Switching antibiotic therapy from injectable to oral to optimise the duration of inpatient care for young infants presenting with moderate-mortality-risk signs of possible serious bacterial infection: an open-label, multicountry, randomised controlled trial

Background: In low-resource settings, challenges in hospitalisation stay for sick young infants younger than 2 months persist. Early discharge of young infants with moderate-mortality-risk possible serious bacterial infection (PSBI) signs might provide a safe and effective alternative. We compared the clinical outcomes of switching parenteral antibiotics to oral antibiotics along with hospital discharge after 48 h of admission with those who continued hospitalisation for 7 days. Methods: An open-label, multicountry, multicentre, individually randomised controlled trial was done in Bangladesh, Ethiopia, India, Nigeria, Pakistan, and Tanzania. Young infants aged 1–59 days presenting with moderate-mortality-risk PSBI signs were screened and hospitalised for inpatient care with injectable ampicillin and gentamicin. After 48 h of admission, young infants without any PSBI sign, and negative C-reactive protein, were randomly assigned to either the intervention (outpatient) group (discontinuation of injectable antibiotics and hospital discharge after switching to oral amoxicillin twice daily for 5 more days) or the control group (continued inpatient care). Treatment received throughout was documented on days 4 and 8 of initiation, and outcomes on days 4, 8, and 15. The primary outcome of poor clinical outcome was a hierarchical composite indicator that included death (any time after randomisation up to day 15 of initiation of therapy), presence of any sign of critical illness (no movement at all, unable to feed at all, or convulsions), or any sign suggestive of another serious infection, such as meningitis, bone or joint infection (on day 4 or day 8 of initiation of therapy), and presence of any sign of clinical severe infection (CSI) (on day 8 of initiation of therapy). The non-inferiority margin was set at 2%. We did a per-protocol analysis to compare the proportions of primary outcome between the two groups and reported risk differences (RDs) with 95% CI. The study is registered with the ISRCTN registry (ISRCTN16872570). Findings: Between June 24, 2021, and Aug 7, 2024, of 6549 young infants with moderate-mortality-risk PSBI signs who were reassessed after 48 h of admission, 5253 (80·3%) were randomly assigned to the outpatient group (n=2635) or the inpatient care group (n=2618). Treatment adherence was 96·7% (2549 of 2635) in the oral amoxicillin group and 95·7% (2506 of 2618) in the inpatient care group (with at least 80% of the antibiotic dosage received). In the per-protocol analysis, the rate of poor clinical outcome was 4·0% (105 of 2616) in the outpatient group and 3·5% (90 of 2603) in the inpatient care group (RD 0·0056 [95% CI –0·0047 to 0·0158]). The most common reason for poor clinical outcome was any sign of CSI at day 8 (3·4% in the outpatient group and 2·6% in the inpatient care group). Six (0·2%) young infants died in the outpatient group and eight (0·3%) in the inpatient care group. Besides deaths, two young infants developed serious adverse events, and both were in the inpatient group. Interpretation: Discontinuation of the injectable antibiotics and switching to oral antibiotics with early hospital discharge in young infants with moderate-mortality-risk PSBI signs was effective and safe in diverse low-income and middle-income countries in Africa and Asia. This could optimise health systems and family resources, as well as decreasing the risk of hospital-acquired infections compared with the currently recommended 7–10 days of inpatient care. Funding: Gates Foundation.