1. How influenza pandemic control can lead to unpreparedness: modelling the ecotoxicity of pharmaceutical usage Andrew Singer acsi@ceh.ac.uk Centre for Ecology & Hydrology Wallingford, UK

2. Summary of 2009 Pandemic in the UK There were two ‘waves’ one immediately following the other. There were significant levels of background immunity among adults. This contributed to the first ‘wave’ peaking at the beginning of the school holidays in mid Summer when contact rates in children reduced. Once schools returned in September, infections grew again until mid October when there were not enough susceptible individuals left to sustain the pandemic. The clinical effects of the influenza infection were similar to those of seasonal flu, but with an increase in the numbers of cases of viral pneumonitis in younger patients. Bacterial infections tended to be focussed in older patients and those with risk factors for severe flu. Antibiotic prescribing in the second and third quarters of 2009 was not distinguishably different compared with the same period in the years preceding and following. This suggests that there was not great pressure on prescribing in primary care, as a result of the relatively mild pandemic.

3. “The Solution to Pollution is Dilution” Question: Will pandemic drug use ever yield enough drug to cause environmental problems? Answer: What drugs are being used? What problems are you looking for? How dilute do you need it to be? Is there enough water for dilution?

4. What is Pandemic Preparedness? … to slow the spread of influenza, through: 1) vaccines, 2) non-pharmaceutical measures 3) Antivirals and Antibiotics Virally-induced damage to the respiratory tract predisposes to bacterial invasion and infection.

5. NH 2 H 3 PO 4 O HN O O O NH 2 O HN O OH O 2 x 75 mg/d for 5 days ? ?? Impact Assessment

6. 1. epidemic model GLEaM – Global Epidemic and Mobility model air mobility layer  3400 airports in 220 countries  20,000 connections  traffic data (IATA, OAG)  >99% commercial traffic commuting mobility layer  daily commuting data  >30 countries in 5 continents  universal law of mobility demographic layer  cells ¼° x ¼°  tessellation around transportation hubs extended to the entire globe Balcan et al. PNAS (2009) www.epiwork.eu

7. Viral Infectivity (R 0 ) Influenza Cases Antiviral Treatment (AVT) Secondary Infections Antibiotic Use R 0 = Basic Reproductive Number, the average number of secondary infections produced by a single infected individual while they are infectious, in an entirely susceptible population. This is a measure of the degree of transmissibility of an infection. Pharmaceutical Use Model During an Influenza Pandemic 54% reduction in pneumonia with antiviral treatment Kaiser (2003) Arch Intern Med; Nicholson (2000) Lancet; Treanor (2000) JAMA; Whitley (2000) Pediatr Infect Dis J “GLeAM”: Global Epidemiology Model AVP R0R0 1.9 2.3 1.65 2% 40% Secondary Infection Rate (pneumonia) 15% No prophylaxis Early stage Prophylaxis - 2w - 4w Treatment 30% cases AVT/AVP

8. Estimated Global Tamiflu stockpile (2009) UK = 70-75% coverage (mostly Tamiflu)

9. Amoxicillin Doxycycline Moxifloxacin Clarithromycin Levofloxacin Erythromycin Cefotaxime Clavulanic acid Cefuroxime β-lactam Cephalosporin Macrolide Tetracycline Quinolone

10. Projected Loss of Antibiotics from Biodegradation

11. LF2000-WQX works Estimates water quality on a reach by reach basis – starting at the top Makes a mass balance of the inputs to the reach – Sewage treatment plants, industrial discharges, tributaries New concentrations calculated at the end of the reach allowing for degradation of the compound of interest Output in GIS format

12. Available Dilution of Wastewater in WWTPs of Thames Catchment, UK

13. Available Dilution of Human Effluent (Global comparison)

14. Interpandemic Antibiotic Use (excreted in England) NHS BSA (2008) http://www.nhsbsa.nhs.uk/PrescriptionServices/Documents/NPC_Antibiotics_July_2008.ppt Those highlighted in red to be used in a pandemic

15. results: antibiotics in WWTPs R 0 = 1.65R 0 = 1.9 (AVT) R 0 = 2.3 (AVT) 1% 13% 252% relative increase to baseline 2007/2008 100% 200% 300%

16. Mean Total Antibiotics In Thames S1 = AVP=0, rate of AVT = 30%, limited supply of Tamiflu S2 = 2wk AVP, AVP=1%, rate of AVT = 30%, limited supply of Tamiflu S3 = 4wk AVP, AVP=1%, rate of AVT = 30%, limited supply of Tamiflu S4 = 2wk AVP, AVP=10%, rate of AVT = 30%, limited supply of Tamiflu S5 = 4wk AVP, AVP=10%, rate of AVT = 30%, limited supply of Tamiflu S6 = AVP=0, rate of AVT = 30%, unlimited supply of Tamiflu

17. Mean Tamiflu In Thames S1 = AVP=0, rate of AVT = 30%, limited supply of Tamiflu S2 = 2wk AVP, AVP=1%, rate of AVT = 30%, limited supply of Tamiflu S3 = 4wk AVP, AVP=1%, rate of AVT = 30%, limited supply of Tamiflu S4 = 2wk AVP, AVP=10%, rate of AVT = 30%, limited supply of Tamiflu S5 = 4wk AVP, AVP=10%, rate of AVT = 30%, limited supply of Tamiflu S6 = AVP=0, rate of AVT = 30%, unlimited supply of Tamiflu

18. Max Tamiflu In Thames

19. Determining Impact Antibiotics Microbial growth inhibition (WWTP & rivers) Tamiflu No acute toxicity Inhibition of microbial biofilms

20. Antiviral Affects on Biofilm Formation * * * * * * Oseltamivir = 1 and 0.1 ug/ml Zanamivir = 0.1 and 0.01 ug/ml * * ** * * *

21. Spatial distribution of toxicity in WWTPs & Rivers % of Thames River length >5% PAF≤ 10≤ 40% of sewage plants >5% PAF≤ 85≤100

22. General Conclusions A mild pandemic with a low rate of secondary infections is not projected to result in problems for sewage works or most UK rivers. A pandemic with an R 0 > ~2.0 is likely to pose operational challenges to sewage works which could result in the release of untreated sewage into receiving rivers.

23. Impact disruption of WWTPs widespread river pollution  contamination of rivers  degradation of drinking water  spread of antiviral and antibiotics resistance  eutrophication :  loss of acquatic ecosystem (fish kill)  temporary loss of ecosystem function

24. Solutions ? VACCINATION!!

25. Priority Research Empirically determine vulnerability of sewage works. Assess the short and long term risks to widespread antiviral and antibiotic release into the environment. Empirically determine vulnerability of drinking water to contamination.

26. Additional Considerations – Compliance: Vaccination rate including pre-pandemic and during pandemic. Antivirals: 53% of those given oseltamivir were 100% compliant with taking their medication, 11% took less than 80% of that given and fewer than 1% did not comply at all. – Diagnostics for bacterial pneumonia Between 3-6 million in the UK will have bacterial pneumonia but another 3-6 million will have viral pneumonia—untreatable by antibiotics, but as diagnosis is syndromic, they will all get antibiotics.

27. Additional Considerations: Investigational Anti-Influenza Agents NA inhibitors (NAIs) – Peramivir, zanamivir (IV) – A-315675 (oral) Long-acting NAIs (LANIs) – Laninamivir (topical) – ZNV dimers (topical) Conjugated sialidase – DAS181 (topical) Protease inhibitors HA inhibitors – Cyanovirin-N, FP – Arbidol (oral) Polymerase inhibitors – Ribavirin (oral, IV, inhaled) – Favipiravir/T-705 (oral) – Viramidine (oral) – siRNA (IV, topical) NP inhibitors (nucleozin) Interferons – IFN inducers – RIG-I activator (5’PPP-RNA) Antibodies (anti-HA, NA, M2) Cationic airway lining modulators (iCALM- topical) http://ow.ly/3GJ4c

28. Combinations Tested in Humans for PK Interactions Combinations Tested or Under Evaluation in Humans for Efficacy Future Considerations for Use in Combinations oseltamivir + amantadine oseltamivir + favipiravir peramivir + rimantadine peramivir + oseltamivir zanamivir + oseltamivir rimantadine + zanamivir oseltamivir + zanamivir amantadine + ribavirin + oseltamivir Polymerase inhibitor (favipiravir/T-705) Sialidase inhibitor (DAS181) Antibody therapies Other NAI (peramivir, laninamivir Interferons Immunomodulators Combination Antiviral Therapy http://ow.ly/3GJ4c

29. Modelling Complications: Interpandemic Antibiotic Use

30. Methodology: The water samples were pre- filtered (0.45 μm filters) and analyzed using an in-line SPE -tandem mass-spectrometry (MS/MS) system. Target compounds were Oseltamivir and 13 antibiotics, compounds included in the UK’s preparedness plans. Results: Found 12 of 15 target chemical. Oseltamivir reached 480 ng/L in Oxford STW (exceeds Japan report of 293 ng/L). Antibiotic levels were consistent with previous studies.

32. Pandemic usage of Pharmaceuticals www.prepare.org.uk

33. Workshop 1: Tamiflu Focus Assess the potential human health impact and environmental hazards associated with use of Tamiflu during an influenza pandemic (risk ranking and identifying knoweldge gaps).

34. Workshop 2: WWTP Focus 1.Antibiotic usage during a pandemic 2.PECs 3.Biodegradation 4.Ecotoxicity of antibiotics to WWTPs. 5.Diversity of WWTPs in UK

35. Future Workshops Post presentations of this workshop on PREPARE website. Literature output from workshop?

36. Thanks to Collaborators...and you! Vittoria Colizza h.schmitt@uu.nl Inst. Risk Assessment Sciences, Univ. Utrecht Duygu Balcan Alessandro Vespignani Indiana University, Bloomington, USA Virginie D. J. Keller Richard J. Williams Centre Ecology & Hydrology Heike Schmitt vcolizza@isi.it ISI, Turin Italy Johanna Andrews Wei E. Huang Dept Civil Structural Engineering, Univ Sheffield, UK