What is the role of oral macrolides (e.g. azithromycin) in non-Cystic Fibrosis (CF) bronchiectasis, as an anti-inflammatory agent or bacterial suppressant?

Role of Oral Macrolides in Non-CF Bronchiectasis

Oral macrolides in non-CF bronchiectasis serve a dual role as both anti-inflammatory agents and bacterial suppressants, with evidence supporting their use to reduce exacerbation frequency in patients with three or more exacerbations per year.

Mechanism of Action

• Macrolides (such as azithromycin, erythromycin) provide both antimicrobial effects and anti-inflammatory/immunomodulatory properties in bronchiectasis 1
• Anti-inflammatory effects include reductions in Th17 cell responses and reduced airway inflammation through markers such as IL8, neutrophil elastase and matrix metalloproteinase-9 1
• Macrolides can inhibit quorum sensing (bacterial communication), which is particularly important in Pseudomonas aeruginosa infections 1

Clinical Evidence for Efficacy

• High-quality evidence from three randomized controlled trials shows that macrolides (azithromycin or erythromycin) taken for 6-12 months significantly reduce exacerbation rates in non-CF bronchiectasis 1, 2
• In the BAT study, azithromycin 250mg daily for 12 months reduced the median number of exacerbations to 0 compared with 2 in the placebo group (p<0.001) 3
• The EMBRACE trial demonstrated that azithromycin 500mg three times weekly for 6 months reduced exacerbation rates by 62% compared to placebo 4
• Meta-analysis shows macrolide therapy significantly reduces the number of patients experiencing exacerbations (RR=1.56,95% CI=1.14-2.14) and bronchiectasis-related hospital admissions (RR=0.46,95% CI=0.23-0.96) 2

Recommendations for Use

• Macrolides should be considered for adults with bronchiectasis who have three or more exacerbations per year (conditional recommendation, moderate quality evidence) 1
• Azithromycin appears to be more effective than other macrolides in reducing exacerbations (RR=2.25,95% CI=1.67-3.02) 2
• For patients with chronic Pseudomonas aeruginosa infection, inhaled antibiotics are the first choice, with macrolides suggested when inhaled antibiotics are contraindicated, not tolerated, or not feasible 1
• For non-Pseudomonas infected patients, macrolides (azithromycin, erythromycin) are suggested as first-line long-term antibiotic therapy 1

Dosing Regimens

• Various regimens have been studied with no clear consensus on optimal dosing:
  • Azithromycin 250mg daily 3
  • Azithromycin 500mg three times weekly 4
  • Azithromycin 250mg three times weekly 1
  • Erythromycin 250mg twice daily 1

Safety Considerations and Adverse Effects

• Gastrointestinal side effects (abdominal pain, nausea, diarrhea) are the most common adverse events, occurring in up to 40% of patients on azithromycin 3
• ECG should be performed prior to initiation of therapy to assess QTc interval; macrolides are contraindicated if QTc is >450ms for men and >470ms for women 1
• Development of macrolide resistance is a significant concern, with resistance rates of up to 88% reported in treated individuals compared to 26% in placebo groups 3, 2
• Monitoring for antimicrobial resistance may be beneficial in those receiving chronic macrolide therapy 1

Important Caveats

• Macrolides should never be used as monotherapy in patients with non-tuberculous mycobacterial (NTM) infections as this can lead to resistance 1
• Patients should be screened for NTM before starting macrolide therapy, and macrolides should be discontinued immediately if NTM is isolated during treatment 1
• Long-term antibiotic therapy should only be considered after optimization of general aspects of bronchiectasis management (airway clearance and treating modifiable underlying causes) 1
• Treatment duration of at least 6-12 months is typically needed to assess efficacy in reducing exacerbations 1

Conclusion

Macrolides in non-CF bronchiectasis function as both anti-inflammatory agents and bacterial suppressants. Their dual mechanism provides clinical benefit primarily through reduction in exacerbation frequency, with the strongest evidence supporting their use in patients with frequent exacerbations (three or more per year).