{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T07:10:13Z","timestamp":1790061013391,"version":"4.0.1"},"reference-count":63,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2015,8,14]],"date-time":"2015-08-14T00:00:00Z","timestamp":1439510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2015,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Influenza A virus (IAV) has its natural reservoir in wild waterfowl, and new human IAVs often contain gene segments originating from avian IAVs. Treatment options for severe human influenza are principally restricted to neuraminidase inhibitors (NAIs), among which oseltamivir is stockpiled in preparedness for influenza pandemics. There is evolutionary pressure in the environment for resistance development to oseltamivir in avian IAVs, as the active metabolite oseltamivir carboxylate (OC) passes largely undegraded through sewage treatment to river water where waterfowl reside. In an\n            <jats:italic>in vivo<\/jats:italic>\n            mallard (\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Anas platyrhynchos<\/jats:named-content>\n            ) model, we tested if low-pathogenic avian influenza A(H7N9) virus might become resistant if the host was exposed to low levels of OC. Ducks were experimentally infected, and OC was added to their water, after which infection and transmission were maintained by successive introductions of uninfected birds. Daily fecal samples were tested for IAV excretion, genotype, and phenotype. Following mallard exposure to 2.5 \u03bcg\/liter OC, the resistance-related neuraminidase (NA) I222T substitution, was detected within 2 days during the first passage and was found in all viruses sequenced from subsequently introduced ducks. The substitution generated 8-fold and 2.4-fold increases in the 50% inhibitory concentration (IC\n            <jats:sub>50<\/jats:sub>\n            ) for OC (\n            <jats:italic>P<\/jats:italic>\n            &lt; 0.001) and zanamivir (\n            <jats:italic>P<\/jats:italic>\n            = 0.016), respectively. We conclude that OC exposure of IAV hosts, in the same concentration magnitude as found in the environment, may result in amino acid substitutions, leading to changed antiviral sensitivity in an IAV subtype that can be highly pathogenic to humans. Prudent use of oseltamivir and resistance surveillance of IAVs in wild birds are warranted.\n          <\/jats:p>","DOI":"10.1128\/aac.00886-15","type":"journal-article","created":{"date-parts":[[2015,6,16]],"date-time":"2015-06-16T03:01:14Z","timestamp":1434423674000},"page":"5196-5202","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":24,"title":["Influenza A(H7N9) Virus Acquires Resistance-Related Neuraminidase I222T Substitution When Infected Mallards Are Exposed to Low Levels of Oseltamivir in Water"],"prefix":"10.1128","volume":"59","author":[{"given":"Anna","family":"Gillman","sequence":"first","affiliation":[{"name":"Section for Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden"},{"name":"Zoonosis Science Centre, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Nykvist","sequence":"additional","affiliation":[{"name":"Section for Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden"},{"name":"Zoonosis Science Centre, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaman","family":"Muradrasoli","sequence":"additional","affiliation":[{"name":"Zoonosis Science Centre, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden"},{"name":"Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"S\u00f6derstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Wille","sequence":"additional","affiliation":[{"name":"Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, Kalmar, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Daggfeldt","sequence":"additional","affiliation":[{"name":"Department of Virology, Immunobiology and Parasitology, Swedish Veterinary Institute, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Br\u00f6jer","sequence":"additional","affiliation":[{"name":"Department of Pathology and Wildlife Disease, Swedish Veterinary Institute, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Waldenstr\u00f6m","sequence":"additional","affiliation":[{"name":"Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, Kalmar, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Olsen","sequence":"additional","affiliation":[{"name":"Section for Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden"},{"name":"Zoonosis Science Centre, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef D.","family":"J\u00e4rhult","sequence":"additional","affiliation":[{"name":"Section for Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden"},{"name":"Zoonosis Science Centre, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/mr.56.1.152-179.1992"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008935"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.2008.1501"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000076"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1122438"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-010-0008-z"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(13)60938-1"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1017\/S1466252310000071"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-010714-112311"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12515"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12392"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14348"},{"key":"e_1_3_3_14_2","article-title":"Human infection with avian influenza A(H7N9) virus\u2014China","author":"World Health Organization","year":"2015","unstructured":"World Health Organization. 2015. 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