March 2026
ABSTRACT
Clostridioides difficile infection (CDI) is challenging to diagnose and treat. Recently published studies and clinical observations have improved our understanding around diagnostic testing and positioning of antibiotics and microbiota-based therapies. This review synthesizes current evidence and guidelines on CDI diagnosis, highlighting the limitations of individual tests and the value of algorithmic approaches. Treatment paradigms are discussed across the spectrum of disease severity, with vancomycin and fidaxomicin as first-line therapies and the diminishing role of metronidazole. For recurrent CDI, newer fecal microbiota-based therapies, including fecal microbiota, live-jslm (Rebyota), and fecal microbiota spores, live-brpk (Vowst), are reviewed. The role of conventional fecal microbiota transplantation, particularly in fulminant CDI, is also addressed, including challenges resulting from US Food and Drug Administration policies around stool bank material. We aim to clarify diagnostic and therapeutic approaches and optimize care for patients with CDI.