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Recurrent Clostridioides difficile infections: Beyond antibiotics

  • Clostridioides difficile is the leading cause of antibiotic- and healthcare-associated infectious diarrhoea in the US.
  • The main cause of the disease is a disturbed bowel flora or ‘microbiome’.
  • Antibiotics can kill Clostridioides difficile but do not restore the good bowel bacteria, resulting in risk from recurrences of infection.
  • Restoring the gut microbiome can stop the infection coming back.
  • Dr Glenn S Tillotson has collaborated with scientists at Ferring Pharmaceuticals to develop a faecal transplant product, REBYOTA, that can restore the healthy bowel flora.

Clostridioides difficile, or ‘C diff’, is the most common cause of antibiotic- and healthcare-associated infectious diarrhoea in the USA. C diff is a bacterium that causes infection of the large intestine and results in diarrhoea, often along with abdominal pain and a high temperature. In some cases, the infection can lead to life-threatening inflammation of the large bowel, called pseudomembranous colitis. In a proportion of patients, surgery is needed to remove the affected tissue. According to the US Center of Disease Control and Prevention, C diff causes approximately half a million infections in the USA every year, resulting in 30,000 deaths.

While two antibiotics (vancomycin and fidaxomicin) are the standard treatment for Clostridioides difficile infection, recurrence of infection is common, occurring in about a quarter of cases. Of these patients, up to 60% then go on to experience subsequent recurrences. The risk of recurrence increases with each C diff infection, largely because antibiotics disrupt the healthy balance within our gut.

Investigating C diff and how it affects our gut is Dr Glenn S Tillotson at GST Micro, USA. Tillotson and colleagues at Ferring extensively studied treatments for C diff that aim to harmonise and restore imbalances within our gut, stopping the infection from returning.

The microbiome

The microbiome is the sum of all the microorganisms in our body, such as bacteria, fungi, and viruses. The gut microbiome, more specifically, is the total of microorganisms that live in our intestines. These microbes protect us against harmful bacteria, synthesise nutrients, and enable us to digest food.

C diff bacteria are part of our gut microbiome in about 5–10% of people and normally live harmlessly inside the bowel in balance with the rest of the microorganisms. Certain factors such as disease or antibiotics alter the gut microbiome by destroying the friendly bacteria – essentially causing an imbalance of the gut flora.

Live biotherapeutic products are based on good science and an understanding of the complexities of the gut.

This reduced richness and diversity in the gut microbiome allows C diff to flourish, which may then cause an infection, produces toxins or poisons that cause massive damage to the cells in the gut. As Tillotson explains, ‘When the gut flora or microbiome is affected by antibiotics such as amoxicillin or ciprofloxacin, the microbiome becomes open to harmful bacteria. These harmful bacteria destroy the protection provided by friendly bacteria. This condition is known as dysbiosis, and it allows C diff to flourish.’

Faecal transplant

Although they are helpful for the initial treatment of C difficile infections, due to their effect on the gut microbiome, antibiotics work less well every time the infection comes back. Faecal transplant is a newer treatment for a recurrent C diff infection following initial antibiotic treatment.

Antibiotic treatment of urinary tract infections is a common trigger of C diff infection.

Faecal transplant has the potential to restore the healthy gut microbiome, or flora. It was in fact first described in China in the 4th century AD. However, in early treatments in the 1950s, these products were not screened for potential infectious organisms, causing multiple serious life-threatening infections in already seriously ill patients.

Live biotherapeutic products

The need to improve the process of faecal transplant and make it safer and more efficient led to the development of two faecal transplant products (known as live biotherapeutic products or LBPs). Two products derived from humans – REBYOTA and VOWST – have been thoroughly screened for 29 pathogens as mandated by the US Food and Drug Administration (FDA). REBYOTA and VOWST are manufactured following a standardised process and have been tested in large clinical trials where they were found to be clinically effective and safe.


REBYOTA consists of a broad consortium of bacteria including Bacteroides organism. REBYOTA is a single dose and FDA approved microbiome-based treatment given by enema to people with a recurrence of a C diff infection. Before its approval, REBYOTA was evaluated in a large study called PUNCH CD3 involving 289 participants who had one or more C difficile infection recurrences. PUNCH CD3 was a randomised, double-blinded trial which means that some of the patients received the actual REBYOTA treatment and the rest received an inactive substitute (placebo) without the patients or the researchers knowing who received what.

The gut microbiome are the microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts.

All patients were treated with antibiotics first. The outcome of the study was that 70.6% of the patients that got the actual treatment were cured from the infection compared to 57.5% of those who received the placebo. Notably, treatment was more successful than the placebo in older individuals, including those affected by other illnesses such as cardiac, kidney, and gastrointestinal diseases compared with younger healthy patients. The side effects were mild or moderate and the product was tolerated well by all age groups. A later ad hoc analysis evaluated the patient quality of life including physical and mental health parameters showing a significant benefit for those treated with REBYOTA compared to the people that were given the placebo.


VOWST is also a microbiome-based treatment based on the spores of Firmicutes which has been recently approved for use in the US. In contrast to REBYOTA, VOWST is given orally as four capsules for three days on an empty stomach after a bowel preparation. Its efficacy and safety were assessed in a large study where it was shown that administration of VOWST was superior to placebo in reducing the risk of the C diff infection coming back (recurrence rate was 12% in VOWST group and 40% in placebo group).

Restoring the normal gut microbiome

Microbiota-based therapies have been shown to be safe and effective, and restoration of the normal gut microbiome is viewed as very beneficial.

Live biotherapeutic products can restore the essential metabolic processes for a healthy microbiome and avoid C diff infection.

Live biotherapeutic products have demonstrated the ability to restore the essential metabolic processes for a healthy microbiome and avoid C diff infection. As Tillotson concludes, ‘C diff results in a particularly complex and difficult infection. Live biotherapeutic products are based on good science and an understanding of the complexities of the gut.’

What inspired you to study the human gut microbiome and more specifically faecal transplants for C difficile infections?

I have been interested in C difficile almost since its discovery in 1978. Indeed, the colitis was termed antibiotic-associated diarrhoea until the discovery of the specific organism. A flurry of drugs were examined over the following decades such as fidaxomicin and ridilinazole, which I was involved with, but it became clear that the damage to the gut landscape was the root of the problem. Moreover, these newer drugs, although showing better efficacy, could not get to the root of the disease that is a disturbed protective health gut flora. Thus the opportunity to work with a pioneering group such as Ferring enabled me to help explore the concept of gut flora restoration. The understanding of the ‘good’ bugs and what they bring to the health of the human is an area I particularly find interesting. The association of how bacteria process certain molecules to either protect against C diff or to spur its growth and produce the disease really highlights how dysbiosis controls disease. The broader use of new-omics tools will enable us to better appreciate the complexity of the microbiome not just in the gut.

Were there any unexpected or surprising findings in the trials and life quality evaluation analysis?

I think the profound association of the positive outcomes after faecal transplant with an LBP should not have been so much of a surprise as we have long known about the gut microbiome–brain axis (GBA). Disturbance of the GBA shows as anxiety, depression, and other conditions. The link between various chemicals produced by a health gut microbiome can reduce or potentially prevent these. Dysbiosis is associated with these conditions. These effects are driven by short chain fatty acids and certain bile acids. Analysis of the quality of life and C diff showed that there are clear links between the infection and poor quality of life (see further reading). Thus use of a validated tool, CDiff32, enabled us to compare the CDIFF 32 changes in patients who received REBYOTA and those who got placebo. Significant improvements were seen with REBYOTA. These positive effects were seen very early post treatment. It will be interesting to see which metabolic changes contributed to these major improvements.

How would you further improve the two available biotherapeutic products? Are there further studies required and what exactly would those investigate?

Both LBPs are manufactured to the highest standards as per FDA. They are both screened against all known pathogens including COVID-19, mPOX, and many other species. How to improve two efficacious products will be driven by the clinical community and more importantly patients. Where next? Well, there are over 300 studies looking at faecal transplantation in a wide range of conditions. Perhaps the ‘low-hanging fruit’ are the psychological conditions such as autism. This has been looked at for over 20 years with some success. But outside of CNS conditions, I would like to see studies on metabolic diseases, such as non-alcoholic steato-hepatitis (NASH) or maybe diabetes. The role of the gut microbiome in certain types of cancer is becoming better understood but further data is needed. I also believe we need to study some conditions which affect both ends of the age range such as children and older people. As the population ages and more comorbidities are growing, the ability to positively impact them could be a major benefit of LBPs. Personally, I believe the broadest, safest approach is needed to make the essential restoration and better health.

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Further reading

• Feuerstadt, P, et al, (2024) Efficacy and health-related quality of life impact of fecal microbiota, live-jslm: A post hoc analysis of PUNCH CD3 patients at first recurrence of Clostridioides difficile infection. Infectious Diseases Therapy, 13, 221–236.

• Orenstein, R, et al, (2023) Two-year durability of REBYOTATM (RBL), a live biotherapeutic for the prevention of recurrent Clostridioides difficile infections.Open Forum Infect Dis, 10(9), ofad456.

• Chopra, R, et al, (2023) Role of the microbiome in essential metabolism in the human gut and its implications for Clostridioides difficile infection.Open Forum Infect Dis, 10(9), ofad447.

• Garey, KW, et al, (2023) Effect of fecal microbial transplantation on Clostridioides difficile infection: dysbiosis, metabolites and health related quality of life. Open Forum Infect Dis, 10(3), ofad113.

• Tillotson, G, et al, (2022) Microbiota-based live biotherapeutic RBX2660 for the reduction of recurrent Clostridioides difficile infection in older adults with underlying comorbidities.Open Forum Infect Dis, 10(1), ofac703.

• Feuerstadt, P, et al, (2022) SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection.New Engl J Med, 386, 220–229.

• Khanna, S, et al, (2022) Efficacy and safety of RBX2660 in PUNCH CD3, a phase III, randomized, double-blind, placebo-controlled trial with a Bayesian primary analysis for the prevention of recurrent Clostridioides difficile infection. Drugs, 82(15), 1527–1538.

• Centers for Disease Control and Prevention. C diff (Clostridioides difficile).[Accessed 21/03/2024].

Dr Glenn S Tillotson

Dr Glenn S Tillotson is a medical microbiologist with over 40 years training of which 35 were in the pharmaceutical industry where he conducted clinical research and global medical education. He has been involved in developing 8 antibiotics. He is the Editor in Chief of Expert Review in Anti-Infective Therapy.

Contact Details

e: [email protected]


  • Ferring Pharmaceuticals, Spero Therapeutics, and Taro Pharmaceuticals.


  • Paul Feuerstadt, Sahil Khanna, Robert Orenstein, Kevin Garey, Teena Chopra.

Competing interest statement

I am a consultant to Ferring Pharmaceuticals, Spero Therapeutics, and Taro Pharmaceuticals. My input to the companies is based on scientific, educational, and strategic initiatives.

Cite this Article

Tillotson, G, (2024) Recurrent Clostridioides difficile infections. Beyond antibiotics,
Research Features, 152.

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(CC BY-NC-ND 4.0) This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Creative Commons License

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