AGA updates C diff care with focus on recurrence prevention

Clinical takeaway: For most adults with nonfulminant C diff infection, fidaxomicin is now the preferred first-line treatment, and clinicians should think proactively about preventing recurrence, including the use of microbiome-based therapies in appropriate patients.

The American Gastroenterological Association (AGA) has released a new Clinical Practice Update on the management of Clostridioides difficile infection (C diff), reflecting a growing emphasis on preventing recurrent disease and preserving the gut microbiome.

The update recommends fidaxomicin as the preferred first-line therapy for most adults with nonfulminant C diff because it is associated with lower recurrence rates than vancomycin. Vancomycin remains an acceptable alternative when fidaxomicin is unavailable, unaffordable, or otherwise impractical.

For patients who develop recurrent infection, the guidance encourages clinicians to assess recurrence risk early and discuss prevention strategies from the outset. For a first recurrence, fidaxomicin or a tapered and pulsed vancomycin regimen are recommended treatment options.

One of the most notable shifts in the update is the expanded role of microbiome restoration. The authors recommend offering FDA-approved microbiota-based therapies or fecal microbiota transplantation (FMT) after a second recurrence (third episode of C diff). Earlier use may also be appropriate in select patients at high risk for additional recurrences, including older adults and those who are immunocompromised.

The guidance also addresses management of severe and fulminant disease. For fulminant C diff, the authors recommend high-dose oral or enteral vancomycin plus IV metronidazole, with rectal vancomycin added when ileus is present. In patients with refractory severe or fulminant disease, multi-dose FMT may be considered and may help reduce mortality.

Several commonly used preventive strategies received a more cautious assessment. The AGA does not recommend probiotics for primary or secondary prevention of C diff and advises against routine oral vancomycin prophylaxis during subsequent systemic antibiotic exposure. Instead, the authors encourage a varied, fiber-rich diet to support recovery of the gut microbiome.

The update also provides practical recommendations on diagnosis and follow-up. Testing should be reserved for patients with compatible symptoms, multistep diagnostic strategies are preferred over PCR alone, and routine stool "test of cure" is discouraged because positive results can persist after clinical resolution.

As the authors note, "Management of CDI is rapidly changing, with some therapies no longer available and several new therapies clinically available," highlighting how the focus of care is shifting beyond antibiotics toward long-term recurrence prevention and microbiome restoration.

What's changed

• Fidaxomicin is now preferred over vancomycin as first-line treatment for most adults with nonfulminant C diff.
• FDA-approved microbiota-based therapies and FMT are recommended after a second recurrence (third episode).
• Earlier microbiome restoration may be considered in selected patients at high risk for recurrence.
• Multi-dose FMT is now recognized as a potential option for refractory severe or fulminant C diff.
• Metronidazole should not be used as sole therapy for nonfulminant disease and is reserved for use with vancomycin in fulminant infection.
• Routine probiotic use for prevention of initial or recurrent C diff is not recommended.
• Routine oral vancomycin prophylaxis during subsequent antibiotic exposure is not recommended.
• Clinicians are encouraged to focus on microbiome recovery, including dietary measures, as part of long-term management.
• Routine stool testing after successful treatment ("test of cure") should be avoided.

Source: Fischer M, et al. (2026 Sep) Clin Gastroenterol Hepatol. AGA Clinical Practice Update on Management of Clostridioides difficile Infection in Adults: Expert Review