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).