Seven-day versus 14-day antibiotic course for culture-proven neonatal sepsis: a multicentre randomised non-inferiority trial in a low and middle-income country

OBJECTIVE: Definitive guidance regarding the duration of antibiotics for neonatal sepsis is lacking. We hypothesised that a 7-day antibiotic course is non-inferior to a 14-day course for treating culture-proven sepsis. DESIGN: Randomised, controlled, non-inferiority trial with masked outcome assessment in eight centres in a low and middle-income country. PATIENTS: Neonates with a birth weight (BW) ≥1000 g and blood culture-proven sepsis were randomised on day 7 of sensitive antibiotic therapy provided sepsis had clinically remitted. EXCLUSIONS: Staphylococcus aureus or fungal sepsis, and infections requiring prolonged antibiotics. We planned to enrol 350 per group, assuming 10% rate of primary outcome, +7% non-inferiority margin, one-sided 5% alpha, 90% power, 10% loss to follow-up. INTERVENTION: 7 days (no further treatment); comparison: 14 days (7 days postrandomisation). OUTCOMES: Primary: relapse (definite or probable) within day 21 postantibiotic completion. SECONDARY OUTCOMES: composite of mortality or definite/probable/secondary sepsis and duration of hospitalisation. One interim analysis (per protocol (PP)) was planned. RESULTS: 126 and 135 subjects were recruited in 7-day and 14-day groups, respectively, with mean (SD) birth weight (BW) 2250.9 (741.1) and 2187.8 (718.8) g. The trial was terminated early, based on interim PP analysis. 2/125 and 6/130 subjects had the primary outcome in 7-day and 14-day groups, respectively (risk difference (RD)=-3.0% (99.5% CI -9.2%, +3.1%), below non-inferiority margin). The composite secondary outcome also favoured the 7-day regimen (RD: -3.7% (99.5% CI -12.4% to +5.1%)). Duration of hospitalisation was shorter in 7-day group (median difference: -4 days (95% CI -5 to -3)). CONCLUSIONS: A 7-day course of antibiotics may be non-inferior to a 14-day course for uncomplicated bacterial neonatal sepsis. TRIAL REGISTRATION NUMBER: NCT03280147.