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.