Clostridioides Difficile Infection

A toxin mediated colitis caused by Clostridioides difficile, an anaerobic, spore forming, Gram positive bacterium. It occurs predominantly following disruption of normal colonic microbiota by antibiotic exposure, which permits proliferation of toxin producing strains and subsequent colonic mucosal injury. It is the leading cause of healthcare associated infectious diarrhoea and carries the potential for severe, life threatening complications in a minority of cases.

Pathophysiology and risk factors

• Toxin A and toxin B, produced by pathogenic strains, disrupt the colonic epithelial cytoskeleton and tight junctions, producing mucosal inflammation, fluid secretion and, in severe disease, the characteristic pseudomembrane formation visible endoscopically.
• Antibiotic exposure is the dominant risk factor, with broad spectrum agents (fluoroquinolones, clindamycin, broad spectrum cephalosporins and co amoxiclav) carrying particularly high associated risk given their profound impact on normal colonic flora.
• Additional risk factors include advanced age, hospitalisation, proton pump inhibitor use, inflammatory bowel disease, immunocompromise and prior episodes of Clostridioides difficile infection, the last being a strong predictor of recurrence.

• Watery diarrhoea, typically frequent and foul smelling, developing during or, commonly, in the weeks following antibiotic exposure, together with abdominal cramping and, in more significant disease, fever and systemic upset.
• Severe disease presents with marked abdominal pain and distension, high fever, and significant leucocytosis (sometimes striking, exceeding 15 x 10⁹ per litre).
• In the most severe cases there are signs of ileus or toxic megacolon with reduced or absent stool output despite ongoing severe colitis. This is an important and easily missed pattern, since the absence of diarrhoea in this specific scenario can be falsely reassuring.
• Fulminant colitis, presenting with hypotension, marked abdominal distension, signs of peritonism and evidence of colonic perforation, represents a surgical emergency requiring immediate combined medical and surgical assessment.
• A history of recent antibiotic exposure, even where discontinued some weeks prior, and any relevant recent hospitalisation, should be actively sought in any patient presenting with significant diarrhoea.

• Stool testing should be performed only in patients with clinically significant diarrhoea (generally defined as three or more unformed stools within 24 hours). This reflects the recognised problem of asymptomatic colonisation, particularly in hospitalised and elderly patients, where testing an unformed but otherwise explained stool risks false attribution and inappropriate treatment.
• A two step testing algorithm is standard. An initial sensitive screening test (glutamate dehydrogenase antigen enzyme immunoassay, or nucleic acid amplification testing for toxin genes) is followed, where positive, by a specific toxin enzyme immunoassay to confirm active toxin production.
• Nucleic acid amplification testing alone can detect the presence of toxigenic organisms including in asymptomatic carriers without confirming active toxin mediated disease.
• Computed tomography of the abdomen is indicated in severe or fulminant disease. It shows colonic wall thickening, pericolonic fat stranding and, in the most severe cases, evidence of toxic megacolon or perforation.
• Abdominal radiography is a useful rapid initial assessment for colonic dilatation where toxic megacolon is a specific concern.
• Endoscopy (flexible sigmoidoscopy, performed cautiously given perforation risk in severe disease) is generally reserved for diagnostic uncertainty. It shows the characteristic yellow white pseudomembranes when present. It is not used routinely given the reliability of stool toxin testing in the great majority of cases.

• Discontinuation of the inciting antibiotic, where clinically feasible, is an important first step alongside specific treatment initiation.
• Oral vancomycin 125 mg four times daily for ten days is first line treatment for an initial episode, whether non severe or severe, given superior efficacy compared with metronidazole demonstrated in contemporary evidence.
• Vancomycin must be given orally for this indication, since intravenous administration does not achieve adequate colonic luminal concentration.
• Oral fidaxomicin 200 mg twice daily for ten days is an alternative first line agent, associated with a lower rate of subsequent recurrence compared with vancomycin, and is increasingly preferred where cost and availability permit, particularly in patients at higher recurrence risk.
• Metronidazole 500 mg orally three times daily for ten days is now generally reserved for non severe disease where vancomycin or fidaxomicin are unavailable, reflecting its inferior efficacy compared with these agents in current evidence.
• Fulminant disease (with hypotension, shock, ileus or toxic megacolon) requires combination treatment:
  • oral vancomycin 500 mg four times daily
  • intravenous metronidazole 500 mg three times daily (given for its systemic effect where ileus may impair delivery of oral vancomycin to the colon)
  • rectal vancomycin instillation (500 mg in 100 mL normal saline as a retention enema four times daily) considered where ileus significantly limits oral drug delivery to the affected colon
• Urgent surgical consultation is required for fulminant colitis, with subtotal colectomy considered for perforation, refractory toxic megacolon, or deteriorating clinical status despite maximal medical therapy, given the substantial mortality of untreated fulminant disease.
• A first recurrence is treated with a prolonged, tapered and pulsed vancomycin regimen, or with fidaxomicin, rather than a standard repeat ten day vancomycin course, reflecting evidence of improved outcomes with these approaches in the recurrent disease setting.
• Multiple recurrences (generally a second or subsequent recurrence) warrant consideration of faecal microbiota transplantation, which has demonstrated high efficacy in restoring normal colonic microbiota and preventing further recurrence.
• Bezlotoxumab (a monoclonal antibody against toxin B, given as a single intravenous infusion of 10 mg per kg alongside standard antibiotic treatment) is an adjunct specifically to reduce recurrence risk in high risk patients.
• Antimotility agents should be avoided given the risk of precipitating toxic megacolon by impairing clearance of toxin from the colon.
• Essential infection prevention and control measures, given the significant nosocomial transmission risk of this organism:
  • antimicrobial stewardship, including avoidance of unnecessary broad spectrum antibiotic prescribing
  • strict contact precautions and hand hygiene using soap and water rather than alcohol based sanitiser alone (given the resistance of Clostridioides difficile spores to alcohol)
  • thorough environmental cleaning with a sporicidal agent