A critical analysis about the supposed role of azithromycin in the treatment of covid-19

Main Article Content

Ruan
https://orcid.org/0000-0002-0117-4497
Bárbara Oliva Barbosa
https://orcid.org/0000-0002-3012-021X
José Rivaldo de Oliveira Soares
https://orcid.org/0000-0002-1982-8567
Rayssa
https://orcid.org/0000-0002-5753-6047
Victória Rafaela Santos
https://orcid.org/0000-0002-2477-5682
Ricardo Guimarães Amaral
https://orcid.org/0000-0002-9266-6840
Luciana Nalone Andrade

Abstract

After over one year, the coronavirus disease 2019 (covid-19) has still affected millions of people. For this reason, global efforts to promote better treatment of covid-19 have been undertaken focused on the repurposing of existing medications.In Brazil, azithromycin, a broad-spectrum antibiotic, has been used in association with other drugs as an immunomodulatory, anti-inflammatory, and anti-viral agent, regardless of bacterial co-infection. Indeed, data from experimental studies have demonstrated the capacity of this drug in reducing the production of infection-induced pro-inflammatory cytokines, such as IL-8, IL-6, and TNF-alpha. However, observational studies revealed conflicting results regarding its effect, whereas well-conducted clinical trials have not shown a considerable effect of this agent on the improvement of clinical outcomes. This narrative review addressed the possible role of this antibiotic in the management of covid-19, based on data from clinical and preclinical studies.



Article Details

How to Cite
1.
Santana RR, Barbosa BO, Soares JR de O, Colombo RM, Santos VR, Amaral RG, et al. A critical analysis about the supposed role of azithromycin in the treatment of covid-19. HSJ [Internet]. 2021 Dec. 22 [cited 2024 Nov. 2];11(4):11-2. Available from: https://portalrcs.hcitajuba.org.br/index.php/rcsfmit_zero/article/view/1184
Section
NARRATIVE REVIEW
Author Biographies

Ruan, Department of Medicine, Federal University of Sergipe

Third-year Medical Student at the Federal University of Sergipe (UFS). Lagarto, Sergipe, Brazil.

Bárbara Oliva Barbosa, Department of Medicine, Federal University of Sergipe

Third-year Medical Student at the Federal University of Sergipe (UFS). Lagarto, Sergipe, Brazil.

José Rivaldo de Oliveira Soares, Department of Medicine, Federal University of Sergipe

Third-year Medical Student at the Federal University of Sergipe (UFS). Lagarto, Sergipe, Brazil.

Rayssa , Department of Medicine, Federal University of Sergipe

Third-year Medical Student at the Federal University of Sergipe (UFS). Lagarto, Sergipe, Brazil.

Ricardo Guimarães Amaral, Department of Physiology, Federal University of Sergipe

Postdoctoral Student in Physiological Sciences at Federal University of Sergipe (UFS). Doctorate in Physiological Sciences from the UFS (2018), Masters in Physiological Sciences from the UFS (2014), Specialization in Clinical Pharmacology from the Faculty of International Technology (2011) and Graduation in Pharmacy from the Tiradentes University (2009).

Luciana Nalone Andrade, Department of Medicine, Federal University of Sergipe

PhD in Biotechnology by RENORBIO-SE (Preclinical Pharmacology and Chemistry of Natural Products) by the Federal University of Sergipe (UFS) and Master in Pharmaceutical Sciences (Pharmacology of Natural Products) by UFS. Adjunct Professor-A, Level 1 at UFS, University Campus "Professor Antônio Garcia Filho", Lagarto, Sergipe, Brazil. She works in the research line of Pharmacology of Natural and Synthetic Products with an emphasis on Pre-Clinical Experimental Oncology and the applicability of pharmaceutical formulations containing bioactives of biotechnological interest. Post-doctorate at the Nanotechnology and Nanomedicine Laboratory of the Institute of Technology and Research - ITP-Unit.

References

Phelan AL, Katz R, Gostin LO. The novel coronavirus originating in Wuhan, China: challenges for global health governance. JAMA. 2020;323(8):709. https://doi.org/10.1001/jama.2020.1097 PMid:31999307

Mohamadian M, Chiti H, Shoghli A, Biglari S, Parsamanesh N, Esmaeilzadeh A. COVID-19: Virology, biology and novel laboratory diagnosis. J Gene Med. 2021;23(2):e3303. https://doi.org/10.1002/jgm.3303 PMid:33305456 PMCid:PMC7883242

Cucinotta D, Vanelli M. WHO Declares COVID-19 a pandemic. Acta Biomed. 2020;91(1):157-60. https://doi.org/10.23750/abm.v91i1.9397 PMid:32191675 PMCid:PMC7569573

WHO. Coronavirus Disease (COVID-2019) Situation Reports [Internet] [cited 2021 Nov 20]. Avaiable from: https://bit.ly/3CIKrDq

Marinho PRD, Cordeiro GM, Coelho HFC, Brandão SCS. Covid-19 in Brazil: A sad scenario. Cytokine Growth Factor Rev. 2021;58:51-54. https://doi.org/10.1016/j.cytogfr.2020.10.010 PMid:33199180

Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19) A Review. JAMA. 2020;323(18):1824-36. https://doi.org/10.1001/jama.2020.6019 PMCid:PMC7492917

Gupta A, Madhavan MV, Sehgal K, Nair N, Mahajan S, Sehrawat TS, et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017-32. https://doi.org/10.1038/s41591-020-0968-3 PMid:32651579

Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010;23(3):590-615. https://doi.org/10.1128/CMR.00078-09 PMid:20610825 PMCid:PMC2901655

Min JY, Jang YJ. Macrolide therapy in respiratory viral infections. Mediators Inflamm. 2012;2012:649570. https://doi.org/10.1155/2012/649570 PMid:22719178 PMCid:PMC3375106

Echeverría-Esnal D, Martin-Ontiyuelo C, Navarrete-Rouco ME, De-Antonio Cuscó M, Ferrández O, Horcajada JP, Grau S. Azithromycin in the treatment of COVID-19: a review. Expert Rev Anti Infec Ther. 2021;19(2):147-63. https://doi.org/10.1080/14787210.2020.1813024 PMid:32853038

Jensen S, Thomsen AR. Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion. J Virol. 2012;86(6):2900-10. https://doi.org/10.1128/JVI.05738-11 PMid:22258243 PMCid:PMC3302314

Chen X, Yang X, Zheng Y, Yang Y, Xing Y, Chen Z. SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex. Protein Cell. 2014;5(5):369-81. https://doi.org/10.1007/s13238-014-0026-3 PMid:24622840 PMCid:PMC3996160

Henry BM, Vikse J, Benoit S, Favaloro EJ, Lippi G. Hyperinflammation and derangement of renin-angiotensin-aldosterone system in COVID-19: A novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis. Clin Chim Acta. 2020;507:167-73. ]https://doi.org/10.1016/j.cca.2020.04.027 PMid:32348783 PMCid:PMC7195008

Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol. 2020;20(6):355-62. https://doi.org/10.1038/s41577-020-0331-4 PMid:32376901 PMCid:PMC7201395

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-4. https://doi.org/10.1016/S0140-6736(20)30628-0

Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison JA, et al. Neutrophil extracellular traps in COVID-19. JCI Insight. 2020;5(11):e138999. https://doi.org/10.1172/jci.insight.138999

Kasal DA, De Lorenzo A, Tibiriçá E. COVID-19 and microvascular disease: pathophysiology of SARS-CoV-2 infection with focus on the renin-angiotensin system. Heart Lung Circ. 2020;29(11):1596-602. https://doi.org/10.1016/j.hlc.2020.08.010 PMid:32972810 PMCid:PMC7467122

Barnes BJ, Adrover JM, Baxter-Stoltzfus A, Borczuk A, Cools-Lartigue J, Crawford JM, et al. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med. 2020;217(6):e20200652. https://doi.org/10.1084/jem.20200652 PMid:32302401 PMCid:PMC7161085

Vardhana SA, Wolchok JD. The many faces of the anti-COVID immune response. J Exp Med. 2020;217(6):e20200678. https://doi.org/10.1084/jem.20200678 PMid:32353870 PMCid:PMC7191310

Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19) A Review. JAMA. 2020;324(8):782-93. https://doi.org/10.1001/jama.2020.12839 PMid:32648899

Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020;71(15):762-8. https://doi.org/10.1093/cid/ciaa248 PMid:32161940 PMCid:PMC7108125

Sreepadmanabh M, Sahu AK, Chande A. COVID-19: Advances in diagnostic tools, treatment strategies, and vaccine development. J Biosci. 2020;45(1):148. https://doi.org/10.1007/s12038-020-00114-6 PMid:33410425 PMCid:PMC7683586

Bakheit AH, Al-Hadiya BM, Abd-Elgalil AA. Azithromycin. Profiles Drug Subst Excip Relat Methodol. 2014;39:1-40. https://doi.org/10.1016/B978-0-12-800173-8.00001-5 PMid:24794904

Li H, Liu DH, Chen LL, Zhao Q, Yu YZ, Ding JJ, et al. Meta-analysis of the adverse effects of long-term azithromycin use in patients with chronic lung diseases. Antimicrob Agents Chemother. 2014;58(1):511-7. https://doi.org/10.1128/AAC.02067-13 PMid:24189261 PMCid:PMC3910718

Bosnar M, Čužić S, Bošnjak B, Nujić K, Ergović G, Marjanović N, et al. Azithromycin inhibits macrophage interleukin-1B production through inhibition of activator protein-1 in lipoplysaccharide induced murine pulmonary neutorphilia. Int Immunopharmacol. 2011;11(4):424-34. https://doi.org/10.1016/j.intimp.2010.12.010 PMid:21195124

Murphy DM, Forrest IA, Corris PA, Johnson GE, Small T, Jones D, et al. Azithromycin attenuates effects of lipopolysaccharide on lung allograft bronchial epithelial cells. J Heart Lung Transp. 2008;27(11):1210-6. https://doi.org/10.1016/j.healun.2008.07.026 PMid:18971093

Lin SJ, Kuo ML, Hsiao HS, Lee PT. Azithromycin modulates immune response of human monocyte-derived dendritic cells and CD4 + T cells. Int Immunopharmacol. 2016;40:318-326. https://doi.org/10.1016/j.intimp.2016.09.012 PMid:27664570

Tsai WC, Rodriguez ML, Young KS, Deng JC, Thannickal VJ, Tateda K, et al. Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection. Am J Respir Crit Care Med. 2004;170(12):1331-9. https://doi.org/10.1164/rccm.200402-200OC PMid:15361366

Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses in bronchial epithelial cells. Eur Respir J. 2010;36(3):646-54. https://doi.org/10.1183/09031936.00095809 PMid:20150207

Oliver ME, Hinks TSC. Azithromycin in viral infections. Rev Med Virol. 2021;31(2):e2163. https://doi.org/10.1002/rmv.2163 PMid:32969125 PMCid:PMC7536932

Parnham MJ, Erakovic Haber V, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin: mechanisms of action and their relevance for clinical applications. Pharmacol Ther. 2014;143(2):225-45. https://doi.org/10.1016/j.pharmthera.2014.03.003 PMid:24631273

Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881-90https://doi.org/10.1056/NEJMoa1003833 PMid:22591294 PMCid:PMC3374857

Labro MT. Anti-inflammatory activity of macrolides: a new therapeutic potential? J Antimicrob Chemother. 1998;41 (Suppl B):37-46. https://doi.org/10.1093/jac/41.suppl_2.37 PMid:9579711

Andreani J, Le Bideau M, Duflot I, Jardot P, Rolland C, Boxberger M, et al. In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect. Microb Pathog. 2020;145:104228. https://doi.org/10.1016/j.micpath.2020.104228 PMid:32344177 PMCid:PMC7182748

Du X, Zuo X, Meng F, Han C, Ouyang W, Han Y, et al. Direct inhibitory effect on viral entry of influenza A and SARS-CoV-2 viruses by azithromycin. Cell Prolif. 2021;54(1):e12953. https://doi.org/10.1111/cpr.12953

Arshad S, Kilgore P, Chaudhry ZS, Jacobsen G, Wang DD, Huitsing K, et al. Henry Ford COVID-19 Task Force. Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19. Int J Infect Dis. 2020;97:396-403. https://doi.org/10.1016/j.ijid.2020.06.099 PMid:32623082 PMCid:PMC7330574

Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Sevestre J, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis. 2020;34:101663. https://doi.org/10.1016/j.tmaid.2020.101663 PMid:32289548 PMCid:PMC7151271

Lauriola M, Pani A, Ippoliti G, Mortara A, Milighetti S, Mazen M, et al. Effect of combination therapy of hydroxychloroquine and azithromycin on mortality in patients with COVID-19. Clin Transl Sci. 2020;13(6):1071-6. https://doi.org/10.1111/cts.12860 PMid:32926573 PMCid:PMC7719367

Morán-Blanco JI, Alvarenga Bonilla JA, Homma S, Suzuki K, Fremont-Smith P, Villar Gómez de Las Heras K. Antihistamines and azithromycin as a treatment for COVID-19 on primary health care - A retrospective observational study in elderly patients. Pulm Pharmacol Ther. 2021;67:101989. https://doi.org/10.1016/j.pupt.2021.101989 PMid:33465426 PMCid:PMC7833340

Başaran NC, Uyaroğlu OA, Telli Dizman G, Özışık L, Şahin TK, Taş Z, et al. Outcome of noncritical COVID-19 patients with early hospitalization and early antiviral treatment outside the ICU. Turk J Med Sci. 2021;51(2):411-20. https://doi.org/10.3906/sag-2006-173 PMid:32718127 PMCid:PMC8203135

Dubernet A, Larsen K, Masse L, Allyn J, Foch E, Bruneau L, et al. A comprehensive strategy for the early treatment of COVID-19 with azithromycin/hydroxychloroquine and/or corticosteroids: Results of a retrospective observational study in the French overseas department of Réunion Island. J Glob Antimicrob Resist. 2020;23:1-3. https://doi.org/10.1016/j.jgar.2020.08.001 PMid:32828896 PMCid:PMC7439827

Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. 2020;323(24):2493-502. https://doi.org/10.1001/jama.2020.8630 PMid:32392282 PMCid:PMC7215635

Ip A, Berry DA, Hansen E, Goy AH, Pecora AL, Sinclaire BA, et al. Hydroxychloroquine and tocilizumab therapy in COVID-19 patients-An observational study. PLoS One. 2020;15(8):e0237693. https://doi.org/10.1371/journal.pone.0237693 PMid:32790733 PMCid:PMC7425928

Rodríguez-Molinero A, Pérez-López C, Gálvez-Barrón C, Miñarro A, Macho O, López GF, et al. COVID-19 research group of CSAPG. Observational study of azithromycin in hospitalized patients with COVID-19. PLoS One. 2020;15(9):e0238681. https://doi.org/10.1371/journal.pone.0238681 PMid:32881982 PMCid:PMC7470304

Satlin MJ, Goyal P, Magleby R, Maldarelli GA, Pham K, Kondo M, et al. Safety, tolerability, and clinical outcomes of hydroxychloroquine for hospitalized patients with coronavirus 2019 disease. PLoS One. 2020;15(7):e0236778. https://doi.org/10.1371/journal.pone.0236778 PMid:32701969 PMCid:PMC7377460

Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, 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;56(1):105949. https://doi.org/10.1016/j.ijantimicag.2020.105949 PMid:32205204 PMCid:PMC7102549

Abbas HM, Al-Jumaili AA, Nassir KF, Al-Obaidy MW, Al Jubouri AM, Dakhil BD, et al. Assessment of COVID-19 treatment containing both hydroxychloroquine and azithromycin: a natural clinical trial. Int J Clin Pract. 2021;75(4):e13856. https://doi.org/10.1111/ijcp.13856 PMCid:PMC7744890

Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, 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):2041-52. https://doi.org/10.1056/NEJMoa2019014 PMid:32706953 PMCid:PMC7397242

Sekhavati E, Jafari F, SeyedAlinaghi S, Jamalimoghadamsiahkali S, Sadr S, Tabarestani M, et al. Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial. Int J Antimicrob Agents. 2020;56(4):106143. https://doi.org/10.1016/j.ijantimicag.2020.106143 PMid:32853672 PMCid:PMC7445147

Furtado R, Berwanger O, Fonseca HA, Corrêa TD, Ferraz LR, Lapa MG, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020;396(10256):959-67. https://doi.org/10.1016/S0140-6736(20)31862-6

RECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10274):605-12. https://doi.org/10.1016/S0140-6736(21)00149-5

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):1063-74. https://doi.org/10.1016/S0140-6736(21)00461-X

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