Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload

OBJECTIVE: To assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis. DESIGN: A single-centre open-label randomised controlled trial. SETTING: Kilifi County Hospital, Kenya. PATIENTS: 120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019. INTERVENTION: We randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days. MAIN OUTCOMES AND MEASURES: Serum sodium, AEs and fosfomycin pharmacokinetics. RESULTS: 61 and 59 infants aged 0-23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 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)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged