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Clostridioides difficile infection

Last updated: August 11, 2021

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Clostridioides difficile (C. difficile; formerly known as Clostridium difficile) is a gram-positive bacillus that can cause antibiotic-associated diarrhea. Rates of C. difficile infection (CDI) are particularly high among hospitalized patients and residents in long-term care facilities because C. difficile spores are easily transmitted (fecal-oral route) and difficult to eradicate. The bacterium is resistant to multiple antibiotics, and colonization with C. difficile most commonly occurs following antibiotic treatment for other diseases. The resulting damage to the intestinal flora promotes C. difficile infection, which typically manifests with diarrhea accompanied by fever and abdominal pain. Severe CDI or fulminant CDI may manifest with paralytic ileus or toxic megacolon. In most cases, however, colonization results in asymptomatic carriage. Diagnosis of symptomatic patients is based on stool tests for CDI, which detect toxins or toxigenic strains of C. difficile or the identification of pseudomembranous colitis on imaging or endoscopy. Vancomycin and fidaxomicin are the preferred antibiotic agents for treating CDI. Once the diagnosis is confirmed, measures to prevent transmission (e.g., patient cohorting or isolation, strict adherence to hygiene measures) should be followed, especially in hospitals and other health care settings.

  • Hospital-acquired CDI: confirmed CDI in an individual with documented inpatient care in a health care facility in the preceding 12 weeks
  • Community-acquired CDI: confirmed CDI in an individual with no documented inpatient care in a health care facility in the preceding 12 weeks
  • Recurrent CDI: recurrence of symptoms and a positive stool test for CDI (NAAT or EIA) after a confirmed episode in the previous 8 weeks

References: [1][2][3]

  • Incidence: ∼ 220,000 cases in hospitalized patients and ∼ 13,000 deaths per year in the US [4]
  • Hospital-acquired CDI: more common in individuals aged > 65 years [5]
  • Community-acquired CDI: affected individuals are typically younger (∼ 50 years) [6]

Epidemiological data refers to the US, unless otherwise specified.

Causative pathogen: Clostridioides difficile

The C. difficile strain must be toxigenic to cause the disease. Intestinal colonization by nontoxigenic strains will result in asymptomatic carriage.

Risk factors for CDI [1][6]

C. difficile possesses a range of virulence factors, the most important of which are toxins A and B. [10][11]

Toxin A (enterotoxin)

Toxin B (cytotoxin)

  • Structure
    • Binding site at C-terminal domain
    • Translocation domain
    • Cysteine protease-containing domain
    • Catalytic domain
  • Mechanism of action: same as in toxin A, but can also cause pore formation within the endosomal membrane via insertion of the translocation domain → release of endosomal content into the cytosol cytopathic effect

Symptoms typically develop during antibiotic treatment or 2–10 days following its initiation; however, 25–40% of cases manifest as late as 10 weeks following treatment.

Clostridioides difficile Causes Difficult Diarrhea.


Approach [1][2]

Patient history and clinical presentation can provide strong indicators for infection, which should be confirmed by stool studies, colonoscopy, or histopathology findings. [1]

Routine laboratory studies [1][2][13]

Findings are nonspecific. [13]

Stool tests for toxins and toxigenic strains of C. difficile [1][2]


  • Adults: unexplained, new-onset loose stools ≥ 3 times in 24 hours
  • Children : Consider stool tests in children with prolonged or worsening diarrhea, especially those with risk factors for CDI.


Suggested testing strategy [1][2]

Consider a multi-test algorithmic approach guided by the pretest probability (PTP) of CDI.

Repeat testing within 7 days of diarrhea is not recommended, and asymptomatic individuals should not be tested. [1][2]

Additional diagnostics

Imaging [1][13]

Endoscopy [1][13]

  • Indication (not routinely required)
    • Consider if the diagnosis remains unclear after initial tests.
    • Consider if the PTP of CDI remains high in patients with insufficient response to empirical antibiotic therapy for CDI.
  • Modalities: colonoscopy or sigmoidoscopy
  • Findings
    • Mucosa may appear normal or erythematous and friable.
    • Possible signs of pseudomembranous colitis
      • Elevated yellow-white plaques that form pseudomembranes over the colonic mucosa
      • May be solitary; widespread; , confluent lesions are seen in severe disease

Endoscopy may not detect cases of nonsevere CDI, in which pseudomembranes may be absent. [13]

The severity of CDI is based on laboratory studies and clinical features and is used to guide disposition, management, and prognosis.

If clinical suspicion is high, initiating antibiotic treatment before laboratory confirmation may be considered, especially in patients with fulminant CDI. [1][2]

Patients with severe or fulminant disease have a higher rate of treatment failure, colectomy, and mortality. [2]

References: [1][2]

General principles [1][2]

Supportive measures [1][2]

Antibiotic therapy for CDI [1][2][3]

C. difficile infection is one of the rare indications for PO vancomycin in adults and children.

Intravenous administration of vancomycin is ineffective for C. difficile infection because vancomycin is insufficiently excreted into the colon.

Antibiotic therapy for C. difficile infection in adults [1][2][3]
Category Treatment options
Initial episode Nonsevere CDI or severe CDI
Fulminant CDI
Recurrent CDI First recurrence
Subsequent recurrences

Consider bezlotoxumab, a monoclonal antibody against the C. difficile toxin B, in adults at risk of recurrent CDI. [2][3]

Fecal microbiota transplantation (FMT) [1][16]

  • Healthy donor stool that is administered via capsules, colonoscopy, or enema
  • Can be considered in the following situations

Surgical management [1][2]

We list the most important complications. The selection is not exhaustive.

Primary prevention of CDI

  • Judicious use of antibiotics and an antibiotic stewardship program can reduce the risk of CDI.
  • There is insufficient evidence to recommend the discontinuation of PPIs or the use of probiotics to prevent CDI.

Secondary prevention of CDI [1]

Contact precautions should be followed for all patients with suspected or diagnosed CDI for at least 48 hours after symptoms subside or until CDI is ruled out. [1]

  • Isolation: A single room with designated bathroom facilities is preferable; consider patient cohorting if this is not feasible.
  • Personal protective equipment: Wear gloves and a protective gown (change after each patient); a mask is not necessary.
  • Hand hygiene
    • Wash hands thoroughly with soap and water; before and after every patient contact (C. difficile spores are resistant to alcoholic disinfectants).
    • Encourage frequent handwashing in patients with CDI.
  • Surface disinfection
  • Medical equipment
    • Use disposable or dedicated equipment if possible.
    • Otherwise, ensure adequate cleaning and disinfection that is effective against spores.
    • Autoclaving is also sporicidal and can be used to sterilize equipment.
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