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By Richard R. Watkins, MD, MS, FACP, FIDSA
Professor of Internal Medicine, Northeast Ohio Medical University; Division of Infectious Diseases, Cleveland Clinic Akron General, Akron, OH
Dr. Watkins reports no financial relationships relevant to this field of study.
SYNOPSIS: In a randomized clinical trial, researchers found the combination of oral vancomycin followed by fecal microbiota transplantation was superior to treatment with fidaxomicin or vancomycin alone for patients with recurrent Clostridioides difficile infection.
SOURCE: Hvas CL, Dahl Jørgensen SM, Jørgensen SP, et al. Fecal microbiota transplantation is superior to fidaxomicin for treatment of recurrent Clostridium difficile infection. Gastroenterology 2019;156:1324-1332.
Despite our nuanced understanding of both the transmission and pathophysiology of Clostridioides difficile infection (CDI), management of recurrent episodes remains challenging. Although multiple therapies are available, including prolonged courses of oral vancomycin, fidaxomicin, and fecal microbiota transplantation (FMT), it is unclear which of these gives the best chance for resolving recurrent CDI.
Hvas and colleagues conducted a randomized, open-label clinical trial at a single center in Denmark. Patients were eligible to participate if they were 18 years of age or older, had at least three liquid stools per day, had a positive PCR result for C. difficile toxin, and received at least one prior treatment for CDI with oral vancomycin or fidaxomicin. Exclusion criteria included pregnancy or breast feeding, sepsis or fulminant colitis, ongoing antibiotic treatment, allergy to vancomycin or fidaxomicin, or inability to give consent. All patients underwent fecal tests for other gastrointestinal pathogens (e.g., Salmonella, Shigella, Campylobacter, and Yersinia). Patients with active inflammatory bowel disease (IBD) were treated concurrently. The participants were randomized to one of three groups: four to 10 days of oral vancomycin followed by FMT (n = 24); 10 days of fidaxomicin (n = 24); or 10 days of vancomycin (n = 16). Patients who could not be randomized received FMT off protocol. The study’s primary end point was clinical resolution and a negative follow-up C. difficile test without the need for a rescue FMT or colectomy eight weeks after initial treatment. Patients who experienced clinical recurrence of CDI and a positive C. difficile test before or at week 8 were offered a rescue FMT.
The median age of randomized patients was 68 years, their comorbidity was low as evident by a median Charlson comorbidity index score of 1, and 15/64 (23%) had IBD. Combined clinical resolution with a negative C. difficile test occurred in 17/24 (71%; 95% confidence interval [CI], 49-87%) in the FMT group, 8/24 (33%; 95% CI, 16-55%) in the fidaxomicin group, and 3/16 (19%; 95% CI, 5-46%) in the vancomycin group (P = 0.009 for FMT vs. fidaxomicin; P = 0.001 for FMT vs. vancomycin; P = 0.31 for fidaxomicin vs. vancomycin). Clinical resolution without a negative follow-up C. difficile test occurred in 22/24 (92%; 95% CI, 73-99%) of those treated with FMT, 10/24 (42%; 95% CI, 22-63%) of those treated with fidaxomicin, and three (19%; 95% CI, 4-46%) of those treated with vancomycin.
All 24 patients who experienced a clinical relapse and a positive C. difficile test before or at week 8 received a rescue FMT. Twenty of these patients experienced clinical resolution and a negative test eight weeks after the rescue FMT. Risk factors for FMT failure included anemia (odds ratio [OR], 6.2; 95% CI, 1.27-30.9), age > 65 years (OR, 3.5; 95% CI, 0.72-17.4), Charlson comorbidity index ≥ 2 (OR, 4.5; 95% CI, 0.92-22.0), hospital admission at inclusion (OR, 2.2; 95% CI, 0.64-8.1), and receipt of immunosuppression therapy (OR, 2.0; 95% CI, 0.55-7.9).
This is an interesting study because the authors randomly compared three commonly used treatments for recurrent CDI. It is notable that fidaxomicin was inferior to FMT since studies have shown it to be more successful than vancomycin for CDI recurrences. The clinical success rate of 92% for FMT aligns with previous reports, most of which demonstrated resolution rates of 70% to 90%. Another notable finding was that five out of seven patients who had a positive C. difficile test eight weeks after a first FMT experienced clinical resolution and did not need a rescue FMT. This supports the current recommendation not to perform a test of cure.1 The significance of a positive test despite clinical resolution is unclear. For example, are these patients at higher risk for recurrence? Are they still shedding spores and, if so, is there a potential to spread disease to family members, healthcare workers, or other patients? Future studies should be undertaken to address these concerns.
The presence of anemia had the highest odds ratio for FMT failure. This was an unexpected finding that has not been observed previously. The authors hypothesized that anemia might be a marker for disease burden and could help identify patients who may need multiple FMTs. Further evaluation of the role of anemia in recurrent CDI and its effects on FMT is warranted.
The study had some limitations. No ribotype 027 strains were identified, so the results might not be generalizable to patients infected with that strain. The study was not blinded, which could have led to observer bias. Because of the small number of patients in the groups, many of the confidence intervals were wide. Indeed, the study is likely underpowered, which affects the ability to detect meaningful differences between the different treatments. Prolonged vancomycin tapers (i.e., more than six weeks) are a common treatment strategy. How this would have compared to FMT was not evaluated. Finally, the study was conducted at a single institution in Denmark, so the results might not be generalizable to other settings and patient populations.
Compared to oral vancomycin alone and fidaxo-micin, oral vancomycin followed by FMT was superior for treating recurrent CDI in this small trial. Larger studies are needed to confirm this finding and to elucidate the optimal timing for FMT in the management of C. difficile recurrences.
Financial Disclosure: Peer Reviewer Patrick Joseph, MD, is a consultant for Genomic Health Reference Laboratory, Siemens Clinical Laboratory, and CareDx Clinical Laboratory. Infectious Disease Alert’s Editor Stan Deresinski, MD, FACP, FIDSA, Updates Author Carol A. Kemper, MD, FACP, Peer Reviewer Kiran Gajurel, MD, Executive Editor Shelly Morrow Mark, Editor Jonathan Springston, and Editorial Group Manager Leslie Coplin report no financial relationships to this field of study.