A study involving more than 1.5 million US hospital patients found that quicker antimicrobial treatment for sepsis did not lead to increased antibiotic use, a finding that may ease antimicrobial stewardship concerns about sepsis treatment guidelines.
The study, published this week in JAMA Internal Medicine, found that, from 2013 through 2018, the adjusted median time to first antibiotic administration in sepsis patients fell by 37 minutes. But during that same period, days of antibiotic therapy among patients with sepsis also declined, and patient outcomes improved.
The authors of the study say the results provide support for the many initiatives over the past decade that have focused on reducing the time to antibiotic treatment for sepsis, which occurs when the body has an immediate, systemic, and overwhelming reaction to an infection that can lead to tissue damage, organ failure, and death. Delayed antibiotic treatment in sepsis patients has been associated with increased mortality.
Emphasis on quick treatment raises concerns
Sepsis contributes to an estimated 50 million hospitalizations and 10 million deaths annually, with some estimates suggesting sepsis accounts for 30% to 50% of deaths in hospitalized patients. Early identification and treatment are considered critical, and national and international guidelines recommend early, broad-spectrum antibiotic therapy for patients with signs and symptoms of sepsis.
But sepsis can be difficult to diagnose with certainty and is not always caused by a bacterial pathogen, raising concerns that the emphasis on quick antibiotic treatment may result in antimicrobial overuse and promotion of resistance. Of particular concern is the high rate of sepsis overdiagnosis—studies have shown that as many as one in three patients who receive antibiotic therapy for suspected bacterial sepsis are later determined to have a non-infectious or viral condition.
In a paper published in 2020, in fact, members of the Infectious Diseases Society of America and five other medical organizations argued that the Centers for Medicare & Medicaid Services' Severe Sepsis and Septic Shock Early Management Bundle—which requires clinicians to administer broad-spectrum antibiotics to suspected sepsis patients within 3 hours and is used to measure hospital performance on sepsis treatment—should be modified.
The authors argued that the bundle does not account for the high rates of sepsis overdiagnosis and has the potential to drive antibiotic overuse.
Faster antibiotic initiation, shorter duration
To determine whether those concerns are warranted, a team led by researchers from the University of Michigan analyzed data on adult patients hospitalized with two or more systemic inflammatory response syndrome (SIRS) criteria from 2013 through 2018 at 152 hospitals in the US Veterans Affairs (VA) and Kaiser Permanente Northern California (KPNC) healthcare systems.
Patients were classified as having sepsis on the basis of objective evidence of suspected infection and acute organ dysfunction—a definition similar to the US Centers for Disease Control and Prevention's (CDC's) Adult Sepsis Event definition.
The primary exposure was the time to first systemic antimicrobial over the study period, calculated as the time from the patient's arrival at the emergency department (ED) to the administration of an antimicrobial drug. Primary outcomes included total days with antimicrobial therapy, broadness of antimicrobial therapy, in-hospital mortality, 30-day mortality, length of hospitalization, and new culture positivity for a multidrug-resistant (MDR) pathogen.
Of the 1,559,253 patients admitted to the ED with two or more SIRS criteria from 2013 through 2018, 273,255 (17.5%) met objective criteria for sepsis. Patients with sepsis had a median age of 69, and 78.9% were men, 70% were White, and 16.4% were Black.
In multivariable models that were adjusted for patient characteristics, the adjusted median time to first antibiotic fell from 4.7 hours in 2013 to 3.9 hours in 2018, while the mean days of antimicrobial therapy declined from 11.4 (95% confidence interval [CI], 11.4 to 11.5 days) to 10.5 (95% CI, 10.5 to 10.6 days). Mean broadness of antibiotic therapy and receipt of broad-spectrum coverage both decreased over time, as well.
"For all antimicrobial prescribing trends examined, there was no correlation and no association with the temporal trend in antimicrobial timing for sepsis," the study authors wrote. "Temporal trends in antimicrobial use, days of therapy, and broadness of antibacterial coverage did not differ according to magnitude of decrease in antimicrobial timing for sepsis."
During the same period, antibiotic use within 48 hours, days of antibiotic therapy, and receipt of broad-spectrum coverage also decreased within the wider cohort of patients with SIRS (which is similar to sepsis but can have non-infectious causes). The declines were observed consistently across hospitals.
Analysis of clinical outcomes showed that, among both patients with sepsis and SIRS, 30-day mortality declined, falling from 16.3% to 12.3% in sepsis patients and 4.3% to 2.9% in SIRS patients. In-hospital mortality, length of hospital stay, and new MDR culture positivity also declined in both groups.
Improving sepsis treatment doesn't impede stewardship
The authors say that, while the declines in antibiotic prescribing were small and may have been facilitated by existing antibiotic stewardship programs at VA and KPNC hospitals, the findings provide no evidence that efforts to accelerate antibiotic treatment for sepsis impeded those stewardship efforts, despite the concerns that have been raised.
"The pushback has been [that time-to-treatment for sepsis] should not be a performance measure because it's going to cause more harm than good, and I think our data shows it probably does more good than harm," lead study author Hallie Prescott, MD, MSc, of the University of Michigan, said in a university press release. "We have shown that 152 hospitals have been able to make improvements in stewardship and sepsis treatment at the same time, contrary to popular belief."
Co-author Vincent Liu, MD, of the Kaiser Permanente Division of Research, said the results add to the conversation about to how to bet treat sepsis.
"It also confirms that we now need to look for new opportunities to mitigate sepsis by finding patients at high risk before they arrive at the hospital, identifying hospitalized patients most likely to benefit from specific treatments, and enhancing their recovery after they survive sepsis," he said.
