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.