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).