For an otherwise healthy non‑pregnant adult with an uncomplicated chest infection, is azithromycin or doxycycline the preferred treatment?

Azithromycin vs. Doxycycline for Chest Infection in Otherwise Healthy Adults

For an otherwise healthy adult with an uncomplicated chest infection (community-acquired pneumonia), azithromycin is the preferred first-line agent over doxycycline based on the most recent high-quality evidence showing superior mortality outcomes and shorter hospital stays.

Primary Recommendation: Azithromycin

The 2025 Mayo Clinic multicenter matched cohort study (n=5,342 matched pairs) demonstrated that azithromycin combined with beta-lactams resulted in significantly lower in-hospital mortality (OR 0.71; 95% CI 0.56-0.9), lower 90-day mortality (HR 0.83; 95% CI 0.73-0.95), and more hospital-free days compared to doxycycline in hospitalized CAP patients. 1

Dosing Regimen for Azithromycin

• Standard 5-day regimen: 500 mg orally on day 1, followed by 250 mg once daily on days 2-5 2, 3
• Alternative 3-day regimen: 500 mg orally once daily for 3 consecutive days, which provides equivalent efficacy due to azithromycin's prolonged tissue half-life of 68 hours 4, 5, 6
• The 3-day regimen delivers the same total dose (1.5 g) and achieves comparable clinical outcomes while improving compliance 5, 6

Rationale for Azithromycin Preference

• Superior mortality outcomes: The 2025 study represents the single most recent and highest-quality comparative evidence, directly addressing the PICO question with matched cohorts controlling for comorbidities and pneumonia severity 1
• Broader spectrum: Azithromycin demonstrates superior activity against Haemophilus influenzae compared to erythromycin and other macrolides, a key pathogen in respiratory infections 7, 6, 8
• Excellent atypical coverage: Azithromycin maintains excellent activity against Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila 7, 6, 8
• Pharmacokinetic advantages: Rapid and extensive tissue concentration in leucocytes, monocytes, and macrophages, with sustained tissue levels allowing once-daily dosing 6, 8
• Better tolerability: Gastrointestinal adverse effects occur less frequently than with erythromycin, improving compliance 6

Alternative Option: Doxycycline

Doxycycline 100 mg orally twice daily for 5-7 days is an acceptable alternative for healthy outpatients without comorbidities, though it carries conditional recommendation with lower quality evidence. 4, 9

When to Consider Doxycycline

• Macrolide contraindications: QT prolongation, concurrent QT-prolonging medications, or documented macrolide allergy 4, 9
• High local macrolide resistance: When pneumococcal macrolide resistance exceeds 25% in your region 4, 9
• Cost considerations: Doxycycline may be more affordable in resource-limited settings 9

Limitations of Doxycycline

• Inferior mortality outcomes: The 2025 study showed higher in-hospital and 90-day mortality compared to azithromycin 1
• Variable pneumococcal coverage: Many Streptococcus pneumoniae isolates demonstrate tetracycline resistance 9
• Limited evidence base: The 2019 ATS/IDSA guidelines acknowledge that doxycycline recommendations are based on limited clinical trial data (low-quality evidence) 4, 9
• Photosensitivity risk: May limit use in certain geographic areas or seasons 9

Critical Implementation Points

Macrolide Resistance Considerations

• Check local resistance patterns: Macrolide monotherapy should only be used when local pneumococcal macrolide resistance is documented to be <25% 4
• In most U.S. regions, macrolide resistance among S. pneumoniae is 20-30%, but azithromycin remains appropriate for otherwise healthy adults with uncomplicated CAP 4

When Neither Agent Is Appropriate as Monotherapy

• Patients with comorbidities (COPD, diabetes, chronic heart/liver/renal disease, malignancy, immunosuppression) require combination therapy with a beta-lactam plus either azithromycin or doxycycline 4, 9
• Hospitalized patients should receive combination therapy (beta-lactam plus azithromycin or doxycycline), not monotherapy 4, 9
• Severe pneumonia requiring ICU admission mandates combination therapy; neither agent should be used alone 4, 9

Dosing Nuances

• First-dose loading: Some experts recommend a 200 mg first dose of doxycycline to achieve adequate serum levels more rapidly 9
• Single-dose azithromycin: A 1 gram single dose is reserved for specific indications like chlamydial infections, not for pneumonia 3

Common Pitfalls to Avoid

• Do not use doxycycline as monotherapy in hospitalized patients—it must be combined with a beta-lactam to ensure adequate S. pneumoniae coverage 9
• Do not assume equivalent efficacy—the 2025 study clearly demonstrates azithromycin's superiority in mortality outcomes 1
• Do not ignore recent antibiotic exposure—if the patient received either agent within the past 90 days, select an alternative class to minimize resistance 4, 9
• Do not use azithromycin in patients with baseline QTc >450 ms (men) or >470 ms (women) without cardiology consultation 3

Follow-Up and Monitoring

• Clinical review at 48 hours to assess symptom resolution, oral intake, and treatment response 4
• Treatment duration: Minimum 5 days, continuing until afebrile for 48-72 hours with no more than one sign of clinical instability 4
• Typical course: 5-7 days for uncomplicated CAP in responding patients 4
• Escalation criteria: No clinical improvement by day 2-3, development of respiratory distress, inability to tolerate oral antibiotics, or new complications warrant hospital referral 4