Bacterial pneumonia and pandemic influenza could there be an Impact on a sewage treatment plant?

http://www.wordle.net/

Andrew SingerCentre for Ecology & Hydrology

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)

Cases/Deaths Since 2003: 408/254 (62%)

Why are we interested in this now?

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

InfluenzaVirus

InfluenzaCases

AntiviralUse

Secondary Infection Cases

AntibioticUse

41

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

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

Viral Infectivity (R0)

InfluenzaCases

AntiviralTreatment

(AVT)

Secondary Infection Cases

AntibioticUse

R0 = number of secondary cases of influenza produced by 1 infected individual

R0

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

EpidemiologyModel

AVP

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)

Amoxicillin

Doxycycline

Moxifloxacin

Clarithromycin

Levofloxacin

Erythromycin

Cefotaxime

Clavulanic acid

Cefuroxime

β-l

acta

mC

eph

alo

spo

rin

Mac

rolid

e

Tetracycline

Qu

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lon

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0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000C

efu

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me

Ce

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(m

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CURB 0-2

CURB 3-5

How much will be given to a patient?

Lim (2007) Thorax

Antivirals

Moderately sick

Severely sick

Baseline Antibiotic Use (excreted in England)

1

10

100

1000

10000F

loxa

cilli

n

Am

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illin

Cef

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Ery

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line

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ocyc

line

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ime

Azi

thro

myc

in

Dox

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line

Oflo

xaci

n

Nor

floxa

cin

Levo

floxa

cin

Mox

iflox

acin

ug

/he

ad

/d

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

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%)!

Probable Excretion to Sewage Works

10

0

10

0

96

95

80

75

61

55

38

0

20

40

60

80

100

120

Ery

thro

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in

Cla

vu

lan

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% E

xc

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d a

s P

are

nt

or

Co

nju

ga

te

Probable Loss in Sewage Works

92

%

54

%

22

%

22

%

22

%

7%

6%

2%

2%

0%

10%

20%30%

40%

50%

60%

70%80%

90%

100%C

lav

ula

na

te

Do

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clin

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% L

os

s in

ST

W

Estimates generated from STPWINTM and an average % removal from the literature

http://www.epa.gov/oppt/exposure/pubs/episuite.htm

Where might the antibiotic concentrations start to hurt

bacteria?

NOEC

0.01

0.1

1

10

Am

oxi

cilli

n

Cla

vulin

ate

Do

xycy

clin

e

Ce

furo

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ug

/L A

nti

bio

tic NOEC

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

R0

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?

Antibiotic risk assessment from modelled scenario

PEC = Predicted environmental concentration (in Sewage)NOEC = Predicted no observable effect concentration

0.1

1

10

100

1000

Am

oxi

cilli

n

Cla

vulin

ate

Do

xycy

clin

e

Ce

furo

xim

e

Ce

fota

xim

e

Ery

thro

myc

in

Cla

rith

rom

ycin

Le

voflo

xaci

n

Mo

xiflo

xaci

n

2%

40%

PE

C

NO

EC

2° Infection

> 1

DangerLevel?

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.

Epidemiology Model TeamV. 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 TeamV.D.J. Keller, R.J. Williams, Centre for Ecology & Hydrology, Wallingford,

U.K

Thankyou to…..

R0

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)

Toxicity in Stretches of River (0% AVP)

Where, Ro=2.7; AVP 0%, AVT 50%, p40%

Where, Ro=2.7; AVP 10%, AVT 50%, p40%

Toxicity in Stretches of River (10% AVP)