Individualised duration of antibiotic treatment in culture-negative early-onset sepsis in late-preterm and term-born neonates in Denmark (DURATION): a multicentre, open-label, randomised, controlled, non-inferiority trial

BACKGROUND: Suspicion of early-onset sepsis (EOS) is a major contributor to antibiotic use in late-preterm and term-born neonates. We aimed to evaluate whether a clinically guided, individualised approach to treatment duration could safely reduce antibiotic exposure compared with standard care.

METHODS: This nationwide, multicentre, open-label, randomised, controlled, non-inferiority trial included late-preterm and term-born neonates (aged 0-3 days, gestational age 35 weeks or more, birthweight 2000 g or more) with culture-negative early-onset sepsis (probable EOS), defined as continuation of antibiotic treatment beyond 36-48 h based on clinical signs of or maternal risk factors for infection in combination with elevated C-reactive protein and symptom onset less than 72 h after birth. Neonates were ineligible if they met the criteria for discontinuing antibiotics before 48 h. Participants were randomised (1:1) to individualised or standard treatment. In the individualised group, antibiotic treatment was discontinued after 24 h without clinical signs of infection, provided that C-reactive protein was declining to ≤30 mg/L. Standard treatment was 5-7 days. The coprimary outcomes were readmission due to bacterial infection (non-inferiority margin 4%) and total antibiotic duration (superiority assessment), performed on both intention-to-treat and per-protocol populations. Safety was assessed in all included neonates. This study was registered with ClinicalTrials.gov (NCT05329701) and is completed.

FINDINGS: Between April 22, 2022, and April 5, 2025, 493 (61%) of 811 eligible neonates were randomly assigned to individualised (n=246) or standard (n=247) duration. Antibiotic therapy was initiated at a median of 22·5 h (IQR 14·4-28·0) after birth in the individualised group and 24·5 h (16·6-28·0) in the standard group. Readmission due to bacterial infection occurred in two (1%) of 246 neonates in the individualised group and one (<1%) of 247 in the standard group (risk difference 0·4% [95% CI -1·5 to 2·6]; pnon-inferiority=0·0032). Median total antibiotic treatment within 28 days was 2·8 days (IQR 2·4-3·4) in the individualised group and 6·8 days (6·6-7·0) in the standard group (difference 4·0 days [95% CI 3·8-4·1]; p<0·0001). No serious adverse events occurred in the individualised group and one (<1%) occurred in the standard group (risk difference -0·4% [95% CI -2·3 to 1·1]). Per-protocol results were consistent.

INTERPRETATION: In neonates with probable EOS, a clinically guided, individualised treatment strategy was non-inferior to standard therapy with respect to infection-related readmission and reduced treatment duration to a median of 3 days. These findings support reduced antibiotic use through individualised treatment duration strategies.

FUNDING: Copenhagen University Hospital Rigshospitalet Research Fund, Innovation Fund Denmark, and Greater Copenhagen Health Science Partners.