Neuraminidase inhibitors (NAIs) are the gold standard treatment for influenza A virus (IAV). Oseltamivir is mostly used, followed by zanamivir (ZA). NAIs are not readily degraded in conventional wastewater treatment plants and can be detected in aquatic environments. Waterfowl are natural IAV hosts and replicating IAVs could thus be exposed to NAIs in the environment and develop resistance. Avian IAVs form the genetic basis for new human IAVs, and a resistant IAV with pandemic potential poses a serious public health threat, as NAIs constitute a pandemic preparedness cornerstone. Resistance development in waterfowl IAVs exposed to NAIs in the water environment has previously been investigated in an in vivo mallard model and resistance development was demonstrated in several avian IAVs after the exposure of infected ducks to oseltamivir, and in an H1N1 IAV after exposure to ZA. The N1 and N2 types of IAVs have different characteristics and resistance mutations, and so the present study investigated the exposure of an N2-type IAV (H4N2) in infected mallards to 1, 10 and 100 µg l−1 of ZA in the water environment. Two neuraminidase substitutions emerged, H274N (ZA IC50 increased 5.5-fold) and E119G (ZA IC50 increased 110-fold) at 10 and 100 µg l−1 of ZA, respectively. Reversion towards wild-type was observed for both substitutions in experiments with removed drug pressure, indicating reduced fitness of both resistant viruses. These results corroborate previous findings that the development of resistance to ZA in the environment seems less likely to occur than the development of resistance to oseltamivir, adding information that is useful in planning for prudent drug use and pandemic preparedness.

中文翻译：

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流感A / H4N2野鸭感染实验进一步表明扎那米韦比oseltamivir更不容易引起环境抗药性的发展。

神经氨酸酶抑制剂（NAIs）是A型流感病毒（IAV）的金标准治疗方法。多数使用Oseltamivir，其次是zanamivir（ZA）。NAI在常规废水处理厂中不易降解，可以在水生环境中检测到。水禽是天然的IAV宿主，因此复制的IAV可能会暴露于环境中的NAI中并产生抵抗力。禽类IAV构成了新人类IAV的遗传基础，而具有大流行潜力的抗性IAV构成了严重的公共卫生威胁，因为NAI构成了大流行防范的基石。先前已经在体内研究了暴露于水环境中NAI的水禽IAV的抗药性在被感染的鸭暴露于奥司他韦后，在几只禽类IAV中以及在暴露于ZA后的H1N1 IAV中，证明了野鸭模型和耐药性的发展。N1和N2型IAV具有不同的特性和抗药性突变，因此，本研究调查了水环境中感染的野鸭中N2型IAV（H4N2）暴露于ZA的1、10和100μgl -1的情况。出现了两个神经氨酸酶替代，分别为10和100 µg l -1的H274N（ZA IC 50升高5.5倍）和E119G（ZA IC 50升高110倍）。ZA。在去除药物压力的实验中，两个替代都观察到了向野生型的回复，表明两种抗性病毒的适应性降低。这些结果证实了先前的发现，即与对奥司他韦的抗药性相比，在环境中对ZA的抗药性似乎不太可能发生，从而增加了对谨慎使用药物和大流行病防范计划的有用信息。