The concentration of eleven antibiotics (trimethoprim, oxytetracycline, ciprofloxacin, azithromycin, cefotaxime, doxycycline, sulfamethoxazole, erythromycin, clarithromycin, ofloxacin, norfloxacin), three decongestants (naphazoline, oxymetazoline, xylometazoline) and the antiviral drug oseltamivir's active metabolite, oseltamivir carboxylate (OC), were measured weekly at 21 locations within the River Thames catchment in England during the month of November 2009, the autumnal peak of the influenza A[H1N1]pdm09 pandemic. The aim was to quantify the pharmaceutical response to the pandemic and compare this to drug use during the late pandemic (March 2010) and the inter-pandemic periods (May 2011). A large and small wastewater treatment plant (WWTP) were sampled in November 2009 to understand the differential fate of the analytes in the two WWTPs prior to their entry in the receiving river and to estimate drug users using a wastewater epidemiology approach. Mean hourly OC concentrations in the small and large WWTP's influent were 208 and 350 ng/L (max, 2070 and 550 ng/L, respectively). Erythromycin was the most concentrated antibiotic measured in Benson and Oxford WWTPs influent (max=6,870 and 2,930 ng/L, respectively). Napthazoline and oxymetazoline were the most frequently detected and concentrated decongestant in the Benson WWTP influent (1650 and 67 ng/L) and effluent (696 and 307 ng/L), respectively, but were below detection in the Oxford WWTP. OC was found in 73% of November 2009's weekly river samples (max=193 ng/L), but only in 5% and 0% of the late- and inter-pandemic river samples, respectively. The mean river concentration of each antibiotic during the pandemic largely fell between 17-74 ng/L, with clarithromycin (max=292 ng/L) and erythromycin (max=448 ng/L) yielding the highest single measure. In general, the concentration and frequency of detecting antibiotics in the river increased during the pandemic. OC was uniquely well-suited for the wastewater epidemiology approach owing to its nature as a prodrug, recalcitrance and temporally- and spatially-resolved prescription statistics.

Department of Chemistry Umeå University Umeå Sweden

Department of Chemistry Umeå University Umeå Sweden; University of South Bohemia in Ceske Budejovice Faculty of Fisheries and Protection of Waters South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses Vodnany Czech Republic

Natural Environment Research Council Centre for Ecology and Hydrology Wallingford United Kingdom

Section of Infectious Diseases Department of Medical Sciences Uppsala University Uppsala Sweden

Section of Infectious Diseases Department of Medical Sciences Uppsala University Uppsala Sweden; Section for Zoonotic Ecology and Epidemiology School of Natural Sciences Linnaeus University Kalmar Sweden

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Azuma T, Nakada N, Yamashita N, Tanaka H (2013) Mass balance of anti-influenza drugs discharged into the Yodo River system, Japan, under an influenza outbreak. Chemosphere 93: 1672–1677. PubMed

Singer AC, Colizza V, Schmitt H, Andrews J, Balcan D, et al. (2011) Assessing the ecotoxicologic hazards of a pandemic influenza medical response. Environ Health Perspect 119: 1084–1090. PubMed PMC

Chang CC, Cheng AC, Chang AB (2014) Over-the-counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults. Cochrane Database Syst Rev 3: CD006088. PubMed PMC

Dollery C (1999) Therapeutic Drugs. London: Harcourt Brace and Company Limited.

Knox C, Law V, Jewison T, Liu P, Ly S, et al. (2011) DrugBank 3.0: a comprehensive resource for ‘omics’ research on drugs. Nucleic Acids Res 39: D1035–1041. PubMed PMC

Edlund A, Ek K, Breitholtz M, Gorokhova E (2012) Antibiotic-induced change of bacterial communities associated with the copepod Nitocra spinipes. PLoS One 7: e33107. PubMed PMC

Singer AC, Nunn MA, Gould EA, Johnson AC (2007) Potential risks associated with the proposed widespread use of Tamiflu. Environmental Health Perspectives 115: 102–106. PubMed PMC

Escher BI, Bramaz N, Lienert J, Neuwoehner J, Straub JO (2010) Mixture toxicity of the antiviral drug Tamiflu) (oseltamivir ethylester) and its active metabolite oseltamivir acid. Aquat Toxicol 96: 194–202. PubMed

Straub JO (2009) An environmental risk assessment for oseltamivir (Tamiflu) for sewage works and surface waters under seasonal-influenza- and pandemic-use conditions. Ecotoxicol Environ Saf 72: 1625–1634. PubMed

Hutchinson TH, Beesley A, Frickers PE, Readman JW, Shaw JP, et al. (2009) Extending the environmental risk assessment for oseltamivir (Tamiflu) under pandemic use conditions to the coastal marine compartment. Environ Int 35: 931–936. PubMed

Chen WY, Lin CJ, Liao CM (2014) Assessing exposure risks for aquatic organisms posed by Tamiflu use under seasonal influenza and pandemic conditions. Environ Pollut 184: 377–384. PubMed

Sacca ML, Accinelli C, Fick J, Lindberg R, Olsen B (2009) Environmental fate of the antiviral drug Tamiflu in two aquatic ecosystems. Chemosphere 75: 28–33. PubMed

Slater FR, Singer AC, Turner S, Barr JJ, Bond PL (2011) Pandemic pharmaceutical dosing effects on wastewater treatment: no adaptation of activated sludge bacteria to degrade the antiviral drug oseltamivir (Tamiflu) and loss of nutrient removal performance. FEMS Microbiol Lett 315: 17–22. PubMed

Singer AC, Howard BM, Johnson AC, Knowles CJ, Jackman S, et al. (2008) Meeting report: risk assessment of tamiflu use under pandemic conditions. Environ Health Perspect 116: 1563–1567. PubMed PMC

Achenbach JE, Bowen RA (2013) Effect of oseltamivir carboxylate consumption on emergence of drug-resistant H5N2 avian influenza virus in Mallard ducks. Antimicrob Agents Chemother 57: 2171–2181. PubMed PMC

Jarhult JD (2012) Oseltamivir (Tamiflu) in the environment, resistance development in influenza A viruses of dabbling ducks and the risk of transmission of an oseltamivir-resistant virus to humans - a review. Infect Ecol Epidemiol 2. PubMed PMC

Gillman A, Muradrasoli S, Söderström H, Nordh J, Bröjer C, et al. (2013) Resistance Mutation R292K Is Induced in Influenza A(H6N2) Virus by Exposure of Infected Mallards to Low Levels of Oseltamivir. PLoS ONE 8: e71230. PubMed PMC

Jarhult JD, Muradrasoli S, Wahlgren J, Soderstrom H, Orozovic G, et al. (2011) Environmental levels of the antiviral oseltamivir induce development of resistance mutation H274Y in influenza A/H1N1 virus in mallards. PLoS One 6: e24742. PubMed PMC

Wellington EM, Boxall AB, Cross P, Feil EJ, Gaze WH, et al. (2013) The role of the natural environment in the emergence of antibiotic resistance in gram-negative bacteria. Lancet Infect Dis 13: 155–165. PubMed

Gaze WH, Krone SM, Larsson DG, Li XZ, Robinson JA, et al.. (2013) Influence of humans on evolution and mobilization of environmental antibiotic resistome. Emerg Infect Dis 19. PubMed PMC

World Health Organization (2010) WHO recommendations for the post-pandemic period: Pandemic (H1N1) 2009 briefing note 23. Available: http://www.who.int/csr/disease/swineflu/notes/briefing_20100810/en/. Accessed 2012 Jun 1.

Bowes MJ, Jarvie HP, Naden PS, Old GH, Scarlett PM, et al. (2014) Identifying priorities for nutrient mitigation using river concentration–flow relationships: The Thames basin, UK. Journal of Hydrology 517: 1–12.

Harvey CL, Dixon H, Hannaford J (2012) An appraisal of the performance of data-infilling methods for application to daily mean river flow records in the UK. Hydrology Research 43: 618–636.

TuTiempo.net (2009) Climate: Benson (November, 2009). Available: http://www.tutiempo.net/en/Climate/Benson/11-2009/36580.htm. Accessed 2012 Oct 26.

Prasse C, Schlusener MP, Schulz R, Ternes TA (2010) Antiviral drugs in wastewater and surface waters: a new pharmaceutical class of environmental relevance? Environ Sci Technol 44: 1728–1735. PubMed

Balcan D, Colizza V, Singer AC, Chouaid C, Hu H, et al. (2009) Modeling the critical care demand and antibiotics resources needed during the Fall 2009 wave of influenza A(H1N1) pandemic. PLoS Curr 1: RRN1133. PubMed PMC

Khan GA, Lindberg R, Grabic R, Fick J (2012) The development and application of a system for simultaneously determining anti-infectives and nasal decongestants using on-line solid-phase extraction and liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal 66: 24–32. PubMed

NHS BSA (2011) Prescribing Analysis Charts: National Antibiotics Charts. Available: http://www.nhsbsa.nhs.uk/PrescriptionServices/2587.aspx. Accessed 2012 Oct.

NHS Information Centre for Health and Social Care (2011) Number of GP Prescriptions by drug by postcode. Available: http://data.gov.uk/apps/number-of-gp-prescriptions-by-drug-by-postcode.

Health Protection Agency (2010) Epidemiological report of pandemic (H1N1) 2009 in the UK (April 2009 - May 2010). Available: http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1284475321350. Accessed 2012 Jun 1.

Rogers S, Sedghi A (2011) Swine flu data in the UK: see how bad cases are where you live. Guardian Available: http://www.guardian.co.uk/news/datablog/2011/jan/06/swine-flu-data-uk#data. Accessed 2012 Jun 1.

The Health and Social Care Information Centre PSU (2012) Average Daily Quantities. Available: http://www.ic.nhs.uk/services/prescribing-support-unit-psu/using-the-service/reference/measures/volume-measures/average-daily-quantities-adq. Accessed 2012 Oct 19.

Davey P, Ferech M, Ansari F, Muller A, Goossens H (2008) Outpatient antibiotic use in the four administrations of the UK: cross-sectional and longitudinal analysis. Journal of Antimicrobial Chemotherapy 62: 1441–1447. PubMed

Singer AC, Jarhult JD, Grabic R, Khan GA, Fedorova G, et al. (2013) Compliance to oseltamivir among two populations in Oxfordshire, United Kingdom affected by influenza A(H1N1) pdm09, November 2009–a waste water epidemiology study. PLoS One 8: e60221. PubMed PMC

Azuma T, Nakada N, Yamashita N, Tanaka H (2012) Synchronous dynamics of observed and predicted values of anti-influenza drugs in environmental waters during a seasonal influenza outbreak. Environ Sci Technol 46: 12873–12881. PubMed

Takanami R, Ozaki H, Giri RR, Taniguchi S, Hayashi S (2012) Antiviral Drugs Zanamivir and Oseltamivir Found in Wastewater and Surface Water in Osaka, Japan. Journal of Water and Environment Technology 10: 57–68.

Leknes H, Sturtzel IE, Dye C (2012) Environmental release of oseltamivir from a Norwegian sewage treatment plant during the 2009 influenza A (H1N1) pandemic. Sci Total Environ 414: 632–638. PubMed

Ghosh GC, Nakada N, Yamashita N, Tanaka H (2010) Occurrence and fate of oseltamivir carboxylate (Tamiflu) and amantadine in sewage treatment plants. Chemosphere 81: 13–17. PubMed

Ghosh GC, Nakada N, Yamashita N, Tanaka H (2010) Oseltamivir carboxylate, the active metabolite of oseltamivir phosphate (Tamiflu), detected in sewage discharge and river water in Japan. Environ Health Perspect 118: 103–107. PubMed PMC

Fick J, Lindberg RH, Tysklind M, Haemig PD, Waldenstrom J, et al. (2007) Antiviral oseltamivir is not removed or degraded in normal sewage water treatment: implications for development of resistance by influenza A virus. PLoS One 2: e986. PubMed PMC

Takanami R, Ozaki H, Giri RR, Taniguchi S, Hayashi S (2010) Detection of antiviral drugs oseltamivir phosphate and oseltamivir carboxylate in Neya River, Osaka Japan. Journal of Water and Environment Technology 8: 363–372.

Kohring GW, Rogers JE, Wiegel J (1989) Anaerobic biodegradation of 2,4-dichlorophenol in freshwater lake sediments at different temperatures. Applied and Environmental Microbiology 55: 348–353. PubMed PMC

Atlas RM (1975) Effects of Temperature and Crude Oil Composition on Petroleum Biodegradation. Applied Microbiology 30: 396–403. PubMed PMC

Michael I, Rizzo L, McArdell CS, Manaia CM, Merlin C, et al. (2013) Urban wastewater treatment plants as hotspots for the release of antibiotics in the environment: a review. Water Res 47: 957–995. PubMed

Luo Y, Guo W, Ngo HH, Nghiem LD, Hai FI, et al. (2014) A review on the occurrence of micropollutants in the aquatic environment and their fate and removal during wastewater treatment. Sci Total Environ 473–474: 619–641. PubMed

Lindberg RH, Ostman M, Olofsson U, Grabic R, Fick J (2014) Occurrence and behaviour of 105 active pharmaceutical ingredients in sewage waters of a municipal sewer collection system. Water Res 58C: 221–229. PubMed

Kardas P (2002) Patient compliance with antibiotic treatment for respiratory tract infections. J Antimicrob Chemother 49: 897–903. PubMed

Llor C, Hernandez S, Bayona C, Moragas A, Sierra N, et al. (2013) A study of adherence to antibiotic treatment in ambulatory respiratory infections. Int J Infect Dis 17: e168–172. PubMed

McNulty CA, Boyle P, Nichols T, Clappison P, Davey P (2007) The public’s attitudes to and compliance with antibiotics. J Antimicrob Chemother 60 Suppl 1: i63–68. PubMed

Ort C, Lawrence MG, Reungoat J, Mueller JF (2010) Sampling for PPCPs in wastewater systems: comparison of different sampling modes and optimization strategies. Environ Sci Technol 44: 6289–6296. PubMed

Ort C, Gujer W (2006) Sampling for representative micropollutant loads in sewer systems. Water Sci Technol 54: 169–176. PubMed

Ort C, Schaffner C, Giger W, Gujer W (2005) Modeling stochastic load variations in sewer systems. Water Sci Technol 52: 113–122. PubMed

Ort C, Lawrence MG, Rieckermann J, Joss A (2010) Sampling for pharmaceuticals and personal care products (PPCPs) and illicit drugs in wastewater systems: are your conclusions valid? A critical review. Environ Sci Technol 44: 6024–6035. PubMed

Gillman A, Muradrasoli S, Soderstrom H, Nordh J, Brojer C, et al. (2013) Resistance mutation R292K is induced in influenza A(H6N2) virus by exposure of infected mallards to low levels of oseltamivir. PLoS One 8: e71230. PubMed PMC

Ivachtchenko AV, Ivanenkov YA, Mitkin OD, Yamanushkin PM, Bichko VV, et al. (2013) A novel influenza virus neuraminidase inhibitor AV5027. Antiviral Res 100: 698–708. PubMed

Wathen MW, Barro M, Bright RA (2013) Antivirals in seasonal and pandemic influenza–future perspectives. Influenza Other Respir Viruses 7 Suppl 1: 76–80. PubMed PMC

Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, et al. (2014) Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev 4: CD008965. PubMed

Drinking Water Inspectorate (2007) Desk based review of current knowledge on pharmaceuticals in drinking water and estimation of potential levels (Defra Project Code: CSA 7184/WT02046/DWI70/2/213). Available: http://googl/nkBVlP.

Perelson AS, Rong L, Hayden FG (2012) Combination Antiviral Therapy for Influenza: Predictions From Modeling of Human Infections. Journal of Infectious Diseases 205: 1642–1645. PubMed PMC

Kim W-Y, Young Suh G, Huh JW, Kim S-H, Kim M-j, et al. (2011) Triple-Combination Antiviral Drug for Pandemic H1N1 Influenza Virus Infection in Critically Ill Patients on Mechanical Ventilation. Antimicrobial Agents and Chemotherapy 55: 5703–5709. PubMed PMC

Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure