A UC San Francisco study has found that the antibiotic azithromycin was no more effective than a placebo in preventing symptoms of COVID-19 among non-hospitalized patients, and may increase their chance of hospitalization, despite widespread prescription of the antibiotic for the disease.
“These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection,” said lead author Catherine E. Oldenburg, ScD, MPH, an assistant professor with the UCSF Proctor Foundation. SARS-CoV-2 is the virus that causes COVID-19.
Azithromycin, a broad-spectrum antibiotic, is widely prescribed as a treatment for COVID-19 in the United States and the rest of the world. “The hypothesis is that it has anti-inflammatory properties that may help prevent progression if treated early in the disease,” said Oldenburg. “We did not find this to be the case.”
The study, which was conducted in collaboration with Stanford University, appears July 16, 2021, in the Journal of the American Medical Association.
The study included 263 participants who all tested positive for SARS-CoV-2 within seven days before entering the study. None were hospitalized at the time of enrollment. In a random selection process, 171 participants received a single, 1.2 gram oral dose of azithromycin and 92 received an identical placebo.
At day 14 of the study, 50 percent of the participants remained symptom free in both groups. By day 21, five of the participants who received azithromycin had been hospitalized with severe symptoms of COVID-19 and none of the placebo group had been hospitalized.
The researchers concluded that treatment with a single dose of azithromycin compared to placebo did not result in greater likelihood of being symptom-free.
“Most of the trials done so far with azithromycin have focused on hospitalized patients with pretty severe disease,” said Oldenburg. “Our paper is one of the first placebo-controlled studies showing no role for azithromycin in outpatients.”
Identifying treatments that can be used to speed recovery and reduce hospitalisations due to COVID-19 in the community is critically important, particularly among older adults and people with comorbidities, who are at a high risk of adverse outcomes.1 Azithromycin, a licensed, widely available, cheap, and generally safe drug has been proposed as a treatment for COVID-19, with in-vitro studies suggesting activity against some viruses, including SARS-CoV-2.2, 3 Azithromycin might increase the pH of the Golgi network and recycling endosome,4 which could in turn interfere with intracellular SARS-CoV-2 activity and replication.
The drug might also reduce levels of the enzyme furin;4 this could interfere with the ability of SARS-CoV-2 to enter cells, as the virus is believed to have a furin-like cleavage site in the spike protein.5
The ability of azithromycin to reduce the levels of proinflammatory cytokines, such as IL-6,6 could reduce the ability of SARS-CoV-2 infection to trigger a cytokine storm, along with associated tissue damage. Furthermore, some patients with viral respiratory illness might develop a secondary bacterial infection or present with a bacterial co-infection, which azithromycin could effectively treat. Azithromycin use in primary care has increased during the COVID-19 pandemic,7 which could contribute to antimicrobial resistance.8
Research in context
Evidence before this study
We searched PubMed on Jan 24, 2021, using the following search terms [(randomised OR trial) AND (azithromycin OR macrolide) AND (COVID* OR SARS-CoV-2 OR SARS-CoV)], with no language restrictions, and identified 243 results. Adding a filter for clinical trials limited the number of results to 16. Of these, we identified two randomised clinical trials with over 100 participants that provided some data on the effectiveness of azithromycin as a treatment for COVID-19 compared with control treatment or usual care. Additional searches of medRxiv and Google Scholar on Jan 24, 2021, using similar search terms with no language restrictions, identified a further randomised clinical trial of azithromycin.
All identified trials were in hospitalised patients. A large randomised trial among patients hospitalised with COVID-19 in the UK found no difference in 28-day mortality, duration of hospital stay or treatment in hospital, or intensive care unit admissions among 2582 participants randomly assigned to receive azithromycin versus 5181 participants randomly assigned to receive usual care alone.
A randomised trial in Brazil among 675 patients admitted to hospital with mild to moderate COVID-19 found no difference in clinical status by 15 days among patients randomly assigned to receive usual care plus azithromycin and hydroxychloroquine versus usual care plus hydroxychloroquine, versus usual care alone. A trial by the same group, among 447 patients admitted to hospital with severe COVID-19, found that patients randomly assigned to azithromycin plus hydroxychloroquine, versus hydroxychloroquine alone, had poorer clinical status at 15 days, although outcomes were more similar between the two groups by 29 days. We identified no randomised clinical trials of azithromycin as a treatment for COVID-19 in the community.
Added value of this study
All three randomised clinical trials that we identified were in hospital settings, and only one assessed azithromycin as a standalone therapy for COVID-19. To our knowledge, PRINCIPLE is the first randomised trial to assess the effectiveness and safety of azithromycin as a standalone treatment for patients with COVID-19 in the community. 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.
Implications of all the available evidence
Taken together, our findings plus the evidence to date suggest that azithromycin is not a sufficiently effective treatment to justify routine use for treatment of COVID-19, neither in the community nor in hospitals.
Randomised trials have found that azithromycin is not an effective treatment for patients who are admitted to hospital with COVID-19, either alone or in combination with hydroxychloroquine.9, 10, 11 However, there is a paucity of evidence regarding the effectiveness of azithromycin for treatment of suspected COVID-19 in the community, where earlier treatment might speed recovery and prevent hospital admissions. We aimed to assess the effectiveness of azithromycin to treat COVID-19 in the platform randomised trial of interventions against COVID-19 in older people (PRINCIPLE) study.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972318/
More information: Catherine E. Oldenburg et al, Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection, JAMA (2021). DOI: 10.1001/jama.2021.11517
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