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Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis.

Gastine, S; Obiero, C; Kane, Z; Williams, P; Readman, J; Murunga, S; Thitiri, J; Ellis, S; Correia, E; Nyaoke, B; et al. Gastine, S; Obiero, C; Kane, Z; Williams, P; Readman, J; Murunga, S; Thitiri, J; Ellis, S; Correia, E; Nyaoke, B; Kipper, K; van den Anker, J; Sharland, M; Berkley, JA; Standing, JF (2022) Simultaneous pharmacokinetic/pharmacodynamic (PKPD) assessment of ampicillin and gentamicin in the treatment of neonatal sepsis. J Antimicrob Chemother, 77 (2). pp. 448-456. ISSN 1460-2091 https://doi.org/10.1093/jac/dkab413
SGUL Authors: Sharland, Michael Roy

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Abstract

OBJECTIVES: This study aimed to simultaneously investigate the pharmacokinetics of ampicillin and gentamicin, currently the WHO standard of care for treating neonatal sepsis. METHODS: Pharmacokinetic data were collected in 59 neonates receiving ampicillin and gentamicin for suspected or proven sepsis in the NeoFosfo trial (NCT03453177). A panel of 23 clinical Escherichia coli isolates from neonates with sepsis, resistant to either ampicillin, gentamicin or both, were tested for susceptibility using chequerboards. Pharmacokinetic/pharmacodynamic (PKPD) modelling and simulations were used to compare single-agent (EUCAST MIC) and combination (chequerboard MIC) target attainment with standard dosing regimens. RESULTS: A model was established that simultaneously estimated parameters of a one-compartment ampicillin model and a two-compartment gentamicin model. A common clearance for both drugs was used (6.89 L/h/70 kg) relating to glomerular filtration (CLGFR), with an additional clearance term added for ampicillin (5.3 L/h/70 kg). Covariate modelling included a priori allometric weight and post-menstrual age scaling of clearance. Further covariate relationships on renal clearance were postnatal age and serum creatinine.Simulation-based PKPD assessments suggest good Gram-positive (MIC ≤ 0.25 mg/L) cover. However, less than one-quarter of neonates were predicted to receive efficacious coverage against Enterobacterales (MIC ≤ 2 mg/L). The benefit of the ampicillin/gentamicin combination was limited, with only 2/23 E. coli clinical strains showing FIC index < 0.5 (synergy) and most in the range 0.5-1 (suggesting additivity). Simulations showed that feasible dosing strategies would be insufficient to cover resistant strains. CONCLUSIONS: PKPD simulations showed ampicillin and gentamicin combination therapy was insufficient to cover Enterobacterales, suggesting the need for alternative empirical treatment options for neonatal sepsis.

Item Type: Article
Additional Information: © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Microbiology, 1115 Pharmacology and Pharmaceutical Sciences, 0605 Microbiology, 1108 Medical Microbiology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: J Antimicrob Chemother
ISSN: 1460-2091
Language: eng
Dates:
DateEvent
2 February 2022Published
23 November 2021Published Online
6 October 2021Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDWellcome Trusthttp://dx.doi.org/10.13039/100004440
UNSPECIFIEDGerman Federal Ministry of Education and Research (BMBF)UNSPECIFIED
MR/M008665/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/M007367/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 35107141
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/114140
Publisher's version: https://doi.org/10.1093/jac/dkab413

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