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 ( ) 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 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 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 (NAAT or EIA) after a confirmed episode in the previous 8 weeks
- Incidence: ∼ 220,000 cases in hospitalized patients and ∼ 13,000 deaths per year in the US 
- Hospital-acquired CDI: more common in individuals aged > 65 years 
- Community-acquired CDI: affected individuals are typically younger (∼ 50 years) 
Epidemiological data refers to the US, unless otherwise specified.
Causative pathogen: Clostridioides difficile
- Gram-positive bacillus, obligate anaerobe
- Can be toxigenic or non-toxigenic; toxigenic strains cause C. difficile infection (CDI)
- Forms environmentally-resistant spores (capable of withstanding heat and acid)
- Highly contagious
- Present ubiquitously
Oral route of transmission
- fecal-oral route :
- : via contaminated surfaces and medical equipment
Risk factors for CDI 
- Recent antibiotic treatment 
- Advanced age
- Gastric acid suppression (e.g., with proton pump inhibitors) or bypass (e.g., enteral feeding)
- Severe illnesses
- Recent hospitalization
- Immune suppression
- Inflammatory bowel disease 
Toxin A (enterotoxin)
- Active site at N-terminal domain
- Central hydrophobic domain
- Binding site at C-terminal domain
- Mechanism of action: binding to brush border of enterocytes: → receptor-mediated endocytosis → change of conformation → exposure of active domain → glycosylation of target proteins (e.g., Rac, Cdc42, RhoA) → disruption of actin cytoskeleton functioning → increase in epithelial permeability and apoptosis → diarrhea
Toxin B (cytotoxin)
- 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.
- Watery diarrhea (C. difficile-associated diarrhea or CDAD)
- Cramping abdominal pain, nausea, anorexia
- Fever and dehydration (especially in severe cases)
- hypovolemia (e.g., due to toxic megacolon, paralytic ileus) may manifest with abdominal distention and severe
Clostridioides difficile Causes Difficult Diarrhea.
- The diagnosis of CDI is based on the presence of typical clinical features (especially in patients with ) and either of the following:
- Initiate measures to prevent and control the spread of infection (see “ ”).
- Patients with diarrhea
- Patients with ileus due to suspected CDI: Consider PCR of rectal swabs.
- Imaging is useful to evaluate undifferentiated abdominal pain or if there is a concern for complications.
- Consider endoscopy if the diagnosis remains uncertain after initial tests or if there is insufficient response to empiric .
- Assess the antibiotic therapy empirically in patients with . and initiate
- Consult gastroenterology and/or infectious diseases if the diagnosis is unclear.
Routine laboratory studies 
Findings are nonspecific. 
- CBC: leukocytosis 
- Blood gases (venous or arterial): ↑ lactate, acidosis
Stool tests for toxins and toxigenic strains of C. difficile 
- 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 .
- Tests with high sensitivity
- Tests with high specificity: EIA for C. difficile toxins A and B
Other available tests
- Cytotoxicity neutralization assay (CCNA): detects toxin in stool
- Culture of toxigenic strains of C. difficile
Suggested testing strategy 
- The initial test should preferably be a high sensitivity test (i.e., NAAT or EIA for GDH).
- Negative NAAT or EIA for GDH: CDI is ruled out.
- Positive NAAT or EIA for GDH: Confirm CDI using a highly specific test, such as EIA for C. difficile toxins
Repeat testing within 7 days of diarrhea is not recommended, and asymptomatic individuals should not be tested. 
- Indications (not routinely required to diagnose CDI)
- Modalities: x-ray abdomen or CT abdomen (with IV and PO contrast)
- Signs of pseudomembranous colitis, which includes pronounced colonic wall thickening (most common sign) associated with any of the following:
- Signs of complications, such as:
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 .
- Modalities: colonoscopy or sigmoidoscopy
Endoscopy may not detect cases of nonsevere CDI, in which pseudomembranes may be absent. 
- Nonsevere CDI: leukocytosis < 15,000 cells/mm3 and serum creatinine < 1.5 mg/dL
- Severe CDI: leukocytosis ≥ 15,000 cells/mm3 or serum creatinine ≥ 1.5 mg/dL
- Fulminant CDI: ≥ 1 criteria of severe CDI plus hypotension, shock, ileus, and/or toxic megacolon
General principles 
- Antibiotic treatment is indicated in all symptomatic patients with CDI and should be guided by the .
- Asymptomatic carriers do not require antibiotic therapy.
- Fecal microbiota transplantation may be indicated in recurrent CDI, severe CDI, or fulminant CDI refractory to antibiotic therapy.
- Surgical intervention may be necessary for critically ill patients or those with complications necessitating surgery.
- Gastroenterology and/or infectious diseases in patients with insufficient treatment response or .
- Pediatrics for and/or infectious diseases for preferred antibiotic therapy in children.
- Surgery for critically ill patients or those with complications necessitating surgery
- Consider intensive care unit consult for patients with fulminant CDI. 
Supportive measures 
- Discontinue any precipitating antibiotic as soon as possible.
- Correct fluid and electrolyte imbalances (see “ ” and “ ”).
- Avoid antidiarrheals (e.g., loperamide) in patients not yet receiving antibiotics and those with fulminant CDI.
Antibiotic therapy for CDI 
|Antibiotic therapy for C. difficile infection in adults |
|Initial episode||Nonsevere CDI or severe CDI|
|Recurrent CDI||First recurrence|
Fecal microbiota transplantation (FMT) 
- Healthy donor stool that is administered via capsules, colonoscopy, or enema
- Can be considered in the following situations
- 48–72 hours of maximum medical therapy.  or with insufficient clinical improvement after
- Adult and pediatric patients with ≥ 2 recurrences despite appropriate antibiotic therapy for CDI 
Surgical management 
- Indications: critically ill patients with or refractory to antibiotic therapy, especially if ≥ 1 of the following are present
We list the most important complications. The selection is not exhaustive.
Primary prevention of CDI
- Judicious use of antibiotics and an 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 
48 hours after symptoms subside or until CDI is ruled out. should be followed for all patients with suspected or diagnosed CDI for at least
- 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
- Surface disinfection
- Medical equipment
- Suspect CDI in patients with unexplained new-onset diarrhea or those with other typical features and .
- Initiate measures to prevent and control the spread of infection: See “ .”
- Discontinue any precipitating antibiotic as soon as possible.
- Order urgent laboratory studies to assess the .
- Correct fluid and electrolyte imbalances: See “ ” and “ .”
- Obtain diarrhea; consider rectal swab PCR for those with paralytic ileus. in patients with
- Consider imaging to assess for complications (e.g., ileus, toxic megacolon, bowel perforation).
- Administer empiric antibiotics for suspected . ; consider
- Consider urgent gastroenterology or infectious diseases consult for severe CDI or fulminant CDI.
- Urgent surgery and ICU consult for suspected complications or critically ill patients