What is the management approach for a patient with suspected or confirmed Clostridioides (C.) difficile infection?

Management of Clostridioides difficile Infection

For initial C. difficile infection, fidaxomicin 200 mg twice daily for 10 days is the preferred treatment, with oral vancomycin 125 mg four times daily for 10 days as an acceptable alternative; metronidazole should only be used for nonsevere disease when the preferred agents are unavailable. 1

Diagnosis and Initial Assessment

Diagnostic Criteria:

• CDI requires diarrhea (≥3 unformed stools in 24 hours) AND either a positive stool test for toxigenic C. difficile or colonoscopic/histopathologic evidence of pseudomembranous colitis 1
• Testing should only be performed in symptomatic patients with diarrhea, not for asymptomatic individuals 1, 2
• Multistep approaches using PCR for toxin genes or single-step PCR on liquid stool samples have the highest sensitivity and specificity 1
• "Test of cure" after treatment is not recommended 1

Severity Classification:

• Nonsevere CDI: WBC ≤15,000 cells/μL AND serum creatinine <1.5 mg/dL 1
• Severe CDI: WBC ≥15,000 cells/μL OR serum creatinine ≥1.5 mg/dL 1
• Fulminant CDI: Hypotension, shock, ileus, megacolon, or colonic perforation 1

Treatment by Disease Severity

Initial Episode - Nonsevere to Severe CDI

Preferred Treatment:

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

Alternative Treatment:

• Vancomycin 125 mg orally four times daily for 10 days 1

Last Resort (only if above unavailable and nonsevere disease):

• Metronidazole 500 mg orally three times daily for 10-14 days 1
• This option is restricted to nonsevere CDI only (WBC ≤15,000 cells/μL and creatinine <1.5 mg/dL) 1

Fulminant CDI

Treatment Regimen:

• Vancomycin 500 mg orally or by nasogastric tube four times daily 1
• PLUS intravenous metronidazole 500 mg every 8 hours 1
• If ileus is present, add rectal vancomycin instillation (500 mg in 500 mL saline as enema four times daily) 1

Recurrent CDI Management

First Recurrence

Preferred Options:

• Fidaxomicin 200 mg twice daily for 10 days, OR fidaxomicin extended regimen (twice daily for 5 days, then once every other day for 20 days) 1
• Vancomycin tapered and pulsed regimen: 125 mg four times daily for 10-14 days, then twice daily for 7 days, then once daily for 7 days, then every 2-3 days for 2-8 weeks 1

Alternative:

• Standard vancomycin 125 mg four times daily for 10 days (especially if metronidazole was used for initial episode) 1

Adjunctive Therapy:

• Bezlotoxumab 10 mg/kg IV once during antibiotic administration may be considered for patients at high risk of recurrence 1
• Risk factors include age >65 years, immunocompromised status, severe initial CDI, or concomitant antibiotic use 1
• Caution: Bezlotoxumab should be reserved for patients with congestive heart failure only when benefits outweigh risks 1

Second or Subsequent Recurrence

Treatment Options (in order of preference):

1. Fidaxomicin 200 mg twice daily for 10 days OR extended regimen 1
2. Vancomycin tapered and pulsed regimen 1
3. Vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days 1
4. Fecal microbiota transplantation (FMT) after at least 2 recurrences (i.e., 3 total CDI episodes) 1, 4

FMT Considerations:

• FMT is associated with 70-90% cure rates in recurrent CDI 5, 4
• Two FDA-approved live biotherapeutic products are now available for prevention of recurrent CDI 4
• FMT should be considered after appropriate antibiotic treatments for at least 2 recurrences 1

Critical Supportive Measures

Antibiotic Stewardship:

• Discontinue the inciting antibiotic immediately if possible 1, 6
• If continued antibiotic therapy is required, switch to lower-risk agents: parenteral aminoglycosides, sulfonamides, macrolides, vancomycin, or tetracycline/tigecycline 1, 6
• Avoid high-risk antibiotics: clindamycin, third-generation cephalosporins, penicillins, and fluoroquinolones 6

Medication Review:

• Discontinue unnecessary proton pump inhibitors 1, 6
• Avoid antimotility agents and opiates 7

Empirical Therapy:

• Empirical therapy should be avoided unless there is strong suspicion for severe CDI 1
• If empirical therapy is initiated for suspected severe CDI, begin treatment while awaiting test results 1

Special Considerations for Concomitant Antibiotic Use

When patients require continued antibiotics for other infections during CDI treatment:

• Fidaxomicin may be preferable to vancomycin due to less microbiome disruption 8
• Minimize the number and duration of concomitant antibiotics 8
• Change to low-risk antibiotic classes when possible 8
• Consider bezlotoxumab if multiple risk factors for recurrence exist 8
• Insufficient evidence supports extending anti-CDI therapy duration 8

Monitoring and Treatment Response

• Clinical improvement (decreased stool frequency, improved consistency) should occur within 3-5 days of starting therapy 1, 7
• Treatment failure is defined as absence of response after 3-5 days 7
• Therapy escalation can be considered sooner based on disease severity 1
• Recurrence is defined as return of symptoms with microbiological evidence after initial response 7

Common Pitfalls to Avoid

• Do not test asymptomatic patients regardless of exposure history 2
• Do not use metronidazole as first-line therapy for adults with CDI 1, 9
• Do not perform "test of cure" after successful treatment 1
• Do not use colonoscopy in fulminant colitis due to perforation risk 1
• Do not test children <12 months due to high rates of asymptomatic colonization 2