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 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 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
- 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
- Toxin A: a 308-kDa enterotoxin
- 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
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
- Watery diarrhoea (≥3 loose stools in 24 hours)
- History of antibiotic exposure
- Fever, abdominal pain, distension
- Bowel dilatation
- Mural thickening and haustral fold thickening ("thumbprinting")
- Toxic megacolon
- Perforation and free intraperitoneal gas
Biochemical diagnosis: the current recommendations are:
- PCR is better than toxin A or B identification
- You should only test loose stools
- You should not re-test.
Sigmoidoscopy (endoscopic diagnosis)
- Confirming biopsy and culture
Is it really Clostridium?
Alternative pathogens include:
- Strongyloides stercoralis
- Staphylococcus aureus
- Clostridium perfringens
- All the enterohaemorrhagic diarrhoea organisms:
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
- Electrolyte disturbance (low potassium, magnesium, etc)
- Fluid depletion
- Severe disease:
- Toxic megacolon
- Intestinal perforation
- Septic shock
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
- 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
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
- 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: