In an older hospitalized adult receiving proton‑pump inhibitors and broad‑spectrum antibiotics (or immunosuppressive therapy), what infectious organisms besides Clostridioides difficile can cause diarrhea?

Infectious Causes of Diarrhea in Hospitalized Patients Beyond C. difficile

In hospitalized adults receiving proton-pump inhibitors and broad-spectrum antibiotics, routine stool cultures for bacterial pathogens (Salmonella, Shigella, Campylobacter) and ova/parasite examination should generally NOT be sent unless the patient was admitted with diarrhea, is HIV-positive, or is part of an outbreak investigation—these organisms rarely cause hospital-acquired diarrhea. 1

The "3-Day Rule" and Why Most Pathogens Don't Matter

Bacterial pathogens causing hospital-acquired diarrhea after 3 days of hospitalization are exceedingly rare. The yield of stool cultures for standard enteric pathogens (Salmonella, Shigella, Campylobacter, Yersinia) in patients developing diarrhea after 3 days of hospitalization is extremely low, and routine testing wastes resources without improving diagnostic accuracy. 1

Community-Acquired vs. Nosocomial Pathogens

The organisms that typically cause infectious diarrhea—Salmonella, Shigella, Campylobacter jejuni, Aeromonas, Yersinia, pathogenic E. coli, Entamoeba histolytica, and most viruses—are community-acquired diseases. 1 They only rarely cause infectious diarrhea acquired after hospital admission in immunocompetent patients. 1

When to Actually Test for Other Pathogens

Specific High-Risk Scenarios Requiring Broader Testing

You should send stool cultures and additional testing in these specific circumstances:

• Patient admitted TO the hospital WITH diarrhea (not diarrhea that developed after admission) 1
• HIV-infected or immunocompromised patients (including those on immunosuppressive therapy) 1
• Age >65 years with comorbid disease or neutropenia 1
• Part of a suspected nosocomial outbreak 1
• Bloody diarrhea or inflammatory features (fever, tenesmus, fecal leukocytes, positive lactoferrin) 1

What to Test For in These High-Risk Patients

When testing IS indicated based on the above criteria:

• Stool culture for Salmonella, Shigella, Campylobacter when bloody diarrhea is present 2, 3
• Shiga toxin-producing E. coli (STEC) testing for bloody diarrhea or severe cramping 2
• Ova and parasite examination for travelers or persistent symptoms 2
• Pathogenic E. coli (including enterotoxigenic, enteropathogenic, and enterohemorrhagic strains) 1, 3
• Rotavirus (particularly in immunocompromised patients) 3

Rare but Documented Nosocomial Pathogens

While exceedingly uncommon, certain organisms have been documented to cause antibiotic-associated diarrhea in hospitalized patients beyond C. difficile:

• Clostridium perfringens (enterotoxin-producing strains) 4
• Staphylococcus aureus (enterotoxin-producing strains) 4
• Klebsiella oxytoca (associated with antibiotic-associated hemorrhagic colitis) 4

Important caveat: These organisms can also colonize healthy individuals, so their presence in stool does not automatically prove causation—clinical correlation is essential. 4

The Dominant Role of C. difficile

C. difficile accounts for 10-25% of all antibiotic-associated diarrhea cases and is by far the most common identifiable infectious cause of diarrhea in healthcare settings. 5, 2 In rehabilitation hospitals, C. difficile was found to be the etiologic agent in 25% of all patients evaluated for diarrhea and 39% of those specifically tested. 6 In contrast, no cases of Salmonella, Shigella, Campylobacter, or Yersinia were identified in that same population. 6

Synergistic Risk with PPIs

Proton pump inhibitors dramatically amplify C. difficile risk, particularly in patients receiving fewer antibiotics. Among hospitalized patients receiving only one antibiotic, PPI use increased C. difficile risk 15.7-fold; this effect diminished to 2.7-fold in patients receiving five or more antibiotics. 7 PPIs independently increase C. difficile risk 3.6-fold overall, and this risk is further elevated 4.5-fold in multivariable analyses. 7, 8

Practical Algorithm for Stool Testing

For hospitalized patients developing diarrhea:

1. Always test for C. difficile toxin (single specimen, EIA for toxins A and B or two-step algorithm) 5, 2

2. Skip routine bacterial cultures and O&P UNLESS:

   • Patient admitted WITH diarrhea 1
   • HIV-positive or immunocompromised 1
   • Age >65 with neutropenia or severe comorbidity 1
   • Bloody diarrhea present 2
   • Suspected outbreak 1

3. If testing IS indicated, send:

   • Stool culture for Salmonella/Shigella/Campylobacter 2
   • STEC testing if bloody 2
   • O&P if travel history or persistent symptoms 2

Critical Pitfall to Avoid

Never use antimotility agents (loperamide, diphenoxylate) when C. difficile or any infectious diarrhea is suspected—these can precipitate toxic megacolon and mask disease progression. 5, 2, 9