Overview
Clostridioides difficile (C. diff)
1. Clinical Overview
Summary
Clostridioides difficile infection (CDI) is an anaerobic, spore-forming, toxin-producing bacterium that is the most common cause of healthcare-associated infectious diarrhoea. Disruption of normal gut flora by antibiotics allows C. difficile overgrowth and toxin production (Toxin A and B), causing watery diarrhoea and colitis. Severity ranges from mild diarrhoea to life-threatening pseudomembranous colitis and toxic megacolon. First-line treatment is oral vancomycin or fidaxomicin. Recurrence is common (20-30%), and faecal microbiota transplantation (FMT) is highly effective for multiply recurrent cases. Prevention relies on antibiotic stewardship and strict infection control. [1,2]
Key Facts
- Incidence: 15-17 cases per 10,000 hospital admissions; increasing in community. [3]
- Mortality: 5% overall; 15-30% in severe/fulminant disease.
- Risk Factors: Antibiotics (especially 4Cs: Cephalosporins, Clindamycin, Co-amoxiclav, Ciprofloxacin), age at least 65, hospitalisation, PPIs.
- Toxins: Toxin A (enterotoxin) and Toxin B (cytotoxin); both contribute to disease.
- Spores: Resistant to alcohol gel; use soap and water for hand hygiene.
- First-Line Treatment: Oral vancomycin or fidaxomicin.
- Recurrence: 20-30% after first episode; FMT highly effective for recurrent.
Clinical Pearls
The "4 Cs" of C. diff: Cephalosporins, Clindamycin, Co-amoxiclav, Ciprofloxacin are the highest-risk antibiotics. Any antibiotic can cause CDI.
Alcohol Gel Does NOT Kill Spores: C. difficile spores are resistant to alcohol-based hand sanitisers. Staff and patients must use soap and water.
Stop the Loperamide: Anti-motility agents (loperamide, codeine) are CONTRAINDICATED in CDI - they delay toxin clearance and increase risk of toxic megacolon.
WCC greater than 15 and Rising Creatinine = Severe: These are key markers of severity. Monitor closely; consider surgical referral if not improving.
2. Epidemiology
Incidence and Demographics
- Hospital Incidence: 15-17 cases per 10,000 admissions.
- Community-Acquired: Increasing (now 30-40% of cases).
- Age: Risk increases with age; at least 65 years at highest risk.
- Recurrence: 20-30% after first episode; 40-60% after second episode.
Risk Factors
| Risk Factor | Mechanism | Relative Risk |
|---|---|---|
| Antibiotic use | Disrupts normal flora | 7-10x |
| Age at least 65 years | Immunosenescence, comorbidities | 3-5x |
| Hospitalisation | Environmental exposure | 3-5x |
| PPI use | Reduced gastric acid barrier | 1.5-2x |
| Prior C. diff infection | Inadequate immune response | 5-10x |
| Immunosuppression | Reduced toxin clearance | 2-3x |
| Chemotherapy | Gut damage, immunosuppression | 2-4x |
| Inflammatory bowel disease | Disrupted barrier, antibiotics | 3x |
| Enteral feeding | Altered gut environment | 1.5x |
High-Risk Antibiotics
| Risk Level | Antibiotics |
|---|---|
| Very High | Clindamycin, Fluoroquinolones (ciprofloxacin), Cephalosporins (especially 2nd/3rd gen) |
| High | Co-amoxiclav, Carbapenems |
| Moderate | Penicillins, Macrolides |
| Low | Tetracyclines, Aminoglycosides, Metronidazole |
Hypervirulent Strain (Ribotype 027)
- Produces more toxins A and B.
- Binary toxin (CDT) production.
- Fluoroquinolone resistance.
- Associated with severe outbreaks and higher mortality.
3. Pathophysiology
Step 1: Disruption of Colonisation Resistance
- Normal gut microbiota provides "colonisation resistance."
- Antibiotics disrupt normal flora → loss of colonisation resistance.
- C. difficile spores survive and germinate.
Step 2: Spore Germination and Colonisation
- Spores ingested (faeco-oral transmission, environmental contamination).
- Spores survive gastric acid (especially if PPI use).
- Spores germinate in colon → vegetative bacteria.
- Vegetative cells colonise colon.
Step 3: Toxin Production
- Toxin A (TcdA): Enterotoxin; causes fluid secretion and inflammation.
- Toxin B (TcdB): Cytotoxin; causes cell damage and death.
- Binary Toxin (CDT): Present in hypervirulent strains; enhances adhesion.
- Both toxins inactivate Rho GTPases → cytoskeletal disruption, cell death.
Step 4: Mucosal Damage and Inflammation
- Toxins cause epithelial cell death.
- Intense inflammatory response.
- Neutrophil infiltration.
- Pseudomembrane formation (fibrin, mucus, necrotic cells, neutrophils).
Step 5: Clinical Disease
ANTIBIOTIC EXPOSURE
↓
MICROBIOME DISRUPTION
(Loss of colonisation resistance)
↓
SPORE GERMINATION
(C. difficile overgrowth)
↓
TOXIN PRODUCTION
(Toxin A + Toxin B)
↓
┌─────────────────────────────────────────┐
│ MUCOSAL DAMAGE AND INFLAMMATION │
│ - Epithelial necrosis │
│ - Pseudomembrane formation │
│ - Fluid secretion │
└─────────────────────────────────────────┘
↓
┌─────────┴─────────┐
↓ ↓
MILD DIARRHOEA SEVERE COLITIS
↓ ↓
Self-limiting Pseudomembranous
with Rx Colitis
↓
┌─────────────┴─────────────┐
↓ ↓
TOXIC MEGACOLON PERFORATION
↓ ↓
SHOCK PERITONITIS
4. Clinical Presentation
Symptoms
| Symptom | Frequency | Description |
|---|---|---|
| Diarrhoea | 90-95% | Watery, non-bloody (unless severe); 3+ loose stools/day |
| Abdominal pain/cramping | 50-70% | Lower abdominal, crampy |
| Fever | 30-50% | Low-grade; higher in severe |
| Nausea/Anorexia | 30% | Non-specific |
| Characteristic odour | Variable | "Horse manure" or "barn-like" smell |
Clinical Features by Severity
| Severity | Clinical Features |
|---|---|
| Mild-Moderate | Diarrhoea (3+/day), WCC less than 15, Cr less than 1.5x baseline |
| Severe | WCC at least 15, Cr at least 1.5x baseline, albumin less than 30 g/L |
| Fulminant | Hypotension/shock, ileus, toxic megacolon, ICU admission |
Timing
Red Flags - "The Don't Miss" Signs
- Toxic megacolon (colon dilation greater than 6cm) → Surgical emergency.
- Ileus or absent bowel sounds → Fulminant disease.
- Peritonitis (rigidity, guarding) → Perforation.
- Hypotension or shock → Sepsis; ICU referral.
- WCC greater than 15 + rising creatinine → Severe disease; close monitoring.
- Lack of diarrhoea with colonic dilatation → Ileus masking severity.
Onset typically 5-10 days after starting antibiotics.
Common presentation.
Can occur up to 8 weeks after antibiotic cessation.
Common presentation.
Community-acquired CDI may have no identifiable antibiotic exposure.
Common presentation.
5. Clinical Examination
General Assessment
- Fever (variable).
- Dehydration (dry mucous membranes, reduced skin turgor).
- Hypotension, tachycardia (severe/fulminant).
Abdominal Examination
Inspection
- Distension (ileus, megacolon).
Palpation
- Tenderness (lower abdominal or diffuse).
- Guarding/rigidity (perforation).
Auscultation
- Hyperactive bowel sounds (early).
- Absent bowel sounds (ileus).
Percussion
- Tympanic (distension).
Signs of Severe Disease
| Sign | Significance |
|---|---|
| Abdominal distension | Ileus, megacolon |
| Diffuse tenderness | Severe colitis |
| Peritonism | Perforation |
| Hypotension | Sepsis, shock |
| Altered consciousness | Septic encephalopathy |
6. Investigations
Stool Testing
Recommended Testing Algorithm
-
GDH Antigen (Glutamate Dehydrogenase)
- Sensitive screening test.
- Detects presence of C. difficile organism.
- Positive = proceed to toxin testing.
-
Toxin EIA (Enzyme Immunoassay)
- Detects Toxin A/B.
- Confirms active infection.
- Lower sensitivity (75-85%).
-
PCR (NAAT)
- Detects toxin gene (tcdB).
- Highly sensitive.
- May detect colonisation without disease.
Interpretation
| GDH | Toxin EIA | PCR | Interpretation |
|---|---|---|---|
| Negative | - | - | CDI unlikely |
| Positive | Positive | - | CDI confirmed |
| Positive | Negative | Positive | Possible CDI or colonisation |
| Positive | Negative | Negative | C. diff present, no toxin - colonisation |
Blood Tests
| Test | Finding | Significance |
|---|---|---|
| WCC | Greater than 15 | Severe disease |
| Creatinine | At least 1.5x baseline | Severe disease; AKI |
| Albumin | Less than 30 g/L | Severe disease marker |
| Lactate | Elevated | Severe sepsis |
| CRP | Elevated | Inflammation |
Imaging
Abdominal X-Ray
- Toxic megacolon: Colon greater than 6cm.
- Thumbprinting: Mucosal oedema.
- Perforation: Free air under diaphragm.
CT Abdomen
- Colonic wall thickening ("accordion sign").
- Pericolonic fat stranding.
- Ascites.
- Megacolon.
Endoscopy
- Generally NOT required for diagnosis.
- If performed, shows pseudomembranes (yellow-white plaques).
- Risk of perforation in severe disease.
7. Management
Management Algorithm
SUSPECTED C. DIFF
(Diarrhoea + risk factors + recent antibiotics)
↓
┌─────────────────────────────────────────────┐
│ INITIAL STEPS │
│ - Send stool for C. diff testing │
│ - Isolate patient (single room) │
│ - STOP causative antibiotics if possible │
│ - STOP anti-motility agents │
│ - IV fluids if dehydrated │
└─────────────────────────────────────────────┘
↓
┌───────────┴───────────┐
↓ ↓
MILD-MODERATE SEVERE/FULMINANT
(WCC less than 15, (WCC at least 15, Cr at least 1.5x,
Cr less than 1.5x) shock, ileus, megacolon)
↓ ↓
┌─────────────────────┐ ┌─────────────────────┐
│ ORAL VANCOMYCIN │ │ ORAL VANCOMYCIN │
│ 125mg QDS x 10 days │ │ 500mg QDS │
│ OR │ │ + Consider IV │
│ FIDAXOMICIN │ │ metronidazole │
│ 200mg BD x 10 days │ │ 500mg TDS │
└─────────────────────┘ │ + Rectal vancomycin │
│ if ileus │
│ + Surgical referral │
│ if megacolon/ │
│ perforation │
└─────────────────────┘
↓
┌────────────────┴────────────────┐
↓ ↓
IMPROVING NOT IMPROVING
↓ ↓
Complete course Consider:
↓ - Escalate therapy
MONITOR FOR - FMT for recurrent
RECURRENCE - Surgery if fulminant
First Episode Treatment
Mild-Moderate
- Oral Vancomycin 125mg QDS for 10 days (first-line). [4]
- OR Fidaxomicin 200mg BD for 10 days (lower recurrence rate).
- Stop causative antibiotics if clinically possible.
Severe
- Oral Vancomycin 500mg QDS.
- + IV Metronidazole 500mg TDS (reaches gut via inflammation).
- If ileus: Rectal Vancomycin enema (500mg in 100mL NS QDS).
Fulminant
- As above + surgical referral.
- Consider subtotal colectomy for toxic megacolon or perforation.
- ICU for haemodynamic support.
Recurrent CDI
| Recurrence | Treatment |
|---|---|
| First Recurrence | Fidaxomicin 200mg BD x 10 days (or extended pulsed vancomycin) |
| Second Recurrence | Consider FMT |
| Third+ Recurrence | FMT highly recommended |
Faecal Microbiota Transplantation (FMT)
- Restores normal gut microbiome.
- Efficacy: 85-90% cure rate for recurrent CDI.
- Via colonoscopy, nasojejunal tube, or capsules.
Infection Control
| Measure | Rationale |
|---|---|
| Single room isolation | Prevents environmental contamination |
| Contact precautions | Gloves and gown |
| Soap and water handwashing | Spores resistant to alcohol |
| Environmental cleaning | Chlorine-based disinfectants for spores |
| Antibiotic stewardship | Reduces risk of CDI |
What NOT to Do
- DO NOT use loperamide or opioid anti-diarrheals → Risk of megacolon.
- DO NOT rely on alcohol gel alone → Spores survive.
- DO NOT delay treatment pending confirmatory tests if high suspicion.
8. Complications
Disease Complications
| Complication | Incidence | Features | Management |
|---|---|---|---|
| Toxic Megacolon | 3-8% | Colon greater than 6cm, systemic toxicity | Surgical referral; colectomy |
| Perforation | 1-3% | Peritonitis, septic shock | Emergency surgery |
| Dehydration/AKI | 10-20% | Reduced urine output, rising creatinine | IV fluids, monitor |
| Septic Shock | 5-10% (severe) | Hypotension, multi-organ failure | ICU, vasopressors |
| Death | 5-15% | Higher in elderly, fulminant | Prevention, early treatment |
Recurrence
- First recurrence: 20-30%.
- After first recurrence: 40-60% risk of further recurrence.
- Risk factors: Age, continued antibiotics, immune suppression.
9. Prognosis and Outcomes
Mortality
| Severity | Mortality |
|---|---|
| Mild-Moderate | 1-5% |
| Severe | 10-20% |
| Fulminant | 30-50% |
| Post-Colectomy | 30-50% |
Prognostic Factors
Poor Prognosis
- Age at least 75 years.
- WCC greater than 20 or less than 1.5.
- Cr at least 2x baseline.
- Albumin less than 25 g/L.
- Hypotension.
- Ileus or megacolon.
- Immunosuppression.
- Delayed treatment.
Recurrence Prevention
- Use fidaxomicin (lower recurrence than vancomycin).
- FMT for recurrent disease.
- Probiotics (limited evidence in adults).
- Bezlotoxumab (monoclonal antibody against Toxin B) for high-risk recurrence.
10. Evidence and Guidelines
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| NICE NG199 | UK | Fidaxomicin or vancomycin first-line; FMT for recurrent |
| IDSA/SHEA 2021 | USA | Vancomycin or fidaxomicin; FMT after 2+ recurrences |
| PHE Guidance | UK | Infection control, antibiotic stewardship |
Landmark Studies
1. Kelly et al. Fidaxomicin vs Vancomycin (2011) [6]
- Question: Is fidaxomicin superior to vancomycin?
- N: Two phase 3 trials, 629 patients.
- Result: Non-inferior for cure; lower recurrence with fidaxomicin (13% vs 27%).
- Impact: Fidaxomicin now first-line option.
- PMID: 21447203.
2. Van Nood et al. FMT for Recurrent CDI (2013) [7]
- Question: Is FMT effective for recurrent CDI?
- N: 43 patients.
- Result: 81% cure with FMT vs 31% with vancomycin.
- Impact: Established FMT as treatment for recurrent CDI.
- PMID: 23323867.
3. Bezlotoxumab (MODIFY Trials 2017)
- Question: Does bezlotoxumab prevent recurrence?
- Result: Reduced recurrence by 40%.
- Impact: Option for high-risk patients.
- PMID: 28103665.
11. Patient and Layperson Explanation
What is C. diff?
Clostridioides difficile (C. diff) is a bacterium that can infect the bowel and cause diarrhoea. It often happens after taking antibiotics, which kill off the normal "good" bacteria in the gut and allow C. diff to grow.
Who Gets It?
- People who have recently taken antibiotics.
- Older adults (65+).
- People staying in hospital or care homes.
- People with weakened immune systems.
What Are the Symptoms?
- Watery diarrhoea (3 or more loose stools per day).
- Stomach cramps.
- Fever.
- Nausea and loss of appetite.
- A distinctive unpleasant smell to stools.
Most cases are mild and get better with treatment.
How is it Diagnosed?
- A stool sample is tested for C. diff toxins.
How is it Treated?
- Stop the antibiotic causing the problem (if possible).
- Antibiotics that work against C. diff: vancomycin or fidaxomicin tablets.
- Fluids to prevent dehydration.
- NO anti-diarrhoea medicines (like loperamide) – these can make it worse.
Can it Come Back?
- Yes, in about 1 in 4 people.
- If it keeps coming back, a treatment called Faecal Microbiota Transplantation (FMT) can help restore normal gut bacteria.
How Can it be Prevented?
- Hand washing: Use soap and water (alcohol gel does not kill C. diff spores).
- Antibiotic stewardship: Only use antibiotics when truly necessary.
- Isolation in hospital: Patients with C. diff are usually in single rooms.
When to Seek Help
- Severe or worsening diarrhoea.
- Blood in stools.
- High fever.
- Severe stomach pain.
- Confusion or feeling very unwell.
12. References
Primary Sources
- McDonald LC, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by IDSA and SHEA. Clin Infect Dis. 2018;66:e1-e48. PMID: 29462280.
- Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372:1539-1548. PMID: 25875259.
- Guh AY, Kutty PK. Clostridioides difficile Infection. Ann Intern Med. 2018;169:ITC49-ITC64. PMID: 30285096.
- NICE Guideline NG199. Clostridioides difficile infection: antimicrobial prescribing. 2021. https://www.nice.org.uk/guidance/ng199.
- Johnson S, et al. Clinical Practice Guideline by IDSA and SHEA: 2021 Focused Update. Clin Infect Dis. 2021;73:e1029-e1044. PMID: 34164674.
- Louie TJ, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364:422-431. PMID: 21288078.
- Van Nood E, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368:407-415. PMID: 23323867.
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