Emergence of Toxin A-Negative, Toxin B-Positive
            <i>Clostridium Difficile</i>
            Strains: Epidemiological and Clinical Considerations

King, Amy McKarral; Mackin, Kate E.; Lyras, Dena

doi:10.2217/fmb.14.115

Cited by 40 publications

(34 citation statements)

References 22 publications

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“…difficile toxins, TcdB. Until now most vaccines and immunotherapeutics have focussed on TcdA alone or have combined TcdA and TcdB, however, many pathogenic strains do not produce TcdA whereas almost all produce TcdB 11 . The importance of TcdB, particularly in severe intestinal damage 22 and severe 8 and systemic disease 13, 22 , has been established, For these reasons, TcdB was selected as a key target for the development of C. difficile colostrum-based therapeutics, together with vegetative cell and spore targets that represent all important infectious cycle components.…”

Section: Discussionmentioning

confidence: 99%

“…TcdA and TcdB are monoglucosyltransferases that modify Rho GTPases leading to disorganisation of the actin cytoskeleton, cell-rounding, death of the intoxicated cell and extensive colonic inflammation 4 . The relative contribution of these two major toxins to disease pathogenesis has long been contentious, however, many studies have now clearly demonstrated the importance of TcdB in disease 1, 5–9 and many strains that produce TcdB but not the other toxins continue to emerge 10, 11 . Targeting TcdB for disease treatment has resulted in the production of a human monoclonal antibody, bezlotoxumab, which reduced rates of recurrent infection in human clinical trials and has recently obtained FDA approval 12 .…”

Section: Introductionmentioning

confidence: 99%

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Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative

Hutton

Cunningham

Mackin

et al. 2017

Sci Rep

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The increased incidence of antibiotic resistant ‘superbugs’ has amplified the use of broad spectrum antibiotics worldwide. An unintended consequence of antimicrobial treatment is disruption of the gastrointestinal microbiota, resulting in susceptibility to opportunistic pathogens, such as Clostridium difficile. Paradoxically, treatment of C. difficile infections (CDI) also involves antibiotic use, leaving patients susceptible to re-infection. This serious health threat has led to an urgent call for the development of new therapeutics to reduce or replace the use of antibiotics to treat bacterial infections. To address this need, we have developed colostrum-derived antibodies for the prevention and treatment of CDI. Pregnant cows were immunised to generate hyperimmune bovine colostrum (HBC) containing antibodies that target essential C. difficile virulence components, specifically, spores, vegetative cells and toxin B (TcdB). Mouse infection and relapse models were used to compare the capacity of HBC to prevent or treat primary CDI as well as prevent recurrence. Administration of TcdB-specific colostrum alone, or in combination with spore or vegetative cell-targeted colostrum, prevents and treats C. difficile disease in mice and reduces disease recurrence by 67%. C. difficile-specific colostrum should be re-considered as an immunotherapeutic for the prevention or treatment of primary or recurrent CDI.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative

Hutton

Cunningham

Mackin

et al. 2017

Sci Rep

Self Cite

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“…It is quite interesting that S.b had an inhibitory effect against all outbreak-associated C. difficile strains in vivo and in vitro, although the molecular and clinical characteristics of these strains are quite diverse. C. difficile ribotype 017 has been associated with several outbreaks CDI (11,47) and is characterized by a toxin A-negative and toxin B-positive genotype (26). According to a mouse study, antibiotic treatment even promotes spore shedding of C. difficile ribotype 017 and subsequent animal-to-animal transmission (31).…”

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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“…The prevalence of these strains, which include PCR ribotype 017, has been increasing, sometimes to epidemic proportions 134 . Recently, the first strain with an intact tcdA gene, but no tcdB gene, in a different genomic context than the PaLoc has been characterized 78 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Clostridium difficile infection

Smits

Lyras

Lacy

et al. 2016

Nat Rev Dis Primers

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697

674

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Infection of the colon with the Gram-positive bacterium Clostridium difficile is potentially life threatening, especially in elderly people and in patients who have dysbiosis of the gut microbiota following antimicrobial drug exposure. C. difficile is the leading cause of health-care-associated infective diarrhoea. The life cycle of C. difficile is influenced by antimicrobial agents, the host immune system, and the host microbiota and its associated metabolites. The primary mediators of inflammation in C. difficile infection (CDI) are large clostridial toxins, toxin A (TcdA) and toxin B (TcdB), and, in some bacterial strains, the binary toxin CDT. The toxins trigger a complex cascade of host cellular responses to cause diarrhoea, inflammation and tissue necrosis — the major symptoms of CDI. The factors responsible for the epidemic of some C. difficile strains are poorly understood. Recurrent infections are common and can be debilitating. Toxin detection for diagnosis is important for accurate epidemiological study, and for optimal management and prevention strategies. Infections are commonly treated with specific antimicrobial agents, but faecal microbiota transplants have shown promise for recurrent infections. Future biotherapies for C. difficile infections are likely to involve defined combinations of key gut microbiota.

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Emergence of Toxin A-Negative, Toxin B-Positive Clostridium Difficile Strains: Epidemiological and Clinical Considerations

Cited by 40 publications

References 22 publications

Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative

Bovine antibodies targeting primary and recurrent Clostridium difficile disease are a potent antibiotic alternative

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

Clostridium difficile infection

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