Clostridium difficile and cytotoxin in feces of patients with antimicrobial agent-associated pseudomembranous colitis

George, W. Lance; Rolfe, Rial D.; Harding, G. K. M.; Klein, Robert; Putnam, Charles W.; Finegold, Sydney M.

doi:10.1007/bf01666910

Cited by 75 publications

(49 citation statements)

References 13 publications

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“…Differences in the levels of production of toxins TcdA and TcdB alone cannot account for the wide spectrum of clinical presentations. Georges et al (21) reported that there were no significant differences between clinical presentations according to the titer of the cytotoxin. Similarly, there was no correlation between virulence in a hamster model of AAC and the production of TcdA and TcdB in vitro (12).…”

Section: Discussionmentioning

confidence: 98%

Prevalence and Characterization of a Binary Toxin (Actin-Specific ADP-Ribosyltransferase) from Clostridium difficile

et al. 2004

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In addition to the two large clostridial cytotoxins (TcdA and TcdB), some strains of Clostridium difficile also produce an actin-specific ADP-ribosyltransferase, called binary toxin CDT. We used a PCR method and Southern blotting for the detection of genes encoding the enzymatic (CDTa) and binding (CDTb) components of the binary toxin in 369 strains isolated from patients with suspected C. difficile-associated diarrhea or colitis. Twenty-two strains (a prevalence of 6%) harbored both genes. When binary toxin production was assessed by Western blotting, 19 of the 22 strains reacted with antisera against the iota toxin of C. perfringens (anti-Ia and anti-Ib). Additionally, binary toxin activity, detected by the ADP-ribosyltransferase assay, was present in only 17 of the 22 strains. Subsequently, all 22 binary toxin-positive strains were tested for the production of toxins TcdA and TcdB, toxinotyped, and characterized by serogrouping, PCR ribotyping, arbitrarily primed PCR, and pulsed-field gel electrophoresis. All binary toxin-positive strains also produced TcdB and/or TcdA. However, they had significant changes in the tcdA and tcdB genes and belonged to variant toxinotypes III, IV, V, VII, IX, and XIII. We could differentiate 16 profiles by using typing methods, indicating that most of the binary toxin-positive strains were unrelated.

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Section: Discussionmentioning

confidence: 98%

Prevalence and Characterization of a Binary Toxin (Actin-Specific ADP-Ribosyltransferase) from Clostridium difficile

et al. 2004

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“…However, in 1978, C. difficile was identified as the primary cause of pseudomembranous colitis and shown to be a primary isolate from the feces of patients undergoing clindamycin treatment (10,57). These seminal observations were followed by a series of reports which further showed a strong correlation between pseudomembranous colitis, antibiotic therapy, C. difficile colonization, and cytotoxin production (6,11,16,36,56,116,166,183). Collectively, these original studies and observations revealed C. difficile as an emerging pathogen capable of causing severe gastrointestinal disease in individuals undergoing antibiotic therapy.…”

Section: Introductionmentioning

confidence: 97%

Clostridium difficileToxins: Mechanism of Action and Role in Disease

2005

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As the leading cause of hospital-acquired diarrhea, Clostridium difficile colonizes the large bowel of patients undergoing antibiotic therapy and produces two toxins, which cause notable disease pathologies. These two toxins, TcdA and TcdB, are encoded on a pathogenicity locus along with negative and positive regulators of their expression. Following expression and release from the bacterium, TcdA and TcdB translocate to the cytosol of target cells and inactivate small GTP-binding proteins, which include Rho, Rac, and Cdc42. Inactivation of these substrates occurs through monoglucosylation of a single reactive threonine, which lies within the effector-binding loop and coordinates a divalent cation critical to binding GTP. By glucosylating small GTPases, TcdA and TcdB cause actin condensation and cell rounding, which is followed by death of the cell. TcdA elicits effects primarily within the intestinal epithelium, while TcdB has a broader cell tropism. Important advances in the study of these toxins have been made in the past 15 years, and these are detailed in this review. The domains, subdomains, and residues of these toxins important for receptor binding and enzymatic activity have been elegantly studied and are highlighted herein. Furthermore, there have been major advances in defining the role of these toxins in modulating the inflammatory events involving the disruption of cell junctions, neuronal activation, cytokine production, and infiltration by polymorphonuclear cells. Collectively, the present review provides a comprehensive update on TcdA and TcdB's mechanism of action as well as the role of these toxins in disease

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“…Clostridium difficile has emerged as the most important cause ofantibiotic-associated colitis in animals ( 1, 2) and humans (3,4) and is one of the most commonly diagnosed nosocomial infections (5). This gram-positive obligate anaerobe produces two protein exotoxins: toxin A and toxin B. Toxin A is a 308-kD (6) enterotoxin that elicits intestinal fluid secretion and inflammation, causes severe destruction of villi, and increases permeability in adult rabbit and guinea pig ileum (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Diminished Clostridium difficile toxin A sensitivity in newborn rabbit ileum is associated with decreased toxin A receptor.

Eglow¹,

Pothoulakis²,

Itzkowitz³

et al. 1992

J. Clin. Invest.

167

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Human infants are relatively resistant to Clostridium difficileassociated diarrhea and colitis compared to adults. In that toxin A is the major cause of intestinal damage with this organism, we compared toxin A receptor binding and biological effects in newborn vs adult rabbit ileum. Purified toxin A (M, 308 kD) was labeled with tritium or biotin with full retention of biologic activity. Appearance of specific toxin A brush border (BB) binding was strongly age dependent with minimal 13Hltoxin A specific binding at 2 and 5 d of life, followed by gradual increase in binding to reach adult levels at 90 d. Absence of toxin A binding sites in newborn and presence in adult rabbits was confirmed by immunohistochemical studies using biotinylated toxin A. Toxin A (50 ng to 20 gg!/ml) inhibited protein synthesis in 90-d-old rabbit ileal loops in a dose-dependent fashion. In contrast, inhibition of protein synthesis in 5-d-old rabbit ileum occurred only at the highest toxin A doses (5 and 20 jug/ml) and at all doses tested was significantly less than the adult rabbit ileum. In addition, toxin A (5 ,ug/ml) caused severe mucosal damage in adult rabbit ileal explants but had no discernable morphologic effect on 5-d-old rabbit intestine. Our data indicate that newborn rabbit intestine lacks BB receptors for toxin A. The absence of the high-affinity BB receptor for toxin A in the newborn period may explain lack of biologic responsiveness to purified toxin, and the absence of disease in human infants infected with this pathogen. (J. Clin. Invest. 1992. 90:822-829.) Key words: brush border receptor -Clostridium difficile -development * enterotoxin A * toxin receptor

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Clostridium difficile and cytotoxin in feces of patients with antimicrobial agent-associated pseudomembranous colitis

Cited by 75 publications

References 13 publications

Prevalence and Characterization of a Binary Toxin (Actin-Specific ADP-Ribosyltransferase) from Clostridium difficile

Prevalence and Characterization of a Binary Toxin (Actin-Specific ADP-Ribosyltransferase) from Clostridium difficile

Clostridium difficileToxins: Mechanism of Action and Role in Disease

Diminished Clostridium difficile toxin A sensitivity in newborn rabbit ileum is associated with decreased toxin A receptor.

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