Clostridioides difficile is a major healthcare-associated pathogen, and infection with this bacteria leads to excess morbidity and mortality, as well as prolonging hospital stays and hospital readmissions. Further, patients who have experienced 1 episode of recurrent C difficile infection (CDI) have a 45% risk for subsequent recurrence.1 Fecal microbiota transplantation (FMT) has shown therapeutic efficacy in recurrent or refractory CDI and superiority compared with vancomycin in randomized clinical trials.2

Fidaxomicin, an orally administered, nonabsorbable antibiotic treatment option for CDI, has a narrow spectrum of activity that preserves the healthy bowel microbiota. Evidence suggests that compared with vancomycin, the efficacy of fidaxomicin as initial therapy is equivalent, but individuals who receive fidaxomicin have a lower recurrence rate. However, previous research has not demonstrated clear evidence of whether fidaxomicin or FMT achieves better cure rates for recurrent CDI.

Hvas and colleagues1 conducted a randomized, open-label clinical trial to compare the performance of FMT with both fidaxomicin and vancomycin (ClinicalTrials.gov identifier: NCT02743234). This single-center study was conducted in Denmark and included individuals who had recurrent CDI with a median of 4 recurrences. Patients were randomly assigned to receive FMT after 4 to 10 days of 125 mg vancomycin, administered 4 times daily by either colonoscopy or nasojejunal tube, or 10 days of twice-daily fidaxomicin (200 mg) or 10 days of standard vancomycin therapy (125 mg, administered 4 times daily). The primary outcome was a combination of clinical resolution and negative polymerase chain reaction testing for C difficile toxin after 8 weeks of treatment.

Sixty-four patients were included in the study. The primary outcome was achieved in 71% (n=17) of patients receiving FMT and vancomycin and in 33% (n=8) of the fidaxomicin group and 19% (n=3) of the vancomycin-alone group (P =.009 and P =.001 for fidaxomicin and vancomycin, respectively, compared with FMT).1 Clinical resolution was demonstrated in 92% of patients who received FMT compared with 42% and 19% of patients who received fidaxomicin and vancomycin, respectively.


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In addition, clinical resolution was achieved in 83% of patients who received rescue FMT after failing antibiotic monotherapy. Also, screened patients who were not randomly assigned because of exclusion criteria achieved 80% cure with off-protocol FMT. Adverse events were prospectively documented, and no differences were observed between the 3 groups in terms of frequency of adverse events or severe adverse events.

To gain more insight on this treatment modality, Infectious Disease Advisor spoke with Christian Lodberg Hvas, MD, PhD, clinical associate professor for the Department of Hepatology and Gastroenterology at Aarhus University Hospital in Denmark.

Infectious Disease Advisor: During recruitment for the study, did you encounter many issues around the acceptability of FMT or the need for extensive counselling?

Dr Hvas: Patients with recurrent CDIs are in distress and share an overwhelming fear of further relapse, both before treatment and after successful FMT. Therefore, counseling was requested, required, and offered by the whole team. We used extensive written and oral standard patient information, and we had consultations with patients and their relatives before and after inclusion in the study. As a part of the study, we asked patients and medical staff if they felt uncomfortable or repelled by the treatment (or the thought of it). We haven’t analyzed the data yet, but our impression was that the reservations are common among the healthy, frequent among health professionals, and completely absent among patients with CDI.

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Infectious Disease Advisor: In the study, you describe a serious adverse event in a woman aged 50 years who experienced a transient “sepsis-like clinical picture” with fever, vomiting, and diarrhea after receiving FMT. Do the study authors have an explanation for this?

Dr Hvas: One-third of all patients experience some type of acute reaction to FMT. It typically appears an hour or so after the procedure and may include fever, shivering, diarrhea, and bloating. Sometimes it is quite dramatic and may resemble sepsis, as in the described case. In all patients, however, all acute adverse effects were short-lived. We think of it as the consequence of engraftment of the donor microbiome, with a subsequent acute reaction. Interestingly, the woman described in the paper resolved completely, and 1 hypothesis could be that those with acute reactions have a better prognosis.

Infectious Disease Advisor: The patients in both parts of the study had a median of 4 C difficile recurrences before randomization. Given the study’s demonstration of superiority of FMT at this stage of disease, should FMT be investigated in individuals with fewer recurrences?

Dr Hvas: Yes, we believe so. It remains at the discretion of the referring physicians how many recurrences they accept before referring for FMT: one may feel tempted to prescribe another vancomycin course or a tapered course. We know that tapered vancomycin is just as bad as standard-length prescription to prevent CDI recurrence, documented by Cammarota and colleagues.3 In my opinion, patients should be referred during treatment for their first recurrence after vancomycin. In some, a trial of fidaxomicin may be justified, depending on factors such as patient age, risk profile, and personal preferences. Regardless of these considerations, vancomycin will only buy you time, and not cure.

Infectious Disease Advisor: For all the patients screened in your study, the previous CDI treatments were typically metronidazole and/or vancomycin, and only rarely (4%-5%) fidaxomicin.1 Given the narrow spectrum of activity of fidaxomicin, do you think that FMT may be less effective if preceding episodes were treated with this agent, as some are advocating?4

Dr Hvas: This is an interesting question that our study can only partly answer. In the study, we offered rescue FMT to those who relapsed after primary antibiotic treatment. In those who failed fidaxomicin, the success of rescue FMT was 9 of 11 (82%), which iscomparable with the effect in the other groups. We haven’t yet analyzed the fecal samples collected in the study because long-term follow-up has not been completed. 

References

1. Hvas, CL, Jorgensen SMD, Jorgensen SP, et al. Fecal microbiota transplantation is superior to fidaxomicin for treatment of recurrent Clostridium difficile infection. Gastroenterology. 2019;156:1324-1332.

2. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-415.

3. Cammarota G, Mascucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection [published online April 2, 2015]. Aliment Pharmacol Ther. doi:10.1111/apt.13144

4. Goldenberg, Brown S, Edwards L, et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven NHS secondary care hospitals in England: a series of local service evaluations. Eur J Clin Microbiol Infect Dis. 2016;35:251-259.