Fecal Microbiota Spores Cut Early Hospitalizations in Recurrent C diff

Fecal microbiota spores, live-brpk (Vowst; Nestlé Health Science) reduced all-cause hospitalizations among adults with recurrent Clostridioides difficile infection (rCDI), with the largest difference in the first 4 weeks after treatment.¹ By week 4, 3.4% of participants receiving the microbiome therapy had been hospitalized vs 16.1% receiving placebo. Paul Feuerstadt, MD, of Yale School of Medicine, presented the exploratory analysis of the phase 3 ECOSPOR III trial at IDWeek 2026, held October 21-24 in Washington, DC.¹

Two additional posters at the meeting examined bezlotoxumab in real-world practice and the microbiome effects of CRS3123, an investigational narrow-spectrum agent.^2,3 Hospitalization is a major cost driver in rCDI, yet data on how microbiome therapies affect admissions have been limited.¹ FDA-approved live biotherapeutic products have shown high efficacy in preventing recurrence.¹

ECOSPOR III Hospitalization Outcomes With Fecal Microbiota Spores in Recurrent CDI

ECOSPOR III (NCT03183128) randomized 182 adults with 3 or more CDI episodes in 12 months to 4 capsules of fecal microbiota spores daily for 3 days (n = 89) or placebo (n = 93) after symptom resolution with antibiotics.¹ The trial enrolled at 56 US and Canadian sites, and 98.9% of participants were managed as outpatients. Mean age was about 65 years in both arms.

The trial previously showed recurrence at week 8 of 12.4% vs 39.8% (relative risk, 0.32; 95% CI, 0.18-0.58).^1,4 This post hoc analysis was not prespecified or powered for hospitalization end points, and P values are nominal.

Cumulative all-cause hospitalization was lower with fecal microbiota spores at every timepoint: 3.4% vs 16.1% at week 4, 7.9% vs 17.2% at week 8, and 16.9% vs 22.6% at week 24.¹ Rate-adjusted hospitalizations per 1000 patient-weeks were 7.9 vs 38.5 at week 4 (P = .006) and 9.6 vs 22.3 at week 8 (P = .004).¹

Hospitalizations related to rCDI occurred in 2.2% (2/89) of the treatment group vs 7.5% (7/93) of the placebo group through week 24.¹ Findings held in an analysis restricted to participants remaining at risk at each timepoint.¹

"Nearly two-thirds of all-cause hospitalizations occurred within the first 8 weeks, the period of highest recurrence risk; and only 1 in 4 hospitalized participants was hospitalized for rCDI itself," Feuerstadt said in a recorded presentation accompanying the poster. "In conclusion, VOS was associated with fewer all-cause and rCDI-related hospitalizations through 24 weeks, with the greatest differences early, warranting further evaluation in real-world settings."

Bezlotoxumab Real-World Outcomes and CRS3123 Microbiome Effects in C difficile

A propensity-matched TriNetX analysis compared 1811 adults with CDI who received bezlotoxumab (Zinplava; Merck) with 1811 who received standard therapy alone.² Mean age was about 62 years, and baseline sepsis, kidney disease, malignancy, immunodeficiency, and steroid use were balanced between cohorts.² Of note, Merck announced discontinuation of bezlotoxumab in the US in late 2024, and later on in the EU in early 2025.

At 30 days, bezlotoxumab was associated with lower risks of sepsis (1.6% vs 3.2%; RR, 0.49; 95% CI, 0.28-0.87; P = .012) and acute kidney injury (1.5% vs 2.9%; RR, 0.50; 95% CI, 0.27-0.96; P = .033).² Mortality was 2.3% vs 5.9% at 30 days (HR, 0.38; 95% CI, 0.27-0.54; P < .001) and 6.0% vs 12.1% at 90 days (HR, 0.46; 95% CI, 0.36-0.58).²

CRS3123 (Crestone) selectively inhibits type 1 methionyl-tRNA synthetase, an enzyme largely restricted to low-GC gram-positive organisms including C difficile.³ In a phase 2 trial, the agent produced equivalent cure rates and lower recurrence than vancomycin (4% vs 23%).³ The investigators analyzed longitudinally collected fecal samples from the trial using 16S sequencing, shotgun metagenomics, metabolomics, and cytokine profiling.³

In fecal samples from 23 CRS3123-treated and 13 vancomycin-treated patients, CRS3123 preserved Bifidobacteria and Bacteroides and limited expansion of vancomycin-resistant enterococci.³ It also maintained secondary bile acid metabolism, which suppresses C difficile growth, while fecal calprotectin and interleukin-1β declined faster than with vancomycin.³ Vancomycin-treated patients showed greater loss of microbial diversity and a buildup of conjugated primary bile acids, which stimulate C difficile spore germination.³

References

1. Feuerstadt P, Allegretti JR, Dubberke ER, et al. Hospitalization outcomes following VOS or placebo for prevention of recurrent Clostridioides difficile infection: an exploratory analysis of the ECOSPOR III trial. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-228.

2. Abu Zahra D, Vatvani A, Shabarek N. Bezlotoxumab and short-term clinical outcomes in patients with Clostridioides difficile infection: a propensity-matched real-world study. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-162.

3. DeGroote MA, Apgar M, Lyon L, et al. Fecal microbiome, metabolome and host biomarker analysis in subjects receiving CRS3123 vs vancomycin for the treatment of Clostridioides difficile infection. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-21.

4. 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