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:

• Question 19 from the second paper of 2021
• Question 1 from the second paper of 2018
• Question 12 from the first paper of 2016
• Question 14 from the first paper of 2014
• Question 3 from the first paper of 2012
• Question 27 from the second paper of 2005

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
  • These spores are highly resistant to dessication, chemicals and extreme temperatures.
  • They can survive the hospital laundry cycle.
  • Only chlorine-based agents inactivate the spores.
• 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.

• Broad spectrum antibiotics in particular clindamycin, quinolones, amoxycillin, cephalosporins

• Immunosuppressive therapy /Cytotoxic chemotherapy

• Gastric acid suppression

• Age > 65

• Prolonged hospitalisation

• Renal impairment

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 

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

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

Clinical suspicion

• Watery diarrhoea (≥3 loose stools in 24 hours)
• History of antibiotic exposure 
• Fever, abdominal pain, distension

Radiological diagnosis:

• Bowel dilatation
• Mural thickening and haustral fold thickening ("thumbprinting")
• Toxic megacolon
• Perforation and free intraperitoneal gas

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

Is it really C.difficile?

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
  • Generally, it seems a rapidly rising WCC is a marker of impending disaster, a looming fulminant C.difficile colitis
• 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:
  • Loose stools
  • SIRS
  • Reactive arthritis and/or iridocyclitis
  • Hypoalbuminaemia
• 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

• Barrier methods:
  • Isolation of affected patients, at least until 48 hours after the resolution of diarrhoea
  • Gowns and gloves
  • Traditional soap-and-water handwashing rather than alcohol rub
  • Individualised equipment in single rooms (turns out it is more cost-effective to buy new thermometers than to treat additional C.difficile cases)
  • Sporicidal bleaching agents should be used to disinfect rooms after patient departure: specifically, unbuffered hypochlorite bleach
• A change in prescribing culture:
  • Antibotic stewardship is strongly recommended: incidence may reduce by 60%
  • The prescribing of PPIs should be rationalised, as the use of PPIs is associated with a 2-fold increase in the risk of C.difficile infection (Deshpande et al, 2012)