The educational content in this post, elaborated in collaboration with Ferring Pharmaceuticals, was independently developed and approved by the GMFH publishing team and editorial board.


This is the third article in a special collection aimed at focusing on the epidemiology, diagnosis and management of C. difficile infection, of relevance to gastroenterologists. See the first article on C. difficile infection prevalence, risk factors and co-occurrence with COVID-19 here and the second article on diagnosis and management of primary and recurrent C. difficile infection here.

 

Why are antibiotics for primary and recurrent C. difficile infection insufficient?

While antibiotics are the current mainstream treatment for C. difficile infection, they do not induce a durable response in some patients and their efficacy declines in patients with multiple recurrences. Such recurrences usually happen within 8 weeks of completing antibiotic treatment, while delayed recurrences are also common. In addition, antibiotics do not address the underlying mechanisms involved in recurrence, which include a persistent altered gut microbiome with reduced diversity.

Further complicating C. difficile management in the clinical setting is the fact that other species co-exist with the bacterium and can induce C. difficile-like symptoms that are age-dependent, according to preliminary findings under peer review.

“Patients with C. difficile infection have very few limited options in terms of really good therapy,” says Dina Kao, professor of medicine and director of the FMT program at the University of Alberta in Canada.

Due to high recurrent C. difficile infection and failure rates for antibiotic therapy, fecal microbiota transplantation (FMT) or investigational microbiota-based biotherapeutics, if available, can be considered for patients with multiple C. difficile infection recurrence, either alone or following a course of antibiotics.

 

Fecal microbiota transplantation for recurrent C. difficile: the pros and cons

C. difficile guidelines suggest using FMT for second recurrence. FMT consisting of donated stool being homogenized, filtered and then administered via colonoscopy, enema or oral capsules has shown a success rate for treating recurrent C. difficile infection that is greater than 85% after one or more treatments, compared to the 40%-to-50% success rate of antibiotics, and survival benefit, compared to antibiotics alone. While FMT appears to be effective in treating medically refractory severe or fulminant C. difficile infection, a recent systematic review concludes that multiple treatments are required and a subset of patients require additional courses of antibiotics to achieve resolution. In addition, the best route of FMT delivery is still unknown.

For now, the U.S. Food and Drug Administration (FDA) allows fecal transplants for patients with C. difficile who have not responded to standard therapies, in an approach known as enforcement discretion. However, several limitations mean clinicians cannot use FMT as the standard of care for treating recurrent CDI.

First, FMT is heterogeneous and has serious risks, including the death of two patients caused by an Escherichia coli infection.

Second, although some studies have suggested that FMT success relies on the composition of the stool donor, the microbiome profile that better predicts FMT response is still a long way from being known. Prof. Sahil Khanna, a gastroenterologist at Mayo Clinic, acknowledged at the 2022 GMFH World Summit that donors with microbiome-related diseases (e.g., obesity, IBS, IBD and neuropsychiatric conditions, among others), stool infections (either by enteric pathogens or multi-drug resistant organisms), blood infections (HIV, viral hepatitis, syphilis and others) and emerging pathogens (i.e., SARS-CoV-2) should be excluded from acting as fecal transplant donors.

It is also important to keep in mind that beyond bacteria, fecal samples are reported to contain viruses (mainly bacteriophages), fungi and many small molecules, such as bile acids and short chain fatty acids, which may contribute to or perpetuate the altered gut microbiome seen in patients with C. difficile infection. This suggests it is time to move away from fecal transplant towards targeted, refined microbiome therapies, according to this opinion article led by Kao and colleagues.

Last, beyond safety-related concerns, and crucially, quality control, the difficulty of setting up and managing a stool bank in a hospital and the cost of fecal transplants  hinder the generalized use of fecal microbiota transplants in clinical practice. On the whole, the variable nature of FMT makes documenting a relationship between fecal strain colonization, impact on the structure and functions of the gut microbiome and clinical efficacy challenging. “There’s just so many unanswered questions when it comes to fecal transplant,” says Kao.

 

Defined consortia of bacteria as an alternative therapeutic to fecal transplants

Specific and carefully characterized stool-derived or synthetic fractions are currently being studied as safer treatments than FMT for recurrent C. difficile.

Phase I, II and III clinical trials report efficacy and safety results of several investigational microbiota-based therapeutics for reducing CDI recurrence and normalizing gut microbiome composition following standard-of-care antibiotic treatment. A sustained clinical response has been shown in a high number of patients receiving live biotherapeutics, highlighting the involvement of microbiome repair, with a safety profile similar to placebo. For instance, some live biotherapeutic products have achieved treatment success rates of up to 80% and most responders remained free of C. difficile occurrence up to 24 months after treatment, thus highlighting both efficacy and durability.

Despite the clinical success of some standardized microbiota-based therapies, no defined microbiome restoration therapies have been approved by regulatory organizations. Indeed, the FDA has yet to regulate them, given they are not a drug, a biologic or a tissue.

Moreover, stool-derived consortia do not contain a defined population of microbes, which may pose regulatory risks compared to products with defined populations of microorganisms. In the latter case, populations cannot vary from lot to lot as the starting material is defined and it seems the stool-derived consortia field is moving in the same direction.

Beyond C. difficile infection, researchers have also been exploring the use of microbiome-based therapies for conditions including inflammatory bowel diseases, hepatic encephalopathy, urinary tract infections by multidrug resistant organisms, food allergies and cancer.

 

Take-home messages

  • Multiple recurrences are common in patients with difficile infection and failure rates for antibiotic therapy are high.
  • While fecal microbiota transplantation has shown a success rate of more than 85% for treating recurrent difficile infection, serious risks remain.
  • Several clinical trials support the investigational use of stool-derived or defined consortia of microbes for treating recurrent difficile infection.

 

Coming soon: A new article in the series focusing on the factors associated with C. difficile outcomes and the long-term complications of C. difficile infection. Stay tuned for upcoming news!

 

References:

Khanna S, Pardi R. Clostridioides difficile infection: curbing a difficult menace. Therap Adv Gastroenterol. 2022; 15:1-3. doi: 10.1177/17562848221089906.

Ferretti P, Wirbel J, Maistrenko OM, et al. C. difficile is overdiagnosed in adults and a commensal in infants. Preprint. Available: https://www.biorxiv.org/content/10.1101/2022.02.16.480740v1 (accessed 1st August 2022).

Khanna S. My treatment approach to Clostridioides difficile infection. Mayo Clin Proc. 2021; 96(8):2192-2204. doi: 10.1016/j.mayocp.2021.03.033.

Sandhu A, Chopra T. Fecal microbiota transplantation for recurrent Clostridioides difficile, safety, and pitfalls. Therap Adv Gastroenterol. 2021; 14:1-10. doi: 10.1177/17562848211053105.

Nong Song Y, Yi Yang D, Veldhuyzen van Zanten S, et al. Fecal microbiota transplantation for severe or fulminant Clostridioides difficile infection: systematic review and meta-analysis. J Can Assoc Gastroenterol. 2021; 5(1):e1-e11. doi: 10.1093/jcag/gwab023.

Wilson BC, Vatanen T, Cutfield WS, et al. The super-donor phenomenon in fecal microbiota transplantation. Front Cell Infect Microbiol. 2019; 9:2. doi: 10.3389/fcimb.2019.00002.

Russell L, Monaghan T, Kao D. The need to move away from fecal transplant towards targeted, refined microbiome therapy. J Thorac Dis. 2018; 10(10):E755-E757. doi: 10.21037/jtd.2018.09.80.

Food and Drug Administration. Use of Fecal Microbiota for Transplantation to Treat Clostridium Difficile. Available: https://www.federalregister.gov/documents/2019/09/11/2019-19643/use-of-fecal-microbiota-for-transplantation-to-treat-clostridium-difficile (accessed 1st August 2022).

Garber K. First microbiome-based drug clears phase III, in clinical trial turnaround. Nat Rev Drug Discov. 2020; 19(10):655-656. doi: 10.1038/d41573-020-00163-4.

Dsouza M, Menon R, Crossette E, et al. Colonization of the live biotherapeutic product VE303 and modulation of the microbiota and metabolites in healthy volunteers. Cell Host Microbe. 2022; 30(4):583-598. doi: 10.1016/j.chom.2022.03.016.

Orenstein R, Dubberke ER, Khanna S, et al. Durable reduction of Clostridioides difficile infection recurrence and microbiome restoration after treatment with RBX2660: results from an open-label phase 2 clinical trial. BMC Infect Dis. 2022; 22(1):245. doi: 10.1186/s12879-022-07256-y.

Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N Engl J Med. 2022; 386(3):220-229. doi: 10.1056/NEJMoa2106516.