What is first-line therapy for Clostridioides difficile infection and how is severe disease defined?

• A. Metronidazole
• B. Oral vancomycin or fidaxomicin; severe disease defined by leukocytosis (WBC >15,000) or elevated creatinine; fulminant disease requires escalation
• C. IV vancomycin
• D. Fidaxomicin alone is sufficient; no severity criteria

Answer: (B)

Treating C. difficile infection effectively hinges on delivering antibiotics that act in the colon where the bacteria are. The first-line options are oral vancomycin or fidaxomicin, because both reach high concentrations in the colon and have better outcomes (and lower recurrence) than older regimens such as metronidazole. Metronidazole is no longer preferred as first-line due to inferior cure rates, especially in more severe cases, and because it achieves less reliable colonic concentrations.

Defining severity helps guide therapy: severe disease is indicated by a white blood cell count above 15,000 per microliter or a rise in serum creatinine, reflecting systemic inflammatory response or dehydration/renal impairment. When disease becomes fulminant—marked by hypotension or shock, ileus, or megacolon—therapy must be escalated. This typically means high-dose oral vancomycin (often with rectal vancomycin if ileus is present) plus intravenous metronidazole, and urgent surgical consultation as needed.