Does fosfomycin (Fosfomycin) cause Clostridioides difficile (C. difficile) infection?

Fosfomycin and Clostridioides difficile Infection Risk

Fosfomycin, like all antibiotics, carries a risk of causing Clostridioides difficile infection (CDI), as stated in its FDA drug label, though it is not considered among the highest-risk antibiotics for this complication.

Risk Classification of Antibiotics for C. difficile

Antibiotics have varying levels of risk for causing C. difficile infections:

High-Risk Antibiotics

• Clindamycin (historically notorious with odds ratio 2.12-42)
• Third-generation cephalosporins
• Fluoroquinolones
• Broad-spectrum penicillins (including piperacillin-tazobactam) 1

Lower-Risk Antibiotics

• Aminoglycosides
• Sulfonamides
• Intravenous vancomycin
• Macrolides (less frequently implicated)
• Doxycycline (potentially offers protective effects) 1

Fosfomycin and C. difficile Risk

The FDA drug label for fosfomycin specifically warns: "Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including fosfomycin tromethamine, and may range in severity from mild diarrhea to fatal colitis" 2. This indicates that while fosfomycin can cause CDI, it is not singled out as having particularly high risk compared to other antibiotics.

Interestingly, one research study suggests that fosfomycin may actually have some anti-sporulation effects against C. difficile, potentially reducing the risk of recurrent CDI 3. This study showed that "C. difficile growth and sporulation is attenuated by... the MurA inhibitor fosfomycin," suggesting a possible beneficial effect in certain contexts.

Mechanism of Antibiotic-Associated CDI

All antibiotics, including fosfomycin, can potentially cause CDI through:

• Disruption of normal gut flora
• Creating an environment favorable for C. difficile overgrowth
• Allowing C. difficile to produce toxins A and B 2

Patient Risk Factors for CDI

Risk is significantly higher in patients with:

• Age ≥65 years
• Prior history of CDI
• Concurrent use of proton pump inhibitors
• Prolonged hospitalization
• Chronic kidney disease
• Inflammatory bowel disease
• Immunodeficiency 1

Clinical Implications

When considering fosfomycin use:

1. Assess patient risk factors for CDI before prescribing
2. Monitor for symptoms of CDI during and after treatment (≥3 loose stools in 24 hours)
3. Consider alternatives in very high-risk patients when appropriate
4. Use the shortest effective duration of therapy
5. Discontinue fosfomycin if CDI is suspected or confirmed 2

Management if CDI Develops

If CDI is suspected during or after fosfomycin treatment:

• Discontinue fosfomycin if possible
• Provide appropriate fluid and electrolyte management
• Consider protein supplementation
• Initiate specific anti-C. difficile treatment (oral vancomycin 125 mg four times daily for 10 days is first-line) 1, 2

Prevention Strategies

To minimize CDI risk when using fosfomycin:

• Practice good antibiotic stewardship
• Use only when clearly indicated
• Prescribe for the shortest effective duration
• Avoid unnecessary concurrent proton pump inhibitors
• Consider the patient's individual risk profile 1

While all antibiotics carry some risk of CDI, fosfomycin is not considered among the highest-risk agents, and in some contexts may even have properties that could be beneficial against C. difficile. Nevertheless, clinicians should remain vigilant about this potential complication with any antibiotic therapy.