Macrolides and Ketolides
Macrolides inhibit bacterial protein synthesis at the 50S ribosomal subunit and are essential for atypical respiratory pathogens and sexually transmitted infections.
## Overview
Macrolides are a class of antibiotics characterized by a macrocyclic lactone ring. They bind the 50S ribosomal subunit and inhibit bacterial protein synthesis. They are primarily bacteriostatic and are essential for treating atypical respiratory pathogens, H. pylori eradication, and sexually transmitted infections.
## Mechanism of Action
Macrolides bind to the 23S rRNA of the 50S ribosomal subunit (peptidyl transferase region), blocking translocation of peptidyl-tRNA and causing premature detachment of nascent peptide chains. They also have clinically important anti-inflammatory properties (reducing IL-8, TNF-α) relevant in chronic airway diseases.
## Individual Agents
**Erythromycin**: The original macrolide; significant GI motility side effects (motilin receptor agonist — used therapeutically for gastroparesis at low doses). Multiple CYP3A4 drug interactions. Now largely replaced by newer agents.
**Azithromycin**: Extended half-life (68 hours), allowing 5-day or Z-pack (3-day or even 1-dose for some STIs) regimens. Concentrates intracellularly (alveolar macrophages, tissue levels exceed serum). Less CYP3A4 inhibition than erythromycin. Community-acquired pneumonia (atypicals), M. avium complex (HIV prophylaxis + treatment), chlamydia (1g single dose), gonorrhea (in combination). QTc prolongation risk — black box warning for cardiovascular risk.
**Clarithromycin**: Active against H. pylori (triple/quadruple therapy), Mycobacterium avium, H. influenzae. Significant CYP3A4 inhibitor (interactions with statins, warfarin, digoxin, colchicine).
## Spectrum
Active against: S. pneumoniae (decreasing resistance), S. pyogenes, atypical bacteria (Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila), Bordetella pertussis, H. pylori (clarithromycin), Mycobacterium avium complex. NOT active against: Enterobacteriaceae, Pseudomonas, or MRSA.
## Ketolides
**Telithromycin** was approved for CAP but withdrawn from most markets due to rare but severe hepatotoxicity. **Omadacycline** and **lefamulin** are newer agents with some structural similarities but different mechanisms.
## Resistance
Macrolide resistance occurs via: methylation of the 23S rRNA ribosomal target (erm genes, the most common), macrolide efflux pumps (mef genes), and ribosomal mutations. MLSB resistance (macrolide-lincosamide-streptogramin B) involves inducible or constitutive erm-mediated methylation affecting all three drug classes.
## Key Takeaways
- Macrolides bind 23S rRNA of the 50S subunit; primarily bacteriostatic with anti-inflammatory effects
- Azithromycin has a long half-life and intracellular accumulation; important for atypical pneumonia and STIs
- Clarithromycin is a strong CYP3A4 inhibitor with important drug interactions
- MLSB resistance mediates cross-resistance to macrolides, clindamycin, and streptogramins