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Abstract

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 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 of ZA in the water environment. Two neuraminidase substitutions emerged, H274N (ZA IC increased 5.5-fold) and E119G (ZA IC increased 110-fold) at 10 and 100 µg l 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.

Funding
This study was supported by the:
  • Vetenskapsrådet (Award 2016-02606)
    • Principle Award Recipient: Josef D. Järhult
  • Svenska Forskningsrådet Formas (Award 2016-00790)
    • Principle Award Recipient: Josef D. Järhult
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2019-12-19
2024-03-29
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References

  1. Olsen B, Munster VJ, Wallensten A, Waldenström J, Osterhaus ADME et al. Global patterns of influenza A virus in wild birds. Science 2006; 312:384–388 [View Article][PubMed]
    [Google Scholar]
  2. Webster RG, Monto AS, Braciale TJ, Lamb RA. Textbook of Influenza John Wiley & Sons; 2014 p 697 p
    [Google Scholar]
  3. Kuiken T. Is low pathogenic avian influenza virus virulent for wild waterbirds?. Proc R Soc B Biol Sci 2013; 280:20130990 [View Article]
    [Google Scholar]
  4. Daoust P-Y, Kibenge FSB, Fouchier RAM, van de Bildt MWG, van Riel D et al. Replication of low pathogenic avian influenza virus in naturally infected mallard ducks (Anas platyrhynchos) causes no morphologic lesions. J Wildl Dis 2011; 47:401–409 [View Article]
    [Google Scholar]
  5. Gubareva LV, Besselaar TG, Daniels RS, Fry A, Gregory V et al. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2015–2016. Antiviral Res 2017; 146:12–20 [View Article]
    [Google Scholar]
  6. Air GM. Influenza neuraminidase. Influenza Other Respi Viruses 2012; 6:245–256 [View Article]
    [Google Scholar]
  7. ALW P, Farndon P, Palmer N. Maximizing the value of drug stockpiles for pandemic influenza. Emerg Infect Dis 2009; 15:1686–1687
    [Google Scholar]
  8. A Study of Intravenous Zanamivir in the Treatment of Hospitalized Patients With Influenza Infection - Full Text View - ClinicalTrials.gov; 2019 https://clinicaltrials.gov/ct2/show/NCT01527110
  9. A Study of Intravenous Zanamivir Versus Oral Oseltamivir in Adults and Adolescents Hospitalized With Influenza - Full Text View - ClinicalTrials.gov; 2019 https://clinicaltrials.gov/ct2/show/NCT01231620
  10. Fick J, Lindberg RH, Tysklind M, Haemig PD, Waldenström J et al. Antiviral oseltamivir is not removed or degraded in normal sewage water treatment: implications for development of resistance by influenza A virus. PLoS One 2007; 2:e986 [View Article]
    [Google Scholar]
  11. Takanami R, Ozaki H, Giri RR, Taniguchi S, Hayashi S. Detection of antiviral drugs oseltamivir phosphate and oseltamivir carboxylate in Neya river, Osaka, Japan. J Water Environ Technol 2010; 8:363–372 [View Article]
    [Google Scholar]
  12. Takanami R, Ozaki H, Giri RR, Taniguchi S, Hayashi S. Antiviral drugs zanamivir and oseltamivir found in wastewater and surface water in Osaka, Japan. J of Wat & Envir Tech 2012; 10:57–68 [View Article]
    [Google Scholar]
  13. Järhult JD, Muradrasoli S, Wahlgren J, Söderström H, Orozovic G et al. Environmental levels of the antiviral oseltamivir induce development of resistance mutation H274Y in influenza A/H1N1 virus in mallards. PLoS One 2011; 6:e24742 [View Article]
    [Google Scholar]
  14. Gillman A, Muradrasoli S, Söderström H, Nordh J, Bröjer C et al. Resistance Mutation R292K Is Induced in Influenza A(H6N2) Virus by Exposure of Infected Mallards to Low Levels of Oseltamivir. PLoS One 2013; 8:e71230 [View Article]
    [Google Scholar]
  15. Gillman A, Nykvist M, Muradrasoli S, Söderström H, Wille M et al. Influenza A(H7N9) virus acquires resistance-related neuraminidase I222T substitution when infected mallards are exposed to low levels of oseltamivir in water. Antimicrob Agents Chemother 2015; 59:5196–5202 [View Article]
    [Google Scholar]
  16. Achenbach JE, Bowen RA. Effect of oseltamivir carboxylate consumption on emergence of drug-resistant H5N2 avian influenza virus in mallard ducks. Antimicrob Agents Chemother 2013; 57:2171–2181 [View Article]
    [Google Scholar]
  17. Nykvist M, Gillman A, Söderström Lindström H, Tang C, Fedorova G et al. In vivo mallard experiments indicate that zanamivir has less potential for environmental influenza A virus resistance development than oseltamivir. J Gen Virol 2017; 98:2937–2949 [View Article]
    [Google Scholar]
  18. Russell RJ, Haire LF, Stevens DJ, Collins PJ, Lin YP et al. The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature 2006; 443:45–49 [View Article]
    [Google Scholar]
  19. Gillman A, Muradrasoli S, Söderström H, Holmberg F, Latorre-Margalef N et al. Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards. In Drake HL. editor Appl Environ Microbiol 81 2015 pp 2378–2383 [View Article]
    [Google Scholar]
  20. Gillman A, Muradrasoli S, Mårdnäs A, Söderström H, Fedorova G et al. Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure. PLoS One 2015; 10:e0139415 [View Article]
    [Google Scholar]
  21. Kapczynski DR, Kogut MH. Measurement of Avian Cytokines with Real-Time RT-PCR Following Infection with the Avian Influenza Virus. In Spackman E. editor Avian Influenza Virus Totowa, NJ: Humana Press; 2008
    [Google Scholar]
  22. Sheu TG, Deyde VM, Okomo-Adhiambo M, Garten RJ, Xu X et al. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother 2008; 52:3284–3292 [View Article]
    [Google Scholar]
  23. Wang MZ, Tai CY, Mendel DB. Mechanism by which mutations at His274 alter sensitivity of influenza A virus N1 neuraminidase to oseltamivir carboxylate and zanamivir. Antimicrob Agents Chemother 2002; 46:3809–3816 [View Article]
    [Google Scholar]
  24. Mishin VP, Hayden FG, Gubareva LV. Susceptibilities of Antiviral-Resistant influenza viruses to novel neuraminidase inhibitors. Antimicrob Agents Chemother 2005; 49:4515–4520 [View Article]
    [Google Scholar]
  25. Gubareva LV, Robinson MJ, Bethell RC, Webster RG. Catalytic and framework mutations in the neuraminidase active site of Influenza viruses that are resistant to 4-Guanidino-Neu5Ac2en. J Virol 1997; 71:6
    [Google Scholar]
  26. Hurt AC, Holien JK, Barr IG. In Vitro Generation of Neuraminidase Inhibitor Resistance in A(H5N1) Influenza Viruses. Antimicrob Agents Chemother 2009; 53:4433–4440 [View Article]
    [Google Scholar]
  27. Tamura D, DeBiasi RL, Okomo-Adhiambo M, Mishin VP, Campbell AP et al. Emergence of multidrug-resistant influenza A(H1N1)pdm09 virus variants in an immunocompromised child treated with oseltamivir and zanamivir. J Infect Dis 2015; 212:1209–1213 [View Article][PubMed]
    [Google Scholar]
  28. Baek YH, Song MS, Lee EY, Kim Y, Kim EH et al. Profiling and characterization of influenza virus N1 strains potentially resistant to multiple neuraminidase inhibitors. J Virol 2015; 89:287–299 [View Article][PubMed]
    [Google Scholar]
  29. Blick TJ, Tiong TAK, Sahasrabudhe A, Varghese JN, Colman PM et al. Generation and characterization of an influenza virus neuraminidase variant with decreased sensitivity to the neuraminidase-specific inhibitor 4-Guanidino-Neu5Ac2en. Virology 1995; 214:475–484 [View Article]
    [Google Scholar]
  30. Zürcher T, Yates PJ, Daly J, Sahasrabudhe A, Walters M et al. Mutations conferring zanamivir resistance in human influenza virus N2 neuraminidases compromise virus fitness and are not stably maintained in vitro. J Antimicrob Chemother 2006; 58:723–732 [View Article][PubMed]
    [Google Scholar]
  31. Kiso M, Mitamura K, Sakai-Tagawa Y, Shiraishi K, Kawakami C et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. The Lancet 2004; 364:759–765 [View Article]
    [Google Scholar]
  32. Baz M, Abed Y, McDonald J, Boivin G. Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an immunocompromised child. Clin Infect Dis 2006; 43:1555–1561 [View Article][PubMed]
    [Google Scholar]
  33. Gubareva LV, Bethell R, Hart GJ, Murti KG, Penn CR et al. Characterization of mutants of Influenza A virus selected with the neuraminidase inhibitor 4-Guanidino-Neu5Ac2en. J Virol 10:
    [Google Scholar]
  34. L’Huillier AG, Abed Y, Petty TJ, Cordey S, Thomas Y et al. E119D Neuraminidase Mutation Conferring Pan-Resistance to Neuraminidase Inhibitors in an A(H1N1)pdm09 Isolate From a Stem-Cell Transplant Recipient. J Infect Dis 2015; Dec 1;212:1726–1734
    [Google Scholar]
  35. Yates PJ, Raimonde DS, Zhao HH, Man CY, Steel HM et al. Phenotypic and genotypic analysis of influenza viruses isolated from adult subjects during a phase II study of intravenous zanamivir in hospitalised subjects. Antiviral Res 2016; 134:144–152 [View Article]
    [Google Scholar]
  36. Bradley JS, Blumer JL, Romero JR, Michaels MG, Munoz FM et al. Intravenous zanamivir in hospitalized patients with influenza. Pediatrics 2017; 140:e20162727 [View Article]
    [Google Scholar]
  37. Govorkova EA, Ilyushina NA, Marathe BM, McClaren JL, Webster RG. Competitive fitness of Oseltamivir-Sensitive and -resistant highly pathogenic H5N1 influenza viruses in a ferret model. J Virol 2010; 84:8042–8050 [View Article]
    [Google Scholar]
  38. Yen HL, Ilyushina NA, Salomon R, Hoffmann E, Webster RG et al. Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo . J Virol 2007; 81:12418–12426 [View Article]
    [Google Scholar]
  39. Staschke KA, Colacino JM, Baxter AJ, Air GM, Bansal A et al. Molecular basis for the resistance of influenza viruses to 4-Guanidino-Neu5Ac2en. Virology 1995; 214:642–646 [View Article]
    [Google Scholar]
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