Ramesh, Mayur

ImportanceSystemic antibiotic use for patients with a non–Clostridioides difficile infection (CDI) is a major risk factor for recurrent CDI. Increasing use of oral vancomycin for secondary prophylaxis against recurrent CDI in this context has uncertain efficacy.ObjectiveTo evaluate whether oral vancomycin prophylaxis compared with placebo is effective against recurrent CDI during and 8 weeks after the end of study treatment.Design, Setting, and ParticipantsThis phase 2, placebo-controlled, double-blind randomized clinical trial was conducted in 4 large health systems across the upper Midwest US. Adults who had completed treatment for CDI within the past 180 days and were taking a systemic antibiotic for a non-CDI indication were enrolled between May 21, 2018, and March 30, 2023, and followed up for 8 weeks after the end of study treatment.InterventionParticipants were randomized 1:1 to 125 mg of oral vancomycin or placebo once daily during antibiotic use for a non-CDI plus 5 days following cessation of those antibiotics.Main Outcomes and MeasuresThe primary outcome was recurrent CDI incidence during treatment and the 8-week follow-up period. The secondary outcome was vancomycin-resistant Enterococcus carriage in stool.ResultsAmong 81 randomized participants (median age, 59 years [IQR, 50-67 years]), all were included in the primary as-randomized analysis (39 in the vancomycin group; 42 in the placebo group). Sixty patients (74.1%) completed 8-week follow-up and were included in the secondary as–completed treatment analysis (31 in the vancomycin group; 29 in the placebo group). Recurrent CDI occurred in 17 of 39 participants in the oral vancomycin group (43.6%) and 24 of 42 in the placebo group (57.1%; absolute difference in percentage, −13.5% [95% CI, −35.1% to 8.0%]). Adverse events occurred in 27 of 39 participants in the oral vancomycin group (69.2%) and 27 of 42 in the placebo group (64.3%). Vancomycin-resistant Enterococcus carriage was found in 15 of 30 patients in the oral vancomycin group (50.0%) and 6 of 25 in the placebo group (24.0%) (P = .048) 8 weeks after treatment.Conclusions and RelevanceIn this randomized clinical trial, the incidence of recurrent CDI was lower (though did not reach significance) in participants taking oral vancomycin compared with those taking placebo. Because the study was underpowered, it was unable to reveal firm conclusions about the efficacy (or lack thereof) of vancomycin prophylaxis with respect to recurrent CDI.Trial RegistrationClinicalTrials.gov Identifier: NCT03462459

ImportanceA safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence.ObjectivesTo evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks.Design, Setting, and ParticipantsThis phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry.InterventionsSER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI.Main Outcomes and MeasuresThe main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population.ResultsOf 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]).Conclusions and RelevanceIn this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI.Trial RegistrationClinicalTrials.gov identifier: NCT03183141