Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards

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

Production of η mesons in 200 AGeV/cS+S and S+Au reactions

Minimum Bias production cross sections of $\eta$ mesons have been measured in 200AGeV S+Au and S+S collisions at the CERN SPS by reconstructing the $\eta\rightarrow\gamma\gamma$ decay. The measurements have been made over the rapidity range $2.1 \leq y \leq 2.9$ using the leadglass spectrometer of WA80. Within the statistical and systematical uncertainties the spectral shapes of $\pi~0$ and $\eta$ mesons yields are identical when their invariant differential cross section is plotted as a function of the transverse mass. The relative normalization of the $\eta$ to $\pi~0$ transverse mass spectra is found to be $0.53 \pm 0.07$ for S+Au and $0.43 \pm 0.15$ for S+S reactions. Extrapolation to full phase space leads to an integrated cross section ratio of $\eta$ to $\pi~0$ mesons of $0.15 \pm 0.02 {\rm (stat.)} \pm 0.02 {\rm (syst.)}$, and $0.12 \pm 0.03 {\rm (stat.)} \pm 0.02 {\rm (syst.)}$ for S+Au and S+S collisions, respectively.Minimum Bias production cross sections of $\eta$ mesons have been measured in 200AGeV S+Au and S+S collisions at the CERN SPS by reconstructing the $\eta\rightarrow\gamma\gamma$ decay. The measurements have been made over the rapidity range $2.1 \leq y \leq 2.9$ using the leadglass spectrometer of WA80. Within the statistical and systematical uncertainties the spectral shapes of $\pi~0$ and $\eta$ mesons yields are identical when their invariant differential cross section is plotted as a function of the transverse mass. The relative normalization of the $\eta$ to $\pi~0$ transverse mass spectra is found to be $0.53 \pm 0.07$ for S+Au and $0.43 \pm 0.15$ for S+S reactions. Extrapolation to full phase space leads to an integrated cross section ratio of $\eta$ to $\pi~0$ mesons of $0.15 \pm 0.02 {\rm (stat.)} \pm 0.02 {\rm (syst.)}$, and $0.12 \pm 0.03 {\rm (stat.)} \pm 0.02 {\rm (syst.)}$ for S+Au and S+S collisions, respectively.Minimum Bias production cross sections of $\eta$ mesons have been measured in 200AGeV S+Au and S+S collisions at the CERN SPS by reconstructing the $\eta\rightarrow\gamma\gamma$ decay. The measurements have been made over the rapidity range $2.1 \leq y \leq 2.9$ using the leadglass spectrometer of WA80. Within the statistical and systematical uncertainties the spectral shapes of $\pi~0$ and $\eta$ mesons yields are identical when their invariant differential cross section is plotted as a function of the transverse mass. The relative normalization of the $\eta$ to $\pi~0$ transverse mass spectra is found to be $0.53 \pm 0.07$ for S+Au and $0.43 \pm 0.15$ for S+S reactions. Extrapolation to full phase space leads to an integrated cross section ratio of $\eta$ to $\pi~0$ mesons of $0.15 \pm 0.02 {\rm (stat.)} \pm 0.02 {\rm (syst.)}$, and $0.12 \pm 0.03 {\rm (stat.)} \pm 0.02 {\rm (syst.)}$ for S+Au and S+S collisions, respectively.Minimum Bias production cross sections of $\eta$ mesons have been measured in 200AGeV S+Au and S+S collisions at the CERN SPS by reconstructing the $\eta\rightarrow\gamma\gamma$ decay. The measurements have been made over the rapidity range $2.1 \leq y \leq 2.9$ using the leadglass spectrometer of WA80. Within the statistical and systematical uncertainties the spectral shapes of $\pi~0$ and $\eta$ mesons yields are identical when their invariant differential cross section is plotted as a function of the transverse mass. The relative normalization of the $\eta$ to $\pi~0$ transverse mass spectra is found to be $0.53 \pm 0.07$ for S+Au and $0.43 \pm 0.15$ for S+S reactions. Extrapolation to full phase space leads to an integrated cross section ratio of $\eta$ to $\pi~0$ mesons of $0.15 \pm 0.02 {\rm (stat.)} \pm 0.02 {\rm (syst.)}$, and $0.12 \pm 0.03 {\rm (stat.)} \pm 0.02 {\rm (syst.)}$ for S+Au and S+S collisions, respectively.Minimum Bias production cross sections of $\eta$ mesons have been measured in 200AGeV S+Au and S+S collisions at the CERN SPS by reconstructing the $\eta\rightarrow\gamma\gamma$ decay. The measurements have been made over the rapidity range $2.1 \leq y \leq 2.9$ using the leadglass spectrometer of WA80. Within the statistical and systematical uncertainties the spectral shapes of $\pi~0$ and $\eta$ mesons yields are identical when their invariant differential cross section is plotted as a function of the transverse mass. The relative normalization of the $\eta$ to $\pi~0$ transverse mass spectra is found to be $0.53 \pm 0.07$ for S+Au and $0.43 \pm 0.15$ for S+S reactions. Extrapolation to full phase space leads to an integrated cross section ratio of $\eta$ to $\pi~0$ mesons of $0.15 \pm 0.02 {\rm (stat.)} \pm 0.02 {\rm (syst.)}$, and $0.12 \pm 0.03 {\rm (stat.)} \pm 0.02 {\rm (syst.)}$ for S+Au and S+S collisions, respectively.Minimum Bias production cross sections of η mesons have been measured in 200 A GeV/ c S+Au and S+S collisions at the CERN SPS by reconstructing the η → γγ decay. The measurements have been made over the rapidity range 2.1 ≤ y ≤ 2.9 using the leadglass spectrometer of WA80. Within the statistical and systematical uncertainties the spectral shapes of π 0 and η mesons yields are identical when their invariant differential cross section is plotted as a function of the transverse mass. The relative normaliz