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