SUMMARY Large clostridial toxins (LCTs) are a family of bacterial exotoxins that infiltrate and destroy target cells. Members of the LCT family include Clostridioides difficile toxins TcdA and TcdB, Paeniclostridium sordellii toxins TcsL and TcsH, Clostridium novyi toxin TcnA, and Clostridium perfringens toxin TpeL. Since the 19th century, LCT-secreting bacteria have been isolated from the blood, organs, and wounds of diseased individuals, and LCTs have been implicated as the primary virulence factors in a variety of infections, including C. difficile infection and some cases of wound-associated gas gangrene. Clostridia express and secrete LCTs in response to various physiological signals. LCTs invade host cells by binding specific cell surface receptors, ultimately leading to internalization into acidified vesicles. Acidic pH promotes conformational changes within LCTs, which culminates in translocation of the N-terminal glycosyltransferase and cysteine protease domain across the endosomal membrane and into the cytosol, leading first to cytopathic effects and later to cytotoxic effects. The focus of this review is on the role of LCTs in infection and disease, the mechanism of LCT intoxication, with emphasis on recent structural work and toxin subtyping analysis, and the genomic discovery and characterization of LCT homologues. We provide a comprehensive review of these topics and offer our perspective on emerging questions and future research directions for this enigmatic family of toxins.

Effect of Liver Cirrhosis on the Severity of Presentation of Clostridiodes Difficile Infection- Read the full article online

Antibiotic resistance in CD has increased since the early 1980s, across the majority of classes. Moxifloxacin resistance determinants may pre-date its introduction.

Bloody diarrhea is a common condition in dogs, but studies evaluating the enteropathogens involved specifically in adult dogs are scarce. In the present study, stool samples from 45 adult dogs with bloody diarrhea were evaluated for the four enteric organisms mainly reported in these cases: canine p …

Females and older patients had higher rates of hospitalizations with CDI than males and younger patients.

A rapid and accurate sample collection is significant for culture results, making an outstanding contribution to the successful treatment.

AbstractBackground. Clostridioides difficile was listed as an urgent antimicrobial resistance (AMR) threat in a report by the CDC in 2019. AMR drives the evolut

Comparative analysis of Clostridioides difficile whole-genome sequencing (WGS) data enables fine scaled investigation of transmission and is increasingly becoming part of routine surveillance. However, these analyses are constrained by the computational requirements of the large volumes of data involved. By decomposing WGS reads or assemblies into k-mers and using the dimensionality reduction technique MinHash, it is possible to rapidly approximate genomic distances without alignment. Here we assessed the performance of MinHash, as implemented by sourmash, in predicting single nucleotide differences between genomes (SNPs) and C. difficile ribotypes (RTs). For a set of 1,905 diverse C. difficile genomes (differing by 0-168,519 SNPs), using sourmash to screen for closely related genomes, at a sensitivity of 100% for pairs ≤10 SNPs, sourmash reduced the number of pairs from 1,813,560 overall to 161,934, i.e., by 91%, with a positive predictive value of 32% to correctly identify pairs ≤10 SNPs (maximum SNP distance 4,144). At a sensitivity of 95%, pairs were reduced by 94% to 108,266 and PPV increased to 45% (maximum SNP distance 1,009). Increasing the MinHash sketch size above 2000 produced minimal performance improvement. We also explored a MinHash similarity-based ribotype prediction method. Genomes with known ribotypes (n=3,937) were split into a training set (2,937) and test set (1,000) randomly. The training set was used to construct a sourmash index against which genomes from the test set were compared. If the closest 5 genomes in the index had the same ribotype this was taken to predict the searched genome’s ribotype. Using our MinHash ribotype index, predicted ribotypes were correct in 780/1000 (78%) genomes, incorrect in 20 (2%), and indeterminant in 200 (20%). Relaxing the classifier to 4/5 closest matches with the same RT improved the correct predictions to 87%. Using MinHash it is possible to subsample C. difficile genome k-mer hashes and use them to approximate small genomic differences within minutes, significantly reducing the search space for further analysis. Impact statement The genetic code, or DNA, of bacteria is increasingly used to track how infection spreads and to guide infection control interventions, as similar or identical DNA sequences are expected in samples from pair of individuals related by transmission. While obtaining the DNA sequence for bacteria is increasingly straightforward, comparing thousands or even millions of sequences requires substantial computing power and time using current approaches. Here we describe how a method for summarising sequencing data, MinHash, can be used to rapidly reduce the number of possible close sequence matches in Clostridioides difficile , an important healthcare-associated pathogen. It can also be used to approximate traditional schemes used to classify C. difficile into smaller subgroups in transmission analyses, such as ribotyping. Data summary The authors confirm all supporting data, code and protocols have been provided within the article or through supplementary data files. ### Competing Interest Statement MHW has received consulting fees from Actelion, Astellas, MedImmune, Merck, Pfizer, Sanofi-Pasteur, Seres, Summit, and Synthetic Biologics; lecture fees from Alere, Astellas, Merck & Pfizer; and grant support from Actelion, Astellas, bioMerieux, Da Volterra, Merck and Summit. SDG has received consulting fees from Abbott, Aquarius Population Health, Astellas and MSD; lecture fees from Astellas, MSD and Orion Diagnostics; and grant support from Astellas. DWE declares lecture fees from Gilead outside the submitted work. No other author has a conflict of interest to declare.

The results of this study showed toxigenic C. difficile with tcdA + /tcdB + profile is a major cause of nosocomial diarrhea in Hamadan, and clinical laboratories should routinely perform C. difficile diagnostic testing on diarrheal specimens of hospi …

The gut bacterial community prevents many pathogens from colonizing the intestine. Previous studies have associated specific bacteria with clearing Clostridioides difficile colonization across different community perturbations. However, those bacteria alone have been unable to clear C. dif …

Females and older patients had higher rates of hospitalizations with CDI than males and younger patients.

The introduction of stable isotopes in vivo via metabolic labeling approaches (SILAC or 15N-labeling) allows, after combination of differentially treated labeled and unlabeled cells or protein extracts, for correction of protein quantification errors implemented during elaborated sample p …

Clostridioides difficile is a Gram positive spore-forming rod and mainly responsible for nosocomial diarrhea in developed nations. Molecular and antimicrobial surveillance is important for monitoring the strain composition including genotypes of high epidemiological importance such as ribotype 027 ( …

The proportion of cases with CDI in perforated appendicitis was found to be greater in comparison to the non-perforated cases.

The majority of C. difficile isolated in Australia did not show reduced susceptibility to antimicrobials recommended for treatment of CDI (vancomycin, metronidazole and fidaxomicin). Resistance to carbapenems and fluoroquinolones was low and MDR was uncommon; however, clindamycin resistance was freq …

Objective: Hospitalized patients with community-acquired pneumonia (CAP) are at risk of developing Clostridioides difficile infection (CDI). We developed and tested clinical decision-rules for identifying CDI risk in this patient population.Methods: The study was a single-center …

Future Microbiol. 2021 Apr 13. doi: 10.2217/fmb-2020-0275. Online ahead of print.ABSTRACTThe COVID-19 pandemic has changed the way we practice medicine

Bacteria that reside in the gastrointestinal tract of healthy humans are essential for our health, sustenance and well-being. About 50-60% of those bacteria have the ability to produce resilient spores that are important for the life cycle in the gut and for host-to-host transmission. A genomic sign …

Leveraging the EHR and genetic data, genome-wide association, and fine-mapping techniques, this study identified variants and genes associated with Clostridioides difficile infection, provided insights into host immune mechanisms, and described the potential for novel treatment strategies for …

They're the next big thing for treating C. diff infection, but developing them is a long process

Clostridioides* difficile infection (CDI) is considered to be a major concern of the healthcare system globally with an increasing need for alternative therapies. OBP-4, a new oxazolidinone-fluoroquinolone hybrid with excellent in vitro activities and good safety, shows promising featu …

We aimed to describe the clinical presentation, treatment, outcome and report on factors associated with mortality over a 90-day period in Clostridioides difficile infection (CDI). Descriptive, univariate, and multivariate regression analyses were performed on data collected in a retrospectiv …

A 20-year-old Caucasian man with a history of psoriasis presented to the emergency department due to a 2-week history of severe polyarthralgia and a 3-week history of non-bloody diarrhoea. The initial workup 2 days prior in an urgent care clinic returned negative for all enteric pathogens including …

Little is known about the role of lineage of strains of Clostridioides difficile (CD) on the clinical presentation of CD infection (CDI) in Latin America, especially regarding the treatment response. We conducted a multicenter, prospective study to investigate the predictive factors and treatment ou …

Clostridioides difficile disproportionally affects the elderly living in nursing homes (NHs). Our objective was to explore the prevalence of C. difficile in NH elders, over time and to determine whether the microbiome or other clinical factors are associated with C. difficile co …