What antibiotics might cause Clostridioides difficile infection?

Antibiotics That Cause Clostridioides difficile Infection

Virtually all antibiotics can cause C. difficile infection, but the highest-risk agents are fluoroquinolones, clindamycin, third- and fourth-generation cephalosporins, and carbapenems, which should be restricted based on local epidemiology to reduce CDI rates. 1

Highest-Risk Antibiotics

The antibiotics most strongly associated with CDI include:

• Fluoroquinolones (levofloxacin, ciprofloxacin, moxifloxacin): Odds ratio 5.65-30.71 depending on setting, with levofloxacin showing an independent OR of 2.0 (95% CI 1.2-3.3) and contributing to 30.8% of cases in outbreak settings 1, 2, 3, 4

• Clindamycin: Adjusted matched odds ratio of 35.31 (95% CI 4.01-311.14), historically one of the most notorious CDI-causing antibiotics 1, 5, 2, 6

• Third- and fourth-generation cephalosporins (ceftriaxone, cefotaxime, cefepime): Odds ratio 4.47-5.3, with ceftriaxone showing OR 5.4 (95% CI 1.8-15.8) 1, 3, 4

• Carbapenems (meropenem, imipenem): Odds ratio 4.7, with meropenem implicated in 27.6% of recent CDI cases 1, 3, 7

• Beta-lactam/beta-lactamase inhibitor combinations (piperacillin-tazobactam, amoxicillin-clavulanate): Adjusted matched odds ratio 9.87 (95% CI 2.76-340.05), with piperacillin-tazobactam now the most commonly associated antibiotic in recent studies (77.6% of cases) 2, 7, 8

Moderate-Risk Antibiotics

• Aminopenicillins (amoxicillin, ampicillin): Consistently associated with CDI risk, with amoxicillin FDA labeling specifically warning of C. difficile-associated diarrhea 1, 9, 8

• Macrolides (azithromycin, clarithromycin): Odds ratio 5.2 (95% CI 1.1-24.0) for CDI, particularly with the epidemic BI/NAP1/027 strain showing 98% resistance to azithromycin 10

Lower-Risk Antibiotics

• Tetracyclines (doxycycline, minocycline): Among the lowest risk antibiotics for CDI, though still capable of causing infection 11

Critical Risk Timeline

The highest risk period is during antibiotic therapy and the first month after exposure (7-10 fold increased risk), with elevated risk persisting up to 3 months post-cessation. 1, 2, 3

• Even single-dose surgical prophylaxis increases C. difficile colonization and symptomatic disease risk 1
• Risk increases with longer duration of antibiotic exposure and use of multiple antibiotics simultaneously 1
• The adjusted hazard ratio for CDI increases dramatically with number of antibiotics: 2.5 for 2 antibiotics, 3.3 for 3-4 antibiotics, and 9.6 for ≥5 antibiotics 1

Mechanism of Risk

Antibiotics disrupt the normal bowel microbiota, creating a "niche" for C. difficile to flourish and produce toxins A and B. 1, 9, 6

• The relative risk depends on local prevalence of strains highly resistant to specific antibiotics 1
• Even topical clindamycin can cause CDI through limited systemic absorption disrupting intestinal microflora 5

Clinical Stewardship Recommendations

Antibiotic stewardship programs should specifically target fluoroquinolones, clindamycin, and cephalosporins (except for surgical prophylaxis) based on strong evidence for reducing CDI rates. 1

• Minimize frequency, duration, and number of high-risk antibiotics prescribed 1
• Formulary restriction strategies and prospective audit-and-feedback programs reduce targeted antibiotic use by 50-90% and CDI incidence by 33-90% 1
• Discontinue the inciting antibiotic immediately when CDI is suspected, as this influences recurrence risk 1, 2

Important Caveats

• No antibiotic is completely safe: Virtually every antibiotic has been associated with CDI over the years 1, 8
• The specific antibiotics to target should be based on local epidemiology and prevalent C. difficile strains 1
• Patient-specific risk factors (age ≥65 years, proton pump inhibitor use, recent hospitalization, immunosuppression) amplify antibiotic-associated CDI risk 1, 2
• Concomitant use of multiple antibiotics or proton pump inhibitors further increases risk 1, 5