Can Long-Term Rifaximin Use Cause C. difficile Infection?
Long-term rifaximin use does not increase the risk of C. difficile infection and appears to be safe even with extended treatment durations exceeding 24 months. 1
Evidence from Long-Term Safety Studies
The most robust evidence comes from a 24-month open-label maintenance study of rifaximin 550 mg twice daily in 392 patients with hepatic encephalopathy, which demonstrated:
- No increase in the rate of C. difficile infections despite median exposure of 427 days (range 2-1427 days) and 510.5 person-years of total exposure 1
- The adverse event profile remained consistent with short-term use, without emergence of new safety signals 1
- No development of bacterial antibiotic resistance was observed during extended treatment 1
Supporting Guideline Evidence
Multiple clinical practice guidelines address this concern directly:
- The Korean Association for the Study of the Liver (2020) explicitly states that while long-term rifaximin treatment raised theoretical concerns about C. difficile infection risk, recent studies found that C. difficile infection was not increased by rifaximin treatment compared with control groups 2
- The IDSA/SHEA guidelines (2018) discuss rifaximin as a treatment option for recurrent C. difficile infection itself, using it after vancomycin therapy (400 mg three times daily for 20 days), which would be contradictory if rifaximin caused CDI 2
Mechanism of Low Risk
Rifaximin's unique properties explain its safety profile:
- Minimal systemic absorption (<0.4% bioavailability) means it acts locally in the gastrointestinal tract with minimal systemic effects 3
- Unlike fluoroquinolones, which are strongly associated with increased C. difficile risk, rifaximin does not share this risk profile 2
- The drug has demonstrated activity against C. difficile itself, with most isolates showing very low MIC values for rifampin (<0.002 μg/mL) 4
Clinical Use in C. difficile Treatment
Rifaximin is actually used to treat recurrent C. difficile infection, not cause it:
- A small RCT showed CDI recurrences in 15% of rifaximin-treated patients versus 31% with placebo (though not statistically significant, p=0.11) 2
- Multiple case series report successful treatment of metronidazole-unresponsive CDI with rifaximin, with resolution rates exceeding 65% 5
- The standard regimen is rifaximin 400 mg three times daily for 20 days following vancomycin therapy for multiply recurrent CDI 2
Important Caveats
While rifaximin does not cause C. difficile infection, clinicians should be aware:
- Rifaximin is not effective for invasive pathogens and should not be used for dysentery or when Campylobacter, Salmonella, or Shigella are suspected 2
- Treatment failure can occur in patients with C. difficile strains that have high rifampin MIC values (>256 μg/mL), though this is uncommon 4, 6
- The drug is unlicensed for inflammatory bowel disease treatment despite some efficacy data 2
In summary, long-term rifaximin use is not associated with increased C. difficile infection risk and maintains an excellent safety profile even with treatment durations exceeding two years. 1