What is the recommended assessment, diagnostic work‑up, severity classification, and treatment plan for a patient with suspected or confirmed Clostridioides difficile infection, including management of non‑severe, severe, fulminant disease, and recurrences?

Assessment, Workup, and Management of Clostridioides difficile Infection

Initial Assessment and Diagnostic Workup

Test only patients with unexplained diarrhea (≥3 unformed stools in 24 hours) using a two-step algorithm: glutamate dehydrogenase (GDH) screening followed by toxin detection to differentiate active disease from colonization. 1

Key Clinical Features to Assess

• Stool frequency and consistency as perceived by the patient over the preceding 24-48 hours 1
• Systemic signs of infection: fever >38.5°C, rigors, hemodynamic instability, or septic shock 1
• Abdominal examination: assess for peritoneal signs (rebound tenderness, guarding), decreased bowel sounds suggesting ileus, or diffuse tenderness 1
• Recent antibiotic exposure within the past 8 weeks and whether the inciting agent can be discontinued 1
• Risk factors for recurrence: age >65 years, continued antibiotic use for other infections, proton pump inhibitor use, severe underlying comorbidities, or prior CDI episodes 1, 2

Essential Laboratory and Imaging Studies

• Complete blood count: WBC ≥15,000 cells/mL or marked left shift (>20% bands) indicates severe disease 1, 3
• Serum creatinine: elevation ≥1.5 times baseline or ≥50% above baseline defines severe disease 1, 3
• Serum albumin: <2.5-3.0 g/dL suggests severe disease 3
• Serum lactate: levels >5.0 mmol/L mandate urgent surgical consultation 1
• CT imaging when severe disease is suspected: look for colonic wall thickening, low-attenuation mural thickening, pericolonic fat stranding, colonic distension, or unexplained ascites 1
• Endoscopy only when diagnosis is uncertain or imaging unavailable; pseudomembranous colitis confirms severe disease 1

Diagnostic Testing Algorithm

Use a multistep algorithm combining GDH screening with nucleic acid amplification testing (NAAT) or toxin enzyme immunoassay (EIA), which achieves sensitivity of 0.91-0.98 and specificity of 0.96-0.98. 1

• Do not repeat testing after negative results; 91% of positive results occur on the first test and repeat testing adds <2.5% yield 1
• Do not perform test-of-cure after treatment; clinical improvement is the endpoint 4
• Avoid testing asymptomatic patients as 10-52% of hospitalized patients are colonized without disease 1

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Severity Classification System

Mild-to-Moderate CDI

Defined by WBC <15,000 cells/µL AND serum creatinine <1.5 times baseline AND absence of systemic signs of severe infection. 1, 3

• Diarrhea without hemodynamic compromise 1, 3
• Stool frequency typically <4 times daily 1
• Mild abdominal cramping may be present 1

Severe CDI

Defined by ANY of the following: WBC ≥15,000 cells/µL OR serum creatinine ≥1.5 mg/dL (or ≥50% rise from baseline). 1, 3

Additional markers supporting severe classification: 1, 3

• Temperature >38.5°C with rigors
• Hemodynamic instability or signs of septic shock
• Peritoneal signs (rebound, guarding, decreased bowel sounds)
• Marked left shift (>20% band neutrophils)
• Elevated serum lactate
• Pseudomembranous colitis on endoscopy
• Colonic wall thickening or distension on imaging

Fulminant (Severe-Complicated) CDI

Characterized by life-threatening features: hypotension requiring vasopressors, ileus, toxic megacolon, colonic perforation, or ICU admission for CDI. 1, 3

• Vomiting with absent stool passage (ileus) 1
• Serum lactate >5.0 mmol/L is a critical threshold for surgical intervention 1
• Altered mental status or end-organ dysfunction 3

Recurrent CDI

Defined as return of gastrointestinal symptoms attributable to CDI within 8 weeks after completion of therapy, with microbiological confirmation. 1, 3

• Stool frequency increases for two consecutive days with looser consistency 1
• Occurs in 10-30% after initial treatment and up to 60% after multiple recurrences 3, 5

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Treatment Algorithm by Severity

Mild-to-Moderate CDI (First Episode)

Oral vancomycin 125 mg four times daily for 10 days is the preferred first-line regimen. 1, 3

Alternative options:

• Fidaxomicin 200 mg twice daily for 10 days for patients at high risk of recurrence (age >65, continued antibiotic use, multiple comorbidities) 1, 3
• Metronidazole 500 mg three times daily for 10 days may be considered only in mild cases in younger patients with no risk factors for recurrence, though it is no longer first-line 1, 4, 5

Critical action: Discontinue the inciting antibiotic immediately if clinically feasible. 1, 4, 6

Severe CDI (First Episode)

Oral vancomycin 125 mg four times daily for 10-14 days is the definitive first-line choice. 1, 3, 4

Alternative:

• Fidaxomicin 200 mg twice daily for 10 days 1, 3

If oral administration is impossible (ileus): 1, 4

• Metronidazole 500 mg IV every 8 hours PLUS
• Rectal vancomycin enema 500 mg in 100-500 mL saline every 4-12 hours AND/OR
• Vancomycin 500 mg via nasogastric tube four times daily

Fulminant CDI

Triple therapy is mandatory: oral vancomycin 500 mg four times daily PLUS rectal vancomycin enema 500 mg in 500 mL saline four times daily PLUS IV metronidazole 500 mg every 8 hours. 3, 4

Immediate multidisciplinary consultation with critical care, surgery, gastroenterology, and infectious disease teams is required 3

Surgical indications (urgent colectomy): 1, 6

• Colonic perforation
• Toxic megacolon
• Severe ileus unresponsive to medical therapy
• Worsening systemic inflammation despite antibiotics
• Serum lactate >5.0 mmol/L
• Perform surgery early, before colitis becomes extremely severe, to improve outcomes 1, 4

Consider fecal microbiota transplantation (FMT) via colonoscopy or flexible sigmoidoscopy if no clinical response within 2-5 days 3

First Recurrence

Repeat the initial treatment regimen based on severity: vancomycin 125 mg four times daily for 10 days or fidaxomicin 200 mg twice daily for 10 days. 1, 3, 4

Second and Subsequent Recurrences

Vancomycin taper-pulse regimen is the preferred strategy: 1, 3

• 125 mg every 6 hours × 1-2 weeks, THEN
• 125 mg every 12 hours × 1 week, THEN
• 125 mg every 24 hours × 1 week, THEN
• 125 mg every 48 hours × 2-8 weeks

Alternative:

• Fidaxomicin 200 mg twice daily for 10 days 1, 3

Fecal microbiota transplantation is highly effective (70-90% success) for multiple recurrences and should be strongly considered. 1, 4

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Critical Management Principles and Pitfalls

Medications to Avoid

Never use antiperistaltic agents (loperamide, diphenoxylate) or opioid analgesics—they precipitate toxic megacolon. 1, 4, 6

Do not use parenteral vancomycin for CDI—it is not excreted into the colon and is completely ineffective. 4

Treatment Response Assessment

Expect clinical improvement (decreased stool frequency or improved consistency) within 3 days; escalate therapy if no response by 72 hours. 1, 3, 6

Treatment failure is defined as absence of improvement after 3 days or development of new signs of severe colitis. 1, 6

Antibiotic Stewardship

If continued antibiotics are required for other infections, choose agents with lower CDI risk: parenteral aminoglycosides, sulfonamides, macrolides, vancomycin, or tetracyclines 4

Avoid prolonged or repeated metronidazole courses due to cumulative, potentially irreversible neurotoxicity. 4, 6

Common Diagnostic Pitfalls

Consider post-infectious irritable bowel syndrome rather than recurrent CDI in patients with mild lingering symptoms after successful treatment. 1, 3

Confirm true recurrent CDI before FMT referral—25% of presumed recurrences are actually IBS (n=18) or IBD (n=3) misdiagnoses, particularly in younger patients. 1

Fidaxomicin Limitations

Do not use fidaxomicin for fulminant or complicated CDI—there are no data supporting its efficacy in this setting. 1, 3