Clarithromycin as an Antiviral:
Both in vitro and in vivo studies have provided evidence of their efficacy in viral respiratory infections including rhinovirus (RV), respiratory syncytial virus (RSV), and influenza virus (45) (46) (47) (48) (49) (50) (51) (52) (53).
Clarithromycin can inhibit the duplication of some influenza viruses. In concentrations of 12.5 and 25 μg/mL, this drug reduces the duplication of H1N1 influenza virus in vitro (54).
It acts at the middle and late stages of virus replication to reduce the duplication of progeny virus in the infected cell (55).
In the early stage of virus infection (2-3 d), the secretion of IL-12 is increased to promote the production of interferon (IFN)-γ and immunoglobulin (Ig) A on the mucous membrane of the respiratory tract in order to enhance the immunity of the mucous membrane (56) (57) (58). During the middle and late stages (after 6d) of a deadly influenza infection model, excess IFN-γ is produced (59). The clinical significance of reducing this immune reaction and its ability to affect the fatality rate are currently being investigated and are expected to be future targets of Macrolide therapy (60)(61).
Clarithromycin as well as other macrolides can inhibit the activation of NF-κB in cell nuclei to reduce transcription and promote anti- inflammatory action (59).
In summary, clarithromycin, a clinically used macrolide, reduces FluA viral titers and cytokines secretion in supernatant fluids, FluA virus RNA replication in the cells, and susceptibility of the cells to infection by the virus (62) (63) (64).
Clarithromycin also reduced the expression of SA 2,6Gal, a receptor for human influenza, on the mucosal surface of human tracheae, and reduced the number of acidic endosomes from which viral RNPs enter into the cytoplasm (63).
Those clarithromycin mechanisms were explained by actions on inhibition protein synthesis by reversibly binding to the 50S ribosomal subunits. This action share with the macrolides that inhibit the translocation of aminoacyl transfer-RNA, and prevents peptide chain elongation. Perhaps this may could acting and explaining the antiviral properties; the SARS-CoV-2 is an RNA virus (65) (66).
Otherwise, the macrolide antibiotics, especially Clarithromycin can decrease the hypersecretion of proinflammatory cytokines and chemokines in vitro, in preclinical models, and chronic inflammatory pulmonary diseases. Other proprieties of the macrolides that could aid their action in pulmonary injuries are the airway epithelial barrier that is due to the stabilization of the epithelial cell membrane, the entry of the virus into the cell (67).
All these findings suggest that a clinically used macrolide antibiotic, clarithromycin, may inhibit many virus, including type A seasonal human influenza virus infection, via reducing its receptor on the airway epithelial cells and via reducing entry of viral RNPs, which contain viral RNA, into the cytoplasm (57)(68)(69).
Macrolides have received considerable attention for their anti-inflammatory and immunomodulatory actions beyond the antibacterial effect. These two properties may ensure some efficacy in a wide spectrum of viral infections (70) (71) (72) (73). They downregulate the inflammatory cascade, attenuate excessive cytokine production in viral infections, and they may reduce virus-related exacerbations (72) (73). The effects of Clarithromycin in patients with Covid-19 and pulmonary disease appear to be also independent of its antimicrobial properties, and maybe more related to immunomodulating pathways that do not affect its antibiotic mechanism. This action could also be required for COVID-19 as there are many descriptions of “cytokines storms” syndromes (67)(68)(69)(70)(73).
Clarithromycin inhibit airway inflammation and may modulate also the severity of influenza infection induced by influenza virus infection. (71).
Much data showed that macrolides reduced different viral titers of ICAM-1, as well as the release of many pro-inflammatory viral infection-induced cytokines including IL-1β, IL-6, IL-8, and TNF-α. Also, lowering of viral titers and RNA of viral replication as well as augmentation of the IL-12 by macrolides, which is essential in reducing virus yield were revealed (59) (62) (64) The demonstration that the macrolides, particularly clarithromycin, have a role on immunomodulation, could also be seen in the potential case of a patient receiving a mesenchymal cell therapy simultaneously attenuating pro-inflammatory cytokines secretion, inflammatory cell recruitment and/or increased alveolar macrophages content specially if that patients could have respiratory distress (21)(73)(74)
Based on all this existing evidence, macrolides, especially Clarithromycin maybe considered as a promising treatment option in treatment of respiratory viral infections and have encouraged a number of researchers to explore further this potential application even us for Covid-19 Treatment and Prophylaxis (22) (23) (24)(74)(75).
Azithromycin pharmacologically is very similar to Clarithromycin (32), but, according to our experience and that of the scientific literature, Clarithromycin, as an antiviral, anti-inflammatory and/or immunomodulatory drug seems to be a lot much better (22) (23) (33) (34) (74) (75).
That’s why it should be better or even essential to use Clarithromycin in any proposed trial of this kind in which a Macrolide would be given as a single agent.