RESUMEN
Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care-associated infections. We developed a protein-free vaccine composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan that improved survival and reduced bacterial burden of mice with invasive blood or lung infections caused by methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, extended-spectrum beta-lactamase-expressing Escherichia coli, and carbapenem-resistant strains of Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. The vaccine also conferred protection against the fungi Rhizopus delemar and Candida albicans. Efficacy was apparent by 24 hours and lasted for up to 28 days after a single vaccine dose, with a second dose restoring efficacy. The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant health care-associated infections.
Asunto(s)
Antiinfecciosos , Infección Hospitalaria , Staphylococcus aureus Resistente a Meticilina , Vacunas , Animales , Ratones , Antibacterianos/farmacología , Infección Hospitalaria/prevención & control , Infección Hospitalaria/microbiología , Antiinfecciosos/farmacología , Inmunidad Innata , Pruebas de Sensibilidad Microbiana , Farmacorresistencia BacterianaRESUMEN
Recently, we reported rifabutin hyperactivity against Acinetobacter baumannii We sought to characterize potential interactions between rifabutin and colistin, the last-resort drug for carbapenem-resistant infections. Rifabutin and colistin were synergistic in vitro and in vivo, and low-dose colistin significantly suppressed emergence of resistance to rifabutin. Thus, this combination is a promising therapeutic option for highly resistant A. baumannii infections.
