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Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection

Peter A.McCulloughMD, MPHabc

Ronan J.KellyMDaGaetanoRuoccoMDdEdgarLermaMDeJamesTumlinMDfKevin R.WheelanMDabcNevinKatzMDgNorman E.LeporMDhKrisVijayMDiHarveyCarterMDjBhupinderSinghMDkSean P.McCulloughBSlBrijesh K.BhambiMDmAlbertoPalazzuoliMD, PhDnGaetano M.De FerrariMD, PhDoGregory P.MilliganMD, MPHaTaimurSafderMD, MPHaKristen M.TecsonPhDbHarvey A.RischMD, PhDq

The American Journal of Medicine

Volume 134, Issue 1, January 2021, Pages 16-22



Azithromycin is a commonly used macrolide antibiotic that has antiviral properties mainly attributed to reduced endosomal transfer of virions as well as established anti-inflammatory effects.27 It has been commonly used in COVID-19 studies initially based on French reports demonstrating markedly reduced durations of viral shedding, fewer hospitalizations, and reduced mortality combination with HCQ as compared to those untreated.28,29 In the large inpatient study (n = 2451) discussed previously, those who received azithromycin alone had an adjusted HR for mortality of 1.05, 95% CI 0.68-1.62, and P = 0.83.23 The combination of HCQ and azithromycin has been used as standard of care in other contexts as a standard of care in more than 300,000 older adults with multiple comorbidities.30 This agent is well-tolerated and like HCQ can prolong the QTc in <1% of patients. The same safety precautions for HCQ listed previously could be extended to azithromycin with or without HCQ. Azithromycin provides additional coverage of bacterial upper respiratory pathogens that could potentially play a role in concurrent or secondary infection. Thus, this agent can serve as a safety net for patients with COVID-19 against clinical failure of the bacterial component of community-acquired pneumonia.31,32 The same safety precautions for HCQ could be extended to azithromycin with or without HCQ. Because both HCQ and azithromycin have small but potentially additive risks of QTc prolongation, patients with known or suspected arrhythmias or taking contraindicated medications or should have more thorough workup (eg, review of baseline electrocardiogram, imaging studies, etc.) before receiving these 2 together. One of many dosing schemes is 250 mg po bid for 5 days and may extend to 30 days for persistent symptoms or evidence of bacterial superinfection.


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