Delaying Antibiotics in Patients with Suspected Infection Increases Risk of Septic Shock
By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A retrospective cohort study found that delaying the first dose of antibiotics in patients suspected of having an infection in the emergency department led to a higher risk of progressing to septic shock and in-hospital mortality. Every hour antibiotics were delayed increased the risk of septic shock by 4%.
SOURCE: Bisarya R, Song X, Salle J, et al. Antibiotic timing and progression to septic shock among patients in the ED with suspected infection. Chest 2022;161:112-120.
Some of the most crucial factors for improving outcomes in sepsis are the timely recognition of infection and the prompt administration of antibiotics. Indeed, the Surviving Sepsis Campaign guidelines recommend that antibiotics be started within one hour of sepsis recognition for patients with either sepsis or septic shock. Bisarya and colleagues sought to further clarify the relationship between the time from presentation to the emergency department (ED) with suspected infection to administration of antibiotics and progression to septic shock.
The study was a retrospective cohort analysis from a single medical center in Kansas. Patients were included who were at least 18 years of age and had sought treatment in the ED for suspected infection between March 2007 and March 2020. The authors defined suspected infection as patients having blood or body fluid cultures obtained and antimicrobials started within four hours of one another. Patients were excluded who had septic shock on presentation or received their initial antimicrobial more than 24 hours after admission. The authors defined progression to septic shock as having vasopressor administration started more than three hours after ED triage time. Clinical variables that were statistically significant from univariate regression models were combined into multivariate logistic regression models to predict septic shock and in-hospital mortality.
There were 74,114 patient encounters in the final analysis, of which 5,510 progressed to septic shock. The most common sources of infection were respiratory/lung (38%), urinary tract (34%), skin and soft tissue (18%), and intra-abdominal (9%). Patients who progressed to septic shock had increased hospital length of stay (12.3 days vs. 3.69 ± 5.0 days; P < 0.001) and increased in-hospital mortality (10.7% vs. 0.60%; P < 0.001) compared to those who did not. Furthermore, patients who progressed to septic shock had a quick Sequential Organ Failure Assessment (qSOFA) score of ≥ 2 (8.78% vs. 2.59%; P < 0.001), and severe sepsis on presentation (16.2% vs. 5.96%; P < 0.001).
The median time to first antimicrobial administration was 1.85 hours for all patients and did not change significantly on an annual basis during the study period. Piperacillin/tazobactam and ceftriaxone were the most common antibiotics administered. For patients who progressed to septic shock, the median time to first administration of antimicrobials was 1.67 hours (interquartile range [IQR], 0.66-3.88 hours) vs. 1.86 hours (IQR, 0.80-3.80 hours) for those who did not progress to septic shock (P < 0.05). The median time to receive antibiotics was 1.8 hours for all patients, and the timing effect for antibiotics was most important within the first five hours of arrival to the ED. Multivariate logistic regression analysis found that time to antibiotic administration was significantly associated with progression to septic shock (odds ratio [OR], 1.03 per one hour of antibiotic delay; 95% confidence interval [CI], 1.02-1.04; P < 0.001).
For every passing hour from ED triage time to antimicrobial administration, the risk of progression to septic shock increased by 4.0% for each one hour up to 24 hours from triage, adjusting for severity of illness. The median time to septic shock with a qSOFA score ≥ 2 was 11.2 hours (range, 5.5-49.7 hours). Finally, the time to first antimicrobial administration had an OR of 1.02 (95% CI, 1.006-1.04; P = 0.007) for in-hospital mortality.
This large cohort study provides compelling evidence that the first few hours for patients with infections in the ED are the most crucial to give antibiotics to prevent the progression of illness. Indeed, the odds of progression to septic shock were highest during the first five hours in the ED, with delays in antibiotic administration for each passing hour from ED triage time associated with increased progression to septic shock. Thus, the Infectious Diseases Society of America’s (IDSA’s) recommendation that administering antibiotics within one hour from when infection is suspected is too aggressive and that more time should be taken to be certain of infection may need to be reconsidered in light of this new evidence.1
It was surprising that the median time to first antibiotic administration was sooner for patients who progressed to septic shock compared to patients who did not develop septic shock. One possible explanation is that some patients entered a trajectory to shock before arriving at the ED. The duration of sepsis before ED presentation likely was a key factor, but this was not able to be analyzed in study data set.
There are some limitations to the study worth mention. First, it only included patients in the ED at a single hospital in the Midwest, so the findings might not be applicable to other geographic regions and healthcare settings. Second, unmeasured confounded variables could have affected the findings because of the retrospective design. However, the investigators addressed this concern by accounting for disease severity at presentation and including time to antibiotics as just one factor in the multivariate logistic regression analysis of all factors associated with the development of septic shock. Finally, the investigators were not able to ascertain the reasons for delays in antibiotic administration, such as late recognition by providers, or whether patients had received antibiotics prior to their presentation to the ED.
The study by Bisarya and colleagues is novel because it evaluated patients suspected of infection at triage in the ED, not just those with sepsis. Their findings highlight the principle of rapid antibiotic administration as soon as infection is recognized. It also draws attention to the need for faster and more accurate methods to diagnose infections early in their clinical course. The continued development of innovative methods to detect infections, such as rapid molecular testing, machine learning, and artificial intelligence, is needed to improve outcomes in sepsis. Moreover, balancing rapid antibiotic administration with the potential downsides, such as promoting antimicrobial resistance and antibiotic toxicities (e.g., Clostridiodes difficile infection, organ damage, and allergic reactions), is challenging and requires further analysis and contemplation.
- Rhee C, Chiotos K, Cosgrove SE, et al. Infectious Diseases Society of America Position Paper: Recommended revisions to the National Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) sepsis quality measure. Clin Infect Dis 2021;72:541-552.
A retrospective cohort study found that delaying the first dose of antibiotics in patients suspected of having an infection in the emergency department led to a higher risk of progressing to septic shock and in-hospital mortality. Every hour antibiotics were delayed increased the risk of septic shock by 4%.
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