What causes Clostridioides difficile (C diff) infection?

Causes of Clostridioides difficile (C. diff) Infection

The primary cause of C. diff infection is disruption of the normal gut microbiota, most commonly due to antibiotic use, which creates a niche for C. difficile to flourish and produce toxins. 1

Main Risk Factors

Disruption of Normal Colonic Microbiome

• Antibiotic exposure: The most important modifiable risk factor for CDI development 1

  • High-risk antibiotics: Third/fourth-generation cephalosporins, fluoroquinolones, carbapenems, and clindamycin 1
  • Risk increases 7-10 fold during and in the first month after antibiotic exposure 1
  • Even limited exposure such as single-dose surgical antibiotic prophylaxis increases risk 1
  • The disruption of intestinal microbiota by antibiotics is long-lasting, with risk extending up to 3 months following cessation of therapy 1

• Other medications that disrupt gut flora:

  • Proton pump inhibitors (PPIs) and histamine-2 blockers may increase risk by altering stomach acid protection, though this remains controversial 1
  • Long-term PPI use has been shown to decrease lower gastrointestinal microbial diversity 1
  • Cancer chemotherapy agents with antibiotic activity 1

Exposure to C. difficile Spores

• Hospital environments (healthcare-associated infection) 1
• Long-term care facilities 1
• Community sources (increasing in prevalence) 2
• Transmission occurs via the oral-fecal route 1
• Spores can survive for months in the environment 1

Host Factors

• Advanced age (>65 years): One of the most important risk factors 1

• Comorbidities and underlying conditions 1:

  • Inflammatory bowel disease 1
  • Immunodeficiency (including HIV infection) 1
  • Malnutrition 1
  • Low serum albumin levels 1
  • Type 2 diabetes mellitus (may present with different characteristics) 1

• Gastrointestinal procedures:

  • GI surgery or manipulation of the gastrointestinal tract 1
  • Tube feeding 1

Pathogenesis

1. Ingestion of C. difficile spores that survive the acidic environment of the stomach 1
2. Germination in the intestine when normal flora is disrupted 1
3. Production of toxins A and B, which act as glucosyltransferases 1:
   • Promote activation of Rho GTPases
   • Lead to disorganization of the colonocyte cytoskeleton
   • Result in cell death and colitis 1
4. Non-toxigenic C. difficile strains are non-pathogenic, confirming that CDI is a toxin-mediated infection 1

Risk Factors for Recurrent CDI

• Advanced age 1
• Continued antibiotic use during follow-up 1
• PPI use 1
• Specific C. difficile strain types 1
• Previous exposure to fluoroquinolones 1
• Continuous PPI use may increase recurrence risk by 50% 1
• Low vitamin D levels 1
• Impaired humoral immunity, particularly against toxin B 1

Clinical Pearls and Pitfalls

• Pitfall: Focusing only on antibiotic discontinuation without addressing other modifiable risk factors 1
• Pitfall: Failing to recognize that even very limited antibiotic exposure can significantly increase CDI risk 1
• Pearl: The relative risk of CDI with a particular antibiotic depends on local prevalence of resistant strains 1
• Pearl: Multi-drug resistant C. difficile strains are increasing, with about 60% of epidemic strains showing resistance to three or more antibiotics 1
• Caveat: While PPI use is associated with CDI in many studies, this may be confounded by underlying severity of illness, non-CDI diarrhea, and duration of hospital stay 1

Prevention Strategies

• Judicious use of antibiotics 3
• Rapid isolation of infected patients 1
• Contact precautions until resolution of diarrhea (formed stool for at least 48 hours) 1
• Hand hygiene with soap and water (alcohol-based sanitizers may not kill spores) 1
• Thorough environmental cleaning and disinfection 1