Patterns of Antibiotic Use in Hospitalized COVID-19 Patients and Association with Secondary Infections and Outcomes

<b>Background/Objectives</b>: Antibiotic exposure is highly prevalent in patients hospitalized with COVID-19, yet the relationship between specific prescribing patterns, microbiologically confirmed secondary infections, and clinical outcomes remains incompletely understood, particularly in settings with high antimicrobial resistance. <b>Methods</b>: This single-center retrospective observational cohort included 395 consecutive adults hospitalized with RT-PCR-confirmed COVID-19 in a tertiary infectious diseases hospital. Data on demographics, comorbidities, baseline disease severity, antimicrobial prescribing (timing, WHO AWaRe class, duration, monotherapy/combination, escalation/de-escalation), microbiological results, and outcomes were extracted from electronic records and the microbiology information system. The primary outcome was microbiologically confirmed secondary infection; secondary outcomes were ICU admission, invasive mechanical ventilation, length of stay, and in-hospital mortality. Multivariable logistic regression and survival analyses assessed associations between antibiotic exposure and outcomes. <b>Results</b>: Overall, 88.4% of patients received systemic antibiotics, predominantly initiated within 24 h of admission and mostly empirical; 58.7% received combination regimens, with frequent use of Watch/Reserve agents. Secondary infections occurred in 28.4% of patients, were hospital-acquired in 82.1%, and involved multidrug-resistant organisms in 41.1% of cases. Any antibiotic exposure was independently associated with secondary infection (adjusted odds ratio, aOR 2.15; 95% CI 1.42-3.27), while prolonged therapy (≥7 days), Watch/Reserve use, and early initiation showed additional risk gradients. Antibiotic exposure was also associated with higher odds of ICU admission, invasive mechanical ventilation, prolonged hospitalization, and in-hospital mortality after adjustment. <b>Conclusions</b>: In this real-world COVID-19 cohort, broad and largely empirical antibiotic use was common and strongly associated with hospital-acquired, often multidrug-resistant secondary infections and worse clinical outcomes. These findings highlight the need for reinforced antimicrobial stewardship focusing on restrictive early broad-spectrum use, AWaRe-guided agent selection, systematic 48-72 h reassessment with de-escalation, and minimization of treatment duration.