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Bacterial pneumonia and pandemic influenza could there be an Impact on a sewage treatment plant? Andrew Singer Centre for Ecology & Hydrology http://www.wordle.net/ A gentle introduction to influenza pandemics! 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) Why are we interested in this now? Cases/Deaths Since 2003: 408/254 (62%) 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 22 November 2007 3) antiviral stockpiling and distribution Schematic of a Pharmaceutical Preparedness Plan 1 Influenza Virus 3 Influenza Cases 4 2 Antiviral Use Secondary Infection Cases 5 Antibiotic Use 1 Clinical cases of influenza 2 Treat with antivirals 3 Antiviral prophylaxis (outbreak and post exposure) 4 Secondary infections 5 Treat with antibiotics 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 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 Developing a Model for Pharmaceutical Use During an Pandemic Influenza Influenza Cases Viral Infectivity (R0) Secondary Infection Cases AVP Robust Pandemic Epidemiology Model Antiviral Treatment (AVT) Antibiotic Use R0 = number of secondary cases of influenza produced by 1 infected individual R0 AVT 3.1 70% AVP 10% Antibiotic 40% 2.7 50% 5% 2.3 2% 30% 1.9 54% reduction in pneumonia with antiviral treatment 0% Kaiser (2003) Arch Intern Med; Nicholson (2000) Lancet; Treanor (2000) JAMA; Whitley (2000) Pediatr Infect Dis J 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) β-lactam Cephalosporin Amoxicillin Clavulanic acid Cefotaxime Macrolide Cefuroxime Erythromycin Clarithromycin Quinolone Tetracycline Levofloxacin Doxycycline Moxifloxacin How much will be given to a patient? 5000 4500 3500 Moderately sick CURB 0-2 Severely sick CURB 3-5 3000 2500 2000 1500 Antivirals 1000 Zanamivir Tamiflu Doxycycline Moxifloxacin Levofloxacin Clarithromycin Erythromycin Amoxicillin Cefotaxime 0 Clavulanate 500 Cefuroxime Dose (mg d-1) 4000 Lim (2007) Thorax 1 NHS BSA (2008) http://www.nhsbsa.nhs.uk/PrescriptionServices/Documents/NPC_Antibiotics_July_2008.ppt Moxifloxacin Levofloxacin Norfloxacin Ofloxacin Doxycycline Azithromycin Cefuroxime Minocycline Sulfamethoxazole Lymecycline Oxytetracycline Clavulanate Cefadroxil Cefaclor Clarithromycin Cefradine Trimethoprim Penicillin V Ciprofloxacin Ampicillin Erythromycin Cefalexin Amoxicillin Floxacillin ug/head/d Baseline Antibiotic Use (excreted in England) 10000 Those highlighted in red to be used in a pandemic 1000 100 10 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%)! % Excreted as Parent or Conjugate Clavulanate Clarithromycin Cefotaxime Amoxicillin Doxycycline 38 55 61 75 80 95 0 Cefuroxime 20 96 40 Levofloxacin 60 100 80 Moxifloxacin 100 100 120 Erythromycin Probable Excretion to Sewage Works 92% Estimates generated from STPWINTM and an average % removal from the literature 2% 2% Moxifloxacin Levofloxacin 6% Erythromycin 22% Cefotaxime 7% 22% Amoxicillin Clarithromycin 22% Cefuroxime 54% http://www.epa.gov/oppt/exposure/pubs/episuite.htm Doxycycline 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Clavulanate % Loss in STW Probable Loss in Sewage Works Where might the antibiotic concentrations start to hurt bacteria? 10 NOEC NOEC 1 Moxifloxacin Levofloxacin Clarithromycin Erythromycin Cefotoxamine Cefuroxime Doxycycline 0.01 Clavulinate 0.1 Amoxicillin ug/L Antibiotic Threshold Toxicity for Pandemic Antibiotics against Model Clinical Microorganisms Note: we see impacts between 0.1 and 2 ug/L concentrations Andrews JM (2001) J Antimicrob Chemother Reynolds et al. (1987) Chemosphere A Realistic Scenario R0 AVP AVT 3.1 10% 2.7 5% 2.3 1% 1.9 70% 2° Infection 40% 50% 30% 2% 0% Will antibiotic concentrations in sewage get to harmful levels under a realistic scenario? Antibiotic risk assessment from modelled scenario PEC = Predicted environmental concentration (in Sewage) NOEC = Predicted no observable effect concentration >1 2° Infection 2% 1000 40% NOEC PEC 100 10 Moxifloxacin Levofloxacin Clarithromycin Erythromycin Cefotaxime Cefuroxime Doxycycline Clavulinate 0.1 Amoxicillin 1 Danger Level? 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? 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. 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? 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. Thankyou to….. 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 Role of AVP on Controlling Antibiotics in the Thames (Realistic Worst Case Scenario) R0 AVP 3.1 AVT 10% 2.7 5% 2.3 1.9 70% 40% 50% 30% 0% 2° Infection 2% Toxicity in Stretches of River (0% AVP) Where, Ro=2.7; AVP 0%, AVT 50%, p40% Toxicity in Stretches of River (10% AVP) Where, Ro=2.7; AVP 10%, AVT 50%, p40%