Clostridium Difficile

For whatever reason, the college examiners love this microbe. However, they don't love it enough to write extensively about it in Oh's Manual. It has been made the main subject of several past paper questions:

In spite of such historical attention, the candidates have not been reading about it. The early 2014 appearance of this microbe in the SAQs prompted the examiners to comment that "Overall, candidates' knowledge of this topic was limited."

An excellent resource for rapid revision is this LITFL page dedicated to pseudomembranous colitis. If one were in need of published material and were to limit oneself to only one source, this 2013 guidelines statement from The American Journal of Gastroenterology would probably be it.

Microbiology of C.difficile

A good solid review of the microbiology can be found in this 1988 article.

  • C.difficile is a spore-forming gram-positive anaerobic rod
  • Most clones produce both Toxin A and Toxin B, but perhaps up to 25% produce neither.
    •  Toxin A: a 308-kDa enterotoxin
      • Cytotoxic for enterocytes
      • Chemoattractant for neutrophils
      • Causes actin disaggregation and intracellular calcium release
    • Toxin B : a 270-kDa enterotoxin
      • Causes depolymerization of filamentous actin
      • A necrotizing enterotoxin 10 times more potent than toxin A
  • Apart from the local effects on the bowel arising from inflammation, systemic features develop due to  toxin-induced release inflammatory mediators from the colon.

Risk factors for C.difficile infection

The risk factors for C.difficile infection are discussed here, in a NEJM article.

Another earlier (1998) article adds several other lesser-known risk factors:

  • Severe underlying illness (i.e. ICU patients in general)
  • Non-surgical gastrointestinal procedures
  • Presence of an NG tube

Features suggestive of C.difficile infection

  • Abdominal pain
  • Loose stools: mucoid, greenish, foul-smelling, watery, possibly with fragments of pseudomembranes and blood
    • It typically starts 3-9 days after the commencement of antibiotics
  • History of broad spectrum antibiotics, particularly Clindamycin
  • Characteristic "thumbprinting" of bowel on plan Xrays
  • Inflamed appearance of bowel on CT
  • Direct confirmation of pseudomembranes on colonoscopy
  • C.difficile toxin A or B on stool PCR
  • Toxic megacolon
  • Perforation and pneumoperitoneum
  • Fever > 38°
  • Renal failure

Diagnostic tests for C.difficile

As for diagnosis of C.difficile, the current recommendations are:

  • PCR is better than toxin A or B identification
  • You should only test loose stools
  • You should not re-test.

Is it really Clostridium?

Not all pseudomembranous colitis is due to C.difficile infection.

Alternative pathogens include:

  • Strongyloides stercoralis
  • Staphylococcus aureus
  • Clostridium perfringens
  • Yersinia
  • CMV
  • Entamoeba
  • Listeria
  • All the enterohaemorrhagic diarrhoea organisms:
    • Salmonella
    • Shigella
    • Campylobacter
    • E.coli

Markers of severity

Markers of "severe" enterocolitis, which means the sort that ends up either killing you or results in a colectomy, are deliniated in this retrospective study. They are as follows:

  • age >70 years
  • maximum leukocyte count >20,000 cells/mL
  • minimum albumin level <25 g/L
  • maximum creatinine level >200 mcg/L
  • small bowel obstruction or ileus
  • CT evidence of colorectal inflammation

To this list, another study adds more markers of severity:

  • Fever (>38.0°)
  • Abdominal distension

Complications of C.difficile infection

  • Inflammation-related:
  • Diarrhoea-related:
    • Electrolyte disturbance (low potassium, magnesium, etc)
    • Fluid depletion
  • Severe disease:
    • Toxic megacolon
    • Intestinal perforation
    • Septic shock
    • Haemorrhage

Management recommendations

The abovementioned guidelines statement makes the following suggestions:

Mild-moderate C.difficile infection:

  • Treat empirically in the absence of positive results, if the pre-test suspicion is strong.
  • Stop the inciting antibiotics
  • Give oral metronidazole for 10 days
    • Change metronidazole to vancomycin if there is no response in 5-7 days
  • For severe infection, just give oral vancomycin straight away(125mg qid for 10 days)
  • Vancomycin enemas are an option
  • Avoid anti-diarrhoea medications

Severe and complicated C.difficile infection:

  • CT of the abdomen is indicated
  • Oral vacomycin PLUS intravenous metronidazole are indicated
  • If there is significant abdominal distension, the vancomycin should be given as an enema

Recurrent C.difficile infection:

  • First recurrence: treat in the same way as the first episode
  • Second recurrence: change to vancomycin
  • Third recurrence: consider a faecal microbiota transplant

When to consider surgery:

  • Hypotension requiring vasopressor therapy
  • Clinical signs of sepsis and organ dysfunction
  • WCC in excess of 50
  • Lactate in excess of 5mmol/L
  • Failure to improve on medical therapy after 5 days

Innovative therapies

  • Probiotics (seem to make no difference)
  • Monoclonal antibodies (seem to make no difference).
    This last statement needs to be qualified somewhat. A recent NEJM publication (Wilcox et al, 2017- the MODIFY-I and MODIFY-II trials) explored the merits of bezlotoxumab, a toxin-binding mab. The results were encouraging - side effect profile similar to placebo, and a 10% reduction in the rate of recurrence. However, the list of industry sponsorship disclosures in that article is longer than the abstract, raising concerns about the influence of Merck on the results.

Supportive management

These suggest themselves on the basis of  the college answer to Question 12 from the first paper of 2016

  • Manage the diarrhoea
    • This includes stool management systems, rectal tubes etc.
  • Manage the symptoms of colitis
    • Adequate pain relief
  • Restore fluid and electrolyte imbalance

Preventative strategies

 

References

Oh's Manual: Chapter 70  (pp. 724)  Nosocomial  infections by James  Hatcher  and  Rishi  H-P  Dhillon - totally useless; there is literally just one paragraph devoted to it here.

Surawicz, Christina M., et al. "Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections." The American journal of gastroenterology 108.4 (2013): 478-498.

Lawrence, Steven J., et al. "Clostridium difficile in the intensive care unit: epidemiology, costs, and colonization pressure." Infection Control 28.02 (2007): 123-130.

Louie, Thomas J., et al. "Fidaxomicin versus vancomycin for Clostridium difficile infection." New England Journal of Medicine 364.5 (2011): 422-431.

Sailhamer, Elizabeth A., et al. "Fulminant Clostridium difficile colitis: patterns of care and predictors of mortality." Archives of surgery 144.5 (2009): 433-439.

Loo, Vivian G., et al. "Host and pathogen factors for Clostridium difficile infection and colonization." New England Journal of Medicine 365.18 (2011): 1693-1703.

Thomas, Claudia, Mark Stevenson, and Thomas V. Riley. "Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review." Journal of antimicrobial chemotherapy 51.6 (2003): 1339-1350.

Anand, Ajay, and Aaron E. Glatt. "Clostridium difficile infection associated with antineoplastic chemotherapy: a review." Clinical Infectious Diseases 17.1 (1993): 109-113.

Cunningham, R., et al. "Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea." Journal of Hospital Infection 54.3 (2003): 243-245.

Pépin, Jacques, Louis Valiquette, and Benoit Cossette. "Mortality attributable to nosocomial Clostridium difficile–associated disease during an epidemic caused by a hypervirulent strain in Quebec." Canadian Medical Association Journal 173.9 (2005): 1037-1042.

Cunney, Robert J., et al. "Clostridium difficile colitis associated with chronic renal failure." Nephrology Dialysis Transplantation 13.11 (1998): 2842-2846.

Surawicz, Christina M., et al. "Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections." The American journal of gastroenterology 108.4 (2013): 478-498.

Henrich, Timothy J., et al. "Clinical risk factors for severe Clostridium difficile–associated disease." Emerging infectious diseases 15.3 (2009): 415.

FujitaniMD, Shigeki, W. Lance GeorgeMD, and A. Rekha MurthyMD. "Comparison of clinical severity score indices for Clostridium difficile infection."Infection Control and Hospital Epidemiology 32.3 (2011): 220-228.

Bignardi, G. E. "Risk factors for Clostridium difficile infection." Journal of Hospital Infection 40.1 (1998): 1-15.

Bakken, Johan S., et al. "Treating Clostridium difficile infection with fecal microbiota transplantation." Clinical Gastroenterology and Hepatology 9.12 (2011): 1044-1049.

Lowy, Israel, et al. "Treatment with monoclonal antibodies against Clostridium difficile toxins." New England Journal of Medicine 362.3 (2010): 197.

Dallal, Ramsey M., et al. "Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications." Annals of surgery 235.3 (2002): 363.

Fekety, Robert. "Diagnosis and management of C. difficile-associated diarrhea and colitis." Am. J. Gastroenterol 92 (1997): 739-750.

Bartlett, John G. "Clostridium difficile: history of its role as an enteric pathogen and the current state of knowledge about the organism." Clinical infectious diseases 18.Supplement 4 (1994): S265-S272.

Rupnik, Maja, Mark H. Wilcox, and Dale N. Gerding. "Clostridium difficile infection: new developments in epidemiology and pathogenesis." Nature Reviews Microbiology 7.7 (2009): 526-536.

Hellickson, L. A., and K. L. Owens. "Cross-contamination of Clostridium difficile spores on bed linen during laundering." American Journal of Infection Control 35.5 (2007): E32-E33.

Johnson, Stuart, et al. "Prospective, controlled study of vinyl glove use to interrupt Clostridium difficile nosocomial transmission." The American journal of medicine 88.2 (1990): 137-140.

Lyerly, David M., Howard C. Krivan, and TRACY D. Wilkins. "Clostridium difficile: its disease and toxins." Clinical microbiology reviews 1.1 (1988): 1-18.

Valiquette, Louis, et al. "Impact of a reduction in the use of high-risk antibiotics on the course of an epidemic of Clostridium difficile-associated disease caused by the hypervirulent NAP1/027 strain." Clinical Infectious Diseases45.Supplement 2 (2007): S112-S121.

Vonberg, R‐P., et al. "Infection control measures to limit the spread of Clostridium difficile." Clinical Microbiology and Infection 14.s5 (2008): 2-20.

Wullt, Marlene, Inga Odenholt, and Mats Walder. "Activity of three disinfectants and acidified nitrite against Clostridium difficile spores." Infection Control 24.10 (2003): 765-768.

Jernigan, John A., et al. "A randomized crossover study of disposable thermometers for prevention of Clostridium difficile and other nosocomial infections." Infection Control 19.07 (1998): 494-499.

Wilcox, M. H., et al. "Comparison of the effect of detergent versus hypochlorite cleaning on environmental contamination and incidence of Clostridium difficile infection." Journal of Hospital Infection 54.2 (2003): 109-114.

Hannonen, P., et al. "Reactive oligoarthritis associated with Clostridium difficile colitis." Scandinavian journal of rheumatology 18.1 (1989): 57-60.

Mallari, Alexander, Joyce Koh, and Emmanuel Gorospe. "Pseudomembranous Colitis from Non-Clostridial Infections: A Systematic Review." AMERICAN JOURNAL OF GASTROENTEROLOGY. Vol. 105. 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA: NATURE PUBLISHING GROUP, 2010.- This is not available even as an abstract!

Janvier, Jack, Susan Kuhn, and Deirdre Church. "Not all pseudomembranous colitis is caused by Clostridium difficile." The Canadian Journal of Infectious Diseases & Medical Microbiology 19.3 (2008): 256.

Deshpande, Abhishek, et al. "Association between proton pump inhibitor therapy and Clostridium difficile infection in a meta-analysis." Clinical Gastroenterology and Hepatology 10.3 (2012): 225-233.

Wilcox, Mark H., et al. "Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection." New England Journal of Medicine 376.4 (2017): 305-317.