Macrolides and viral infections: focus on azithromycin in COVID-19 pathology

Abstract

The emergence of the new COVID-19 virus is proving to be a challenge in seeking effective therapies. Since the most severe clinical manifestation of COVID-19 appears to be a severe acute respiratory syndrome, azithromycin has been proposed as a potential treatment. Azithromycin is known to have immunomodulating and antiviral properties. In vitro studies have demonstrated the capacity of azithromycin in reducing production of pro-inflammatory cytokines such as IL-8, IL-6, TNF alpha, reduce oxidative stress, and modulate T-helper functions. At the same time there are multiple clinical evidences of the role of azithromycin in acute respiratory distress syndrome and against Middle East Respiratory syndrome (MERS). Some preliminary evidence has demonstrated controversial results regarding efficacy of azithromycin in combination with hydroxychloroquine in COVID-19. First, a French trial demonstrated 100% virological negativizing of six patients treated with azithromycin plus hydroxychloroquine vs. 57.1% of patients treated with only hydroxychloroquine and 12.5% of the control group ( P < 0.05). On the other hand, another case series revealed no efficacy at all on 11 patients treated with the same combination and doses. Furthermore, there are some concerns regarding the association of azithromycin and hydroxychloroquine because of potential QT prolongation. In fact, both drugs have this as a potential side effect and evidence regarding the safe use of this combination is controversial. Despite the necessity to quickly find solutions for COVID-19, extreme caution must be used in evaluating the risk-benefit balance. However, based on preclinical and clinical evidence and some preliminary results in COVID-19, azithromycin could have potential in the fight against this new disease.

Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection

“…Azithromycin is a commonly used macrolide antibiotic that has antiviral properties mainly attributed to reduced endosomal transfer of virions as well as established anti-inflammatory effects. 27 It has been commonly used in COVID-19 studies initially based on French reports demonstrating markedly reduced durations of viral shedding, fewer hospitalizations, and reduced mortality combination with HCQ as compared to those untreated. 28 , 29 In the large inpatient study (n = 2451) discussed previously, those who received azithromycin alone had an adjusted HR for mortality of 1.05, 95% CI 0.68-1.62, and P = 0.83.…”

Drugs against SARS‐CoV‐2: What do we know about their mode of action?

“…111 Interestingly, the MoA of azithromycin and HCQ may be related to the modulation of the endosomal and trans-Golgi network pH. 112,113 In addition, azithromycin plays a role in regulating interleukin production that might help to control the immune response and prevent symptom worsening. [114][115][116] Azithromycin may also inhibit viral invasion by interfering with the CD147-mediated recognition mechanism.…”

“…Azithromycin is an antibiotic that has also antiviral activity in respiratory viral infections 111 . Interestingly, the MoA of azithromycin and HCQ may be related to the modulation of the endosomal and trans‐Golgi network pH 112,113 . In addition, azithromycin plays a role in regulating interleukin production that might help to control the immune response and prevent symptom worsening 114‐116 .…”

New putative insights into Neprilysin (NEP)-dependent pharmacotherapeutic role of Roflumilast in treating COVID-19

“…Azithromycin was detected to possess anti-inflammatory and immunomodulating actions in addition to antiviral properties because of its ability to minimize the production of pro-inflammatory cytokines particularly IL-6 and TNF-α, noxious oxidative radicals as well as to improve T-helper functions. However, the preliminary studies have demonstrated that using azithromycin should be in caution due to its potential arrhythmogenic threat, especially in highly risk COVID-19 patients (Pani et al, 2020).…”