What are the appropriate dosing regimens, indications, contraindications, common adverse effects, and alternative therapies for azithromycin in otherwise healthy adults and children?

Azithromycin: Comprehensive Clinical Guide

Primary Indications and Dosing

For uncomplicated chlamydial infections in adults, azithromycin 1 gram orally as a single dose is the preferred first-line treatment, achieving 97-98% cure rates and offering the critical advantage of directly observed therapy. 1, 2

Adult Dosing by Indication

• Chlamydial urethritis/cervicitis: 1 gram orally as a single dose provides therapeutic tissue concentrations for approximately 10 days due to azithromycin's prolonged tissue half-life 1, 2
• Non-gonococcal urethritis: 1 gram orally as a single dose, equally effective as doxycycline 100 mg twice daily for 7 days 1, 2
• Community-acquired pneumonia (outpatient): 500 mg orally once daily for 3 days, which provides equivalent efficacy to traditional 5-day regimens 3
• Respiratory tract infections: 500 mg on day 1, followed by 250 mg once daily on days 2-5 (standard Z-pack regimen) 3
• Chronic bronchiectasis with ≥3 exacerbations/year: 500 mg three times weekly for at least 6 months 3

Pediatric Dosing

• Children ≥8 years weighing >45 kg: 1 gram orally as a single dose for chlamydial infections 1, 2, 4
• Children <45 kg with chlamydia: Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into four doses daily for 14 days 1, 2
• Pertussis (infants <6 months): 10 mg/kg per day for 5 days 3
• Pertussis (infants and children >6 months): 10 mg/kg (maximum 500 mg) on day 1, followed by 5 mg/kg per day (maximum 250 mg) on days 2-5 3
• Chlamydial conjunctivitis in neonates: 20 mg/kg body weight per day orally once daily for 3 days 3

Pregnancy Considerations

Azithromycin 1 gram orally as a single dose is the preferred first-line treatment for chlamydial infections during pregnancy. 2, 4

• Alternative option: Amoxicillin 500 mg orally three times daily for 7 days 2
• Absolute contraindications in pregnancy: Doxycycline, ofloxacin, levofloxacin, and all fluoroquinolones 2
• Erythromycin estolate is contraindicated during pregnancy due to drug-related hepatotoxicity 2
• Alternative erythromycin regimens: Erythromycin base 500 mg orally four times daily for 7 days OR erythromycin ethylsuccinate 800 mg orally four times daily for 7 days 2

Alternative Regimens When First-Line Therapy Cannot Be Used

• Erythromycin base: 500 mg orally four times daily for 7 days (less efficacious than azithromycin or doxycycline; gastrointestinal side effects frequently discourage compliance) 1
• Erythromycin ethylsuccinate: 800 mg orally four times daily for 7 days 1
• Ofloxacin: 300 mg orally twice daily for 7 days (similar efficacy to azithromycin but more expensive with no compliance advantage) 1
• Levofloxacin: 500 mg orally once daily for 7 days (88-94% efficacy versus 97-98% for first-line agents; lacks clinical trial validation for chlamydia) 1, 2

Administration and Compliance Optimization

To maximize compliance, medications should be dispensed on-site with the first dose directly observed, particularly in populations with erratic healthcare-seeking behavior or unpredictable follow-up. 1, 3, 2

• Azithromycin should always be available to treat patients for whom compliance is questionable 1
• Single-dose regimens have the advantage of improved compliance and directly observed treatment 1, 3
• Patients must abstain from sexual intercourse for 7 days after initiating treatment and until all sex partners have been adequately treated 1, 2, 4

Common Adverse Effects

• Gastrointestinal symptoms: Abdominal discomfort/pain, diarrhea, nausea, vomiting (generally mild to moderate severity) 3
• Other effects: Headache and dizziness 3
• Azithromycin is better tolerated than erythromycin, with only 0.7% of patients discontinuing therapy versus 2.6% for comparable drugs 5
• Gastrointestinal symptoms are less frequent than with erythromycin 3

Critical Safety Considerations

Cardiovascular Risks

• QT prolongation warning: Obtain ECG to assess QTc interval before initiating long-term therapy 3
• Contraindication: QTc >450 ms (men) or >470 ms (women) 3
• Increased cardiovascular deaths (HR 2.88; 95% CI 1.79-4.63) with 5-day azithromycin therapy in Tennessee Medicaid cohort, most pronounced in patients with high baseline cardiovascular risk 3
• Avoid in patients taking QT-prolonging medications without careful risk assessment 3

Drug Interactions

• If taken with aluminum or magnesium-containing antacids, absorption may be reduced 3
• No evidence of interaction with theophylline, terfenadine, or cimetidine 6

Monitoring for Long-Term Therapy

• Measure baseline liver function tests 3
• Review patients 6-monthly with assessment of efficacy, toxicity, and continuing need 3
• Ensure at least one negative respiratory nontuberculous mycobacteria (NTM) culture before starting long-term macrolides 3

Partner Management and Coinfection

All sex partners from the preceding 60 days must be evaluated, tested, and empirically treated without waiting for test results, even if asymptomatic. 2, 4

• Partners should receive the same treatment regimen as the index patient 2
• Coinfection with gonorrhea: If gonorrhea is confirmed or prevalence is high (>5%), treat for both infections concurrently with ceftriaxone 250 mg IM single dose PLUS azithromycin 1 gram orally single dose 1, 2
• Coinfection rates are 20-40% in populations with high gonorrhea prevalence 2
• Failing to treat sex partners leads to reinfection in up to 20% of cases 2

Follow-Up and Test-of-Cure

Test-of-cure is NOT recommended for non-pregnant patients treated with azithromycin unless symptoms persist or reinfection is suspected. 2, 4

• Cure rates exceed 97% with recommended regimens 2
• Testing before 3 weeks post-treatment is unreliable because nucleic acid amplification tests can yield false-positive results from dead organisms 2
• Pregnant women: Always undergo test-of-cure, preferably by culture, 3-4 weeks after treatment completion 2

Reinfection Screening

• All women with chlamydia should be retested approximately 3 months after treatment to screen for reinfection, regardless of whether partners were reportedly treated 2, 4
• Reinfection rates are high (up to 39% in some adolescent populations) 2
• Repeat infections carry elevated risk for pelvic inflammatory disease and other complications 2
• Men may also benefit from retesting at approximately 3 months, though evidence is more limited 2

Special Clinical Situations

Persistent or Recurrent Urethritis

• If symptoms persist after completing treatment, consider testing for Mycoplasma genitalium using NAAT on first-void urine or urethral swab 2
• For confirmed M. genitalium infection, moxifloxacin 400 mg orally once daily for 7 days is highly effective, particularly for macrolide-resistant strains 2
• Do NOT retreat based on symptoms alone without documenting objective signs of urethral inflammation or laboratory evidence of infection 2

Renal Impairment

• Exercise caution in patients with severe renal impairment (creatinine clearance <10 mL/min), as AUC increases by 35% and Cmax increases 61% 3
• Assess renal function using estimated GFR rather than serum creatinine alone, particularly in elderly patients who may have falsely reassuring creatinine levels due to reduced muscle mass 3

Hepatic Impairment

• Use with caution and increase monitoring if underlying liver disease is present 3

Critical Pitfalls to Avoid

• Do NOT use azithromycin as monotherapy for gonorrhea due to widespread resistance; always combine with ceftriaxone for suspected gonococcal infection 3
• Do NOT wait for test results if compliance with return visit is uncertain in high-prevalence populations—treat presumptively 2
• Do NOT assume partners were treated—directly verify or use expedited partner therapy strategies 2
• Do NOT perform test-of-cure in asymptomatic patients treated with recommended regimens, as this wastes resources and may yield false-positive results 2
• Do NOT use levofloxacin as first-line therapy for chlamydia; it has inferior evidence (88-94% cure rates) and lacks clinical trial validation 2

FDA Pregnancy Category

• Azithromycin is classified as FDA Pregnancy Category B 3
• Preferred over erythromycin in infants <1 month due to lower risk of infantile hypertrophic pyloric stenosis 3