Original Investigation 

Less Is More

Antibiotic De-Escalation in Adults Hospitalized for Community-Onset Sepsis

Ashwin B. Gupta, Megan Heath, Emily Walzl, et al

JAMA Intern Med Published Online: December 22, 2025

doi: 10.1001/jamainternmed.2025.6919

Key Points

Question  Is broad-spectrum antibiotic de-escalation on encounter day 4 safe among patients hospitalized with community-onset sepsis who have no positive test result for multidrug-resistant organisms (MDROs)?

Findings  In this target trial emulation study including 36 924 patients with community-onset sepsis, de-escalation from methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa coverage were associated with similar 90-day all-cause mortality, fewer days of antibiotic therapy, and shorter length of hospitalizations compared with continued broad-spectrum coverage.

Meaning  These results suggest that de-escalation of broad-spectrum antibiotics among patients with community-onset sepsis and no positive MDRO test results is associated with similar safety outcomes and may reduce antibiotic exposure and length of hospitalization.

Abstract

Importance  Prolonged exposure to broad-spectrum antibiotics (BSA) may be associated with patient harm.

Objective  To assess outcomes of BSA de-escalation compared with continuation on encounter day 4 in patients hospitalized for community-onset sepsis.

Design, Setting, and Participants  This target trial emulation study was conducted at 67 hospitals participating in the Michigan Hospital Medicine Safety Consortium. Patients 18 years and older hospitalized for community-onset sepsis from June 2020 through September 2024 who initiated empiric BSA therapy without evidence of multidrug-resistant organism infection were included. Data were analyzed from September 2024 to November 2025.

Exposure  Inverse probability of treatment–weighted cohort exposed to de-escalation of BSA vs continuation at day 4.

Main Outcomes and Measures  The primary outcome was 90-day all-cause mortality. Secondary outcomes included in-hospital mortality, 30-day mortality, length of hospitalization, and days of antibiotic therapy.

Results  Among 36 924 patients with community-onset sepsis, 18 559 (50.3%) were female, 18 365 (49.7%) were male, and the median (IQR) age was 71 (61-80) years. A total of 6926 (18.8%) and 11 149 (30.2%) were eligible for target trial emulations evaluating de-escalation of anti–methicillin-resistant Staphylococcus aureus (MRSA) and anti–Pseudomonas aeruginosa(PSA; or other resistant gram-negative bacteria) antibiotics, respectively. Of these, 2993 (43.2%) and 2493 (22.4%) were de-escalated from anti-MRSA and anti-PSA coverage. After weighting, patients who were de-escalated vs continued on BSA were well balanced on baseline characteristics. In weighted analyses, anti-MRSA and anti-PSA de-escalation were associated with similar 90-day mortality as continued BSA therapy (anti-MRSA: odds ratio, 1.00; 95% CI, 0.88-1.14; anti-PSA: odds ratio, 0.98; 95% CI, 0.86-1.13). Additionally, anti-MRSA and anti-PSA de-escalation were associated with fewer days of antibiotics to day 14 (anti-MRSA de-escalation: risk ratio [RR], 0.91; 95% CI, 0.89-0.93; anti-PSA de-escalation: RR, 0.91; 95% CI, 0.88-0.93) and shorter length of hospitalization (anti-MRSA de-escalation: RR, 0.88; 95% CI, 0.85-0.92; anti-PSA de-escalation: RR, 0.91; 0.88-0.93). All other secondary outcomes were similar. Across 67 hospitals, the proportion of eligible patients de-escalated from BSA varied more than 2-fold (anti-MRSA de-escalation, 27.3% to 61.7%; anti-PSA de-escalation, 6.9% to 37.7%).

Conclusions and Relevance  In this study, de-escalation of empiric BSA therapy at day 4 was associated with similar safety outcomes, fewer antibiotic days, and shorter length of hospitalization among patients with community-onset sepsis compared with those who continued BSA therapy but varied widely in practice.