White Paper (Patient Evaluation)

OpenBiome and our manufacturer, the University of Minnesota, maintain access to investigational fecal microbiota transplantation for the treatment of C. difficile infections not responding to standard therapies.

Evaluating Patients for Investigational FMT

Investigational Fecal Microbiota Transplantation (FMT) has been shown to treat 80-90% of C. difficile infections (CDI) not responsive to antibiotics in clinical trials and real-world settings. However, the utility of investigational FMT depends on accurate CDI diagnosis and patient selection. As much as 25% of patients may be incorrectly referred for investigational FMT.

This page covers the considerations when evaluating patients for investigational FMT for the treatment of C. difficile infections

Learning Objectives

Diagnose C. difficile infections using a two-step algorithm
Consider alternative (non C. difficile infection) etiologies that may explain symptoms
Diagnose fulminant C. difficile infections
Distinguish between C. difficile infection and IBD flares

This article was written by Madji Osman, MD MPh and Justin Chen, PhD and last updated on December 20, 2023.

The guidance presented below are general principles drawn from the experience and medical opinions of OpenBiome’s Clinical team. Physicians should use their own discretion when evaluating their patients and consider each patient’s unique medical needs.

Investigational fecal microbiota transplantation (FMT) is not an FDA-approved therapy. Physicians and patients should determine whether an investigational FMT is a suitable treatment option depending on the patient's unique medical history and treatment goals.

Introduction

Over the past decade, investigational Fecal Microbiota Transplantation (FMT) has developed from a fringe medical procedure to a treatment option for recurrent C. difficile infections (CDI), as defined in guidelines from medical professional societies (See "Additional Resources under Diagnosing C. difficile").

Data from clinical trials and real-world settings has demonstrated that investigational FMT can resolve between 80-90% of recurrent and severe/fulminant C. difficile infections. However, the success of investigational FMT depends on accurate CDI diagnosis, as misdiagnosis could unnecessarily expose patients to the risks of FMT and associated procedures with no added benefit.

A retrospective review from 2016 highlights the need for rigorous patient evaluation by demonstrating that 25% of patients referred to a health care facility for investigational FMT were erroneously diagnosed with CDI.

An icon of a clinician with a stool sample

Diagnosing C. difficile Infections

Consensus-based guidelines from multiple groups (see "Additional Resources") recommend a two-step algorithm for more accurate diagnosis combining molecular screening for the C. difficile toxin gene and immunoassay for the detection of the toxin produced by C. difficile.

This approach aims to distinguish between colonization and active infection to minimize the risk that a patient is colonized by C. difficile, but a different etiology is responsible for their diarrhea.

First, patients should take a test with high sensitivity and negative prediction value such as enzyme immunoassay for glutamate dehydrogenase (GDH EIA) or a nucleic acid amplification test (NAAT).

These tests, which detect enzymes produced by C. difficile or C. difficile genetic material respectively, test for the presence of C. difficile.

If the test is negative, no additional testing regarding C. difficile needs to be performed and the physician should consider alternative explanations for the patient’s symptoms.

If the test is positive, patients should undergo a second test with high specificity and positive prediction value such as enzyme immunoassay for toxin A/B (Toxin A/B EIA).

A negative test indicates that the patient may be colonized with C. difficile bacteria that are not producing toxins or have not yet produced enough toxin to be detected. In this case, the patient’s symptoms are likely due to an alternative etiology if the clinical index of suspicion for C. difficile infection is low.

A positive test indicates that the patient should be treated for C. difficile infection.

Key Takeaway
Accurate C. difficile diagnosis relies on a two-step testing algorithm—where a patient first undergoes a highly sensitive test before a highly specific test— to distinguish true infection from colonization.

Additional Resources

More information on the diagnosis and treatment of C. difficile infections as well as the use of investigational FMT can be found in the following medical guidelines.

ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections

Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)

The use of faecal microbiota transplant as treatment for recurrent or refractory Clostridium difficile infection and other potential indications: joint British Society of Gastroenterology (BSG) and Healthcare Infection Society (HIS) guidelines

Alternative Etiologies

Persistent diarrhea that is characteristic of C. difficile infection (CDI) may be caused by infectious and non-infectious etiologies which are reviewed below.

According to a study of 117 patients referred to a health care center for presumed C. difficile infection, patients who are non-responsiveness to anti-CDI therapy and/or show intermittent non-progressive symptoms may have a non CDI illness. Additionally, fewer past episodes of CDI and prior diagnosis of IBS were positively correlated with an alternative diagnosis.

Diarrheal infections may be caused by bacteria (e.g., V. cholerae, S. sonnei, S. flexneri, S. dysenteriae , S. boydii, enteropathogenic E. coli (EPEC), enterohemorrhagic E. coli (EHEC), enterotoxigenic E. coli (ETEC), enetroaggregative E. coli (EAEC), enteroinvasive E. coli and diffusely adherent E. coli (DAEC), viruses (e.g., norovirus, sapovirus, adenovirus, rotavirus and astroviruses), or parasites (e.g., Giardia lamblia and E. histolytica) and can be diagnosed via viral panels or stool cultures.

In particular, Staphylococcus aureus, Klebsiella oxytoca, Clostridium perfringens, and Salmonella spp have been implicated as causes of antibiotic-associated diarrhea. These infections can be diagnosed by stool culture and/or stool multiplex nucleic acid testing.

Diagnosing Severe and Fulminant C. difficile Infections

Up to 8% of patients with C. difficile infections develop severe or fulminant infections, which are often life threatening and require more urgent medical management.

Severe CDI is defined as leukocytosis with a white blood cell count of ≥15,000 cells/mL or a serum creatinine level >1.5 mg/dL (or 132 µmol/L).
Fulminant CDI, is defined as a C. difficile infection contributing to hypotension or shock, ileus and megacolon

Key Recommendations:

Crucially, severe or fulminant CDI may not be accompanied by diarrhea as stool may be absent due to pooling in a dilated, atonic colon. Hospitalized patients with unexplained leukocytosis should be tested for CDI.
Investigational FMT may be a treatment option for severe and fulminant C. difficile infections that obviates the need for colectomy in patients who are poor candidates for surgery due to and comorbidities. The studies on the right evaluate the appropriateness of investigation FMT in this vulnerable patient population.

Additional Resources

Fecal Microbiota Transplantation for Fulminant Clostridioides Difficile Infection: A Combined Medical and Surgical Case Series

Fecal Microbiota Transplantation for Severe or Fulminant Clostridioides difficile Infection: Systematic Review and Meta-analysis

Fecal microbiota transplant in severe and severe-complicated Clostridium difficile: A promising treatment approach

Considerations for Patients with Inflammatory Bowel Disease

In order to optimize treatment, physicians must distinguish C. difficile infections (CDI) from an active IBD flare. However both indications have similar presentations—primarily, diarrhea and abdominal pain. Furthermore, endoscopic and histological features are not reliable markers as pseudomembranes typically associated with CDI may be absent in CDI positive patients with IBD.

Key Recommendation:
Because of the difficulty of diagnosis based on symptoms, the American College of Gastroenterology guidelines recommend that IBD patients with worsening symptoms undergo screening for C. difficile using a two-step algorithm (described above) that distinguishes between active CDI infection and colonization.

Additional Resources

Management of Clostridium difficile Infection in Inflammatory Bowel Disease: Expert Review from the Clinical Practice Updates Committee of the AGA Institute

Diagnosing C. difficile in Inflammatory Bowel Disease: Challenges and Pitfalls (Webinar hosted by Dr. Sahil Khanna)

Making the Appropriate Diagnosis of C. diff in IBD Patients (Webinar hosted by Dr. Jessica Allegretti)