Fidaxomicin inhibits Clostridium difficile toxin A-mediated enteritis in the mouse ileum.
Antimicrob Agents Chemother
; 58(8): 4642-50, 2014 Aug.
Article
em En
| MEDLINE
| ID: mdl-24890583
ABSTRACT
Clostridium difficile infection (CDI) is a common, debilitating infection with high morbidity and mortality. C. difficile causes diarrhea and intestinal inflammation by releasing two toxins, toxin A and toxin B. The macrolide antibiotic fidaxomicin was recently shown to be effective in treating CDI, and its beneficial effect was associated with fewer recurrent infections in CDI patients. Since other macrolides possess anti-inflammatory properties, we examined the possibility that fidaxomicin alters C. difficile toxin A-induced ileal inflammation in mice. The ileal loops of anesthetized mice were injected with fidaxomicin (5, 10, or 20 µM), and after 30 min, the loops were injected with purified C. difficile toxin A or phosphate-buffered saline alone. Four hours after toxin A administration, ileal tissues were processed for histological evaluation (epithelial cell damage, neutrophil infiltration, congestion, and edema) and cytokine measurements. C. difficile toxin A caused histologic damage, evidenced by increased mean histologic score and ileal interleukin-1ß (IL-1ß) protein and mRNA expression. Treatment with fidaxomicin (20 µM) or its primary metabolite, OP-1118 (120 µM), significantly inhibited toxin A-mediated histologic damage and reduced the mean histology score and ileal IL-1ß protein and mRNA expression. Both fidaxomicin and OP-1118 reduced toxin A-induced cell rounding in human colonic CCD-18Co fibroblasts. Treatment of ileal loops with vancomycin (20 µM) and metronidazole (20 µM) did not alter toxin A-induced histologic damage and IL-1ß protein expression. In addition to its well known antibacterial effects against C. difficile, fidaxomicin may possess anti-inflammatory activity directed against the intestinal effects of C. difficile toxins.
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Base de dados:
MEDLINE
Assunto principal:
Toxinas Bacterianas
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Enterotoxinas
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Células Epiteliais
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Fibroblastos
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Aminoglicosídeos
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Anti-Inflamatórios
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Antibacterianos
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article