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October - 2017


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The Timing of Early Antibiotics and Hospital Mortality in Sepsis

V.X Liu, V Fielding-Singh, J.D Greene, J.M Baker, T.J Iwashyna, J Bhattacharya, G.J Escobar Am J Resp Crit Care Med, 2017, 196(7);856–863


Early administration of antibiotics in sepsis and septic shock is a widely accepted measure of quality care. The exact timing thresholds remain elusive. This US, retrospective study of 35,000 adult patients with sepsis who received antibiotics within 6-hours of presentations from 21 EDs in Northern California from 2010-2013 examines this relationship.


What did they do;

  • Identified patients using the former sepsis-septic shock criteria from electronic databases using ICD sepsis codes + received antibiotics within 6-hours
  • Randomly selected 5,000 patients hospitalized in 2010 and 10,000 patients hospitalized in each year between 2011 and 2013
  • Collected granular data including vital signs, laboratory values, number of obs, and severity of illness indices. They used this to try and account for severity of illness that may have influenced the clinician decision to administer antibiotics 

What did they find;

  • Characteristics: 13.3% met criteria for septic shock, 52.0% for severe sepsis. Mortality was 3.9%, 8.8%, and 26.0% in patients with sepsis, severe sepsis, and septic shock, respectively
  • Comparisons between groups were highly significant. For example, the frequency of elevated band forms was 10.1% in sepsis vs 31.4% in septic shock. Shock patients had highest mean lactate value (4.6 [4.0–5.9] mmol/L). Among patients with septic shock, 2.4% and 43.4% had vasopressors initiated within 1 and 6 hours
  • Overall median time to antibiotics was 2.1 hrs, shortest in septic shock (1.7 h) and longest in sepsis (2.3 h; P , 0.001). Patients receiving earlier antibiotics had greater severity of illness compared with those receiving later antibiotics based on acuity level, acute severity of illness (LAPS2), vital signs, and laboratory values.
  • Patients receiving early antibiotics also had highest unadjusted mortality (11.4% and 9.5% for Hour 1 and Hour 2). I
  • Most common antibiotic  ceftriaxone, then azithromycin (sepsis), vancomycin (severe sepsis), and pipercillin-tazobactam (septic shock).
  • Primary outcome: Fully adjusted OR for hospital mortality based on antibiotic timing was 1.09 (95% CI, 1.05–1.13) per elapsed hour after ED presentation. This  was similar for patients with sepsis (1.09; 95% CI, 1.00–1.19; P = 0.046) and severe sepsis (1.07; 95% CI, 1.01–1.24; P = 0.014), whereas they were increased in septic shock (1.14; 95% CI, 1.06–1.23; P = 0.001). 
  • The absolute increase in mortality associated with an hour’s delay in antibiotic administration was 0.3% (95% CI, 0.01–0.6%; P = 0.04) for sepsis, 0.4% (95% CI, 0.1–0.8%; P = 0.02) for severe sepsis, and 1.8% (95% CI, 0.8–3.0%; P = 0.001) for shock. 
  • In subgroup analysis, delays in broad antibiotic administration were associated with an increased effect size (1.08; 95% CI, 1.01–1.16; P = 0.02) compared with delays in narrow antibiotic administration (OR 1.05; 95% CI, 1.01–1.10; P = 0.03).

What does it mean:

  • sure it is retrospective, but it is big, granular, and we are unlikely to see an RCT..
  • Increased time to antibiotics in ED was associated with increased mortality in all sepsis severity groups, greatest in septic shock.
  • These findings “support currently held beliefs that administering early antibiotics to infected patients with systemic inflammation is beneficial for reducing mortality.”
  • Although antibiotics given within the first hour of registration were associated with the greatest benefit, antibiotics given between hours 2 and 5 were associated with similar odds of mortality.



Rationale: Prior sepsis studies evaluating antibiotic timing have shown mixed results.

Objectives: To evaluate the association between antibiotic timing and mortality among patients with sepsis receiving antibiotics within 6 hours of emergency department registration.

Methods: Retrospective study of 35,000 randomly selected inpatients with sepsis treated at 21 emergency departments between 2010 and 2013 in Northern California. The primary exposure was antibiotics given within 6 hours of emergency department registration. The primary outcome was adjusted in-hospital mortality. We used detailed physiologic data to quantify severity of illness within 1 hour of registration and logistic regression to estimate the odds of hospital mortality based on antibiotic timing and patient factors.

Measurements and Main Results: The median time to antibiotic administration was 2.1 hours (interquartile range, 1.4–3.1 h). The adjusted odds ratio for hospital mortality based on each hour of delay in antibiotics after registration was 1.09 (95% confidence interval [CI], 1.05–1.13) for each elapsed hour between registration and antibiotic administration. The increase in absolute mortality associated with an hour’s delay in antibiotic administration was 0.3% (95% CI, 0.01–0.6%; P = 0.04) for sepsis, 0.4% (95% CI, 0.1–0.8%; P = 0.02) for severe sepsis, and 1.8% (95% CI, 0.8–3.0%; P = 0.001)

Conclusions: In a large, contemporary, and multicenter sample of patients with sepsis in the emergency department, hourly delays in antibiotic administration were associated with increased odds of hospital mortality even among patients who received antibiotics within 6 hours. The odds increased within each sepsis severity strata, and the increased odds of mortality were greatest in septic shock.


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