Mechanism of Action of Azithromycin
Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit, blocking protein synthesis by inhibiting the transpeptidation/translocation step and by inhibiting the assembly of the 50S ribosomal subunit. 1
Primary Mechanism
Azithromycin, an azalide antimicrobial agent structurally related to macrolides, works through a specific interaction with bacterial ribosomes:
- Binds specifically to the 23S rRNA component of the 50S ribosomal subunit 1
- Blocks protein synthesis through two primary mechanisms:
- Inhibits the transpeptidation/translocation step of protein synthesis
- Prevents proper assembly of the 50S ribosomal subunit 1
This mechanism differs slightly from tetracyclines, which bind to the 30S ribosomal subunit and prevent binding of t-RNA 2.
Unique Pharmacokinetic Properties Enhancing Efficacy
Azithromycin's clinical effectiveness is enhanced by several distinctive pharmacokinetic properties:
- Concentrates extensively in phagocytes and fibroblasts - intracellular to extracellular concentration ratio >30 after one hour 1
- Demonstrates tissue selectivity with concentrations in respiratory tract tissues remaining above MICs for several days 3
- Features a large volume of distribution (23 L/kg) with extensive tissue distribution 4
- Has a biphasic elimination with a terminal half-life of up to 5 days 4
- Concentrates in phagocytes which may contribute to drug distribution to inflamed tissues 1
Antimicrobial Spectrum
Azithromycin is effective against:
- Gram-positive bacteria: Staphylococcus aureus, Streptococcus species (including S. pneumoniae, S. pyogenes, S. agalactiae) 1
- Gram-negative bacteria: Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae 1
- Atypical pathogens: Chlamydophila pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae 1
Azithromycin shows better gram-negative coverage than erythromycin and is more active against H. influenzae than other macrolides 5.
Resistance Mechanisms
The primary mechanism of resistance to azithromycin involves:
- Modification of the 23S rRNA at positions corresponding to A2058 and A2059 (E. coli numbering system) 1
- Cross-resistance with other macrolides, lincosamides, and streptogramins B that bind to overlapping ribosomal sites 1
- Increasing resistance rates globally, particularly for S. pneumoniae 5
Clinical Implications of Mechanism
Understanding azithromycin's mechanism of action has important clinical implications:
- The long half-life allows for once-daily dosing regimens, potentially increasing patient compliance 6
- High tissue concentrations make it effective for respiratory, skin, and sexually transmitted infections 3
- The prolonged post-antibiotic effect against gram-positive cocci and H. influenzae means efficacy correlates with AUC:MIC ratio rather than time above MIC 2
Caution and Resistance Concerns
- Azithromycin's long half-life creates prolonged periods of subinhibitory concentrations, potentially promoting resistance development 5
- An AUC:MIC ratio of approximately 25 is needed for maximal efficacy 2
- Resistance rates are increasing globally, with extensive macrolide use providing strong selective pressure 5
Azithromycin's unique mechanism at the ribosomal level, combined with its distinctive pharmacokinetic profile, explains both its clinical utility and the concerns regarding resistance development that must be considered when prescribing this antibiotic.