antibiotic resistance: a tragedy of the commons, prof. jan kluytmans
TRANSCRIPT
Jan KluytmansThe Netherlands
UMC Utrecht, Amphia Breda
Antibiotic ResistanceA tragedy of the commons
Topics
The problemUnderlying mechanisms
Transfer between animal species, including humansCurrent actions
The future
The problem
Rather than see expenditure on antimicrobial policies as a cost, we should think of it as an
insurance policy
Resistance is high and increasing and there are no new drugs
AMR in 2050
Classical model
But also
The perfect storm
• Lack of sanitation• Lack of basic hygiene• High and uncontrolled use of antibiotics
A metaphor for a complex societal problem with ecological consequences?
AMR:a tragedy of the commons?
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.
The role of non-human use
• Most antibiotics are given to animals• Most animals that receive antibiotics are
healthy
70%
6%9%
15%Animals non-therapeuticAnimals therapeuticHumans therapeuticOther (pesticides etc)
Comparison of biomass-corrected consumption of antimicrobials in humans and food-producing
animals by country in 26 EU/EEA countries in 2012
Antibiotic use in Livestock
• Huge variation between countries• Huge variation within countries• Huge variation between various species
Antibiotic use in Livestock
• General picture– Frequent use– Low dosages – Bad hygiene– Crowding– Frequent transfer of animals
PEW CHARITABLE TRUSTS
SAVEANTIBIOTICS.ORG
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.
The facts
PEW CHARITABLE TRUSTS
SAVEANTIBIOTICS.ORG
v
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 animalsusing 2011 and 2012 data currently available from their relevant five EU monitoring networks
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
p- value < 0.05;
OR = 2.415; 95 % PL CI: [1.596, 3.652]
HumansFluoroquinolones use and resistance
p-value < 0.001;
OR = 1.614; 95 % PL CI: [1.383, 1.886]
the more you use itthe sooner you loose it
Humans and other animals
Fluoroquinolones use in animals and resistance in humans
p-value < 0.001;
OR = 1.112; 95 % PL CI: [1.063, 1.162]
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???
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
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?
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
Mathematical model
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
From mathematical models to real life
The Netherlands
The current situation (Hospitals)
The current situation (community)
Use in animals
The Dutch paradox
Livestock 2004-2007 outpatient 2004-2007 hospitals 2004-2007
Humans versus animals in kilogramsThe Netherlands 2004-2007
>90% is used in livestock
Am
ount
of a
ntibi
otics
in k
g
population
Every disadvantage has its advantage
• Low use in humans• High use in animals• Perfect setting to monitor emergence of
resistance in humans from livestock
Recent examples
• MRSA• ESBL• Focus on findings in The Netherlands
It always starts with one case2004 Preoperative screening > MRSAEradication failed repeatedly
Non-typable
Father was a pig farmer
Several other non-typable cases related to pig farmers
Study group: 23% positive
MLST: CC398
MRSA (human cases)
LA-MRSA contact with animals
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
Human to human transmission
LA-MRSA in veterinarians (1 year)
137 veterinarians
41 persistentMRSA carrier (30%)
42 intermittentMRSA carrier (31%)
54 no MRSA carrier (39%)
LA-MRSA in household (1 year)
137 veterinarians
41 persistentMRSA carrier (30%)
42 intermittentMRSA 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
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
calculated spatial odds for LA-MRSA compared with those for T-MRSA, the Netherlands, 2003–2005.
• 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
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 factorscontact with livestockunknown source
22% LA-MRSA (ST-398)
Other transmission routes?
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
Danmark
Any good news ?
Transmissibility of LA-MRSA
Bootsma et al. J.R. Soc Interface 2010 (september)
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
VirulenceSeveral 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 infections2) Invasive infections with CC398 MSSA are increasing in several areas
Among the 271 BJI isolates included, 43 (15.9%) belonged to CC398
LA-MRSA evolution recent increase of MSSA 398 bacteremia in France, merger of ST398, ST9 and a prophage
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
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
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
Source in the community Some reports on ESBL in meat (Spain,
USA, Asia)
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 meatOther
Perc
enta
ge E
SBL
posi
tive
Meat as a source of ESBL
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
yellow = poultry blue = human (intestinal carriage) red = human (bacteremia)
145 strains>100 genetic markersHierarchical cluster analysisColours indicate source groups
yellow = poultry blue = human (intestinal carriage) red = human (bacteremia)
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)
P=0.003 P=0.001
P>0.05
Model of transmission and invasion : virulent strains
Barrier against invasion
Barrier against invasion
Food source
GI flora Bloodstream
yellow = poultry blue = human (intestinal carriage) red = human (bacteremia)
Prediction model
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
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
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
Phylogeny of reconstructed IncI1 and IncK plasmids and their closest relatives
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
more food for thought
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
Meat consumption as a risk factor
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
Results
What about vegetables?
Is this a risk?
Resistance in soil over time
ESBL in soil
Only in The Netherlands?
The clean Swiss lakes
21 of 58 samples were ESBL positive (mainly E. coli)1 Carbapenemase producing K. pneumoniae was found
ESBL and CRE (VIM) below 1000 m
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
The last resort
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
Bye bye beta-lactams
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?
Awareness
• WHO• ECDC• CDC• WEF
• It is on the agenda
But
• No sign of action against AMR in food products – 15% of meat contains MRSA– 90% of poultry contains ESBL
Contrast
Reaction on resistance…..
No limits?
• What if – Carbapenemases enter the food chain?– LA-MRSA becomes hypervirulent?– You name it……
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
Measuring and transparency
• Europe is improving– EFSA, ECDC, EMA
• US is far behind• Asia, South America ???
Netherlands is changing, why?
• 2005 LA-MRSA• 2009 ESBL in poultry• and
– 2007-2009 Q-fever
Huge outbreak>3500 confirmed human cases (small area)At least 25 acute deathsMany chronic cases
Positive goat farms were known but not communicated to public health officials Control measures were delayed
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
Minister of agriculture
50% reduction of antimicrobial use in 5 years
Install an independent body to monitor this and take appropriate action (SDA)
Benchmark indicators
Antibiotic use: Veal calve (white meat)
Antibiotic use: Poultry
Yes, we can
Livestock 2004-2007 outpatient 2004-2007 hospitals 2004-2007
Humans versus animals in kilogramsThe Netherlands 2004-2007
Am
ount
of
anti
biot
ics
in k
g
population
Reduction
Use in 2012
Reduction is almost 10 times the total annual amount in humans
Effects for humans??
ESBL in poultry meat from supermarkets
2009 2013 20150
10
20
30
40
50
60
70
80
90
% ESBL
Promising, but Is this achievable in other parts of the
world Alternative solutions? Imagine……………….
Make antibiotics expensive Make the commons expensive Antibiotic tax
Would definitely work How about antibiotics for developing
countries? Globalization makes this almost impossible
What should be done De-escalation At least do not allow the use of critical
antibiotics for livestock Carbapenems Glycopeptides Polymixins Cephalosporins Fluoroquinolones
Cross the border
Take home message
Take home message 2