Clostridium difficile

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
Test Name and Number Recommended Use Limitations Follow Up
Clostridium difficile toxin B gene (tcdB) by PCR 2002838
Method: Polymerase Chain Reaction

Use for rapid and clinically relevant diagnosis; test is highly sensitive

   
Clostridium difficile Cytotoxin Cell Assay 0060851
Method: Cell Culture Assay/Confirmation by Anti-Toxin Neutralization

Use for clinically relevant diagnosis; test is the most specific and is highly sensitive

May take up to 48 hours to get results

 
Clostridium difficile Toxins (A & B) by EIA 0065146
Method: Enzyme Immunoassay

Use for rapid and clinically relevant diagnosis; test is less sensitive (70-90%) than culture or cell assay

False-negative results are common

 
Clostridium difficile Culture with reflex to Cytotoxin Cell Assay 0060140
Method: Standard reference procedures for anaerobic bacterial culture and identification

Use for epidemiological purposes, such as strain typing during suspected outbreak

Culture alone does not distinguish toxin-producing strains

Requires up to 72 hours for report

 
Clostridium difficile Cytotoxin Antibody 2002552
Method: Neutralization

Research use only; not for initial diagnosis of C. difficile-associated diarrhea