What is the mechanism of action (MOA) of Azithromycin (Zithromax)?

Mechanism of Action of Azithromycin

Azithromycin inhibits bacterial protein synthesis by binding to the 23S rRNA of the 50S ribosomal subunit, specifically blocking the transpeptidation/translocation step and preventing assembly of the 50S ribosomal subunit. 1

Primary Mechanism

Ribosomal Binding and Protein Synthesis Inhibition:

• Azithromycin binds to the 23S rRNA component of the bacterial 50S ribosomal subunit, specifically at the polypeptide exit region 2
• This binding blocks RNA-dependent protein synthesis by inhibiting the transpeptidation/translocation step 1
• The drug prevents the assembly of the 50S ribosomal subunit, thereby halting bacterial protein production 1
• Although generally bacteriostatic, azithromycin exhibits bactericidal activity against autolytic species such as pneumococci 2

Cellular Pharmacodynamics

Intracellular Concentration:

• Azithromycin demonstrates remarkable intracellular accumulation, with the ratio of intracellular to extracellular concentration exceeding 30:1 after one hour of incubation 1
• The drug concentrates extensively in phagocytes and fibroblasts, which contributes to its distribution to inflamed tissues 1
• This intracellular concentration allows azithromycin to be effective against intracellular pathogens 1

Pharmacodynamic Profile:

• Azithromycin exhibits time-dependent killing with a prolonged postantibiotic effect against gram-positive cocci and H. influenzae 2
• The key pharmacodynamic parameter correlating with efficacy is the AUC:MIC ratio (approximately 25 in animal models), rather than time above MIC 2
• The drug's long serum half-life (68 hours) results in prolonged tissue concentrations, allowing for once-daily dosing and shorter treatment courses 2

Enhanced Gram-Negative Activity

Structural Advantage:

• Azithromycin demonstrates superior activity against gram-negative bacteria compared to erythromycin 2
• This enhanced activity is attributed to the molecule's improved ability to penetrate the outer cell envelope of gram-negative bacteria such as Enterobacteriaceae, Pseudomonas, and Acinetobacter species 2
• The azalide structure (15-membered lactone ring with a methyl-substituted nitrogen) provides better tissue penetration than traditional 14-membered macrolides 2

pH-Dependent Activity

Environmental Considerations:

• Azithromycin exhibits better antibacterial activity in neutral to basic pH environments 2
• At low pH, azithromycin becomes positively charged (carrying a double-positive charge) and does not readily cross biological membranes 2
• This pH sensitivity is more pronounced for azithromycin than for other macrolides 2

Common Pitfalls

Resistance Mechanisms to Consider:

• The most frequent resistance mechanism involves modification of 23S rRNA at positions A2058 and A2059, which reduces drug binding affinity 1
• Cross-resistance exists with other macrolides (erythromycin, clarithromycin) and may extend to lincosamides and streptogramin B antibiotics that bind overlapping ribosomal sites 1
• The prolonged half-life creates an extended "window" of subinhibitory drug concentrations (14-20 days for complete elimination), potentially promoting selection of resistant strains 2
• Gram-negative bacteria may exhibit intrinsic resistance through reduced outer membrane permeability or efflux pump mechanisms 2