Comparative Safety of Empirical Antibiotic Classes in Newly Hospitalized COVID-19 Patients

Background: Empirical antibiotic use is common in hospitalized patients with COVID-19 despite the low prevalence of bacterial coinfection, raising concerns about antimicrobial resistance and inappropriate prescribing. However, the comparative safety of commonly used antibiotic classes in this context remains unclear. Methods: We conducted a retrospective cohort study using real-world clinical data standardized through the Observational Medical Outcomes Partnership Common Data Model from 1 January 2020 to 31 May 2025. Adults with confirmed COVID-19 who were administered empirical antibiotics on the admission day were included. Empirical antibiotic exposure was categorized as third-generation cephalosporins (3GCs), fluoroquinolones, or aminopenicillins with β-lactamase inhibitors (PEN–BLis). Results: Compared with 3GCs, fluoroquinolone use was associated with significantly higher risks of mechanical ventilation (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 1.12–2.00), ICU admission (HR: 1.54; 95% CI: 1.10–2.15), vasopressor use (HR: 1.35; 95% CI: 1.11–1.63), all-cause in-hospital mortality (HR: 1.55; 95% CI: 1.22–1.96), and the composite outcome (HR: 1.32; 95% CI: 1.10–1.60). PEN–BLis showed no significant differences from 3GCs across outcomes. Conclusions: Empirical fluoroquinolone use at COVID-19 admission may be associated with greater risks of critical care interventions and in-hospital mortality compared to those of 3GCs. These findings highlight the need for careful patient selection and clinical judgment when initiating empirical antibiotic therapy for viral respiratory infections such as COVID-19.