Time to Antibiotic Administration in the Treatment of Sepsis: A Retrospective Cohort Study

Background The 2026 Surviving Sepsis Campaign (SSC) guidelines recommend antimicrobial therapy within 1 hour for probable septic shock, while the Centers for Medicare and Medicaid Services (CMS) mandates a 3-hour window. Current literature presents conflicting evidence on whether these universal time thresholds yield a definitive survival benefit. This study aims to evaluate the real-world impact of delayed antibiotic administration on patient mortality and length of stay (LOS). Methods A retrospective cohort study was conducted analyzing 62 153 adult encounters with severe sepsis or septic shock at emergency departments (EDs) between December 31, 2023, and December 31, 2025. Time to first antibiotic was categorized into 5 intervals (<1, 1-3, 4-12, 13-24, >24 hours). The primary outcome, in-hospital mortality, was analyzed using multivariable logistic regression. The secondary outcome, LOS, was analyzed among survivors using a gamma generalized linear model to calculate adjusted mean ratios (aMR). Results The cohort was clinically complex, with 63.5% of patients demonstrating a high Elixhauser comorbidity score (≥ 4). Only 2.8% of patients received antibiotics within the first hour. Mortality odds were significantly higher for patients receiving antibiotics after 24 hours compared to the less than 1 hour baseline (odds ratio = 1.52, 95% confidence interval: 1.18-1.95, P = .001). No statistically significant mortality difference was observed for the 1-3, 4-12, and 13-24 hour intervals relative to baseline. However, delayed administration increased LOS incrementally, with a 9% longer stay for the 13-24 hour group (adjusted means ratio [aMR] = 1.09, P = .003) and a 56% longer stay for the >24 hour group (aMR = 1.56, P < .001). Conclusion Achieving a less than 1-hour door-to-antibiotic time is operationally challenging. Delays up to 24 hours did not significantly increase mortality risk compared to immediate administration, though administering antibiotics before 13 hours offered modest improvements in hospital LOS.