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antimicrobial use and resistance insights from a veterinary perspective
1. Antimicrobial use and resistance:
Background from a veterinary perspective
Prof. Dr. Jeroen Dewulf
Jeroen.Dewulf@UGent.be
Unit for Veterinary Epidemiology,
Faculty of Veterinary Medicine
Ghent University
Centre of excellence AMCRA
2. Content
The epidemiology of
antimicrobial resistance in
animals
Antimicrobial consumption
Transmission of resistance from
animals too humans and vice versa
4. Antimicrobial resistance genes are naturally
present in the environment
• Development of antimicrobial
resistance is independant of
antimicrobial use
• Function of the genes is often unknown
9. Selection of resistance
• Selection of antimicrobial resitance is the result of :
Antimicrobial
use!
Non-use risk factors (persistance and spread):
Stress
Feed
Hygiene
Housing
…
10. Introduction of antimicrobials and development of
resistance in Staphylococcus aureus
Year of
introduction of
the
antimicrobial
Year of first detection
of resistance
12. Linking antimicrobial use to antimicrobial resistance in 7 EU countries based
on surveillance data
(a) Aminopenicillins (ampicillin)
(b) Third generation Cephalosporins (cefotaxime)
0.12
0.5
0.4
y = -0,0002x2 + 0,0255x - 0,0707
R² = 0,93
0.2
0.1
0
0.1
0.08
0.06
0.04
0.02
10
20
30
40
Antimicrobial use (mg/PCU)
50
0
0.1
Arcsin % AM resistance
Arcsin % AM resistance
0.15
0.1
0.05
0.2
0.3
0.4
Antimicrobial use (mg/PCU)
0.5
0
0.6
0.2
0.4
0.6
Antimicrobial use (mg/PCU)
0.8
0.6
0.05
0.04
0.03
y = -0,0021x2 + 0,0241x - 0,0188
R² = 0,80
0.02
0.01
0.8
1
0.5
0.4
y = -0,0149x2 + 0,1752x + 0,0057
R² = 0,81
0.3
0.2
0.1
0
0
0
0.4
0.6
Antimicrobial use (mg/PCU)
0.1
(e) Aminoglycosids (gentamicin)
0.06
y = 0,1313x2 + 0,1234x - 0,0112
R² = 0,99
0.2
0.2
0.15
(f) Aminoglycosids (streptomycin)
(d) Amphenicols (chloramphenicol)
0
0.3
0.25
0
60
0.25
0.2
0.35
0.05
0
0
y = 1,1278x2 - 0,2875x + 0,0221
R² = 0,99
0.4
y = 0,6887x2 - 0,1812x + 0,0135
R² = 0,94
Arcsin % AM resistance
0.3
0.45
Arcsin % AM resistance
0.6
(c) Fluoroquinolons (ciprofloxacin)
0.14
Arcsin % AM resistance
Arcsin % AM resistance
0.7
0
2
4
6
Antimicrobial use (mg/PCU)
8
0
1
2
3
4
5
Antimicrobial use (mg/PCU)
6
Chantziaras et al., 2013
7
13. Linking antimicrobial use to antimicrobial resistance in 7 EU countries based
on surveillance data
Average antimicrobial resistance ranking
7
Belgium
6
Netherlands
5
Switzerland
4
Austria
3
Denmark
Norway
2
Sweden
1
1
2
3
4
5
6
7
Average antimicrobial use ranking
Chantziaras et al., 2013
14. Belgian broilers:
35 – 40% E. coli
resistant for ceftiofur
60% of broilers carrier of
ESBL
Persoons et al., 2010
21. Epidemiology of antimicrobial resistance
Fase I:
Development of AR
Fase II:
Selection of AR
resistance
Fase III:
Persistance of AR
resistance
Fase IV:
Reduction of AR
resistance
23. Epidemiology of antimicrobial resistance
Where do we find resistance?
•
Production animals?
•
Companion animals?
•
Wildlife?
•
Environment?
24. E.Coli in different ecological niches
Occurrence of multiresistance
percentage of strains
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
resistant against ... antimicrobials
fattening pig
broilers
dairy cows
hare
human sewage
surface water
Casteleyn et al., 2007
25. E.Coli in different ecological niches
Occurrence of multiresistance
percentage of strains
70
60
50
40
30
20
10
0
0
1
2
3
4
5
6
7
8
9
10
11 12
13 14
resistant against ... antimicrobials
dairy cows
hare
Casteleyn et al., 2007
26. E.Coli in different ecological niches
Occurrence of multiresistance
percentage of strains
25
20
15
10
5
0
0
1
2
3
4
5
6
7
8
9
10
11 12
13 14
resistant against ... antimicrobials
human sewage
surface water
Casteleyn et al., 2007
27. E.Coli in different ecological niches
percentage of strains
Occurrence of multiresistance
18
16
14
12
10
8
6
4
2
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
resistant against ... antimicrobials
fattening pig
Broilers
Casteleyn et al., 2007
28. Content
The epidemiology of
antimicrobial resistance in
animals
Antimicrobial consumption
Transmission of resistance from
animals too humans and vice versa
29. Antimicrobials in veterinary medicine
• Use:
Curative (all animals)
Metaphylactic (predominantly production animals)
Prophylactic (only production animals)
• Administration:
Vets (all animals)
Owner / farmer (predominantly production animals)
Feed industry (only production animals)
30. Use of antimicrobials in broiler production
600
500
production cycle 1
production cycle 2
Treatment Incidence
400
300
200
100
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
farm
Average treatment incidence
121.4
131.8
(udd)
(ddd)
Persoons et al., 2010
31. Classification of antimicrobials according to
importance in human medicine
II
III
I
Use of antimicrobials in broiler production
flumequin
TIddd
tilmicosin
penicillin
TIudd
enrofloxacin
tylosin
amoxicillin
doxycycline
linco-spec
trim-sulfa
lincomycin
0
10
20
30
40
50
60
70
chickens per 1000
Persoons et al., 2010
32. Use of antimicrobials in pig
production
600
Total TIDDDpig/herd
Total TIUDDpig/herd
DDDpig or UDDpig/1000 pigs at risk/day
500
400
300
200
100
0
1
3
5
7
9
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
41
43
45
47
49
Farm num ber
Timmerman et al., 2005
33. Use of antimicrobials in pig
production
TIudd
1000
TI for 50 herds
TIadd
average TIadd
average TIudd
900
800
700
600
500
400
300
200
100
0
0
10
20
herd
30
40
Callens et al., 2011
50
34. Use of antimicrobials in pig
production
Prophylactic vs metaphylactic use
Percentage
100
80
60
2003
2010
40
20
0
preventief
metafylactisch
Callens et al., 2011
36. Doseringen
Doseringen
P
e 100.00
r 80.00
c 60.00
e
40.00
n
t 20.00
a
0.00
g
e
93
80
What is a correct dosis?
47
40 Correct dosis for what?
31
29 29
2003
2010
23
12
8
Callens et al., 2011
39. Antimicrobial use in veal calves
• 15 herds
• TI DDD = 416,8
• 96% oral group treatments
• 12% profylactisch
• 88% metafylactisch
• 44% of the grouptreatments underdosed
Pardon et al., 2012
39
40. Antimicrobial use in veal calves
100.0
90.0
Percentage of veal cohorts
80.0
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0.0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Weeks on feed
respiratory disease
arrival prophylaxis
diarrhea
dysbacteriosis
enterotoxaemia
idiopathic peritonitis
Figure 1: Percentage of veal cohorts (n=15) receiving antimicrobial group treatment at
least four days of the week by indication and by week of production (20072009, Belgium)
Pardon et al., 2012
40
41. Treatment incidence on UDD (animals/1000 daily
treaed)
Antimicrobial use in livestock in Belgium
600
500
400
300
200
100
0
poultry
Persoons et al., 2012
pigs
Callens et al., 2012
dairy cattle
beef cattle
Catry et al., under revision
veal calves
veal calves (164
kg)
Bron: Bart Pardon, Ugent
42. Which antimicrobials are critical?
WHO:
Critically Important Antimicrobials for Human Medicine:
Categorization for the Development of Risk Management Strategies to
contain Antimicrobial Resistance due to Non-Human Antimicrobial Use
CONCLUSIONS
The prioritization of classes of antimicrobials to be addressed most urgently in terms
of risk management strategies for non-human use of antimicrobials resulted in the
selection of three groups of drugs: quinolones,
3rd /4th
generation cephalosporins, and macrolides.
51. EMA-ESVAC
Antimicrobial use in mg/PCU (ESVAC)
450
400
350
300
250
200
150
100
50
0
MG/PCU 2010
MG/PCU 2011
Data 2011
www.belvetsac.ugent.be
52. Content
The epidemiology of
antimicrobial resistance in
animals
Antimicrobial consumption
Transmission of resistance from
animals too humans and vice versa
57. Assessment of human exposure to cephalosporin resistant E.coli
(CREC) from chicken through consumption of broiler meat
Probability of the exposure to CREC through consumption of a meal
containing chicken meat and in function of 4 arbitrarily chosen infection
doses.
Infection doses (arbitrarily chosen)
10000 cfu 1000 cfu
100 cfu
10 cfu
Exposure through insufficient heating of
chicken meat preparations
0%
0%
0%
0,03
bought cooked / prepared)
0,39%
1,53%
3,26%
6,97%
Total exposure
0,39%
1,53%
3,26%
7%
Exposure through cross contamination
(all types of chicken excl. chicken meat
De Poorter et al., 2012
58. Transfer of antimicrobial resistance in the gut
In vitro simulation of the human gut
1,00E+08
1,00E+07
CFU/ml
1,00E+06
1,00E+05
E. coli (human)
1,00E+04
B1-54
1,00E+03
acceptor
transconjugants
ESBL-donor pluimvee
1,00E+02
1,00E+01
1,00E+00
0
1
2
3
4
6
7
8
9
10 11 12 13 14 16 17
time after inoculation (days)
Inoculatie ESBLsource strain
Cefotaxime
treatment
Smet et al., 2011
58
60. Conclusions
AMR is selected for by use of
antimicrobials
Once AMR is present it is difficult
to get rid of again
AM are often used unnecessary
AMR may spread from animals to
humans through food, direct
contact and environment
Lots of unknowns
61. Thank you for your attention
Prof. Dr. Jeroen Dewulf
Jeroen.Dewulf@UGent.be
Unit for Veterinary Epidemiology,
Faculty of Veterinary Medicine
Ghent University
Centre of expertise AMCRA
Notes de l'éditeur
Op een melkveebedrijf worden de meeste diergeneesmiddelen ingezet in kader van de uiergezondheid, vandaar dat dit project specifiek op de uiergezondheid gericht is. Ook niet overroepen: uit gegevens van Nederland (in Nederland is sinds 2009 een programma gestart (reductie AB van 20% in 2011, 50% in 2013)) is gebleken dat het gebruik van diergeneesmiddelen in de melkveehouderij meevalt relatief ten opzichte van de kalver-, varkens-, en pluimveehouderij. Doch, er is ruimte voor verbetering en zolang er geen gegevens beschikbaar zijn over het werkelijke gebruik van antibiotica in de melkveehouderij, kunnen we ons ook niet verdedigen tegenover dergelijke beschuldigingen ivm resistentie. In dit project willen we de uiergezondheid verbeteren wat logischerwijs zou moeten resulteren in een verminderd, of alleszins meer verantwoord gebruik van diergeneesmiddelen. Elke schakel in de zuivelsector heeft dus baat bij het project.
Op een melkveebedrijf worden de meeste diergeneesmiddelen ingezet in kader van de uiergezondheid, vandaar dat dit project specifiek op de uiergezondheid gericht is. Ook niet overroepen: uit gegevens van Nederland (in Nederland is sinds 2009 een programma gestart (reductie AB van 20% in 2011, 50% in 2013)) is gebleken dat het gebruik van diergeneesmiddelen in de melkveehouderij meevalt relatief ten opzichte van de kalver-, varkens-, en pluimveehouderij. Doch, er is ruimte voor verbetering en zolang er geen gegevens beschikbaar zijn over het werkelijke gebruik van antibiotica in de melkveehouderij, kunnen we ons ook niet verdedigen tegenover dergelijke beschuldigingen ivm resistentie. In dit project willen we de uiergezondheid verbeteren wat logischerwijs zou moeten resulteren in een verminderd, of alleszins meer verantwoord gebruik van diergeneesmiddelen. Elke schakel in de zuivelsector heeft dus baat bij het project.
