Potential Risks Associated with the Proposed Widespread Use of Tamiflu

Background The threat of pandemic influenza has focused attention and resources on virus surveillance, prevention, and containment. The World Health Organization has strongly recommended the use of the antiviral drug Tamiflu both to treat and prevent pandemic influenza infection. A major concern for the long-term efficacy of this strategy is to limit the development of Tamiflu-resistant influenza strains. However, in the event of a pandemic, hundreds of millions of courses of Tamiflu, stockpiled globally, will be rapidly deployed. Given its apparent resistance to biodegradation and hydrophilicity, oseltamivir carboxylate (OC), the active antiviral and metabolite of Tamiflu, is predicted to enter receiving riverwater from sewage treatment works in its active form. Objective Our objective in this study was to determine the likely concentrations of OC released into U.S. and U.K. river catchments using hydrologic modeling and current assumptions about the course and management of an influenza pandemic. Discussion We predict that high concentrations of OC (micrograms per liter) capable of inhibiting influenza virus replication would be sustained for periods of several weeks, presenting an increased risk for the generation of antiviral resistance and genetic exchange between influenza viruses in wildfowl. Owing to the apparent recalcitrance of OC in sewage treatment works, widespread use of Tamiflu during an influenza pandemic also poses a potentially significant, uncharacterized, ecotoxicologic risk in each affected nation’s waterways. Conclusion To gauge the hazard presented by Tamiflu use during a pandemic, we recommend a) direct measurement of Tamiflu persistence, biodegradation, and transformation in the environment; b) further modeling of likely drug concentrations in the catchments of countries where humans and waterfowl come into frequent close contact, and where significant Tamiflu deployment is envisaged; and c) further characterization of the risks of generating Tamiflu-resistant viruses in OC-exposed wildfowl.

[1]  G. Air,et al.  The neuraminidase of influenza virus , 1989, Proteins.

[2]  N. Chirgadze,et al.  A single sequence change destabilizes the influenza virus neuraminidase tetramer. , 1997, Virology.

[3]  F. Soriano,et al.  In-vitro antimicrobial activity of HMR 3004 (RU 64004) against erythromycin A-sensitive and -resistant Corynebacterium spp. isolated from clinical specimens. , 1998, The Journal of antimicrobial chemotherapy.

[4]  A. J. Hall.  Infectious diseases of humans: R. M. Anderson & R. M. May. Oxford etc.: Oxford University Press, 1991. viii + 757 pp. Price £50. ISBN 0-19-854599-1 , 1992 .

[5]  C Revillard,et al.  [Clinical pharmacokinetics]. , 1976, Schweizerische medizinische Wochenschrift.

[6]  K. Thomas,et al.  Investigating the environmental transport of human pharmaceuticals to streams in the United Kingdom. , 2004, The Science of the total environment.

[7]  Lynda B. M. Ellis,et al.  Encoding microbial metabolic logic: predicting biodegradation , 2004, Journal of Industrial Microbiology & Biotechnology.

[8]  R. Sidwell,et al.  Oral Administration of a Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 Protects Mice and Ferrets against Influenza Infection , 1998, Antimicrobial Agents and Chemotherapy.

[9]  Hideo Goto,et al.  Avian flu: Isolation of drug-resistant H5N1 virus , 2005, Nature.

[10]  F. Hayden,et al.  Neuraminidase Sequence Analysis and Susceptibilities of Influenza Virus Clinical Isolates to Zanamivir and Oseltamivir , 2003, Antimicrobial Agents and Chemotherapy.

[11]  D. Cummings,et al.  Strategies for mitigating an influenza pandemic , 2006, Nature.

[12]  Norbert Bischofberger,et al.  Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071 , 1998, Antimicrobial Agents and Chemotherapy.

[13]  B. Lina,et al.  Sensitivity of influenza viruses to zanamivir and oseltamivir: a study performed on viruses circulating in France prior to the introduction of neuraminidase inhibitors in clinical practice. , 2005, Antiviral research.

[14]  Peter Shanahan,et al.  Screening analysis of human pharmaceutical compounds in U.S. surface waters. , 2004, Environmental science & technology.

[15]  P. Ward,et al.  Clinical Pharmacokinetics of the Prodrug Oseltamivir and its Active Metabolite Ro 64-0802 , 1999, Clinical pharmacokinetics.

[16]  P. Kaye.  Infectious diseases of humans: Dynamics and control , 1993 .

[17]  R. Stevens,et al.  Influenza Neuraminidase Inhibitors Possessing a Novel Hydrophobic Interaction in the Enzyme Active Site: Design, Synthesis, and Structural Analysis of Carbocyclic Sialic Acid Analogues with Potent Antiinfluenza Activity. , 1997 .

[18]  I. Bracken,et al.  The Generation of Spatial Population Distributions from Census Centroid Data , 1989, Environment & planning A.

[19]  A. Gustard,et al.  A new approach to estimating Mean Flow in the UK , 2002 .

[20]  R. Sidwell,et al.  Influenza virus resistance to neuraminidase inhibitors. , 1998, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[21]  W. Lew,et al.  Metabolism of the influenza neuraminidase inhibitor prodrug oseltamivir in the rat. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[22]  R. Williams,et al.  A practical demonstration in modelling diclofenac and propranolol river water concentrations using a GIS hydrology model in a rural UK catchment. , 2007, Environmental pollution.

[23]  R. Compans,et al.  Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA): mechanism of action. , 1976, The Journal of general virology.

[24]  D. Moravec.  The American Hospital Formulary Service. , 1958, Hospital management.

[25]  Charles J. Russell,et al.  The Genesis of a Pandemic Influenza Virus , 2005, Cell.

[26]  D J Alexander,et al.  A review of avian influenza in different bird species. , 2000, Veterinary microbiology.

[27]  R A Ford,et al.  Estimation of toxic hazard--a decision tree approach. , 1978, Food and cosmetics toxicology.

[28]  A R Young,et al.  Low Flows 2000: a national water resources assessment and decision support tool. , 2003, Water science and technology : a journal of the International Association on Water Pollution Research.

[29]  M. Hughes.  Regulation of salt gland, gut and kidney interactions. , 2003, Comparative biochemistry and physiology. Part A, Molecular & integrative physiology.

[30]  W G Laver,et al.  Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. , 1997, Journal of the American Chemical Society.

[31]  W. J. Bean,et al.  Intestinal influenza: Replication and characterization of influenza viruses in ducks , 1978, Virology.

[32]  D. Bennett,et al.  Retrograde movement of urine into the gut of salt water acclimated Mallards (Anas platyrhynchos) , 1999 .

[33]  G. Air,et al.  Three‐dimensional structure of neuraminidase of subtype N9 from an avian influenza virus , 1987, Proteins.

[34]  D. M. Ryan,et al.  Rational design of potent sialidase-based inhibitors of influenza virus replication , 1993, Nature.

[35]  D. Normile.  Wild Birds Only Partly to Blame in Spreading H5N1 , 2006, Science.

[36]  K. Thomasb,et al.  Investigating the environmental transport of human pharmaceuticals to streams in the United Kingdom , 2004 .

[37]  M. Hughes,et al.  Total body water volume and turnover rate in fresh water and sea water adapted glaucous-winged gulls, Larus glaucescens , 1978 .

[38]  I. Barr,et al.  Susceptibility of human influenza viruses from Australasia and South East Asia to the neuraminidase inhibitors zanamivir and oseltamivir. , 2004, Antiviral research.

[39]  Yi Guan,et al.  Oseltamivir resistance during treatment of influenza A (H5N1) infection. , 2005, The New England journal of medicine.