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Järhult JD, Muradrasoli S, Wahlgren J, Söderström H, Orozovic G, et al. (2011) Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards. PLoS ONE 6(9): e24742. doi:10.1371/journal.pone.0024742
1 Section of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, 2 Section of Bacteriology and Food Safety, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden, 3 Swedish Institute for Infectious Disease Control and Karolinska Institute, Microbiology and Tumor Biology Center, Stockholm, Sweden, 4 Department of Chemistry, Umeå University, Umeå, Sweden, 5 Section for Zoonotic Ecology and Epidemiology, School of Natural Sciences, Linnaeus University, Kalmar, Sweden, 6 Aquatic Biology and Chemistry Group, Kristianstad University, Kristianstad, Sweden, 7 National Veterinary Institute, Uppsala, Sweden, 8 Section of Pathology, Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden, 9 Research Institute of Fish Culture and Hydrobiology, Faculty of Fisheries and Protection of Waters, University of South Bohemia in Ceske Budejovice, Vodnany, Czech Republic, 10 Section of Clinical Virology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Abstract Top
Oseltamivir (Tamiflu®) is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008–2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried the mutation H274Y in the neuraminidase gene which causes resistance to the drug. The active metabolite of oseltamivir, oseltamivir carboxylate (OC), is poorly degraded in sewage treatment plants and surface water and has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance. To assess if resistance can develop under these circumstances, we infected mallards with influenza A/H1N1 virus and exposed the birds to 80 ng/L, 1 µg/L and 80 µg/L of OC through their sole water source. By sequencing the neuraminidase gene from fecal samples, we found that H274Y occurred at 1 µg/L of OC and rapidly dominated the viral population at 80 µg/L. IC50 for OC was increased from 2–4 nM in wild-type viruses to 400–700 nM in H274Y mutants as measured by a neuraminidase inhibition assay. This is consistent with the decrease in sensitivity to OC that has been noted among human clinical isolates carrying H274Y. Environmental OC levels have been measured to 58–293 ng/L during seasonal outbreaks and are expected to reach µg/L-levels during pandemics. Thus, resistance could be induced in influenza viruses circulating among wild ducks. As influenza viruses can cross species barriers, oseltamivir resistance could spread to human-adapted strains with pandemic potential disabling oseltamivir, a cornerstone in pandemic preparedness planning. We propose surveillance in wild birds as a measure to understand the resistance situation in nature and to monitor it over time. Strategies to lower environmental levels of OC include improved sewage treatment and, more importantly, a prudent use of antivirals.
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024742
1 Section of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, 2 Section of Bacteriology and Food Safety, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden, 3 Swedish Institute for Infectious Disease Control and Karolinska Institute, Microbiology and Tumor Biology Center, Stockholm, Sweden, 4 Department of Chemistry, Umeå University, Umeå, Sweden, 5 Section for Zoonotic Ecology and Epidemiology, School of Natural Sciences, Linnaeus University, Kalmar, Sweden, 6 Aquatic Biology and Chemistry Group, Kristianstad University, Kristianstad, Sweden, 7 National Veterinary Institute, Uppsala, Sweden, 8 Section of Pathology, Pharmacology and Toxicology, Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden, 9 Research Institute of Fish Culture and Hydrobiology, Faculty of Fisheries and Protection of Waters, University of South Bohemia in Ceske Budejovice, Vodnany, Czech Republic, 10 Section of Clinical Virology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Abstract Top
Oseltamivir (Tamiflu®) is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008–2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried the mutation H274Y in the neuraminidase gene which causes resistance to the drug. The active metabolite of oseltamivir, oseltamivir carboxylate (OC), is poorly degraded in sewage treatment plants and surface water and has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance. To assess if resistance can develop under these circumstances, we infected mallards with influenza A/H1N1 virus and exposed the birds to 80 ng/L, 1 µg/L and 80 µg/L of OC through their sole water source. By sequencing the neuraminidase gene from fecal samples, we found that H274Y occurred at 1 µg/L of OC and rapidly dominated the viral population at 80 µg/L. IC50 for OC was increased from 2–4 nM in wild-type viruses to 400–700 nM in H274Y mutants as measured by a neuraminidase inhibition assay. This is consistent with the decrease in sensitivity to OC that has been noted among human clinical isolates carrying H274Y. Environmental OC levels have been measured to 58–293 ng/L during seasonal outbreaks and are expected to reach µg/L-levels during pandemics. Thus, resistance could be induced in influenza viruses circulating among wild ducks. As influenza viruses can cross species barriers, oseltamivir resistance could spread to human-adapted strains with pandemic potential disabling oseltamivir, a cornerstone in pandemic preparedness planning. We propose surveillance in wild birds as a measure to understand the resistance situation in nature and to monitor it over time. Strategies to lower environmental levels of OC include improved sewage treatment and, more importantly, a prudent use of antivirals.
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0024742