The increased incidence of antimicrobial resistance during coronavirus disease 2019 (COVID-19) is a very important collateral damage of global concern. The cause is multifactorial and is particularly related to the high rates of antibiotic use in COVID-19 patients with a relatively low rate of secondary co-infection. To this end, we conducted a retrospective observational study of 1269 COVID-19 patients admitted during the years 2020, 2021 and 2022 in two Italian hospitals, with a focus on bacterial co-infections and antimicrobial therapy. Multivariate logistic regression was used to analyze the association between bacterial co-infection, antibiotic use and hospital death after adjustment for age and comorbidity. Bacterial co-infection was detected in 185 patients. The overall mortality rate was 25% (n= 317). Concomitant bacterial infections were associated with increased hospital mortality (β = 1.002,p< 0.001). A total of 83.7% (n= 1062) of patients received antibiotic therapy, but only 14.6% of these patients had an obvious source of bacterial infection. There was a significantly higher rate of hospital mortality in patients who received antibiotics than in those who did not (χ2= 6.22,p= 0.012). Appropriate prescribing and the rational use of antimicrobials according to the principles of antimicrobial stewardship can help prevent the emergence of antibiotic resistance.