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

Abstract

<b>Rationale:</b> 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.<b>Objectives:</b> Identify patient characteristics associated with greater benefit from shorter time-to-antibiotics.<b>Methods:</b> 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: <i>1</i>) conditional average treatment effects of shorter (⩽3 h) versus longer (>3-12 h) time-to-antibiotics on 30-day mortality using multivariable Poisson regression; <i>2</i>) causal forest to identify characteristics associated with greatest benefit from shorter time-to-antibiotics; and <i>3</i>) logistic regression with time-to-antibiotics modeled as a spline.<b>Measurements and Main Results:</b> 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, <i>P</i> < 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, <i>P</i> = 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, <i>P</i> < 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.<b>Conclusions:</b> 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.