Macrolides, as a drug class, appear to exhibit inhibitory activity on various cell-signaling pathways. For azithromycin, various studies have documented activity on NF-κB, inflammasome, PLA2, and ERK 1/2 signaling pathways. When NF-κB is inhibited in alveolar macrophages, there is suppressed induction of pro-inflammatory genes along with cytokines (e.g., TNF-α and IL-1) and chemokine products, which leads to reducing immune cell infiltration, preserving epithelial barrier function, and interfering with the mechanisms that promote immune cell adhesion and migration. Macrolides also reduce the activation of transcription factors AP-1 and NF-κB in airway epithelial cells, which helps to reduce inflammation. PLA2 signals the production of arachidonic acid, eicosanoids, and other cytokine/chemokines within immunomodulating cells. A decrease in PLA2 substrate was observed to promote anti-inflammatory properties in a rat model. ERK 1/2 partly regulates AP-1 activity, which is part of a signaling process in neutrophils. Azithromycin can also decrease the mRNA stability of NLRP3 inflammasome production in human monocytes, which may hold anti-inflammatory properties but is not defined in detail. [1], [2], [3]
Some of azithromycin's anti-inflammatory effects hinge upon its dosing and duration; in diffuse panbronchiolitis (DPB), a chronic obstructive pulmonary disease found primarily in Japan, chronic administration of low doses of macrolides diminishes interleukin-8 (IL-8), a cytokine responsible for the chemotaxis of neutrophils to the lungs which then causes an overabundance of neutrophils. In Pseudomonas aeruginosa colonization, which may subsequently lead to biofilm production from mucoid strains, bactericidal activity by azithromycin against P. aeruginosa and its virulence factors (e.g., autoinducer 3-oxo-C12-HSL) leads to decreased IL-8 production. [1], [2], [3]
These benefits translate over to community-acquired pneumonia, where decreased chemokine and IL-6 serum concentrations were observed with a down-regulation of the oxidative burst and an increase in neutrophil apoptosis, without pro-inflammatory intracellular products spilling in the process, up to 28 days following azithromycin dosing. These biphasic effects appear to allow minimization, if not suppression, of any further inflammation that may cause ongoing local and/or systemic damage; however, the author exhorts replication in an animal model in order to confirm the existence of this mechanism and notes that previous research regarding the extent of these anti-inflammatory benefits have been highly variable. Regardless, the author concludes that macrolides overall may have a very large number of potential immunomodulatory uses and may become a favored agent for patients who require systemic corticosteroids chronically, without the immunosuppressive nature of corticosteroids. [1], [2], [3]
A 2021 systematic review analyzed seven randomized controlled trials (RCTs) to evaluate the comparative efficacy of azithromycin versus clarithromycin in combination with beta-lactams for treating community-acquired pneumonia (CAP) in hospitalized adults. The primary outcome was defined as clinical success at the end of therapy, measured by standard parameters such as normalization of vital signs and symptom resolution. The findings showed that the treatment success rate for azithromycin–beta-lactam regimens was notably higher, averaging 87.55% over 10–14 days, compared to 75.42% for clarithromycin–beta-lactam combinations over 5–7 days. Streptococcus pneumoniae was the most frequently isolated pathogen, with 130 isolates in the clarithromycin cohort and 80 in the azithromycin group. Intriguingly, the clarithromycin–beta-lactam regimen was associated with a shorter mean hospitalization duration of 7.25 days, compared to 8.45 days observed with azithromycin-based therapy. Among the beta-lactams studied, ceftriaxone was most commonly used, often administered alongside azithromycin. These findings underscore the potential clinical benefit of azithromycin in achieving higher cure rates while highlighting clarithromycin's role in reducing hospital length of stay, suggesting therapy optimization may depend on specific treatment goals and local antimicrobial susceptibility patterns. Of note was the lack of statistical power for the presented findings. [4]
Another systematic review and meta-analysis synthesized data from 23 studies, including 18 observational cohort studies and 5 randomized controlled trials (RCTs), evaluating the association between macrolide-based regimens (clarithromycin, azithromycin, erythromycin, roxithromycin) and mortality in hospitalized adults with community-acquired pneumonia (CAP). The analysis included 137,574 patients, with macrolides compared to nonmacrolide regimens in primary analyses and macrolide/beta-lactam combinations versus respiratory fluoroquinolones in secondary analyses. Meta-analytic pooling demonstrated a 22% relative reduction in mortality among macrolide users compared to nonmacrolide regimens (risk ratio [RR] 0.78; 95% confidence interval [CI], 0.64–0.95; p= 0.01), though heterogeneity was high (I² = 85%). In subgroup analyses restricted to guideline-concordant regimens, such as macrolide/beta-lactam versus fluoroquinolone monotherapy, no mortality difference was observed (RR 1.17; 95% CI, 0.91–1.50; p= 0.22; I² = 43%). Additionally, analyses limited to RCTs revealed no statistically significant mortality benefit of macrolides (RR 1.13; 95% CI, 0.65–1.98; p= 0.66; I² = 0%). Potential confounding or bias, including confounding by indication, and substantial heterogeneity in observational studies, were highlighted as crucial limitations. While macrolides exhibited a possible mortality advantage in pooled observational data, the lack of significant benefit in RCTs and guideline-concordant regimens suggests that the choice of antibiotic regimen adherence to guidelines may be more critical than specific antibiotic selection. Of note, eight of the 23 studies included azithromycin, but the findings were not further stratified by specific macrolid agents. [5]
A 2024 systematic review synthesized data from phase III RCTs evaluating the efficacy of ivermectin, chloroquine/Hydroxychloroquine (CQ/HCQ), and azithromycin for managing COVID-19. The review included three for azithromycin, focusing on outcomes such as disease progression, mortality, need for mechanical ventilation, viral clearance, and clinical improvement. Similar to ivermectin and CQ/HQ, analysis of azithromycin demonstrated no improvement in survival or hospital discharge rates among hospitalized COVID-19 patients. Consistently, the reviewed evidence indicated no clinically significant benefit of azithromycin in improving COVID-19 outcomes, even when combined with other agents like HCQ. These findings underscore the lack of efficacy of these repurposed drugs in the treatment of COVID-19 and highlight the importance of evidence-driven clinical decisions. [6]
A 2024 systematic review and meta-analysis (N= 738) evaluated the efficacy of azithromycin in managing acute bronchiolitis and wheezing episodes among children under two years of age, analyzing data from seven RCTs conducted globally. Azithromycin dosing strategies varied, predominantly involving daily regimens of 10 mg/kg for 3–14 days, with some studies employing higher single or weekly doses. The meta-analysis revealed that azithromycin demonstrated a modest reduction in hospitalization duration by an average of 0.27 days (95% CI –0.47 to –0.07), categorized as moderate-quality evidence. However, no benefit was seen in reducing the need for pediatric intensive care admission, recurrence of wheezing episodes within follow-up periods ranging from 3 months to 4 years, or subsequent asthma diagnoses, with evidence quality ranging from low to very low. Cumulative adverse events (AEs), including gastrointestinal symptoms, were comparable between azithromycin and placebo groups, with no significant differences reported. The findings suggest limited clinical utility for routine use of azithromycin in acute wheezing or prophylaxis for wheezing recurrence in young children, emphasizing the need for earlier initiation of therapy to optimize potential antiviral or immunomodulatory effects. On the contrary, another systematic review and meta-analysis (23 studies, N= 2210) found no significant differences in length of stay, duration of oxygen demand, symptoms and signs of respiratory distress, or re-admission rates observed in hospitalized pediatrics with childhood wheezing disease undergoing macrolide treatment. Further subgroup analysis by macrolide category confirmed azithromycin had comparable LOS to the placebo group (azithromycin: -0.038 days, range: -0.207 to 0.131 days, p= 0.658, I2 = 0%). [7], [8]