Can Doxycycline and Azithromycin Be Given Together?
Yes, doxycycline and azithromycin can be given together and are frequently combined in clinical practice, particularly for treating sexually transmitted infections where co-infection with multiple pathogens is suspected or confirmed. 1
Clinical Context for Combination Therapy
Sexually Transmitted Infections
Combination therapy with doxycycline and azithromycin is explicitly recommended in several clinical scenarios:
Gonococcal infections with presumed chlamydial co-infection: When treating gonorrhea with ceftriaxone or cefixime, concurrent treatment for chlamydia is appropriate since co-infection occurs frequently. Either doxycycline or azithromycin can be added to the cephalosporin regimen. 1
Treatment failure scenarios: Observational studies suggest that cefixime combined with other antibiotics (including both azithromycin and doxycycline) may be more efficacious for pharyngeal gonococcal infections than monotherapy, with persistent infection rates of 1.8% for combination therapy versus 5.8% for ceftriaxone alone. 1
Mycoplasma genitalium infections: Combination doxycycline (7 days) followed by azithromycin achieved 93% cure rates for macrolide-susceptible infections, demonstrating safety and efficacy of sequential use. 2
Mechanism and Safety
There are no pharmacological contraindications to combining these antibiotics:
Both are bacteriostatic agents that inhibit protein synthesis, but through different mechanisms (doxycycline binds 30S ribosomal subunit; azithromycin binds 50S ribosomal subunit). 1
No significant drug-drug interactions have been reported between doxycycline and azithromycin in clinical practice. 1
Adverse effects are predominantly gastrointestinal for both drugs and are additive rather than synergistic, occurring in 40-46% of patients receiving combination therapy but generally mild. 2
Important Caveats
When NOT to Combine
Current guidelines increasingly favor doxycycline monotherapy over combination therapy for uncomplicated chlamydial infections:
Doxycycline demonstrates superior efficacy (100%) compared to azithromycin (97%) for genital chlamydia, with non-inferiority of azithromycin not established. 1
For anorectal chlamydia in women, doxycycline achieved 94% cure versus 85% for azithromycin (adjusted OR 0.43,95% CI 0.21-0.91, p=0.0274). 3
For rectal chlamydia, pooled efficacy shows doxycycline at 99.6% (95% CI 98.6%-100%) versus azithromycin at 82.9% (95% CI 76.0%-89.8%), with an efficacy difference of 19.9% favoring doxycycline. 4
Resistance Considerations
Azithromycin resistance is increasing, limiting its utility:
Azithromycin efficacy for Mycoplasma genitalium has declined from 85.3% (before 2009) to 67.0% (since 2009). 1
The FDA has issued safety warnings about azithromycin, and WHO guidelines recommend it only when doxycycline has failed, is contraindicated, or when adherence to a 7-day doxycycline regimen is questionable. 1
Clinical Algorithm
For suspected or confirmed STI with multiple pathogens:
Gonorrhea + Chlamydia co-infection: Ceftriaxone 250-500 mg IM/IV PLUS doxycycline 100 mg twice daily for 7 days (preferred) OR azithromycin 1 g single dose (if compliance concerns). 1
Treatment failure of gonorrhea: Consider combination regimens including both doxycycline and azithromycin with cephalosporins for pharyngeal infections. 1
Uncomplicated chlamydia alone: Use doxycycline 100 mg twice daily for 7 days as monotherapy; reserve azithromycin for compliance concerns only. 1, 5
Mycoplasma genitalium: Use resistance-guided therapy with doxycycline 7 days followed by azithromycin (if macrolide-susceptible) or moxifloxacin (if macrolide-resistant). 2
The combination is safe and can be used together when clinically indicated, but monotherapy with doxycycline is increasingly preferred for most chlamydial infections due to superior efficacy. 1, 3, 4