What are the primary causes of Clostridioides difficile (C. diff) infection?

Primary Causes of Clostridioides difficile (C. diff) Infection

The primary cause of C. difficile infection is the disruption of normal intestinal microbiota due to antibiotic use, which allows C. difficile to proliferate and produce toxins A and B that damage the intestinal epithelium. 1

Pathogenesis and Transmission

C. difficile is an anaerobic, spore-forming, Gram-positive bacillus that spreads via the fecal-oral route. The infection process involves:

1. Spore ingestion: C. difficile spores survive the acidic environment of the stomach and germinate in the intestine 2
2. Colonization: The bacteria colonize the intestine when normal gut flora is disrupted
3. Toxin production: Toxigenic strains produce toxins A and B, which act as glucosyltransferases that disrupt the cytoskeleton of colonocytes, leading to cell death 2
4. Inflammation and tissue damage: The toxins cause epithelial necrosis, inflammatory infiltrates, and fluid shifts resulting in diarrhea 2

Major Risk Factors

Antibiotic Exposure

• Highest risk antibiotics:

  • Clindamycin (historically associated with highest rates) 1
  • Third-generation cephalosporins 1
  • Penicillins (especially amoxicillin/clavulanate) 1
  • Fluoroquinolones 1

• The risk of CDI increases up to six times during antibiotic therapy and in the month following administration, even with limited exposure such as a single dose for surgical prophylaxis 1

Healthcare Exposure

• Hospitalization (current or recent) 2
• Longer duration of hospital stay 2
• Residence in long-term care facilities 2
• Exposure to contaminated healthcare environments 2

Host Factors

• Advanced age (especially ≥65 years) 2
• Immunocompromised status 3
• Comorbid conditions (chronic kidney disease, inflammatory bowel disease) 2
• Proton pump inhibitor use 2
• Chemotherapy 2
• Use of feeding tubes 2

Transmission Routes

1. Healthcare-associated transmission:

   • Contact with contaminated surfaces 2
   • Healthcare personnel's hands 2
   • Patient-to-patient spread 2

2. Community-associated transmission:

   • Increasing in prevalence 3
   • Often linked to outpatient healthcare exposure 2
   • Environmental sources (C. difficile is found in soil and water) 4

Epidemiology

• C. difficile is the most common cause of healthcare-associated diarrhea 5
• Approximately 64.7% of cases are healthcare-associated, with 37% hospital-onset, 36% originating in long-term care facilities, and 28% community-onset but healthcare-associated 2
• Even among community-associated cases, 82% have had recent outpatient healthcare exposure 2

Strain Virulence

• The emergence of hypervirulent strains, particularly the epidemic BI/NAP1/027 strain, has contributed to increased incidence and severity of CDI since the early 2000s 2, 4
• These epidemic strains often show resistance to multiple antibiotics, including fluoroquinolones 4
• Approximately 60% of epidemic strains show resistance to three or more antibiotics 2

Prevention Strategies

• Antimicrobial stewardship to reduce unnecessary antibiotic use 6
• Isolation of infected patients 1
• Hand hygiene with soap and water (preferred over alcohol-based products during outbreaks) 6
• Contact precautions 1
• Environmental cleaning with sporicidal agents 1

Clinical Implications

Understanding the causes of C. difficile infection is crucial for both prevention and treatment. The disruption of intestinal microbiota by antibiotics remains the most significant modifiable risk factor. Healthcare facilities should implement comprehensive prevention strategies focusing on antimicrobial stewardship, infection control measures, and environmental cleaning to reduce the burden of this increasingly common and potentially severe infection.