Azithromycin Dosing for Community-Acquired Pneumonia
For outpatient community-acquired pneumonia, azithromycin should be dosed as 500 mg on day 1, followed by 250 mg once daily on days 2-5 (total 1.5g over 5 days), but only as monotherapy in previously healthy patients without comorbidities in regions where macrolide resistance is documented to be <25%. 1, 2, 3
Outpatient Dosing Algorithm
Previously Healthy Adults WITHOUT Comorbidities
- Standard regimen: Azithromycin 500 mg on day 1, then 250 mg daily for days 2-5 (total 1.5g) 1, 2, 3
- Alternative 3-day regimen: Azithromycin 500 mg once daily for 3 days (total 1.5g) 2, 3
- Critical restriction: Use azithromycin monotherapy ONLY if local pneumococcal macrolide resistance is documented <25% 1, 2
- Preferred first-line: Amoxicillin 1g three times daily is actually preferred over azithromycin for this population, with azithromycin as an alternative 1
Adults WITH Comorbidities (COPD, diabetes, heart failure, age >65, recent antibiotics, immunosuppression)
- Azithromycin monotherapy is contraindicated 2
- Required regimen: High-dose amoxicillin (1g three times daily) or amoxicillin-clavulanate (875mg/125mg twice daily) PLUS azithromycin 500mg day 1, then 250mg daily for days 2-5 1, 2
- Alternative: Respiratory fluoroquinolone monotherapy (levofloxacin 750mg daily or moxifloxacin 400mg daily) 1, 2
Hospitalized Patient Dosing
Non-ICU Medical Ward Patients
- Mandatory combination therapy: β-lactam (ceftriaxone 1-2g daily, cefotaxime 1-2g every 8 hours, or ampicillin-sulbactam 1.5-3g every 6 hours) PLUS azithromycin 500mg daily 2, 4
- Azithromycin monotherapy is never appropriate for hospitalized patients 2
ICU/Severe CAP Patients
- Required regimen: β-lactam (as above) PLUS azithromycin 500mg daily 2
- Alternative: β-lactam PLUS respiratory fluoroquinolone 2
Pediatric Dosing (Age ≥6 months)
- Standard 5-day regimen: 10 mg/kg on day 1, then 5 mg/kg daily on days 2-5 3
- Alternative 3-day regimen: 10 mg/kg once daily for 3 days 3
- Maximum single dose: Do not exceed adult dosing 3
Treatment Duration Considerations
- Minimum duration: 5 days, with patient afebrile for 48-72 hours and no more than one sign of clinical instability before discontinuation 2
- Standard duration: Generally should not exceed 8 days in a responding patient 2
- Extended duration (10-14 days): Required for atypical pathogens (Mycoplasma, Chlamydophila, Legionella) or if initial therapy was inadequate 2
- Legionella/Staphylococcus/Gram-negative bacilli: Extend to 14-21 days 1
Critical Pitfalls to Avoid
- Never use azithromycin monotherapy if the patient received antibiotics in the past 3 months - this selects for resistant organisms 2
- Never use azithromycin monotherapy in areas with ≥25% macrolide resistance - clinical failures occur with resistant S. pneumoniae isolates, requiring hospitalization and β-lactam rescue therapy 2
- Never use azithromycin monotherapy for any patient with comorbidities - breakthrough pneumococcal bacteremia is significantly more common 1, 2
- Check QTc interval before initiating in patients with cardiac risk factors - avoid if QTc >450ms (men) or >470ms (women) 2
Evidence Quality Notes
The 5-day regimen (500mg/250mg) is FDA-approved and guideline-recommended 3, 1, while the 3-day regimen (500mg daily × 3) is equally effective based on multiple randomized trials showing 94-97% clinical cure rates 5, 6, 7, 8. Both deliver the same total dose of 1.5g, which is the critical factor for efficacy 5, 6. The choice between regimens can be based on patient preference and adherence considerations, though the FDA label lists the 5-day regimen as standard 3.