CME Author: Zeena Nackerdien
Study Authors: Christian L. Has, Simon M.D. Jørgenson, et al.
Target Audience and Goal Statement:
Gastroenterologists and infectious disease specialists
The goal was to explore evidence from a single-center randomized trial to compare the effects of fecal microbiota transplantation (FMT) with those of fidaxomicin and vancomycin in adults with recurrent Clostridium difficile infection (rCDI).
Study investigators addressed the following questions:
- Could high rCDI resolution rates seen in observational studies with FMT be replicated in a randomized clinical trial?
- How would FMT, applied by colonoscopy or nasojejunal tube after 4–10 days of vancomycin (FMTv) compare with active comparators, such as vancomycin and fidaxomicin?
Synopsis and Perspective:
CDI is one of the most important causes of healthcare-associated diarrhea, and has become the most commonly identified cause of healthcare-associated infections (HAIs) in U.S. adults. The pathogenicity of C. difficile is mediated via two exotoxins (toxin A and toxin B) and its clinical impact has, thus far, mainly been observed in the elderly and immunocompromised patients.
When the commensal “harmless” bacteria in the gut is eliminated with antibiotic use, the net result is likely to be a primary CDI, and a treatment course of following antibiotics with more antibiotics leads to a ≥30% increased risk of disease recurrence, according to one review.
Until 2011, oral vancomycin was the only FDA-approved therapy to treat CDI. Risk and duration of the infection increase with any given antibiotic dose, particularly for fluoroquinolones. The emergence of multidrug-resistant strains of C. difficile has elevated the risk for disease relapse. Multidrug-resistant C. difficile ribotype 027 is on the decline in Europe, but remains one of the most commonly identified strains in the U.S., especially for healthcare-associated CDIs.
FMT — the administration of a solution of fecal matter from a donor into the intestinal tract of a recipient in order to directly change the recipient’s gut microbial composition and confer a health benefit — has been shown to resolve up to 90% of rCDI cases, based on observational studies and clinical trial subgroups. But there was an unmet need to compare FMT to the clinical trial gold standard, vancomycin, and recently developed, oral, non-absorbable antibiotics such as fidaxomicin.
From 2016 to 2018, 120 consecutive referred patients were screened for participation, according to Christian Lodberg Hvas, MD, PhD, of Aarhus University Hospital in Denmark, and colleagues. Those who were frail, septic, or already on antibiotics were excluded. A total of 64 adults with documented rCDI (median age 68; median Charlson comorbidity index score 1; four median number of prior CDI episodes) were randomized to receive colonoscopy- or nasojejunal tube-delivered FMTv (n=24), fidaxomicin, (n=24) or vancomycin (n=16). By gender, 83%, 69%, and 54% were female in the the three arms, respectively.
Rescue FMTv was administered to non-randomized patients, or those with disease recurrence following the current course of treatment. The CD test consisted of PCR targeting genes for toxin A (in-house only), toxin B, and binary toxin, as well as the deletion in position 117 in the tcdC gene (tcdC-Δ-117) to detect CD ribotype 027. Any combination of toxins was considered to be a positive CD result.
The primary outcome was combined clinical resolution and a negative CD test without the need for rescue FMTv or colectomy 8 weeks after the initial treatment. Secondary outcomes included clinical resolution at week 8, a negative CD test at week 8, combined clinical resolution and negative CD test at week 1, clinical resolution at week 1, and a negative CD test at week 1. Post hoc outcome measure was defined as resolution of CD-associated diarrhea (clinical resolution or persistent diarrhea with a negative CD test).
The numbers of patients with a negative CD test and clinically resolved disease were 17 (71%, 95% CI 49-87%), eight (33%, 95% CI 16-55%), and three (19%, 95% CI 5-46%), for the FMTv, fidaxomicin, and vancomycin study arms, respectively. Clinical resolution was observed in 92% of FMTv-treated cases compared with 42% of fidaxomicin-treated and 19% of vancomycin-treated cases. Similar outcomes were observed between patients who received FMTv as their initial therapy and patients who received rescue FMTv.
A total of 48 adverse events (AE) and serious adverse events (SAE), excluding rCDI, occurred in 29 patients >2 days and up to 8 weeks after treatment with the study agents. Overall, 10 patients (42%) experienced AEs, including one case each of transient abdominal pain and constipation, five cases of bloating, and three of diarrhea.
Of the 24 patients allocated to FMTv, 14 (58%, 95% CI 95% 37-78%) had no adverse effects. Only one SAE may have been related to FMTv, the authors reported.
Purna C. Kashyap, MBBS, of the Mayo Clinic in Rochester, Minnesota, told MedPage Today, “This is a really interesting, well done study that further affirms the benefit of FMT in recurrent CDI. The main take-home is that fecal transplant is better than fidaxomicin or vancomycin alone in treating recurrent CDI in patients predominantly in the outpatient setting.”
As in previous studies, the investigators did not find that donor type or route of administration made a difference, added Kashyap, who was not involved in the study.
However, he noted that since sicker and hospitalized patients were disproportionately excluded, the findings would not be as applicable to a frailer population. “But the biggest limitation is the lack of blinding, which they tried to mitigate in part by testing for CD, which provides an objective endpoint,” he stated.
Another study limitation was that none of the patients were infected with CD ribotype 027, according to the authors.
Source Reference: Gastroenterology, Dec. 26, 2018, DOI:10.1053/j.gastro.2018.12.019
Study Highlights: Explanation of Findings
This study showed that FMT delivered by either colonoscopy or a nasojejunal tube following a short course of vancomycin was superior to both fidaxomicin and standard dose vancomycin monotherapies in the treatment of adults with rCDI. Similar clinical results were found following the delivery of rescue FMT to non-randomized patients and those with disease recurrence following their primary allocated treatment.
Overall, the clinical FMTv effect of 92% was similar to literature reports. Because comparable resolution rates were observed in patients who were randomized to primary FMTv, in those who received rescue FMTv following failure of initial FMTv and antibiotics treatment, and in patients who received FMTv following screen failure, the authors concluded that the study had a high degree of generalizability. However, the absence of patients infected with CD ribotype 027 was a study limitation.
The study also found that a low baseline hemoglobin was the strongest and only significant predictor of FMT failure, with an odds ratio of 0.5 (95% CI 4.8-7.2) per point increase in hemoglobin. “This new finding may prove clinically relevant and could be useful for a priori identification of patients who would benefit from multiple FMT procedures,” the authors wrote. “The presence of anemia may reflect the overall burden of disease and longstanding inflammation and better reflects frailty than variables such as patient age and comorbidity.”
Future studies are needed to validate these findings in other patient cohorts, the authors suggested, adding that more studies to examine if toxin carrier status is a risk factor for future CDI recurrence or for dissemination of CDI spores causing nosocomial infection.
Original story for MedPage Today by Diana Swift
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco