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Strategies for Diagnosis and Management of Initial and Recurrent Clostridioides Difficile Infection

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Sahil Khanna, MBBS, MS

Professor of Medicine 
Division of Gastroenterology and Hepatology
Mayo Clinic
Rochester, Minnesota


Sahil Khanna, MBBS, MS, has received funds for research support from Finch, Pfizer, Rebiotix/Ferring, and Vedanta and consulting fees from Shire/Takeda.


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Released: January 21, 2022

Clostridioides difficile infection (CDI) due to antibiotic exposure has been a consistent public health threat for more than 2 decades. Initially considered a cause of diarrhea in hospitalized elderly patients, recent data show that C difficile also causes diarrhea in younger populations, including children, and in otherwise low-risk patient populations. In recent years, the incidence of primary C difficile infection (CDI) and recurrent CDI has increased. The pathophysiology of recurrent infections includes ongoing microbiome disruption due to the treatment of CDI with antibiotics, which perpetuate spore germination and subsequent infections. Epidemiologic studies demonstrate a higher economic and societal burden of recurrent CDI compared with primary CDI.  

Several advances in the diagnosis and management of CDI are reflected in the latest treatment guidelines from the American College of Gastroenterology, the European Society of Clinical Microbiology and Infectious Diseases in 2021, and the Infectious Diseases Society of America (IDSA) in 2017 and 2021.

Diagnosis of CDI
In addition to delineating the risk factors for CDI in patients, taking a detailed symptom history from patients with suspected CDI is pertinent. Typical symptoms include unexplained diarrhea, defined as watery or unformed stools 3 or more times per day for multiple days. In patients with chronic diarrhea due to another cause, such as inflammatory bowel disease (ulcerative colitis or Crohn disease), worsening of usual diarrhea would prompt an evaluation for CDI. The most frequently used stool test for the diagnosis of CDI is a polymerase chain reaction (PCR) test, which has high sensitivity and high specificity for the bacterium but does not measure actual toxin production. A PCR assay is useful in patients with unexplained diarrhea, but colonization by C difficile is common in patients with inflammatory bowel disease, so PCR-only testing may not be helpful in this case or in others with multifactorial diarrhea.

A 2-step assay combining detection of glutamate dehydrogenase (GDH) produced by C difficile and other clostridial species followed by an enzyme immunoassay (EIA) for production of toxins A and B is being used in clinical practice and is recommended in patients with inflammatory bowel disease or in those with multifactorial diarrhea or in instances where an accurate diarrhea assessment may not be available. Assays for GDH are highly sensitive for CDI but lack specificity. Therefore, a positive GDH is followed by an EIA for toxin detection, and when both are positive, a diagnosis of CDI is made. In the case of discordance, that is, a positive GDH but a negative EIA for toxin production, a PCR-based assay is used for arbitration.

CDI Treatment With Antibiotics
In addition to advances in testing, advances in antibiotic treatment of CDI have also been made. The 2021 IDSA guidelines suggest using fidaxomicin for a first episode of nonfulminant CDI over vancomycin, as fidaxomicin is associated with fewer recurrences. Metronidazole is no longer recommended in most instances. In the phase IIIb/IV EXTEND trial, an interesting regimen of a fidaxomicin pulse with 20 doses spread over 25 days had a very low rate of recurrence in hospitalized patients 60 years of age or older with CDI. In patients with risk factors for recurrence (eg, immunocompromised, age older than 65 years), intravenous bezlotoxumab in addition to standard-of-care antibiotics is recommended. A first recurrence can be managed with a vancomycin taper, and bezlotoxumab may be considered for patients who are at high risk for recurrence. Multiple recurrences are managed through restoration of the gut microbiota with therapies such as fecal microbiota transplantation.

New Data on CDI Diagnosis and Treatment at IDWeek 2021
Several interesting studies were presented at IDWeek 2021 that advanced our understanding of CDI. Two studies examined CDI diagnosis technologies. In the first, Crone and colleagues studied the clinical and microbiologic characteristics of CDI after a change in the diagnostic testing algorithm from a stool PCR test only to a 2-step algorithm consisting of stool PCR reflexed to toxin testing. The investigators found that cases diagnosed by positive stool PCR and positive toxin tests had more typical risk factors for CDI, had a lower PCR cycle threshold, and were more likely to have been treated for CDI. This study reinforces the need for an accurate diagnosis of CDI and suggests the benefits of a 2-step vs a 1-step assay for making a more accurate diagnosis. A similar study by Dolan and colleagues demonstrated that adoption of a 2-step PCR plus toxin testing algorithm for hospital-onset CDI reduced the frequency with which toxin-negative patients received therapy, but most patients were still treated. Most healthcare professionals considered a positive PCR indicative of CDI, regardless of toxin status, likely due to the lack of high sensitivity of the toxin assay. A highly sensitive and specific toxin assay for C difficile will help further advance the accurate diagnosis of CDI.

Finally, Dubberke and colleagues examined changes in C difficile antibiotic use and clinical outcomes among Medicare beneficiaries with C difficile before vs after the 2017 IDSA guideline update. The investigators found that the 2017 IDSA guideline update was associated with increased vancomycin use and decreased metronidazole use, whereas fidaxomicin use rates remained low (<2%). Overall, CDI outcomes did not improve the postguideline update despite the shift to guideline-indicated vancomycin. This may be because vancomycin was not linked with meaningfully improved outcomes compared with metronidazole. These improved outcomes with fidaxomicin relative to vancomycin or metronidazole suggest potential benefits with greater use, but this may be limited by cost.

More on CDI: Virtual Symposium
To hear more on diagnosis and management of initial and recurrent CDI, join us for an upcoming live virtual symposium. The program will include practical management strategies and perspectives from me and my colleagues Teena Chopra, MD, MPH; Paul Feuerstadt, MD, FACG, AGAF; and Kevin Garey, PharmD, MS.

Your Thoughts?
In your practice, have you altered your diagnostic workup for CDI and/or the drugs you use to treat recurrent CDI? Join the conversation by posting in the discussion section.

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