GY48LS6

Macrolides may have immunomodulatory properties in pulmonary inflammatory disorders. They may downregulate inflammatory responses and reduce the excessive cytokine production associated with respiratory viral infections; however, their direct effects on viral clearance are uncertain. Immunomodulatory mechanisms may include reducing chemotaxis of neutrophils (PMNs) to the lungs by inhibiting cytokines (i.e., IL-8), inhibition of mucus hypersecretion, decreased production of reactive oxygen species, accelerating neutrophil apoptosis, and blocking the activation of nuclear transcription factors.

In an open-label, non-randomized clinical trial of hydroxychloroquine, azithromycin was administered in combination with hydroxychloroquine to prevent bacterial superinfection in 6 patients.

• Preliminary data suggest the potential for benefit as adjunct therapy.
• On day 6, all patients treated with the combination (hydroxychloroquine and azithromycin) were virologically cured compared to 57.1% of patients treated with hydroxychloroquine alone.

In a retrospective analysis of a multicenter cohort study (n = 349) in patients with MERS-CoV, 136 patients received macrolide therapy in combination with antiviral treatment.

• Macrolide therapy was not associated with a reduction in 90-day mortality compared to the control group (adjusted OR: 0.84; 95% CI: 0.47 to 1.51; p = 0.56).
• Sensitivity analysis excluding patients who received macrolides after day 3 showed similar results (adjusted OR: 0.7; 95% CI: 0.39 to 1.28; p = 0.25).

A prospective review assessed virologic and clinical outcomes of 11 hospitalized patients who received hydroxychloroquine and azithromycin.

• Within 5 days, 1 patient died, 2 were transferred to the ICU, and 1 patient had therapy discontinued due to QT prolongation.
• Nasopharyngeal swabs were still positive for SARS-CoV-2 in 8 of 10 patients 5 to 6 days after treatment initiation.

Safety Concerns:

• Risk of cardiac arrhythmias (e.g., QT prolongation)
• Significant drug interactions

Philip Carlucci, Tania Ahuja, Christopher M Petrilli, Harish Rajagopalan, Simon Jones, Joseph Rahimian. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients. May 08, 2020. DOI: 0.1101/2020.05.02.20080036. 

Ehud Chorin, Lalit Wadhwani, et al. QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin. Heart Rhythm. May 01, 2020. DOI: 10.1016/j.hrthm.2020.05.014. 

Julien Andreani, Marion Le Bideau, et al. In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect. Microbial Pathogenesis. Volume 145, August 2020, 104228. DOI: 10.1016/j.micpath.2020.104228.

R. Choudhary, A.K. Sharma. Potential use of hydroxychloroquine, ivermectin and azithromycin drugs in fighting COVID-19: trends, scope and relevance. New Microbes and New Infections. Volume 35, May 2020, 100684. DOI: 10.1016/j.nmni.2020.100684.

Oliver J Hulme, Eric-Jan Wagenmakers, et al. A Bayesian reanalysis of the effects of hydroxychloroquine and azithromycin on viral carriage in patients with COVID-19. DOI: 10.1101/2020.03.31.20048777. 

Ehud Chorin, Lalit Wadhwani, et al. QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin. DOI: 10.1101/2020.04.27.20074583. 

Amir Sarayani, BrianCicali, et al. Safety signals for QT prolongation or Torsades de Pointes associated with azithromycin with or without chloroquine or hydroxychloroquine. Research in Social and Administrative Pharmacy. 19 April 2020. DOI: 10.1016/j.sapharm.2020.04.016.

Archana Ramireddy, Harpriya S. Chugh, et al. Experience with Hydroxychloroquine and Azithromycin in the COVID-19 Pandemic: Implications for QT Interval Monitoring. DOI: 0.1101/2020.04.22.20075671. 

Ehud Chorin, Matthew Dai, et al. The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin. DOI: 10.1101/2020.04.02.20047050. 

Gautret P, Lagier J, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020 Mar 20. PMID: 32205204.

Arabi YM, Deeb A, Al-Hameed, et al. Macrolides in critically ill patients with Middle East Respiratory Syndrome. Int J Infect Dis 2019;81:184-190. PMID: 30690213.