Effect of metronidazole on growth and toxin production by epidemic Clostridium difficile PCR ribotypes 001 and 027 in a human gut model

Abstract

Duration of cytotoxin production by C. difficile ribotype 027 markedly exceeds that of ribotype 001. Sub-optimal gut concentrations of metronidazole, possibly due to inactivation by components of normal gut flora, are associated with continued toxin production. These findings may help to explain the increased severity of symptoms and higher case-fatality ratio associated with infections due to C. difficile ribotype 027.

Effect of broad- and narrow-spectrum antimicrobials on Clostridium difficile and microbial diversity in a model of the distal colon

“…1B). This inability to recover metronidazole has been previously noted (18), and it has been suggested that inactivation of metronidazole by human gut microbiota such as enterococci may be responsible for the lack of activity (19,20).…”

“…Although vancomycin and metronidazole (both antibiotics) and lacticin 3147 (a member of the lantibiotic class I bacteriocins) are all active against C. difficile (15,17,18), their relative antimicrobial activity has not been compared to date. To address this issue, the ability of these three broad-spectrum antimicrobials to control C. difficile ribotype 001 was assessed using a model of the distal colon.…”

“…An inevitable consequence of the use of broad-spectrum antimicrobials to treat C. difficile, including vancomycin, metronidazole, and lacticin 3147, is the potential for impact on the other members of the gut microbiota. Although the impact of these three antimicrobials on the gut microbial composition has been assessed to some extent previously (15,18,21), none of these assessments has benefitted from the detailed analysis of bacterial populations that becomes possible through massively parallel sequencing of variable regions of the 16s rRNA gene. To facilitate such an analysis, samples were taken at 24 h from the simulated human distal colon experiments already described, and total metagenomic DNA was extracted.…”

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

“…Las esporas de C. difficile son resistentes a todos los antimicrobianos conocidos, principalmente debido a que son metabólicamente inactivos y a que la membrana interna es impermeable a la difusión de moléculas pequeñas, lo que impide el ingreso de antimicrobianos hacia el núcleo de la espora [84][85][86][87] . Los principales antibacterianos utilizados en el tratamiento de las IACD son metronidazol, vancomicina y recientemente fidaxomicina 88 .…”

“…Los principales antibacterianos utilizados en el tratamiento de las IACD son metronidazol, vancomicina y recientemente fidaxomicina 88 . Estudios in vitro han demostrado que, tanto metronidazol como vancomicina, no inhiben la formación de esporas de C. difficile 84,85 , lo que es consistente con las elevadas tasas de recurrencia de IACD observadas en estudios clínicos 89 . En contraste, fidaxomicina, a concentraciones sub-inhibitorias, inhibe la formación de esporas de C. difficile in vitro 42 , y los estudios clínicos han demostrado que reduce a la mitad los episodios de recurrencia de IACD, comparado con vancomicina 41,90 , debido posiblemente a la inhibición de la formación de esporas durante el tratamiento.…”