Introduction: The effect of anti-infective agents in COVID-19 is unclear. The impact of changes in practice on prognosis over time has not been evaluated. Methods: Single center, retrospective study in adults hospitalized in a medicine ward for COVID-19 from March 5 th to April 25 th 2020. Patient characteristics were compared between two periods (before/after March 19 th ) considering French guidelines. The aim of the study was to evaluate how medical care im- pacted unfavorable outcome, namely admission to intensive care unit (ICU) and/or death. Results: A total of 132 patients were admitted: mean age 59.0 ±16.3 years; mean C-reactive protein (CRP) level 84.0 ±71.1 mg/L; 46% had a lymphocyte count < 10 0 0/mm 3 . Prescribed anti-infective agents were lopinavir-ritonavir (n = 12), azithromycin (AZI) (n = 28) and AZI combined with hydroxychloroquine (HCQ) (n = 52). There was a significant decrease in ICU admission, from 43% to 12%, between the two periods ( P < 0.0 0 01). Delays until transfer to ICU were similar between periods ( P = 0.86). Pulmonary computerized tomography (CT)-scans were performed significantly more often with time (from 50% to 90%, P < 0.0 0 01), and oxygen-dependency (53% vs 80%, P = 0.001) and prescription of AZI ±HCQ (from 25% to 76%, P < 0.0 0 01) were also greater over time. Multivariate analyses showed a reduction of unfavorable outcome in patients receiving AZI ±HCQ (hazard ratio [HR] = 0.45, 95% confidence interval [CI: 0.21-0.97], P = 0.04), particularly among an identified category of individuals (lymphocyte ≥10 0 0/mm 3 or CRP ≥100 mg/L). Conclusion: The present study showed a significant decrease in admission to ICU over time, which was probably related to multiple factors, including a better indication of pulmonary CT-scan, oxygen therapy, and a suitable prescription of anti-infective agents.