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Background Antimicrobial resistance threatens to undermine reductions in child mortality worldwide and new treatment options are urgently needed. Fosfomycin is identified as ‘critically important’ by the WHO but limited safety data exists in neonates. Paediatric and neonatal dosing recommendations for intravenous fosfomycin are divergent and there are no published oral dosing regimens. Methods We conducted a randomised controlled trial among neonates weighing >1500g with suspected sepsis and treated with standard-of-care antibiotics: ampicillin and gentamicin (SOC). We randomly assigned half the participants to receive additional intravenous followed by oral fosfomycin at 100mg/kg twice daily for up to 7 days (SOC-F). We evaluated safety for 28 days and fosfomycin pharmacokinetics. Findings 61 and 59 infants aged 0-4 days were assigned to SOC-F and SOC respectively. We observed 35 adverse events (AEs) among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1,560 and 1,565 infant/days observation respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference -0.95 events/100 infant-days [95% CI -2.1 to 0.20], p=0.11). 4 SOC-F and 3 SOC participants died. There was no evidence of impact of fosfomycin on serum sodium or diarrhoea. From 238 PK samples, modelling indicates an intravenous dose of 150/mg/kg twice daily to be appropriate in most children, reduced to 100mg/kg twice daily in neonates aged <7 days or weighing <1500g. Interpretation Fosfomycin in combination with other antimicrobial agents offers a safe and potentially affordable regimen with a simple dosing schedule for neonatal sepsis in hospital settings.



Lancet Infectious Diseases



Publication Date



Neonatal; sepsis; bacterial infection; antimicrobial; antibiotic; resistance; trial; pharmacokinetics; modelling; dose; mortality; low- and middle income.