Clostridioides 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:

Owing to this historical attention and to the weird predictability of the biannual appearance of these questions, the candidates have been performing better and better in their answers. In the early 2014 appearance of this microbe the examiners commented on how "Overall, candidates' knowledge of this topic was limited." On the other hand, of the late 2018 candidates, 97.1% passed the question and some bacteriology genius got a mark of 8.7. 

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 2021 update statement from the IDSA would probably be it.

Incidentally, in 2016, Clostridium difficile was renamed Clostridioides difficile because the genus Clostridium was reserved for organisms genetically similar to C.butyricum, and C.difficile was more closely related to peptostreptococci. This excellent article from the Lancet outlines the nightmarish taxonomic work done by the CDC in this space.

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.

Assessment of suspected C.difficile infection

What might make you raise a suspicious eyebrow at the loose stool? Loose stool is not uncommon in the ICU. What makes it so difficileIn general, a question on any diagnostic topic in the CICM fellowship exam will probably take a "history, examination, investigations" sort of pattern. "History" in this context could be discussed mostly in terms of the risk factors for C.difficile, because that is what is likely to be the most prominent in any given presentation from the ICU perspective. Consider: these people will usually be referred to the ICU following a long hospital stay.  

Risk factors for C.difficile infection

These are the features you would look for on history. The risk factors for C.difficile infection are discussed here, in a NEJM article.

  • Broad spectrum antibiotics, and in particular:
    • clindamycin, quinolones, amoxycillin, cephalosporins (Thomas et al, 2003)
    • piperacillin/tazobactam, meropenem, vancomycin,  ciprofloxacin, ceftriaxone, and levofloxacin (Rafey et al, 2023)

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

To this, the college answers also add, on the basis of Leffler et al (2015):

  • Inflammatory bowel disease
  • exposure to an infected individual
  • Nursing home/health care facility resident 

Natural history

  • It typically starts 3-9 days after the commencement of antibiotics

Significant take-home points from Curry et al (2023)

  • 10%–60% of patients end up developing infection, the rest can be asymptomatic carriers
  • Transient colonosation is possible (i.e. you are briefly positive, but asymptomatic

Examination findings suggestive of C.difficile infection

C.difficile colitis looks like every other colitis. Stil, the following findings are suspicious:

  • Watery diarrhoea (≥3 loose stools in 24 hours) - the literature is disgustingly explicit about the nature of these, using words like "mucoid",  "foul", "malodorous" and "watery". They are supposed to be greenish and possibly with fragments of pseudomembranes and blood.
  • Abdominal pain (only in 22%)
  • Fever > 38° (in 28%)
  • Distension and constipation develops late (severe colitis ends up with ileus and megacolon rather than diarrhoea)

Diagnostic tests for C.difficile

For specific diagnostic investigations for C.difficile, you could do no better than the ASID guidelines (Cheng et al, 2011)

Supportive biochemistry

  • Renal failure
  • Hypoalbuminaemia (due to losses from bowel wall)
  • Stool leukocytosis

Radiological diagnosis:

  • Bowel dilatation
  • Mural thickening; "double halo" sign (IV contrast outlining two discontinuous layers of the oedematous bowel wall)
  • Haustral fold thickening ("thumbprinting") on plan Xrays or CT
  • Toxic megacolon
  • There should be no small bowel involvement, because C. difficile
    is typically restricted to the colon.

Biochemical diagnosis: 

  • Stool PCR for C.difficile toxin A or B
  • Enzyme immunoassay for C.difficile GDH antigen
  • Nucleic acid amplification test (NAAT) for C. difficile toxin gene
  • Cell culture cytotoxicity assay
  • Selective stool anaerobic culture confirming toxin-secreting C.difficile organisms

The diagnostic recommendations are:

  • PCR is better than toxin A or B identification
  • NAT is better than PCR
  • You should only test loose stools
  • You should test rectal swabs for patients with ileus
  • You should not re-test.

Sigmoidoscopy (endoscopic diagnosis)

  • Pseudomembranes
  • Confirming biopsy and culture

Other causes of pseudomembranous colitis

Not all pseudomembranous colitis is due to C.difficile infection. According to Bartlett et al (2008), "only 10%–25% of stool specimens submitted for C. difficile toxin testing have positive results".

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

Features  which define severe C.difficile infection

Again, from ASID:

  • Clinical features:
    • High fever, over 38.5º C
    • Toxic megacolon
    • An acute abdomen, peritonitis
    • Presence of ileus or evidence of bowel obstruction
  • Biochemistry
    • WCC > 15 
    • Raised lactate
    • Acute kidney injury (Creatinine increase by 50%)
    • Albumin < 25
  • Imaging:
    • Large intestine distension, colonic wall thickening, fat stranding, unexplained ascites 
  • Endoscopy:
    • The finding of pseudomembranous colitis

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
  • Fidaxomicin is increasingly favoured as an alternative to, or as replacement of, vancomycin for the initial course.

Severe and complicated C.difficile infection:

  • CT of the abdomen is indicated
  • Oral vacomycin or fidaxomicin 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 or fidaxomicin; think about adding rifaximin
  • Third recurrence: consider a faecal microbiota transplant
  • Bezlotoxumab, a monoclonal antibody to the B toxin, is also recommended for severe and recurrent infections, particularly where the patient is immunocompromised. 

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.

Faecal microbiota transplant

As it had become the specific topic of Question 1 from the second paper of 2018, this therapy has attracted more words here than its importance merits. On the stage of C.difficile management, it is a minor actor, with no speaking lines. The college called it a Faecal Microbial Transplant, even though the literature specifically refers to microbiota. The latter is a scientific term referring to a collection of microorganisms which inhabit a particular site or system. 

In summary, the rationale is:

  • C.difficile colitis is characterised by a loss of colonic biodiversity, which is attributed to the abuse of broad-spectrum antibiotics
  • Processed stool from healthy donors can promote a restoration of this "dysbiosis"

Guidelines (ISDA/SHEA, 2018) recommend faecal microbiota transplantation for patients with multiple recurrences of C.difficile infection who have failed appropriate antibiotic treatments

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

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