Inpatient versus outpatient management of young infants with a single low-mortality-risk sign of possible serious bacterial infection in sub-Saharan Africa and south Asia: an open-label, multicentre, two-arm, randomised controlled trial.

BACKGROUND Research has shown low mortality in young infants with a single low-mortality-risk possible serious bacterial infection (PSBI) sign. Outpatient treatment of young infants (age <2 months) with a single low-mortality-risk PSBI sign might be as effective and safe as hospitalisation. Outpatient treatment overcomes the challenges of hospitalisation and improves access in low-resource settings. Our aim was to assess clinical outcomes in patients with one low-mortality-risk PSBI sign treated as outpatients compared with inpatient treatment. METHODS We did an open-label, multicentre, two-arm, randomised controlled trial at seven sites across Bangladesh, Ethiopia, India, Nigeria, Pakistan, and Tanzania. Young infants presenting to study hospitals with one of three low-mortality-risk PSBI signs (ie, fast breathing if age <7 days, body temperature ≥38°C, or severe chest indrawing) were randomly assigned (1:1) to the outpatient treatment group (2-day injectable gentamicin plus 7-day oral amoxicillin) or the inpatient treatment group (7-day injectable ampicillin plus gentamicin, with supportive care). The primary outcome was poor clinical outcome, which was a composite of any one of the following: death, critical illness, signs of other serious infections, new PSBI signs on days 2, 4, 8, and 15 or persistence of the presenting sign on day 8 after randomisation. We evaluated superiority and non-inferiority using the Farrington-Manning score test. The trial is registered with the ISRCTN Registry (ISRCTN44033252). FINDINGS Between June 24, 2021, and April 26, 2024, 7001 young infants were enrolled and randomly assigned to the outpatient treatment group (n=3501) or the inpatient treatment group (n=3500), and were part of the intention-to-treat (ITT) population. Poor clinical outcomes occurred in 269 (7·7%) of 3501 outpatients and 272 (7·8%) of 3500 inpatients in the ITT analysis (risk difference -0·0009 [95% CI -0·0134 to 0·0116]; p=1·0000 for superiority analysis). Deaths were significantly lower in the outpatient group (nine [0·3%] of 3501) than in the inpatient group (23 [0·7%] of 3500; risk difference -0·0040 [-0·0072 to -0·0008]). In the per-protocol analysis, outpatient treatment (266 [7·7%] of 3455) was non-inferior to inpatient treatment (269 [7·9%] of 3416) for poor clinical outcomes (risk difference -0·0018 [-0·0144 to 0·0109]; p=0·0012 for non-inferiority). Apart from deaths, there were no treatment-related serious adverse events. INTERPRETATION Outpatient treatment (gentamicin injection and oral amoxicillin) for infants with a single low-mortality-risk PSBI sign was non-inferior to standard inpatient treatment, with significantly lower mortality in the outpatient treatment group. FUNDING Bill and Melinda Gates Foundation.