Clostridioides difficile Infection

Clostridioides 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.

(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)

• hospitalization

• 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.

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 difficile Infections. 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 treatment for CDI. Oral 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, in a tapered and pulsed regimen; however, vancomycin in a tapered and pulsed regimen, bezlotoxumab (antitoxin therapy; see below), and fecal transplantation 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, high-dose oral vancomycin with intravenous metronidazole and surgical consultation is advised.

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

Bezlotoxumab is a monoclonal antibody given as a one-time infusion that binds the C. difficile toxin and has been shown to decrease the recurrence risk for CDI. However, it is not used as a primary treatment for CDI.

Fecal microbiota transplantation (FMT) 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, a 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.

• In 2022, the FDA approved the first commercially available FMT therapy (fecal microbiota, live-jslm; Rebyota) for the prevention of recurrence of CDI in adults. Rebyota is manufactured from healthy donor stool and administered rectally.

• In 2023, the FDA approved SER-109 (Vowst) as the first oral microbiome therapy for the prevention of recurrence of CDI following antibiotic treatment. These oral capsules with purified Firmicutes spores have been shown to reduce the recurrence rate following a standard antibiotic treatment course for CDI.

• Neither Rebyota nor Vowst are included in current CDI guidelines, and recommended use cases are uncertain.

(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 and avoiding gastric acid suppression (e.g., proton pump inhibitors) are 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. The role for low-dose oral vancomycin as secondary prevention when a patient with recent CDI is started on broad-spectrum antibiotics remains controversial.