Azithromycin and Risk of C. difficile Infection
Azithromycin does carry a risk of Clostridioides difficile infection, though it appears to have a lower risk compared to other antibiotic classes such as fluoroquinolones, clindamycin, and cephalosporins.
Evidence on Azithromycin and C. diff Risk
The FDA drug label for azithromycin explicitly warns about C. difficile-associated diarrhea (CDAD), stating that "CDAD has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhea to fatal colitis" 1. This establishes a clear association between azithromycin use and C. diff infection.
The 2019 World Society of Emergency Surgery (WSES) guidelines on C. difficile management identify specific antibiotics with higher risk profiles, noting that while nearly all antibiotics have been associated with CDI, certain classes pose greater risk 2:
- Highest risk: Clindamycin (OR 35.31), fluoroquinolones (OR 30.71), cephalosporins (OR 19.02)
- Also high risk: Beta-lactams/beta-lactamase inhibitor combinations (OR 9.87)
While macrolides like azithromycin are not specifically listed among the highest-risk antibiotics in these guidelines, a 1999 study identified azithromycin as one of the antibiotics most often associated with antibiotic-associated diarrhea in Turkey 3.
Comparative Risk
Recent research suggests azithromycin may have a lower C. diff risk profile compared to some other antibiotics:
A 2024 study found that doxycycline was associated with a 17% decreased risk of CDI compared to azithromycin when used with ceftriaxone for community-acquired pneumonia treatment 4. This suggests azithromycin has a higher CDI risk than doxycycline.
A 2022 study in mice showed that while doxycycline treatment significantly reduced ceftriaxone-induced overgrowth of a C. difficile strain, azithromycin treatment did not reduce ceftriaxone-induced overgrowth 5. This suggests azithromycin may have less protective effect against C. diff than doxycycline.
Risk Factors That May Increase C. diff Risk with Azithromycin
The risk of C. diff with azithromycin appears to be heightened in certain circumstances:
Prolonged or repeated courses: A 2023 case report described a patient who developed C. difficile infection after a 6-week course of azithromycin (500mg three times weekly) for acne vulgaris, which was her second antibiotic course within 10 months 6.
Combination with other antibiotics: The risk may be increased when azithromycin is used alongside other antibiotics, particularly high-risk classes 2.
Patient-specific factors: Advanced age, hospitalization, comorbidities (particularly cardiac disease, chronic kidney disease, and inflammatory bowel disease), and prior history of CDI all increase the baseline risk of developing C. diff infection 2.
Clinical Implications
When prescribing azithromycin:
- Consider the risk-benefit ratio, especially for prolonged courses or in high-risk patients
- Use the shortest effective duration of therapy
- Avoid unnecessary combination with other antibiotics, particularly high-risk classes
- Monitor for symptoms of C. diff infection (diarrhea, abdominal pain, fever)
- Consider alternative antibiotics with potentially lower C. diff risk (like doxycycline) when appropriate for the clinical indication
Conclusion
While azithromycin does carry a risk of C. difficile infection as stated in its FDA label, it appears to have a lower risk profile than antibiotics like clindamycin, fluoroquinolones, and cephalosporins. However, the risk increases with prolonged use, repeated courses, combination with other antibiotics, and in patients with additional risk factors.