Clostridium difficile: Diagnosis and the Consequence of Over Diagnosis

Clostridium difficile infection (CDI) is a leading cause of healthcare-associated infections, accounting for significant disease burden and mortality. The clinical spectrum of C. difficile ranges from asymptomatic colonization to toxic megacolon and fulminant colitis. CDI is characterized by new onset of ≥ 3 unformed stools in 24 h and is confirmed by laboratory test for the presence of toxigenic C. difficile. Currently, laboratory tests to diagnose CDI include toxigenic culture, glutamate dehydrogenase (GDH), nucleic acid amplification test (NAAT), and toxins A/B enzyme immunoassay (EIA). The sensitivities of these tests are variable with toxin EIA ranging from 53 to 60% and with NAAT at about 95%. Overall, the specificity is > 90% for these methods. However, the positive predictive value (PPV) depends on the disease prevalence with lower CDI rates associated with lower PPVs. Notably, the widespread use of the highly sensitive NAAT and its relatively lower clinical specificity have led to overdiagnosis of C. difficile by identifying carriers when NAAT is used as the sole diagnostic method. Overdiagnosis of C. difficile has resulted in unwarranted treatment, possibly attributing to resistance to metronidazole and vancomycin, increased risk for overgrowth of vancomycin-resistant enterococci strains in stool specimens, and increased hospitalization thereby impacting patient safety and healthcare costs. Strategies to optimize the clinical sensitivity and specificity of current laboratory tests are critical to differentiate the clinical CDI from colonization. To achieve high diagnostic yield, if preagreed institutional criteria for stool submission are not used, a multistep approach to CDI diagnosis is recommended, such as either GDH or NAAT followed by toxins A/B EIA in conjunction with laboratory stewardship by evaluating C. difficile test orders for appropriateness and providing feedback. Furthermore, antimicrobial stewardship, along with provider education on appropriate testing for C. difficile, is vital to differentiate CDI from colonization.