1. Bacterial pneumonia and pandemic influenza could there be an Impact on a sewage treatment plant? http://www.wordle.net/ Andrew Singer Centre for Ecology & Hydrology

2. A gentle introduction to influenza pandemics!

3. What is an influenza pandemic? Pandemic Influenza = global spread of influenza infection in humans. Pandemic influenza is a rare but inevitable event: –1918 “Spanish influenza” (H1N1) –1957 “Asian influenza” (H2N2) –1968 “Hong Kong influenza” (H3N3)

4. Cases/Deaths Since 2003: 408/254 (62%) Why are we interested in this now?

5. One aim of the pandemic preparedness plan is to slow the spread of influenza, through: 1) vaccine development, stockpiling and distribution, 2) non-pharmaceutical measures, and 3) antiviral stockpiling and distribution 22 November 2007

6. Influenza Virus Influenza Cases Antiviral Use Secondary Infection Cases Antibiotic Use 4 1 2 5 5 Treat with antibiotics 2 Treat with antivirals 1 Clinical cases of influenza 4 Secondary infections 3 3 Antiviral prophylaxis (outbreak and post exposure) Schematic of a Pharmaceutical Preparedness Plan

7. UK Guidelines This document is intended for use in the UK in the event that the World Health Organization declares that an influenza pandemic has started

8. What do we need to know to predict the arrival of antibiotics at a sewage treatment plant during a pandemic? Part I The scale of influenza infection (R0) The scale of prophylactic antiviral use (AVP) The scale of antiviral use to combat actual infections (AVT) The likelihood of secondary infections

9. Viral Infectivity (R 0 ) Influenza Cases Antiviral Treatment (AVT) Secondary Infection Cases Antibiotic Use R 0 = number of secondary cases of influenza produced by 1 infected individual R0R0 2.3 2.7 3.1 1.9 AVP 5% 10% 0% 30% 50% 70% AVT 2% 40% Antibiotic Developing a Model for Pharmaceutical Use During an Pandemic Influenza 54% reduction in pneumonia with antiviral treatment Kaiser (2003) Arch Intern Med; Nicholson (2000) Lancet; Treanor (2000) JAMA; Whitley (2000) Pediatr Infect Dis J Robust Pandemic Epidemiology Model AVP

10. What do we need to know to predict the arrival of antibiotics at a sewage treatment plant during a pandemic? Part II What antibiotics would be used during a pandemic (how does this compare to baseline)? How much of these would be excreted? How much of these might be lost in the sewer/sewage treatment plant? How this predicted concentration (PEC) compares to thresholds of microbial toxicity (NOEC)

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

12. How much will be given to a patient? Lim (2007) Thorax Antivirals Moderately sick Severely sick

13. Baseline 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

14. So as an example, today we might use 3.7 mg amoxicillin/d/capita (baseline), but in a pandemic this would rise an additional 1.3 to 74 mg/d/capita (an increase of 35 to 2000%)!

15. Probable Excretion to Sewage Works

16. Probable Loss in Sewage Works Estimates generated from STPWIN TM and an average % removal from the literature http://www.epa.gov/oppt/exposure/pubs/episuite.htm

17. Where might the antibiotic concentrations start to hurt bacteria?

18. Threshold Toxicity for Pandemic Antibiotics against Model Clinical Microorganisms Andrews JM (2001) J Antimicrob Chemother Reynolds et al. (1987) Chemosphere Note: we see impacts between 0.1 and 2 ug/L concentrations

19. R0R0 2.3 2.7 3.1 1.9 AVP 1% 5% 10% 0% 30% 50% 70% AVT 2% 40% 2° Infection A Realistic Scenario Will antibiotic concentrations in sewage get to harmful levels under a realistic scenario?

20. Antibiotic risk assessment from modelled scenario PEC = Predicted environmental concentration (in Sewage) NOEC = Predicted no observable effect concentration PEC NOEC 2° Infection > 1 Danger Level?

21. Under a realistic pandemic influenza scenario most of the individual predicted antibiotic concentrations exceed the NOEC for laboratory bacteria But what would it do to sewage bacteria?

22. Conclusions Pandemic usage of total antibiotics will greatly exceed (50-1000%) that of baseline use It is important to note that increased antiviral prophylaxis might lower antibiotic use. Individual antibiotics in sewage are predicted to exceed concentrations required to inhibit laboratory test microorganisms.

23. Key Scientific Questions Might high antibiotic concentrations harm the complex microbial consortium in a sewage works (rather than just laboratory bugs)? How important are additive effects of combined antibiotic usage (similar modes of action)? Are antibiotics in unlimited supply?

24. Further Concerns Risk to sewage works failure & ‘downstream’ implications. Risk to drinking water under current models and after sewage treatment plant “failure.” Increasing antibiotic resistance problem.

25. Epidemiology Model Team V. Colizza, Complex Networks and Systems Group, ISI Foundation, Turin, Italy D. Balcan, A. Vespignani, School of Informatics, Indiana University, Bloomington, IN, USA River Flow Model Team V.D.J. Keller, R.J. Williams, Centre for Ecology & Hydrology, Wallingford, U.K Thankyou to…..

26. R0R0 2.3 2.7 3.1 1.9 AVP 5% 10% 0% 30% 50% 70% AVT 2% 40% 2° Infection Role of AVP on Controlling Antibiotics in the Thames (Realistic Worst Case Scenario)

27. Toxicity in Stretches of River (0% AVP) Where, Ro=2.7; AVP 0%, AVT 50%, p40%

28. Where, Ro=2.7; AVP 10%, AVT 50%, p40% Toxicity in Stretches of River (10% AVP)