Macrolide Antibiotics
Macrolide antibiotics include erythromycin, azithromycin, and clarithromycin as the three primary agents available in North America, with additional members like roxithromycin and dirithromycin available in other regions. 1
Structural Classification
Macrolides are defined by their macrocyclic lactone ring structure containing 12 or more elements: 1
- 14-membered ring macrolides: Erythromycin, clarithromycin, roxithromycin 1, 2
- 15-membered ring macrolides (azalides): Azithromycin 1, 3
- 16-membered ring macrolides: Available in some regions 3, 4
Commonly Used Macrolides in Clinical Practice
First-Generation Agent
- Erythromycin: The original macrolide launched commercially in 1952, remains the least expensive but is limited by gastrointestinal intolerance and lack of activity against H. influenzae 1
Newer-Generation Agents
- Azithromycin: A 15-membered azalide with once-daily dosing, 5-day treatment course, and superior activity against gram-negative bacteria including H. influenzae and M. catarrhalis 1, 5
- Clarithromycin: A 14-membered macrolide with twice-daily dosing (or once-daily extended-release formulation), enhanced activity against H. influenzae, and the most potent activity against Mycobacterium avium complex 1, 2, 5
Less Commonly Used Agents
- Roxithromycin: A 14-membered macrolide with intermediate half-life, available outside North America 3, 4
- Dirithromycin: A prodrug macrolide with very long half-life, available in select regions 3, 6
Key Antimicrobial Spectrum
All macrolides share activity against: 1
- Gram-positive bacteria (particularly Streptococcus pneumoniae)
- Atypical respiratory pathogens (Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella species)
- Some mycobacterial species
Critical limitation: Macrolides are not effective anti-pseudomonal agents and should not be used for Pseudomonas aeruginosa infections 7
Important Clinical Distinctions
Azithromycin and clarithromycin offer significant advantages over erythromycin: 1, 5
- Better gastrointestinal tolerability with fewer and milder side effects
- More convenient dosing schedules (once or twice daily vs. four times daily)
- Shorter treatment courses (5-7 days vs. 14 days)
- Superior activity against H. influenzae and M. catarrhalis
Drug interaction profile varies significantly: 3
- Erythromycin and clarithromycin inhibit cytochrome P450 (CYP3A4) and cause frequent drug interactions
- Azithromycin does not inhibit CYP3A4 and has minimal drug interaction potential 1, 5
Common Pitfalls
Resistance concerns: Approximately 25% of S. pneumoniae isolates in the United States demonstrate macrolide resistance, with regional variation from 17% in the Northeast to 35% in the Southeast 1
Cross-resistance exists between macrolides and lincosamides (such as clindamycin) due to shared resistance mechanisms, particularly erm gene-mediated methylation of 23S ribosomal RNA 8
Age-specific safety considerations: For infants <1 month, azithromycin is preferred over erythromycin or clarithromycin due to the association between erythromycin and infantile hypertrophic pyloric stenosis 1