What are the risk factors for recurring Clostridium (C.) difficile infection?

Risk Factors for Recurrent Clostridioides difficile Infection

The most critical risk factor for recurrent CDI is previous episodes of CDI (OR 3.87), followed by concurrent antibiotic use (RR 1.76) and advanced age >65 years (RR 1.63). 1

Primary Risk Factors

Previous CDI Episodes

• Prior CDI is the strongest predictor of recurrence, with an odds ratio of 3.87 1
• First recurrence occurs in 6-23% of patients after initial CDI treatment 1
• Second recurrence occurs in 20-36% of patients who experienced a first recurrence 1
• Risk increases incrementally with each subsequent recurrence 1

Antibiotic Exposure

• Concurrent antibiotic use during or after CDI treatment carries a risk ratio of 1.76 for recurrence 1
• Continued use of non-C. difficile antibiotics after CDI diagnosis has an odds ratio of 4.23 (95% CI 2.10-8.55) 1
• Prior fluoroquinolone exposure increases risk (RR 1.42,95% CI 1.28-1.57) 1
• Clindamycin, cephalosporins, and fluoroquinolones are most strongly associated with CDI and recurrence 1

Age-Related Factors

• Age ≥65 years carries a relative risk of 1.63 (95% CI 1.24-2.14) for recurrence 1
• Advanced age contributes to immunological senescence, impairing immune responses to C. difficile toxins 2
• Older patients demonstrate inadequate anti-toxin antibody responses, differentiating them from asymptomatic carriers 2

Medication-Related Risk Factors

Proton Pump Inhibitors

• PPI use increases recurrence risk with RR 1.58 (95% CI 1.13-2.21) 1
• Antacid medications overall have an odds ratio of 2.15 (95% CI 1.13-4.08) for recurrence 1
• While epidemiologic association exists, robust evidence for PPI discontinuation as primary prevention remains lacking 1

Comorbidity-Related Risk Factors

Renal Disease

• Chronic kidney disease and renal failure carry RR 1.59 (95% CI 1.14-2.23) for recurrence 1
• End-stage renal disease is an established risk factor for both initial and recurrent CDI 1

Immunocompromising Conditions

• Inflammatory bowel disease significantly increases recurrence risk 1
• Solid-organ transplantation predisposes to recurrent episodes 1
• Active chemotherapy treatment increases vulnerability 1
• Hypogammaglobulinemia impairs immune response to C. difficile toxins 1

Other Comorbidities

• Prolonged hospital stay increases exposure and recurrence risk 1
• Severe underlying illness (reflected by high Horn index score) predicts recurrence 2
• Hematopoietic stem cell transplantation 1
• Oncological diseases 1
• Mechanical ventilator support requirement 1

Disease-Specific Factors

Severity and Strain Characteristics

• More severe initial disease presentation correlates with higher recurrence rates 1
• Hypervirulent strains (particularly BI/NAP1/027) increase recurrence likelihood 1
• Hypoalbuminemia at presentation indicates severe disease and higher recurrence risk 1

Microbiological Factors

• Recurrence results from either relapse with the same strain or reinfection with a different strain 1
• Recurrence is not predominantly due to antibiotic resistance evolution but rather persistence of risk factors 1
• Ongoing gut microbiome disruption promotes C. difficile growth 1

Pediatric-Specific Risk Factors

Major Risk Factors in Children

• Presence of malignancy is a major risk factor for pediatric recurrent CDI 1
• Chronic underlying diseases including diabetes, chronic liver disease, chronic kidney disease, and neurodegenerative diseases 1
• Concomitant antibiotic use during CDI treatment 1

Minor Risk Factors in Children

• Recent antibiotic exposure within three months before diagnosis 1
• Number of antibiotic classes used 1
• Recent hospitalization 1
• Recent gastrointestinal surgery 1
• Use of acid blockers 1
• Immunosuppressant drug therapy 1

Clinical Prediction Considerations

A validated clinical prediction tool identifies three highly predictive factors: age >65 years, severe underlying disease (Horn index score), and continued antibiotic use for non-CDI infections 2. These factors enable early identification of high-risk patients requiring aggressive monitoring and potentially alternative treatment strategies such as vancomycin tapering regimens or fecal microbiota transplantation 3, 4.

Common Pitfalls to Avoid

• Do not assume all patients have equal recurrence risk—stratify based on the presence of multiple risk factors 2
• Avoid continuing non-essential antibiotics after CDI diagnosis, as this quadruples recurrence risk 1
• Do not overlook the cumulative effect of multiple risk factors, as patients with several factors face exponentially higher recurrence rates 1
• Recognize that inadequate immune response to C. difficile toxins, not antibiotic resistance, drives most recurrences 1