Clostridium difficile

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Severe or persistent diarrhea in patients with risk factors – predominantly previous antibiotic use
  • Hospitalized patients with >72 hours diarrhea – or sooner with clinical indications present

Laboratory Testing

  • CDC testing recommendations
  • Initial testing
    • CBC – often demonstrates leukocytosis; if leukocytosis not present, consider testing 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 on unformed stool – multiple repeats in 24-hour period and test of cure are not recommended; cannot be used to monitor therapy
    • Test stools only from symptomatic patients (diarrhea) (American College of Gastroenterology [ACG], 2013)
      • Laboratory testing cannot distinguish between colonization and infection
    • Toxin B gene by PCR
      • High sensitivity and specificity
      • Rapid platforms available
      • Recommended initial test by ACG (2013)
    • Glutamate dehydrogenase enzyme immunoassay (EIA) – initial rapid test but sensitivity depends on strain
      • Does not identify toxin production (only presence of clostridium), and therefore, must be followed by toxin testing (so-called two-step test)
        • Most sensitive confirmatory test is PCR for toxin
    • Cytotoxin cell test – sensitive and specific; may require >48 hours for results
      • Performance based on transport time, pretreatment of patient
      • Variable sensitivity and extended turnaround time have reduced use of this test
    • Stool culture for C. difficile with cytotoxin cell assay
      • Reference method
    • Test of cure – do not perform
  • Endoscopy
    • Classic exam demonstrates pseudomembranous colitis
    • Test is invasive
    • Sensitivity is low – 50% for disease
  • Strain typing can be done for epidemiologic purposes using a variety of methods (eg, PCR ribotyping, pulsed field gel electrophoresis)
    • No proven clinical utility
    • Not routinely performed by clinical laboratories

Differential Diagnosis

Clostridium difficile-Associated Disease (CDAD) Testing Algorithm

Clostridium difficile causes 15-25% of all antibiotic-associated diarrhea (AAD) and >90% of antibiotic-associated pseudomembranous colitis (PMC).

Epidemiology

  • Incidence – 336,000 C. difficile-related hospital stays documented in 2009, representing nearly 1% of all U.S. hospital stays (AHRQ, 2012)

Organism

  • Gram-positive, spore-forming, anaerobic rod
  • Produces toxins – A, B, and binary
    • Toxin production is necessary to produce disease
    • A and B activate cytokines
    • Binary toxin (eg, ribotype 027 [B1/NAP1], ribotype 078 [ST-11])
      • Produced by hypervirulent strain
      • Tends to induce drug resistance
  • Cultured in the stools of up to 50% 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
  • Extraintestinal – blood, abdominopelvic wound, lung (Gupta 2014)

Clinical Presentation

  • Asymptomatic carrier state
  • Mild – non-bloody diarrhea (bacterial, parasitic, viral), abdominal cramping, >3 stools/day, afebrile
  • Severe – abdominal pain, severe diarrhea
  • Complicated – toxic megacolon, paralytic ileus, fever, anorexia, nausea, malaise, peritonitis, respiratory distress
  • Recurrent disease (15-25% of patients) – typically occurs within 4 weeks of completion of therapy

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

Clostridium difficile toxin B gene (tcdB) by PCR 2002838
Method: Qualitative Polymerase Chain Reaction

Clostridium difficile Cytotoxin Cell Assay 0060851
Method: Cell Culture/Neutralization

Limitations

May take up to 48 hours to get results

Clostridium difficile Culture with Reflex to Cytotoxin Cell Assay 0060140
Method: Culture/Identification

Limitations

Culture alone does not distinguish toxin-producing strains

Requires up to 72 hours for report

Additional Tests Available

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Comments

Aid in determining cause of diarrhea; leukocytosis suggests bacterial etiology

Stool Culture and E. coli Shiga-like Toxin by EIA 0060134
Method: Culture/Identification

Comments

Preferred test for suspected bacterial diarrhea evaluation

Routine stool culture includes culture for Salmonella, Shigella, Campylobacter, and E. coli 0157 as well as EIA for Shiga-like toxin from E. coli

For C. difficile testing, refer to Clostridium difficile toxin B gene (tcdB) by PCR

Clostridium difficile Cytotoxin Antibody by Neutralization 2002552
Method: Antibody Neutralization

Comments

Do not order for diagnosis of C. difficile-associated diarrhea; for research interest/epidemiological purposes only

Guidelines

Cohen S, Gerding D, Johnson S, Kelly C, Loo V, McDonald C, Pepin J, Wilcox M, Society for Healthcare Epidemiology of America, Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31(5): 431-55. PubMed

Crobach M, Dekkers O, Wilcox M, Kuijper E. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficile-infection (CDI). Clin Microbiol Infect. 2009; 15(12): 1053-66. PubMed

Surawicz C, Brandt L, Binion D, Ananthakrishnan A, Curry S, Gilligan P, McFarland L, Mellow M, Zuckerbraun B. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013; 108(4): 478-98; quiz 499. PubMed

General References

Bagdasarian N, Rao K, Malani P. Diagnosis and treatment of Clostridium difficile in adults: a systematic review. JAMA. 2015; 313(4): 398-408. PubMed

Bartlett J, Gerding D. Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis. 2008; 46 Suppl 1: S12-8. PubMed

Burnham C, Carroll K. Diagnosis of Clostridium difficile infection: an ongoing conundrum for clinicians and for clinical laboratories. Clin Microbiol Rev. 2013; 26(3): 604-30. PubMed

Eckert C, Jones G, Barbut F. Diagnosis of Clostridium difficile infection: the molecular approach. Future Microbiol. 2013; 8(12): 1587-98. PubMed

Gupta A, Patel R, Baddour L, Pardi D, Khanna S. Extraintestinal Clostridium difficile infections: a single-center experience. Mayo Clin Proc. 2014; 89(11): 1525-36. PubMed

Hessen M. In the clinic. Clostridium difficile Infection. Ann Intern Med. 2010; 153(7): ITC41-15; quiz ITC416. PubMed

Larson A, Fung A, Fang F. Evaluation of tcdB real-time PCR in a three-step diagnostic algorithm for detection of toxigenic Clostridium difficile. J Clin Microbiol. 2010; 48(1): 124-30. PubMed

Leffler D, Lamont T. Clostridium difficile infection. N Engl J Med. 2015; 372(16): 1539-48. PubMed

Novak-Weekley S, Marlowe E, Miller J, Cumpio J, Nomura J, Vance P, Weissfeld A. Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J Clin Microbiol. 2010; 48(3): 889-93. PubMed

O'Horo J, Jones A, Sternke M, Harper C, Safdar N. Molecular techniques for diagnosis of Clostridium difficile infection: systematic review and meta-analysis. Mayo Clin Proc. 2012; 87(7): 643-51. PubMed

Pawlowski S, Warren C, Guerrant R. Diagnosis and treatment of acute or persistent diarrhea. Gastroenterology. 2009; 136(6): 1874-86. PubMed

Planche T, Aghaizu A, Holliman R, Riley P, Poloniecki J, Breathnach A, Krishna S. Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review. Lancet Infect Dis. 2008; 8(12): 777-84. PubMed

Winslow B, Onysko M, Thompson K, Caldwell K, Ehlers G. Common questions about Clostridium difficile infection. Am Fam Physician. 2014; 89(6): 437-42. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Couturier B, Schlaberg R, Konzak C, Nicholes J, Law C, She R. tcdA As a diagnostic target in a loop-mediated amplification assay for detecting toxigenic Clostridium difficile. J Clin Lab Anal. 2013; 27(3): 171-6. PubMed

Schlaberg R, Mitchell M, Taggart E, She R, Microbiology Resource Committee of the College of American Pathologists. Verification of performance specifications for a US Food and Drug Administration-approved molecular microbiology test: Clostridium difficile cytotoxin B using the Becton, Dickinson and Company GeneOhm Cdiff assay. Arch Pathol Lab Med. 2012; 136(1): 20-5. PubMed

She R, Durrant R, Petti C. Evaluation of enzyme immunoassays to detect Clostridium difficile toxin from anaerobic stool culture. Am J Clin Pathol. 2009; 131(1): 81-4. PubMed

Medical Reviewers

Last Update: January 2016