The core understanding of CDI: it is a disease of antibiotic-disrupted gut microbiome. Antibiotics reduce the colonisation resistance of the normal gut microbiota, allowing C. difficile spores (present in the environment and in the gut of approximately 3 per cent of healthy adults and 20 to 30 per cent of hospitalised patients) to germinate, colonise the colon, and produce toxins. C. difficile infection is not simply "having the bacteria present" but is defined by the combination of clinical symptoms (diarrhoea) and laboratory evidence of C. difficile toxin or toxin-producing organisms.
Pathogenesis: Toxins A and B
C. difficile produces two primary toxins: toxin A (TcdA, enterotoxin) and toxin B (TcdB, cytotoxin). Both toxins are glucosyltransferases that inactivate Rho GTPases in colonic epithelial cells. Rho GTPase inactivation disrupts the actin cytoskeleton of epithelial cells, causing cell rounding and apoptosis, disrupting tight junctions, and increasing intestinal permeability.
Toxin B is approximately 1,000 times more potent than toxin A in tissue culture and is now considered the primary virulence factor. Some hypervirulent strains (BI/NAP1/027, associated with severe outbreaks in North America and Europe in the 2000s) produce a binary toxin (CDT, Clostridium difficile transferase) in addition to toxins A and B. Binary toxin modifies actin in epithelial cells by a different mechanism and may contribute to increased virulence.
The Diagnostic Algorithm: A Two-Step Approach
CDI diagnosis requires a combination of clinical assessment and laboratory testing. The most important clinical criterion: new onset of unformed stool (Bristol Stool Chart types 5, 6, or 7) occurring three or more times in 24 hours, not attributable to other causes, in a patient who has received antibiotics in the past 12 weeks.
Current best-practice CDI diagnostic algorithm (per ESCMID 2021 guidelines):
Step 1: Glutamate dehydrogenase (GDH) enzyme immunoassay (EIA). GDH is a cell wall antigen expressed in large amounts by all C. difficile strains (toxigenic and non-toxigenic). GDH EIA is highly sensitive (greater than 95 per cent) but not specific for toxigenic strains (non-toxigenic C. difficile gives a positive GDH). A negative GDH result effectively excludes CDI with high confidence. A positive GDH result requires step 2.
Step 2: Toxin A/B EIA or NAAT (nucleic acid amplification test, PCR) for toxin genes. Toxin EIA detects free toxin in stool (clinical proof that toxin is actually being produced in the gut). NAAT detects toxin gene sequences. The key distinction: toxin EIA has lower sensitivity (70 to 75 per cent) but higher specificity for active CDI; NAAT is highly sensitive but detects toxin genes in asymptomatic colonised patients as well as those with true CDI.
The two-step algorithm identifies: GDH negative (CDI excluded) / GDH positive + toxin positive (CDI confirmed) / GDH positive + toxin negative (possible CDI, repeat testing or NAAT if clinical suspicion high).
Severity Assessment: From Mild to Fulminant
Severity stratification guides treatment intensity and setting of care.
Mild-moderate CDI: diarrhoea without systemic features (no fever above 38.5 degrees Celsius, no leucocytosis above 15 x 10^9/L, no rising creatinine). First episode. Treat with vancomycin 125 mg four times daily for 10 days (superior to metronidazole by clinical outcome data) or fidaxomicin 200 mg twice daily for 10 days (superior to vancomycin for sustained cure and reduction of recurrence, particularly for non-NAP1/027 strains).
Severe CDI: leucocytosis above 15 x 10^9/L, creatinine above 50 per cent of baseline, albumin below 30 g/L, temperature above 38.5 degrees Celsius, or endoscopy showing pseudomembranous colitis. Treat with vancomycin 125 mg four times daily (or 500 mg four times daily for very severe cases) or fidaxomicin. Monitor closely for deterioration.
Fulminant CDI: hypotension or shock, ileus, toxic megacolon (colonic diameter above 6 cm), peritonitis, or requirement for ICU admission. Urgent surgical consultation (early colectomy may be life-saving, with better outcomes before the development of multi-organ failure). Treat with vancomycin 500 mg four times daily via nasogastric tube AND intrarectal vancomycin AND intravenous metronidazole. Consider bezlotoxumab (monoclonal antibody against toxin B) for high-risk patients at risk of recurrence.
Recurrent CDI
Recurrent CDI occurs in approximately 20 to 25 per cent of patients after successful initial treatment. Multiple recurrences occur in 45 to 65 per cent of those who have one recurrence.
Management of first recurrence: fidaxomicin if not used initially. Vancomycin taper-pulse regimen (gradually reducing and spacing doses over 6 weeks) if fidaxomicin is not available.
Management of multiple recurrences: faecal microbiota transplant (FMT) is the most effective intervention for recurrent CDI, with cure rates of 80 to 90 per cent for multiply recurrent cases. FMT restores colonisation resistance by transplanting a normal donor microbiome into the recipient. SER-109 (Vowst) and RBX2660 (Rebyota), standardised microbiota-based products, received FDA approval in 2023 as alternatives to FMT for recurrent CDI.
Bezlotoxumab: a human monoclonal antibody against C. difficile toxin B, given as a single intravenous infusion during CDI treatment. Reduces recurrence rate by approximately 10 percentage points in high-risk patients (age above 65, immunocompromised, prior CDI episodes, severe disease).
Infection Control for CDI
C. difficile spores are resistant to most alcohol-based hand rubs and standard disinfectants. Specific infection control measures are required beyond standard precautions.
Patient isolation in a single room with dedicated toilet. Contact precautions (gloves and apron for all patient contact). Hand hygiene with soap and water (physical removal of spores) rather than alcohol gel for CDI contacts. Environmental cleaning with hypochlorite solution (1,000 ppm for routine cleaning, 5,000 ppm for outbreak situations). Minimising toilet flushing with the lid open (aerosol generation distributing spores). Review of antibiotic prescribing on the ward as a mandatory component of outbreak investigation.
Frequently Asked Questions
What is CDI?
Clostridioides difficile infection (CDI) is an infection of the colon caused by the gram-positive spore-forming anaerobe Clostridioides difficile, characterised by diarrhoea, abdominal pain, and sometimes colitis. It is almost always preceded by antibiotic use and is the most common cause of antibiotic-associated diarrhoea in hospitals.
What are C. difficile toxins?
C. difficile produces two primary virulence toxins: toxin A (TcdA) and toxin B (TcdB), both glucosyltransferases that inactivate Rho GTPases in colonic epithelial cells, causing disruption of the epithelial barrier, inflammation, and diarrhoea. Toxin B is approximately 1,000 times more potent than toxin A and is now considered the primary virulence factor.
What antibiotics most commonly cause CDI?
The highest-CDI-risk antibiotics are: clindamycin (historically the classic cause), broad-spectrum cephalosporins (especially third-generation), fluoroquinolones (ciprofloxacin, levofloxacin), ampicillin and amoxicillin. Lower-risk antibiotics include: vancomycin, metronidazole, tetracyclines. The risk reflects how severely each antibiotic disrupts the gut microbiome.
What is GDH and why is it used in CDI diagnosis?
Glutamate dehydrogenase (GDH) is a metabolic enzyme expressed abundantly by all C. difficile strains (both toxigenic and non-toxigenic). GDH enzyme immunoassay is used as the sensitive first step in CDI diagnosis: a negative result effectively excludes CDI. A positive result requires toxin testing to confirm that the C. difficile present is toxigenic and producing toxin.
What is pseudomembranous colitis?
Pseudomembranous colitis (PMC) is the severe form of CDI where colonoscopy or sigmoidoscopy reveals creamy-yellow plaques (pseudomembranes) adhering to the inflamed colonic mucosa. Pseudomembranes consist of fibrin, mucus, inflammatory cells, and cellular debris overlying areas of colonic epithelial necrosis. PMC indicates severe CDI and is associated with higher risk of fulminant course.
What is fidaxomicin and when is it preferred?
Fidaxomicin is a macrolide antibiotic with very poor systemic absorption, acting locally in the colon against C. difficile. It is preferred over vancomycin for: first or first recurrent CDI in patients at high risk of recurrence (age above 65, ongoing antibiotic use, immunocompromised), as it achieves higher sustained cure rates and lower recurrence rates than vancomycin in randomised controlled trials (particularly for non-NAP1/027 strains).
What is FMT and how effective is it for CDI?
Faecal microbiota transplant (FMT) is the transfer of stool from a healthy screened donor into the colon of a CDI patient via colonoscopy, enema, or oral capsule. FMT restores colonisation resistance by reintroducing a diverse healthy microbiome that outcompetes C. difficile. For multiply recurrent CDI, FMT achieves cure rates of 80 to 90 per cent, far exceeding antibiotic treatment alone. Recent FDA-approved products (Vowst, Rebyota) provide standardised microbiota-based alternatives.
Why doesn't alcohol hand gel kill C. difficile?
C. difficile forms heat- and chemical-resistant spores. Alcohol-based hand rubs are effective against vegetative bacteria and enveloped viruses but do not reliably kill bacterial endospores. Spores require physical removal (hand washing with soap and water, which dislodges spores from skin) or exposure to sporicidal chemicals (hypochlorite). This is why CDI wards require handwashing over alcohol gel for patient-contact hand hygiene.
What is toxic megacolon in CDI?
Toxic megacolon is a life-threatening complication of severe CDI characterised by colonic dilatation (typically transverse colon diameter above 6 cm on abdominal X-ray) with systemic toxicity (fever, tachycardia, hypotension, leucocytosis). It results from transmural colonic inflammation and functional ileus. It carries a mortality of 50 to 80 per cent without surgery. Emergency colectomy (subtotal colectomy with end ileostomy) is often required.
When should surgery be considered for CDI?
Surgical consultation should be sought urgently for: toxic megacolon, clinical deterioration despite maximal medical therapy, colonic perforation, severe ileus preventing delivery of oral vancomycin. Subtotal colectomy with end ileostomy is the standard surgical procedure. Studies show better outcomes when surgery is performed before the development of multi-organ failure, so early surgical involvement in severe CDI is strongly recommended.