Abstract
Background
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.
Methods
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.
Results
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).
Conclusions
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.
This single-arm, phase 2a study was the first validation of ibezapolstat in adult patients with Clostridioides difficileinfection. Ten of 10 patients achieved sustained clinical cure and demonstrated favorable pharmacokinetics, minimal adverse events, and beneficial microbiome and bile acids results.
Antimicrobial resistance is emerging in clinical strains of
. Ibezapolstat (IBZ) is a DNA polymerase IIIC inhibitor that has completed phase II clinical trials. IBZ has potent
activity against ...wild-type, susceptible strains but its effect on
strains with reduced susceptibility to metronidazole (MTZ), vancomycin (VAN), or fidaxomicin (FDX) has not been tested. The primary objective of this study was to test the antibacterial properties of IBZ against multidrug-resistant
strains. The
activity, bactericidal, and time-kill activity of IBZ versus comparators were evaluated against 100 clinical strains of which 59 had reduced susceptibility to other
antibiotics. Morphologic changes against a multidrug resistance strain were visualized by light and scanning electron microscopy. The overall IBZ MIC
values (µg/mL) for evaluated
strains were 4/8, compared with 2/4 for VAN, 0.5/1 for FDX, and 0.25/4 for MTZ. IBZ MIC
values did not differ based on non-susceptibility to antibiotic class or number of classes to which strains were non-susceptible. IBZ bactericidal activity was similar to the minimum inhibitory concentration (MIC) and maintained in wild-type and non-susceptible strains. Time-kill assays against two laboratory wild-type and two clinical non-susceptible strains demonstrated sustained IBZ activity despite reduced killing by comparator antibiotics for IBZ and VAN non-susceptible strains. Microscopy visualized increased cell lengthening and cellular damage in multidrug-resistant strains exposed to IBZ sub-MIC concentrations. This study demonstrated the potent antibacterial activity of IBZ against a large collection of
strains including multidrug-resistant strains. This study highlights the therapeutic potential of IBZ against multidrug-resistant strains of
.
C. difficile spores are frequently isolated from hospital and non-healthcare settings but a worldwide analysis has not been done. The study objectives were to assess C. difficile spore contamination ...in the hospital and non-healthcare environments across a variety of countries.
Field studies assessed hospital vs. non-healthcare C. difficile spore contamination in hospitals, non-healthcare buildings, outdoor environments, and shoes. Swabs were cultured anaerobically for C. difficile and typed using PCR-fluorescent ribotyping. C. difficile contamination by swabbing area and geographic locations were compared.
A total of 7,857 unique samples were collected primarily from the USA (89%) in addition to 9 other countries. The global prevalence of C difficile from environmental samples was 25.3% and did not differ between countries. In USA based studies, C. difficile contamination rates were similar for healthcare buildings (23.2%), non-healthcare buildings (23.4%), and outdoor spaces (24.7%). Floor samples had significantly higher (p < 0.001) C. difficile contamination rate (46.5%) followed by non-floor samples (21.1%), and bathrooms (15.3%). In a comparison of USA to other country samples, C. difficile contamination rates were similar for USA samples (21.5%) compared to rest of world samples (22.3%; p = 0.61). The most common ribotypes included F014-020 (15.7%), F106 (12.6%), F010 (8.9%), F027 (8.8%), and F002 (8.1%) and did not differ significantly between USA and non-USA samples. Finally, 546 of 1,218 (44.8%) shoe soles swabbed from the USA were contaminated with C. difficile spores.
This large surveillance study of several countries demonstrated high prevalence of toxigenic C. difficile in non-healthcare environments with high contamination rates from floors and shoe soles.
•This global project studied C. difficile community environmental contamination.•7,857 unique samples were collected from the USA (89%) and 9 other countries.•The global prevalence of C difficile from environmental samples was 25.3%.
Beef flavor continues to be one of the largest drivers of beef demand and a differentiation point of beef from other competing proteins. Tenderness has long been identified as the most important ...palatability trait for consumer satisfaction. However, as technological advancements and industry practices evolve and improve in response to tenderness management, flavor has emerged as a key driver of consumer satisfaction. In response, the beef industry has recently invested in research focused on beef flavor development, measurement, and management to better understand the factors impacting flavor and help beef maintain this advantage. The current review paper is the second of two such papers focused on summarizing the present knowledge and identifying knowledge gaps. While the other review focuses on current practices related to beef flavor measurement, this review will cover research findings related to beef flavor management. Numerous production and product management factors influence beef flavor. Pre-harvest factors including marbling level, animal genetics/cattle type, diet, and animal age, can influence beef flavor. Moreover, numerous post-harvest product management factors, including product type, aging length and conditions, cookery methods, product enhancement, muscle-specific factors, packaging, retail display factors, and antimicrobial interventions, have all been evaluated for their impact on beef flavor characteristics. Results from numerous studies evaluating many of these factors will be outlined within this review in order to present management and production chain factors that can influence beef flavor.
Historically, consumer acceptance of beef was determined by tenderness. Developments in genetics and management over the last couple of decades have improved tenderness to the point that it is ...secondary to other factors in beef's taste. Flavor, however, is an extraordinarily complex taste attribute dependent on biological sensors in the mouth, sinus cavity, and jaws. The culinary industry has recently focused on innovative ways to give consumers new products satisfying their curiosity about different foods, especially proteins. Competition from plant-based, cell-based, and even other animal-based proteins provides diversity in consumers' ability to select a protein that satisfies their desire to include unique products in their diet. Consequently, the beef industry has focused on flavor for the last 10 to 15 years to determine whether it can provide the guardrails for beef consumption in the future. The U.S. beef industry formed a Flavor Working Group in 2012 composed of the authors listed here to investigate new and innovative ways to manage and measure beef flavor. The results of this working group have resulted in dozens of papers, presentations, abstracts, and symposia. The objective of this manuscript is to summarize the research developed by this working group and by others worldwide that have investigated methodologies that measure beef flavor. This paper will describe the strengths of the research in beef flavor measurement and point out future needs that might be identified as technology advances.
Genetic factors impact alcohol consumption and use disorder (AUD), with large-scale genome-wide association studies (GWAS) identifying numerous associated variants. Aggregate genetic methods in ...combination with important environmental factors (e.g., interpersonal trauma IPT) can be applied to expand our understanding of the ways by which genetic and environmental variables work together to influence alcohol consumption and disordered use. The present study aimed to detail the relationships between genome-wide polygenic scores (PGS) for alcohol phenotypes (i.e., alcohol consumption and AUD status) and IPT exposure as well as the interaction between them across ancestry.
Data were drawn from the Spit for Science (S4S) study, a US college student population, where participants reported on IPT exposure prior to college and alcohol consumption and problems during college (N = 9,006; ancestry: 21.3% African AFR, 12.5% Admixed Americas AMR, 9.6% East Asian EAS, 48.1% European EUR, 8.6% South Asian SAS). Two trans-ancestry PGS were constructed, one for alcohol consumption and another for AUD, using large-scale GWAS summary statistics from multiple ancestries weighted using PRS-CSx. Regression models were applied to test for the presence of associations between alcohol-PGS and IPT main and interaction effects.
In the meta-analysis across ancestry groups, IPT exposure and PGS were significantly associated with alcohol consumption (β
= 0.31,
= 0.0002; β
= 0.09,
= 0.004) and AUD (OR
= 1.12,
= 3.5 × 10
; OR
= 1.02,
= 0.002). No statistically significant interactions were detected between IPT and sex nor between IPT and PGS. When inspecting ancestry specific results, the alcohol consumption-PGS and AUD-PGS were only statistically significant in the EUR ancestry group (β
= 0.09,
= 0.04; OR
= 1.02,
= 0.022, respectively).
IPT exposure prior to college was strongly associated with alcohol outcomes in this college-age sample, which could be used as a preventative measure to identify students at high risk for problematic alcohol use. Additionally, results add to developing evidence of polygenic score association in meta-analyzed samples, highlighting the importance of continued efforts to increase ancestral representation in genetic studies and inclusive analytic approaches to increase the generalizability of results from genetic association studies.
Our aim was to compare neuropsychological and psychiatric outcomes across three encephalitis aetiological groups: Herpes simplex virus (HSV), other infections or autoimmune causes (Other), and ...encephalitis of unknown cause (Unknown).
Patients recruited from NHS hospitals underwent neuropsychological and psychiatric assessment in the short-term (4 months post-discharge), medium-term (9-12 months after the first assessment), and long-term (>1-year). Healthy control subjects were recruited from the general population and completed the same assessments.
Patients with HSV were most severely impaired on anterograde and retrograde memory tasks. In the short-term, they also showed executive, IQ, and naming deficits, which resolved in the long-term. Patients with Other or Unknown causes of encephalitis showed moderate memory impairments, but no significant impairment on executive tests. Memory impairment was associated with hippocampal/medial temporal damage on magnetic resonance imaging (MRI), and naming impairment with left temporal and left frontal abnormalities. Patients reported more subjective cognitive complaints than healthy controls, with tiredness a significant problem, and there were high rates of depression and anxiety in the HSV and the Other encephalitis groups. These subjective, self-reported complaints, depression, and anxiety persisted even after objectively measured neuropsychological performance had improved.
Neuropsychological and psychiatric outcomes after encephalitis vary according to aetiology. Memory and naming are severely affected in HSV, and less so in other forms. Neuropsychological functioning improves over time, particularly in those with more severe short-term impairments, but subjective cognitive complaints, depression, and anxiety persist, and should be addressed in rehabilitation programmes.
Fecal microbiota transplantation (FMT) aims to cure Clostridioides difficile infection (CDI) through reestablishing a healthy microbiome and restoring colonization resistance. Although often ...effective after one infusion, patients with continued microbiome disruptions may require multiple FMTs. In this N-of-1 study, we use a systems biology approach to evaluate CDI in a patient receiving chronic suppressive antibiotics with four failed FMTs over two years.
Seven stool samples were obtained between 2016-18 while the patient underwent five FMTs. Stool samples were cultured for C. difficile and underwent microbial characterization and functional gene analysis using shotgun metagenomics. C. difficile isolates were characterized through ribotyping, whole genome sequencing, metabolic pathway analysis, and minimum inhibitory concentration (MIC) determinations.
Growing ten strains from each sample, the index and first four recurrent cultures were single strain ribotype F078-126, the fifth was a mixed culture of ribotypes F002 and F054, and the final culture was ribotype F002. One single nucleotide polymorphism (SNP) variant was identified in the RNA polymerase (RNAP) β-subunit RpoB in the final isolated F078-126 strain when compared to previous F078-126 isolates. This SNV was associated with metabolic shifts but phenotypic differences in fidaxomicin MIC were not observed. Microbiome differences were observed over time during vancomycin therapy and after failed FMTs.
This study highlights the importance of antimicrobial stewardship in patients receiving FMT. Continued antibiotics play a destructive role on a transplanted microbiome and applies selection pressure for resistance to the few antibiotics available to treat CDI.
•This patient level investigation used microbiologic and genomic techniques to investigate FMT failure.•A single C difficile strain was noted for the majority of the entire study period.•One single nucleotide polymorphism (SNP) variant was identified in the RNA polymerase (RNAP) β-subunit RpoB.•This SNV was associated with metabolic shifts but phenotypic differences in fidaxomicin MIC were not observed.•Microbiome differences were observed over time during antibiotic therapy and after failed FMTs.
Epidemiology of Clostridioides difficile (syn. Clostridium difficile) infection (CDI) in Bangladesh is poorly understood. This study assessed the epidemiology of CDI in hospitalized patients and ...hospital environmental contamination of toxigenic C. difficile at two large urban Bangladesh hospitals. This 12-month prospective observational cohort study collected stool samples from adults with diarrhea and recent antimicrobial exposure during 2017. Environmental samples were collected by swabbing surfaces of hospital common areas. Samples underwent toxigenic culture. C. difficile isolates were tested for toxins A and B and PCR-ribotyped. Of 208 stool samples, 18 (8.7%) were positive for toxigenic C. difficile. Of 400 environmental samples, 45 (11%) were positive for toxigenic C. difficile. Ribotypes present in ≥10% of stool isolates were 017 (38%), 053–163 (13%), and a novel ribotype (FP435 13%). Common ribotypes in environmental isolates were 017 (22%), 053–163 (11%), 106 (24%). This is the first report describing current epidemiology of CDI in at risk hospitalized adult patients in Bangladesh.
•Epidemiology of toxigenic C. difficile in Bangladesh is poorly understood.•9% of 208 diarrheal stool samples from hospitalized adults had toxigenic C. difficile.•Most common ribotype in stool toxigenic C. difficile isolates was 017 (38%).•11% of 400 hospital environmental samples were positive for toxigenic C. difficile.•Common ribotypes in environmental toxigenic C. difficile isolates were 017 and 106.
To assess whether it is feasible to quantify acute change in temporal lobe volume and total oedema volumes in herpes simplex virus (HSV) encephalitis as a preliminary to a trial of corticosteroid ...therapy.
The study analysed serially acquired magnetic resonance images (MRI), of patients with acute HSV encephalitis who had neuroimaging repeated within four weeks of the first scan. We performed volumetric measurements of the left and right temporal lobes and of cerebral oedema visible on T2 weighted Fluid Attenuated Inversion Recovery (FLAIR) images using stereology in conjunction with point counting.
Temporal lobe volumes increased on average by 1.6% (standard deviation (SD 11%) in five patients who had not received corticosteroid therapy and decreased in two patients who had received corticosteroids by 8.5%. FLAIR hyperintensity volumes increased by 9% in patients not receiving treatment with corticosteroids and decreased by 29% in the two patients that had received corticosteroids.
This study has shown it is feasible to quantify acute change in temporal lobe and total oedema volumes in HSV encephalitis and suggests a potential resolution of swelling in response to corticosteroid therapy. These techniques could be used as part of a randomized control trial to investigate the efficacy of corticosteroids for treating HSV encephalitis in conjunction with assessing clinical outcomes and could be of potential value in helping to predict the clinical outcomes of patients with HSV encephalitis.
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