Clinical question: Is de-escalation of broad-spectrum antibiotics (BSAs) safe on encounter day four in patients with community-onset sepsis with no positive tests for multidrug-resistant organisms (MDROs)?
Background: Studies have shown that BSAs covering MDROs have been associated with lower mortality in patients with increased risk of MDRO infections and are recommended by the 2021 Surviving Sepsis Guidelines. However, their use is associated with Clostridioides difficile infections and antibiotic resistance.
Study design: Two target-trial emulation studies (observational)
Setting: A total of 67 hospitals in the Michigan Hospital Medicine Safety Consortium
Synopsis: Of 36,924 patients with community-onset sepsis on BSAs on encounter day four, 6,926 patients were eligible for the methicillin-resistant Staphylococcus aureus (MRSA) trial, and 11,119 patients were eligible for the Pseudomonas aeruginosa (PSA) trial. Inclusion criteria included receiving BSAs on day three and no positive MRSA or PSA testing on day one or two. Inverse probability of treatment weighting was used to balance patient factors, including chronic health conditions, site of infection, and predicted 30-day mortality on presentation. A total of 43.2% of patients were de-escalated from anti-MRSA coverage, and 22.4% from anti-PSA coverage. The patients who were de-escalated by day four had similar 90-day all-cause mortality (anti-MRSA OR, 1.00; 95% CI, 0.88-1.14 and anti-PSA OR, 0.98; 95% CI, 0.86-1.13). The de-escalated patients also had shorter lengths of stay and fewer days on antibiotics compared to patients who continued to receive BSAs. The study’s main limitation is that it was observational and may have had confounding. These findings are similar to those of trials such as the SIMPLIFY trial, though further randomized controlled trials are needed.
Bottom line: De-escalation of empiric BSAs by day four was associated with similar 90-day mortality and shorter length of stay.
Citation: Gupta AB, et al. Antibiotic de-escalation in adults hospitalized for community-onset sepsis. JAMA Intern Med. 2026;186(2):192-202. doi:10.1001/jamainternmed.2025.6919.
Dr. Bellamy
Dr. Bellamy is a hospitalist and assistant professor of internal medicine at the University of North Carolina in Chapel Hill, N.C.