Current Controversies in Sepsis Management

Stephanie R. Moss, MD; Hallie C. Prescott, MD, MSc


Semin Respir Crit Care Med. 2019;40(5):594-603. 

In This Article

Antibiotic Timing—Should all Patients With Suspected Sepsis Receive Antibiotics Within 1 Hour?

In 2016, the Surviving Sepsis Campaign (SSC) released updated guidelines, which recommend initiating antibiotics within 1 hour for any patient with suspected sepsis or septic shock.[8] In 2018, this recommendation was also incorporated into a new 1-hour sepsis care bundle.[9]

The recommendation is supported by several large observational studies demonstrating measurable increases in mortality with every hour delay in antibiotic administration.[7,10] Additionally, delays in antibiotic delivery have been associated with increased length of stay and severity of organ dysfunction.[11–13]

However, despite the evidence that delays in antibiotics are associated with worse clinical outcomes among septic patients, there is substantial concern that striving for 1-hour antibiotic delivery in all patients with suspected sepsis may cause harm. Over the past 2 years, several editorials, perspectives, and blogposts have criticized the 1-hour threshold.[14–17] Moreover, the Infectious Diseases Society of America did not endorse the 2016 SSC guidelines, in part due to concerns that the 1-hour antibiotic goal may lead to indiscriminate antibiotic use.[18] The most compelling arguments against a 1-hour antibiotic threshold are as follows.

Diagnostic uncertainty: Most studies supporting earlier antibiotics are retrospective studies focusing on patients deemed to have sepsis at the time of hospital discharge. However, early on in a patient's course when initial antibiotic decisions must be made, clinicians are often uncertain regarding sepsis diagnosis. Physicians frequently disagree about sepsis diagnosis in standardized vignettes, [19] and in one cohort study, 43% of patients admitted to the intensive care unit (ICU) with a presumptive diagnosis of sepsis were determined to have no (13%) or only possible (30%) sepsis at hospital discharge. [20] Enforcing early treatment decisions in the setting of diagnostic ambiguity is likely to increase unnecessary antibiotic use, contributing to antibiotic-associated harms and resistance.
Unequal benefit across patients: The current guidelines recommend a 1-hour threshold for both sepsis and septic shock. However, studies consistently show that the benefit of earlier antibiotics is greater for sicker patients—in particular, patients with septic shock requiring vasopressors. [7,10]
Distrust of observational data: Studies supporting earlier antibiotics are observational studies which adjust for differences in illness severity using regression. The opportunity for residual confounding always exists, but quantitative bias analysis suggests that a strong and common unmeasured confounder would be needed to negate the results. [7] The 2,698-patient PHANTASi trial randomized patients to antibiotic delivery in the ambulance en route to the hospital versus routine care. Despite speeding up the delivery of antibiotics by a median of 96 minutes in the intervention arm, there was no improvement in 28-day mortality. [21] This study has been interpreted by some as refuting the findings of observational studies. However, even if the hourly relative risk reduction values of earlier antibiotics were identical to those of the observational studies, one would not expect to see a significant impact on mortality in a study population of 2,698 patients with a baseline 28-day mortality rate of 8%. Rather, the lack of effect in the PHANTASi trial is likely a reflection of the lower baseline illness severity in enrolled patients.

For now, clinicians should focus their efforts on administering antibiotics within 1 hour to those patients with the most severe presentations (e.g., those with shock, respiratory failure, altered mentation, or lactic acidosis), acknowledging that the risks of inappropriately withholding antibiotics are greater in sicker patients.[22] Additional studies are needed to empirically define the threshold of illness severity below which is it safe to delay antibiotics to complete additional diagnostic evaluation to confirm or refute the presence of infection to clarify the source of infection.