What is the most appropriate treatment approach for a patient with suspected or confirmed C. diff infection, considering the severity of symptoms and overall health status?

C. difficile Infection Severity Classification and Treatment

Defining Disease Severity

Severe CDI is defined as leukocyte count ≥15,000 cells/L and/or serum creatinine ≥1.5 mg/dL, while fulminant CDI presents with shock, ileus, or megacolon. 1, 2

Clinical Features Indicating Severe Disease

Look for these specific markers when assessing severity:

Laboratory markers:

• Marked leukocytosis (WBC >15 × 10⁹/L) 1
• Marked left shift (band neutrophils >20% of leukocytes) 1
• Rise in serum creatinine (>50% above baseline or ≥1.5 mg/dL) 1
• Elevated serum lactate 1

Clinical signs:

• Temperature >38.5°C 1
• Rigors with uncontrollable shaking 1
• Hemodynamic instability or septic shock 1
• Signs of peritonitis (decreased bowel sounds, abdominal tenderness, rebound tenderness, guarding) 1
• Signs of ileus (vomiting, absent stool passage) 1, 3

Imaging findings:

• Pseudomembranous colitis on endoscopy 1
• Distension of large intestine 1
• Colonic wall thickening with low-attenuation mural thickening 1
• Pericolonic fat stranding 1
• Ascites not explained by other causes 1

Treatment Algorithm by Severity

Initial Episode - Nonsevere CDI

Fidaxomicin 200 mg orally twice daily for 10 days is the preferred first-line treatment for initial CDI. 2, 4

• Oral vancomycin 125 mg four times daily for 10 days is an acceptable alternative 2
• Metronidazole 500 mg orally three times daily for 10-14 days should only be used as a last resort when preferred agents are unavailable, and only for patients with WBC ≤15,000 cells/μL and creatinine <1.5 mg/dL 2

Initial Episode - Severe CDI

Oral vancomycin 125 mg four times daily for 10 days is the preferred treatment for severe CDI. 1, 2, 5

• Fidaxomicin is an acceptable alternative for severe disease 5
• If oral therapy is impossible, use metronidazole 500 mg IV three times daily plus intracolonic vancomycin 500 mg in 100 mL normal saline every 4-12 hours and/or vancomycin 500 mg four times daily by nasogastric tube 1

Fulminant CDI

For fulminant CDI, administer vancomycin 500 mg orally or by nasogastric tube four times daily PLUS intravenous metronidazole 500 mg every 8 hours. 2

• Consider conventional fecal microbiota transplant (FMT) via colonoscopy or flexible sigmoidoscopy if not responding to antibiotics within 2-5 days 1
• FMT is contraindicated in patients with bowel perforation, obstruction, or severe immunocompromise 1
• Most patients with severe or fulminant CDI will need repeat FMT every 3-5 days based on treatment response 1

Surgical Intervention

Colectomy should be performed for:

• Perforation of the colon 1
• Systemic inflammation and deteriorating clinical condition not responding to antibiotic therapy 1
• Toxic megacolon or severe ileus 1
• Operate before serum lactate exceeds 5.0 mmol/L 1

Recurrent CDI Management

First Recurrence

Fidaxomicin 200 mg twice daily for 10 days, or fidaxomicin extended regimen, is preferred for first recurrence. 2

• Consider bezlotoxumab 10 mg/kg IV once during antibiotic administration for high-risk patients (age >65 years, immunocompromised, severe initial CDI, or concomitant antibiotic use) 2

Second and Subsequent Recurrences

Vancomycin 125 mg four times daily orally for at least 10 days with a taper/pulse strategy is recommended. 1

• Example taper: decrease daily dose by 125 mg every 3 days 1
• Example pulse: 125 mg every 3 days for 3 weeks 1

Critical Supportive Measures

Immediately discontinue the inciting antibiotic if possible. 2, 5

• Avoid high-risk antibiotics: clindamycin, third-generation cephalosporins, penicillins, and fluoroquinolones 2
• Switch to lower-risk agents if continued antibiotic therapy is required: parenteral aminoglycosides, sulfonamides, macrolides, vancomycin, or tetracycline/tigecycline 2
• Avoid antiperistaltic agents and opiates 1

Monitoring Treatment Response

Clinical improvement should occur within 3-5 days of starting therapy. 2

• Treatment response is defined as decreased stool frequency or improved consistency after 3 days with no new signs of severe colitis 1
• Treatment failure is absence of response after 3-5 days 1, 2
• Monitor stool output, white blood cell count, and C-reactive protein in severe/fulminant cases 1

Common Pitfalls

Do not perform "test of cure" after treatment completion - this is not recommended and can lead to unnecessary treatment of colonization rather than active infection. 2

Recognize ileus presentation - CDI in critically ill patients may present with ileus rather than diarrhea, requiring high clinical suspicion and potentially different diagnostic approaches. 3

Empirical treatment considerations - only initiate empirical therapy in patients with strong suspicion for severe CDI while awaiting test results; stable patients with mild-to-moderate suspected CDI should have diagnostic testing guide treatment decisions. 5