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Infectious Diseases - Clostridium difficile Infection - Fast Facts | NEJM Resident 360

Clostridium difficile is an anaerobic, spore-forming, gram-positive bacillus that is responsible for significant health-care–associated diarrhea. C. difficile infection (CDI) should be suspected with acute onset of three or more unformed (liquid) stools in 24 hours. CDI typically presents as watery diarrhea and can result in more than 20 bowel movements a day. In this section, we review the following topics related to CDI:

• Pathophysiology

• Diagnosis

• Treatment

• Prevention

Pathophysiology

C. difficile is transmitted via the fecal–oral route through highly resistant spores that can withstand heat, antibiotics, air, and acid. These spores are ubiquitous in the hospital environment and found in the community as well. Once ingested, C. difficile releases exotoxins A and B that inactivate pathways mediated by the Rho family of guanosine triphosphatases (Rho GTPases) and cause colitis, colonocyte cell death, and loss of intestinal barrier integrity, resulting in diarrhea. Areas of cell death coalesce to form pseudomembranous colitis.

Pathogenesis of C. Difficile Infection

(Source: Clostridium difficile Infection. N Engl J Med 2015.)

Risk Factors for C. Difficile Infection

The likelihood of colonization progressing to active infection is determined by the following host risk factors and bacterial virulence:

• antibiotics (the most important risk factor)

• age >65 years

• chronic kidney disease

• organ transplantation

• chemotherapy

• exposure to an infected individual

(Source: Clostridium difficile Infection. N Engl J Med 2015.)

Diagnosis

C. difficile infection is diagnosed from an unformed stool sample generally with one of the following tests:

• enzyme immunoassay (EIA) for toxins or glutamate dehydrogenase (a protein present in all C. difficile isolates)

• nucleic acid amplification test (NAAT) for specific toxigenic strains

EIA testing is relatively fast and specific because it detects toxin production. The NAAT has higher sensitivity but also detects clinically insignificant colonization. The negative predictive value of both negative NAAT and EIA is estimated to be >95%.

Algorithms for diagnosis of CDI are primarily institution dependent. Because many asymptomatic patients may be colonized, diagnostic tests should only be ordered for patients presenting with diarrhea. For similar reasons, repeat testing to confirm eradication is not recommended.

Diagnosis can also be made via colonoscopy and visualization of pseudomembranous colitis, although the sensitivity of this method is much lower than the other diagnostic tests and the disease must be more advanced clinically.

Proposed CDI Testing Algorithm

Abbreviations: CDI, Clostridioides difficile infection; EIA, enzyme immunoassay; GDH, glutamate dehydrogenase; NAAT, nucleic acid amplification testing.
(Source: ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficileInfections. Am J Gastroenterol 2021.)

C. difficile infection is classified by severity as follows:

• nonsevere

• severe

• fulminant

C. difficile infection can also be classified by the setting associated with acquisition of the infection:

• health-care-facility–onset

• community-onset

• health-care-facility–associated

• community-associated

Although CDI is often thought of as an inpatient disease, community-acquired and outpatient antibiotic-associated infection have recently been found to make up a substantial portion of CDI cases.

Treatment

(Source: 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.)

Prompt treatment is important for controlling CDI. Inciting antibiotics should be discontinued promptly, and antibiotics should be avoided after an episode to minimize the risk of recurrent disease. Duration and type of treatment are determined by severity of infection (see table above).

Antibiotic treatment: Fidaxomicin is the preferred mainstay of initial CDI treatment. Vancomycin remains an acceptable alternative if implementation of fidaxomicin is not possible due to cost or other barriers. Fidaxomicin is also the preferred treatment for recurrences; however, vancomycin may be used for the first recurrence, whereas vancomycin and rifampin, fecal transplants are additional options for recurrent CDI.

After first infection, the risk of recurrence is 20%; after multiple infections, the risk increases to 60%. For patients with severe colitis or complicated infection, treatment options are limited.

Emergency colectomy in patients with severe CDI is associated with high mortality.

Fecal microbiome infusion for CDI was first performed in 1958. In recent years, it has become more common for treatment of CDI associated with multiple recurrences. However, the exact details of how fecal infusion improves CDI is still being determined. In 2013, one study showed that in patients with recurrent CDI, cure rates were higher with vancomycin plus nasoduodenal-tube infusion of healthy donor feces when compared with vancomycin alone.

(Source: Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. N Engl J Med 2013.)** 

Prevention

The hospital environment can be colonized with C. difficile spores that are resistant to alcohol-based sanitizer. To prevent transmission, hands need to be washed with soap and water and providers caring for patients with active CDI should wear disposable gown and gloves. Patients with active infection should be isolated until 48 hours after diarrhea resolves (the quality of evidence for this recommendation is weak). In addition, antibiotic stewardship to reduce antibiotic use is a cornerstone of CDI prevention. Using probiotics as a preventative measure against CDI remains an ongoing area of research. Use of antiperistaltic agents should be avoided to prevent progression to more-severe disease.

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