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Ridinilazole, a novel targeted antibacterial being developed for the treatment of C. difficile infection (CDI) and prevention of recurrence, was shown in a recent Phase 2 study to be superior to vancomycin with regard to the primary efficacy measure, sustained clinical response (SCR), with the superiority being driven primarily by marked reductions in the rates of CDI recurrence within 30 days. Tolerability of ridinilazole was comparable to that of vancomycin. The current nested cohort study compared the effects of ridinilazole and vancomycin on fecal microbiota during and after treatment among participants in the Phase 2 study. Changes in the microbiota were assessed using qPCR and high-throughput sequencing on participants' stools collected at multiple time-points (baseline [Day 1], Day 5, end-of-treatment [EOT; Day 10], Day 25, end-of-study [EOS; Day 40], and at CDI recurrence). qPCR analyses showed profound losses of Bacteroides, C. coccoides, C. leptum, and Prevotella groups at EOT with vancomycin treatment, while ridinilazole-treated participants had a modest decrease in C. leptum group levels at EOT, with levels recovering by Day 25. Vancomycin-treated participants had a significant increase in the Enterobacteriaceae group, with this increase persisting beyond EOT. At EOT, alpha diversity decreased with both antibiotics, though to a significantly lesser extent with ridinilazole (p <0.0001). Beta diversity analysis showed a significantly larger weighted Unifrac distance from baseline-to-EOT with vancomycin. Taxonomically, ridinilazole had a markedly narrower impact, with modest reductions in relative abundance in Firmicutes taxa. Microbiota composition returned to baseline sooner with ridinilazole than with vancomycin. Vancomycin treatment resulted in microbiome-wide changes, with significant reductions in relative abundances of Firmicutes, Bacteroidetes, Actinobacteria, and a profound increase in abundance of Proteobacteria. These findings demonstrate that ridinilazole is significantly less disruptive to microbiota than vancomycin, which may contribute to the reduced CDI recurrence observed in the Phase 2 study.

Whole-genome sequencing was used to determine whether the reductions in recurrence of Clostridium difficile infection observed with fidaxomicin in pivotal phase 3 trials occurred by preventing relapse of the same infection, by preventing reinfection with a new strain, or by preventing both outcomes. Paired isolates of C. difficile were available from 93 of 199 participants with recurrences (28 were treated with fidaxomicin, and 65 were treated with vancomycin). Given C. difficile evolutionary rates, paired samples ≤2 single-nucleotide variants (SNVs) apart were considered relapses, paired samples >10 SNVs apart were considered reinfection, and those 3-10 SNVs apart (or without whole-genome sequences) were considered indeterminate in a competing risks survival analysis. Fidaxomicin reduced the risk of both relapse (competing risks hazard ratio [HR], 0.40 [95% confidence interval {CI}, .25-.66]; P = .0003) and reinfection (competing risks HR, 0.33 [95% CI, 0.11-1.01]; P= .05).

Clostridioides difficile is an anaerobic, spore‐forming, Gram‐positive pathogenic bacterium. This study aimed to analyze the effect of two samples of healthy fecal microbiota on C. difficile gene expression and growth using an in vitro coculture model. The inner compartment was cocultured with spores of the C. difficile polymerase chain reaction (PCR)‐ribotype 078, while the outer compartment contained fecal samples from donors to mimic the microbiota (FD1 and FD2). A fecal‐free plate served as a control (CT). RNA‐Seq and quantitative PCR confirmation were performed on the inner compartment sample. Similarities in gene expression were observed in the presence of the microbiota. After 12 h, the expression of genes associated with germination, sporulation, toxin production, and growth was downregulated in the presence of the microbiota. At 24 h, in an iron‐deficient environment, C. difficile activated several genes to counteract iron deficiency. The expression of genes associated with germination and sporulation was upregulated at 24 h compared with 12 h in the presence of microbiota from donor 1 (FD1). This study confirmed previous findings that C. difficile can use ethanolamine as a primary nutrient source. To further investigate this interaction, future studies will use a simplified coculture model with an artificial bacterial consortium instead of fecal samples. The presence of microbiota did not affect the growth of Clostridioides difficile in this study. However, it did influence the expression of C. difficile genes related to sporulation, germination, and virulence, which are crucial for the transmission of the pathogen. In the presence of microbiota, C. difficile activates defence mechanisms to survive competition, such as adapting to an iron‐limited environment and utilizing ethanolamine metabolism.

Clostridium difficile disease has recently increased to become a dominant nosocomial pathogen in North America and Europe, although little is known about what has driven this emergence. Here we show that two epidemic ribotypes (RT027 and RT078) have acquired unique mechanisms to metabolize low concentrations of the disaccharide trehalose. RT027 strains contain a single point mutation in the trehalose repressor that increases the sensitivity of this ribotype to trehalose by more than 500-fold. Furthermore, dietary trehalose increases the virulence of a RT027 strain in a mouse model of infection. RT078 strains acquired a cluster of four genes involved in trehalose metabolism, including a PTS permease that is both necessary and sufficient for growth on low concentrations of trehalose. We propose that the implementation of trehalose as a food additive into the human diet, shortly before the emergence of these two epidemic lineages, helped select for their emergence and contributed to hypervirulence. Two hypervirulent ribotypes of the enteric pathogen Clostridium difficile , RT027 and RT078, have independently acquired unique mechanisms to metabolize low concentrations of the disaccharide trehalose, suggesting a correlation between the emergence of these ribotypes and the widespread adoption of trehalose in the human diet. The rise of an intestinal epidemic Clostridium difficile is an intestinal pathogen and a major cause of antibiotic-associated diarrhoea. In epidemics in recent years, hypervirulent ribotypes that cause severe disease have emerged, but the factors that contribute to their emergence are unclear. In this study, Robert Britton and colleagues show that two phylogenetically distinct hypervirulent ribotypes, RT027 and RT078, have independently acquired mechanisms to metabolize low concentrations of the disaccharide trehalose. The team also show that this ability to metabolize trehalose correlates with disease severity in a humanized mouse model. These data suggest a correlation between the emergence of these ribotypes and the widespread adoption and use of trehalose as a sugar additive in the human diet.

Many intestinal pathogens, including Clostridioides difficile , use mucus-derived sugars as crucial nutrients in the gut. Commensals that compete with pathogens for such nutrients are therefore ecological gatekeepers in healthy guts, and are attractive candidates for therapeutic interventions. Nevertheless, there is a poor understanding of which commensals use mucin-derived sugars in situ as well as their potential to impede pathogen colonization. Here, we identify mouse gut commensals that utilize mucus-derived monosaccharides within complex communities using single-cell stable isotope probing, Raman-activated cell sorting and mini-metagenomics. Sequencing of cell-sorted fractions reveals members of the underexplored family Muribaculaceae as major mucin monosaccharide foragers, followed by members of Lachnospiraceae, Rikenellaceae, and Bacteroidaceae families. Using this information, we assembled a five-member consortium of sialic acid and N-acetylglucosamine utilizers that impedes C. difficile ’s access to these mucosal sugars and impairs pathogen colonization in antibiotic-treated mice. Our findings underscore the value of targeted approaches to identify organisms utilizing key nutrients and to rationally design effective probiotic mixtures. Here, the authors employ Raman-Activated Cell Sorting (RACS) and metagenomics to identify organisms that can forage on O -glycan monosaccharides in the mouse gut, which they use to construct a bacterial consortium able to reduce Clostridioides difficile colonization based on competition for mucosal sugars.

Antimicrobial resistance (AMR) in Clostridioides difficile remains a significant threat to global healthcare systems, not just for the treatment of C. difficile infection (CDI), but as a reservoir of AMR genes that could be potentially transferred to other pathogens. The mechanisms of resistance for several antimicrobials such as metronidazole and MLSB-class agents are only beginning to be elucidated, and increasingly, there is evidence that previously unconsidered mechanisms such as plasmid-mediated resistance may play an important role in AMR in this bacterium. In this review, the genetics of AMR in C. difficile will be described, along with a discussion of the factors contributing to the difficulty in clearly determining the true burden of AMR in C. difficile and how it affects the treatment of CDI.

Clostridioides difficile is a bacterial pathogen that causes a range of clinical disease from mild to moderate diarrhea, pseudomembranous colitis, and toxic megacolon. Typically, C. difficile infections (CDIs) occur after antibiotic treatment, which alters the gut microbiota, decreasing colonization resistance against C. difficile . Disease is mediated by two large toxins and the expression of their genes is induced upon nutrient depletion via the alternative sigma factor TcdR. Here, we use tcdR mutants in two strains of C. difficile and omics to investigate how toxin-induced inflammation alters C. difficile metabolism, tissue gene expression and the gut microbiota, and to determine how inflammation by the host may be beneficial to C. difficile . We show that C. difficile metabolism is significantly different in the face of inflammation, with changes in many carbohydrate and amino acid uptake and utilization pathways. Host gene expression signatures suggest that degradation of collagen and other components of the extracellular matrix by matrix metalloproteinases is a major source of peptides and amino acids that supports C. difficile growth in vivo. Lastly, the inflammation induced by C. difficile toxin activity alters the gut microbiota, excluding members from the genus Bacteroides that are able to utilize the same essential nutrients released from collagen degradation. The effects of antibiotics on the gut microbiota can lead to enhanced colonization of Clostridioides difficile ( C. difficile ) and toxin-mediated pathogenesis. Here, using defined toxin-mutant strains and a murine model, the authors provide insights into how toxin-induced inflammation alters C. difficile metabolism, host tissue gene expression and gut microbiota, together influencing a beneficial niche for infection.

Clostridium difficile is an important cause of hospital-associated diarrhea. In this report from the CDC, the U.S. burden of C. difficile infection is estimated at nearly 500,000 cases and 30,000 deaths in 2011, with an increasing burden among nonhospitalized persons. Changes in the epidemiology of Clostridium difficile infections have occurred since the emergence of the North American pulsed-field gel electrophoresis type 1 (NAP1) strain, which has been responsible for geographically dispersed hospital-associated outbreaks. 1 – 3 In the United States, hospitalizations for C. difficile infection among nonpregnant adults doubled from 2000 through 2010 and were projected to continue to increase in 2011 and 2012, especially as laboratories transition to more sensitive C. difficile assays, such as the nucleic acid amplification test (NAAT). 4 – 6 On the basis of data from U.S. death certificates, C. difficile infection is the leading cause of gastroenteritis-associated death . . .

Metronidazole was until recently used as a first-line treatment for potentially life-threatening Clostridioides difficile (CD) infection. Although cases of metronidazole resistance have been documented, no clear mechanism for metronidazole resistance or a role for plasmids in antimicrobial resistance has been described for CD. Here, we report genome sequences of seven susceptible and sixteen resistant CD isolates from human and animal sources, including isolates from a patient with recurrent CD infection by a PCR ribotype (RT) 020 strain, which developed resistance to metronidazole over the course of treatment (minimal inhibitory concentration [MIC] = 8 mg L −1 ). Metronidazole resistance correlates with the presence of a 7-kb plasmid, pCD-METRO. pCD-METRO is present in toxigenic and non-toxigenic resistant ( n  = 23), but not susceptible ( n  = 563), isolates from multiple countries. Introduction of a pCD-METRO-derived vector into a susceptible strain increases the MIC 25-fold. Our finding of plasmid-mediated resistance can impact diagnostics and treatment of CD infections. Cases of C. difficile (CD) resistant to metronidazole have been reported but the mechanism remains enigmatic. Here the authors identify a plasmid, which correlates with metronidazole resistance status in a large international collection of CD isolates, and demonstrate that the plasmid can confer metronidazole resistance.

Antibiotic-induced modulation of the intestinal microbiota can lead to Clostridioides difficile infection (CDI), which is associated with considerable morbidity, mortality, and healthcare-costs globally. Therefore, identification of markers predictive of CDI could substantially contribute to guiding therapy and decreasing the infection burden. Here, we analyze the intestinal microbiota of hospitalized patients at increased CDI risk in a prospective, 90-day cohort-study before and after antibiotic treatment and at diarrhea onset. We show that patients developing CDI already exhibit significantly lower diversity before antibiotic treatment and a distinct microbiota enriched in Enterococcus and depleted of Ruminococcus , Blautia, Prevotella and Bifidobacterium compared to non-CDI patients. We find that antibiotic treatment-induced dysbiosis is class-specific with beta-lactams further increasing enterococcal abundance. Our findings, validated in an independent prospective patient cohort developing CDI, can be exploited to enrich for high-risk patients in prospective clinical trials, and to develop predictive microbiota-based diagnostics for management of patients at risk for CDI. Clostridioides difficile infection (CDI) is the most common cause of antibiotic-associated diarrhoea (AAD); however, markers predictive of CDI or AAD development are as yet lacking. Here, to identify markers predictive of CDI, the authors profile the intestinal microbiota of 945 hospitalised patients from 34 hospitals in 6 different European countries and show distinct microbiota enriched in Enterococcus and depleted of Ruminococcus, Blautia, Prevotella and Bifidobacterium compared to non-CDI patients.