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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%