RESUMEN
The novel antibiotic MBX-500, dosed at 100, 200, or 400 mg/kg twice daily for 7 days, was evaluated for the treatment of Clostridium difficile infection (CDI) in the gnotobiotic pig model. MBX-500 increased survival at all doses and at high doses improved clinical signs and reduced lesion severity, similar to vancomycin. Our results show that MBX-500 is an effective antibiotic for the treatment of diarrhea associated with CDI and prevents severe systemic disease.
Asunto(s)
Antibacterianos/farmacología , Clostridioides difficile/patogenicidad , Infecciones por Clostridium/tratamiento farmacológico , Diarrea/tratamiento farmacológico , Fluoroquinolonas/farmacología , Pirimidinonas/farmacología , Animales , Colon/microbiología , Colon/patología , Diarrea/microbiología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Vida Libre de Gérmenes , Estimación de Kaplan-Meier , Índice de Severidad de la Enfermedad , Porcinos , Resultado del Tratamiento , Vancomicina/farmacologíaRESUMEN
BACKGROUND: Shiga toxin (Stx)-producing Escherichia coli (STEC), especially O157:H7, cause bloody diarrhea, and in 3%-15% of individuals the infection leads to hemolytic uremic syndrome (HUS) or other complications. Use of antibiotics to treat STEC infections is controversial. Here, we describe the use of piglets to evaluate the efficacy and mechanism of action of antibiotics in these infections. METHODS: The effects of 2 antibiotics on STEC toxin production and their mechanisms of action were first determined by enzyme-linked immunosorbent assay and subsequently evaluated clinically in the gnotobiotic piglet infection model. RESULTS: In vitro treatment of clinical and isogenic strains with ciprofloxacin increased the production of Stx2 via phage induction but not the production of Stx1. Azithromycin caused no significant increase in toxin production. After treatment with ciprofloxacin, infected piglets had diarrhea and the severe fatal neurological symptoms associated with Stx2 intoxication. Characteristic petechial hemorrhages in the cerebellum were more severe in ciprofloxacin-treated animals than in control animals. In contrast, azithromycin-treated piglets survived the infection and had little or no brain hemorrhaging. CONCLUSIONS: The increased in vitro toxin production caused by ciprofloxacin was strongly correlated with death and an increased rate of cerebellar hemorrhage, in contrast to the effect of azithromycin. The piglet is a suitable model for determining the effectiveness and safety of antibiotics available to treat patients.