Are any commercially available fecal microbiota transplantation (FMT) products currently available on the US market? If not, what are the recommended alternatives for C. difficile infection?

Background

A 2022 meta-analysis compared the recurrence rate of Clostridioides difficile infection (CDI) of fidaxomicin versus vancomycin. Randomized and observational studies of adult patients with recurrence rates for each treatment group were included for analysis. Use of fecal microbiota transplantation led to study exclusion. From a total of 6 included studies (N= 3944), the CDI recurrence rate was 16.1% in the fidaxomicin group versus 25.4% in the vancomycin group, equating to a 31% risk reduction of recurrence for fidaxomicin (risk ratio 0.69; 95% confidence interval [CI] 0.52 to 0.91). A similar trend was observed when analyzing subgroups of patients with initial CDI, first recurrent CDI, non-severe and severe CDI, and in both inpatient and outpatient settings. While the results may seem to favor fidaxomicin, a high heterogeneity was reported between studies. Many observational studies tend to focus on patient populations with high risk of recurrence, and the difference in definition and outcomes can influence the high heterogeneity. [1]

A 2022 systematic review and meta-analysis compared the effectiveness of fecal microbiota transplantation (FMT) and medical therapy (MT) for CDI. A total of seven randomized controlled studies (N= 238 patients) were included in the meta-analysis. Adult patients with CDI receiving any form of FMT (including esophagogastroduodenoscopy, colonoscopy, nasogastric tube, nasoduodenal tube, or oral capsule) were included. Patients in the control group could have received any MT approved for use in CDI (including metronidazole, vancomycin, fidaxomicin, bezlotoxumab, ridinilazole). Pooled results for the primary efficacy outcome of diarrhea resolution and/or negative C. difficile testing revealed no significant difference in the number of patients responding to the first session of FMT vs. MT (RR 1.52; 95% CI 0.90 to 2.58; p= 0.12; I2= 77%). Additionally, no significant difference was found for patients receiving multiple sessions of FMT vs. MT (RR 1.68; 95% CI 0.96 to 2.94; p= 0.07; I2= 82%). For the secondary outcome, FMT had a statistically higher relative risk of responders compared to MT (RR 2.41; 95% CI 1.20 to 4.83, I2= 78%) amongst patients with recurrent CDI; no significant difference was found between groups for primary CDI. These results indicate a promising outlook with FMT for recurrent CDI, while MT may be preferred for primary CDI. [2]

A 2020 network meta-analysis compared the effectiveness of fidaxomicin vs. metronidazole for treatment of CDI. To perform this analysis, comparative studies of fidaxomicin vs. vancomycin, and metronidazole vs. vancomycin were sought for inclusion. None of the included studies directly compared fidaxomicin and metronidazole. A total of seven studies, with eight datasets, were included for analysis. The results suggest a significant difference in favor of fidaxomicin vs. metronidazole for clinical cure rate (odds ratio [OR] 1.77; 95% credible interval [Crl] 1.11 to 2.83), recurrence rate (OR 0.44; 95% CrI 0.27 to 0.72), and sustained cure without recurrence (OR 2.39; 95% CrI 1.65 to 3.47). Compared to vancomycin, fidaxomicin was associated with a statistically significant difference in recurrence rate (OR 0.50; 95% CrI 0.37 to 0.68) and sustained cure rate (OR 1.61; 95% CrI 1.27 to 2.05). Safety was not assessed. In summary, fidaxomicin could potentially exhibit a higher efficacy than metronidazole in terms of cure rate, in addition to demonstrating superior effectiveness in preventing CDI recurrence when compared to vancomycin. [3]

A 2018 meta-analysis compared and ranked the various treatment options for non-multiply recurrent CDI in adults. Studies had to report primary symptomatic cure and recurrence of diarrhea, and were excluded if intent-to-treat analysis was not available or several drugs were used for treatment. A total of 24 studies, comprising 13 different pharmacologic interventions, were included for analysis. The P score, valued between 0 and 1, was used to rank the best treatment. For the primary outcome of sustained symptomatic cure, fidaxomicin observed the highest quality of evidence and most frequent sustained cure rate; treatment was more effective than vancomycin. While teicoplanin and ridinilazole ranked higher in terms of P scores, the certainty of results were lowered due to the poor quality of their studies. [4]

Relevant Prescribing Information

Rebyota (donor human stool suspension) for fecal microbiota transplantation was FDA approved in 2022. [5]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Are any commercially available FMT products currently available on the US market? If not, what are the recommended alternatives for CDI.

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-2 for your response.

*SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile* Infection**
Design	Phase 3, double-blind, randomized, placebo-controlled trial N= 182
Objective	To investigate effects of SER-109 (Vowst) compared to placebo in reducing risk of Clostridioides difficile (C. difficile) infection (CDI) recurrence
Study Groups	SER-109 (n= 89) Placebo (n= 93)
Inclusion Criteria	Age ≥ 18 years with 3 or more episodes of CDI within 12 months
Exclusion Criteria	Toxic megacolon and/or known small bowel ileus, use of antibacterial therapy other than standard-of-care (SOC) antibiotics for most recent episode of CDI, major gastrointestinal surgery within 3 months prior to enrollment, history of active inflammatory bowel disease, admitted to intensive care unit for medical reasons
Methods	Patients were randomized 1:1 to SER-109 (approximately 3 × 10⁷ spore colony-forming units) or placebo administered as four matching oral capsules once daily over 3 consecutive days. Magnesium (10 oz) was administered the night prior to treatment to limit inactivation of SER-109 due to residual vancomycin or fidaxomicin, which can persist up to 5-7 days after discontinuation.
Duration	Trial: July 2017 to September 2020 Efficacy period: 8 weeks Follow-up: 16 weeks
Outcome Measures	CDI recurrence at 8 weeks after dosing
Baseline Characteristics		SER-109 (n= 89)	Placebo (n= 93)
	Age, years < 65 ≥ 65	65.6 46% 54%	65.5 41% 59%
	Female	67%	53%
	Race Asian Black White Other	1% 4% 92% 2%	0 4% 95% 1%
	Episodes of CDI, including qualifying episode 3 ≥ 4 Missing data	55% 44% 1%	66% 34% 0
	Previous antibiotic regimen Vancomycin Fidaxomicin	72% 28%	74% 26%
Results	Endpoint	SER-109 (n= 89)	Placebo (n= 93)	Relative risk (95% confidence interval); p-Value
	Patients with CDI recurrence Age < 65 years Age ≥ 65 years Previous vancomycin Previous fidaxomicin	11 (12%) 3 (7%) 8 (17%) 10 (16%) 1 (4%)	37 (40%) 12 (31%) 25 (46%) 26 (38%) 11 (46%)	0.32 (0.18 to 0.58); p< 0.001 0.24 (0.07 to 0.78) 0.36 (0.18 to 0.72) 0.41 (0.22 to 0.79) 0.09 (0.01 to 0.63)
	Sustained clinical response	88%	60%	N/A
	Most recurrence events occurred rapidly, with onset as early as day 4 post-randomization. Of the 48 total recurrences documented in the overall trial population at 8 weeks, 36 (75%) occurred within 2 weeks and 41 (85%) occurred within 4 weeks after SER-109 or placebo.
Adverse Events	The most common adverse events were gastrointestinal disorders, mostly mild to moderate in severity. No serious adverse events were deemed to be related to SER-109. Three deaths were reported in the SER-109 group, but none were considered to be drug-related.
Study Author Conclusions	In patients with recurrent C. difficile infection, achievement of a sustained clinical response can be made more likely with a two-pronged treatment paradigm of antibiotics followed by a microbiome therapeutic. SER-109 was superior to placebo in reducing the risk of recurrence, with an observed safety profile similar to that of placebo.
InpharmD Researcher Critique	The vast majority of included patients were white. The full impact of SER-109 on microbiome could not be assessed due to the lack of a baseline stool specimen prior to administration of antibiotic treatment.

References:

Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. N Engl J Med. 2022;386(3):220-229. doi:10.1056/NEJMoa2106516

*Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile* Infection: A Phase 3, Open-Label, Single-Arm Trial**
Design	Phase 3, open-label, single-arm trial N= 263
Objective	To evaluate the safety and rate of Clostridioides difficile infection (CDI) recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks
Study Groups	Cohort 1 (n= 29) Cohort 2 (n= 234)
Inclusion Criteria	Age ≥ 18 years; Cohort 1 had a CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) within 8 weeks after receipt of either SER-109 or placebo (rollover patients from ECOSPOR III trial); Cohort 2 included de novo patients with at least 1 CDI recurrence (i.e., ≥2 CDI episodes inclusive of the current episode)
Exclusion Criteria	Toxic megacolon and/or known small bowel ileus, use of antibacterial therapy other than standard-of-care (SOC) antibiotics for most recent episode of CDI, major gastrointestinal surgery within 3 months prior to enrollment, history of active inflammatory bowel disease, admitted to intensive care unit for medical reasons
Methods	Patients received a single daily dose of SER-109 with a target of 3 × 10⁷ spore colony–forming units per dose in 4 capsules, administered over 3 consecutive days. First dose of study drug was administered within 4 days following antibiotic treatment completion. Patients were to take 10 oz of magnesium citrate 1 day prior to treatment initiation for washout of residual antibiotic.
Duration	Trial: October 2017 to April 2022 Primary efficacy period: 8 weeks Follow-up: 16 weeks
Outcome Measures	Primary: safety and tolerability (treatment emergent adverse events [TEAS]) up to 24 weeks Secondary: CDI recurrence at weeks 4, 8, 12, and 24
Baseline Characteristics		All patients (N= 263)
	Age, years < 65 ≥ 65	64.0 47.9% 52.1%
	Female	68.4%
	Race White Black Asian	92.4% 5.3% 1.9%
	CDI episodes 2 ≥ 3	29.3% 70.0%
	Antibiotic regimen for qualifying CDI episode Vancomycin Fidaxomicin	72.6% 27.4%
Results	Endpoint	SER-109 (n= 4)*	Placebo (n= 25)*	Cohort 2 (n= 234)	Total (N= 263)
	TEAEs Any Mild to moderate Serious Related/possibly related to study drug Resulting in withdrawal Resulting in death	4 (100%) 3 (75%) 1 (25%) 0 0 0	15 (60%) 14 (56.0%) 0 0 0 0	122 (52.1%) 98 (41.9%) 32 (13.7%) 0 0 8 (3.4%)	141 (53.6%) 115 (43.7%) 33 (12.5%) 0 0 8 (3.0%)
	CDI recurrence at week (95% CI): 4 8 12 24	0 (0.0 to 60.2) 0 (0.0 to 60.2) 0 (0.0 to 60.2) 1 (25%) (0.6 to 80.6)	4 (16%) (4.5 to 36.1) 4 (16%) (4.5 to 36.1) 5 (20%) (6.8 to 40.7) 5 (20%) (6.8 to 40.7)	10 (4.3%) (2.1 to 7.7) 19 (8.1%) (5.0 to 12.4) 23 (9.8%) (6.3 to 14.4) 30 (12.8%) (8.8 to 17.8)	14 (5.3%) (2.9 to 8.8) 23 (8.7%) (5.6 to 12.8) 28 (10.6%) (7.2 to 15.0) 36 (13.7%) (9.8 to 18.4)
	*Cohort 1
Adverse Events	The most common adverse events overall were diarrhea (22.8%), flatulence (7.6%), nausea (7.6%), abdominal pain (6.8%), urinary tract infection (4.9%), fatigue (4.9%), and abdominal distension (4.2%)
Study Author Conclusions	In this phase 3, open-label, single-arm trial of patients with a history of recurrent CDI, SER-109 was well tolerated and the overall rate of recurrent CDI was low, consistent with the ECOSPOR III placebo-controlled randomized clinical trial. The baseline prevalence of multiple comorbidities was high, reflective of expanded populations with recurrent CDI. With this potential first-in-class purified microbiome therapeutic, the rate of recurrent CDI after symptom resolution after antibiotic treatment was low at week 8 and durable through week 24 regardless of the number of recurrences before study entry. Earlier treatment with SER-109 at the time of first recurrence may be associated with reduced morbidity from recurrent CDI.
InpharmD Researcher Critique	This study implemented an open-label design. For Cohort 2, no comparator group was included.

References:

Sims MD, Khanna S, Feuerstadt P, et al. Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile Infection: A Phase 3, Open-Label, Single-Arm Trial. JAMA Netw Open. 2023;6(2):e2255758. Published 2023 Feb 1. doi:10.1001/jamanetworkopen.2022.55758