What is azithromycin, a macrolide (macrolide) antibiotic?

What is Azithromycin?

Azithromycin is an azalide antibiotic—a subclass of macrolide antibiotics—that inhibits bacterial protein synthesis by binding to the 23S rRNA component of the bacterial 50S ribosomal subunit, blocking the transpeptidation/translocation step. 1

Chemical Structure and Classification

• Azithromycin is structurally derived from erythromycin but differs by incorporating a methyl-substituted nitrogen atom into the lactone ring, creating a 15-membered ring structure that defines it as the first azalide antibiotic 1, 2
• The molecular formula is C₃₈H₇₂N₂O₁₂ with a molecular weight of 749 (or 785 as the dihydrate form) 1
• It is available as azithromycin dihydrate in oral formulations including tablets (250 mg and 500 mg), capsules, and suspension 1

Mechanism of Action

• Azithromycin binds specifically to the 23S rRNA at the polypeptide exit region of the bacterial 50S ribosomal subunit, blocking RNA-dependent protein synthesis by inhibiting transpeptidation/translocation and preventing assembly of the 50S ribosomal subunit 3, 1
• While generally bacteriostatic, azithromycin exhibits bactericidal activity against autolytic species such as pneumococci 3
• The drug demonstrates time-dependent killing with a prolonged postantibiotic effect, particularly against gram-positive cocci and Haemophilus influenzae 3

Antimicrobial Spectrum

Gram-Positive Activity

• Active against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae 1
• Marginally less potent than erythromycin against gram-positive organisms in vitro, though this difference is clinically insignificant given achievable tissue concentrations 4

Enhanced Gram-Negative Activity

• Azithromycin demonstrates superior activity against gram-negative bacteria compared to erythromycin, attributed to improved penetration of the outer cell envelope of gram-negative organisms 3, 5
• Particularly effective against Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, and Haemophilus ducreyi 1, 4

Atypical Pathogens

• Highly effective against intracellular pathogens including Chlamydophila pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, Legionella pneumophila, and Ureaplasma urealyticum 1, 6

Other Organisms

• Active against Bordetella pertussis, Campylobacter species, and certain anaerobes 5

Unique Pharmacokinetic Properties

• Azithromycin exhibits rapid and extensive tissue penetration with intracellular accumulation, achieving tissue concentrations exceeding 30 times the extracellular concentration 1, 2
• Serum concentrations remain relatively low (approximately 0.4 mcg/mL after 500 mg dose) with only 37% oral bioavailability, but this reflects extensive tissue distribution rather than poor absorption 7
• The large volume of distribution (23 L/kg) and prolonged terminal elimination half-life (up to 5 days) allow for once-daily dosing and short-course therapy 7, 8
• Concentrates in phagocytes and fibroblasts, with drug delivery to infection sites enhanced by phagocytic cell transport 1, 6
• Exhibits pH-dependent activity, performing better in neutral to basic environments; at low pH it becomes positively charged and does not readily cross biological membranes 3

Clinical Applications

Respiratory Infections

• Used for community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, and acute sinusitis 5
• For long-term prophylaxis in chronic respiratory diseases (asthma, COPD, bronchiectasis), azithromycin 500 mg three times weekly or 250 mg daily is recommended for patients with ≥3 exacerbations in the previous 12 months after optimizing other therapies 5

Sexually Transmitted Infections

• A single 1-gram dose of azithromycin is CDC-recommended first-line therapy for uncomplicated urethritis/cervicitis caused by Chlamydia trachomatis, offering a distinct compliance advantage 2, 5
• Also effective for chancroid (H. ducreyi) and donovanosis (Klebsiella granulomatis) 5
• For gonorrhea, azithromycin is no longer recommended as monotherapy due to rising resistance; ceftriaxone alone is now preferred when susceptibilities are unknown 5

Pertussis

• For pertussis treatment and postexposure prophylaxis, azithromycin is the preferred macrolide, especially for infants <1 month, dosed at 10 mg/kg/day for 5 days (infants <6 months) or 10 mg/kg day 1 then 5 mg/kg days 2-5 (children ≥6 months and adults: 500 mg day 1, then 250 mg days 2-5) 5

Gastrointestinal Infections

• Empirical treatment of choice for Campylobacter diarrhea given rising fluoroquinolone resistance 5

Mycobacterial Infections

• Azithromycin is a key component of treatment regimens for Mycobacterium avium complex (MAC) infections, with macrolides being the only agents showing correlation between in vitro susceptibility and clinical response 5
• Azithromycin 600 mg daily achieved 67% sputum conversion rates at 6 months when combined with companion drugs 5

Resistance Considerations

Mechanisms of Resistance

• Most common mechanism is modification of 23S rRNA at positions A2058 and A2059, conferring cross-resistance to all macrolides, lincosamides, and streptogramin B antibiotics 1, 5
• Gram-negative bacteria may exhibit intrinsic resistance through reduced outer membrane permeability or efflux pumps 5, 3
• Organisms resistant to erythromycin are also resistant to azithromycin 4

Clinical Impact of Resistance

• Long-term azithromycin use increases the risk of macrolide resistance among respiratory pathogens 2.7-fold compared to placebo, though the immediate clinical impact for individual patients remains unclear 5
• For MAC infections, development of macrolide resistance (clarithromycin MIC ≥32 mcg/mL) results in very poor long-term treatment success, far worse than treating susceptible organisms 5

Critical Safety Considerations

Cardiac Effects

• Azithromycin causes dose- and concentration-dependent QTc interval prolongation; when co-administered with chloroquine, maximum QTcF increases ranged from 5-14 ms depending on azithromycin dose (500-1500 mg) 1

Nontuberculous Mycobacterial Disease Screening

• Prior to initiating long-term low-dose azithromycin monotherapy, patients must be screened for current or previous NTM infection; current NTM disease is an absolute contraindication to macrolide monotherapy due to risk of inducing resistance 5
• If clinical suspicion exists, sputum examination is mandatory before starting therapy 5

Infantile Hypertrophic Pyloric Stenosis

• For infants <1 month receiving azithromycin for pertussis, monitoring for IHPS and other serious adverse events is required, though azithromycin has not been associated with IHPS to date (unlike erythromycin) 5

Common Adverse Effects

• Primarily gastrointestinal (nausea, diarrhea, abdominal pain), with better tolerance than erythromycin 7, 8
• Minimal laboratory abnormalities reported in clinical trials 7

Important Clinical Pitfalls

• The prolonged half-life creates an extended window of subinhibitory drug concentrations, potentially promoting selection of resistant strains—this is a key consideration when prescribing azithromycin 3
• Serum concentrations are poor predictors of efficacy; tissue concentrations at the infection site are the relevant pharmacodynamic parameter 6
• Co-administration with aluminum- or magnesium-containing antacids reduces absorption rate and should be avoided 5
• Large meals may reduce absorption by up to 50% 7