Heterogeneity of Benefit from Earlier Time-to-Antibiotics for Sepsis

Abstract Rationale Shorter time-to-antibiotics improves survival from sepsis, particularly among patients in shock. There may be other subgroups for whom faster antibiotics are particularly beneficial. Objectives Identify patient characteristics associated with greater benefit from shorter time-to-antibiotics. Methods Observational cohort study of patients hospitalized with community-onset sepsis at 173 hospitals and treated with antimicrobials within 12 hours. We used three approaches to evaluate heterogeneity of benefit from shorter time-to-antibiotics: 1) conditional average treatment effects of shorter (≤3 h) versus longer (3–12 h) time-to-antibiotics on 30-day mortality using multivariable Poisson regression; 2) causal forest to identify characteristics associated with greatest benefit from shorter time-to-antibiotics; and 3) logistic regression with time-to-antibiotics modeled as a spline. Measurements and Main Results Among 273,255 patients with community-onset sepsis, 131,094 (48.0%) received antibiotics within 3 hours. In Poisson models, shorter time-to-antibiotics was associated with greater absolute mortality reduction among patients with metastatic cancer (5.0% 95% confidence interval; CI: 4.3–5.7 vs. 0.4% 95% CI: 0.2–0.6 for patients without cancer, P 0.001); patients with shock (7.0% 95% CI: 5.8–8.2% vs. 2.8% 95% CI: 2.7–3.5% for patients without shock, P = 0.005); and patients with more acute organ dysfunctions (4.8% 95% CI: 3.9–5.6% for three or more dysfunctions vs. 0.5% 95% CI: 0.3–0.8 for one dysfunction, P 0.001). In causal forest, metastatic cancer and shock were associated with greatest benefit from shorter time-to-antibiotics. Spline analysis confirmed differential nonlinear associations of time-to-antibiotics with mortality in patients with metastatic cancer and shock. Conclusions In patients with community-onset sepsis, the mortality benefit of shorter time-to-antibiotics varied by patient characteristics. These findings suggest that shorter time-to-antibiotics for sepsis is particularly important among patients with cancer and/or shock.