If a CT abdomen and pelvis shows colitis suggestive of pseudomembranous colitis but the Clostridioides difficile polymerase chain reaction test is negative, should C. difficile infection still be considered?

C. difficile Remains a Concern Despite Negative PCR

Even with a negative C. difficile PCR test, C. difficile infection should still be considered when CT imaging shows colitis concerning for pseudomembranous colitis, particularly if clinical suspicion remains high based on symptoms, antibiotic exposure, and disease severity. 1

Why Testing Can Be Falsely Negative

The diagnostic challenge stems from the fact that no single C. difficile test has perfect sensitivity, and PCR testing—while highly sensitive—can still miss cases, particularly when stool samples are inadequate or when disease is localized to the right colon 2. The 2018 IDSA/SHEA guidelines emphasize that stand-alone PCR tests have very high negative predictive value (typically >99%), but this assumes proper specimen collection and testing conditions 1.

Clinical Context Overrides Laboratory Results

Laboratory testing cannot distinguish between colonization and true infection, which is why diagnosis requires both clinical symptoms (diarrhea) AND positive testing or endoscopic evidence 1. In your scenario:

• CT findings of pseudomembranous colitis represent direct visualization of disease and carry significant diagnostic weight 3
• Pseudomembranes on imaging are highly specific for severe colonic inflammation, with C. difficile being the most common cause 4, 3
• When endoscopic or radiologic evidence of pseudomembranous colitis exists, this fulfills diagnostic criteria even without positive stool testing 1

When to Pursue C. difficile Despite Negative Testing

Repeat testing should be considered when clinical suspicion remains high, particularly if symptoms worsen or if the patient has risk factors including recent antibiotic exposure, hospitalization, or severe disease 1. However, routine repeat testing within 7 days yields only approximately 2% additional diagnostic benefit 1, 5.

Key Decision Points:

• If the patient is critically ill with imaging showing pseudomembranous colitis, empiric vancomycin therapy (125-500 mg orally four times daily) should be initiated while awaiting confirmatory testing 1, 6
• Stool specimens may be rejected by laboratories if they don't meet testing criteria (formed stool), yet pseudomembranous colitis can still be present 2
• Right-sided colonic involvement may be associated with atypical presentations and testing challenges 2

Alternative Diagnoses to Consider

Pseudomembranes are not pathognomonic for C. difficile—other causes include ischemic colitis, inflammatory bowel disease (particularly ulcerative colitis), Behçet's disease, other infectious organisms, and certain drugs 7, 3. Therefore:

• Obtain comprehensive stool studies including bacterial cultures, viral pathogens, and parasites 6, 5
• Consider CMV testing in immunocompromised patients or those with severe disease unresponsive to initial therapy 6
• Measure stool inflammatory markers (lactoferrin or calprotectin) to assess inflammation severity 6

Practical Management Algorithm

1. If CT shows pseudomembranous colitis with negative C. difficile PCR:

   • Start empiric oral vancomycin 125 mg four times daily if the patient has severe symptoms, recent antibiotic exposure, or systemic toxicity 1, 6
   • Stop any precipitating antibiotics immediately 6, 5
   • Consider flexible sigmoidoscopy (NOT full colonoscopy due to perforation risk) to visualize pseudomembranes and obtain biopsies 6, 3

2. Monitor for disease progression:

   • Daily assessment for peritoneal signs, toxic megacolon (colon >5.5 cm), or clinical deterioration 6
   • Repeat inflammatory markers; CRP >45 mg/L predicts treatment failure 6

3. If symptoms improve on empiric therapy:

   • Complete 10-14 day course of vancomycin 1
   • Do NOT perform "test of cure" as >60% remain PCR-positive after successful treatment 1

Critical Pitfalls to Avoid

• Never delay treatment in severely ill patients while awaiting repeat testing 6
• Do not use antiperistaltic agents or opiates as they may precipitate toxic megacolon 6
• Avoid full colonoscopy in acute severe colitis due to perforation risk; flexible sigmoidoscopy is safer and visualizes 95% of inflammatory changes 6
• Remember that approximately 35% of patients with recurrent diarrhea after CDI treatment will test negative for toxin 1

The combination of CT findings suggestive of pseudomembranous colitis plus appropriate clinical context (diarrhea, antibiotic exposure, systemic symptoms) warrants empiric C. difficile treatment regardless of initial negative PCR, with consideration for endoscopic confirmation and alternative diagnoses if the patient fails to improve 1, 6, 3.