Clostridioides difficile infection

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

• 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, antibiotics, and acid)
• Germination of spores turns them into functional bacilli
• Highly contagious
• Present ubiquitously
• Oral route of transmission
  • Community-acquired CDI: fecal-oral route
  • Hospital-acquired CDI: via contaminated surfaces and medical equipment

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]

• Recent antibiotic treatment ; ^[7][8]
  • High-risk antibiotics (odds ratio ≥ 5)
    • Clindamycin
    • Cephalosporins
    • Fluoroquinolones
  • Moderate risk antibiotics (odds ratio 1 to 5)
    • Penicillin
    • Macrolides
• Advanced age
• Gastric acid suppression (e.g., with proton pump inhibitors) or bypass (e.g., enteral feeding)
• Recent hospitalization
• Severe illnesses
• Immune suppression
• Inflammatory bowel disease ^[9]

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

Toxin A (enterotoxin)

• Structure
  • 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)

• 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.

• Watery diarrhea (C. difficile-associated diarrhea or CDAD)
  • ≥ 3 stools per day associated with a characteristic odor
  • May contain traces of mucus or occult blood
  • Hematochezia and melena are both rare.
• Cramping abdominal pain, nausea, anorexia
• Abdominal tenderness
• Fever and dehydration (especially in severe cases)
• Fulminant CDI may manifest with abdominal distention and severe hypovolemia (e.g., due to toxic megacolon, paralytic ileus)

Clostridioides difficile Causes Difficult Diarrhea.

References:^[12]

Approach ^[1][2]

• The diagnosis of CDI is based on the presence of typical clinical features (especially in patients with risk factors for CDI) and either of the following:
  • C. difficile toxins or toxigenic strains of C.difficile detected on stool tests for CDI
  • Pseudomembranous colitis confirmed on endoscopy or histopathology
• Initiate measures to prevent and control the spread of infection (see “Secondary prevention of CDI”).
• Patients with diarrhea
  • Consider other etiologies for diarrhea : See “Diagnostic workup of diarrhea.”
  • Suspect CDI in patients with unexplained new-onset diarrhea, especially those with risk factors for CDI.
  • Initial tests: stool analysis for toxins and toxigenic strains of C. difficile
• 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 antibiotic therapy for CDI.
• Assess the severity of CDI and initiate antibiotic therapy empirically in patients with fulminant CDI.
• Consult gastroenterology and/or infectious diseases if the diagnosis is unclear.

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 and may include the following. ^[13]

• CBC: : leukocytosis ^[1][2]
• BMP
  • ↑ Serum creatinine
  • Electrolyte imbalance, particularly hypokalemia
  • ↓ Serum albumin
• Blood gases (venous or arterial): ↑ lactate, acidosis

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

Indications

• 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.

Modalities

• Tests with high sensitivity
  • Enzyme immunoassay (EIA) for C. difficile glutamate dehydrogenase antigen (GDH)
  • NAAT (e.g., PCR) for C. difficile toxins
• 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 ^[1][2]

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

• 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
  • Positive EIA for C. difficile toxins: Diagnosis is confirmed.
  • Negative EIA for C. difficile toxins
    • High PTP for CDI
      • Consider NAAT if not already performed as the initial test.
      • Consider empirical antibiotic therapy for CDI.
    • Low or moderate PTP for CDI: Consider alternative diagnoses.

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

Additional diagnostics

Imaging ^[1][13]

• Indications (not routinely required to diagnose CDI)
  • Suspected complications of CDI (e.g., bowel perforation, toxic megacolon, ileus)
  • To assess for severity of CDI
  • Initial workup of undifferentiated abdominal pain or distension
• Modalities: x-ray abdomen or CT abdomen (with IV and PO contrast)
• Findings ^[14][15]
  • Signs of pseudomembranous colitis, which includes pronounced colonic wall thickening (most common sign) associated with any of the following:
    • Accordion sign (on contrast-enhanced CT): alternating areas of low attenuation (due to edematous haustra) and high attenuation (due to contrast material trapped between the thickened haustral folds)
    • Colonic wall nodularity
    • Pericolonic stranding
    • Ascites
  • Signs of complications, such as:
    • Bowel perforation: free intraperitoneal air
    • Toxic megacolon: dilated colon (transverse colon diameter > 6 cm) with loss of haustration
    • Paralytic ileus: dilated small and large bowel with no evidence of mechanical obstruction

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.

• 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

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]

• Antibiotic treatment is indicated in all symptomatic patients with CDI and should be guided by the severity of CDI.
• 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.
• Consultations
  • Gastroenterology and/or infectious diseases in patients with insufficient treatment response or recurrent CDI.
  • Surgery for critically ill patients or those with complications necessitating surgery
  • Consider intensive care unit consult for patients with fulminant CDI. ^[13]

Supportive measures ^[1][2]

• Discontinue any precipitating antibiotic as soon as possible.
• Correct fluid and electrolyte imbalances (see “Initial fluids for dehydration and hypovolemia” and “Electrolyte repletion”).
• Avoid antidiarrheals (e.g., loperamide) in patients not yet receiving antibiotics and those with fulminant CDI.

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.

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
  • Severe CDI or fulminant CDI with insufficient clinical improvement after 48–72 hours of maximum medical therapy. ^[2][16]
  • Adult and pediatric patients with ≥ 2 recurrences despite appropriate antibiotic therapy for CDI ^[1][2]

Surgical management ^[1][2]

• Indications: critically ill patients with severe CDI or fulminant CDI refractory to antibiotic therapy, especially if ≥ 1 of the following are present
  • Factors associated with increased mortality, e.g., severe leukocytosis or serum lactate
  • Complications, e.g., toxic megacolon, ischemia, or bowel perforation
• Procedures
  • Total colectomy with end ileostomy and stapled rectal stump
  • Diverting loop ileostomy with colonic lavage followed by intraluminal vancomycin administration

• Toxic megacolon
• Paralytic ileus
• Peritonitis, perforation, abscess formation, sepsis

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
  • Consistent disinfection of potentially contaminated surfaces with sporicidal oxidants (e.g., peracetic acid, sodium hypochlorite)
  • During outbreaks, daily and terminal disinfection with sporicidal agents may be beneficial.
• 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.

Clostridioides difficile in infants ^[17][18]

Most infants with C. difficile colonization; are asymptomatic and do not develop pseudomembranous colitis.

• Risk factors for symptomatic disease: prematurity and anatomical abnormalities (e.g., Hirschsprung disease, intestinal malrotation, colonic strictures)
• Treatment: oral vancomycin or metronidazole

• Initiate isolation precautions (see “Secondary prevention of CDI”).
• Discontinue any precipitating antibiotic as soon as possible.
• Check CBC, BMP, and assess the severity of CDI.
• Correct fluid and electrolyte imbalances: See “Initial fluids for dehydration and hypovolemia” and “Electrolyte repletion.”
• Check stool tests for CDI in patients with diarrhea; consider rectal swab PCR for those with paralytic ileus.
• Consider imaging to assess for complications (e.g., ileus, toxic megacolon, bowel perforation).
• Administer antibiotic therapy for CDI; consider empiric antibiotics for suspected fulminant CDI.
• 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