• Clinical science

Clostridioides difficile infection (Clostridium difficile infection)

Summary

Clostridioides difficile (C. difficile; formerly known as Clostridium difficile) is a gram-positive bacillus that may cause antibiotic-associated diarrhea. Rates of C. difficile infection 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, so colonization with C. difficile most commonly occurs following antibiotic treatment of other diseases. The resulting damage to the intestinal flora promotes infection, which may be accompanied by high fever, abdominal pain, and foul-smelling diarrhea. The most severe form of C. difficile infection is pseudomembranous colitis, which can lead to ileus, sepsis, and toxic megacolon. In most cases, however, colonization results in asymptomatic carriage. Diagnosis is usually made via detection of the C. difficile toxin, C. difficile glutamate dehydrogenase antigen, and/or corresponding genes in stool samples. C. difficile infection is treated with oral vancomycin or oral fidaxomicin. Following diagnosis, strict adherence to hygiene measures and patient isolation is essential, especially in hospitals and other healthcare settings.

Epidemiology

  • ∼ 220,000 cases in hospitalized patients and ∼ 13,000 deaths per year in the US [1]
  • Individuals > 65 years old are at increased risk for the hospital-acquired infection. [2]
  • Patients affected by community-acquired infections are typically younger (average age 50 years). [3]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

The C. difficile strain must be toxigenic to cause the disease. Intestinal colonization by nontoxigenic strains will result in asymptomatic carriage.

Pathophysiology

C. difficile possesses a range of virulence factors, the most important of which are toxins A and B. [9][10]

Toxin A (enterotoxin)

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

Clinical features

Symptoms of C. difficile-associated diarrhea (CDAD) usually 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, characteristically foul-smelling
    • Mild disease manifests with ≥ 3 stools per day; patients with fulminant colitis may have up to 20 stools per day.
    • May contain traces of mucus or occult blood
    • Hematochezia and melena are both rare.
  • Cramping abdominal pain, nausea, anorexia
  • Fever and dehydration (especially in severe cases)
  • Fulminant colitis: abdominal distention and severe hypovolemia
  • Recurrent disease: symptom reoccurrence 2–8 weeks following the end of treatment

Clostridioides difficile Causes Difficult Diarrhea.

References:[11][12]

Diagnostics

Patient history and clinical presentation are strong indicators for diagnosis of infection, which is then confirmed by identification of the pathogen's genes or corresponding toxins in the stool. Further diagnostics, such as blood tests or imaging, may be used to assess the severity of disease and/or the presence of complications.

History

  • Treatment with antibiotics in the last three months
  • Recent hospitalization

Stool tests [13]

Blood tests

Imaging

Contrast-enhanced abdominal CT scan/x-ray to detect the following:

Endoscopy [11]

  • Not indicated if C. difficile is suspected based on clinical findings, laboratory tests, and/or response to empiric treatment
  • Perform cautiously (increased risk of perforation).
  • Findings

Disease severity [16]

References:[17][11][14][12][15][13]

Treatment

General measures [12]

Medical therapy [13]

If clinical suspicion for CDAD is high, empiric antibiotic treatment may be initiated before laboratory confirmation of C. difficile. [12]

C. difficile infection is one of the rare indications for oral administration of vancomycin!

Medical therapy in children [13]

Fecal microbiota transplantation (FMT) [13]

  • Indication: recurrent C. difficile infections in a patient who has not responded to at least two appropriate antibiotic regimens
  • Implementation: Sterile normal saline solution is added to donor stool and the mixture is blended to a smooth, liquid consistency.
  • Administration
    • Enema
    • Colonoscopy
    • Nasogastric or jejunal tube

References:[12][4][14][15][13]

Complications

We list the most important complications. The selection is not exhaustive.

Prevention

  • Detection: C. difficile toxin stool test for at-risk patients with recent onset of diarrhea
  • Isolation
    • Single-bed room with designated bathroom facilities (up to 2 days after symptoms subside)
    • Cohort isolation is possible if control measures are implemented.
  • Control measures
    • Personal protective equipment: Wear gloves and a protective gown (change after each patient); a mask is not necessary.
    • Hand hygiene: Wash thoroughly with soap and water (C. difficile spores are resistant to alcoholic disinfectants).
    • Consistent disinfection of potentially contaminated surfaces with sporicidal oxidants such as peracetic acid or sodium hypochlorite; ; autoclaving is also sporicidal and can be used to sterilize equipment.
  • 1. CDC. Antibiotic Resistance Threats in the United States, 2019 - Clostridioides difficile. https://www.cdc.gov/drugresistance/biggest-threats.html#cdiff. Updated November 14, 2019. Accessed December 30, 2019.
  • 2. Jump RL. Clostridium difficile infection in older adults. Aging health. 2013; 9(4): pp. 403–414. doi: 10.2217/ahe.13.37.
  • 3. Khanna S, Gupta A. Community-acquired Clostridium difficile infection: an increasing public health threat. Infection and Drug Resistance. 2014: p. 63. doi: 10.2147/idr.s46780.
  • 4. Lamont JT. Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. http://www.uptodate.com/contents/clostridium-difficile-in-adults-epidemiology-microbiology-and-pathophysiology. Last updated December 16, 2016. Accessed January 10, 2017.
  • 5. Aberra FN. Clostridium Difficile Colitis. In: BS Anand. Clostridium Difficile Colitis. New York, NY: WebMD. http://emedicine.medscape.com/article/186458. Updated November 2, 2016. Accessed January 10, 2017.
  • 6. Hickson M. Probiotics in the prevention of antibiotic-associated diarrhoea and Clostridium difficile infection. Therap Adv Gastroenterol. 2011; 4(3): pp. 185–197. doi: 10.1177/1756283X11399115.
  • 7. Deshpande A, Pasupuleti V, Thota P, et al. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother. 2013; 68(9): pp. 1951–1961. doi: 10.1093/jac/dkt129.
  • 8. Issa M, Ananthakrishnan AN, Binion DG. Clostridium difficile and inflammatory bowel disease. Inflamm Bowel Dis. 2008; 14(10): pp. 1432–1442. doi: 10.1002/ibd.20500.
  • 9. Di Bella S, Ascenzi P, Siarakas S, Petrosillo N, di Masi A. Clostridium difficile Toxins A and B: Insights into Pathogenic Properties and Extraintestinal Effects. Toxins. 2016; 8(5): p. 134. doi: 10.3390/toxins8050134.
  • 10. Abt MC, McKenney PT, Pamer EG. Clostridium difficile colitis: pathogenesis and host defence. Nature Reviews Microbiology. 2016; 14(10): pp. 609–620. doi: 10.1038/nrmicro.2016.108.
  • 11. Lamont JT. Clostridium difficile infection in adults: Clinical manifestations and diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. http://www.uptodate.com/contents/clostridium-difficile-infection-in-adults-clinical-manifestations-and-diagnosis. Last updated October 26, 2016. Accessed January 10, 2017.
  • 12. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013; 108(4): pp. 478–498. doi: 10.1038/ajg.2013.4.
  • 13. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018; 66(7): pp. e1–e48. doi: 10.1093/cid/cix1085.
  • 14. Kelly CP, Lamont T, Bakken JS. Clostridioides (Formerly Clostridium) Difficile Infection in Adults: Treatment and Prevention. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/clostridioides-formerly-clostridium-difficile-infection-in-adults-treatment-and-prevention. Last updated September 27, 2016. Accessed January 10, 2017.
  • 15. Shen EP, Surawicz CM. Current Treatment Options for Severe Clostridium difficile-associated Disease. Gastroenterol Hepatol (N Y). 2008; 4(2): pp. 134–139. url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3088840/.
  • 16. Beck J, Nassal M. Hepatitis B virus replication. World J Gastroenterol. 2007; 13(1): pp. 48–64. pmid: 17206754.
  • 17. Schroeder MS. Clostridium difficile–Associated Diarrhea. American Family Physician. 2005; 71(5): pp. 921–928. url: http://www.aafp.org/afp/2005/0301/p921.html.
  • Herold G. Internal Medicine. Cologne, Germany: Herold G; 2014.
last updated 11/17/2020
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