Azithromycin plus usual care does not speed up COVID-19 symptom recovery in community

The addition of azithromycin to usual care does not hasten symptom recovery or reduce hospitalization risk in community-dwelling individuals with suspected COVID-19 who are at an increased risk of complications, according to the UK-based PRINCIPLE trial.

“We found that azithromycin did not substantially improve time to recovery and found little evidence of an effect on admissions to hospital, when used in the community to treat COVID-19,” said the investigators.

“[O]ur findings show that azithromycin should not be used routinely to treat COVID-19 in the community in older adults, in the absence of additional indications,” they said.

Participants in this primary care, prospective, multi-arm platform, open-label trial were 2,265 community-dwelling individuals with an increased risk of adverse clinical course (age ≥65 years or ≥50 years with ≥1 comorbidity*) who had been unwell for ≤14 days (median 6 days) with suspected COVID-19. They were randomized to receive either usual care alone (n=875), azithromycin (500 mg/day for 3 days) plus usual care (n=540), or usual care plus other interventions (n=850). Of these, 94 percent were included in the primary analysis, 823, 500, and 797 in the usual care alone, usual care plus azithromycin, and usual care plus other intervention groups, respectively. The present analysis compares the 1,388 patients assigned to usual care alone and azithromycin plus usual care (mean age 60.7 years, 57 percent female, 82 percent White, 88 percent with comorbidities).

Recovery within 28 days was reported by 80 and 77 percent of patients in the azithromycin plus usual care and usual care alone groups, respectively.

Time to first self-reported recovery within 28 days did not differ between patients assigned to azithromycin plus usual care and usual care alone (median 7 vs 8 days). There was no evidence of a meaningful benefit with azithromycin plus usual care vs usual care alone (hazard ratio [HR], 1.08, 95 percent Bayesian credibility interval [BCI], 0.95–1.23), with an estimated benefit in median time to first recovery of 0.94 days with azithromycin plus usual care. There was a 0.23 probability of a clinically meaningful benefit of at least 1.5 days in time to recovery. [Lancet 2021;doi:10.1016/S0140-6736(21)00461-X]

A comparable proportion of patients in the azithromycin plus usual care and usual care alone groups required hospitalization for COVID-19 within 28 days (n=16 vs 28; 3 percent in each group; absolute percentage benefit, 0.3 percent). No deaths occurred in either group.

Hospitalization for non-COVID-19–related reasons was reported by two and four patients in the azithromycin plus usual care and usual care alone groups, respectively. One patient experienced side effects due to azithromycin and withdrew from the study.

There was no between-group difference pertaining to daily well score over the 28 days or WHO wellbeing score, and no benefit exerted by azithromycin plus usual care for time to first or sustained alleviation of symptoms, or time to first reduction in symptom severity. Patients assigned to azithromycin plus usual care had more GP care consultations than those assigned to usual care alone, and had faster sustained recovery from nausea, vomiting, and diarrhoea.

Subgroup analysis showed that the outcomes were consistent regardless of age (<65 vs ≥65 years), presence of comorbidities, or duration or severity of symptoms pre-randomization.

In a subgroup analysis of patients who tested positive for SARS-CoV-2, there was a median 1.4-day benefit among patients assigned to azithromycin plus usual care vs usual care alone (median 9 vs 13 days; HR, 1.12, 95 percent BCI, 0.91–1.38).

“[In patients with PCR-confirmed SARS-CoV-2 infection,] the estimated [primary outcome] benefits of azithromycin remained below the predefined thresholds of clinically meaningful benefit,” the researchers said.

Randomization to azithromycin was recommended to be stopped for futility on November 30, 2020.

No benefit for azithromycin in the community setting

Several trials have shown that azithromycin does not improve COVID-19–related outcomes, including mortality, in hospitalized patients. [Lancet 2021;397:605-612; Lancet 2020;396:959-967; N Engl J Med 2020;383:2041-2052]

“These data, in conjunction with our findings, suggest that despite potential antiviral and anti-inflammatory properties, azithromycin is not effective in treating COVID-19 without additional indications, even when used in the community and earlier in the course of the disease,” the researchers said.

Furthermore, a meta-analysis showed that bacterial co-infection rates are low among hospitalized COVID-19 patients. [Clin Microbiol Infect 2020;26:1622-1629]

“[T]herefore, a beneficial effect through an antibacterial mechanism of action is unlikely in this setting,” the researchers noted.

Nonetheless, they acknowledged that the study did not account for the effects of azithromycin beyond 28 days.

The results also have bearing on antibiotic stewardship, particularly as antibiotic use in the UK increased during the pandemic, they said. [medRxiv 2021;doi:10.1101/2021.02.02.21250902]

“[I]nappropriate use of antibiotics leads to increased antibiotic resistance,” they continued. “Using antibiotics to treat COVID-19 might also encourage patients to believe that antibiotics are an appropriate treatment for other viral respiratory infections, and our findings guide clinicians to avoid prescribing antibiotics to patients seeking treatment for COVID-19 in the absence of an additional indication.”