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This is the second 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.

 

When to suspect C. difficile infection

C. difficile infection (CDI) still remains the most common cause of infectious diarrhea in hospitals in most countries, with a parallel burden in the community in the US. The risk factors that predispose an individual to acquire CDI include:

  • Modifiable risk factors: antibiotic exposure (in high numbers, taken for longer time periods and with the broadest spectrum being the worst of all), gastric acid suppression use, chemotherapy and immunosuppressive medications, exposure to hospital and long-term care facilities, and coming into contact with patients infected with the pathogen.
  • Non-modifiable risk factors: advanced age, comorbid conditions (cancers, chronic kidney diseases, inflammatory bowel disease, heart conditions and liver cirrhosis).

In an online interview with GMFH editors, Sahil Khanna, a gastroenterologist at Mayo Clinic, explained that anything that alters or decreases the diversity of the gut microbiome can potentially be a risk factor for C. difficile.

Dr. Khanna also acknowledged that, in the past, it was thought that C. difficile only affected the elderly, especially those subject to the aforementioned risk factors. However, it has recently been observed that 40% of all C. difficile infections happen in the community in younger people with unexplained diarrhea and a lack of exposure to traditional modifiable risk factors.

Typical symptoms from a patient with suspected C. difficile infection include otherwise unexplained watery diarrhea (Bristol type 6 or type 7 stools) three or more times a day for more than a day, abdominal pain, nausea or vomiting and fever can also happen. In rare cases, patients with severe CDI in the intensive care unit may present constipation.

CDI in patients with inflammatory bowel disease (IBD) reflects poor disease control, as the infection can trigger an IBD flare-up, while an IBD flare-up can also trigger a CDI. This explains how cases of both severe IBD flare-ups and reaggravation after an initial response to treatment would prompt an evaluation for CDI.

It is tricky to identify C. difficile infection in patients with multifactorial diarrhea. Dr. Khanna stated that in order to make a differential diagnosis between C. difficile infection and other causes of diarrhea, such as IBS and IBD, clinicians should look at: 1) taking a detailed baseline symptom history from patients; 2) identifying if the patient has been exposed to risk factors for C. difficile; 3) the worsening of the underlying diarrhea; and 4) obtaining stool testing (if negative, C. difficile infection can be ruled out with a high level of confidence).

 

How to make an accurate diagnosis

While in the past the diagnosis of C. difficile infection was based on looking for the presence of pseudomembranes, the typical diagnostic modality for C. difficile nowadays is stool-based testing in patients with clinical suspicion of CDI, which consists of detecting the organism or what it is doing.

While PCR assay is highly accurate and sensitive to detecting the organism’s presence, Dr. Khanna highlighted that the problem with the test is that it sometimes detects patients with asymptomatic colonization. In that case, the data should be understood in the context of the patient’s symptoms. Indeed, if a clinician is not sure whether a patient has CDI, a PCR is not the preferred test.

The alternative testing regime recommended in the updated Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) 2017 guideline and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines is a multi-step process that starts with assessing glutamate dehydrogenase (GDH), which is an enzyme produced in large quantities by C. difficile. If the test for GDH is positive (meaning that the large bowel is colonized by C. difficile), the second enzyme immunoassay (EIA) test will look for the toxins produced by the bacterium.

If both the GDH and EIA tests are positive, a CDI diagnosis can be made. If one of the tests is negative and the other positive, a PCR-based assay is used to arbitrate the discordance.

 

The current situation of C. difficile diagnosis outside the USA, Canada and Europe

While the prevalence of CDI in the USA, Canada and Europe is high, that is not the case in other regions suggesting the infection gets overlooked. Dr. Khanna acknowledged that in some parts of Africa tests for diagnosing C. difficile are not readily available, while in some parts of India and South Asia where the tests are available, they are expensive. For instance, in India, other infectious causes of diarrhea (e.g., bacteria such as Escherichia coli, viruses and parasites) are considered more often over C. difficile. In South America, many countries have access to tests, especially in specialized centers and hospital-based settings, and they can be done a few times a week instead of on a daily basis.

 

What available clinical guidelines say about C. difficile infection management

The optimal management of C. difficile infection still remains a challenge. Assessing the severity of C. difficile infection as fulminant, severe or mild-to-moderate disease is an important step not only in determining the treatment choice but also in predicting recurrence rates and response to therapies.

As an initial step, all patients with CDI should be isolated and infection control measures should be maintained until discharge. Concomitant acid suppressant medications, opioid medications and systemic antibiotics should be stopped, as they increase the risk of recurrence.

 

Treating the first episode and first recurrence of nonsevere CDI (primary CDI)

The IDSA/SHEA 2021 guideline and AGA 2021 guideline recommend oral fidamoxicin at 200 mg twice a day or oral vancomycin at 125 mg four times a day for 10 days for initial CDI episodes. The major drawbacks to vancomycin use are the higher risk of selecting antibiotic-resistant forms of other gut bacteria and the lack of activity against C. difficile spores, which leaves the patient vulnerable to recurrences. Fidaxomicin is preferred compared to vancomycin and metronidazole, if cost or insurance coverage allows, especially in patients who are at high risk of recurrence, due to the advantageous effect of fidaxomicin, with up to a 50% decrease in the odds of recurrence compared to vancomycin and a 60% decrease in the odds of recurrence compared to metronidazole.

In patients at a high risk of recurrence (i.e., the elderly, immunocompromised or those with severe non fulminant CDI), a single dose of bezlotoxumab is recommended.

In countries outside the USA, when a clinician has a strong suspicion that a patient has C. difficile, Dr. Khanna stated that sending patient’s fecal samples to a specialized lab for testing takes place in parallel with starting treatment.

 

Treating the second and subsequent recurrences of nonsevere CDI

The risk of recurrences for patients with two or more episodes of CDI is 60% higher and management of such recurrences includes vancomycin taper and pulse or fidaxomicin or vancomycin followed by rifamixin.

In patients who have two or more recurrences or multiple episodes of CDI, Dr. Khanna suggested that the way to proceed is to think about restoring the gut microbiome through treatments that include fecal microbiota transplantation and standardized microbiome restoration therapies, the latest currently being investigated in clinical trials.

If a patient does not respond with an appropriate antibiotic treatment for the initial episode of CDI and at least two recurrences, fecal microbiota transplantation is recommended by the IDSA/SHEA 2021 guideline and AGA 2021 guideline—preferably through colonoscopy or capsules—to prevent further recurrences.

Some clinical trials have also shown the efficacy, safety and durability of defined standardized microbiota-based investigational live biotherapeutics (e.g, CP101, MET-2, RBX2660, RBX7455, SER-109, SER-262 and VE303) as a means of restoring the gut microbiome and preventing multiple recurrent CDI.

In this online interview, Dr. Khanna acknowledges the benefits and risks of microbiome replacement therapies for CDI, and where microbiome replacement therapies fit in the patient journey:




 

Other treatments being evaluated for preventing recurrent CDI include monoclonal antibodies actoxumab and bezlotoxumab, which act against C. difficile toxins; nontoxigenic C. difficile spores that protect against colonization by toxigenic strains; vancomycin prophylaxis; and vaccines.

 

Take-home messages

  • C. difficile infection is a common cause of diarrhea, not only in the hospital setting but also in the community.
  • While exposure to antibiotics, hospitalization and advanced age are known risk factors for difficile infection, young and adult patients with unexplained diarrhea and a lack of exposure to traditional modifiable risk factors are also candidates for C. difficile.
  • The latest clinical guidelines on difficile management recommend against using metronidazole for initial CDI. They also recommend the addition of fidaxomicin and bezlotoxumab.
  • Fecal microbiota transplantation and standardized microbiome treatments can help managing recurrent difficile infection through addressing the disrupted microbiome, which is not targeted by current therapies for recurrent C. difficile infection.

 

Coming soon: A new article in this series focusing on live microbiome-based therapeutics vs FMT for managing C. difficile infection. Stay tuned for more news about developments in the field!

 

References: 

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Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis. 2021; 73(5):e1029-e1044. doi: 10.1093/cid/ciab549.

Kelly CR, Fischer M, Allegretti JR, et al. ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile infections. Am J Gastroenterol. 2021; 116(6):1124-47. doi: 10.14309/ajg.0000000000001278.

Nitzan O, Elias M, Chazan B, et al. Clostridium difficile and inflammatory bowel disease: role in pathogenesis and implications in treatment. World J Gastroenterol. 2013; 19(43):7577-7585. doi: 10.3748/wjg.v19.i43.7577.

Khanna S, Shin A, Kelly CP. Management of Clostridium difficile infection in inflammatory bowel disease: expert review from the clinical practice updates committee of the AGA Institute. Clin Gastroenterol Hepatol. 2017; 15(2):166-174. doi: 10.1016/j.cgh.2016.10.024.

McDonald LC, Gerding DN, Johnson S, et al. 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). Clin Infect Dis. 2018; 66(7):987-994. doi: 10.1093/cid/ciy149.

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Okumura H, Fukushima A, Taieb V, et al. Fidaxomicin compared with vancomycin and metronidazole for the treatment of Clostridioides (Clostridium) difficile infection: A network meta-analysis. J Infect Chemother. 2020; 26(1):43-50. doi: 10.1016/j.jiac.2019.08.005.

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.

Cheng YW, Phelps E, Nemes S, et al. Fecal microbiota transplant decreases mortality in patients with refractory severe or fulminant Clostridioides difficile infection. Clin Gastroenterol Hepatol. 2020; 18(10):2234-2243.e1. doi: 10.1016/j.cgh.2019.12.029.