What is the difference between doxycycline and azithromycin in treating bacterial infections?

Doxycycline vs Azithromycin for Bacterial Infections

Direct Comparison

Doxycycline is superior to azithromycin for most sexually transmitted infections, particularly rectal and pharyngeal chlamydia, with cure rates of 97-100% versus 74-76% for azithromycin. 1, 2, 3

---

Treatment Selection by Infection Type

Sexually Transmitted Infections

For chlamydial infections:

• Doxycycline 100 mg twice daily for 7 days is the first-line treatment 1
• Azithromycin 1 g single dose should only be used when doxycycline has failed, is contraindicated, or when adherence to a 7-day regimen is a major concern 1
• The efficacy of azithromycin has decreased in recent years, and the FDA has issued safety warnings about this antibiotic 1

Evidence supporting doxycycline superiority:

• For rectal chlamydia in men who have sex with men: doxycycline achieved 96.9-100% cure rates versus 74-76% for azithromycin 2, 3
• For pharyngeal chlamydia: doxycycline had 98% cure rate versus 90% for azithromycin (treatment failure 2% vs 10%, p=0.041) 4
• For genital chlamydia: doxycycline efficacy was 100% compared to azithromycin's 97%, with non-inferiority of azithromycin not established 1

For Mycoplasma genitalium:

• Azithromycin efficacy has declined dramatically from 85.3% before 2009 to 67.0% since 2009 1
• This represents a critical resistance trend that limits azithromycin utility 1

For gonorrhea with presumed chlamydial co-infection:

• Use ceftriaxone 250-500 mg IM/IV PLUS doxycycline 100 mg twice daily for 7 days (preferred) 5
• Azithromycin 1 g single dose may be substituted only if compliance is a concern 5

Respiratory Infections

For community-acquired pneumonia:

• Both agents provide adequate coverage for Streptococcus pneumoniae and Mycoplasma pneumoniae 6
• Doxycycline can be used as an alternative to macrolides for pneumococcal coverage 6
• Selection should be based on severity and comorbidities, not inherent superiority of either agent 1

For atypical pathogens (Mycoplasma pneumoniae):

• Both provide excellent coverage 6

Skin and Soft Tissue Infections

For suspected community-acquired MRSA:

• Doxycycline provides effective coverage against CA-MRSA 6
• Azithromycin lacks reliable MRSA coverage and should not be used as monotherapy when MRSA is suspected 6
• This represents the most clinically relevant coverage difference between these agents 6

Other Infections

For cholera:

• Azithromycin is more effective than fluoroquinolones and is the first-choice treatment 1
• Doxycycline is an acceptable alternative second-choice 1

For brucellosis:

• Doxycycline combined with streptomycin is the standard regimen 7
• Azithromycin has inadequate activity and does not cure experimental brucellosis 8

---

Safety and Adverse Events

Gastrointestinal adverse events:

• Azithromycin: 45.1% of patients reported nausea, diarrhea, or vomiting 2
• Doxycycline: 33.8% of patients reported similar symptoms 2
• Risk difference: 11.3 percentage points fewer adverse events with doxycycline 2

Cardiovascular concerns:

• The FDA has issued warnings about increased cardiovascular events with azithromycin 1

Drug interactions:

• No significant drug-drug interactions between doxycycline and azithromycin when used in combination 5
• Both are bacteriostatic agents that inhibit protein synthesis through different mechanisms 5

---

Key Clinical Pitfalls

Common errors to avoid:

1. Using azithromycin as first-line for uncomplicated chlamydia—doxycycline is superior 1, 2, 3
2. Assuming azithromycin and doxycycline are interchangeable for STIs—they are not 1
3. Using azithromycin for suspected MRSA skin infections—it lacks reliable coverage 6
4. Failing to recognize declining azithromycin efficacy for Mycoplasma genitalium 1

When azithromycin is appropriate:

• Single-dose convenience is critical for adherence 1
• Doxycycline is contraindicated (pregnancy, children <8 years) 1
• Cholera treatment as first-line 1
• Combination therapy for gonorrhea when compliance is a concern 5