[Skip to Content]
[Skip to Content Landing]

Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 InfectionA Randomized Clinical Trial

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Does a single oral dose of azithromycin lead to absence of symptoms at day 14 in outpatients with COVID-19 compared with placebo?

Findings  In this randomized trial that included 263 participants with SARS-CoV-2 infection, treatment with a single oral dose of azithromycin, 1.2 g, vs placebo resulted in self-reported absence of COVID-19 symptoms at day 14 in 50% vs 50%; this was not statistically significant.

Meaning  Among outpatients with SARS-CoV-2 infection, treatment with a single dose of oral azithromycin compared with placebo did not result in a greater likelihood of being free of symptoms at day 14.

Abstract

Importance  Azithromycin has been hypothesized to have activity against SARS-CoV-2.

Objective  To determine whether oral azithromycin in outpatients with SARS-CoV-2 infection leads to absence of self-reported COVID-19 symptoms at day 14.

Design, Setting, and Participants  Randomized clinical trial of azithromycin vs matching placebo conducted from May 2020 through March 2021. Outpatients from the US were enrolled remotely via internet-based surveys and followed up for 21 days. Eligible participants had a positive SARS-CoV-2 diagnostic test result (nucleic acid amplification or antigen) within 7 days prior to enrollment, were aged 18 years or older, and were not hospitalized at the time of enrollment. Among 604 individuals screened, 297 were ineligible, 44 refused participation, and 263 were enrolled. Participants, investigators, and study staff were masked to treatment randomization.

Interventions  Participants were randomized in a 2:1 fashion to a single oral 1.2-g dose of azithromycin (n = 171) or matching placebo (n = 92).

Main Outcomes and Measures  The primary outcome was absence of self-reported COVID-19 symptoms at day 14. There were 23 secondary clinical end points, including all-cause hospitalization at day 21.

Results  Among 263 participants who were randomized (median age, 43 years; 174 [66%] women; 57% non-Hispanic White and 29% Latinx/Hispanic), 76% completed the trial. The trial was terminated by the data and safety monitoring committee for futility after the interim analysis. At day 14, there was no significant difference in proportion of participants who were symptom free (azithromycin: 50%; placebo: 50%; prevalence difference, 0%; 95% CI, −14% to 15%; P > .99). Of 23 prespecified secondary clinical end points, 18 showed no significant difference. By day 21, 5 participants in the azithromycin group had been hospitalized compared with 0 in the placebo group (prevalence difference, 4%; 95% CI, −1% to 9%; P = .16).

Conclusions and Relevance  Among outpatients with SARS-CoV-2 infection, treatment with a single dose of azithromycin compared with placebo did not result in greater likelihood of being symptom free at day 14. These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection.

Trial Registration  ClinicalTrials.gov Identifier: NCT04332107

Sign in to take quiz and track your certificates

Buy This Activity
We are currently experiencing technical difficulties that may affect log in and other features. Thank you for your understanding.

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Catherine E. Oldenburg, ScD, MPH, Francis I. Proctor Foundation, University of California, San Francisco, 490 Illinois St, Floor 2, San Francisco, CA 94143 (catherine.oldenburg@ucsf.edu).

Accepted for Publication: June 25, 2021.

Published Online: July 16, 2021. doi:10.1001/jama.2021.11517

Author Contributions: Drs Oldenburg and Arnold had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Oldenburg, Brogdon, Hinterwirth, Lebas, Redd, Lietman, Arnold, Doan.

Acquisition, analysis, or interpretation of data: Oldenburg, Pinsky, Brogdon, Chen, Ruder, Zhong, Nyatigo, Cook, Lebas, Redd, Porco, Arnold, Doan.

Drafting of the manuscript: Oldenburg, Arnold, Doan.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Oldenburg, Nyatigo, Arnold.

Obtained funding: Oldenburg, Lietman, Doan.

Administrative, technical, or material support: Oldenburg, Pinsky, Brogdon, Chen, Ruder, Zhong, Nyatigo, Cook, Hinterwirth, Lebas, Redd, Lietman, Doan.

Supervision: Oldenburg, Lebas, Doan.

Conflict of Interest Disclosures: Ms Cook reported receipt of grants from the National Institutes of Health. Dr Lietman reported receipt of grants from Pfizer Inc, the National Institutes of Health, and the Bill & Melinda Gates Foundation. Dr Arnold reported receipt of grants from the Bill & Melinda Gates Foundation and the National Institute of Allergy and Infectious Diseases and hotel/airfare reimbursement to attend global health meetings from the Bill & Melinda Gates Foundation. No other disclosures were reported.

Funding/Support: This trial was supported by the Bill & Melinda Gates Foundation (grant INV-017026). Azithromycin and matching placebo were donated by Pfizer Inc. Dr Doan was supported in part by a Research to Prevent Blindness Career Development Award.

Role of the Funder/Sponsor: The study sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank Chris Damman, MD, and Rebecca Brander, PhD, program officers from the trial’s sponsor, the Bill & Melinda Gates Foundation. We thank Charles Knirsch, MD, Pfizer Inc, for advice on azithromycin dosing. We also thank the members of the DSMC: Art Reingold, MD, University of California, Berkeley; Emily Gower, PhD, University of North Carolina; and David Glidden, PhD, University of California, San Francisco. Drs Reingold, Gower, and Glidden received honoraria for their role in the DSMC. We thank William Hernandez, RN, and Ada Victoria Cevallos, MS, for translation services. Mr Hernandez and Ms Cevallos were compensated for their roles in the study. We thank J. Daniel Kelly, MD, Seth Blumberg, MD, and Ying Lin, MS, for advice and logistical support during the conduct of the trial. These individuals were employees of the University of California, San Francisco, at the time of the study and were paid as part of their employment but did not receive additional compensation for their role in the study. We also thank the study participants.

References
1.
Oliver  ME , Hinks  TSC .  Azithromycin in viral infections.   Rev Med Virol. 2021;31(2):e2163. doi:10.1002/rmv.2163PubMedGoogle Scholar
2.
O’Brien  KS , Emerson  P , Hooper  PJ ,  et al.  Antimicrobial resistance following mass azithromycin distribution for trachoma: a systematic review.   Lancet Infect Dis. 2019;19(1):e14-e25. doi:10.1016/S1473-3099(18)30444-4PubMedGoogle ScholarCrossref
3.
PRINCIPLE Trial Collaborative Group.  Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.   Lancet. 2021;397(10279):1063-1074. doi:10.1016/S0140-6736(21)00461-XPubMedGoogle ScholarCrossref
4.
Cavalcanti  AB , Zampieri  FG , Rosa  RG ,  et al; Coalition Covid-19 Brazil I Investigators.  Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19.   N Engl J Med. 2020;383(21):2041-2052. doi:10.1056/NEJMoa2019014PubMedGoogle ScholarCrossref
5.
RECOVERY Collaborative Group.  Azithromycin in the treatment of patients admitted to the hospital with severe COVID-19: the COALITION II randomised clinical trial.   Lancet. 2021;397(10274):605-612. doi:10.1016/S0140-6736(21)00149-5PubMedGoogle ScholarCrossref
6.
Johnston  C , Brown  ER , Stewart  J ,  et al; COVID-19 Early Treatment Study Team.  Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: a randomized clinical trial.   EClinicalMedicine. 2021;33:100773. doi:10.1016/j.eclinm.2021.100773PubMedGoogle Scholar
7.
Cao  B , Wang  Y , Wen  D ,  et al.  A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19.   N Engl J Med. 2020;382(19):1787-1799. doi:10.1056/NEJMoa2001282PubMedGoogle ScholarCrossref
8.
Gyselinck  I , Liesenborghs  L , Landeloos  E ,  et al; DAWn-Azithro Consortium.  Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2—azithromycin trial.   Trials. 2021;22(1):126. doi:10.1186/s13063-021-05033-xPubMedGoogle ScholarCrossref
9.
Little  RJ , D’Agostino  R , Cohen  ML ,  et al.  The prevention and treatment of missing data in clinical trials.   N Engl J Med. 2012;367(14):1355-1360. doi:10.1056/NEJMsr1203730PubMedGoogle ScholarCrossref
10.
Lachin  JM .  A review of methods for futility stopping based on conditional power.   Stat Med. 2005;24(18):2747-2764. doi:10.1002/sim.2151PubMedGoogle ScholarCrossref
11.
RECOVERY Collaborative Group.  Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.   Lancet. 2021;397(10274):605-612. doi:10.1016/S0140-6736(21)00149-5PubMedGoogle ScholarCrossref
12.
Spinato  G , Fabbris  C , Polesel  J ,  et al.  Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection.   JAMA. 2020;323(20):2089-2090. doi:10.1001/jama.2020.6771PubMedGoogle ScholarCrossref
13.
Nehme  M , Braillard  O , Alcoba  G ,  et al; COVICARE Team.  COVID-19 symptoms: longitudinal evolution and persistence in outpatient settings.   Ann Intern Med. 2021;174(5):723-725. doi:10.7326/M20-5926PubMedGoogle ScholarCrossref
14.
Sié  A , Dah  C , Bountogo  M ,  et al; Gamin Study Group.  Adverse events and clinic visits following a single dose of oral azithromycin among preschool children: a randomized placebo-controlled trial.   Am J Trop Med Hyg. 2020;104(3):1137-1141. doi:10.4269/ajtmh.20-1002PubMedGoogle Scholar
15.
Ayele  B , Gebre  T , House  JI ,  et al.  Adverse events after mass azithromycin treatments for trachoma in Ethiopia.   Am J Trop Med Hyg. 2011;85(2):291-294. doi:10.4269/ajtmh.2011.11-0056PubMedGoogle ScholarCrossref
16.
Astale  T , Sata  E , Zerihun  M ,  et al.  Self-reported side effects following mass administration of azithromycin to eliminate trachoma in Amhara, Ethiopia: results from a region-wide population-based survey.   Am J Trop Med Hyg. 2019;100(3):696-699. doi:10.4269/ajtmh.18-0781PubMedGoogle ScholarCrossref
17.
 Antimicrobial resistance in the age of COVID-19.   Nat Microbiol. 2020;5(6):779. doi:10.1038/s41564-020-0739-4PubMedGoogle ScholarCrossref
18.
Afshinnekoo  E , Bhattacharya  C , Burguete-García  A ,  et al; MetaSUB Consortium.  COVID-19 drug practices risk antimicrobial resistance evolution.   Lancet Microbe. 2021;2(4):e135-e136. doi:10.1016/S2666-5247(21)00039-2PubMedGoogle ScholarCrossref
19.
Lipsitch  M , Samore  MH .  Antimicrobial use and antimicrobial resistance: a population perspective.   Emerg Infect Dis. 2002;8(4):347-354. doi:10.3201/eid0804.010312PubMedGoogle ScholarCrossref
20.
Doan  T , Worden  L , Hinterwirth  A ,  et al.  Macrolide and nonmacrolide resistance with mass azithromycin distribution.   N Engl J Med. 2020;383(20):1941-1950. doi:10.1056/NEJMoa2002606PubMedGoogle ScholarCrossref
21.
Oldenburg  CE , Hinterwirth  A , Sié  A ,  et al.  Gut resistome after oral antibiotics in preschool children in Burkina Faso: a randomized, controlled trial.   Clin Infect Dis. 2020;70(3):525-527. doi:10.1093/cid/ciz455PubMedGoogle ScholarCrossref
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close
Close

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close