Objetivo
Proporcionar un resumen oportuno, riguroso y continuamente actualizado de la evidencia disponible sobre el papel de los macrólidos para el tratamiento de pacientes con COVID-19.

Diseño
Revisión sistemática viva.

Base de datos
La búsqueda de evidencia se realizó en el repositorio centralizado L·OVE (Living OVerview of Evidence) COVID-19; una plataforma que mapea las preguntas PICO para identificar la evidencia en la base de datos Epistemonikos. En respuesta a la emergencia de COVID-19, L·OVE se adaptó para ampliar el rango de evidencia que cubre y hoy se mantiene a través de búsquedas regulares en 39 bases de datos.

Métodos
Se incluyeron estudios experimentales que evaluaban el efecto de los macrólidos, como monoterapia o en combinación con otros fármacos, versus placebo o ningún tratamiento en pacientes con sospecha o confirmación de COVID-19. Se buscó identificar experimentos clínicos aleatorizados que evaluaran macrólidos en infecciones causadas por otros coronavirus, como MERS-CoV y SARS-CoV. Dos revisores examinaron de forma independiente la elegibilidad de cada estudio, extrajeron los datos y evaluaron el riesgo de sesgo. Se evaluó el efecto de los macrólidos sobre la mortalidad por todas las causas; necesidad de ventilación mecánica invasiva; oxigenación por membrana extracorpórea, duración de la estancia hospitalaria, insuficiencia respiratoria, eventos adversos graves, tiempo hasta la negatividad de la RT-PCR del SARS-CoV-2. La certeza de la evidencia para cada desenlace se evaluó siguiendo la aproximación GRADE. Esta revisión se mantendrá viva y disponible abiertamente durante la pandemia de COVID-19. Se someterán actualizaciones de su publicación cada vez que cambien las conclusiones o cuando haya actualizaciones sustanciales.

Resultados
Se identificó un experimento clínico aleatorio que evaluó el uso de azitromicina en combinación con hidroxicloroquina en comparación con el uso de hidroxicloroquina sola, en pacientes hospitalizados por COVID 19. Las estimaciones para todos los resultados evaluados resultaron en un poder estadístico insuficiente para llegar a conclusiones válidas. La calidad de la evidencia para los resultados principales fue baja a muy baja.

Conclusiones
El uso de macrólidos en el tratamiento de pacientes con COVID 19 no ha mostrado efectos beneficiosos en comparación con el tratamiento estándar. La evidencia para todos los desenlaces no es concluyente. Se necesitan estudios sobre un mayor número de pacientes con COVID 19, para determinar los efectos del uso de macrólidos sobre los desenlaces relacionados con la enfermedad.

Systematic review registration
PROSPERO Registration number: CRD42020181032
Protocol preprint DOI: 10.31219/osf.io/rvp59

Authors: Catalina Verdejo[1], Laura Vergara-Merino[2], Nicolás Meza[2], Javier Pérez-Bracchiglione[3], Natalia Carvajal-Juliá[1], Eva Madrid[2], Gabriel Rada[4], María Ximena Rojas Reyes[5]

Affiliation:
[1] School of Medicine, Cochrane Chile Associated Centre, Universidad de Valparaíso, Chile
[2] Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Cochrane Chile Associated Centre, Valparaíso, Chile
[3] Interdisciplinary Centre for Health Studies (CIESAL), Universidad de Valparaíso, Cochrane Chile Associated Centre, Viña del Mar, Chile
[4] Fundación Epistemonikos, Santiago, Chile
[5] Department of Research, Fundación Cardioinfantil, Cochrane Colombia Affiliate Centre, Bogotá, Colombia

E-mail: mxrojas@cardioinfantil.org

Author address:
[1] Calle 163A # 13B-60,
Bogotá D.C.,
Colombia

Citation: Verdejo C, Vergara-Merino L, Meza N, Pérez-Bracchiglione J, Carvajal-Juliá N, Madrid E, et al. Macrolides for the treatment of COVID-19: a living, systematic review. Medwave 2020;20(11):e8073 doi: 10.5867/medwave.2020.11.8073

Submission date: 13/8/2020

Acceptance date: 26/10/2020

Publication date: 14/12/2020

Origin: Not commissioned

Type of review: Externally peer-reviewed by three reviewers, double-blind

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World Health Organization. WHO Director-General’s remarks at the media briefing on 2019-nCoV on 11 February 2020. Geneva: WHO; 2020. [On line]. | Link |

Hui DS, I Azhar E, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health - The latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis. 2020 Feb;91:264-266. | CrossRef | PubMed |

Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020 May;20(5):533-534. | CrossRef | PubMed |

Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. | CrossRef | PubMed |

Tavakoli A, Vahdat K, Keshavarz M. Novel Coronavirus Disease 2019 (COVID-19): An Emerging Infectious Disease in the 21st Century. ISMJ. 2020;22(6):432-50. | CrossRef |

Li LQ, Huang T, Wang YQ, Wang ZP, Liang Y, Huang TB, et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J Med Virol. 2020 Jun;92(6):577-583. | CrossRef | PubMed |

The Centre for Evidence-Based Medicine. Global Covid-19 Case Fatality Rates. CEBM; 2020. [On line]. | Link |

Amsden GW. Anti-inflammatory effects of macrolides--an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J Antimicrob Chemother. 2005 Jan;55(1):10-21. | CrossRef | PubMed |

Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin Microbiol Rev. 2010 Jul;23(3):590-615. | CrossRef | PubMed |

Ninomiya K, Fukui T, Imai T, Matsui M, Matsuoka K. Effect of maclorides on duration and resolution of symptoms and complication of pneumonia in children with influenza. J Nippon Med Sch. 2002 Feb;69(1):53-7. | CrossRef | PubMed |

Kakeya H, Seki M, Izumikawa K, Kosai K, Morinaga Y, Kurihara S, et al. Efficacy of combination therapy with oseltamivir phosphate and azithromycin for influenza: a multicenter, open-label, randomized study. PLoS One. 2014 Mar 14;9(3):e91293. | CrossRef | PubMed |

Shinahara W, Takahashi E, Sawabuchi T, Arai M, Hirotsu N, Takasaki Y, et al. Immunomodulator clarithromycin enhances mucosal and systemic immune responses and reduces re-infection rate in pediatric patients with influenza treated with antiviral neuraminidase inhibitors: a retrospective analysis. PLoS One. 2013 Jul 17;8(7):e70060. | CrossRef | PubMed |

Hung IFN, To KKW, Chan JFW, Cheng VCC, Liu KSH, Tam A, et al. Efficacy of Clarithromycin-Naproxen-Oseltamivir Combination in the Treatment of Patients Hospitalized for Influenza A(H3N2) Infection: An Open-label Randomized, Controlled, Phase IIb/III Trial. Chest. 2017 May;151(5):1069-1080. | CrossRef | PubMed |

Kneyber MC, van Woensel JB, Uijtendaal E, Uiterwaal CS, Kimpen JL; Dutch Antibiotics in RSV Trial (DART) Research Group. Azithromycin does not improve disease course in hospitalized infants with respiratory syncytial virus (RSV) lower respiratory tract disease: a randomized equivalence trial. Pediatr Pulmonol. 2008 Feb;43(2):142-9. | CrossRef | PubMed |

McCallum GB, Morris PS, Chatfield MD, Maclennan C, White AV, Sloots TP, et al. A single dose of azithromycin does not improve clinical outcomes of children hospitalised with bronchiolitis: a randomised, placebo-controlled trial. PLoS One. 2013 Sep 25;8(9):e74316. | CrossRef | PubMed |

Pinto LA, Pitrez PM, Luisi F, de Mello PP, Gerhardt M, Ferlini R, et al. Azithromycin therapy in hospitalized infants with acute bronchiolitis is not associated with better clinical outcomes: a randomized, double-blinded, and placebo-controlled clinical trial. J Pediatr. 2012 Dec;161(6):1104-8. | CrossRef | PubMed |

Martín-Loeches I, Bermejo-Martin JF, Vallés J, Granada R, Vidaur L, Vergara-Serrano JC, et al. Macrolide-based regimens in absence of bacterial co-infection in critically ill H1N1 patients with primary viral pneumonia. Intensive Care Med. 2013 Apr;39(4):693-702. | CrossRef | PubMed |

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 Jul;56(1):105949. | CrossRef | PubMed |

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 Mar-Apr;34:101663. | CrossRef | PubMed |

Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015 Jan 1;4(1):1. | CrossRef | PubMed |

Rada G, Verdugo-Paiva F, Ávila C, Morel-Marambio M, Bravo-Jeria R, Pesce F, et al. Evidence synthesis relevant to COVID-19: a protocol for multiple systematic reviews and overviews of systematic reviews. Medwave. 2020 Apr 1;20(3):e7868. | CrossRef | PubMed |

Verdejo C, Vergara-Merino L, Carvajal-Juliá N, Meza N, Madrid E, Rada G, et al. Macrolides for the treatment of COVID-19: A living systematic review protocol. OSF Preprints. 2020. | CrossRef |

GitHub repository. 2020. [On line]. | Link |

Methods & report of the Special L·OVE of Coronavirus (COVID-19). L·OVE. [On line]. | Link |

Epistemonikos Foundation. Epistemonikos database methods. Epistemonikos; 2020. [On line]. | Link |

Jin X, Pang B, Zhang J, Liu Q, Yang Z, Feng J, et al. Core Outcome Set for Clinical Trials on Coronavirus Disease 2019 (COS-COVID). Engineering (Beijing). 2020 Mar 18. | CrossRef | PubMed |

COVID-19-COS. COVID-19 Core Outcomes. 2020. [On line]. | Link |

Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, et al. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013 Feb;66(2):158-72. | CrossRef | PubMed |

Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898. | CrossRef | PubMed |

The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Copenhagen. [On line]. | Link |

Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008 Apr 26;336(7650):924-6. | CrossRef | PubMed |

Guyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, et al. GRADE guidelines: 13. Preparing summary of findings tables and evidence profiles-continuous outcomes. J Clin Epidemiol. 2013 Feb;66(2):173-83. | CrossRef | PubMed |

Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, et al. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med. 2020 Nov 19;383(21):2041-2052. | CrossRef | PubMed |

Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020 May 15. | CrossRef | PubMed |

Wu R, Wang L, Kuo HD, Shannar A, Peter R, Chou PJ, et al. An Update on Current Therapeutic Drugs Treating COVID-19. Curr Pharmacol Rep. 2020 May 11:1-15. | CrossRef | PubMed |

Ohe M, Shida H, Jodo S, Kusunoki Y, Seki M, Furuya K, et al. Macrolide treatment for COVID-19: Will this be the way forward? Biosci Trends. 2020 May 21;14(2):159-160. | CrossRef | PubMed |

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