The use of antimicrobial in humans and animals, the consequences of this use, the political and economic barriers to improve prudent use and possible solutions for this problem.

1. Jan Kluytmans
The Netherlands
UMC Utrecht, Amphia Breda
Antibiotic Resistance
A tragedy of the commons

3. Topics
The problem
Underlying mechanisms
Transfer between animal species, including humans
Current actions
The future

4. The problem

6. Rather than see expenditure on antimicrobial
policies as a cost, we should think of it as an
insurance policy

7. Resistance is high and increasing
and there are no new drugs

10. AMR in 2050

11. Classical model

12. But also

17. The perfect storm
• Lack of sanitation
• Lack of basic hygiene
• High and uncontrolled use of antibiotics

18. Figure 23. Exchange of resistance mechanisms and bacteria between different reservoirs

19. A metaphor for a complex societal
problem with ecological consequences?

20. AMR:
a tragedy of the commons?

22. Tragedy of the commons
• a commons =a natural resource shared by many
individuals.
• In this context, "shared" means that each individual
does not have a claim to any part of the resource, but
rather, to the use of a portion of it for his/her own
benefit.
• The tragedy is that, in the absence of regulation, each
individual will have a tendency to exploit the commons
to his/her own advantage, typically without limit.
• Under this state of affairs, the commons is depleted
and eventually ruined.

25. The role of non-human use

26. • Most antibiotics are given to animals
• Most animals that receive antibiotics are healthy
70%
6%
9%
15%
Animals non-therapeutic
Animals therapeutic
Humans therapeutic
Other (pesticides etc)

27. Comparison of biomass-corrected consumption of
antimicrobials in humans and food-producing
animals by country in 26 EU/EEA countries in 2012

28. Antibiotic use in Livestock
• Huge variation between countries
• Huge variation within countries
• Huge variation between various species

29. Antibiotic use in Livestock
• General picture
– Frequent use
– Low dosages
– Bad hygiene
– Crowding
– Frequent transfer of animals

33. Search Opin
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Antibiotics, Farm Animals and You
Published: April 4, 2013
To the Editor:
Re “Antibiotics and the Meat We Eat,”
by David A. Kessler (Op-Ed, March
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Farmers and ranchers share consumer
concerns about antibiotic-resistant
bacteria and are continuously
improving herd health practices to
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LETTER
Antibiotics, Farm Animals and You
Published: April 4, 2013
To the Editor:
Re “Antibiotics and the Meat We Eat,”
by David A. Kessler (Op-Ed, March
28):
Farmers and ranchers share consumer
concerns about antibiotic-resistant
bacteria and are continuously
improving herd health practices to
minimize risk.
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About a third of livestock antibiotics
used today are not used at all in human medicine. And in
accordance with the Food and Drug Administration’s
Guidance 209 and 213, antibiotics important to human
medicine used for growth purposes will be eliminated from
farm use within three years.
There is no proven link to antibiotic treatment failure in
humans because of antibiotic use in animals for
consumption — a critical point that is often missed.
Antibiotics are used judiciously under veterinary guidance
and F.D.A. guidelines, and are primarily used to treat sick
animals or prevent illness.
According to the Centers for Disease Control and Prevention, antibiotic-resistant diseases
with the greatest effect on human health, like the contagious staph bacteria MRSA, are
spread by human-to-human contact. No clinical case of MRSA in a human related to
livestock has been identified in the United States.
Let’s keep this dialogue focused on the facts, and lose the hyperbole and fear-mongering.
CHARLES L. HOFACRE
Athens, Ga., March 29, 2013
The writer, a professor of veterinary medicine at the University of Georgia and a
member of its Center for Food Safety, is an adviser to the U.S. Farmers and Ranchers
Alliance.
MOST
1.
2.
3.
4.
5.
There is no proven link to antibiotic treatment failure in humans because of
antibiotic use in animals for consumption — a critical point that is often missed.
Antibiotics are used judiciously under veterinary guidance and F.D.A. guidelines,
and are primarily used to treat sick animals or prevent illness.
Let’s keep this dialogue focused on the facts, and lose the hyperbole and fear-
mongering.

34. The facts

36. v
30 January 2015
636088/2013
ECDC/EFSA/EMA first joint report on the integrated
analysis of the consumption of antimicrobial agents and
occurrence of antimicrobial resistance in bacteria from
humans and food-producing animals1
Joint Interagency Antimicrobial Consumption and Resistance Analysis
(JIACRA) Report
Abstract

37. ECDC, EFSA and EMA have for the first time
jointly explored associations between
• consumption of antimicrobials in humans and food-
producing animals, and
• antimicrobial resistance in bacteria from humans and
food-producing animals
using 2011 and 2012 data currently available
from their relevant five EU monitoring networks

38. ure 1. Available fields of data related to antimicrobial consumption and resistance in humans an
d-producing animals in the reporting countries and the possible relationships investigated in this
ort
Antimicrobial
consumption in
humans
Antimicrobial
consumption in
animals
Antimicrobial
resistance in
humans
Antimicrobial
resistance in
animals
1. Consumption of antimicrobials by humans and food-producing
imals
1.1. Numerator
a on the quantity of antimicrobials sold for systemic use in humans in 2012 (ATC group J01) are

39. Animals
Logistic regression analysis curves with OR estimates and 95 % PL CIs
of the national consumption of fluoroquinolones and other quinolones in
food-producing animals and the probability of “microbiological”
resistance to ciprofloxacin in indicator E. coli isolates (MIC > 0.03
mg/L) from cattle, domestic fowl and pigs, dots represent the countries
involved in the analysis
Countries included: AT, BE, CH, DE, DK, ES, FR, NL, PL
p-value < 0.05; OR = 1.170; 95 % PL CI: [1.015, 1.344]
b.
p- value < 0.05;
OR = 2.415; 95 % PL CI: [1.596, 3.652]

40. Humans
Fluoroquinolones
use and resistance
o fluoroquinolones in E. coli isolates from human BSIs for the y
tries involved in the analysis
p-value < 0.001;
OR = 1.614; 95 % PL CI: [1.383, 1.886]

41. the more you use it
the sooner you loose it

42. Humans
andother
animals
Fluoroquinolones
use in animals and resistance in humans
b.
p-value < 0.001;
OR = 1.112; 95 % PL CI: [1.063, 1.162]

43. conclusions
The results show that the occurrence of
resistance in E. coli causing BSIs in humans
could be correlated with consumption of
antimicrobials in food-producing animals and
in humans
One important exception:
# 3rd & 4th generation cephalosporins???

44. Ceftiofur
• Is not approved for use in poultry
• Almost all chickens are treated with it
• Quote in 2010 (National Newspaper):
– the antibiotics that veterinarians want to ban from
now on were already illegal (Dik Mevius)
• Illegal use is widespread, this is not included in
the analysis of ECDC, EFSA, EMEA

45. Summary
• High use of antibiotics in livestock
• Large variations
• High resistance rates in livestock
• Relevance to human health is likely based on
large scale epidemiology
• More evidence?

46. Complex epidemiology
• Relations are often indirect and non-linear
• Data on antibiotic use and resistance are not
always available
• Human use certainly plays a role
– Varies between countries
– Varies over time
• Economical and political implications of
veterinary use are enormous

47. Figure 23. Exchange of resistance mechanisms and bacteria between different reservoirs

48. Mathematical model

49. After AMR is common in humans, infection control and prudent Medical AU are more
likely to reduce the prevalence of AMR in hospitals than eliminating Animal AU.
Restricting Animal AU in new resistance classes would likely maximize the time when
AMR in humans is rare, suggesting that the best time to regulate Animal AU is before
AMR appears
If heavy Animal AU and Medical AU are concurrent, multidrug resistance may evolve in
animal populations and move into human populations.
Animal use is most important at the initial stage
and has an important role at the introduction of
antimicrobial resistance
Selection by human use plays a major role in the
subsequent amplification in humans

50. From mathematical models to real life
The Netherlands

51. The current situation (Hospitals)SURVEILLANCE REPORT Surveillance of antimicrobial consumption in Europe, 2010
Figure 4.1. Consumption of antibacterials for systemic use (ATC group J01) in the hospital sector in
EU/EEA countries, 2010, at group level 3, expressed as DDD per 1 000 inhabitants and per day.
0
1
2
3
Latvia
Finland(a)
Lithuania
France
Italy
Luxembourg
Belgium
Malta
Estonia
Ireland
Denmark
Slovenia
Sweden
Bulgaria
Norway
Portugal(b)
Hungary
Netherlands
DDDper1000inhabitantsandperday
Other J01 classes
Sulfonamides and trimethoprim (J01E)
Quinolones (J01M)
Macrolides, lincosamides and streptogramins (J01F)
Tetracyclines (J01A)
Cephalosporins and other beta-lactams (J01D)
Penicillins (J01C)

52. Surveillance of antimicrobial consumption in Europe, 2010 SURVEILLANCE REPO
Figure 3.2. Consumption of antibacterials for systemic use (ATC group J01) at ATC group level 3 in
the community, EU/EEA countries, 2010, expressed as DDD per 1 000 inhabitants and per day
(a) Greece and Iceland provided total care data, i.e. including the hospital sector. On average, 90% of total care data correspo
The current situation
(community)

53. Use in animals

54. The Dutch paradox

55. Livestock 2004-2007 outpatient 2004-2007 hospitals 2004-2007
Humans versus animals in kilograms
The Netherlands 2004-2007
>90% is used
in livestock
Amountofantibioticsinkg
population

56. Every disadvantage has its advantage
• Low use in humans
• High use in animals
• Perfect setting to monitor emergence of
resistance in humans from livestock

57. Recent examples
• MRSA
• ESBL
• Focus on findings in The Netherlands

58. It always starts with one case
2004 Preoperative screening > MRSA
Eradication failed repeatedly
Non-typable
Father was a pig farmer
Several other non-typable cases
related to pig farmers
Study group: 23% positive
MLST: CC398

59. MRSA (human cases)

60. LA-MRSA contact with animals

61. High carriage rates in pig farmers
• Prevalence of MRSA carriage: 70%
• Almost all pig farms were MRSA positive
• Wearing of mouth masks during work had a
strong protective effect (ARR: 0.13)
Clinical Microbiology and Infection

62. Human to human transmission

63. LA-MRSA in veterinarians (1
year)
137 veterinarians
41 persistent
MRSA carrier (30%)
42 intermittent
MRSA carrier (31%)
54 no MRSA
carrier (39%)

64. LA-MRSA in household (1 year)
137 veterinarians
41 persistent
MRSA carrier (30%)
42 intermittent
MRSA carrier (31%)
54 no MRSA
carrier (39%)
25 HHM
≥ 1 MRSA (20%)
12 HHM
≥ 1 MRSA (10%)
5 HHM
≥ 1 MRSA (3%)
CC398 is transmitted from human to human

65. 16 healthy human volunteers were
inoculated with a mixture of the
human MSSA strain 1036 (CC8) and
the bovine MSSA strain 5062 (CC398)
CC398 was able to colonize the
human nose at least as good as the
human variant

66. 66

67. calculated spatial odds for LA-MRSA compared with those for T-MRSA, the Netherlands, 2003–2005.

68. • doubling pig, cattle, and veal calf densities per
municipality increased the odds of LA-MRSA
carriage over carriage of other types of MRSA
by 24.7%, 76.9% and 24.1%, respectively
• model adjusted for
– direct animal contact
– living in a rural area
– the probable source of MRSA carriage

69. LA-MRSA in the community
• 17 hospitals 2 year prospective follow-up
• 1023 new cases of MRSA
14.3
59.2
26.5
classical risk factors
contact with livestock
unknown source
22% LA-MRSA
(ST-398)

70. Other transmission routes?

72. LA-MRSA: food for thought
• MRSA is found frequently in retail meat
• Largest survey: 12%
• LA-MRSA and other types
• Risk for consumers unclear
• Potentially it is huge

73. Danmark
Health
Jobs
Money
Housing
Dating
Community
More
Every fifth pack of pork carries MRSA
Published: 24 Sep 2014 10:37 GMT+02:00
An analysis of pork products in Denmark’s supermarkets found that every fifth pack is contaminated
with MRSA. Just five years ago, a similar analysis found the bacteria in just five percent of products.
Over a dozen babies infected with MRSA (19 Sep 14)
Health
Photo: V. Meadu/CCAFS/CGIAR/Flickr
MRSA cases in Denmark doubled in just one year
Published: 12 Feb 2015 08:16 GMT+01:00
The variant of MRSA that can be transmitted from livestock to humans used to account for just two
percent of all MRSA cases but in 2014 the pig-borne bacteria accounted for 43 percent - "an epidemic
that is out control", an expert warned.
Two thirds of Danish pig farms have MRSA (22 Dec 14)
Second Danish death attributed to MRSA (15 Nov 14)
Danish MRSA pork found in Sweden (14 Nov 14)

74. Any good news ?

75. Transmissibility of LA-MRSA
Bootsma et al. J.R. Soc Interface 2010 (september)

76. Transmissibility of LA-MRSA
Bootsma et al. J.R. Soc Interface 2010 (september)
ST398 MRSA is 5.9 times less transmissible than non-ST398 MRSA
 allows for less stringent IC measures for LA-MRSA

77. Virulence
Several studies indicate that this strain has at present a limited virulence
However:
1) Veterinarians who were persistent carriers had higher incidence of skin and
soft tissue infections
2) Invasive infections with CC398 MSSA are increasing in several areas
O412
Abstract (oral session)
Unexpectedly high prevalence of the emerging CC398 methicillin-susceptible Staphylococcus aureus
clonal complex in bone and joint infections
F. Valour*, J. Tasse, S. Trouillet-Assant, J.-P. Rasigade, M. Bès, E. Chanard, B. Lamy, F. Vandenesch, T.
Ferry, F. Laurent on behalf of the Lyon Bone and Joint Infection Study Group
Objectives: To describe the prevalence of the emerging CC398 methicillin-susceptible S. aureus (MSSA) clone
in bone and joint infections (BJI). Methods: Retrospective study including patients with MSSA BJI (n=271) in 3
Among the 271 BJI isolates included, 43 (15.9%) belonged to CC398

78. LA-MRSA evolution
recent increase of MSSA 398 bacteremia in
France, merger of ST398, ST9 and a prophage

79. Conclusions
• LA-MRSA has recently emerged
• There is a huge reservoir in pigs, veal calves and
poultry
• People who work with livestock have extremely high
carriage rates
• There is also spread in the community which may be
related to meat consumption and to livestock density
• Invasive infections with CC398 (MSSA) are increasing
• CC398 is at the dawn of its evolution and close
monitoring of this zoonotic threat is warranted

83. Resistance is high and increasing
• Klebsiella pneumonia mainly reflects
differences in healthcare systems
– e.g. antibiotic use and infection control
• Escherichia coli with 3rd gen cephalosporin
resistance shows limited variation between
European countries

84. ESBL: The Netherlands
 Rapid increase since 2005
 Mainly community-acquired infections
 On admission 5% of patients carry ESBL
 Transmission in hospital is rare
 Source outside the hospital

85. Source in the community
 Some reports on ESBL in meat (Spain, USA,
Asia)

86. Meat survey
86,5%
17,6% 17,5%
40,9%
11,1%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Chicken Beef Pork Ground meat Other
PercentageESBLpositive

87. Meat as a source of ESBL

88. Comparison of sources
 Strains from humans and poultry (n=145)
 >100 genetic markers
 Resistance genes
 Plasmids
 House keeping genes
 Phylogenetic groups
 Virulence factors
 Humans: GI carriage and invasive infections

90. yellow = poultry blue = human (intestinal carriage) red = human (bacteremia)
145 strains
>100 genetic markers
Hierarchical cluster analysis
Colours indicate source groups

91. yellow = poultry blue = human (intestinal carriage) red = human (bacteremia)

92. Most studies compare
chicken with human
invasive infections
Bias by selection proces
based on virulence
factors
yellow = poultry blue = human (intestinal carriage) red = human (bacteremia)

93. P=0.003 P=0.001
P>0.05

94. Model of transmission and invasion
: virulent strains

95. Barrier against invasion

96. Barrier against invasion

97. Food source
GI flora Bloodstream

98. yellow = poultry blue = human (intestinal carriage) red = human (bacteremia)

99. Prediction model

100. Conclusions
• Meat (especially poultry) is frequently
contaminated with ESBL
• The strains in poultry are similar to what is
found in humans carriers (estimate 40%)
• The invasive strains consist of a non-random
sample from the carriage strains which should
be taken in consideration when comparing the
proposed source with strains causing invasive
infections

101. Old study, new methods
by applying high-resolution, whole-genome sequencing methods, we did not find evidence
for transmission of bacteria through the food-chain
by employing a novel approach for the reconstruction of mobile genetic elements from
whole-genome sequence data, we discovered that genetically unrelated E. coli isolates from
both humans and animal sources carried nearly identical plasmids that encode third-
generation cephalosporin resistance determinants

102. Farmers and pigs were linked in time
and place
and
carriage strains
Chicken, chicken meat and humans
were not linked in time and place
and
In humans strains from infections
Note:
also no match between chicken and
chicken meat

103. Phylogeny of reconstructed IncI1 and IncK plasmids and their closest relatives

104. conclusions
• We found that none of the human E. coli strains in our
dataset were closely related to strains from poultry
– Comment: only 32 strains in the analysis, no human
carriage strains, collected thoughout the country whereas
meat was bought in one city at another time
• In contrast, nine out of 17 human isolates (53%)
contained a blaCTX-M-1 or a blaCMY-2 gene located on
plasmids that were highly similar to those found in
poultry
– Very likely that plasmids play a role
• Epidemiology of the strains is important

105. more food for thought

106. Meat as a source of E. coli
Multiple lines of evidence suggest that many of the ExPEC strains
encountered in humans with urinary tract infection, sepsis, and other
extraintestinal infections, especially the most extensively antimicrobial-
resistant strains, may have a food animal source, and may be
transmitted to humans via the food supply

107. Meat consumption as a risk factor

108. Methods
• matched case-control study
– Cases were defined as patients colonized with
community-acquired ESBL (+) E. coli identified
72 h after hospital admission
– Controls were patients that carried no ESBL-
positive bacteria but an ESBL-negative E.coli
identified ,72 h after hospital admission

109. Results

110. What about vegetables?

111. Is this a risk?

112. Resistance in soil over time

114. ESBL in soil

115. Only in The Netherlands?

116. The clean Swiss lakes
21 of 58 samples were ESBL positive (mainly E.
coli)
1 Carbapenemase producing K. pneumoniae was
found

117. ESBL and CRE (VIM) below
1000 m

118. Conclusion
 High rate of ESBL in Swiss lakes and rivers
 Both human and animal related ESBL types
 Several E. coli ST-131 strains
 One Klebsiella pneumoniae with VIM
 Ecological polution is extensive

120. The last resort

122. Final conclusions
 The worldwide emergence of a variety of
ESBL genes is likely to result in a new wild
type E. coli / Klebsiella spp
 Then we will enter the triple-B-era

123. Bye bye beta-lactams

124. Conclusions:
• Antimicrobial resistance is increasing all over the world
in humans, animals, vegetables, soil and water
• Veterinary use of antimicrobials plays a role, especially
considering the ecological (long term) effects
• Current livestock production is an optimal system to
amplify antimicrobial resistance
• What are the political actions?

125. Awareness
• WHO
• ECDC
• CDC
• WEF
• It is on the agenda

126. But
• No sign of action against AMR in food
products
– 15% of meat contains MRSA
– 90% of poultry contains ESBL

127. Contrast

128. Reaction on resistance…..

130. No limits?
• What if
– Carbapenemases enter the food chain?
– LA-MRSA becomes hypervirulent?
– You name it……

131. FranciscodeQuito,Ecuador.
kswing@usfq.edu.ec
Ban resistant strains
from food chain
Noreliabletreatment is
availablefor humansinfected
with carbapenem-resistant
productsshouldbeachievable.
Weurgepoliticiansanddecision-
makerstoprotect publichealth
byactingpromptly,beforethe
problem becomeswidespread
andunmanageable.
JanKluytmans* VU University
Medical Center,Amsterdam,the
Netherlands.
jankluytmans@gmail.com
3 1 6 | N A T U R E | V O L 5 0 1 | 1 9 S E P T E M B E R 2 0 1 3
© 2013 Macmillan Publis
Correspondence
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go.nature.com/qahy4bfor full list).

134. We all play a role in this tragedy
• Pharmaceutical companies
– profit from sale of antibiotics for human and non human use
– benefit from need for new antibiotics
• Farmers
– produce cheap meat using antibiotics to mask failures in
production systems
• Consumers
– want cheap meat
– want antibiotics for rapid recovery
• Medical doctors
– restrictive use is rare

137. Measuring and transparency
• Europe is improving
– EFSA, ECDC, EMA
• US is far behind
• Asia, South America ???

138. Netherlands is changing, why?
• 2005 LA-MRSA
• 2009 ESBL in poultry
• and
– 2007-2009 Q-fever

139. Huge outbreak
>3500 confirmed human cases (small area)
At least 25 acute deaths
Many chronic cases
Positive goat farms were known but not
communicated to public health officials
Control measures were delayed

140. Netherlands is changing
• 2005 LA-MRSA
• 2007-2009 Q-fever
• 2009 ESBL in poultry
• Lots of media attention
• Society did not accept negative consequences
of industrial live-stock production anymore
• Political action

141. Minister of agriculture
50% reduction of antimicrobial use in 5 years
Install an independent body to monitor this
and take appropriate action (SDA)

142. Contact
Benchmark indicators

143. Contact
Antibiotic use: Veal calve (white meat)

144. Contact
Antibiotic use: Poultry

145. Yes, we can

147. Livestock 2004-2007 outpatient 2004-2007 hospitals
2004-2007
Humans versus animals in
kilograms
The Netherlands 2004-2007
Amountofantibiotics
inkg
population
Reduction
Use in 2012
Reduction is almost 10 times the total annual amount in
humans

148. Effects for humans??

149. ESBL in poultry meat from
supermarkets
0
10
20
30
40
50
60
70
80
90
2009 2013 2015
% ESBL

152. Promising, but
 Is this achievable in other parts of the world
 Alternative solutions?
 Imagine……………….

153. Make antibiotics expensive
 Make the commons expensive
 Antibiotic tax
 Would definitely work
 How about antibiotics for developing countries?
 Globalization makes this almost impossible

154. What should be done
 De-escalation
 At least do not allow the use of critical
antibiotics for livestock
 Carbapenems
 Glycopeptides
 Polymixins
 Cephalosporins
 Fluoroquinolones

155. Cross the border

156. Take home message

157. Take home message 2