Why Do C. Diff Infections Occur?

The underlying cause of repeat C. diff infections is an altered bacterial composition in the gut.

C. diff infection recurrence is most likely in individuals who are:

  • exposed to hospitals and long term care facilities
  • over the age of 65
  • starting, finishing, or currently taking a course of antibiotics not related to  C. diff treatment
  • completing a course of antibiotics related to C. diff treatment
  • taking medication to reduce stomach acid
  • suffering from weakened immune system and/or severe underlying illness

Treatment Options for Recurrent C. Diff



Vancomycin (brand name: VancocinⓇ) is considered the antibiotic standard of care for treating C. diff infections.  However, vancomycin targets a wide range of bacteria, resulting in high rates of recurrence. If an infection recurs after a standard course of the antibiotic, the Infectious Disease Society of America (IDSA) guidelines recommend a pulsed or tapered dosage over time. A pulsed or tapered dosage more effectively targets dormant C. diff spores as they become active to reduce recurrence.


Fidaxomicin (brand name: DificidⓇ) is an antibiotic approved by the FDA in 2011 to treat C. diff infections. Fidaxomicin targets C. diff spores more specifically—reducing disruption to the gut’s bacterial balance. In a randomized controlled trial,  fidaxomicin showed significantly lower rates of recurrence. The Infectious Disease Society of America (IDSA) recommends a 10-day fixed course of this drug as an alternative to a tapered dosage of vancomycin if recurrence occurs after a course of vancomycin.

Fecal Microbial Transplant

A Fecal Microbial Transplant (FMT) is also known as a stool transplant and requires a colonoscopy. Because the underlying cause of C. diff infection recurrence is an altered bacterial balance in the gut, stool transplants have been a successful way of treating recurrent infections. According to the IDSA treatment guidelines, FMT is recommended for patients with multiple recurrences of C. diff infections who have failed appropriate antibiotic treatments.


Bezlotoxumab (brand name ZinplavaⓇ) isn’t actually a treatment for C. diff, but it can be prescribed for use alongside antibacterial drug treatments in order to reduce the recurrence of C. diff infection. Bezlotoxumab is a human monoclonal antibody that is administered via an IV, which binds to Clostridioides difficile toxin B and can be prescribed for patients 18 years or older who are receiving antibiotic treatment for CDI and are at high risk for recurrence. Bezlotoxumab is currently only approved for use in those over 18.

Treatment Options for Recurrent C. Diff Infections
Treatment Type Considerations
Most common side effects
Vancomycin Oral Antibiotic
  • Standard of care for C. diff 

  • Has been associated with C.diff recurrence

Nausea (17%), abdominal pain (15%), and low potassium levels (13%).
Fidaxomicin Oral Antibiotic
  • Lower chance of C. diff recurrence

  • High price-point may be inaccessible

Nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal bleeding (4%), anemia (2%), and neutropenia (2%)
Fecal microbial transplant (FMT) Stool transplant
  • FMT is recommended under IDSA guidelines, but is not approved by the FDA for C. diff

  • Replenish normal bacterial gut flora from donor sample

  • Invasive

  • Usually reserved as last option to treat recurrence


Because FMT is not approved by the FDA there is no official label including common side effects. Side-effects reported in academic publishings include cramping, bloating, diarrhea, gas, constipation, blood in

the stool, vomiting, and severe swelling of the abdomen.

Bezlotoxumab Intravenous infusion - monoclonal antibody
  • Not a treatment for CDI

  • Can be prescribed alongside antibiotic treatments to reduce C. diff recurrence

  • High price-point may be inaccessible in addition to the cost of treatment

Nausea (≥4%), fever (≥4%), and headache (≥4%).

Investigational Options

In addition to the existing treatment options for C. diff that are available for prescription, researchers around the world are testing new potential treatments for C. diff, and C. diff recurrence, that they hope may potentially push the envelope on what’s achievable with medicine, creating new options that may potentially be more effective or have fewer side effects than today’s approved treatments.

The final phases of testing before FDA approval are clinical trials, where these new potential options are used with volunteers. If you’re interested in exploring clinical trials as an option for you or a loved one, Clara Health is a free platform and service that can help guide your journey to find available options, and help you apply to take part in a study of your choosing. We’ve highlighted a sample of interventional clinical trials for recurrent C. diff below, and you can search through all 65 currently running interventional studies for C. diff using Clara Health here.

In this breakdown of some of the available clinical trials, we refer to terms such as control arms and placebos, phases, sponsors, and more. You can learn about these topics and many more in Clara Health’s clinical trial guides directory.

Ridinilazole targeted antibiotic

Ridinilazole is a new investigational drug that is being tested to determine its safety and efficacy in treating C. diff and potentially reducing recurrence by targeting the C. diff bacteria specifically — potentially reducing negative impact on gut health. Ridinaloze’s phase 3 clinical trial, run by Summit Therapeutics, is comparing the investigational drug against vancomycin, the current standard of care for treating C. diff, so participants who are randomized into the control arm of the study will still receive treatment.

SER-109 oral ecology of bacteria

Seres Therapeutics is running a phase 3 clinical trial testing SER-109 (named ECOSPOR III) for the potential to reduce recurrence in CDI post-treatment by potentially replenishing beneficial bacteria in the intestines.  SER-109 is composed of bacterial spores (the inactive form of bacteria) purified from a healthy donor and placed in capsules that are taken orally. This clinical trial is placebo controlled where the comparator is a sugar pill (92% glycerol and 8% normal saline).

RBX2660 Microbiota Restoration Therapy

Two phase 3 clinical trials are being run by Rebiotix testing RBX2660, which is an enema of microbiota suspension of intestinal microbes aiming to potentially reduce recurrence of C. diff. RBX2660 is not itself being tested as a treatment for C. diff, and must be administered alongside or after a treatment for C. diff. Of the two clinical trials being run, PUNCH CD3-OLS does not have a control arm (meaning any accepted participants will receive the investigational enema), and PUNCHCD3 does have a placebo control arm where randomized participants may receive a normal saline enema.

VE303 live biotherapeutic

Vedanta Biosciences is evaluating the safety and efficacy of a new biotherapeutic containing 8 clonal human commensal bacterial strains for use following treatment of CDI aiming to potentially reduce future recurrence. VE303 is not being evaluated as a treatment for C. diff and is administered only after participants have fully recovered from an episode of CDI. The phase 2 clinical trial is comparing high and low doses of VE303 against an inactive placebo.

MGB-BP-3 antibiotic

This phase 2a clinical trial being run by MGB Biopharma is testing the safety, tolerability, and efficacy of their investigational MGB-BP-3 bactericidal antibiotic in treating C. diff associated diarrhea. The study is accepting participants with diarrhea associated with both initial and recurrent C. diff infections, and focusing not just on potentially reducing recurrence but on potentially treating the present C. diff infection. In contrast with currently approved treatments for C. diff, MGB-BP-3 has the potential to kill C. difficile in its vegetative form prior to sporulation, which may possibly accelerate recovery and reduce the likelihood of future recurrence. The phase 2a clinical trial does not have a placebo arm and is comparing different dosing levels of the investigational antibiotic.

CP101 Oral Full-Spectrum Microbiota

Finch Therapeutics was running an extension study to their phase 2 clinical trial (PRISM-EXT) for recurrent C. diff infection, which has now completed. The investigational treatment, called CP101, is a capsule designed to deliver a full community of beneficial bacteria to the areas of the intestine affected by C. difficile. The study drug, like fecal microbiota transplantation (FMT), is intended to restore the ecosystem found in a healthy human gut. But unlike traditional fecal transplants, which usually involve colonoscopies or enemas, CP101 is an odorless capsule taken orally. As an open-label extension study, PRISM-EXT does not have a control arm with a placebo, instead, all participants will have access to CP101.

Investigational Options for Recurrent C. Diff Infections
Treatment Treatment Type Considerations Trial Phase
Study Sponsor Control Group
Ridinilazole Oral antibiotic
  • Specifically targets C. diff spores 

  • Studied for potential to treat and reduce recurrence of C. diff



Summit Therapeutics Control group uses standard of care (vancomycin)
 SER-109 Oral capsule - ecology of bacterial spores
  • Preparation of bacterial spores highly purified from stool donations obtained from healthy, screened donors and put into capsules. 

  • Taken after CDI treatment to potentially prevent recurrence

  • Not a potential treatment for a present C. diff infection



Seres Therapeutics Control group receives inactive placebo 
 RBX2660 Microbiota enema
  • Taken alongside or after CDI treatment to potentially prevent recurrence

  • Not a potential treatment for a present C. diff infection

  • Invasive


 Rebiotix PUNCH CD3-OLS has no control group, and PUNCH CD3 has a control group receiving a placebo saline enema.
 VE303 Oral capsule
  • Utilizes 8 clonal human commensal bacterial strains

  • Taken after CDI treatment to potentially prevent recurrence

  • Not a potential treatment for a present C. diff infection

 2 Vedanta Biosciences  Control group receives inactive placebo
 MGB-BP-3 Oral antibiotic
  • Studied for potential to treat and reduce recurrence of C. diff-associated diarrhea

  • Antibiotic designed to rapidly kill C. difficile prior to sporulation

MGB Biopharma 

Study arms receive different doses of the antibiotic, but every participant will receive the study investigational drug. 

 CP101 Oral capsule containing lyophilized microbiota from healthy human donors
  • Aims to provide similar benefits of FMT without the need for an invasive procedure

  • Taken after CDI treatment to potentially prevent recurrence

  • Not a potential treatment for a present C. diff infection

2 extension  Finch Therapeutics  There is no control arm for this study, all participants will receive CP101. 

Summit Pharmaceuticals is evaluating an investigational drug called ridinilazole to determine its safety and efficacy in treating Clostridioides difficile (C. diff) and to help reduce the risk of C. diff coming back. Ridinilazole is designed specifically to target the C. diff bacteria, which could potentially mean less damage to the gut and a reduced chance of another infection.

If you’re ready to help researchers put a stop to repeat C. diff infections, click here to learn more about the clinical study.

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