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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. Summary of 2009 Pandemic in the UK.

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slide1

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

summary of 2009 pandemic in the uk
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.
the solution to pollution is dilution
“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?

slide4
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.

slide5

O

O

O

HN

NH2 • H3PO4

O

O

O

OH

HN

NH2

O

2 x 75 mg/d for 5 days

?

Impact Assessment

?

?

slide6

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

www.epiwork.eu

Balcan et al. PNAS (2009)

extended to the entire globe

slide7

R0

Secondary Infection Rate (pneumonia)

40%

2.3

15%

1.9

1.65

2%

Pharmaceutical Use Model During an Influenza Pandemic

Influenza

Cases

Viral Infectivity (R0)

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

slide8

Estimated Global Tamiflu stockpile (2009)

UK = 70-75% coverage (mostly Tamiflu)

slide9

β-lactam

Cephalosporin

Macrolide

Tetracycline

Quinolone

Amoxicillin

Clavulanic acid

Cefotaxime

Cefuroxime

Erythromycin

Clarithromycin

Doxycycline

Levofloxacin

Moxifloxacin

lf2000 wqx works
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
interpandemic antibiotic use excreted in england
Interpandemic Antibiotic Use (excreted in England)

Those highlighted in red to be used in a pandemic

NHS BSA (2008) http://www.nhsbsa.nhs.uk/PrescriptionServices/Documents/NPC_Antibiotics_July_2008.ppt

slide15

results: antibiotics in WWTPs

300%

252%

200%

relative increase to baseline 2007/2008

100%

13%

1%

R0 = 1.65

R0 = 1.9

(AVT)

R0 = 2.3

(AVT)

mean total antibiotics in thames
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

mean tamiflu in thames
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

slide19

Determining Impact

No acute toxicity

Inhibition of microbial biofilms

Tamiflu

Microbial growth inhibition

(WWTP & rivers)

Antibiotics

antiviral affects on biofilm formation
Antiviral Affects on Biofilm Formation

*

*

*

*

*

*

*

*

*

*

*

*

*

Oseltamivir = 1 and 0.1 ug/ml

Zanamivir = 0.1 and 0.01 ug/ml

slide21

Spatial distribution of toxicity in WWTPs & Rivers

% of sewage plants >5% PAF

≤ 85

≤100

% of Thames River length >5% PAF

≤ 10

≤ 40

general conclusions
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 > ~2.0 is likely to pose operational challenges to sewage works which could result in the release of untreated sewage into receiving rivers.
slide23

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
solutions
Solutions ?

VACCINATION!!

priority research
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.
additional considerations
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.
additional considerations investigational anti influenza agents
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

slide30

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.
workshop 1 tamiflu focus
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).

workshop 2 wwtp focus
Workshop 2: WWTP Focus

Antibiotic usage during a pandemic

PECs

Biodegradation

Ecotoxicity of antibiotics to WWTPs.

Diversity of WWTPs in UK

future workshops

Future Workshops

Post presentations of this workshop on PREPARE website.

Literature output from workshop?

slide36

Thanks to Collaborators...and you!

Vittoria Colizza

Heike Schmitt

Duygu BalcanAlessandro Vespignani

Indiana University, Bloomington, USA

Virginie D. J. Keller

Richard J. Williams

Centre Ecology &

Hydrology

vcolizza@isi.it

ISI, Turin Italy

h.schmitt@uu.nl

Inst. Risk Assessment

Sciences, Univ. Utrecht

Johanna Andrews

Wei E. Huang

Dept Civil Structural

Engineering,

Univ Sheffield, UK