Antimicrobial susceptibility and ribotypes of Clostridium difficile isolates from a Phase 2 clinical trial of ridinilazole (SMT19969) and vancomycin

Snydman, David R.; McDermott, L. A.; Thorpe, Cheleste M.; Chang, Julia Yu Fong; Wick, Jenna; Walk, Seth T.; Vickers, Richard

doi:10.1093/jac/dky135

Cited by 17 publications

(10 citation statements)

References 33 publications

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“…The most commonly identified ribotype in Texas was the grouping of 014 and 020 ribotypes, regardless of community-or hospital-onset designation. Although this differs from the CDC surveillance, which reports these two ribotypes independently, similar findings have been demonstrated in other North American reports [28][29][30]. Furthermore, the group of ribotypes 014-020 was identified as the most common across Europe in 2008 [11], and more recent reports able to separate the two ribotypes indicate an increase in 014 may be responsible for the increasing prevalence of the group [17].…”

Section: Discussionsupporting

confidence: 77%

PCR ribotypes of Clostridioides difficile across Texas from 2011 to 2018 including emergence of ribotype 255

Gonzales-Luna

Carlson

Dotson

et al. 2020

Emerging Microbes & Infections

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Clostridioides difficile infection (CDI) is the most prevalent healthcare-associated infection in the United States and carries a significant healthcare system burden. As part of an ongoing, active surveillance system of C. difficile throughout Texas, the objective of this study was to assess changes in C. difficile ribotypes of clinical isolates obtained from hospitalized patients in Texas over the past seven years. Fifty hospitals located in Texas, USA sent C. difficile positive stool specimens to a centralized laboratory for PCR ribotyping and toxin characterization between 2011 and 2018. Data collected included specimen collection date, patient age, and sex. Strain genotypes were compiled, and changes in ribotype distribution over time were assessed. Overall, 7796 samples were ribotyped from predominately female patients (58.4%) aged 62 ± 19 years. Samples were obtained from all geographic regions of Texas including Houston/Southwest region (n = 5129; 85%), Dallas/North Texas (n = 579, 9.6%), Central Texas (n = 164; 2.7%), and South Texas (n = 162; 2.6%). The 10 most common ribotypes comprised 73% of all isolates tested during the study period. The most common ribotypes were 027 (17.5%), followed by 014-020 (16.1%), 106 (11.6%), and 002 (9.1%). The prevalence of ribotypes 027, 001, and 078-126 declined significantly over time, while ribotypes 106 and 054 increased in prevalence (P < 0.001). Furthermore, the emergence of a novel ribotype 255 strain was observed. Differences in ribotype distribution were also noted based on age and geographic distribution (P < 0.001, each). This seven-year study demonstrated changing molecular epidemiology of C. difficile in Texas, including the emergence of a novel ribotype 255.

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Section: Discussionsupporting

confidence: 77%

PCR ribotypes of Clostridioides difficile across Texas from 2011 to 2018 including emergence of ribotype 255

Gonzales-Luna

Carlson

Dotson

et al. 2020

Emerging Microbes & Infections

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“…Ribotype F014-020 has been most frequently isolated from the environments in our previous study [9] and also from other investigators in the USA [18], hospitalized patients in Europe [19] and animals and the environment including water in Slovenia [20]. Ribotype 106 has become one of the more common ribotypes in the USA and Europe, this is the first reported case of ribotype 106 in Bangladesh [21,22]. The comparison with clinically relevant strains was not possible due to the absence of toxigenic strains in the clinical samples.…”

Section: Notesupporting

confidence: 68%

Clostridioides difficile ribotypes isolated from domestic environment and from patients in Bangladesh

et al. 2019

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Clostridioides difficile infection (CDI) is an emerging but often understudied infectious disease in developing countries. This study was aimed to isolate and characterize C. difficile from shoe sole swabs and diarrheal patient's stool samples in Bangladesh. We collected 94 shoe sole swabs samples from urban communities in Dhaka and 208 diarrheal stool samples from hospitalized patients over a period of 4 months. Samples were incubated anaerobically for C. difficile growth, confirmed toxigenic, and PCR-ribotyped. Eleven of 94 (11.7%) shoe sole swabs and 4 of 208 (1.9%) stool samples were culture positive of which 9 shoe sole isolates were toxigenic. Six PCR ribotypes from the 9 toxigenic isolates were identified with ribotype F014-020 being the most common (n = 4; 44%). The recently identified ribotype 106 strain was also identified. To the best of our knowledge, this is the first report of C. difficile culture, isolation and characterization from environmental sources in Bangladesh.

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“…Ridinilazole (RDZ), currently in late-stage Phase 3 clinical development, has been developed speci cally to treat CDI and address CDI associated recurrence through a targeted, precision approach. It has potent in vitro activity against C. di cile clinical isolates 8,9 , but minimal disruption of other gut bacteria and their metabolites that contribute to CDI colonization resistance 10,11 . Ridinilazole also preserves secondary bile acids which play a key role in suppressing the growth of toxin producing vegetative C. di cile cells 12 .…”

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confidence: 99%

The novel DNA binding mechanism of ridinilazole, a precision Clostridiodes difficile antibiotic.

Mason

Avis

Hu³

et al. 2022

Preprint

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Clostridioides difficile infection (CDI) causes substantial morbidity and mortality worldwide with limited antibiotic treatment options. Ridinilazole is a precision bisbenzimidazole antibiotic being developed to treat CDI and reduce unacceptably high rates of infection recurrence in patients. Although in Phase 3 clinical development, the precise mechanism of action by which ridinilazole elicits its bactericidal activity has remained elusive. Here we present conclusive biochemical and structural data to demonstrate that ridinilazole has a primary DNA binding mechanism, with a co-complex structure confirming binding to the DNA minor groove. Additional RNA-seq data indicated early pleiotropic changes to transcription, with broad effects on multiple C. difficile compartments and significant effects on energy generation pathways particularly. DNA binding and genomic localization was confirmed through confocal microscopy utilizing the intrinsic fluorescence of ridinilazole upon DNA binding. As such, ridinilazole has the potential to be the first antibiotic approved with a DNA minor groove binding mechanism of action.

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Antimicrobial susceptibility and ribotypes of Clostridium difficile isolates from a Phase 2 clinical trial of ridinilazole (SMT19969) and vancomycin

Abstract: Ridinilazole potently inhibited recovered C. difficile isolates. Recurrence was not associated with altered susceptibility.

Cited by 17 publications

References 33 publications

PCR ribotypes of Clostridioides difficile across Texas from 2011 to 2018 including emergence of ribotype 255

PCR ribotypes of Clostridioides difficile across Texas from 2011 to 2018 including emergence of ribotype 255

Clostridioides difficile ribotypes isolated from domestic environment and from patients in Bangladesh

The novel DNA binding mechanism of ridinilazole, a precision Clostridiodes difficile antibiotic.

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