What are the treatment options for a patient with Clostridioides difficile (C. diff) infection?

Treatment of Clostridioides difficile Infection

For initial nonsevere C. difficile infection, oral vancomycin 125 mg four times daily for 10 days is the preferred first-line treatment, with fidaxomicin 200 mg twice daily for 10 days as an equally acceptable alternative. 1, 2, 3

Initial Episode: Nonsevere Disease

Disease Definition:

• Nonsevere CDI is characterized by white blood cell count ≤15,000 cells/μL and serum creatinine <1.5 mg/dL 3

First-Line Treatment Options:

• Oral vancomycin 125 mg four times daily for 10 days is the preferred treatment, demonstrating superior clinical outcomes compared to metronidazole 1, 2, 3
• Fidaxomicin 200 mg twice daily for 10 days is equally acceptable as first-line therapy, particularly for patients at high risk for recurrence (elderly, multiple comorbidities, or requiring concurrent antibiotics) 1, 2, 3, 4
• Metronidazole is no longer recommended as first-line therapy for adults due to inferior outcomes and cumulative neurotoxicity risk with prolonged use 1, 2, 3

Initial Episode: Severe or Fulminant Disease

Disease Definition:

• Severe disease: white blood cell count >15,000 cells/μL, serum creatinine ≥1.5 mg/dL, or other clinical markers of severity 3
• Fulminant disease: hypotension/shock, ileus, or megacolon 1, 3

Treatment Protocol:

• Oral vancomycin 125 mg four times daily for 10 days for severe CDI 1, 2, 3
• For fulminant CDI, escalate to oral vancomycin 500 mg four times daily by mouth or nasogastric tube 1, 3
• Add intravenous metronidazole 500 mg every 8 hours in conjunction with oral vancomycin, especially if ileus is present (IV metronidazole achieves therapeutic concentrations in inflamed colon when oral delivery is impaired) 1, 3
• Consider rectal vancomycin instillation (500 mg in 100 mL normal saline every 4-12 hours as retention enema) if ileus prevents oral administration, though unclear if sufficient drug reaches beyond the left colon 1, 3

Surgical Considerations:

• Early surgical consultation is critical for patients with fulminant colitis 1, 3
• Rising white blood cell count ≥25,000 or rising lactate ≥5 mmol/L is associated with high mortality and identifies patients requiring early surgery 1, 3
• Subtotal colectomy is the established procedure for megacolon, colonic perforation, acute abdomen, or septic shock with organ failure 1
• Loop ileostomy with antegrade vancomycin lavage is a colon-preserving alternative that warrants consideration 1

First Recurrence

Treatment Options (in order of preference):

• Fidaxomicin 200 mg twice daily for 10 days demonstrates lower recurrence rates compared to vancomycin 1, 2, 3
• Extended fidaxomicin regimen (200 mg twice daily for 5 days, then once every other day for 20 days) may be considered 3
• Tapered and pulsed vancomycin regimen: 125 mg four times daily for 10-14 days, then 125 mg twice daily for 7 days, then 125 mg once daily for 7 days, then 125 mg every 2-3 days for 2-8 weeks 1, 2, 3
• Standard vancomycin 125 mg four times daily for 14 days if metronidazole was used for the initial episode 1
• Metronidazole is not recommended for recurrent CDI due to lower sustained response rates and neurotoxicity concerns 1, 2

Multiple Recurrences (Second or Subsequent)

Fecal Microbiota Transplantation (FMT):

• FMT is strongly recommended after failure of appropriate antibiotic treatments for at least 2 recurrences (3 total CDI episodes), with clinical resolution rates of 87-92% compared to 40-50% with antibiotics alone 1, 2, 3
• Administer oral vancomycin 125 mg four times daily for 4-10 days as a lead-in before FMT 2
• FMT can be delivered via colonoscopy or nasojejunal tube with similar efficacy 2

Alternative Antibiotic Approaches:

• Vancomycin tapered and pulsed regimen (as detailed above) is the most evidence-supported antibiotic approach for multiple recurrences 1, 2
• Standard vancomycin course followed by rifaximin is an alternative option 1

Essential Supportive Measures

Antibiotic Management:

• Discontinue the inciting antibiotic immediately if clinically possible, as this is critical for treatment success 1, 2, 3, 5
• If continued antibiotic therapy is necessary, switch to lower-risk antibiotics: parenteral aminoglycosides, sulfonamides, macrolides, vancomycin, or tetracyclines/tigecycline 1, 2, 3, 5
• Avoid high-risk antibiotics: clindamycin, third-generation cephalosporins, fluoroquinolones, and penicillins are strongly associated with CDI 1, 2, 3

Other Supportive Care:

• Discontinue proton pump inhibitors if not absolutely required, as they increase CDI risk and recurrence 1, 2, 3
• Avoid antiperistaltic agents and opiates, which can worsen disease 3
• Provide aggressive supportive care including IV fluid resuscitation, electrolyte replacement, and albumin supplementation for severe hypoalbuminemia (<2 g/dL) 1, 2

Adjunctive Therapies

Bezlotoxumab:

• Bezlotoxumab (monoclonal antibody against C. difficile toxin B) may prevent recurrences, particularly in patients with CDI due to the 027 epidemic strain, immunocompromised patients, and those with severe CDI 1

Probiotics:

• Limited evidence supports probiotics as adjunctive treatment for first episodes in immunocompetent patients 1, 2
• Probiotics are contraindicated in immunocompromised patients due to bacteremia/fungemia risk 2

Pediatric Considerations

For children 6 months to <18 years:

• Fidaxomicin is FDA-approved for pediatric patients aged 6 months and older 4
• Weight-based dosing for oral suspension: 80-200 mg twice daily depending on weight (4 kg to ≥12.5 kg) 4
• For children weighing ≥12.5 kg who can swallow tablets: 200 mg tablet twice daily for 10 days 4

For initial nonsevere CDI in children:

• Either metronidazole or vancomycin may be used 3
• Metronidazole: 7.5 mg/kg/dose three or four times daily (maximum 500 mg per dose) for 10 days 3
• Vancomycin: 10 mg/kg/dose four times daily (maximum 125 mg per dose) for 10 days 3

Critical Monitoring Parameters

Watch for warning signs requiring escalation:

• White blood cell count ≥25,000 or rising 1, 2
• Lactate ≥5 mmol/L 1, 2
• Ileus, toxic megacolon, or peritoneal signs 1, 2
• Hypotension, shock, or organ failure 1

Common Pitfalls to Avoid

• Do not use intravenous vancomycin for CDI, as it is not excreted into the colon and has no effect on CDI 5
• Do not use metronidazole for severe disease, recurrent disease, or long-term therapy due to inferior outcomes and neurotoxicity 1, 2, 3
• Do not delay surgical consultation in patients with fulminant colitis, as early surgery before severe deterioration improves outcomes 1, 3
• Consider treatment extension to 14 days if delayed response occurs, particularly with metronidazole 3