Efficacy and safety of short-course (<14 days) vs. standard-course (≥14 days) antibiotic therapy for neonatal sepsis: a systematic review and meta-analysis

Neonatal sepsis remains a leading cause of global infant mortality, necessitating effective antibiotic regimens that balance efficacy with safety and antimicrobial stewardship. This systematic review and meta-analysis aimed to compare the efficacy and safety of short-course (<14 days) vs. standard-course (≥14 days) antibiotic therapy for neonatal sepsis. We conducted a comprehensive search across Web of Science, PubMed, EMBASE, and CENTRAL, including only randomized controlled trials (RCTs) with a minimum 28-day follow-up. Study quality was assessed using the Cochrane Risk of Bias 2 (ROB 2) tool, and data were pooled using meta-analysis in R. Three RCTs ( n = 434) were included. The pooled risk ratio (RR) for the primary composite outcome of treatment failure or mortality was 0.995 (95% confidence interval [CI]: 0.144 to 6.890; p = 0.993), indicating no statistically significant difference but with extreme imprecision. Statistical heterogeneity was absent (I 2 = 0%). However, sensitivity analyses revealed the pooled estimate was fragile, and risk of bias assessment indicated only one study had a low overall risk. While formal tests were underpowered, the Trim and Fill method suggested potential publication bias. In conclusion, current evidence is insufficient to determine the non-inferiority of short-course therapy due to very low precision, a limited number of studies, and methodological concerns. Large, rigorously designed RCTs are urgently needed to provide definitive guidance on optimal antibiotic duration for neonatal sepsis.