What are the risk factors, diagnostic approach, severity criteria, and management—including antimicrobial therapy and fecal microbiota transplantation—for Clostridioides difficile infection?

Clostridioides difficile Infection: Risk Factors, Diagnosis, Severity, and Management

Risk Factors

The three major categories of CDI risk factors are host factors, exposure to C. difficile spores, and factors disrupting the normal colonic microbiome. 1

Host Factors

• Age >65 years is a primary risk factor 1
• Comorbidities and underlying conditions 1
• Immunodeficiency (including HIV infection, particularly with low CD4 counts) 1
• Malnutrition and low serum albumin level 1
• Inflammatory bowel disease (IBD) 1, 2
• Solid organ transplant recipients due to ongoing immunosuppression 1
• Cancer patients, particularly those receiving chemotherapy 1

Exposure to C. difficile Spores

• Hospitalizations and long-term care facilities 1
• Community sources (community-acquired CDI represents 35% of total CDI burden) 1, 2
• Environmental contamination (spores can survive for months) 1

Factors Disrupting Colonic Microbiome

• Antibiotic exposure is the central risk factor 1
• Highest-risk antibiotics: clindamycin, third-generation cephalosporins, penicillins, and fluoroquinolones 1
• Acid-suppression medications (proton pump inhibitors) 1, 2
• Surgery 1

Diagnosis

A prompt and precise diagnosis requires clinical symptoms plus laboratory confirmation—testing should only be performed on patients with diarrhea (≥3 unformed stools in 24 hours). 1, 3

Diagnostic Approach

• Use a two-step algorithm: first a highly sensitive test (GDH antigen or nucleic acid amplification test), followed by a highly specific test (toxin A/B enzyme immunoassay) 2
• This approach differentiates active disease from colonization 1
• Single tests have very high negative predictive value (typically >99%) 3

Critical Testing Principles

• Do NOT test asymptomatic patients or perform routine testing after treatment completion 3, 4
• Over 60% of successfully treated patients remain C. difficile positive despite clinical resolution 3
• Laboratory testing cannot distinguish between asymptomatic colonization and active infection 3
• Repeat testing within 7 days has only 2% diagnostic yield 3
• Only retest if diarrhea recurs after initial symptom resolution 3

Diagnostic Pitfalls

• Up to 25% of patients referred for FMT with presumed recurrent CDI actually have alternative diagnoses (most commonly IBS or IBD) 1
• Testing should not be repeated without clear changes in clinical presentation 3
• Diagnosis of cure should be based on clinical criteria (resolution of diarrhea), not laboratory testing 3

Severity Classification

Severity determines treatment intensity and must be assessed immediately to guide management decisions.

Non-Severe CDI

• White blood cell count ≤15,000 cells/mL 1
• Serum creatinine <1.5 mg/dL 1

Severe CDI

Multiple criteria indicate severe disease: 1

• Age >65 years
• Body temperature >38.5°C
• ≥10 bowel movements within 24 hours
• Severe abdominal pain due to CDI
• White blood cell count ≥15,000 cells/mL
• Serum creatinine >1.5 mg/dL or increase of ≥50% from baseline
• Active malignancy
• Albumin <2.5 mg/dL

Fulminant CDI

• Hypotension or shock 1
• Ileus 1
• Toxic megacolon 1
• Colonic perforation 1
• End-organ failure 1

Management

Initial Episode: Non-Severe

Vancomycin 125 mg orally four times daily for 10 days OR fidaxomicin 200 mg orally twice daily for 10 days are first-line treatments. 1

• Metronidazole is no longer favored as first-line therapy due to resistance concerns 5
• Metronidazole may be considered as an alternative for non-severe CDI in resource-limited settings 1
• Stop unnecessary antibiotics immediately 1
• Consider extending treatment to 14 days if delayed response occurs 1

Initial Episode: Severe

Vancomycin 125 mg orally four times daily for 10 days OR fidaxomicin 200 mg orally twice daily for 10 days. 1

• Teicoplanin 200 mg twice daily for 10 days is an alternative option 1
• If continued antibiotic therapy is required for other infections, use agents less frequently implicated with CDI 1

Initial Episode: Fulminant

Vancomycin 500 mg orally four times daily PLUS metronidazole 500 mg intravenously every 8 hours. 1

• If ileus is present, consider adding rectal instillation of vancomycin (0.25-1 gram twice to four times daily per rectum) 1
• Prompt surgical evaluation is mandatory 1
• Colectomy with preservation of the rectum may be necessary 1

First Recurrence

Use vancomycin in a prolonged tapered and pulsed regimen (125 mg four times daily for 10-14 days, then twice daily for a week, once daily for a week, then every 2-3 days for 2-8 weeks) if a standard regimen was used initially. 1

Alternative options: 1

• Fidaxomicin 200 mg twice daily for 10 days if vancomycin was used initially
• Vancomycin 125 mg four times daily for 10 days if metronidazole was used initially

Second or Subsequent Recurrence

Fecal microbiota transplantation (FMT) is recommended after multiple recurrences that have failed appropriate antibiotic treatments (typically after at least 2 recurrences, meaning 3 total CDI episodes). 1

Other options include: 1

• Vancomycin tapered and pulsed regimen
• Vancomycin 125 mg four times daily for 10 days followed by rifaximin 400 mg three times daily for 20 days
• Fidaxomicin 200 mg twice daily for 10 days
• Bezlotoxumab IV for recurrent episodes 1

Fecal Microbiota Transplantation

FMT has strong evidence for multiple recurrences, with primary cure rates of 82% for recurrent CDI. 1

Key considerations:

• Lower success rates in severe (72% failure) and severe-complicated (52.9% failure) CDI compared to recurrent CDI (11.9% failure) 1
• Inpatient status is associated with higher failure rates, likely reflecting disease severity 1
• Do NOT perform routine testing for C. difficile toxin after FMT 3
• Testing only appropriate for persistent symptoms or suspected relapse 3

Special Populations

Inflammatory Bowel Disease Patients

• No evidence that one antibiotic regimen is superior 1
• Ongoing immunosuppression can be maintained; avoid escalation 1
• Early surgical consultation is key for severe disease 1

Immunocompromised Patients

• Higher risk in solid organ transplant recipients, cancer patients, and HIV/AIDS patients 1
• Standard treatment protocols apply 2

Infection Control Measures

Hand hygiene with soap and water is essential—alcohol-based sanitizers do not kill C. difficile spores. 1, 2

Additional measures: 1

• Contact (enteric) precautions until resolution of diarrhea (passage of formed stool for ≥48 hours)
• Private room with en suite facilities preferred
• Environmental cleaning and disinfection
• Antimicrobial stewardship is critical for prevention 2

Post-Treatment Considerations

• Symptoms resolve within hours to 4-5 days on average after successful treatment 3
• Up to 35% of patients experience recurrent symptoms due to transient functional bowel disorder in the first two weeks following resolution 3
• Patients may have reduced health scores and altered bowel habits for months, potentially representing post-infectious IBS rather than recurrent infection 3