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

Details

Serval ID
serval:BIB_5EAFB9C19B3A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Amoxicillin Dosing Regimens for the Treatment of Neonatal Sepsis: Balancing Efficacy and Neurotoxicity.
Journal
Neonatology
Author(s)
van Donge T., Fuchs A., Leroux S., Pfister M., Rodieux F., Atkinson A., Giannoni E., van den Anker J., Bielicki J.
ISSN
1661-7819 (Electronic)
ISSN-L
1661-7800
Publication state
Published
Issued date
2020
Peer-reviewed
Oui
Volume
117
Number
5
Pages
619-627
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Large variability in neonatal amoxicillin dosing recommendations may reflect uncertainty about appropriate efficacy and toxicity targets.
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.
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.
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.
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.
Keywords
Amoxicillin, Dosing regimen, Model-based simulations, Neonates, Neurotoxicity, pharmacokinetic/pharmacodynamic targets
Pubmed
Web of science
Open Access
Yes
Create date
02/09/2020 9:39
Last modification date
04/02/2021 6:25
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