Despite known anti-viral properties, addition of azithromycin to standard care in mild-to-moderate COVID-19 showed no benefit.
The oral macrolide antibiotic, azithromycin, has antibacterial, anti-inflammatory and anti-viral properties and in a study examining drugs that could be repositioned for the management of COVID-19, azithromycin was identified as a potential candidate. Moreover, an in vitro study has also identified a synergistic effect between azithromycin and hydroxychloroquine. While based on only 20 patients, one preliminary study of hydroxychloroquine in COVID-19, found that adding azithromycin to prevent bacterial super-infection resulted in significantly more efficient elimination of the virus. However, despite these theoretical advantages, large-scale studies of patients hospitalised with COVID-19 have not demonstrated any benefit from the drug. For example, in the RECOVERY trial, among patients hospitalised because of COVID-19, addition of azithromycin did not lead to improved patient outcomes compared to standard care.
Nevertheless, as most studies have occurred within a hospital setting, it remained unclear whether the use of azithromycin could prevent disease progression and hence avoid the need for hospitalisation. With this important remaining gap in the current evidence, a team from the Respiratory Medicine Unit and National Institute for Health Research, Oxford University, undertook a prospective, open-label, randomised trial, among patients with mild-to-moderate COVID-19, to determine if azithromycin was effective at reducing the need for hospital admission. Eligible participants were adults (18 years and over) assessed in an acute hospital, where symptom onset was within 14 days. All eligible patients were randomised to either azithromycin 500mg daily plus standard care or standard care alone. Disease severity was assessed using an ordinal scale from 0 to 8, with higher scores indicating more severe disease. Subsequent assessments were performed after 14 and 28 days and the primary outcome was the proportion of participants with hospital admission or death (from any cause) within 28 days of randomisation. Secondary outcomes included the proportion of patients with admitted to hospital with respiratory failure or requiring non-invasive mechanical ventilation with 28 days of randomisation.
A total of 295 participants were enrolled and randomised to either arm. Among the 147 allocated to azithromycin, the mean age was 45.5 years (48% female) and the majority (73%) did not have any co-morbidities. More than 60% of participants in both arms had low baseline severity scores (either 0 or 1) and there was no difference in peak severity scores between the groups (odds ratio, OR = 0.91, 95% CI 0.57–1.46, p = 0.69). A total of 15 (10%) and 17(12%) of those assigned to azithromycin and standard care respectively, were hospitalised or died. The primary outcome was not significantly different between the two groups (OR = 0.91, 95% CI 0.43–1.92, p = 0.80) and there was also no difference in the time to hospitalisation.
Based on their findings, the authors concluded that the use of azithromycin in those with mild-to-moderate COVID-19 managed in an ambulatory care setting had no impact on hospital admissions or other relevant disease outcomes such as respiratory failure or death. They suggested that azithromycin should not be used in the management of COVID-19.
Hinks TSC et al. Azithromycin versus standard care in patients with mild-to- moderate COVID-19 (ATOMIC2): an open-label, randomised trial. Lancet 2021