Clostridioides difficile Colitis
Toxin-mediated colitis after antibiotic disruption of gut microbiota; ranges from diarrhea to toxic megacolon.
Also known as: C. difficile, Clostridioides difficile, C diff, pseudomembranous colitis, CDI
Overview
Colitis caused by toxin-producing Clostridioides difficile (formerly Clostridium difficile), an anaerobic Gram-positive spore-forming bacillus. Spectrum from mild diarrhea to fulminant pseudomembranous colitis with toxic megacolon, perforation, and death.
Epidemiology
Most common healthcare-associated infection in the US; ~500,000 infections and ~30,000 deaths annually. Community-acquired CDI rising. Recurrence after first episode 15-25%; after second, 40-60%.
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Risk factors
- Recent antibiotic exposure — clindamycin, fluoroquinolones, broad-spectrum cephalosporins, carbapenems (highest risk); virtually any antibiotic can precipitate
- Healthcare exposure (hospitalization, long-term care)
- Age >65
- Proton pump inhibitor and H2 receptor blocker use (modest association)
- Immunosuppression (chemotherapy, transplant, IBD, HIV)
- Inflammatory bowel disease
- Prior CDI (risk of recurrence)
- Tube feeding, GI surgery
- Toxigenic strain BI/NAP1/027 — hypervirulent, associated with severe disease and outbreaks
Pathophysiology
Antibiotic-induced disruption of normal colonic microbiota allows C. difficile spores ingested fecal-orally to germinate. Vegetative cells produce toxins A (enterotoxin) and B (cytotoxin), and binary toxin (CDT) in some strains, which disrupt the cytoskeleton, induce inflammation, and damage colonic epithelium → pseudomembranes (fibrin, mucus, leukocytes, sloughed cells).
Clinical presentation
Symptoms
- Watery diarrhea (≥3 unformed stools per 24 h) — hallmark
- Lower abdominal cramping
- Low-grade fever
- Anorexia, nausea
- Blood is unusual (consider IBD, ischemia, infection if present)
- Severe disease: high fever, marked leukocytosis, severe abdominal pain, distension
- Fulminant disease: shock, ileus, toxic megacolon (loss of diarrhea due to ileus)
Signs / physical exam
- Abdominal tenderness
- Distension (severe disease)
- Fever, tachycardia
- Hypotension if severe
- Peritonitis suggests perforation
- Diminished bowel sounds in ileus / toxic megacolon
- Often normal exam in mild disease
Classic findings
Watery diarrhea, low-grade fever, leukocytosis, and abdominal pain following recent antibiotic exposure and/or hospitalization.
Differential diagnosis
- Antibiotic-associated diarrhea (non-CDI) — Mild, no fever or leukocytosis, no toxin, no pseudomembranes; resolves with antibiotic cessation
- Inflammatory bowel disease (Crohn, UC) — Chronic course, blood, extraintestinal features; biopsy distinct
- Ischemic colitis — Older patient, watershed areas, atherosclerotic risk factors
- Infectious diarrhea (Salmonella, Shigella, Campylobacter, E. coli O157, Yersinia, norovirus) — Stool studies, exposure history
- Microscopic colitis — Watery non-bloody diarrhea in older women; macroscopically normal colonoscopy
- Diverticulitis — LLQ pain, fever, leukocytosis; CT findings
- CMV colitis — Immunocompromised; biopsy with inclusion bodies
- Functional / IBS — Chronic, no infection, normal labs
Diagnostic workup
Diagnostic criteria
Clinical (≥3 unformed stools/24 h not otherwise explained) + positive stool test (NAAT for toxin gene, or toxin EIA, or both with multi-step algorithm). IDSA 2018 severity: Non-severe (WBC ≤15,000 AND Cr <1.5 mg/dL); Severe (WBC >15,000 OR Cr ≥1.5); Fulminant (hypotension, shock, ileus, megacolon).
Labs
- Stool C. difficile testing — multi-step algorithm preferred: NAAT (PCR) alone or NAAT + toxin enzyme immunoassay
- GDH antigen + toxin EIA; if discordant, reflex to NAAT
- TEST ONLY in patients with clinically significant diarrhea (≥3 unformed stools/24h); do NOT test asymptomatic patients (colonization is common and not infection)
- CBC — leukocytosis (WBC >15,000 = severe disease); leukemoid reaction (WBC >30,000) is poor prognostic
- BMP — AKI (Cr >1.5× baseline = severe disease)
- Lactate (severe disease)
- Albumin (low in severe disease)
- Stool studies for other pathogens if epidemiologically appropriate
Imaging
- CT abdomen/pelvis — for severe or complicated disease; colonic wall thickening (mural thickening, 'accordion sign' from contrast trapped between thickened folds), pericolonic stranding, megacolon, ascites, perforation
- Abdominal radiograph — toxic megacolon (colonic dilation >6 cm)
- Flexible sigmoidoscopy/colonoscopy — visualization of pseudomembranes (yellow-white plaques) is diagnostic but rarely needed and contraindicated in severe disease (perforation risk)
Diagnostic algorithm
| IDSA Severity | Criteria | Preferred Therapy |
|---|---|---|
| Non-severe | WBC ≤15,000 AND Cr <1.5 mg/dL | Fidaxomicin 200 mg PO BID × 10 days (preferred) or oral vancomycin 125 mg QID × 10 days |
| Severe | WBC >15,000 OR Cr ≥1.5 mg/dL | Fidaxomicin (preferred) or oral vancomycin 125 mg QID × 10 days |
| Fulminant | Hypotension/shock, ileus, or megacolon | IV metronidazole 500 mg q8h + oral vancomycin 500 mg q6h (+ rectal vancomycin if ileus); early surgical consult |
| First recurrence | After initial cure | Fidaxomicin BID × 10 d, or tapered/pulsed vancomycin, ± bezlotoxumab |
| Multiply recurrent (≥2) | After multiple recurrences | Fecal microbiota transplantation (FMT) or oral microbiome therapeutics |
Treatment
First-line
- DISCONTINUE inciting antibiotic if possible
- Initial episode, non-severe: fidaxomicin 200 mg PO BID × 10 days (PREFERRED — lower recurrence) OR oral vancomycin 125 mg PO QID × 10 days
- Initial episode, severe: fidaxomicin (preferred) or oral vancomycin 125 mg PO QID × 10 days
- Fulminant disease (hypotension, shock, ileus, megacolon): IV metronidazole 500 mg q8h + oral vancomycin 500 mg q6h (and rectal vancomycin if ileus) ± early surgical consultation
- Avoid antimotility agents (loperamide) in active disease — risk of toxic megacolon
- Infection control: contact precautions, soap and water (alcohol does NOT kill spores), dedicated equipment
First recurrence
- Fidaxomicin 200 mg BID × 10 days (preferred — lower recurrence than vancomycin)
- Tapered/pulsed oral vancomycin: 125 mg QID × 10-14 d, then BID × 7 d, then daily × 7 d, then q2-3 days × 2-8 wk
- Bezlotoxumab — anti-toxin B monoclonal antibody (single IV infusion adjunct to standard therapy for patients at high recurrence risk)
Multiply recurrent CDI (≥2 recurrences)
- Fecal microbiota transplantation (FMT) — highly effective (~85-90% cure); via colonoscopy, enema, NG tube, capsules, or FDA-approved oral formulations (SER-109 — Vowst; RBX2660 — Rebyota)
- Tapered/pulsed vancomycin or extended fidaxomicin
- Add bezlotoxumab
Fulminant CDI
- Combination IV metronidazole + oral high-dose vancomycin (+ rectal vancomycin if ileus)
- Early surgical consultation
- Surgical options: subtotal colectomy with end ileostomy (traditional), or loop ileostomy with antegrade colonic vancomycin lavage (Neal procedure — colon-sparing alternative)
Complications
- Recurrence (15-25% after first episode; 40-60% after second)
- Severe colitis: dehydration, electrolyte imbalance, hypotension, AKI
- Toxic megacolon — colonic dilation >6 cm with systemic toxicity
- Perforation
- Sepsis, septic shock
- Death (~5% overall; up to 80% with fulminant disease and shock)
- Bowel obstruction from inflammatory stricture (rare)
- Reactive arthritis (rare)
PANCE pearls
- TEST ONLY symptomatic patients — colonization is common (3-15% of hospitalized adults) and testing asymptomatic patients leads to over-diagnosis.
- DO NOT use IV vancomycin for CDI — does not reach colonic lumen. Oral vancomycin is essential for colonic delivery.
- Fidaxomicin is now PREFERRED over vancomycin for initial CDI (IDSA 2021 update) due to lower recurrence — cost-prohibitive in some settings.
- Oral metronidazole is NO LONGER first-line for initial CDI (IDSA 2017/2018) due to inferior efficacy — reserved for IV use in fulminant disease combined with oral vancomycin.
- Avoid antimotility agents (loperamide, diphenoxylate) in active CDI — risk of toxic megacolon.
- Alcohol-based hand sanitizer does NOT kill C. difficile spores — wash hands with soap and water.
- Fecal microbiota transplantation (FMT) for recurrent CDI is highly effective (~90% cure) — FDA-approved oral formulations now available (Vowst, Rebyota).
- Bezlotoxumab is a monoclonal antibody against toxin B — adjunct for patients at high risk of recurrence (age >65, prior CDI, severe disease, immunocompromised).
- Toxic megacolon: colonic dilation >6 cm on imaging + systemic toxicity — STOP antimotility/opioids/anticholinergics; aggressive medical management; early surgical consultation.
- Surgical options for fulminant CDI: subtotal colectomy or diverting loop ileostomy with antegrade colonic vancomycin lavage (colon-sparing).
- IBD patients with CDI: continue IBD therapy; CDI worsens IBD outcomes and recurs more often.
References
- IDSA/SHEA 2017 — McDonald LC et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the IDSA and SHEA. Clin Infect Dis 2018;66:e1-e48
- IDSA/SHEA 2021 Focused Update — Johnson S et al. Clinical Practice Guideline by the IDSA and SHEA: 2021 Focused Update on Management of CDI in Adults. Clin Infect Dis 2021;73:e1029-e1044
- ACG 2021 — Kelly CR et al. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. Am J Gastroenterol 2021;116:1124-1147
- MODIFY I/II Bezlotoxumab — Wilcox MH et al. Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection. NEJM 2017;376:305-317
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