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This is the fifth article in a special collection that focuses on the epidemiology, diagnosis and management of C. difficile infection, which is of relevance to gastroenterologists. See the first article on C. difficile infection prevalence, risk factors and co-occurrence with COVID-19 here, the second article on diagnosing and managing primary and recurrent C. difficile infection here, the third article on the pros and cons of fecal transplants and defined commensal consortia for recurrent C. difficile infection here, and the fourth article on how doctors, patients and caregivers feel about fecal microbiota transplantation (FMT) for treating C. difficile infection patients here.


The loss of microbiota richness and diversity in modern societies provides more opportunities for C. difficile to thrive in the gut ecosystem

C. difficile infection (CDI) development involves a loss of colonization resistance, which is a key function of the microbiota that provides a barrier against pathogens. We conducted an online interview with Joël Doré, a trained gut microbial ecologist with 40 years’ experience in both basic science and translational developments in preventive nutrition and microbiome-based therapies. He explained that we should be more familiar with the fact that carrying C. difficile as a sub-dominant component of one’s intestinal microbiota is not an abnormal condition, as it is a bacterium sufficiently well adapted to the gut ecosystem. However, we have seen a gradual loss of microbiota richness/diversity in modern societies, with the subsequent loss of said microbiota’s barrier effect against pathogens. Such a scenario leaves ecological space in the gut for C. difficile to proliferate, establish a dominant presence and produce the toxins involved in the colitis that characterizes CDI.

Recent data reveal that CDI is not only an illness seen in health care facilities, but is a community illness. Exposure to antibiotics is the main risk factor for community-acquired and recurrent CDI, typically occurring during antibiotic use or up to one month after. However, an increasing number of patients under 65 develop community-acquired CDI without hospitalization or antibiotic exposure taking place in the 12 weeks prior to diagnosis.

Doré acknowledged that while there is no consensus tool to classify the severity of C. difficile infection, the disease course can be anticipated as complicated in individuals who do not respond to initial antibiotic therapy and frail, elderly subjects or patients with multiple co-morbidities.


Preserving gut microbiome richness is vital in managing C. difficile infection, but current antibiotics work in the opposite way

Antibiotics are the mainstream treatment for CDI, but can further disrupt the gut microbiota, which is already involved in the onset of the disease. That explains why microbiome-targeted treatments are attracting interest as a mean of managing C. difficile. Indeed, such microbiome-based treatments make sense from an ecological point of view, as Doré states, in the way that the well-documented evidence of the efficacy of fecal microbiota transfer in preventing and curing CDI is a clear illustration of an ecological treatment for an ecological disease. Displacement of the pathogen and the disrupted microbiome and its replacement with a balanced and diverse ecosystem are the key features of microbiome-targeted treatment modalities. That is the case, for instance, with Rebiotix’s current Good Manufacturing Practice standardized version of fecal microbiota transfer, which has received a positive return from the Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee that issued a positive vote on September 22, 2022 opening the door for an approval shortly.

Complications of CDI include toxic megacolon, colectomy, perforations that need intensive care unit admission, and death. A recent systematic review and cross-sectional findings have identified some risk factors for unfavorable outcomes. Older age (80-plus years), underlying medical comorbidities (e.g., renal failure), abnormal blood tests (decreased albumin and high white blood cell count, blood urea nitrogen and C-reactive protein), abnormal vital signs (high heart and respiratory rates) and strain type (i.e., ribotype 027) are independently associated with mortality and complications.

In particular, European and American guidelines for managing CDI in adults suggest the use of laboratory parameters and clinical and radiological data to define patients at risk of a complicated CDI, for whom the initial treatment includes vancomycin or fidaxomicin to lower the risk of complications. As information on the risk factors mentioned above is readily available to healthcare professionals at the time of diagnosis, incorporating them into routine clinical practice could help identify patients who need close monitoring and may improve clinical decision making.


Strategies to prevent the risk of C. difficile complications should focus on reducing disturbance to the gut microbiome

Strategies to prevent or mitigate risk for recurrence vary and some are controversial. Characterizing asymptomatic colonization from true infections is a critical step, with individuals with clinical signs of C. difficile infection having an increased risk of recurrences and complications.

When it comes to reducing recurrence of CDI and further complications, fidaxomicin is now recommended in various guidelines as an initial CDI treatment option, given its lower incidence of recurrence compared to oral vancomycin. Meanwhile, standard of care plus bezlotoxumab or fecal microbiota transfers (FMT) are typically recommended only in recurrent CDI cases, including the use of FMT as a cost-effective strategy for first recurrent CDI.

Standard prevention strategies focus more on primary prevention, not recurrence, through classic infection prevention strategies, isolation, disinfection/sterilization, hand hygiene and antibiotic stewardship. In contrast, discontinuation of proton pump inhibitors are not recommended and the use of anti-CDI options (i.e., metronidazole, vancomycin, fidaxomicin) are controversial, according to European and American guidelines.

However, minimizing gut microbiome alteration is of paramount importance to prevent future complications. According to Doré: “Implementing strategies to strengthen microbiome resistance to modification upon stress and to improve its resilience following stress would make a lot of sense to prevent the microbiome disturbances that precede the onset of C. difficile infection. Accompanying antibiotics with probiotics, such as those recommended by the World Gastroenterology Organisation, should be considered to minimize the risk of dominant microbiota alteration. The use of rifaximin, which induces minimal alterations among dominant gut commensals, is also recommended in patients who cannot receive fecal microbiota transfer.”


Take-home messages

  • An increasing number of patients under 65 develop difficile infection without hospitalization or antibiotic exposure, highlighting that the condition has switched from the hospital to the community setting.
  • While current antibiotic treatments do not target the disrupted gut microbiome that is a hallmark feature of difficile colonization, preserving gut microbiome richness is vital to helping the gut ecosystem cure C. difficile infection.
  • The ability to identify patients at high risk of CDI complications and mortality early on in the diagnosis could improve clinical decision making.
  • Strategies for preventing recurrence should focus on strengthening gut microbiome resistance and resilience to prevent the microbiome disturbances that precede the onset of difficile infection.



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