#494 C. diff, Diarrhea, the Microbiome, and New Therapies with Dr. Cynthia Sears. Live from Johns Hopkins Grand Rounds

August 11, 2025 | By Matthew Watto, MD

Audio

Video

Transcript available via YouTube

Dominate C. diff! Learn to distinguish colonization from infection, select first-line therapies, and counsel patients on recurrence prevention and microbiome recovery. We’re joined by IDSA past president and expert on foodborne and intestinal infections, Dr. Cindy Sears (Johns Hopkins University) for a comprehensive update on Clostridioides difficile (C. diff, Cdiff, CDAD, CDI).

Claim CME for this episode at curbsiders.vcuhealth.org!

Patreon | Episodes | Subscribe | Spotify | YouTube | Newsletter | Contact | Swag! | CME

Show Segments

• 00:00 Intro
• 03:00 Guest bio and hobby
• 04:25 Case of Charles Fleur Fontaine
• 06:00 Risk factors and epidemiology
• 08:00 Antibiotic hierarchy of risk
• 10:00 Diagnosis, testing strategies
• 14:00 Defining severity
• 17:30 Treatment options
• 20:00 Microbiome recovery strategies
• 24:00 Probiotics and postbiotics
• 27:00 Infection control counseling
• 30:00 C. diff and colon cancer
• 32:00 Recurrent C. diff strategies
• 35:00 Why some FMT and bezlotoxumab were discontinued
• 38:00 Microbiota replacement therapies
• 43:00 Prophylaxis strategies
• 45:00 Future therapies and ongoing research
• 47:00 Audience Q&A
• 52:00 Outro

Disclosures

Dr. Sears reports no relevant financial disclosures. Dr. Williams financial relationships disclosed include a Merck grant or research support. This relationship has not ended.

C. diff Pearls

1. Confirm true diarrhea with ≥3 watery stools/day that run to the edge of the container.
2. PCR tests (NAAT) are sensitive; combine them with EIA for toxin B antigen for specificity (Guh, 2018).
3. First C. diff infection: Vancomycin remains widely used due to cost, but fidaxomicin is preferred due to less microbiome disruption and decreased risk of recurrence (Louie, 2011, IDSA CPG 2021). Metronidazole is associated with higher mortality in patients 65 and older (Haley, 2019).
4. Probiotic supplements may delay microbiome reassembly post-treatment—generally not recommended (Suez, 2018). Psyllium fiber (prebiotic) or kefir (a fermented, probiotic yogurt drink) are reasonable to trial.
5. Prevent spread at home through hand hygiene and 10% bleach for infection control (expert opinion). Use separate bathrooms if able. The spores are resilient and easily spread.
6. Two new microbiome restoration therapies are now available. One is a live, branded rectal suspension, and the other live, oral fecal microbiota spore capsules. 
7. Traditional FMT is no longer available without an investigational new drug application as of December 31, 2024. 
8. Bezlotoxomab is no longer available for treatment of C. diff as off January 31, 2025 (empr.com/news Story on C. diff prevention accessed July 2025).
9. Antibiotic exposure, even as little as 15 days, as long as 10 years prior to diagnosis is associated with an increased risk of colon cancer, and risk increases with greater exposure. (Boursi, 2015; Zhang, 2019; Liu, 2025).

C. Diff In-Depth Show Notes

History

Confirm the patient has true diarrhea with ≥3 watery stools/day that run to the edge of the container. Dr. Sears points out that people with diarrhea usually present on day 5 or later. Ask if the diarrhea is post-prandial, nocturnal, and if there is blood in the stool. Are others sick at home? Any children in day care?

PPIs

In observational studies, proton pump inhibitors are associated with a small absolute increased risk of C. diff (Finke, 2025). Paul can probably rest easy if he wants to keep taking his PPI.

Antibiotic hierarchy: 

Higher risk of C. diff with clindamycin, beta-lactams, and fluoroquinolones. (Kociolek, 2022)

Lower risk of C. diff with macrolides, tetracyclines, TMP-SMX, and aminoglycosides. (Kociolek, 2022)

Diagnostics

Dr. Sears prefers a multi-pathogen panel as a first line test for patients presenting with acute diarrhea (expert opinion). It is then on the clinician to integrate this information with the clinical syndrome for management decisions.

Cdiff specific testing

NAAT and GDH are sensitive, but not specific tests that can detect C. diff colonization, but do not prove active infection.

1. Nucleic acid amplification testing (NAAT) detects the tcdB (toxin B) gene. Toxin B is required for virulence.
2. Glutamate dehydrogenase (GDH) is an enzyme present in C. diff strains

Pair the NAAT or GDH with an enzyme immunoassay (EIA) for toxin B to prove active infection (ACG Clinical Guidelines, 2021). The EIA test is specific, but not sensitive. In many instances, a patient should be treated if the clinical picture fits C. diff and the NAAT is positive even if the EIA is negative (expert opinion). 

Severe C. diff is defined as a WBC over 15,000 (which can occur before the onset of diarrhea) and a creatinine above 1.5 mg/dL (ACG Clinical Guidelines, 2021), but Dr. Sears points out the definition may change.

Who should be admitted for diarrhea?

Patients with dehydration, low blood pressure, extremes of age, or patients who don’t pass the eyeball test (expert opinion).

Treatment of initial C. diff infection

Dr. Sears prefers fidaxomicin because it is not absorbed to a great extent. It is more specific than vancomycin and friendlier to the microbiome (Louie, 2011).

Vancomycin “blows up” the microbiome when taken orally including gram negative anaerobes including Bacteroides species, which are important for gut health (Isaac, 2017).

Dr. Sears regards metronidazole as a poor choice. It was never FDA approved for C. diff, it’s primarily absorbed in the proximal gut, not the colon(Lamp, 1999), and it is associated with increased mortality in adults 65 and older (Haley, 2019)

Can we give anti-diarrheals?

In general, Dr. Sears does not recommend anti-diarrheals in C. diff for fear of precipitating megacolon (expert opinion).  She regards loperamide as relatively mild, and diphenoxylate as a more powerful inhibitor of motility (expert opinion) though we could not find specific head-to-head comparisons.

Microbiome

An unhealthy microbiome, the collection of bacteria in the gut, can contribute to C. diff risk. 

Prebiotics are substances that cannot be digested by the human body and serve as “food” for gut bacteria, which then make short chain fatty acids, including butyrate.  Psyllium is a prebiotic that pushes gut bacteria to make short chain fatty acids, especially in constipated subjects (Jalanka, 2019). 

Dr. Sears mentions, Kefir,  a fermented yogurt drink and a natural probiotic food as reasonable for those looking to boost their microbiome. On the contrary, probiotic supplements taken after antibiotics might delay recovery of the microbiome when compared to FMT (Suez, 2018). Consequently, Dr. Sears discourages probiotic supplements because they are expensive and the literature is devoid of good science (expert opinion). Many times, when studied, the supplements contain dead bacteria or organisms that differ from the labeling. Saccharomyces boulardii has been linked with case reports of fungemia (Vinayagamoorthy, 2023). It is expensive and largely ineffective so Dr. Sears recommends against it (expert opinion).

Lactobacillus is the most common probiotic despite two negative trials in children with acute gastroenteritis published in NEJM (Schnadower, 2018,  Freedman, 2018). The ACG guidelines give a “conditional” recommendation for certain probiotic strains based on low quality evidence for adults or children taking antibiotic therapy (Preidis, 2020) .

Bottom line: Dr. Sears regards prebiotic and probiotic foods and supplements as a “soft science”. There is a lot of hype and we are still collecting evidence.

How should patients avoid transmission to family members?

C. diff is transmitted by spores, which go everywhere. The spores are resilient and easily spread. Prevent spread at home through hand hygiene and 10% bleach for infection control (expert opinion). Use separate bathrooms if able. 

Kids and C. diff

Children under the age of 2 years do not tend to get clinical C. diff, but can be colonized (Tougas, 2021). Thus, Dr. Sears considers C. diff for a mother with an infant at home who suddenly develops new diarrhea (expert opinion).

Colon cancer and the microbiome

Antibiotic exposure, even as little as 15 days, as long as 10 years prior to diagnosis is associated with an increased risk of colon cancer, and risk increases with greater exposure. (Boursi, 2015; Zhang, 2019; Liu, 2025).

This story is evolving, but Dr Sears’ lab has found that dense communities of bacteria sit on the surface of about half of colon cancers (Maxwell, 2024). Escherichia coli containing polyketide synthetase (pks) has been associated with colorectal cancer (Miyasaka, 2024, Jans, 2025). The incidence of colon cancer in patients under 50 years old is rising and this may be related to changes in the microbiome (Jans, 2025).

C. Diff recurrence

Recurrence begets recurrence with risk going from approximately 20 to 40 to 60% after first, second, and third C. diff infection, respectively (Leffler, 2015).

Dr. Sears recommends repeat C. diff testing or a broad stool panel if recurrent symptoms develop.

Fidaxomicin twice daily for five days then every other day for 20 days (IDSA update, 2022)

Or

Vancomycin four times a daily for 10-14 days, then twice a day for at least a week, then once a day, then once every other day, and so forth for a long slow taper lasting as long as 8 weeks (IDSA update, 2022).

Bezlotoxomab, a monoclonal antibody against toxin B, administered during antimicrobial therapy for C. diff to prevent recurrence is no longer available as of January 31, 2025 (empr.com/news Story on C. diff prevention accessed July 2025). A manuscript for a newer monoclonal antibody was submitted for review, but neither our team nor Dr. Sears has been able to confirm if it was accepted or rejected at the time of this post.

Traditional fecal microbiota transplants (FMT) has been cut off by the FDA as of December 31, 2024 for two reasons. First, there have been rare adverse events including mortality (DeFlipp, 2019, Marcella, 2021). Second, there are now two FDA approved, quality controlled agents. One is a live, rectal suspension of fecal microbiota and the other are capsules with live, fecal microbiota spores. The rectal suspension reduced recurrence by about 13% (PUNCH CD3, 2022) and the live, fecal microbiota spores reduce recurrence by about 28% (ECOSPOR III, 2022). These preparations are given a few days after the antibiotic taper is completed.

Prophylaxis with Vancomycin

This is largely left to the art of medicine. Some physicians will give vancomycin (or fidaxomicin) once daily for patients with a history of C. diff who need antibiotics for another reason (e.g. pneumonia). The prophylaxis is usually continued for about one week after the other antibiotics are completed (expert opinion).

Future therapies

VE303, is a novel product with eight Clostridial species with strong performance in phase 2 trials (Louie, 2023).

Audience questions

Antibiotic associated diarrhea (AAD) is common, and of this about 20% (Nasiri, 2018) represents C. diff. Dr. John Bartlett and colleagues discovered C. diff in 1970s while investigating AAD (Gorbach, 2014).

Patients in long-term care facilities may be colonized with C. diff, especially in facilities with prior outbreaks (Ziakas, 2015) so it can be difficult to interpret testing.

Links

1. Dr. Sears, aka Spinderella, is a member, of the Fierce Chicks Rock cycling team 
2. Moveable Feast is a non-profit in Baltimore

Goal

Listeners will develop a comprehensive, evidence-based approach to diagnosing, treating, and preventing recurrent Clostridioides difficile infection.

Learning objectives

After listening to this episode, listeners will be able to:

1. Identify key risk factors and diagnostic tests for C. diff.
2. Apply criteria for severe disease and treatment escalation.
3. Compare vancomycin vs. fidaxomicin based on efficacy and microbiome impact.
4. Counsel patients on microbiome recovery and infection control.
5. Recognize current and emerging therapies for recurrent C. diff.

Citation

Watto MF, Sears C, Williams PN. “494 C. diff diarrhea, the Microbiome, and New Therapies with Dr. Cynthia Sears. Live from Johns Hopkins Grand Rounds”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast Final publishing date August 11, 2025.