<i>gyrA</i>Mutations in Fluoroquinolone-resistant<i>Clostridium difficile</i>PCR-027

Drudy, Denise; Kyne, Lorraine; O’Mahony, Rebecca; Fanning, Séamus

doi:10.3201/eid1303.060771

Cited by 62 publications

(52 citation statements)

References 10 publications

(16 reference statements)

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“…We identified 11 nonsynonymous nucleotide substitutions that distinguished members of a subset of Canadian NAP1 isolates that consists of QCD-32g58 , 1985). This set of 11 SNPs includes the previously described mutation responsible for resistance to fluoroquinolones (10).…”

Section: Resultsmentioning

confidence: 99%

Fourteen-Genome Comparison Identifies DNA Markers for Severe-Disease-Associated Strains of Clostridium difficile

et al. 2011

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Clostridium difficile is a common cause of infectious diarrhea in hospitalized patients. A severe and increased incidence of C. difficile infection (CDI) is associated predominantly with the NAP1 strain; however, the existence of other severe-disease-associated (SDA) strains and the extensive genetic diversity across C. difficile complicate reliable detection and diagnosis. Comparative genome analysis of 14 sequenced genomes, including those of a subset of NAP1 isolates, allowed the assessment of genetic diversity within and between strain types to identify DNA markers that are associated with severe disease. Comparative genome analysis of 14 isolates, including five publicly available strains, revealed that C. difficile has a core genome of 3.4 Mb, comprising ϳ3,000 genes. Analysis of the core genome identified candidate DNA markers that were subsequently evaluated using a multistrain panel of 177 isolates, representing more than 50 pulsovars and 8 toxinotypes. A subset of 117 isolates from the panel had associated patient data that allowed assessment of an association between the DNA markers and severe CDI. We identified 20 candidate DNA markers for species-wide detection and 10,683 single nucleotide polymorphisms (SNPs) associated with the predominant SDA strain (NAP1). A species-wide detection candidate marker, the sspA gene, was found to be the same across 177 sequenced isolates and lacked significant similarity to those of other species. Candidate SNPs in genes CD1269 and CD1265 were found to associate more closely with disease severity than currently used diagnostic markers, as they were also present in the toxin A-negative and B-positive (A-B؉) strain types. The genetic markers identified illustrate the potential of comparative genomics for the discovery of diagnostic DNA-based targets that are species specific or associated with multiple SDA strains.

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Section: Resultsmentioning

confidence: 99%

Fourteen-Genome Comparison Identifies DNA Markers for Severe-Disease-Associated Strains of Clostridium difficile

et al. 2011

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“…C. difficile ribotype 027 is one of the most serious outbreak-associated C. difficile strains responsible for multiple outbreaks in North America, Europe, and beyond (7,53). It produces both toxin A and toxin B and an additional toxin, the CDT binary toxin (12). Although the mechanism of its hypervirulence is not fully elucidated, this strain is fluoroquinolone resistant (12) and appears to produce more toxin A and toxin B than any other C. difficile strains (35).…”

Section: Discussionmentioning

confidence: 99%

ProbioticSaccharomyces boulardiiCNCM I-745 prevents outbreak-associatedClostridium difficile-associated cecal inflammation in hamsters

Koon

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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. difficile infection (CDI) is a common debilitating nosocomial infection associated with high mortality. Several CDI outbreaks have been attributed to ribotypes 027, 017, and 078. Clinical and experimental evidence indicates that the nonpathogenic yeast Saccharomyces boulardii CNCM I-745 (S.b) is effective for the prevention of CDI. However, there is no current evidence suggesting this probiotic can protect from CDI caused by outbreak-associated strains. We used established hamster models infected with outbreak-associated C. difficile strains to determine whether oral administration of live or heat-inactivated S.b can prevent cecal tissue damage and inflammation. Hamsters infected with C. difficile strain VPI10463 (ribotype 087) and outbreakassociated strains ribotype 017, 027, and 078 developed severe cecal inflammation with mucosal damage, neutrophil infiltration, edema, increased NF-B phosphorylation, and increased proinflammatory cytokine TNF␣ protein expression. Oral gavage of live, but not heated, S.b starting 5 days before C. difficile infection significantly reduced cecal tissue damage, NF-B phosphorylation, and TNF␣ protein expression caused by infection with all strains. Moreover, S.b-conditioned medium reduced cell rounding caused by filtered supernatants from all C. difficile strains. S.b-conditioned medium also inhibited toxin A-and B-mediated actin cytoskeleton disruption. S.b is effective in preventing C. difficile infection by outbreak-associated via inhibition of the cytotoxic effects of C. difficile toxins. (46). C. difficile is an anaerobic bacterium that produces two toxins -toxin A and toxin B -that mediate diarrhea, inflammation, and apoptosis of the mucosal epithelium in animals and humans (32). The effects of the toxin in target intestinal cells involve inactivation of the Rho family of GTPase, leading to cytoskeletal disorganization, epithelial cell apoptosis, and ultimately cell death (42, 54). C. difficile toxins also stimulate transcription of several proinflammatory genes, including tumor necrosis factor-␣ (TNF␣) (19) and activate transcription factors and mitogen-activated protein kinases involved in their proinflammatory effects (18,25). The mainstream CDI regimen includes the use of metronidazole, vancomycin, and fidaxomicin (55). However, many C. difficileinfected patients may also suffer from recurrent infections (13), while the recent epidemics that also involve new epidemic outbreak-associated strains (29) pose a major medical problem and epidemiological concern. These challenges have been met with a broad range of preventive approaches against CDI, including the use of probiotics, most notably Saccharomyces boulardii (S.b) alone or in combination with established antibiotic treatment (23,24).S.b is a nonpathogenic yeast that represents one of the well-studied probiotics against CDI in both experimental and clinical settings (24,40). Randomized double-blind placebocontrolled clinical trials have shown that S.b CNCM I-745 is an effective probiotic in the prophylaxis of antibi...

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“…10 Re-analysis of the 630, R20291 and CD196 genomes toxin in several strains, point mutations in the negative toxin regulator particularly in 027 strains and point C. difficile have undergone point mutations. These include multiple mutations in the actin-specific ADP-ribosylating Figure 1.…”

Section: Difficile Point Mutationsmentioning

confidence: 99%

In-depth genetic analysis ofClostridiumdifficilePCR-ribotype 027 strains reveals high genome fluidity including point mutations and inversions

Stabler

Valiente

Dawson³

et al. 2010

Gut Microbes

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gyrAMutations in Fluoroquinolone-resistantClostridium difficilePCR-027

Cited by 62 publications

References 10 publications

Fourteen-Genome Comparison Identifies DNA Markers for Severe-Disease-Associated Strains of Clostridium difficile

Fourteen-Genome Comparison Identifies DNA Markers for Severe-Disease-Associated Strains of Clostridium difficile

ProbioticSaccharomyces boulardiiCNCM I-745 prevents outbreak-associatedClostridium difficile-associated cecal inflammation in hamsters

In-depth genetic analysis ofClostridiumdifficilePCR-ribotype 027 strains reveals high genome fluidity including point mutations and inversions

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