Sepsis
Corey Diamond, PharmD
There is now little question that early administration of antibiotics when there is clinical suspicion of sepsis improves outcomes, but the optimal timing of that decision is still hotly debated. How early is “early”? Researchers who published a new study in Annals of Emergency Medicine investigated if administration of broad-spectrum antibiotics within an “immediate” 1-hour window of sepsis/septic shock onset has additional benefits or risks over a more “early” 3-hour window.
Previous research, specifically a 2017 study by Seymour and colleagues published in the New England Journal of Medicine, has shown that a delay in antibiotic administration of more than 3 hours after sepsis recognition may lead to an increase in patient deaths. But 3 hours is still a significant grey area when it comes to sepsis, so the question is now shifting to the benefits or risks of a narrower time window.
To investigate this further, Rothrock and colleagues conducted a meta-analysis that pooled data on more than 33,000 patients from 13 observational studies. They looked at the difference in mortality rates when septic patients received “immediate” broad-spectrum antibiotic administration (within 1 hour) versus “early” administration (within 1 to 3 hours) of sepsis. The study included patients from 249 different hospitals.
The researchers observed no significant difference in deaths between patients receiving “immediate” administration and those receiving “early” administration of antibiotics. They also found that a delay of 1 to 3 hours was favorable for mortality in patients with severe sepsis.
It is important to note that sepsis protocols and order sets often vary considerably between hospitals. The study authors did not adjust for differences in antibiotic formularies and nonantibiotic protocols (e.g., timing of fluids and vasopressors) between the designated groups, raising a slight concern for a false negative.
“Only a prospective study controlling for each of these factors and randomization of antibiotic timing to immediate versus early periods would definitively show a benefit of antibiotics within either specified period,” wrote the authors.
Controversy
The 2016 Surviving Sepsis Campaign (SSC) guidelines strongly recommend initiation of broad-spectrum antibiotics with a minimum target of 1 hour upon clinical suspicion of sepsis. Earlier may not always be better, however. Recent literature has called into question the necessity of the 1-hour time limit, with opponents advocating for a more flexible window of decision making.
The Infectious Diseases Society of America (IDSA), among other societies, currently does not endorse the 1-hour minimum recommendation from the SSC. In a 2018 position statement, the organization warned that an overly rigid time criteria “may lead to unintended consequences, namely, an increased likelihood that broad-spectrum antibiotics will be given more frequently to uninfected patients.”
Clinical implications
These studies’ findings underscore the need for a more nuanced approach to dealing with initial sepsis recognition. Implementing a protocol with a time pressure on administration of broad-spectrum antibiotics raises several concerns. Less time for practitioners to assess the patient before antibiotic initiation may lead to misdiagnosis and cause unwarranted exposure and risk to patients that might not have an infection to begin with.
Some of the unintended consequences IDSA warned about may have already occurred in some hospitals. A 2017 internal study conducted by Heinisch and colleagues reported an uptick of Clostridium difficile infections at Mount Sinai Hospital in New York after the facility implemented protocols in accordance with the SSC guidelines, leading to increased antibiotic use. The study was published in the American Journal of Infection Control.
A 1-hour minimum also presents logistical problems. “Pushing the requirement to 3 hours makes a lot of practical sense,” said Bethany Shoulders, PharmD, BCCCP, an intensive care pharmacy specialist at the University of Florida Health Shands Hospital in Gainesville. “Oftentimes, after sepsis work-up begins, there is not enough venous access to administer broad-spectrum antimicrobial coverage [often multiple antibiotics] within this time frame.” She added that since the infection source is often being worked up during this time, the right antibiotic might not be revealed until further diagnostic work-up occurs.