Anti-inflammatory Clarithromycin for Improving COVID-19 Infection Early

Humanity is experiencing since December 2019 a new pandemic by the novel SARS Coronavirus-19
(SARS-CoV-2). As of March 25 2020 418,099 documented case were reported worldwide; 18,608
patients died. The analysis of the clinical characteristics of these patients showed that the
natural course of this disease, known with the acronym COVID-19, is several times
unpredictable. Most patients who develop pneumonia do not have worrying symptoms although
their chest X-ray or chest computed tomography may be positive for diffuse infiltrates.
Suddenly a certain proportion of these patients deteriorate into severe respiratory failure;
this usually takes place between the 5th and the 10th day of illness and arrives without any
preceding symptom. Published evidence suggests that this is due to the sudden arrival of an
acute pro-inflammatory reaction of the host. With this in mind, it is reasonable to make the
assumption than the early treatment with an agent that can efficiently modulate the host
response and prevent sudden hyper-inflammatory reaction may prevent the development of severe
respiratory failure (SRF).

The new guidelines published by the American Thoracic Society in 2019 clearly suggest that
the management of community-acquired pneumonia (CAP) should rely on the combination of
β-lactam antibiotics with macrolides. This position statement is pretty much influenced by
the retrospective analyses of observational studies and of their meta-analyses in showing
that the addition of a macrolide improves survival from severe CAP. Since patients leave in
an era of antimicrobial resistance, it is profound that survival benefit is linked to the
anti-inflammatory properties of the macrolide class of antibiotics. These properties are not
only limited to the attenuation of the production of pro-inflammatory mediators but they
involve the enhancement of pathogen clearance.

With this in mind, a small open-label trial among patients with COVID-19 showed better viral
containment as assessed by the persistence of the virus in respiratory secretions, when
patients were treated with a combination of azithromycin and hydroxychloroquine. However, the
clinical benefit coming from this study has not yet been published. Contrary to azithromycin,
clinical evidence suggests that clarithromycin is associated with substantial clinical
benefit among critically ill patients. Two randomized clinical studies in a total of 800
patients with sepsis have shown 28-day survival benefit among the most severe cases. One of
these studies enrolled patients with sepsis and ventilator-associated pneumonia; among 100
patients allocated to placebo treatment 40% survived until day 90; this was 57% among
clarithromycin-treated patients.

In recent publication coming from the research network of the Hellenic Sepsis Study Group
(HSSG) 130 patients with CAP were treated with a combination of β-lactam and clarithromycin.
These patients were compared with 130 patients treated with a combination of β-lactam and
azithromycin. Groups were well-matched for severity and comorbidities; 28-day mortality was
20.8% and 33.8% respectively.

Based on the above analysis, it seems likely that treatment of patients with COVID-19 with
oral clarithromycin will substantially increase their anti-inflammatory properties and
decrease the chances for development of severe respiratory failure.

As stated above, the efficacy of the treatment combination of hydroxychloroquine with
azithromycin is based on results coming from only six patients. Since the publication of
these data other, yet unpublished, reports have appeared in the internet challenging the
treatment efficacy of this combination. These results show that treatment with
hydroxychloroquine either single or in combination with azithromycin have either an
indifferent effect on viral replication or even a deleterious effect on the patient due to
cardiotoxicity. With this in mind it is obvious that macrolide treatment in COVID-19 patients
many of which have coronary heart disease and chronic heart failure as comorbidities should
be administered without hydroxychloroquine.