Trends in U.S. Burden of <i>Clostridioides difficile</i> Infection and Outcomes

Guh, Alice; Mu, Yi; Winston, Lisa G; Johnston, Helen; Olson, Danyel M; Farley, Monica M.; Wilson, Lucy; Holzbauer, Stacy; Phipps, Erin C; Dumyati, Ghinwa; Beldavs, Zintars G.; Kainer, Marion A.; Karlsson, Maria; Gerding, Dale N.; McDonald, L. Clifford

doi:10.1056/nejmoa1910215

Cited by 563 publications

(566 citation statements)

References 31 publications

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“…Their spores are widespread and can colonize human and animal colons after disruption of the gut microflora, most notably due to antibiotic treatment. C. difficile infection (CDI) results in a range of symptoms from self-limiting diarrhea to severe pseudomembranous enterocolitis and death [2][3][4][5][6][7] . It is the most frequent cause of healthcare-associated gastrointestinal infections across developed countries worldwide [2][3][4][5]8 .…”

Section: Introductionmentioning

confidence: 99%

Phylogenomics of 8,839Clostridioides difficilegenomes reveals recombination-driven evolution and diversification of toxin A and B

Mansfield

Tremblay

Zeng

et al. 2020

Preprint

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AbstractClostridioides difficile is the major worldwide cause of antibiotic-associated gastrointestinal infection. A pathogenicity locus (PaLoc) encoding one or two homologous toxins, toxin A (TcdA) and toxin B (TcdB) is essential for C. difficile pathogenicity. However, toxin sequence variation poses major challenges for the development of diagnostic assays, therapeutics, and vaccines. Here, we present a comprehensive phylogenomic analysis 8,839 C. difficile strains and their toxins including 6,492 genomes that we assembled from the NCBI short read archive. A total of 5,175 tcdA and 8,022 tcdB genes clustered into 7 (A1-A7) and 12 (B1-B12) distinct subtypes, which form the basis of a new method for toxin-based subtyping of C. difficile. We developed a haplotype coloring algorithm to visualize amino acid variation across all toxin sequences, which revealed that TcdB has diversified through extensive homologous recombination throughout its entire sequence, and formed new subtypes through distinct recombination events. In contrast, TcdA varies mainly in the number of repeats in its C-terminal repetitive region, suggesting that recombination-mediated diversification of TcdB provides a selective advantage in C. difficile evolution. The application of toxin subtyping is then validated by classifying 351 C. difficile clinical isolates from Brigham and Women’s Hospital in Boston, demonstrating its clinical utility. Subtyping partitions TcdB into binary functional and antigenic groups generated by intragenic recombinations, including two distinct cell-rounding phenotypes, whether recognizing frizzled proteins as receptors, and whether can be efficiently neutralized by monoclonal antibody bezlotoxumab, the only FDA-approved therapeutic antibody. Our analysis also identifies eight universally conserved surface patches across the TcdB structure, representing ideal targets for developing broad-spectrum therapeutics. Finally, we established an open online database (DiffBase) as a central hub for collection and classification of C. difficile toxins, which will help clinicians decide on therapeutic strategies targeting specific toxin variants, and allow researchers to monitor the ongoing evolution and diversification of C. difficile.

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Section: Introductionmentioning

confidence: 99%

Phylogenomics of 8,839Clostridioides difficilegenomes reveals recombination-driven evolution and diversification of toxin A and B

Mansfield

Tremblay

Zeng

et al. 2020

Preprint

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“…Of the model's 6 input parameters (see Table 1, Supplementary Digital Content 1, http://links.lww.com/CTG/A406 ), 4 were adapted from Rajasingham et al ( 5 ) and 2 were drawn from other literature ( 1 , 6 ). The model had 3 outcomes: the annual number of FMTs performed, the proportion of CDI episodes that are multiple recurrent episodes, and the number needed to treat (see Table 2, Supplementary Digital Content 1, http://links.lww.com/CTG/A406 ).…”

Section: Methodsmentioning

confidence: 99%

“…Clostridioides difficile infection (CDI), the most common hospital-acquired infection in the United States, is a major public health threat, with more than 450,000 US cases in 2017 ( 1 ). Aside from severe diarrhea and other associated health conditions, recurrent CDI can lead to social isolation, humiliation, difficulty keeping a job because of days lost from work and an inability to leave the home, and emotional trauma ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Fecal Microbiota Transplants Annually and Their Positive Clinical Impact

Mamoon

Olesen

2020

Clinical and Translational Gastroenterology

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INTRODUCTION: Although fecal microbiota transplantation (FMT) is a recommended, clinically efficacious, and cost-effective treatment for recurrent Clostridioides difficile infection (CDI), the scale of FMT use in the United States is unknown. METHODS: We developed a population-level CDI model. RESULTS: We estimated that 48,000 FMTs could be performed annually, preventing 32,000 CDI recurrences. DISCUSSION: Improving access to FMT could lead to tens of thousands fewer C. difficile episodes per year.

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“…In the past two decades, there has been an increasing incidence of CDI, with recent data showing a reduction of hospital acquired CDI but an increase in the incidence of CDI in the community. 7 The striking part of the epidemiology of CDI is an increase in community-acquired CDI; in individuals who are younger; have lower risk of antibiotic exposure and have not been hospitalized. 8 A proportion of the patients who get community-acquired CDI are those who have underlying IBD and they fit the demographic and risk factor profile.…”

Section: Epidemiology Of CDI In Ibdmentioning

confidence: 99%

Management of Clostridioides difficile infection in patients with inflammatory bowel disease

Khanna

2021

Intest Res

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tered gut microbiota is colonization and infection with opportunistic microorganisms such as Clostridioides difficile. Studies over the years have demonstrated that the commonest infectious complication and the leading cause of a disease flareup in patients with IBD is C. difficile infection (CDI). 3 In contrast, non-C. difficile bacterial infections are uncommon in IBD patients with a disease flare. 4 Clostridioides difficile (formerly Clostridium difficile also known as C. difficile or C. diff) is an anaerobic Gram-positive spore forming bacterium that is ubiquitous in our environment. 5 Exposure to the C. difficile bacterium (spore or vegetative form) can lead to spectrum of outcomes ranging from no effect and no colonization to asymptomatic colonization to mild-moderate illness to severe diarrhea to fulminant lifethreatening infection. 6 It is now well-recognized that IBD patients are at a high risk of developing CDI even in the absence of other traditional risk factors. 3 In 2017, the American Gastroenterological Association released an expert clinical practice

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Trends in U.S. Burden of Clostridioides difficile Infection and Outcomes

Cited by 563 publications

References 31 publications

Phylogenomics of 8,839Clostridioides difficilegenomes reveals recombination-driven evolution and diversification of toxin A and B

Phylogenomics of 8,839Clostridioides difficilegenomes reveals recombination-driven evolution and diversification of toxin A and B

Fecal Microbiota Transplants Annually and Their Positive Clinical Impact

Management of Clostridioides difficile infection in patients with inflammatory bowel disease

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