Appropriate Antibiotic Delay in Bloodstream Infections: How Long Is Too Long?

It has long been established that effective antimicrobial treatment is paramount to reducing morbidity and mortality in patients with bloodstream infections (BSIs). The Surviving Sepsis Campaign guidelines recommend initiating antibiotics in adult patients with septic shock within 1 hour after sepsis is recognized.¹ The impact of antibiotics is most pronounced in patients with septic shock, with each additional hour after emergency department arrival increasing the odds of in-hospital mortality.² In patients with sepsis without septic shock, the recommendation for initiating antibiotics is extended to 3 hours after sepsis is first suspected. Early antibiotics allow for stabilization of sepsis-induced tissue hypoperfusion but must be balanced against potential harms associated with administering unnecessary antibiotics, antimicrobial resistance, kidney injury, thrombocytopenia, hypersensitivity reactions, and/or Clostridioides difficile infection.
 
For patients with microbiologically confirmed BSI, less is known about the exact impact antibiotic delay has on mortality. Van Heuverswyn et al studied the impact time-to-appropriate antimicrobial treatment has on 30-day mortality in adult patients with BSIs.³ This was a retrospective cohort study on patients with BSI using electronic health data from Karolinska University Hospital, a large academic medical center in Stockholm, Sweden, between 2012 and 2019. Using the reported in vitro susceptibility reports, the antimicrobials chosen were classified as either appropriate or inappropriate. Therefore, the study focused not only on the mortality impact of time-to-antibiotics, but also on the time to start the right antibiotic(s).
 
Demographics, hospital administrative data, comorbidities, antimicrobials, vital signs, and laboratory/microbiologic data were collected. Mortality data were derived from the national personal data register. Only the first BSI episode per admission was assessed. Participants were followed for 30 days from the first positive blood culture. To capture a patient population in whom clinicians were inclined to treat promptly, the authors included episodes in which patients received antibiotics within 24 hours from blood culture collection. To be considered appropriate, at least one antimicrobial drug must be received within 24 hours and in accordance with the in vitro susceptibility data. BSI episodes occurring within 48 hours after hospital admission were considered community onset, whereas BSI episodes occurring after 48 hours were considered hospital onset.
 
BSI episodes occurred 10,628 times in 9291 unique patients, of whom 56.8% were female. This corresponded to 12,223 unique pathogens of which Escherichia coli, Staphylococcus aureus, and viridans streptococci were the most prevalent. The most common empirical antimicrobials were cefotaxime (46.5%), piperacillin-tazobactam (35.7%), and meropenem (12.1%). The patients’ median age was 69 years. Only 4% of the episodes featured an antimicrobial-resistant pathogen. Polymicrobial BSI was found in 11.5% of patients. Appropriate antibiotics were administered within the first hour in 30.7% of the episodes and within 3 hours in 50.4% of the episodes. Afterwards, 17.2% of the episodes received appropriate therapy by 3 to 12 hours, 7.1% between 12 and 24 hours, 6.4% between 24 and 48 hours, and 4.9% between 48 and 72 hours. The source of the infection was unknown in nearly half the patients, followed by urinary source, pulmonary source, and abdominal source.
 
The crude 30-day mortality was 11.8% in the overall population. Of the 13.7% of patients who received appropriate antibiotics within 1 hour after blood culture collection, 9.7% had septic shock, 10.9% required intensive care unit (ICU) admission, and 40.6% received combination therapy. In the overall population, septic shock was present in 24.3% of patients. There was a lack of mortality protection when antibiotics were delayed at the 1-, 3-, and 6-hour marks after blood culture collection.
 
Surprisingly, even receiving inappropriate treatment at 1 hour was associated with lower risk of death. However, after 12 hours, the risk of death increased with inappropriate treatment and continued to increase gradually at 24, 48, and 72 hours. This estimate held regardless of the patient’s Sequential Organ Failure Assessment (SOFA) score on admission. These findings are similar to the data published by Kadri et al, which showed the greatest increase in mortality risk in patients with BSI having discordant antimicrobial treatment was at 24 hours.⁴ Mortality was also high at all times in patients with BSI caused by antimicrobial-resistant pathogens.
 
This study has several limitations. First, there is the issue of bias when studies evaluate antimicrobial time-to-treatment in patients with sepsis. The authors illustrate the effect of potential biases on the current body of evidence for time-to-treatment with antimicrobials, including efforts to adjust for the severity of disease (indication bias) as critically ill patients are more likely to receive antibiotics and/or die with scarcity of data analyzing time-to-treatment in patients who survive long enough to be switched to appropriate treatment (immortal time bias). Second, there is uncertainty regarding the onset of time zero. The authors establish time zero as the time blood cultures are collected, which can be drastically different from the time the patient arrived in the emergency department. Third, although inappropriate antibiotics were administered, mortality could have been heavily affected by other supportive measures, including IV fluids, vasopressors, respiratory support, and/or time-to-adequate infectious source control.

Other limitations include the lack of generalizability of their antibiograms, inclusion of only patients with BSI, monocentric observational design, subjectivity toward determining whether an organism is a pathogen or contaminant, and exclusion of patients with BSI onset in the ICU or obstetric unit. Recent studies have demonstrated that 8.5% of patients with sepsis require ICU admission.⁵ Patients may have been swiftly admitted to the ICU before blood cultures were collected and therefore excluded. The authors acknowledge the limitation of including a relatively small number of patients with septic shock, therefore underpowering the ability to draw meaningful conclusions in this subgroup. Finally, appropriateness of antibiotics was based only on antibiotic choice, not dosing, route, or duration, which could have affected the results.
 
The results of this study call into question the recommendation by the Surviving Sepsis Campaign to use aggressive broad-spectrum empiric antibiotics within 3 hours of sepsis recognition in patients with suspected BSI without septic shock or meningitis.¹ Others articles have also reported on appropriate antibiotics in patients with BSI. Xu et al showed that one in every three patients with gram-negative BSI received inappropriate empiric antibiotic therapy, of which 48.28% died.⁶ Data have also illustrated pathogen-specific optimal antimicrobial treatment windows, including 24 hours for Klebsiella pneumoniae BSI, 48.1 hours for enterococci BSI, and 52 hours for Pseudomonas aeruginosa BSI.^7-9 Therefore, while the general consensus is that early antibiotic administration lowers mortality, the promotion for antibiotics to be administered within 3 hours in patients with BSI who lack septic shock is now even more debatable.


References:

1. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2021. Crit Care Med. 2021 Nov 1;49(11):e1063-e1143.
2. Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017 Jun 8;376(23):2235-2244.
3. Van Heuverswyn J, Valik JK, van der Werff SD, Hedberg P, Giske C, Nauclér P. Association between time to appropriate antimicrobial treatment and 30-day mortality in patients with bloodstream infections: a retrospective cohort study. Clin Infect Dis. 2023 Feb 8;76(3):469-478.
4. Kadri SS, Lai YL, Warner S, et al; National Institutes of Health Antimicrobial Resistance Outcomes Research Initiative (NIH-ARORI). Inappropriate empirical antibiotic therapy for bloodstream infections based on discordant in-vitro susceptibilities: a retrospective cohort analysis of prevalence, predictors, and mortality risk in US hospitals. Lancet Infect Dis. 2021 Feb;21(2):241-251.
5. Skei NV, Nilsen TIL, Mohus RM, et al. Correction: Trends in mortality after a sepsis hospitalization: a nationwide prospective registry study from 2008 to 2021. Infection. 2023 Dec;51(6):1871-1873.
6. Xu S, Song Z, Han F, Zhang C. Effect of appropriate empirical antimicrobial therapy on mortality of patients with gram-negative bloodstream infections: a retrospective cohort study. BMC Infect Dis. 2023 May 23;23(1):344.
7. Falcone M, Bassetti M, Tiseo G, et al. Time to appropriate antibiotic therapy is a predictor of outcome in patients with bloodstream infection caused by KPC-producing Klebsiella pneumoniae. 2020 Jan 30;24(1):29.
8. Zasowski EJ, Claeys KC, Lagnf AM, Davis SL, Rybak MJ. Time is of the essence: the impact of delayed antibiotic therapy on patient outcomes in hospital-onset Enterococcal bloodstream infections. 2016 May 15;:1242-1250.
9. Lodise TP Jr, Patel N, Kwa A, et al. Predictors of 30-day mortality among patients with Pseudomonas aeruginosa bloodstream infections: impact of delayed appropriate antibiotic selection. 2007 Oct;:3510-3515.