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Clostridioides (Clostridium) difficile

Medical Experts

Contributor

Couturier

Marc R. Couturier, PhD

Former Head of Clinical Operations for Clinical Microbiology and Immunology; Medical Director, Emerging Public Health Crises, Parasitology/Fecal Testing, and Infectious Disease Antigen Testing, ARUP Laboratories

Clostridioides difficile (formerly known as Clostridium difficile) is a potentially toxigenic bacterium transmitted from person to person through the fecal-oral route. C. difficile infection (CDI), defined as acute-onset diarrhea with evidence of toxigenic C. difficile overgrowth and no other apparent cause, is the most frequent cause of infectious diarrhea in clinical settings.^, The possibility of asymptomatic colonization (by toxigenic and nontoxigenic strains) complicates diagnosis, and inappropriate testing can lead to overdiagnosis.^,

Guidelines currently recommend stool toxin enzyme immunoassay (EIA) testing, glutamate dehydrogenase (GDH) testing, and/or nucleic acid amplification testing (NAAT). Testing should be performed in a multistep approach unless institutional specimen submission criteria are in place to limit inappropriate testing and ensure a high pretest probability of CDI. Initial testing is best performed close to the point of care to enable quick turnaround times.

Quick Answers for Clinicians

Who should be tested for Clostridioides difficile infection?

Testing for Clostridioides difficile infection (CDI) is indicated in adults and adolescents with new-onset diarrhea that is not clearly attributable to another cause, with three or more unformed stools in 24 hours. Although rare, it is possible for patients with an ileus and complicated disease to have formed stool, in which case testing should be performed with laboratory guidance on specimen submission. Refer to the Recommended Testing section for the appropriate approach in these cases.

Indications for testing in children and infants vary by age group. In children 2 years or older, persistent or worsening diarrhea in the presence of CDI risk factors should prompt testing. In toddlers 1 to 2 years of age, testing is only recommended once other infectious and noninfectious causes of diarrhea have been ruled out. Finally, routine testing for CDI is not recommended in neonates and infants 12 months or younger, as loose stool and asymptomatic C. difficile colonization are prevalent in this age group; however, testing can be considered in cases of pseudomembranous colitis, toxic megacolon, or otherwise unexplained, clinically significant diarrhea.

What are the risk factors for Clostridioides difficile infection?

Certain risk factors increase the pretest probability of Clostridioides difficile infection (CDI). Healthcare-facility exposure, particularly due to a long stay in a hospital or other medical facility, is a primary risk factor for CDI. Additional risk factors include treatment with antibiotics or proton pump inhibitors, advanced age, and illnesses such as inflammatory bowel disease (IBD), chronic kidney disease, end-stage renal disease, and HIV. Patients undergoing solid organ or hematopoietic stem cell transplantations, chemotherapy, gastrointestinal surgery, and tube feeding are also at increased risk, as are patients who have had CDI previously. Although risk factors in children are similar to those in adults (mainly antibiotic use, hospitalization, organ transplantation, and chronic conditions such as IBD or cancer), an additional risk factor is the use of gastrostomy or jejunostomy tubes.

Is repeat testing for Clostridioides difficile infection recommended?

Guidelines recommend against repeat testing for Clostridioides difficile infection (CDI) within 7 days during a single episode of diarrhea. Studies indicate that nucleic acid amplification testing (NAAT) repeated during a 7-day window has a low diagnostic yield (approximately 2%). Exceptions to this recommendation are only advised in the context of an institutional epidemic; in patients with recurrent or persistent symptoms following treatment for CDI; or in patients with negative CDI results and worsening symptoms in whom the clinical suspicion for CDI is high.^,

Guidelines also discourage tests of cure. Enzyme immunoassay (EIA) and toxigenic culture tests for both toxins A and B may give positive results for up to 30 days in patients whose symptoms have resolved, so false-positive tests of cure may result in unnecessary or prolonged treatment.^,

Indications for Testing

Adults and Adolescents

The Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) recommend CDI testing be performed in adults and adolescents with new-onset diarrhea that is not clearly attributable to another cause (e.g., laxative use within the past 48 hours), with three or more unformed stools within 24 hours.

Children and Infants

In children 2 years or older, persistent or worsening diarrhea along with CDI risk factors is an indication for CDI testing. In toddlers younger than 2 years, the IDSA and SHEA recommend testing only after other infectious/noninfectious causes have been ruled out. In neonates and infants (12 months or younger), CDI testing is not routinely recommended.

Laboratory Testing

Diagnosis

The American College of Gastroenterology (ACG) recommends that CDI testing be performed only on diarrheal stools, except in patients with suspected ileus caused by C. difficile (in these circumstances, contact the performing laboratory for guidance before submitting a specimen). The IDSA and SHEA have issued similar guidance, further recommending a multistep approach to testing unless institutional criteria are in place to limit inappropriate testing (e.g., testing of specimens from asymptomatic individuals, specimens from patients whose symptoms are likely due to another cause, etc.) and ensure a high pretest probability for CDI. Repeat testing, except in specific circumstances, is not recommended.^, Because patients can test positive for C. difficile even after the conclusion of effective treatment, tests of cure are also discouraged.^,

When testing is indicated, initial testing is best performed close to the point of care to hasten test turnaround times. Guidelines recommend stool toxin EIA testing, GDH testing, and/or NAAT.^, IDSA-SHEA’s multistep algorithm entails the use of either of the following test combinations:

Stool toxin EIA plus NAAT, or
Stool toxin EIA plus GDH (plus NAAT if EIA and GDH results are discordant)

Recommended Testing

Nucleic Acid Amplification Testing

NAAT can be used to detect C. difficile toxin genes tcdA or tcdB. When institutional specimen submission criteria are in place to limit inappropriate testing, standalone NAAT may be used. Otherwise, NAAT should be used as part of a multistep testing strategy, in conjunction with stool toxin testing (EIA) or to confirm equivocal results from stool toxin and GDH testing. Although uncommon, it is possible for patients who have an ileus and complicated disease to have formed stool rather than diarrhea; in these cases, rectal swabs can be tested by NAAT. Contact the performing laboratory for additional guidance before submitting a nonstandard specimen.

Stool Toxin Testing

EIAs can be used to detect C. difficile toxins in stool, but available tests vary widely in sensitivity. The IDSA and SHEA recommend that only the higher sensitivity toxin EIA tests be offered in clinical laboratories. When ordered, this testing should be performed in conjunction with GDH testing and/or NAAT.

Glutamate Dehydrogenase Testing

GDH is an enzyme produced by both toxigenic and nontoxigenic C. difficile. An EIA can be used to detect GDH antigen. Although the GDH test is a rapid initial test, it detects only the presence of the C. difficile organism and cannot distinguish between toxigenic and nontoxigenic strains. As such, GDH testing is sensitive but not specific for CDI.^,

Other Testing (Useful Only in Certain Situations)

Toxigenic Culture

Toxigenic culture (TC), formerly the gold standard test, involves the culturing of C. difficile from stool; cytotoxic assays are then used to test isolates for cytotoxin production. This method can require several days to produce results and has limited diagnostic utility.

Cell Culture Cytotoxicity Assay

Another reference standard is the cell culture cytotoxic assay, which can detect toxins in stool filtrate. This test can be used to identify cell rounding that is characteristic of cell exposure to toxins, and is more likely to detect toxin B than toxin A. The cell culture cytotoxicity assay is qualitative, subjective, requires 24 to 48 hours for incubation, and is not widely used.

Strain Typing

Strain typing can be useful for epidemiologic tracking, and a variety of methods, such as restriction endonuclease analysis (REA) typing and polymerase chain reaction (PCR) ribotyping, are available. Such methods can be used to identify new C. difficile strains and assess the relatedness of different strains.^,