RESUMEN
Bacillus anthracis is a Gram-positive Centers for Disease Control and Prevention category "A" biothreat pathogen. Without early treatment, inhalation of anthrax spores with progression to inhalational anthrax disease is associated with high fatality rates. Gepotidacin is a novel first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is being evaluated for use against biothreat and conventional pathogens. Gepotidacin selectively inhibits bacterial DNA replication via a unique binding mode and has in vitro activity against a collection of B. anthracis isolates including antibacterial-resistant strains, with the MIC90 ranging from 0.5 to 1 µg/mL. In vivo activity of gepotidacin was also evaluated in the New Zealand White rabbit model of inhalational anthrax. The primary endpoint was survival, with survival duration and bacterial clearance as secondary endpoints. The trigger for treatment was the presence of anthrax protective antigen in serum. New Zealand White rabbits were dosed intravenously for 5 days with saline or gepotidacin at 114 mg/kg/d to simulate a dosing regimen of 1,000 mg intravenous (i.v.) three times a day (TID) in humans. Gepotidacin provided a survival benefit compared to saline control, with 91% survival (P-value: 0.0001). All control animals succumbed to anthrax and were found to be blood- and organ culture-positive for B. anthracis. The novel mode of action, in vitro microbiology, preclinical safety, and animal model efficacy data, which were generated in line with Food and Drug Administration Animal Rule, support gepotidacin as a potential treatment for anthrax in an emergency biothreat situation.
Asunto(s)
Acenaftenos , Vacunas contra el Carbunco , Carbunco , Bacillus anthracis , Compuestos Heterocíclicos con 3 Anillos , Infecciones del Sistema Respiratorio , Conejos , Humanos , Animales , Carbunco/microbiología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Modelos Animales de Enfermedad , Vacunas contra el Carbunco/uso terapéuticoRESUMEN
El presente estudio incluyó doce recién nacido prematuros con perforaciones gastrointestinales "espontáneas", estudiados retrospectivamente durante tres años. Se encontró que le problema fue más frecuente en niños extremadamente prematuros con síndrome de dificultad respiratoria y persistencia de conducto arterioso. Se hizo correlación anatomo patológiuca con las biopsias o estudios post-mortem y se sugiere que las perforaciones intestinales "espontáneas" probablemante representan una forma de enterocolitis necrosante. perforación intestinal; enterocolitis necrosante; recién nacido