Clostridioides difficile infection is the most frequent cause of diarrhea acquired during hospitalization because it commonly occurs after antibiotic use, which disrupts normal gut flora. This leads to overgrowth of C. difficile and toxin production, causing colitis and diarrhea. It is a major healthcare-associated infection with significant morbidity. Other causes like norovirus or Giardia are less common in hospital settings, and antibiotic-associated diarrhea without infection lacks the severity and frequency seen with C. difficile.

Reference: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 9th Edition, Volume 2, Chapter 152, p. 3274.