key: cord-253170-mjy4culg
authors: Parra-Lara, Luis Gabriel; Martínez-Arboleda, Juan José; Rosso, Fernando
title: Azithromycin and SARS-CoV-2 infection: where we are now and where we are going
date: 2020-07-01
journal: J Glob Antimicrob Resist
DOI: 10.1016/j.jgar.2020.06.016
sha: 
doc_id: 253170
cord_uid: mjy4culg

• Due to its mechanism of action and various anti-inflammatory effects, azithromycin is a promising medicine for the treatment of the coronavirus COVID-19. • The studies that have been done so far on the use of azithromycin in the management of the COVID-19 coronavirus have had various methodological limitations. At the moment, no conclusions can be drawn about the efficacy of this drug as an adjunct to hydroxychloroquine. • Azithromycin has serious cardiac adverse effects such as QT prolongation. Hydroxychloroquine also has them. The combination of these two drugs should be determined with caution. • At the moment 21 clinical trials are being carried out on the use of azithromycin in COVID-19.

 Azithromycin has serious cardiac adverse effects such as QT prolongation.

Hydroxychloroquine also has them. The combination of these two drugs should be determined with caution.

 At the moment 21 clinical trials are being carried out on the use of azithromycin in COVID-19.

Azithromycin is a macrolide antibiotic with a 15-membered lactone ring. It has excellent tissue penetration and antimicrobial activity due to inhibition of the 50s subunit of the ribosome that prevents the synthesis of proteins from a wide range of Gram-positive and Gram-negative bacteria. Anti-inflammatory effects include modulating the production of pro-inflammatory cytokines such as IL-6, IL-1beta and acceleration of phagocytosis capacity of macrophages, classifying Azithromycin as a senolytic drug that selectively attacks and kills senescent cells, with an efficiency of almost 97% (1) (2) (3) . This macrolide has also been shown to have antiviral properties for respiratory viruses, such as rhinoviruses, by decreasing the synthesis of intercellular adhesion molecules such as ICAM-1 which are used by the virus for their adhesion (4) . Everything mentioned has generated new hypotheses and opened a new panorama in older adult patients with high mortality from COVID-19, which should be evaluated in future research.

In combination with hydroxychloroquine, it was recently shown that azithromycin inhibits the replication of the coronavirus COVID-19, in an open-label clinical trial conducted in France (5) . However, the effects of azithromycin alone were not evaluated. In this study 36 patients were included (20 hydroxychloroquine and 16 control) who were positive for J o u r n a l P r e -p r o o f COVID-19 by PCR, the researchers demonstrated that hydroxychloroquine (14/20, 70%) was superior to standard management (2/16, 12.5%; p=0.001) for the eradication of COVID-19.

Azithromycin was prescribed to 6 patients with the initial goal of preventing bacterial superinfection and it was found that in this subgroup viral eradication was much higher (6/6, 100%) on the 6th day of treatment, compared to those who received hydroxychloroquine as monotherapy (8/14, 57%). The dose was 500mg on day 1 followed by 250mg day for the next four days. However, these data must be interpreted with caution. The group of patients who received hydroxychloroquine as monotherapy had significantly higher viral loads than those who received the combined therapy with azithromycin, so the true adjuvant efficacy of this drug may be overestimated in the virus eradication rates.

Other authors suggest that with the findings of this study, together with previous research on the effect of macrolides on rhinoviruses, respiratory syncytial virus, influenza, and Zika, among others, it makes, for example, medications such as erythromycin be conspicuous for future research on COVID-19 (6) . However, the mechanism by which the combination of a macrolide with hydroxychloroquine stops the production of the SARS-CoV-2 virus remains unknown, and to date no in vitro studies have been reported with results in this regard. A wide variety of azithromycin-related adverse effects that involve all the body's systems have been described, these vary in severity and frequency. Among the most frequent are gastrointestinal disorders such as nausea, vomiting, and diarrhea, which are seen in up to 10% of cases. Albeit at low frequency, severe side-effects can predispose patients to lifethreatening scenarios and arrhythmias such as QT prolongation. The mechanism by which the QT interval is prolonged is by blocking the external flow of potassium ions from ventricular myocytes to the extracellular fluid which stimulates ventricular repolarization.

Hydroxychloroquine has also been shown to have cardiac effects including QT prolongation, therefore, the concomitant use of hydroxychloroquine with azithromycin could potentiate these effects, an aspect that should be considered when prescribing these combinations. The potential of hydroxychloroquine to prolong ventricular repolarization is not as well documented, but cases of QT prolongation have been reported during chronic treatment(9).

Only a few clinical studies have analyzed the cardiovascular effects of these drugs in the past(10), and they have concluded that indeed they have an effect on the QT interval and when combined, this effect is increased. Studies in COVID-19 patients that have been carried out lately show this additive effect; for example, a study conducted in Boston showed that in a cohort of 90 patients given hydroxychloroquine, those receiving concomitant azithromycin Despite the mentioned cardiac effects, their appearance may be reduced in a controlled clinical setting. Giudicessi et al. proposed that together with other parameters such as J o u r n a l P r e -p r o o f electrolytes and comorbidities, depending on the length of the QT, it can be determined whether or not the patient is a candidate for the use of these drugs. Patients with QT less than 460ms are candidates for pharmacological therapy categorized in green, while those with QT greater than 460ms (categorized as yellow or red) are at greater risk of complications such as torsade de pointes, so the cost-benefit ratio of the management should be very well evaluated.

Their data is encouraging since they estimate that the vast majority of patients (90%) will be categorized as green turning them into candidates (12) .

Finally, regulatory entities such as the European Medicines Agency (EMA), although they do not fully recommend the use of the aforementioned combination of drugs due to their adverse effects, they support their use under strict medical supervision and always considering the possibility of the aforementioned adverse effects. Therefore, in the context of COVID-19, these drugs should only be used as part of clinical trials or parallel to national security protocols (13) . Future research should consider, in addition to their combined efficacy, their combined safety profile.

There are currently 21 clinical trials registered on ClinicalTrials.gov for azithromycin related to COVID-19 (see Table 1 ). Eight studies have already started the patient recruitment process, thirteen will be carried out in a single center and eight will be carried out in the USA.

Ongoing trials varied in design, comparison group, drug dose and duration, target population, and primary endpoints. Only five studies included safety outcomes. The foregoing is an international call and effort to seek therapeutic strategies to control the COVID-19 pandemic that currently affects 180 countries on all continents. Based on these results, therapeutic guidelines can be established for patients with the disease based on scientific evidence and will clarify the effectiveness of azithromycin against SARS-CoV-2. J o u r n a l P r e -p r o o f 

COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection?

An eye for azithromycin: review of the literature

Anti-inflammatory mechanism of action of azithromycin in LPS-stimulated J774A.1 cells

Azithromycin induces anti-viral responses in bronchial epithelial cells

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Macrolide treatment for COVID-19: Will this be the way forward? Biosci Trends

Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19)

COVID-19: reminder of risk of serious side effects with chloroquine and hydroxychloroquine

Funding: PO