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

Abstract

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.

Figure 1

Trial profile PSBI=possible serious bacterial infection.

Figure 2

Poor clinical outcome of the intention-to-treat population Data are n (%), unless stated otherwise. The black dotted line represents the non-inferiority margin.

Figure 3

Poor clinical outcome of the per-protocol population Data are n (%), unless stated otherwise. The black dotted line represents the non-inferiority margin.