Describe Clostridioides difficile infection with its pathogenesis, diagnosis and management.

Organism and Pathogenesis

• Clostridioides (formerly Clostridium) difficile — a gram-positive, spore-forming, obligate anaerobic bacillus; part of the normal gut flora in a small proportion of adults and in most neonates
• Named "difficile" because it was difficult to isolate and grow
• Two toxins — toxin A (enterotoxin) causes fluid secretion and mucosal damage, and toxin B (cytotoxin) is far more potent and disrupts the cytoskeleton by glucosylating Rho GTPases. The hypervirulent NAP1/BI/027 strain produces more of both together with binary toxin

An antibiotic disrupts the normal colonic flora → colonisation resistance is lost → C. Difficile — already present, or acquired as spores from the environment — multiplies unopposed → Toxins A and B damage the mucosa and provoke intense inflammation → Yellowish plaques of fibrin, mucus and inflammatory cells form — pseudomembranous colitis → Profuse watery diarrhoea, cramps, fever and leucocytosis → May progress to toxic megacolon, perforation and death

• Risk factors — antibiotics above all (classically clindamycin, but in practice most cases follow cephalosporins, fluoroquinolones and broad-spectrum penicillins because these are used far more often); proton pump inhibitors; advanced age; prolonged hospital stay; and immunosuppression

Diagnosis

• A two-step or three-step algorithm is standard — GDH screen, then toxin detection, with PCR resolving discrepancies
• Test only patients with diarrhoea; testing formed stool detects carriers and leads to unnecessary treatment

Treatment and Prevention

• Stop the precipitating antibiotic wherever the primary infection allows — the single most important step
• Oral vancomycin or fidaxomicin is now first-line; metronidazole has been relegated to second-line as it is less effective
• Oral vancomycin works because it is not absorbed, so it reaches a high concentration in the colonic lumen; intravenous vancomycin does not work for this indication, and confusing the routes is a serious error
• Severe or fulminant disease — oral vancomycin with intravenous metronidazole, and surgical colectomy for toxic megacolon or perforation
• Recurrent disease — occurs in about 20%; treated with a tapered vancomycin regimen, fidaxomicin, bezlotoxumab (an antitoxin B antibody), or faecal microbiota transplantation, which restores the flora and is strikingly effective
• Antimotility drugs such as loperamide are contraindicated — they retain toxin in the colon and precipitate toxic megacolon
• Infection control — isolation with contact precautions, hand-washing with soap and water, and environmental cleaning with a sporicidal agent such as hypochlorite

Applied Aspects

• Consider C. Difficile in any patient with diarrhoea during or within 8 weeks of antibiotic treatment, and isolate promptly rather than after confirmation
• Antimicrobial stewardship is the primary prevention — reducing unnecessary cephalosporin and fluoroquinolone use lowers incidence more than any infection control measure alone
• Review the proton pump inhibitor, which is frequently continued without indication and independently increases risk
• Do not treat asymptomatic carriers; they do not benefit, and treatment selects resistance and disturbs the flora further
• C. Difficile is under-recognised in India, partly because testing is not widely available and partly because antibiotic-associated diarrhoea is attributed to the drug itself; the burden is probably substantially greater than reported
• Faecal microbiota transplantation demonstrates that the flora is itself therapeutic — restoring colonisation resistance succeeds where further antibiotics fail, which is a conceptually important result