When to use azithromycin (AZI), clarithromycin (CLA), and doxycycline (DOXY)?

When to Use Azithromycin, Clarithromycin, and Doxycycline

Azithromycin is the preferred first-line macrolide for most community-acquired respiratory infections, sexually transmitted infections, and pertussis due to its superior pharmacokinetics, once-daily dosing, and excellent tolerability; clarithromycin is reserved for specific indications like H. pylori eradication and nontuberculous mycobacterial infections; doxycycline is the drug of choice for atypical pneumonia pathogens, tick-borne diseases, and as an alternative for chlamydial infections.

Azithromycin: Primary Indications

Respiratory Tract Infections

• Community-acquired pneumonia (CAP): Azithromycin 500 mg on day 1, then 250 mg daily for days 2-5 covers atypical pathogens (Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella) and is recommended as first-line therapy for outpatient CAP 1
• Acute bacterial sinusitis and otitis media: 3-day course (10 mg/kg/day in children) or 5-day course (10 mg/kg day 1, then 5 mg/kg days 2-5) is as effective as longer courses of other antibiotics 2, 3
• Pertussis: Azithromycin is the CDC's first-line agent for all ages, especially infants <1 month (10 mg/kg/day for 5 days), due to significantly lower risk of infantile hypertrophic pyloric stenosis compared to erythromycin 4

Sexually Transmitted Infections

• Uncomplicated chlamydial infections: Single 1-gram dose is equally effective as doxycycline 100 mg twice daily for 7 days, with superior compliance 1
• Non-gonococcal urethritis/cervicitis: 1 gram single dose is the preferred regimen when compliance is uncertain 1

Other Key Indications

• Cholera in children: First-choice agent in epidemic situations where single-dose treatment is critical (20 mg/kg single dose, maximum 1 gram) 1
• Bartonellosis (bacillary angiomatosis): Alternative to erythromycin/doxycycline at 5-12 mg/kg/day (maximum 600 mg) 1
• Nontuberculous mycobacterial infections: Component of multi-drug regimens for M. avium complex and M. abscessus when macrolide-susceptible 1

Pharmacokinetic Advantages

• Tissue concentrations remain therapeutic for 7-10 days after a 5-day course due to prolonged tissue half-life (approximately 3 days), enabling shorter treatment durations 5, 6, 3
• Concentrates 10-100 times higher in tissues than serum, particularly in respiratory tract, gynecological tissues, and phagocytic cells 3
• Minimal drug interactions compared to clarithromycin and erythromycin (does not inhibit cytochrome P450) 4, 6

Clarithromycin: Specific Indications

When to Choose Clarithromycin Over Azithromycin

• Nontuberculous mycobacterial pulmonary disease: Clarithromycin is preferred over azithromycin for M. avium complex when macrolide-susceptible, though both are acceptable 1
• Alternative for atypical pneumonia: Clarithromycin 500 mg twice daily for 10 days is an alternative when azithromycin is unavailable, though it requires twice-daily dosing 1
• Chlamydial infections in pregnancy: Not recommended due to lack of safety data; erythromycin or amoxicillin preferred 1

Important Limitations

• Drug interactions: Clarithromycin inhibits cytochrome P450 enzymes, causing significant interactions with digoxin, triazolam, ergot alkaloids, and other medications 4
• Infantile hypertrophic pyloric stenosis risk: Contraindicated in infants <1 month, similar to erythromycin 4
• Reduced serum concentrations: When used with rifampin for mycobacterial infections, therapeutic drug monitoring may be necessary 1

Doxycycline: Primary Indications

Respiratory Infections with Atypical Pathogens

• Mycoplasma pneumoniae: Doxycycline 100 mg twice daily for 7-14 days is the preferred first-line agent (alternative: azithromycin) 1
• Chlamydophila pneumoniae: Doxycycline 100 mg twice daily for 10 days is an alternative to azithromycin 1
• Community-acquired pneumonia: Add to beta-lactam therapy for hospitalized patients to cover atypical pathogens 1

Sexually Transmitted Infections

• Chlamydial infections: Doxycycline 100 mg twice daily for 7 days is equally effective as azithromycin 1-gram single dose, but requires better compliance 1
• Contraindicated in pregnancy: Use erythromycin or amoxicillin instead 1

Tick-Borne and Vector-Borne Diseases

• Lyme disease prophylaxis: Single dose of 4 mg/kg (maximum 200 mg) within 72 hours of high-risk Ixodes scapularis tick bite in children ≥8 years 7
• Bartonellosis: Doxycycline 2-4 mg/kg/day (maximum 100-200 mg) for 3 months is preferred over erythromycin for cutaneous bacillary angiomatosis 1

Age Restrictions

• Avoid in children <8 years: Risk of permanent tooth discoloration and enamel hypoplasia, except when benefits outweigh risks (e.g., life-threatening infections) 7
• Pregnancy category D: Contraindicated in pregnancy 1

Clinical Decision Algorithm

For Respiratory Tract Infections:

1. Outpatient CAP or atypical pneumonia suspected: Start azithromycin 500 mg day 1, then 250 mg days 2-5 1
2. Confirmed Mycoplasma or Chlamydophila pneumonia: Doxycycline 100 mg twice daily for 7-14 days is preferred 1
3. Hospitalized CAP: Add azithromycin to beta-lactam for atypical coverage 1
4. Pertussis (any age): Azithromycin is first-line; avoid erythromycin in infants <6 months 4

For Sexually Transmitted Infections:

1. Uncomplicated chlamydia with uncertain compliance: Azithromycin 1 gram single dose 1
2. Uncomplicated chlamydia with reliable follow-up: Doxycycline 100 mg twice daily for 7 days (lower cost) 1
3. Pregnancy: Use erythromycin base 500 mg four times daily for 7 days or amoxicillin 500 mg three times daily for 7-10 days 1

For Nontuberculous Mycobacterial Infections:

1. Macrolide-susceptible M. avium complex: Either azithromycin or clarithromycin as part of multi-drug regimen 1
2. Macrolide-resistant strains: Include macrolide for immunomodulatory effects only, not as active agent 1

Common Pitfalls and Caveats

Azithromycin

• Do not administer with aluminum/magnesium antacids: Reduces absorption significantly 4
• Not effective for MRSA or Pseudomonas: Add clindamycin/vancomycin or antipseudomonal beta-lactam if suspected 1
• Resistance concerns: Increasing macrolide resistance in S. pneumoniae may limit effectiveness in some regions 1

Clarithromycin

• Check for drug interactions: Particularly with statins, anticoagulants, and antiarrhythmics due to P450 inhibition 4
• Avoid in infants <1 month: Risk of infantile hypertrophic pyloric stenosis 4

Doxycycline

• Administer with 8 ounces of fluid: Reduces esophageal irritation risk 7
• Photosensitivity warning: Advise sun avoidance during treatment 7
• Not for children <8 years or pregnant women: Except in life-threatening situations where benefits outweigh risks 7
• Take with food: Reduces gastrointestinal intolerance without significantly affecting absorption 7