Clostridium difficile

Diagnostic Algorithm

  Clostridium difficile-Associated Disease (CDAD) Testing Algorithm

Clinical Background

Clostridium difficile is the major cause of antibiotic-associated diarrhea (AAD) and pseudomembranous colitis (PMC).

Epidemiology

• Incidence – 112/100,000 in U.S. for adult Clostridium difficile-associated disease (CDAD) hospitalizations (CDC, 2005)
• C. difficile causes 15-25% of all AAD and more than 90% of documented cases of antibiotic-associated PMC

Organism

• Gram-positive, spore-forming rod
• Obligate anaerobe
• Produces toxins – A, B and binary
  • Toxin production is necessary to produce disease
  • A and B activate cytokines
  • Binary toxin is less well understood – produced by NAP1 strain (NAP1/B1/027)
    • This strain also produces A and B toxins in much higher quantities than other strains
    • May be a hyper-virulent strain
    • Testing of patient specimens to identify this strain has no proven clinical utility and is mainly for epidemiologic purposes
• Cultured from the stool of up to half of healthy neonates (<1 year), 3% of healthy adults and 35% of hospitalized patients

Risk Factors

• Antimicrobial administration within previous 60 days – >90% of cases have this risk factor
• Age >65 years
• Previous history of C. difficile disease
• Prior or current hospitalization
• Residence in long-term care center
• Severe underlying illness

Clinical Presentation

• Asymptomatic carrier state
• Mild – non-bloody diarrhea, abdominal cramping, >3 stools/day
• Severe – abdominal pain, severe diarrhea, fulminant disease (toxic megacolon and paralytic ileus) with fever, anorexia, nausea and malaise
• Recurrent disease (15-25% of patients)
  • Typically occurs within 4 weeks of completion of therapy

Treatment

• Often difficult to eradicate
• In symptomatic patients, treatment is usually necessary

Diagnosis

Indications for testing

• Severe or persistent diarrhea in patients with risk factors (predominantly previous antibiotic use); may occur up to several months after antibiotic use

Laboratory testing

• Initial testing
  • CBC – often demonstrates leukocytosis; if leukocytosis not present, may want to rule out other organisms as the cause of diarrhea
  • Culture stool for Campylobacter, Salmonella, Shigella, E. coli (Shiga toxin producing strains)
• Testing for presence of toxins A and B (multiple repeats in 24-hour period are not recommended); should not be used to monitor therapy.
  • Cytotoxin cell assay – may require 48 hours for results
  • Enzyme immunoassay (EIA) – rapid but less sensitive than cytotoxin cell assay (sensitivity ~80% for stool specimen)
  • PCR of stool for presence of cytotoxin genes
    • Emerging gold standard with high sensitivity and specificity
    • Rapid platforms available
  •  Stool culture for C. difficile
    • Requires up to 72 hours
    • Does not distinguish toxin-producing strains; toxin testing of isolates delays final results
    • Individuals without disease may have positive culture; perform only in symptomatic patients
    • Useful for epidemiological purposes
• Endoscopy – classic exam effectively demonstrates pseudomembranous colitis but sensitivity is low (50%) for CDAD
• Strain typing can be done for epidemiologic purposes using a variety of methods (PCR ribotyping, pulsed field gel electrophoresis, etc), but it has no proven clinical utility and is not routinely performed by clinical laboratories

Differential Diagnosis

• Other bacterial diarrhea
• Diarrhea, viral evaluation
• Diarrhea, parasitic evaluation
• Inflammatory bowel disease

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory