Assessment of flomoxef combined with amikacin in a hollow-fibre infection model for the treatment of neonatal sepsis in low- and middle-income healthcare settings


Darlow, Christopher A ORCID: 0000-0002-5400-3413, McEntee, Laura, Johnson, Adam, Farrington, Nicola ORCID: 0000-0003-2300-9430, Unsworth, Jennifer, Jimenez-Valverde, Ana ORCID: 0000-0003-4284-5629, Jagota, Bhavana, Kolamunnage-Dona, Ruwanthi ORCID: 0000-0003-3886-6208, Da Costa, Renata MA, Ellis, Sally et al (show 6 more authors) (2022) Assessment of flomoxef combined with amikacin in a hollow-fibre infection model for the treatment of neonatal sepsis in low- and middle-income healthcare settings. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 77 (12). pp. 3349-3357. ISSN 0305-7453, 1460-2091

Access the full-text of this item by clicking on the Open Access link.

Abstract

<h4>Background</h4>Annual mortality from neonatal sepsis is an estimated 430 000-680 000 infants globally, most of which occur in low- and middle-income countries (LMICs). The WHO currently recommends a narrow-spectrum β-lactam (e.g. ampicillin) and gentamicin as first-line empirical therapy. However, available epidemiological data demonstrate high rates of resistance to both agents. Alternative empirical regimens are needed. Flomoxef and amikacin are two off-patent antibiotics with potential for use in this setting.<h4>Objectives</h4>To assess the pharmacodynamics of flomoxef and amikacin in combination.<h4>Methods</h4>The pharmacodynamic interaction of flomoxef and amikacin was assessed in chequerboard assays and a 16-arm dose-ranged hollow-fibre infection model (HFIM) experiment. The combination was further assessed in HFIM experiments mimicking neonatal plasma exposures of clinically relevant doses of both drugs against five Enterobacterales isolates with a range of flomoxef/amikacin MICs.<h4>Results</h4>Flomoxef and amikacin in combination were synergistic in bacterial killing in both assays and prevention of emergence of amikacin resistance in the HFIM. In the HFIM assessing neonatal-like drug exposures, the combination killed 3/5 strains to sterility, (including 2/5 that monotherapy with either drug failed to kill) and failed to kill the 2/5 strains with flomoxef MICs of 32 mg/L.<h4>Conclusions</h4>We conclude that the combination of flomoxef and amikacin is synergistic and is a potentially clinically effective regimen for the empirical treatment of neonatal sepsis in LMIC settings and is therefore suitable for further assessment in a clinical trial.

Item Type: Article
Uncontrolled Keywords: Humans, Cephalosporins, Amikacin, Anti-Bacterial Agents, Microbial Sensitivity Tests, Infant, Infant, Newborn, Delivery of Health Care, Neonatal Sepsis
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Population Health
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 17 Jan 2023 17:04
Last Modified: 12 Jun 2025 00:41
DOI: 10.1093/jac/dkac323
Open Access URL: https://doi.org/10.1093/jac/dkac323
Related Websites:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3167108
Altmetric
CORE (COnnecting REpositories)