Patients with inflammatory bowel disease (IBD) who develop Clostridioides difficile infection (CDI) should receive fidaxomicin as the preferred first-line antibiotic, continue necessary IBD-directed immunosuppressive therapy, and consider microbiome-based treatments after recurrence, according to a recent American Gastroenterological Association Clinical Practice Update.

“The 2026 Clinical Practice Update on CDI affecting IBD patients is a substantial update from the 2017 guidance, which focused [on] testing IBD flares for C difficile, screening for recurrence, favoring vancomycin over metronidazole, hospitalizing patients with severe illness, individualizing immunosuppression decisions, and referring patients with recurrent CDI for fecal microbiota transplantation,” lead author Sahil Khanna, MBBS, MS, professor of medicine, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News.

Khanna explained the motivation for authorship of the new paper. “CDI in IBD remains a high-risk clinical problem, and the evidence base and therapeutic landscape have changed substantially since 2017,” he said. “Patients with IBD continue to have higher CDI risk, more severe disease, and greater recurrence risk than the general population. CDI can mimic or trigger an IBD flare, leading to hospitalization, escalation or failure of IBD therapy, and surgery.”

Several advances made an update timely, he continued. Diagnostic testing has become “more nuanced.” Treatment has also evolved, with CDI antibiotic management shifting toward fidaxomicin because of lower recurrence and microbiome preservation and with the FDA approval of microbiome-directed treatments. Additionally, “there was a need to provide guidance on the common dilemma of whether to continue, hold, or escalate IBD immunosuppression during acute CDI.”

A Multistep, Toxin-Based Diagnostic Approach

“Do not assume worsening diarrhea in IBD is simply an IBD flare,” Khanna stated. “CDI should be excluded in any patient with IBD who has new or worsening diarrhea, particularly with colonic disease, and clinicians should also consider CDI in patients with an ileal pouch or end ileostomy who develop increased output.”

The authors pointed out that serum inflammatory markers, fecal calprotectin, and imaging studies, typically used to predict or identify an IBD flare, have “altered diagnostic performance” during active CDI and should be “viewed as adjunctive rather than discriminatory tools in patients with IBD and CDI.”

For testing, Khanna said, “a multistep toxin-based diagnostic approach is preferred to better distinguish true infection from colonization as patients with IBD have higher rates of C difficile carriage.”

Start with attempting to detect the organism with a highly sensitive assay, the authors advised, via glutamate dehydrogenase or polymerase chain reaction/nucleic acid amplification (PCR/NAA) test. If this is positive, then an enzyme immunoassay (EIA) — a “highly specific assay” for detecting toxins A/B — can “confirm active infection.”

A tricky scenario ensues if the NAA/PCR test is positive but the EIA for toxins A/B is negative. The patient is likely a carrier and not releasing toxin and is presumed not to have active CDI. But it’s still possible for the EIA to yield a false-negative result. So “if suspicion is high, clinical judgment must be exercised.”

Patients with IBD and recent CDI should be retested using the two-step testing algorithm ≥ 72 hours after stopping vancomycin to avoid false-negative results.

Initiating Treatment

“Fidaxomicin is a preferred first-line therapy for an initial CDI episode in IBD, with oral vancomycin as an alternative when fidaxomicin is unavailable, whereas metronidazole should not be used,” Khanna said.

Fidaxomicin, a narrow-spectrum antibiotic, targets C difficile and preserves gut microbiota diversity, with cure rates similar to those for vancomycin but significantly lower recurrence. And metronidazole is “not recommended for CDI due to high resistance and treatment failure.”

If the patient hasn’t responded within 48-72 hours to antimicrobials, then other diagnoses (eg, IBD flare or cytomegalovirus) should be considered and investigated endoscopically.

Patients with severe colitis or systemic toxicity “should be hospitalized and managed collaboratively with gastroenterology, infectious diseases, and surgery when needed,” Khanna summarized.

The Arsenal of Therapies

Immunosuppressive therapy is a known risk factor for CDI (as well as other gastrointestinal [GI] infections) in patients with ulcerative colitis, but “for IBD therapy during CDI, immunosuppression should not be reflexively held,” Khanna emphasized. The authors recommended selecting a biologic or small-molecule agent for the management of IBD based on what’s best for the patient’s IBD rather than potential CDI risk.

“A major challenge is that in many hospitalized patients with IBD with an acute flare, their CDI status is initially uncertain,” Khanna observed. “In some centers, waiting for CDI test results may delay treatment of severe colitis. So when clinical suspicion of an IBD flare is high, particularly in patients who are systemically ill or at risk of rapid deterioration, initiation of advanced therapy or corticosteroids should not be withheld due to pending CDI diagnostics.”

If CDI test results are expected to be delayed, then starting CDI-directed antibiotics (after a stool sample is obtained) at the same time is “appropriate to treat both inflammatory drivers,” Khanna said. He cautioned that obtaining a stool test after initiation of antibiotics may lead to false-negative results.

“Concurrent treatment of IBD is critical, and needed immunomodulators, biologics, or small molecules should generally be continued, with corticosteroids used when clinically necessary while CDI is treated,” Khanna said.

He noted that the update “incorporates microbiome-based therapies as we now have FDA-approved donor-derived microbiota therapies. These should be offered to patients with IBD after at least one CDI recurrence to prevent future episodes.” Microbiome-based therapies “restore intestinal microbial eubiosis to eradicate the spore phase of infection and reduce the risk of recurrence after antibiotic therapy.”

Antimotility Therapies Aren’t Taboo, but Probiotics Should Be Avoided

It has traditionally been “considered taboo” to use antimotility agents (eg, loperamide) in patients with ongoing CDI, the authors said. They clarified that although clinicians should indeed avoid prescribing them while a workup is underway in untreated CDI or fulminant infection, once patients have initiated anti-CDI antibiotics and are clinically improving, loperamide may safely be used in outpatients with ongoing diarrheal symptoms.

However, probiotics should not be used for primary or secondary prevention. “For selected high-risk patients with prior CDI who need systemic antibiotics, oral vancomycin prophylaxis can be considered after shared decision-making,” Khanna said.

The authors noted that their Best Practice Advice statements were drawn from a review of the best available published evidence, “including existing clinical studies, systematic reviews and practice guidelines, and expert opinion.” But because they hadn’t conducted a formal systematic review, the current statement “does not carry formal ratings of the quality of evidence or strength of the presented considerations.”

Challenging and Nuanced

Commenting for Medscape Medical News, Bruce Hirsch, MD, infectious disease specialist, North Shore University Hospital at Northwell Health, Manhasset, New York, said he “welcomes” the practice update because “C difficile has some nuances and a very, very challenging nuance is when it seems to come back over and over again.”

Hirsch, a member of the Peggy Lillis Foundation Scientific Advisory Board, noted that it’s “long been observed that individuals with other GI problems, specifically IBD, have an increased vulnerability to get C difficile, an increased frequency of colonization with C difficile and poor response to treatment with C difficile. That makes these patients very difficult to manage.”

The guidelines “reinforce good clinical practice,” he said, for example, “regarding the fact that these patients often require more frequent hospitalization and supporting some of the products to bring back a healthy microbiome in these patients.”

Khanna reported receiving research support from Vedanta Biosciences and serving as a consultant for Ferring Pharmaceuticals, Probiotech International, Takeda Pharmaceuticals, and Rise Therapeutics. The other authors’ disclosures are listed on the original paper. Hirsch reported having no relevant financial relationships. 

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books, as well as Behind the Burqa: Our Life in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).