Human gut microbiota are critical to both the development of and recovery from Clostridioides difficile infection (CDI). Antibiotics are the mainstay of CDI treatment, yet inherently cause further imbalances in the gut microbiota, termed dysbiosis, complicating recovery. A variety of microbiota-based therapeutic approaches are in use or in development to limit disease- and treatment-associated dysbiosis and improve rates of sustained cure. These include the recently FDA-approved fecal microbiota, live-jslm (formerly RBX2660) and fecal microbiota spores, live-brpk (formerly SER-109), which represent a new class of live biotherapeutic products (LBPs), traditional fecal microbiota transplantation (FMT), and ultra-narrow-spectrum antibiotics. Here, we aim to review the microbiome changes associated with CDI as well as a variety of microbiota-based treatment approaches.

Antimicrobial resistance to treatments for Clostridioides difficile infection (CDI) poses a significant threat to global health. C. difficile is widely thought to be susceptible to oral vancomycin, which is increasingly the mainstay of CDI treatment. However, clinical labs do not conduct C. difficile susceptibility testing, presenting a challenge to detecting the emergence and impact of resistance. In this systematic review, we describe gene determinants and associated clinical and laboratory mechanisms of vancomycin resistance in C. difficile, including drug-binding site alterations, efflux pumps, RNA polymerase mutations, and biofilm formation. Additional research is needed to further characterize these mechanisms and understand their clinical impact.

This study was the first human validation of the gram-positive bacterial DNA polymerase IIIC target in patients with Clostridioides difficile infection. The primary objectives were to assess clinical cure rates and adverse events (AEs). Secondary objectives were to evaluate plasma/fecal pharmacokinetics, microbiologic eradication, microbiome and bile acid effects, and sustained clinical cure (SCC) with ibezapolstat. This single-arm, open-label, phase 2a study enrolled adults with C. difficile infection at 4 US centers. Patients received ibezapolstat 450 mg orally every 12 hours for 10 days and followed for an additional 28 days to assess study objectives. Ten patients with a mean (standard deviation [SD]) age of 49 [15] years were enrolled. Seven AEs were reported classified as mild-moderate. Plasma levels of ibezapolstat ranged from 233 to 578 ng/mL while mean (SD) fecal levels were 416 (494) µg/g stool by treatment day 3 and >1000 µg/g stool by days 8–10. A rapid increase in alpha diversity in the fecal microbiome was noted after starting ibezapolstat therapy, which was maintained after completion of therapy. A proportional decrease in Bacteroidetes phylum was observed (mean change [SD], −10.0% [4.8%]; P = .04) with a concomitantly increased proportion of Firmicutes phylum (+14.7% [5.4%]; P = .009). Compared with baseline, total primary bile acids decreased by a mean (SD) of 40.1 (9.6) ng/mg stool during therapy (P < .001) and 40.5 (14.1) ng/mg stool after completion of therapy (P = .007). Rates of both initial clinical cure and SCC at 28 days were 100% (10 of 10 patients). In this phase 2a study, 10 of 10 patients achieved SCC, demonstrated favorable pharmacokinetics, minimal AEs, and beneficial microbiome and bile acids results. These results support continued clinical development.

Epidemiologic studies have shown decreasing vancomycin susceptibility among clinical Clostridioides difficile isolates, but the impact on patient outcomes is unknown. We hypothesized that reduced vancomycin susceptibility would be associated with decreased rates of sustained clinical response (SCR). This multicenter cohort study included adults with C. difficile infection (CDI) treated with oral vancomycin between 2016-2021. C. difficile isolates underwent agar dilution vancomycin susceptibility testing, ribotyping, and Sanger sequencing of the vancomycin resistance vanR gene. Reduced susceptibility was defined as vancomycin minimum inhibitory concentration (MIC) >2 μg/mL. The primary outcome was 30-day SCR; secondary outcomes were 14-day initial cure, 30-day recurrence, and 30-day mortality. Exploratory analysis assessed the association between the VanR Thr115Ala polymorphism, susceptibility, and outcomes. A high proportion (34%, 102/300) of C. difficile isolates exhibited reduced vancomycin susceptibility (range: 0.5-16 μg/mL, MIC_50/90 = 2/4 μg/mL). Ribotype (RT) 027 accounted for the highest proportion (77.4%, 41/53) of isolates with reduced vancomycin susceptibility. Overall, 83% (249) of patients achieved 30-day SCR. Reduced vancomycin susceptibility was associated with lower rates of 30-day SCR (76%, 78/102) than vancomycin susceptible strains (86%, 171/198; P=0.031). A significantly lower rate of 14-day initial cure was also observed among individuals infected with strains with reduced vancomycin susceptibility (89% vs. 96%; P=0.04). Reduced susceptibility remained an independent predictor of 30-day SCR in multivariable modeling (odds ratio, 0.52, 95% confidence interval 0.28-0.97; P=0.04). Reduced vancomycin susceptibility in C. difficile was associated with decreased odds of 30-day SCR and lower 14-day initial cure rates in the studied patient cohort.

Clostridioides difficile infection (CDI) is the most prevalent healthcare-associated infection in the United States and carries a significant healthcare system burden. As part of an ongoing, active surveillance system of C. difficile throughout Texas, the objective of this study was to assess changes in C. difficile ribotypes of clinical isolates obtained from hospitalized patients in Texas over the past seven years. Fifty hospitals located in Texas, USA sent C. difficile positive stool specimens to a centralized laboratory for PCR ribotyping and toxin characterization between 2011 and 2018. Data collected included specimen collection date, patient age, and sex. Strain genotypes were compiled, and changes in ribotype distribution over time were assessed. Overall, 7796 samples were ribotyped from predominately female patients (58.4%) aged 62 ± 19 years. Samples were obtained from all geographic regions of Texas including Houston/Southwest region (n = 5129; 85%), Dallas/North Texas (n = 579, 9.6%), Central Texas (n = 164; 2.7%), and South Texas (n = 162; 2.6%). The 10 most common ribotypes comprised 73% of all isolates tested during the study period. The most common ribotypes were 027 (17.5%), followed by 014–020 (16.1%), 106 (11.6%), and 002 (9.1%). The prevalence of ribotypes 027, 001, and 078–126 declined significantly over time, while ribotypes 106 and 054 increased in prevalence (P < 0.001). Furthermore, the emergence of a novel ribotype 255 strain was observed. Differences in ribotype distribution were also noted based on age and geographic distribution (P < 0.001, each). This seven-year study demonstrated changing molecular epidemiology of C. difficile in Texas, including the emergence of a novel ribotype 255.