Clostridioides difficile

References & Evidence Notes

Each numbered entry below is either a source you can follow or a note setting out what the evidence does and does not support. Both are numbered together so the markers in the text line up.

Last reviewed October 20, 2026. Supplement entries are cross-checked against the NIH National Center for Complementary and Integrative Health and the Linus Pauling Institute Micronutrient Information Center.⁸ C. difficile is a bacterial infection treated with antibiotics, specifically vancomycin or fidaxomicin. Nothing on this page treats it. Do not stop the course early because you feel better, because incomplete treatment is a common route to relapse. Severe C. difficile can progress to toxic megacolon and perforation, so worsening pain, abdominal distension, a swollen tender abdomen, diarrhea with fever and blood, signs of dehydration or shock, or a drop in the number of stools after severe diarrhea are reasons to go to emergency care now, not signs of improvement. The microbiome support on this page is for recovering after treatment; it is not established for preventing recurrence. It is an adjunct to antibiotics and never a replacement for them.

1. On the mechanism: C. difficile is an opportunistic infection that follows disruption of the normal colonic microbiota, most often by antibiotics. The ranking depends on where the infection was acquired, which is easy to miss. For infection associated with a healthcare facility, a 2021 systematic review and meta-analysis found carbapenems and third- and fourth-generation cephalosporins most strongly associated, with cases more than twice as likely to have had recent exposure to them, and only modest associations for fluoroquinolones, clindamycin and beta-lactamase-inhibitor penicillins, PubMed 33787887. In community-onset disease clindamycin carries the largest effect of any antibiotic: an odds ratio of 16.8 against no antibiotic exposure, PubMed 23478961, and the highest risk of any outpatient antibiotic across 36.6 million patients, PubMed 36377887. Nearly any antibacterial can precipitate it. Advanced age, hospitalization, gastric acid suppression and immunosuppression raise risk further. ↩
2. On treatment: current guidance from the Infectious Diseases Society of America and the American College of Gastroenterology places oral vancomycin and fidaxomicin as first-line therapy, with fidaxomicin associated with lower recurrence. Metronidazole has been demoted and is now reserved for situations where the preferred agents are unavailable. Bezlotoxumab, a monoclonal antibody against toxin B, was once added to reduce recurrence in selected high-risk patients, but it was withdrawn from the market in January 2025. Recurrence after a first episode is common, in the region of 20 to 25%: a review of recurrent infection puts it at about a quarter of first episodes (one population study found 22%); the risk rises with each episode, to about 40% after one recurrence and about 60% after two or more, PubMed 25930686. ↩
3. On severity: severe and fulminant disease is marked by hypotension, shock, ileus or toxic megacolon, and is treated differently from ordinary infection, PubMed 42538089. Antimotility agents such as loperamide are generally avoided in acute C. difficile colitis because slowing transit retains toxin. Paradoxical improvement in diarrhea alongside worsening abdominal distension is a warning sign, not a recovery sign. ↩
4. On testing: a positive toxin test in someone without diarrhea usually reflects colonization rather than infection, and treating asymptomatic carriers is not recommended. Repeat testing to prove cure is also not recommended, because the assay can stay positive for weeks after symptoms resolve. This matters because it prevents unnecessary further antibiotic courses, which are themselves a risk factor. ↩
5. On fecal microbiota transplantation: FMT is well established for recurrent C. difficile, with cure rates above 90% in observational studies, PubMed 37274301. That meta-analysis is worth reading for its main point rather than its headline: efficacy measured in randomized controlled trials is lower than the observational figure, so treat the commonly quoted number as the optimistic end. It is recommended after multiple recurrences rather than for a first episode. Two FDA-approved microbiota-based products are now available for preventing recurrence in adults, delivered rectally and orally respectively, which places this firmly within prescribed medical care. ↩
6. On probiotics, including the trial that did not work: Saccharomyces boulardii and multi-strain probiotics have reasonable evidence for reducing antibiotic-associated diarrhea in general. For C. difficile specifically the picture is weaker. PLACIDE (Allen SJ, et al. Lancet. 2013;382:1249-⁠1257) randomized 2,981 older inpatients on antibiotics to a multi-strain preparation or placebo and found no significant reduction in C. difficile diarrhea. The 2021 American College of Gastroenterology guideline recommends against probiotics for prevention of C. difficile infection. Meta-analyses are more favorable than the largest single trial, which is usually a reason for caution rather than confidence. Probiotics are optional here because the downside is small and the recovery rationale is reasonable, but they should not be read as established. ↩
7. On do-it-yourself fecal transplant: the FDA has issued safety communications after transmission of drug-resistant organisms through inadequately screened donor stool, including invasive infection and a patient death, and subsequently after transmission of pathogenic E. coli. Clinical FMT depends on donor screening, laboratory testing and quarantine, and the screening is not an administrative formality but the part that makes it safe. Home FMT using stool from a friend or relative bypasses all of it. Anyone with recurrent C. difficile should be asking for referral to a gastroenterologist, who now has both FMT and approved microbiota products available. ↩
8. National Center for Complementary and Integrative Health (NIH), nccih.nih.gov, and the Linus Pauling Institute Micronutrient Information Center, lpi.oregonstate.edu/mic. ↩
9. On first-episode treatment: the 2021 IDSA and SHEA focused update suggests fidaxomicin rather than a standard course of vancomycin for an initial episode, with vancomycin an acceptable alternative. The standard regimens are fidaxomicin 200 mg twice daily for 10 days and vancomycin 125 mg four times daily for 10 days, IDSA/SHEA, 2021. ↩
10. On bezlotoxumab: two randomized trials in 2,655 adults on antibiotics for C. difficile infection found recurrence of 17% against 28% with placebo in one trial and 16% against 26% in the other, adjusted differences of about 10 percentage points, PubMed 28121498; it was withdrawn from the market by its sole supplier on January 31, 2025, PubMed 41446417. ↩
11. On how common C. difficile is: the CDC estimates almost half a million infections in the US each year and says people are up to 10 times more likely to get it while taking an antibiotic and during the month after finishing one, CDC, About C. diff. ↩
12. On acid-suppressing medicines and recurrence: in 16 observational studies of 7,703 people with C. difficile, recurrence was 22.1% in those taking stomach acid-suppressing medicines against 17.3% in those not, an odds ratio of 1.52, with the authors cautioning that observational data may be confounded, PubMed 28346595. ↩
13. On C. difficile infection: the NHS describes infection after antibiotics upset the balance of gut bacteria, higher risk over 65, in long hospital or care home stays, with a weakened immune system, with stomach acid-reducing medicines and after a past infection, treatment with a new 10-⁠day course of a different antibiotic with improvement in a few days and clearance in 1 to 2 weeks, avoiding anti-diarrhea medicine, and a fecal microbiota transplant after 2 or more recurrences, NHS. ↩
14. On risk and warning signs: MedlinePlus notes that C. difficile can occur in people with inflammatory bowel disease even without antibiotics, advises people who have had it to tell clinicians before taking antibiotics again, and advises contacting a clinician for bloody stools, five or more episodes of diarrhea a day for more than 1 to 2 days, severe abdominal pain or signs of dehydration, MedlinePlus. ↩
15. On dehydration and shock: the NHS advises emergency care when dehydration comes with pale, blue, gray or blotchy skin, cold skin, fast breathing or confusion, which can be signs of shock, NHS. ↩
16. On vitamin D: a meta-analysis of eight observational studies with 4,479 patients found lower vitamin D levels in people with C. difficile infection, and that a level below 20 ng/mL was linked with higher odds of severe infection, an odds ratio of 1.61, but not with recurrence, PubMed 26701764. ↩
17. On hyperimmune bovine colostrum: it is made by vaccinating cows during pregnancy so that their colostrum carries antibodies against C. difficile, PubMed 23435084; a randomized trial of immune whey made this way in recurrent infection treated 18 people before it was stopped early when its sponsor went bankrupt, and its authors called it preliminary, PubMed 19086244. ↩