Clostridium difficileinfection: molecular pathogenesis and novel therapeutics

Abstract

The Gram-positive anaerobic bacterium Clostridium difficile produces toxins A and B, which can cause a spectrum of diseases from pseudomembranous colitis to C. difficile-associated diarrhea. A limited number of C. difficile strains also produce a binary toxin that exhibits ADP ribosyltransferase activity. Here, the structure and the mechanism of action of these toxins as well as their role in disease are reviewed. Nosocomial C. difficile infection is often contracted in hospital when patients treated with antibiotics suffer a disturbance in normal gut microflora. C. difficile spores can persist on dry, inanimate surface for months. Metronidazole and oral vancomycin are clinically used for treatment of C. difficile infection but clinical failure and concern about promotion of resistance are motivating the search for novel non-antibiotic therapeutics. Methods for controlling both toxins and spores, replacing gut microflora by probiotics or fecal transplant, and killing bacteria in the anaerobic gut by photodynamic therapy are discussed.

Disease Progression and Resolution in Rodent Models of Clostridium difficile Infection and Impact of Antitoxin Antibodies and Vancomycin

“…CDI pathogenesis is associated with use of antimicrobials that disrupt the intestinal microbiota, reducing the host's ability to resist colonization by, and expansion of, C. difficile (4,5). These conditions allow C. difficile spores to germinate, with resultant production of two toxins, TcdA and TcdB, that cause the symptoms of the disease (6)(7)(8). The infection is normally treated with antibiotics such as vancomycin and metronidazole which have potent activity against C. difficile (1,8).…”

“…These conditions allow C. difficile spores to germinate, with resultant production of two toxins, TcdA and TcdB, that cause the symptoms of the disease (6)(7)(8). The infection is normally treated with antibiotics such as vancomycin and metronidazole which have potent activity against C. difficile (1,8). However, the broad antibacterial spectra of these agents perpetuate gut dysbiosis, leading to high rates of disease recurrence following withdrawal of therapy, during which surviving or newly acquired C. difficile spores take advantage of persistent disruption of the gut microbiome to cause another episode of CDI (9)(10)(11).…”

Diarrea asociada a Clostridium difficile en niños

“…Frente al estrés del medio, la bacteria produce endosporas que le permite tolerar condiciones ambientales extremas, resistencia a los cambios físicos y químicos como altas temperaturas, luz ultravioleta y exposición a desinfectantes que no contienen cloruros 12,13 . Se ha aislado por meses en centros de salud y por más de 40 días en pacientes después del egreso hospitalario 2,9 .…”

“…La toxina B, a su vez, cruza a través de la alteración de las uniones estrechas hacia el lado baso-lateral de la célula epitelial 17 . La acción de ambas toxinas se traduce en un daño epitelial intenso con edema celular y secreción luminal abundante (diarrea secretoria) 12,13 . El daño tóxico a la mucosa colónica produce acumulación de fibrina, mucina y detritus celulares generando las pseudomembranas.…”

Esporas de Clostridium difficile y su relevancia en la persistencia y transmisión de la infección

“…La resistencia de las esporas de C. difficile a los antimicrobianos es tal, que éstas pueden persistir después de un curso terapéutico de metronidazol y vancomicina 72 . Se ha postulado que la presencia de diverticulosis en el colon podría actuar como un potencial reservorio de esporas de C. diffiicle, contribuyendo a la persistencia de las IACD; sin embargo, estudios recientes no avalan esta hipótesis 73 .…”