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

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.