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Detection of the antiviral drug oseltamivir in aquatic environments
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
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2009 (English)In: PloS one, ISSN 1932-6203, Vol. 4, no 6, e6064- p.Article in journal (Refereed) Published
Abstract [en]

Oseltamivir (Tamiflu) is the most important antiviral drug available and a cornerstone in the defence against a future influenza pandemic. Recent publications have shown that the active metabolite, oseltamivir carboxylate (OC), is not degraded in sewage treatment plants and is also persistent in aquatic environments. This implies that OC will be present in aquatic environments in areas where oseltamivir is prescribed to patients for therapeutic use. The country where oseltamivir is used most is Japan, where it is used to treat seasonal flu. We measured the levels of OC in water samples from the Yodo River system in the Kyoto and Osaka prefectures, Japan, taken before and during the flu-season 2007/8. No OC was detected before the flu-season but 2-58 ng L(-1) was detected in the samples taken during the flu season. This study shows, for the first time, that low levels of oseltamivir can be found in the aquatic environment. Therefore the natural reservoir of influenza virus, dabbling ducks, is exposed to oseltamivir, which could promote the evolution of viral resistance.

Place, publisher, year, edition, pages
2009. Vol. 4, no 6, e6064- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-113800DOI: 10.1371/journal.pone.0006064ISI: 000267424600012PubMedID: 19557131OAI: oai:DiVA.org:uu-113800DiVA: diva2:291948
Available from: 2010-02-04 Created: 2010-02-04 Last updated: 2012-01-03Bibliographically approved
In thesis
1. Tamiflu® - Use It and Lose It?
Open this publication in new window or tab >>Tamiflu® - Use It and Lose It?
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Influenza A viruses cause seasonal and pandemic outbreaks that range from mild infections to the disastrous Spanish Flu. Resistance to neuraminidase inhibitors (NAIs) is a growing problem as these drugs constitute a vital part of treatment strategies and pandemic preparedness plans worldwide. Oseltamivir (Tamiflu®) is the mostly used NAI. Its active metabolite, oseltamivir carboxylate (OC), is excreted from treated patients and degrades poorly in sewage treatment plants and surface water. Thus, OC can enter aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance and resistance could develop. If NAI resistance is established in influenza viruses circulating among wild birds, the resistance can form part of a virus re-entering the human population either by reassortment or by direct transmission.

In this thesis, evidence is presented that OC is present in the waterways during a seasonal influenza outbreak in Japan, a country in which oseltamivir is liberally used. Furthermore, when mallards were infected with an influenza A/H1N1 virus and subjected to low, environmental-like concentrations of OC, resistance developed through acquisition of the well-known resistance mutation H274Y. The influenza infection in the mallards was mainly intestinal, had a rapid onset and was progressing in a longitudinal fashion in the intestine. Finally, influenza A viruses isolated from wild mallards in Sweden and containing resistance-related mutations were examined by a neuraminidase inhibition assay. The viruses did not have a decreased sensitivity to NAIs, but had mutations with a resistance-enhancing potential.

Thus, OC is present in the environment and environmental-like concentrations of OC induce resistance in influenza viruses of dabbling ducks. The present resistance situation among wild birds is not well understood but the existence of H274Y among wild birds, though rare, and the spread of the former seasonal A/H1N1 virus containing H274Y among humans indicate that resistance mutations could establish themselves also among wild birds. An oseltamivir-resistant pandemic or a human-adapted highly-pathogenic avian influenza virus are frightening scenarios as oseltamivir is a cornerstone in the defense in those situations. There is a need for further studies, surveillance in wild birds and for a prudent use of antivirals.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 725
Keyword
influenza, oseltamivir, Tamiflu, resistance development, H274Y, environment, pharmaceuticals, mallard, dabbling duck, avian influenza, influensa, resistensutveckling, miljö, läkemedel, gräsand
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:uu:diva-160974 (URN)978-91-554-8225-1 (ISBN)
Public defence
2011-12-17, Gustavianum, Auditorium minus, Akademigatan 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2011-11-25 Created: 2011-11-03 Last updated: 2012-02-29Bibliographically approved

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