3.5- Antiviral and immunomodulatory clinical efficacy
Macrolides have shown their clinical efficacy in a wide variety of
respiratory viral infections[52]. Specifically, azithromycin has
been studied in influenza and Middle East Respiratory Syndrome
coronavirus (MERS-CoV) infections[53–57]. The clinical studies of
azithromycin in viral infections were summarized in Table 1.
Lee et al. concluded that in hospitalized patients with influenza
A pneumonia, the addition of azithromycin to oseltamivir significantly
reduced the synthesis of proinflammatory cytokines [57]. A trend
towards a faster symptom resolution was noticed, with no differences in
viral load change or culture negativity among groups [57]. The mean
time from symptom onset to randomization was 2 days. Kakeya etal. showed that the treatment with azithromycin and oseltamivir,
if initiated within 48h of the onset of symptoms, in patients with mild
influenza A pneumonia was associated with a significant faster
resolution of fever and sore throat, without differences in the
expression levels of cytokines and chemokines [56]. The low baseline
values of these substances, however, may have affected the outcomes
[56]. These studies are not without limitations, since they were
open-label clinical trials with a small number of patients included.
Subjective outcomes were analyzed, which does not seem to be the most
appropriate measures in an open-label trial.
On the contrary, Martin-Loeches et al. did not show a survival
benefit of macrolides in the treatment of influenza A pneumonia in
critically ill patients [53]. However, this was a secondary analysis
of an observational study and, importantly, both clarithromycin and
azithromycin were included. Given that clarithromycin has shown less
immunomodulatory activity, the potential benefits of azithromycin in
this setting may have been underestimated[37,38]. In addition, the
dose and duration of macrolide therapy was not described, and the
treatment was initiated late in the disease (5 days).
Recently, in hospitalized patients presenting after 48h of symptoms
onset with influenza A pneumonia, the addition of azithromycin
(initiated 6-8h after diagnosis) significantly improved meaningful
clinical outcomes as length of stay or the need for respiratory support
during hospitalization[55]. In patients with age ≥50 years,
furthermore, a significant reduction in vasopressor use was
noticed[55]. Although groups were well balanced in admission and
adjusted in the multivariate model, it was a retrospective observational
study so other confounding factors may have also been present.
A group of experts recommended the use of macrolides in combination with
antivirals for the treatment of H1N1 influenza severe disease to reduce
the systemic inflammatory response[58].
In MERS-CoV infection, macrolides were not associated with a significant
benefit[54]. Again, it was a secondary analysis of an observational
study, macrolides were grouped, and the dose and duration of the
treatment were not reported. In addition, the sum of the patients
treated with macrolides (147) was higher than stated (136) and no data
concerning the time from symptom onset to treatment initiation was
shown.
Only two studies reported safety data showing that azithromycin was well
tolerated[56,57]. The incidence and the severity of adverse events
and the rate of treatment discontinuations was similar among studied
groups.
Beyond its antibacterial and potential antiviral activity, the
immunomodulatory action of azithromycin may provide further clinical
benefits[7]. In chronic diseases as asthma, chronic obstructive
pulmonary disease, bronchiectasis, diffuse panbronchiolitis orPseudomonas aeruginosa colonization, azithromycin use was
associated with positive clinical outcomes and reduced risk of
exacerbations[7,59,60].
In the treatment of community-acquired pneumonia (CAP) its use is
recommended in combination with beta-lactams, including in those
admitted to the intensive care unit (ICU)[61]. For patients with
bacteremic pneumococcal pneumonia, not adding a macrolide to a
beta-lactam-based initial antibiotic regimen was an independent
predictor of in-hospital mortality[62]. In a systematic review and
meta-analysis that included 10,000 critically ill patients with CAP,
macrolide use was associated with a significant reduction in
mortality[42]. The immunomodulatory properties of macrolides may
account for this difference, given that these benefits were even
demonstrated in infections produced by macrolide-resistant
strains[42,48].
In a secondary analysis of a multicenter, randomized controlled clinical
trial, 235 patients were included with acute lung injury[63]. After
adjusting for confounding factors, the treatment with macrolides was
associated with a reduction in the time to successful ventilator
discontinuation (HR 1.93 [95% CI 1.18-3.17]) and 180-day mortality
(HR 0.46 [95% CI 0.23-0.92]). Acute lung injury was mainly due to
pneumonia and macrolides were started within 60 h of diagnosis with a
median duration of 4 days (dose unknown). These differences may be due
to immunomodulatory properties as were not seen with fluoroquinolones or
cephalosporines. A single center, retrospective, propensity-score
matched analysis included 124 patients with moderate-severe
ARDS[19]. The adjunctive therapy with azithromycin was associated
with a shorter time to successful discontinuation of mechanical
ventilation (HR 1.74 [95% CI 1.07-2.81]) and a reduction in 90-day
mortality (HR 0.49 [95% CI 0.27-0.87]). The main causes of ARDS
were pneumonia and sepsis. Azithromycin was initiated within 24h of
diagnosis and used for 5 days (dose unknown).