How Important Is the Timing of Antibiotics for Surviving Sepsis?

Sepsis is a common, life-threatening organ dysfunction driven by a dysregulated host response to infection. Outcomes have improved over the years in line with a focus on intravenous fluids, appropriate antimicrobials, and other supportive measures, but for septic shock, mortality remains at 30% to 50%. The 2017 Surviving Sepsis Campaign guidelines¹ endorse a focus on rapidity of treatment once sepsis has been identified, with a strong recommendation for the administration of antimicrobial drugs within 1 hour; however, the quality of the supporting evidence is evaluated as moderate.

Data from multiple observational studies have addressed the question of whether early antibiotic administration is associated with improved survival. In a retrospective analysis of patients with sepsis admitted to intensive care units (ICUs) from 1989 to 2004, Kumar and colleagues found an average 7.6% decrease in survival with every hour delay in receiving antibiotics after the onset of hypotension.²

Other studies have shown a much less dramatic effect size or indeed no effect. Importantly, the heterogeneity of outcome of these studies may represent the degree to which confounding factors were controlled. A large study by Ferrer et al. analyzed data from 17,990 patients admitted to 165 ICUs in Europe, the United States, and South America.³ Delay in antibiotic administration was associated with increased mortality only after adjusting for sepsis severity score, location prior to ICU admission, and geographic region, and there was an hour-by-hour effect gradient. A 2015 meta-analysis by Sterling and colleagues concluded that there was no overall benefit to rapid antibiotic administration, although it is noteworthy that this result was largely driven by inclusion of the study by Ferrer and colleagues, but the analysis did not adjust for illness severity.⁴

In general, retrospective time-to-intervention studies are fraught with confounding elements because a treatment delay may be caused by factors that affect mortality independently. Confounding factors include patient complexity (more complex patients may be more diagnostically challenging), hospital arrival time/time of clinical deterioration (outside of regular hours there may be fewer and less experienced staff), quality of medical facility (lower-quality facilities may perform less well in multiple areas that relate to outcome).

Recently Alam and colleagues presented the results of the PHANTASi trial (ClinicalTrials.gov identifier: NCT01988428) in Lancet Respiratory Medicine.⁵ This study is the first prospective, randomized, controlled trial comparing administration of prehospital antibiotics with standard care in The Netherlands. Participants were adults with temperature above 38 °C or below 36 °C in addition to either heart rate >90 beats per minute or respiratory rate >20 per minute (systemic inflammatory response criteria, excluding abnormal white-blood cell count) who were recruited by specifically training emergency medical services (EMS) personnel. Eligible individuals were randomly assigned to receive either open-label ceftriaxone in the ambulance (following collection of one blood culture sample) or usual care with intravenous fluids and supplemental oxygen. The primary outcome was all-cause mortality at 28 days with an intention-to-treat analysis.

A total of 2698 patients were enrolled, with 1535 in the intervention group and 1137 in the control group. No difference was found in primary outcome, with a mortality rate of 8% in both groups (relative risk 0.95, 95% CI, 0.74-1.24). The median time to antibiotics was 26 minutes (interquartile range 19-34) before emergency department arrival for the intervention group and 70 minutes (interquartile range 36-128) after arrival for the control group. Important features of the study that influence interpretation are the low proportion of patients with septic shock (3.3% in the usual-care group and 4.3% in the intervention group) and an acknowledged protocol violation where overenthusiasm for early antibiotics so that, “some EMS personnel purposefully opened the envelopes until they found an envelope instructing randomisation to the intervention group.”

Infectious Disease Advisor discussed the results of the PHANTASi trial with Prabath W. B. Nanayakkara, MD, PhD, FRCP, from the department of internal medicine at VU University Medical Center in Amsterdam, The Netherlands, and senior PHANTASi trial investigator, and Anand Kumar, MD, professor of critical care medicine and infectious diseases at the University of Manitoba in Canada.

Infectious Disease Advisor: Was the PHANTASi trial sufficiently powered to identify a benefit for early antibiotic administration in those with the most severe infections?

Prabath W. B. Nanayakkara, MD, PhD, FRCP: We had a high percentage of patients with severe sepsis but only 4% [of the patients had] septic shock. About 9% were admitted to the ICU. The study is not powered to make any conclusions on septic shock. But we think that the study has enough [patients with] severe sepsis to conclude that early antibiotics are not always indicated.

Infectious Disease Advisor: Given the difference of only 96-minutes between intervention and control groups, do you think this result is generalizable to a nontrial setting or to countries with a longer ambulance response time?

Dr Nanayakkara: No, we don’t think so. Countries with longer response time should still consider giving antibiotics, especially in patients with septic shock.

Although the PHANTASi trial did not reveal a benefit to prehospital antibiotics for cases identified by systemic inflammatory response syndrome criteria, feasibility of prehospital recognition and treatment of sepsis was demonstrated. EMS personnel obtained blood cultures and gave antibiotics in 99% of patients in the intervention group. No antibiotic-related allergic reactions were observed. It was noted that more gram-positive bacteria were isolated from blood cultures in the intervention group than in the usual-care group, suggesting a higher rate of contamination. Also, fewer positive urine cultures were found after admission likely due to the effect of the first dose of antibiotics. Antibiotics were not given during admission for 9% in each group, mainly because viral infection was suspected.

Infectious Disease Advisor: Dr Kumar, why was there a significant difference between the PHANTASi trial and your 2006 study?

Anand Kumar, MD: It probably has to do with the fact that only a handful of the patients had septic shock. The reason that sepsis without shock and septic shock are different in my mind is that with septic shock, there is a delay-dependent risk for irreversible and irreplaceable organ failure. In other words, wait long enough — just a few hours with septic shock — and you start getting one, two, three, and then more organ failures. While we can replace one or two effectively, we can’t replace 4 or 5. You don’t tend to see that with sepsis, at least not at the same pace.

Infectious Disease Advisor: Should we manage sepsis differently from septic shock?

Dr Kumar: The Surviving Sepsis Campaign does recommend fast antimicrobials for both sepsis and septic shock, but you’ll note that the 2 conditions are separately evaluated and referenced (as opposed to saying that fast antimicrobials apply to all sepsis). That is because we recognized the different evidence for the 2 groups. Personally, I don’t think that faster antimicrobials make a difference in sepsis without shock, but the group overall did.

Infectious Disease Advisor: Do you think a prehospital study looking specifically at septic shock would be a possible area for future research?

Dr Kumar: Absolutely. I believe there are several groups working on that.

Conclusion

The concept of early antibiotic administration in treating infection has evident biological plausibility; however, time sensitivity to outcome appears to be most relevant in septic shock. Further prehospital studies may help to reveal the presence of a benefit for speed at the expense of precision in this sicker patient group.

Reference

1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock. Crit Care Med. 2017;45(3):486-552.
2. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.
3. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42(8):1749-1755.
4. Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. The impact of timing of antibiotics on outcomes in severe sepsis and septic shock: a systematic review and meta-analysis. Crit Care Med. 2015;43(9):1907-1915. 
5. Alam N, Oskam E, Stassen PM, et al; PHANTASi Trial Investigators and the ORCA (Onderzoeks Consortium Acute Geneeskunde) Research Consortium the Netherlands. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. Lancet Respir Med. 2018;6(1):40-50.