Macrolides Used for MERS:
In patients with Middle East Respiratory Syndrome (MERS), macrolides are often prescribed as part of the empiric treatment regimen for pneumonia, often before the detection of MERS coronavirus (MERS-CoV). Using a cohort of critically ill patients with MERS, the aim of one study was to determine whether there was an association between macrolide therapy and 90-day mortality and RNA clearance in critically ill patients with MERS. Of 349 critically ill MERS patients, 136 (39%) received macrolide therapy. Azithromycin was most commonly used (97/136; 71.3%). Macrolide therapy was commonly started before the patient arrived in the intensive care unit (ICU) (51/136; 37.5%), or on day1 in ICU (53/136; 39%). Patients received macrolide treatment (Azithromycin, Clarithromycin) within three days before admission to ICU, or at any time during their stay in ICU, up to 28 days and a ‘no macrolide therapy’ (control) group. Macrolide therapy was not independently associated with a significant difference in 90-day mortality or improvement in MERS-CoV RNA clearance (76). But due to the nature of the population of this study (critically ill patients), this study did not measure the difference in symptoms improvement between the group who received macrolides and the group who did not. Also the category of these patients as they were all critically ill, might have not been, the best one to start with this kind of treatment. If the patients could have received the treatment before being critically ill maybe the results could have been completely different. Also, this study was a retrospective one.
The French Studies with Hydroxychloroquine and the Macrolide Azithromicyn for COVID-19 (17) (77) (78):
The small studies using the combination of Hydroxychloroquine and Azithromycin ”showed a significant reduction in viral load” after six days of treatment and a ”much shorter average viral load duration” compared to patients who received another treatment. Six patients in one of the trials were asymptomatic and 22 had symptoms of upper respiratory tract infection. Eight patients had lower respiratory tract infections. Twenty cases were treated in the study, with untreated patients acting as negative controls. Hydroxychloroquine treatment was found to significantly reduce viral load in patients with COVID-19, and had an improved effect when azithromycin was included in the treatment. Interestingly, a patient who continued to test positive after being treated with Hydroxychloroquine alone was given Azithromycin starting on the eighth day and tested negative the following day (79).
This fact is of outmost importance since it would be inferred from said results that macrolide drugs could have an antiviral effect inherent to them.
However, Hydroxychloroquine an antimalarial and antirheumatic drug has many adverse reactions such as cardiac, liver and eye disorders among others. Thus, checkups are needed before using Hydroxychloroquine in patients with chronic diseases who are the most affected by COVID-19 (16) (17)(78) (79) (80).
This risk could have been lowered by using Hydroxychloroquine at a lower dosage but still achieving a good, and more stable concentration in the blood. This fact could have been better achieved combining Hydroxychloroquine with Clarithromycin which is in many ways superior to Azithromycin (33) (81).
Also, that risk is no longer a problem, if Hydroxychloroquine is not used in such a combination and, any macrolide specially Clarithromycin alone could be left as a single agent as we have postulated (22) (23) (24).
It has been usually wrongly believed that azithromycin, in all those different COVID-19 clinical studies, has mainly acted as an antibacterial agent especially for associated-pneumonias (77) (78) (81).
When comparing the effect of Hydroxychloroquine treatment as a single drug and the effect of Hydroxychloroquine and Azithromycin in combination, the proportion of patients that had negative PCR results in nasopharyngeal samples was significantly different between the two groups at days 3-4-5 and six post-inclusion. At day six post-inclusion, 100% of patients treated with Hydroxychloroquine and Azithromycin combination were virologicaly cured comparing with 57.1% in patients treated with Hydroxychloroquine only, and 12.5% in the control group (p<0.001). Of note, one patient who was still PCR-positive at day 6-post inclusion under Hydroxychloroquine treatment only received Azithromycin in addition to hydroxychloroquine at day eight post inclusion and cured her infection at day-9 post-infection (77) (78).
How did Hydroxychloroquine and Azithromycin Worked Together and Could have Azithromycin Been the Most Active Drug in that Combination? :
The results obtained in those Hydroxychloroquine-Azithromycin studies (77) (78), could only be explained by three simple possible ways:
1) Azithromycin only acts as an antibacterial agent for associated pneumonia;
2) Azithromycin acts synergistically with Hydroxychloroquine;
3) Azithromycin has an antiviral effect independent of that of Hydroxychloroquine.
No one has come out to completely open the scene on this yet.
“ From all the cited scientific literature and our own clinical experience we are more inclined to think that the action of macrolides in these situations could have been basically antiviral ” (48) (22).