How influenza pandemic control can lead to unpreparedness: modelling the ecotoxicity of pharmaceutical usage

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How influenza pandemic control can lead to
unpreparedness modelling the ecotoxicity of
pharmaceutical usage
Andrew Singer acsi_at_ceh.ac.uk
Centre for Ecology Hydrology Wallingford, UK
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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.

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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?

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• What is Pandemic Preparedness?
• to slow the spread of influenza, through
• vaccines,
• 2) non-pharmaceutical
  measures
• 3) Antivirals and Antibiotics

Virally-induced damage to the respiratory tract
predisposes to bacterial invasion and infection.
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2 x 75 mg/d for 5 days
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Impact Assessment
?
?
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GLEaM Global Epidemic and Mobility model

• air mobility layer
• 3400 airports in 220 countries
• 20,000 connections
• traffic data (IATA, OAG)
• gt99 commercial traffic

• commuting mobility layer
• daily commuting data
• gt30 countries in 5 continents
• universal law of mobility

• demographic layer
• cells ¼ x ¼
• tessellation around
• transportation hubs

www.epiwork.eu
Balcan et al. PNAS (2009)
extended to the entire globe
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Pharmaceutical Use Model During an Influenza
Pandemic
Viral Infectivity (R0)
Influenza Cases
Secondary Infections
AVP
GLeAM Global Epidemiology Model
Antiviral Treatment (AVT)
Antibiotic Use
R0 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.
AVT/AVP

• No prophylaxis
• Early stage Prophylaxis
• - 2w
• - 4w
• Treatment 30 cases

54 reduction in pneumonia with antiviral
treatment
Kaiser (2003) Arch Intern Med Nicholson (2000)
Lancet Treanor (2000) JAMA Whitley (2000)
Pediatr Infect Dis J
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UK 70-75 coverage (mostly Tamiflu)
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Amoxicillin
Clavulanic acid
Cefotaxime
Cefuroxime
Erythromycin
Clarithromycin
Doxycycline
Levofloxacin
Moxifloxacin
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Projected Loss of Antibiotics from Biodegradation
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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

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Available Dilution of Wastewater in WWTPs of
Thames Catchment, UK
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Available Dilution of Human Effluent (Global
comparison)
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Interpandemic Antibiotic Use (excreted in
England)
Those highlighted in red to be used in a pandemic
NHS BSA (2008) http//www.nhsbsa.nhs.uk/Prescripti
onServices/Documents/NPC_Antibiotics_July_2008.ppt
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300
252
200
relative increase to baseline 2007/2008
100
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R0 1.65
R0 1.9 (AVT)
R0 2.3 (AVT)
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Mean Total Antibiotics In Thames
S1 AVP0, rate of AVT 30, limited supply of
Tamiflu S2 2wk AVP, AVP1, rate of AVT 30,
limited supply of Tamiflu S3 4wk AVP, AVP1,
rate of AVT 30, limited supply of Tamiflu S4
2wk AVP, AVP10, rate of AVT 30, limited
supply of Tamiflu S5 4wk AVP, AVP10, rate of
AVT 30, limited supply of Tamiflu S6 AVP0,
rate of AVT 30, unlimited supply of Tamiflu
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Mean Tamiflu In Thames
S1 AVP0, rate of AVT 30, limited supply of
Tamiflu S2 2wk AVP, AVP1, rate of AVT 30,
limited supply of Tamiflu S3 4wk AVP, AVP1,
rate of AVT 30, limited supply of Tamiflu S4
2wk AVP, AVP10, rate of AVT 30, limited
supply of Tamiflu S5 4wk AVP, AVP10, rate of
AVT 30, limited supply of Tamiflu S6 AVP0,
rate of AVT 30, unlimited supply of Tamiflu
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Max Tamiflu In Thames
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No acute toxicity Inhibition of microbial biofilms
Tamiflu
Microbial growth inhibition (WWTP rivers)
Antibiotics
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Antiviral Affects on Biofilm Formation













Oseltamivir 1 and 0.1 ug/ml Zanamivir 0.1
and 0.01 ug/ml
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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 R0 gt 2.0 is likely to pose
  operational challenges to sewage works which
  could result in the release of untreated sewage
  into receiving rivers.

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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

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Solutions ?

• VACCINATION!!

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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.

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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
  pneumoniauntreatable by antibiotics, but as
  diagnosis is syndromic, they will all get
  antibiotics.

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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 (5PPP-RNA)
• Antibodies (anti-HA, NA, M2)
• Cationic airway lining modulators (iCALM- topical)

http//ow.ly/3GJ4c
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Combination Antiviral Therapy
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
http//ow.ly/3GJ4c
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Modelling Complications Interpandemic Antibiotic
Use
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• 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 UKs
  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.

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

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Future Workshops

• Post presentations of this workshop on PREPARE
  website.
• Literature output from workshop?

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Vittoria Colizza
Heike Schmitt
Duygu BalcanAlessandro Vespignani Indiana
University, Bloomington, USA Virginie D.
J. Keller Richard J. Williams Centre Ecology
Hydrology
vcolizza_at_isi.it ISI, Turin Italy
h.schmitt_at_uu.nl Inst. Risk Assessment Sciences,
Univ. Utrecht
Johanna Andrews Wei E. Huang Dept Civil
Structural Engineering, Univ Sheffield, UK