Addressing Multiple Negatives During Clostridioides difficile Testing

Clostridioides difficile (C difficile) is a significant nosocomial infection primarily linked to antibiotic use, and its severity varies from asymptomatic carriers to severe complicated disease. The diagnosis of C difficile infections (CDI) is complex, with multiple testing modalities available. This case report discusses a patient with multiple negative C difficile toxin and GDH tests but a high clinical suspicion of CDI, leading to a colonoscopy that revealed pseudomembranous colitis and the subsequent successful treatment with oral vancomycin. A recent case highlights the importance of considering different testing approaches and indications for colonoscopy to distinguish between false-negative testing and active CDI.

C difficile is a leading cause of diarrhea, with a significant impact on health care systems in North America and Europe. It is responsible for approximately half a million infections annually, with a 5.8% mortality rate within 30 days of diagnosis. Mortality rates are higher in older individuals, particularly those over 65. The primary risk factor for CDI is antibiotic use, with penicillins, cephalosporins, and clindamycin being common culprits. Other contributing factors include proton pump inhibitor use, previous CDI, chronic liver and kidney disease, and malnutrition. CDI usually presents as acute watery diarrhea in about 21% of patients, but it can progress to severe complications, including pseudomembranous colitis, sepsis, and toxic megacolon, in 10% of cases.

Several diagnostic tests are available for CDI, each with varying sensitivities and specificities. These include cytotoxicity assays, enzyme-linked immunoassays (EIA) for the detection of glutamate dehydrogenase (GDH) antigen, toxigenic culture, and nucleic acid amplification testing (NAAT). GDH antigen testing is commonly used as a screening tool due to its effectiveness. However, the multimodal approach is recommended for rapid and accurate diagnosis, especially in symptomatic CDI cases.

This case of a 79-year-old male with a history of chronic obstructive pulmonary disease and pulmonary hypertension. He experienced a week of worsening diarrhea, abdominal pain, and vomiting, leading to a sepsis diagnosis upon admission. Initial treatment with metronidazole for suspected bacterial gastroenteritis showed minimal improvement. Imaging revealed large bowel inflammation consistent with colitis, and various cultures and tests were conducted. The patient's condition deteriorated, requiring intensive care and vasopressor support. Despite multiple negative C difficile GDH antigen and toxin A/B tests, the patient's diarrhea persisted.

The infectious diseases team recommended another set of C. difficile screening tests, which also came back negative. However, a repeat CT scan showed worsening colitis. At this point, the patient was transferred to a tertiary care center where he received intravenous antibiotics and was evaluated by gastroenterology. Due to the high clinical suspicion of CDI, treatment with oral vancomycin was initiated until a repeat C difficile toxin screening could be conducted at the new facility.

The case underscores the importance of considering direct visualization of the colon through colonoscopy when multiple C. difficile tests are negative, but clinical suspicion remains high. Pseudomembranes in the colon are typically associated with C difficile colitis, especially in high-risk populations. In rare instances, patients may have multiple false-negative test results, leading to inappropriate antibiotic use and treatment failure.

In conclusion, C difficile is a significant healthcare-associated infection with potentially severe consequences. Diagnosis can be challenging due to the various testing modalities and their limitations. In cases of high clinical suspicion with negative C difficile tests, colonoscopy can be a valuable tool for accurate diagnosis and timely treatment initiation, particularly in at-risk populations. This case highlights the importance of a comprehensive diagnostic approach to effectively manage CDI.

Reference:

Bassi R, Prakash P, Oyetoran A, et al. (January 27, 2023) A Review on Clostridioides Difficile Testing and How to Approach Patients With Multiple Negative Tests: A Case Report. Cureus 15(1): e34285. DOI 10.7759/cureus.34285