Linezolid Restrictions Linked to Higher Mortality in VRE-Screen-Positive Patients

Linezolid restriction policies at an academic medical center were associated with lower linezolid use and less linezolid resistance among Enterococcus isolates but also with higher in-hospital mortality among patients with a positive vancomycin-resistant Enterococcus (VRE) screen, according to a quasi-experimental study published in Clinical Infectious Diseases.

Investigators used a difference-in-differences design to analyze electronic health record data from 521,493 admissions at 2 academic medical centers from 2008 through 2019. Hospital 1 formalized prior authorization with dedicated stewardship pager coverage in 2011 and, in 2014, added written linezolid criteria that generally excluded empiric use, along with enhanced review after 72 hours. Hospital 2, which made no policy changes, served as the control.

Relative to the control hospital, the combined policies were associated with a 0.9-percentage-point reduction in linezolid use, a 27% relative decline from Hospital 1’s pre-policy level, and a 1.0-percentage-point reduction in the share of Enterococcus isolates resistant to linezolid, a 41% relative decline. Overall in-hospital mortality did not increase. Among VRE-screen-positive patients, however, mortality at Hospital 1 rose 4.7 percentage points relative to the control after both policies (95% CI, 1.9-7.5), a 33% relative increase, with larger increases among those with bacteremia or sepsis.

VRE-screen-positive patients accounted for 3.7% of admissions but 30.1% of linezolid use. In this group, empiric linezolid use fell by 59% after both policies, and the investigators identified delayed treatment as a potential mechanism. Linezolid approval rates fell relative to other restricted antibiotics after the stricter criteria took effect, followed by fewer requests. The policies were not associated with changes in negative control outcomes, including outpatient linezolid use.

The authors described the mortality findings as exploratory and hypothesis-generating. Limitations included reliance on 2 hospitals, nonrandomized policies, and all-cause rather than cause-specific mortality. The investigators concluded that screening-informed safeguards may help restriction policies preserve timely treatment for high-risk patients.

Source: Kong EL, Kubiak DW, Shenoy ES, Letourneau AR. Antibiotic stewardship, resistance, and mortality in vancomycin-resistant Enterococcus: a quasi-experimental study of linezolid restrictions. Clin Infect Dis. Published online October 16, 2026. doi:10.1093/cid/ciag656