Adding azithromycin to standard care yields no survival benefit in ambulatory managed COVID-19

The addition of azithromycin to standard care did not reduce hospitalization or mortality risk in patients with mild-to-moderate COVID-19 who underwent ambulatory management, according to results of the ATOMIC2 trial presented at ECCMID 2021.

“In this trial of people with clinically diagnosed mild-to-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospital admission or death, or of time to hospital admission,” the investigators said.

This prospective UK-based open-label trial included 292 adults (mean age 45.9 years, 49 percent female, 68 percent White) who were deemed suitable for initial ambulatory care management after presenting to hospitals with clinically diagnosed, highly probable, or confirmed COVID-19 infection with symptoms for <14 days (median 6.02 days). They were randomized 1:1 to receive standard care (as per local guidelines) either alone or in addition to oral azithromycin (500 mg QD) for 14 days.

Twenty-four percent of the patients had comorbidities. Of 231 patients who had definitive SARS-CoV-2 PCR results from nasopharyngeal swabs, 66 percent were confirmed positive, 76 patients each in the azithromycin and standard care groups (intention-to-treat [ITT] positive group).

Within 28 days post-randomization, there was no significant difference in hospitalization or any-cause death between patients in the azithromycin or standard care groups (10 percent vs 12 percent; adjusted odds ratio [adjOR], 0.91, 95 percent confidence interval [CI], 0.43–1.92; p=0.80). [ECCMID 2021, abstract 2782-6; Lancet Respir Med 2021;doi:10.1016/S2213-2600(21)00263-0]

Time to hospitalization also did not significantly differ between groups (adjusted hazard ratio [adjHR], 0.95, 95 percent CI, 0.46–1.96; p=0.89). 

The findings were consistent in the ITT positive population with regard to hospitalization or death (adjOR, 1.02; p=0.97) and time to hospitalization (adjHR, 1.17; p=0.72).

Two patients in each group died or required level 2 or 3 ventilation, with no significant between-group difference. There was also no between-group difference pertaining to all-cause death (one patient in each group) and progression to pneumonia (two in the standard care group and none in the azithromycin group; p=0.24), with none of the patients progressing to severe pneumonia. 

At peak severity score, a comparable proportion of patients in the azithromycin and standard care groups reported no limitation of activities (50 percent vs 46 percent), while 40 and 44 percent, respectively, reported limitation of simple activities. Peak severity score did not differ between groups (adjOR, 0.91; p=0.69).

Sixteen and 26 percent of patients in the azithromycin and standard care groups were prescribed additional antibiotics during follow-up, 6 and 13 percent, respectively, inhaled corticosteroids, and 11 percent in each group systemic corticosteroids.

No serious adverse events were reported in either group. Three and four patients in the azithromycin and standard care groups, respectively, experienced complications during hospitalization.

According to the investigators, previous trials have shown no benefit derived from azithromycin for COVID-19 among hospitalized patients. [Lancet 2020;396:959-967; Lancet 2021;397:605-612]

A reason for this could be that antivirals may only be effective in the early viraemic stage of the disease, they said.

“[N]one of these trials assessed the potential for efficacy in early, milder disease,” they continued. “[Additionally,] no studies have assessed azithromycin in patients presenting to hospital with substantial symptoms, but early enough in the disease process to be managed in ambulant care, and neither have previous studies assessed high-dose, long-duration azithromycin therapy in early disease.”

“Our findings, taken together with existing data, suggest there is no evidence that azithromycin reduces hospital admission, respiratory failure, or death compared with standard care, either in early disease in the community, or those admitted to hospital with severe disease, or in those with moderate disease managed on an ambulatory pathway,” they said. “[The primary outcome result] provides strong confirmation that azithromycin is not effective in treating COVID-19.”

“The ATOMIC2 adds much to our knowledge, but the body of evidence is not yet complete,” pointed out Dr Alejandro Rodríguez-Molinero from the Consorci Sanitari de l’Alt Penedès i Garraf, Barcelona, Spain, in a commentary. [Lancet Respir Med 2021;doi:10.1016/S2213-2600(21)00289-7]

“There is still room for studies with power to demonstrate modest therapeutic effects, and for studies focused on other outcomes that are of great interest … such as symptomatic persistence in COVID-19, its sequelae, and other results that need longer follow-up,” he said.