Is a single dose of Rocephin (Ceftriaxone) immediately followed by a 10-day course of Augmentin (Amoxicillin-Clavulanate) likely to cause Clostridioides difficile (C diff) infection?

Risk of C. difficile Infection with Single-Dose Ceftriaxone Followed by 10-Day Augmentin Course

While this antibiotic regimen does carry some risk for C. difficile infection (CDI), the absolute risk is relatively low but not negligible, with the extended 10-day duration of Augmentin being the primary concern rather than the single dose of ceftriaxone.

Understanding the Risk Factors

Antibiotic Duration as Primary Driver

• Longer antibiotic courses substantially increase CDI risk: A 10-day course incurs 12% more risk compared to a 7-day course, and a 14-day course increases risk by 27% 1
• The risk of CDI is elevated up to sixfold during antibiotic therapy and in the subsequent month afterward 2
• Even very limited exposure, such as single-dose surgical antibiotic prophylaxis, can increase patients' risk for both C. difficile colonization or infection 2

Specific Antibiotic Considerations

Ceftriaxone (Rocephin):

• Third-generation cephalosporins, including ceftriaxone, have traditionally been considered to pose significant CDI risk 2
• Ceftriaxone's unique biliary excretion in its active form makes it particularly problematic for disrupting gut microbiota 3
• However, a single dose carries substantially less risk than prolonged courses 2
• In research settings, ceftriaxone was identified as an independent predictor of CDI incidence when used repeatedly 3

Amoxicillin-Clavulanate (Augmentin):

• Penicillins, including amoxicillin-clavulanate, are among the antibiotics traditionally associated with increased CDI risk 2
• The FDA label explicitly warns that patients can develop watery and bloody stools (C. difficile-associated diarrhea) even as late as 2 or more months after having taken their last dose 4
• The 10-day duration is the more concerning factor here, as duration directly correlates with CDI risk 1

Quantifying the Risk

Comparative Risk Assessment

• Among antibiotics used for similar indications, amoxicillin actually represents one of the lower-risk options compared to fluoroquinolones 1
• For context, moxifloxacin results in 121% more CDI risk than amoxicillin for 7-day courses 1
• The combination of a single ceftriaxone dose plus 10 days of amoxicillin-clavulanate represents moderate risk—higher than no antibiotics or shorter courses, but lower than high-risk regimens involving clindamycin, fluoroquinolones, or prolonged third-generation cephalosporin use 2, 1

Clinical Risk Stratification

High-Risk Patient Populations

Consider the patient's individual risk factors, as these substantially modify CDI likelihood 2:

• Age >65 years 2
• Immunocompromised status or use of immunosuppressive therapy 2
• Recent hospitalization or healthcare facility exposure 2
• Proton pump inhibitor (PPI) use, which increases CDI risk (OR 1.26-1.39) 2
• Previous CDI episode, which dramatically increases recurrence risk 2
• Severe underlying disease or advanced comorbidities 2

Protective Factors

• Younger, healthier patients without the above risk factors have substantially lower baseline CDI risk 2
• Outpatient antibiotic use carries lower risk than inpatient use 2

Practical Management Recommendations

Monitoring Strategy

• Counsel patients that diarrhea can develop during or after antibiotic treatment, and severe or persistent diarrhea (especially with blood, cramps, or fever) warrants immediate medical attention 4
• Symptoms can appear as late as 2 months after completing antibiotics 4
• If severe diarrhea develops lasting more than 2-3 days, patients should contact their physician immediately 4

Risk Mitigation

• Avoid unnecessary PPI use during and after this antibiotic course, as PPIs independently increase CDI risk 2
• Minimize antibiotic duration whenever clinically appropriate—if the infection can be adequately treated with fewer than 10 days of Augmentin, consider shortening the course 1
• There is insufficient evidence to recommend prophylactic anti-C. difficile agents (like vancomycin) for patients receiving this regimen unless they have multiple prior CDI episodes 2

Bottom Line

The regimen you describe—one dose of ceftriaxone plus 10 days of amoxicillin-clavulanate—carries a measurable but relatively modest CDI risk in average-risk patients. The 10-day duration of Augmentin is the primary concern, while the single ceftriaxone dose adds minimal additional risk 2, 1. In high-risk patients (elderly, immunocompromised, PPI users, prior CDI), heightened vigilance and patient education about warning signs are warranted 2, 4. For most otherwise healthy patients, this represents an acceptable risk profile when antibiotics are clinically indicated 2.