Study supports de-escalation of broad-spectrum antibiotics in certain Community-Onset Sepsis patients: JAMA
USA: Researchers have found in a new study that de-escalation of empiric broad-spectrum antibiotic therapy on day 4 in community-onset sepsis was associated with comparable safety outcomes, reduced antibiotic exposure, and shorter hospital stays compared with continued broad-spectrum therapy, although practice patterns varied widely.
Broad-spectrum antibiotics are routinely initiated in patients hospitalized with sepsis to ensure early coverage of potential multidrug-resistant organisms. However, prolonged exposure to these agents has been linked to adverse effects, including antimicrobial resistance, drug toxicity, and secondary infections.
To better understand whether stepping down therapy is safe once resistant pathogens are ruled out, investigators led by Ashwin B. Gupta from the Medicine Service at the VA Ann Arbor Healthcare System conducted a large, real-world evaluation of antibiotic de-escalation practices.
The study, published in JAMA Internal Medicine, employed a target trial emulation design. It included adults aged 18 years and older who were hospitalized with community-onset sepsis across 67 hospitals participating in the Michigan Hospital Medicine Safety Consortium. Patients were enrolled between June 2020 and September 2024 if they had started empiric broad-spectrum antibiotics without evidence of infection due to multidrug-resistant organisms. Outcomes were assessed by comparing patients who underwent de-escalation of therapy on hospital day 4 with those who continued broad-spectrum coverage.
A total of 36,924 patients were included in the analysis, with a median age of 71 years. Approximately half of the cohort were women. Subgroups eligible for de-escalation analyses included patients receiving empiric coverage for methicillin-resistant Staphylococcus aureus (MRSA) and those receiving anti–Pseudomonas aeruginosa or other resistant gram-negative coverage. Using inverse probability of treatment weighting, the researchers ensured that baseline characteristics were well balanced between patients who were de-escalated and those who continued broad-spectrum therapy.
The study led to the following findings:
- De-escalation of anti-MRSA or anti-pseudomonal antibiotics on day 4 was not associated with an increased risk of mortality.
- Ninety-day all-cause mortality was comparable between patients who underwent de-escalation and those who continued broad-spectrum therapy.
- In-hospital and 30-day mortality rates were also similar between the two groups.
- Patients in the de-escalation group received fewer days of antibiotic therapy within the first 14 days of hospitalization.
- De-escalation was associated with a shorter length of hospital stay compared with continued broad-spectrum treatment.
- Substantial variation in de-escalation practices was observed across hospitals.
- The proportion of eligible patients undergoing de-escalation varied more than twofold between participating centers, reflecting differences in clinical practice patterns.
The authors note that while the study was observational and cannot fully exclude residual confounding, extensive adjustment methods were applied to strengthen confidence in the results. Some outcomes, such as readmissions and Clostridioides difficile infections, may have been incompletely captured and were considered exploratory.
"Overall, the findings support the safety of timely antibiotic de-escalation in patients with community-onset sepsis who test negative for multidrug-resistant organisms. The results reinforce antimicrobial stewardship efforts by showing that reducing unnecessary antibiotic exposure can be achieved without compromising patient safety, while also shortening hospital stays," the authors concluded.
Reference:
Gupta AB, Heath M, Walzl E, et al. Antibiotic De-Escalation in Adults Hospitalized for Community-Onset Sepsis. JAMA Intern Med. Published online December 22, 2025. doi:10.1001/jamainternmed.2025.6919
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