CONTINUING EDUCATION :: C DIFFICILE
Testing for Clostridioides difficile and its disease
By Jodie Y. Lee, MS, MBA, and David M. Lyerly, PhD C
. difficile is an opportunistic anaerobic bacterial pathogen that causes diarrhea and colitis especially in hospital settings. There are other causes of hospital-acquired
diarrheas (e.g., norovirus outbreaks, medications, laxatives, etc.), but C. difficile is a major cause, accounting for 5% to 15% of hospital-acquired diarrheas. Outside of C. difficile infections (CDI), the cause of many hospital-acquired diar- rheas remains undiagnosed. Variants of C. difficile continue to cause problems in our healthcare systems. The most recognized variant is ribotype 027, which appeared in the early 2000s. This ribotype caused numerous outbreaks in Europe and North America because of its resistance to flouroquinolone antibiotics. However, it now is on the decline. Treatment does not differ between infections caused by the 027 ribotype and other ribotypes. As new hypervirulent strains continue to emerge, surveillance testing is important to help identify and proactively counteract these new threats. CDI develops in persons who have a compromised intestinal microbiota. Hospitalized elderly patients receiving antibiotics are a prime target for the disease. Antibiotics kill the microbiota, allowing C. difficile spores to germinate, grow in the intestine, and produce two very potent tissue-damaging and inflamma- tory toxins designated A and B that cause CDI. The spores, which persist in the patient, cause recurrent disease in about 25% of CDI cases and are difficult to eradicate from hospital environments. A closer examination of data over the past decade sug-
gests a shift in the epidemiology in hospital-acquired versus community-acquired CDI.1
Hospital-acquired CDI is defined
as those patients who develop CDI while in a healthcare facility. Community-acquired CDI is defined as those patients who develop CDI prior to or shortly after admission to a hospital. The numbers most typically cited for CDI in the U.S. — 400,000 cases of CDI with up to 30,000 deaths — include both hospital-acquired and community-acquired cases. Lower rates of hospital-acquired CDI may be due to fewer cases caused by the hypervirulent
Earning CEUs
See test on page 14 or online at
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LEARNING OBJECTIVES Upon completion of this article, the reader will be able to:
1. Discuss the role of C. difficile as an opportunistic pathogen and the challenges of diagnosing CDI versus carriers
2. Recognize the advantages and limitations of laboratory tests for CDI
3. Describe how a diagnostic approach based on an algorithm provides optimal test results
4. Discuss treatment options for CDI 8 JANUARY 2022
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fluoroquinolone-resistant ribotype 027, along with reduced use of fluoroquinolone antibiotics and greater attention to preven- tive measures. Community-acquired CDI, on the other hand, appears to be increasing, and may account for almost half of the cases of CDI, as indicated in more recently cited numbers.1 Overdiagnosis continues to be a challenge because of the large numbers of hospitalized patients who are carriers of C. difficile but who do not have CDI. Guidelines stipulate that carriers should not be treated because inappropriate treatment predisposes the patient to CDI and is not a good practice of antibiotic stewardship, possibly leading to antibiotic-resistant strains. (See Figure 1)
Gold standard tests for CDI The more than 50 laboratory tests cleared by the U.S. Food and Drug Administration (FDA) for C. difficile all have the same intended use and patient population. Importantly, results with all of these tests are to be used in conjunction with clinical history when diagnosing CDI. About half of the FDA-cleared tests are immunoassays that detect toxins A and B or gluta- mate dehydrogenase (GDH). Immunoassay formats include microwell-based and rapid membrane tests. NAAT (nucleic acid amplification test) assays, representing the other half, detect the toxin genes as single gene targets or as part of multiplex gastrointestinal panels. The gold standard tests, developed about 40 years ago to
help diagnose CDI, continue to be used today as comparator tests to establish performance of newer laboratory tests. The gold standard tests include: • the cell cytotoxicity neutralization assay (CCNA) for the detection of toxin in fecal specimens
• toxigenic culture on selective media (typically cycloserine cefoxitin fructose agar [CCFA]) followed by CCNA. CCNA detects the cell-rounding activity (i.e., cytopathic effect) of the toxins, with confirmation by neutralization with specific C. difficile antitoxin. For toxigenic culture, colonies are picked from CCFA and further tested by CCNA to confirm the isolate is toxigenic. The gold standard tests are very accurate and sensitive.
CCNA detects picograms of toxin, and CCFA can detect <100 colony-forming units per gram feces. However, both are tedious and time-consuming, requiring 2 days minimum for CCNA and 4 to 5 days for toxigenic culture. For these reasons, these tests are seldom used in today’s clinical labo- ratory. Instead, clinical labs have moved toward more rapid and easier-to-use formats.2
Toxin Immunoassays There are variant strains that produce only toxin A or only toxin B. This is why immunoassays that detect both toxins must be used since variant strains that produce only one toxin are capable of causing severe and life-threatening CDI. Toxin immunoas- says exhibit higher specificity, in some cases >99%, than GDH and NAAT assays because they detect the toxins that directly damage the intestinal mucosa and trigger the inflammation that occurs in CDI. The higher specificity results in higher positive
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