria monocytogenes (MIC 1 mg/L) when targeting ≤70%fT > MIC. In contrast, none of the regimens resulted in a PTA ≥90% targeting ≥70%fT > 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. CONCLUSIONS: 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.

Item Type: Article
Additional Information: © 2020 The Author(s).Published by S. Karger AG, Basel This is an Open Access article licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense), applicable to the online version of the article only. Usage and distribution for commercial purposes requires written permission.
Keywords: Amoxicillin, Dosing regimen, Model-based simulations, Neonates, Neurotoxicity, pharmacokinetic/pharmacodynamic targets, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, Pediatrics
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Neonatology
ISSN: 1661-7819
Language: eng
Dates:
DateEvent
January 2021Published
25 August 2020Published Online
21 June 2020Accepted
Publisher License: Creative Commons: Attribution-Noncommercial 4.0
PubMed ID: 32841941
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112570
Publisher's version: https://doi.org/10.1159/000509751

Actions (login required)

Edit Item Edit Item