RESUMEN
Avian influenza H5N1 infections can cause severe, lethal human infections. Whether influenza A virus treatments effectively ameliorate avian influenza H5N1 human infections is uncertain. The research objective was to evaluate the efficacy of novel zinc and other metallo-ion formulations in two influenza A mouse models. Mice infected with influenza A/Duck/MN/1525/81 (H5N1) virus were treated orally 48 h before virus exposure and then twice daily for 13 days with ZnAL42. The optimal dosing regimen for ZnAL42 was achieved at 17.28 mg/kg 48 h prior to virus exposure, twice daily for 7 days. The survival rate was 80% compared with 10% in the untreated control group and a 100% survival rate with ribavirin (75 mg/kg/day, twice a day for 5 days, beginning 4 h before virus exposure). ZnAL42 treatment significantly lessened the decline in arterial oxygen saturation (SaO2; P < 0.001). This regimen was also well tolerated by the mice. Manganese and selenium formulations were not inhibitory to virus replication when given therapeutically. Mice were also infected with influenza A/NWS/33 (H1N1) virus and were treated 48 h before virus exposure with three dosages of ZnAL42 (8.64, 1.46 or 0.24 mg/kg/day). Treatment was by oral gavage twice daily for 13 days. The highest dose of ZnAL42 was significantly inhibitory to the virus infection as seen by prevention of deaths and lessening of decline in SaO2. The data suggest that the prophylactic use of ZnAL42 is effective against avian influenza H5N1 or H1N1 virus infection in mice and should be further explored as an option for treating human influenza virus infections.
Asunto(s)
Compuestos de Aluminio/farmacología , Antivirales/farmacología , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/prevención & control , Compuestos de Zinc/farmacología , Administración Oral , Animales , Antivirales/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Humanos , Manganeso/farmacología , Ratones , Ratones Endogámicos BALB C , Oxígeno/sangre , Ribavirina/administración & dosificación , Ribavirina/farmacología , Selenio/farmacología , Organismos Libres de Patógenos Específicos , Análisis de SupervivenciaRESUMEN
OBJECTIVES: We investigated three novel highly charged copper-based inorganic biocidal formulations for their activity against organisms highly relevant to healthcare-associated infection. METHODS: The three copper-based formulations were tested: (i) against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), Legionella pneumophila, Acinetobacter calcoaceticus/baumannii (ACCB), glycopeptide-resistant Enterococcus and spores of Clostridium difficile in time-kill assays; (ii) for their ability to decontaminate ultramicrofibre (UMF) cloths; and (iii) for their cytotoxicity to human skin and intestinal epithelial cells. RESULTS: All three copper-based formulations were potently biocidal down to concentrations of 1 ppm for both stationary- and log-phase organisms, and they were all active against C. difficile spores. At 150 ppm, they achieved a complete (>6 log10) kill of MRSA and ACCB mostly within 1 h. This biocidal activity was not achieved by copper sulphate or the inorganic binders used in the formulations. All three copper-based formulations completely decontaminated UMF cloths containing MRSA, ACCB or C. difficile spores, suggesting that any of these copper-based formulations would be highly beneficial in the healthcare environment. All three copper-based formulations and copper sulphate were not cytotoxic to human epithelial cells up to concentrations of 100-200 ppm. CONCLUSIONS: All three of the novel copper-based biocidal formulations, but not their components (copper sulphate and inorganic binders), have potent activity against organisms highly relevant to healthcare-associated infections.