Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance.



Darlow, Christopher A ORCID: 0000-0002-5400-3413, Docobo-Perez, Fernando, Farrington, Nicola, Johnson, Adam, McEntee, Laura, Unsworth, Jennifer, Jimenez-Valverde, Ana, Gastine, Silke, Dona, Ruwanthi Kolamunnage, de Costa, Renata MA
et al (show 8 more authors) (2021) Amikacin Combined with Fosfomycin for Treatment of Neonatal Sepsis in the Setting of Highly Prevalent Antimicrobial Resistance. Antimicrobial Agents and Chemotherapy.

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Abstract

Antimicrobial resistance (particularly by extended spectrum β-lactamase and aminoglycoside modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, causing significant mortality. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis; ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance.The combination was studied in a 16 arm dose ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented emergence of resistance compared to monotherapy of either antibiotic. Modelling of the experimental quantitative outputs and data from checkerboard assays, indicated synergy.We further assessed the combination regimen at clinically relevant doses in HFIM with nine Enterobacterales strains with high fosfomycin/amikacin MICs and demonstrated successful kill to sterilisation in 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales - MIC<sub>F</sub> * MIC<sub>A</sub> < 256 (where MIC<sub>F</sub> and MIC<sub>A</sub> are MICs for fosfomycin and amikacin). Monte Carlo simulations predict that a standard fosfomycin/amikacin neonatal regimen will achieve a >99% probability of pharmacodynamic success for strains with MICs below this threshold.We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empiric treatment of neonatal sepsis and is suitable for further clinical assessment in a randomised controlled trial.

Item Type: Article
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: 23 Jun 2021 09:43
Last Modified: 17 Nov 2021 21:27
DOI: 10.1128/aac.00293-21
URI: https://livrepository.liverpool.ac.uk/id/eprint/3127179