Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 65, Issue 7, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00293-21
Keywords
amikacin; combination antibiotics; fosfomycin; hollow fiber; mathematical modelling; neonatal sepsis; synergy; aminoglycosides; antimicrobial resistance; pharmacodynamics
Categories
Funding
- Global Antibiotic Research and Development Partnership (GARDP)
- German Federal Ministry of Health, Medecins Sans Frontieres
- U.K. Department for International Development
- U.K. National Institute of Health Research
- North West England Medical Research Council Fellowship Scheme in Clinical Pharmacology and Therapeutics - Medical Research Council [MR/N025989/1]
- Roche Pharma
- Eli Lilly and Company Limited
- UCB Pharma
- University of Liverpool
- University of Manchester
- German Federal Ministry of Education and Research
- Netherlands Ministry of Health, Welfare, and Sport
- Novartis
- MRC [MR/N025989/1] Funding Source: UKRI
Ask authors/readers for more resources
Antimicrobial resistance in neonatal sepsis is a global issue, with high mortality rates in low- and middle-income countries. A combination therapy of fosfomycin and amikacin shows enhanced bactericidal activity and synergy against resistant strains. Monte Carlo simulations support the efficacy of this combination regimen for the treatment of neonatal sepsis.
Antimicrobial resistance (particularly through extended-spectrum beta-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., 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 the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF x MICA, 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve >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 empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available