Optimizing Sepsis Time Zero Definitions Through Associations between Antibiotic Timing and Mortality.

Authors

Chanu Rhee, Theodore R Pak, Jessica Young, Robert Jin, Laura DelloStritto, Jeffrey Guy, Kenneth E Sands, Russell E Poland, Caroline S McKenna, Anna Agan, Claire N Shappell, Michael R Filbin, Sayon Dutta, Edward J Septimus, Sameer S Kadri, Henry Masur, Michael Klompas

Published in

American journal of respiratory and critical care medicine. Nov 12, 2026. Epub Nov 12, 2026.

Abstract

Sepsis performance measures require operational definitions of "time zero", but SEP-1's heterogeneous organ dysfunction criteria may not all identify patients vulnerable to harm from antibiotic delays.
To determine which SEP-1 organ dysfunctions identify patients in whom antibiotic delays are associated with increased mortality.
We analyzed adults with suspected infection using electronic health record data from 145 U.S. hospitals (2018-2023). We estimated associations between antibiotic timing (1-3 vs. 0-1h and 3-6 vs. 0-3h) and in-hospital mortality for each SEP-1 organ dysfunction criterion, alone and in combination: hypotension, elevated lactate, respiratory failure, renal dysfunction, hyperbilirubinemia, thrombocytopenia, and coagulopathy. We used inverse probability weighting to adjust for baseline and time-varying confounders.
Among 1,849,729 encounters with suspected infection, 624,416 had ≥1 organ dysfunction and received antibiotics within 6h of time zero. Antibiotics at 1-3 vs. 0-1h were associated with higher mortality when time zero was defined by hypotension (aRR 1.07; 95% CI, 1.03-1.10) or lactate ≥4.0mmol/L (aRR 1.10; 1.05-1.15), but not for other dysfunctions alone or in combination. Among patients without hypotension or lactate ≥4.0mmol/L, antibiotics at 3-6 vs. 0-3h were only associated with higher mortality in patients with acute respiratory failure (aRR 1.11; 1.05-1.18).
Mortality associations with antibiotics beyond 1 hour were most evident when sepsis time zero was defined by hypotension or lactate ≥4.0mmol/L, and with antibiotics beyond 3 hours when defined by acute respiratory failure. These findings could inform refinements to sepsis time zero definitions to better guide antibiotic urgency and performance measurement.

PMID:
43016314
Bibliographic data and abstract were imported from PubMed on 12 Nov 2026.

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