Rationale for azithromycin in COVID-19: an overview of existing evidence

Abstract

Azithromycin has rapidly been adopted as a repurposed drug for the treatment of COVID-19, despite the lack of high-quality evidence. In this review, we critically appraise the current pharmacological, preclinical and clinical data of azithromycin for treating COVID-19. Interest in azithromycin has been fuelled by favourable treatment outcomes in other viral pneumonias, a documented antiviral effect on SARS-CoV-2 in vitro and uncontrolled case series early in the pandemic. Its antiviral effects presumably result from interfering with receptor mediated binding, viral lysosomal escape, intracellular cell-signalling pathways and enhancing type I and III interferon expression. Its immunomodulatory effects may mitigate excessive inflammation and benefit tissue repair. Currently, in vivo reports on azithromycin in COVID-19 are conflicting and do not endorse its widespread use outside of clinical trials. They are, however, mostly retrospective and therefore inherently biased. The effect size of azithromycin may depend on when it is started. Also, extended follow-up is needed to assess benefits in the recovery phase. Safety data warrant monitoring of drug-drug interactions and subsequent cardiac adverse events, especially with hydroxychloroquine. More prospective data of large randomised controlled studies are expected and much-needed. Uniform reporting of results should be strongly encouraged to facilitate data pooling with the many ongoing initiatives.

Keywords: COVID-19; respiratory infection; viral infection.

Figure 1

Chronology of the different disease-stages of COVID-19.

Figure 2

Azithromycin effects in the pathophysiology of COVID-19 after receptor-mediated endocytosis, both viral (PAMP) and host released (DAMP) molecules trigger antiviral pathways. SARS-CoV-2 induces a strong NF-KB pathway activation but supresses interferon-related gene transcription. This promotes macrophage activation and the release of pro-inflammatory cytokines and supresses an effective cellular immune answer. In severe COVID-19, this imbalanced immune answer causes a so called ‘cytokine storm’. Neutrophils are drawn to the site of inflammation. Together with activated endothelial cells they contribute to hypercoagulation. They also contribute to a strong fibroblast activation, raising the concern for fibrotic complications in the long term. Current data shows that an effective Th2 response is more likely to occur in severe infection. It remains uncertain whether immunoglobulin release is beneficial or rather enhances the acute inflammation by mechanisms such as antibody-dependent enhancement. Azithromycin stimulatory and inhibitory immunomodulatory effects. Ang II, angiotensin I; CCL5, C-C motif chemokine ligand 5 (=RANTES); CTL, cytotoxic T-cell; CXCL, C-X-C motif chemokine ligand; DAMP, danger associated molecular pattern, GMCSF, granulocyte macrophage colony stimulating factor; IFN, interferon, IL, interleukin; IRF, interferon inducible factors; NET, neutrophil extracellular traps; NF-KB, nuclear factor kappa beta; NK, natural killer cell; NLRP3, nod-like receptor pyrin domain containing 3; P2RX, purinergic receptor P2X; PAMP, pathogen associated molecular pattern; PDGF, platelet-derived growth factor; RIG, retinoic acid inducible gene 1; Th, T helper cell; TLR, toll like receptor; TNF, tumour necrosis factor.