Clinical Outcomes of Linezolid Monotherapy versus Combination Therapy in Vancomycin-Resistant Enterococcal Infections

• Invasive VRE infections are associated with high mortality rates in critically ill patients. • Linezolid-based combination therapy does not offer a significant survival advantage over monotherapy. • Combination therapy significantly accelerates microbiological clearance and reduces post-infection length of stay. • Progressive thrombocytopenia manifests early (median 10 days), while hemoglobin and ANC remain relatively stable. Vancomycin-resistant Enterococcus (VRE) infections cause significant morbidity and mortality in critically ill patients. Linezolid-based combinations are increasingly used despite limited comparative data. We compared real-world outcomes of linezolid monotherapy versus combination therapy and characterized longitudinal hematologic trends. This retrospective study (2014–2024) evaluated adults receiving definitive linezolid-based therapy for VRE at a tertiary-care hospital. Propensity score matching (PSM) based on APACHE II scores compared clinical outcomes between treatment arms. Longitudinal hematologic parameters were analyzed to assess safety. Post-PSM, 36 patients were analyzed (n=18 per group). No significant differences occurred in in-hospital 30-day mortality or overall in-hospital mortality. However, combination therapy significantly shortened median time to microbiological clearance (4 vs. 6 days; p =0.02) and post-infection length of stay (18 vs. 30 days; p =0.04). Safety analysis revealed progressive platelet decline (159.0 to 98.0 × 10⁹/L) within a median of 10 days, while hemoglobin and ANC remained stable. Linezolid-based combination therapy did not demonstrate a survival benefit over monotherapy but was associated with accelerated microbiological clearance and reduced hospital stay. The early onset of hematologic changes across the cohort underscores the necessity for rigorous monitoring during linezolid administration.