Clostridioides difficile Infection: AMJ, March 2026

This review highlights that CDI management now requires both accurate diagnosis and a strategy to prevent recurrence. Diagnosis should not rely on a single test alone, because PCR is highly sensitive but may detect colonization, whereas toxin EIA is more specific but less sensitive. Therefore, the preferred approach is algorithmic testing with PCR or GDH screening followed by toxin EIA, interpreted in the right clinical context.

For initial CDI, vancomycin and fidaxomicin are the main first-line therapies. Metronidazole now has a much smaller role because of inferior efficacy, more side effects, and higher recurrence risk; it is mainly reserved for selected nonsevere cases or as part of combination therapy in fulminant disease. Fidaxomicin is attractive because it better preserves the microbiota and reduces recurrence, although cost remains an issue. Vancomycin remains the practical standard in many settings.

For fulminant CDI, management should be aggressive: ICU-level care, surgical input, oral vancomycin plus intravenous metronidazole, and rectal vancomycin if ileus is present.

For recurrent CDI, treatment extends beyond antibiotics. After a first recurrence, fidaxomicin or a vancomycin taper/pulse regimen is recommended. After second recurrence or in high-risk patients, microbiota restoration therapy becomes central. Options now include fecal microbiota, live-jslm (Rebyota) and fecal microbiota spores, live-brpk (Vowst), both of which reduce recurrence substantially. Conventional FMT still has an important role, especially in severe or fulminant CDI, although FDA policy and stool-bank access have made this more complicated.

Overall, the key principle is: treat the acute vegetative infection with antibiotics, then restore the microbiome to prevent relapse.