Pathogenesis and treatment of <i>Clostridium difficile</i> infection

Tonna, Ivan; Welsby, Philip D

doi:10.1136/pgmj.2004.028480

Cited by 63 publications

(39 citation statements)

References 41 publications

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“…[7][8][9] While effective, these antibiotics may contribute to a very high recurrence rate ranging from 20-35%. 10,11 A recent computer simulation shows that vaccination could be the cost-effective approach in the prevention and treatment of CDI, especially the recurrent CDI. 12 It was initially reported that anti-TcdA antibodies were sufficient to protect the host against CDI.…”

Section: Introductionmentioning

confidence: 99%

A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity againstClostridium difficileinfection in mice and hamsters

Wang

Yan

Kim

et al. 2015

Human Vaccines & Immunotherapeutics

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Section: Introductionmentioning

confidence: 99%

A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity againstClostridium difficileinfection in mice and hamsters

Wang

Yan

Kim

et al. 2015

Human Vaccines & Immunotherapeutics

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“…In addition to gastrointestinal disease, systemic complications of infection like ascites (15), pleural effusion (7,38), hepatic abscess (30), and renal failure (11) have also been reported. Standard treatment for CDI is use of the antibiotic metronidazole or vancomycin, although neither of these antibiotics is fully effective (37), and an estimated 20 to 35% of those who appear cured by the initial treatment develop a second episode of the disease (4,34). The rate of occurrence of further episodes of CDI in patients who have already had one recurrence can be more than 50% (27), and a subset of patients will have multiple recurrences.…”

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confidence: 99%

Mouse Relapse Model of Clostridium difficile Infection

et al. 2011

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Clostridium difficile is the causative agent of primary and recurrent antibiotic-associated diarrhea and colitis in hospitalized patients. The disease is caused mainly by two exotoxins, TcdA and TcdB, produced by the bacteria. Recurrent C. difficile infection (CDI) constitutes one of the most significant clinical issues of this disease, occurs in more than 20% of patients after the first episode, and may be increasing in frequency. However, there is no well-established animal model of CDI relapse currently available for studying disease pathogenesis, prevention, and therapy. Here we report the establishment of a conventional mouse model of recurrence/relapse CDI. We found that the primary episode of CDI induced little or no protective antibody response against C. difficile toxins and mice continued shedding C. difficile spores. Antibiotic treatment of surviving mice induced a second episode of diarrhea, while a simultaneous reexposure of animals to C. difficile bacteria or spores elicited a full spectrum of CDI similar to that of the primary infection. Moreover, mice treated with immunosuppressive agents were prone to more severe and fulminant recurrent disease. Finally, utilizing this model, we demonstrated that vancomycin only delayed disease recurrence, whereas neutralizing polysera against both TcdA and TcdB completely protected mice against CDI relapse. In conclusion, we have established a mouse relapse CDI model that allows for future investigations of the role of the host immune response in the disease's pathogenesis and permits critical testing of new therapeutics targeting recurrent disease.Clostridium difficile, a Gram-positive, anaerobic, and sporeforming bacterium, is an etiologic agent of pseudomembranous colitis and accounts for a quarter of all cases of antibioticassociated diarrhea (10). With the recent emergence of hypervirulent antibiotic-resistant strains, the incidence of C. difficile-associated diarrhea and intestinal inflammatory disease (collectively designated CDI) has increased significantly in both North America and Europe, causing lengthy hospitalizations and substantial morbidity and mortality (24,26). CDI is now considered an important reemerging disease.C. difficile produces metabolically dormant spores that are excreted from infected patients. The infectious spores persist in the environment and are highly resistant to commonly used disinfectants. Spores survive exposure to gastric acidity and germinate in the gut. The use of antibiotics that spare C. difficile but suppress the intestinal microbiota allows C. difficile to proliferate and produce two exotoxins, TcdA and TcdB, which cause intestinal tissue damage and inflammation. Therefore, antibiotic exposure is the most significant risk factor for the diseases (6). CDI ranges from mild diarrhea to life-threatening fulminant colitis (5,8,26). In addition to gastrointestinal disease, systemic complications of infection like ascites (15), pleural effusion (7, 38), hepatic abscess (30), and renal failure (11) have also been reported. ...

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“…This disease is known as Clostridium difficile-associated disease (CDAD) and is responsible for approximately 25% of all antibiotic-associated diarrhea (37). Contamination of hospital environments with C. difficile spores is a key factor associated with infection spread (5).…”

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Mapping Interactions between Germinants and Clostridium difficile Spores

2011

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Germination of Clostridium difficile spores is the first required step in establishing C. difficile-associated disease (CDAD). Taurocholate (a bile salt) and glycine (an amino acid) have been shown to be important germinants of C. difficile spores. In the present study, we tested a series of glycine and taurocholate analogs for the ability to induce or inhibit C. difficile spore germination. Testing of glycine analogs revealed that both the carboxy and amino groups are important epitopes for recognition and that the glycine binding site can accommodate compounds with more widely separated termini. The C. difficile germination machinery also recognizes other hydrophobic amino acids. In general, linear alkyl side chains are better activators of spore germination than their branched analogs. However, L-phenylalanine and L-arginine are also good germinants and are probably recognized by distinct binding sites. Testing of taurocholate analogs revealed that the 12-hydroxyl group of taurocholate is necessary, but not sufficient, to activate spore germination. In contrast, the 6-and 7-hydroxyl groups are required for inhibition of C. difficile spore germination. Similarly, C. difficile spores are able to detect taurocholate analogs with shorter, but not longer, alkyl amino sulfonic acid side chains. Furthermore, the sulfonic acid group can be partially substituted with other acidic groups. Finally, a taurocholate analog with an m-aminobenzenesulfonic acid side chain is a strong inhibitor of C. difficile spore germination. In conclusion, C. difficile spores recognize both amino acids and taurocholate through multiple interactions that are required to bind the germinants and/or activate the germination machinery.

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Pathogenesis and treatment of Clostridium difficile infection

Abstract: This paper reviews the pathogenesis and management of Clostridium difficile diarrhoea, in particular the management of recurrent episodes.

Cited by 63 publications

References 41 publications

A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity againstClostridium difficileinfection in mice and hamsters

A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity againstClostridium difficileinfection in mice and hamsters

Mouse Relapse Model of Clostridium difficile Infection

Mapping Interactions between Germinants and Clostridium difficile Spores

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