Background This study was the first human validation of the gram-positive bacterial DNA polymerase IIIC target in patients with Clostridioides difficile infection (CDI). The primary objectives were to assess clinical cure rates and adverse events (AE). Secondary objectives were to evaluate plasma/fecal pharmacokinetics (PK), microbiologic eradication, microbiome and bile acid effects, and sustained clinical cure (SCC) of ibezapolstat. Methods This single-arm, open-label, phase 2a study enrolled adults with CDI at four 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. Results Ten patients aged 49±15 years were enrolled. Seven AEs were reported classified as mild-moderate. Plasma levels of ibezapolstat ranged from 233-578 ng/mL while fecal levels averaged 416±494 µg/g (mean±SD) stool by treatment day 3 and >1,000 µg/g stool by days 8-10. A rapid increase in alpha diversity in the fecal microbiome was noted after starting ibezapolstat therapy that was maintained following completion of therapy. A proportional decrease in Bacteroidetes phylum was observed (10.0±4.8% decrease; p=0.043) with a concomitantly increased proportion of Firmicutes phylum (14.7±5.4% increase; p=0.009). Compared to baseline, total primary bile acids decreased by 40.1±9.6 ng/mg stool during therapy (p=0.0002) and 40.5±14.1 ng/mg stool after completion of therapy (p=0.0066). Rates of both initial clinical cure and SCC at 28 days were 100% (10 of 10 patients). Conclusions In this phase 2a study, ten of ten patients achieved SCC, demonstrated favorable pharmacokinetics, minimal adverse events, and beneficial microbiome and bile acids results. These results support continued clinical development.

Reduction of Clostridioides difficile infection (CDI) recurrence is an essential endpoint for CDI-directed antibiotic development that is often not evaluated until Phase III trials. The purpose of this project was to use a functional and metagenomic approach to predict the potential anti-CDI recurrence effect of ibezapolstat, a DNA polymerase IIIC inhibitor, in clinical development for CDI.

Objective: This article describes a CDI outbreak in a long-term care (LTC) facility that used molecular typing techniques and whole-genome sequencing to identify widespread dissemination of the clonal strain in the environment which was successfully removed after terminal cleaning. Setting: This study was conducted in a long-term care facility in Texas. Methods: A recently hospitalized LTC patient was diagnosed with CDI followed shortly thereafter by 7 subsequent CDI cases. A stool specimen was obtained from each patient for culturing and typing. An environmental point-prevalence study of the facility was conducted before and after terminal cleaning of the facility to assess environmental contamination. Cultured isolates were typed using ribotyping, multilocus variant analysis, and whole-genome sequencing. Results: Stool samples were available for 5 of 8 patients; of these specimens, 4 grew toxigenic C. difficile ribotype 027. Of 50 environmental swab samples collected throughout the facility prior to the facility-wide terminal cleaning, 19 (38%) grew toxigenic C. difficile (most commonly ribotype 027, 79%). The terminal cleaning was effective at reducing C. difficile spores in the environment and at eradicating the ribotype 027 strain (P < .001). Using multilocus variance analysis and whole-genome sequencing, clinical and environmental strains were highly related and, in some cases, were identical. Conclusion: Using molecular typing techniques, we demonstrated reduced environmental contamination with toxigenic C. difficile and the eradication of a ribotype 027 clone. These techniques may help direct infection control efforts and decrease the burden of CDI in the healthcare system.

Background Candida auris is an emerging new multi-drug-resistant fungal pathogen spreading globally. C. auris is associated with outbreaks due to the bloodstream, ear, and wound infections with a high mortality rate (30 to 60%). As part of our multi-pathogen surveillance system, we began screening for C. auris to understand the ecology, sources, and epidemiology of this important pathogen from leftover stool samples collected from hospitalized patients.MethodsFour hundred and seventeen stool samples were collected, enriched in brain heart infusion broth for 2–3 days at 37°C, and sub-cultured onto selective Candida agar plates. Agar plates were incubated at 37°C for another 2–3 days and suspected Candida colonies were stocked for DNA extraction, PCR identification, and whole-genome sequencing. PCR amplicons were sequenced to confirm the identification C. auris. Enrichment samples were also screened by PCR to directly detect C. auris. Minimum inhibitory concentration (MIC) of various anti-fungal drugs was determined by the micro-dilution method using a commercial MIC plate (Sensititre “YeastOne”).ResultsThree C. auris samples were identified by PCR (0.7%; 3/417) of which one was able to be cultured. The isolated strain was resistant to fluconazole, itraconazole, voriconazole, posaconazole, and caspofungin. WGS data analysis demonstrates our isolate has high similarity with the Pakistani strains.ConclusionWe have detected C. auris from stool samples of hospitalized patients in Texas for the first time. WGS data indicate our isolate has high similarity with South Asian patient strains. Long-term surveillance of C. auris is essential to understand the infection or colonization sources and epidemiology of this newly emerging fungal pathogen.Disclosures All authors: No reported disclosures.

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