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.

Keywords: antibacterial agents; sepsis; septic shock.

Figure 1.

(A) Adjusted relative risk in 30-day mortality with shorter time-to-antibiotics by presence of shock, with time-to-antibiotics modeled as a continuous variable through spline regression. (B) Adjusted relative risk in 30-day mortality with shorter time-to-antibiotics by presence of metastatic cancer, with time-to-antibiotics modeled as a continuous variable through spline regression. This spline analysis demonstrates a nonlinear association of time-to-antibiotics with outcomes, but cannot be used to recommend specific treatment timing thresholds because the splines knots that inform the bends are set by the underlying distribution of time-to-antibiotics, as is recommended best practice for parameterizing splines (34). The restricted cubic spline included K = 3 knots at 0.1, 0.5, and 0.9 quantiles of time-to-antibiotics. For the figures, we set all covariates at their means, report predicted probabilities of 30-day mortality, and include 95% confidence intervals for predictions.

Figure 2.

Prevalence of patient characteristics by causal forest-generated quartile from least (Quartile 1) to greatest (Quartile 4) estimated mortality benefit with shorter time-to-antibiotics. Quartiles generated by causal forest analysis partitioning sample by estimated least (Quartile 1) to greatest (Quartile 4) mortality benefit with shorter time-to-antibiotics. Heatmap colors indicate lower (green) to higher (red) proportion of the sample with a particular characteristic. *Coefficient of variation (CV) is a measure of relative variability, where larger values indicate more variation between groups. WBC = white blood cells.