This document discusses emerging issues related to antibiotic resistance linked to antibiotic use in food animals. It provides an overview of recent conferences and publications on the topic. It discusses the concept of microbes and antibiotic resistance residing in environmental reservoirs and how industrial antibiotic use can amplify resistance. Specific concerns discussed include vancomycin-resistant enterococci, multidrug-resistant Salmonella, ESBL-producing Enterobacteriaceae, livestock-associated MRSA, and colistin-resistant E. coli harboring the mcr-1 gene. The document also examines evidence regarding the public health impacts of issues like LA-MRSA in Denmark and the United States. It concludes by noting increasing scrutiny of antibiotic use in food animals and the

1. Emerging Issues in Antibiotic Resistance
Linked to Use in Food Animals
Peter Davies BVSc, PhD
College of Veterinary Medicine, University of Minnesota

2. This week in Antibiotic Resistance
• World Antimicrobial Resistance Congress in DC
• EU Joint action on antimicrobial resistance (EU-JAMRAI)
launched in Paris
• EMA/ECDC joint meeting with WHO - London (9/19)
• PACCARB meeting in DC
• >60 new peer reviewed publications (= 2016)
• 17,600 web postings (down from 421,300 in 2016)
• 660 news items (down from 3,090 in 2016)

3. The 60….. year argument

4. Evolving paradigms
• Understanding AMR in ‘ecosytems’ vs.
‘reductionist’ approaches
• Increasing breadth and depth of research
– Wider scope: ‘One Health’
• Humans, animals, environment
– Sharper tools
• Metagenomics, microbiome, resistome,….
• Whole genome sequencing, bioinformatics,…
• Observations precede understanding
– Increased ‘finger pointing’ potential
– Guilty until proven innocent

5. Lessons from the Environmental Antibiotic Resistome
Surette MD, Wright GD (2017) Annual Review of Microbiology
• Soil, aquatic, atmospheric, animal-associated, and
built ecosystems are home to microbes harboring
resistance elements and the means to mobilize them
• Soil is the largest reservoir of resistant organisms
• Antibiotic use has increased AMR in all reservoirs

6. Lessons from the Environmental Antibiotic Resistome
Surette MD, Wright GD (2017) Annual Review of Microbiology
• Diversity/abundance of resistance in the environment
reflects ancient origins of Abx and associated AMR
• We have failed to view AMR as the product of evolution in
all ecological niches over geologic time periods
• Industrialization of Abx production and use in humans and
animals creates global selective pressures for the
amplification, diversification, and dissemination of
resistance
– never experienced before by microbes at this scale

7. • MDR bacteria likely the norm rather than exception
• Clusters likely present in many bacterial taxa
– Enrichment largely independent of phylogenetic composition
• Clusters contain resistance genes independent of
particular antibiotic uses on the farms
• Coselection: clusters enriched by use of a subset of
compounds (or only one) to which resistance occurs
• Managing this resistance reservoir is important for
minimizing human risk

8. Reservoir of pathogen
CDC
• Habitat in which an infectious agent normally lives,
grows, and multiplies
• Reservoirs include humans, animals, and the
environment
• Reservoir may or may not be the source from which
an agent is transferred to a host
– Largest reservoir of Clostridium botulinum is soil
– Most human botulism infections due to improperly canned
food containing C. botulinum spores
• Sizes of reservoirs not proportional to rates of
transmission

9. Livestock may be largest animate
reservoir of some resistant organisms

10. % of ‘non typhoid’ Salmonella resistant
to >3 classes of antibiotics (NARMS 2013)
17%
9.8%
MDR more prevalent in
in food animal reservoirs

11. Antibiotic resistance threats in the USA
(CDC, Am Fam Physician. 2014 Jun 15;89(12):938-941.)
Urgent
• Clostridium difficile
• Carbapenem-resistant
Enterobacteriaceae
• Drug-resistant N. gonorrhea
Concerning
• Vancomycin-resistant S. aureus
• Erythromycin-resistant group A
Streptococcus
• Clindamycin-resistant group B
Streptococcus
Serious
• Multidrug-resistant Acinetobacter
• Drug-resistant Campylobacter
• Fluconazole-resistant Candida
• ESBL–producing Enterobacteriaceae
• Vancomycin-resistant Enterococcus
• MDR Pseudomonas aeruginosa
• Non-typhoidal Salmonella
• Salmonella serotype Typhi
• Drug-resistant Shigella
• MRSA
• MDR Streptococcus pneumoniae
• Drug-resistant tuberculosis

12. Urgent
• Clostridium difficile
• Carbapenem-resistant
Enterobacteriaceae
Concerning
Serious
• Multidrug-resistant Acinetobacter
• Drug-resistant Campylobacter
• ESBL–producing Enterobacteriaceae
• Vancomycin-resistant Enterococcus
• Non-typhoidal Salmonella
• MRSA
• Colistin resistant Enterobacteriaceae
Antibiotic resistance threats in the USA
Foodborne and/or livestock reservoir

13. Driving the debate
Tangible concerns
 Vancomycin resistant enterococci (1990s)
 MDR Salmonella
 S. typhimurium DT104 (1990s)
 S. Newport (2000s), …..
 ESBL Enterobacteriaceae
 ‘Livestock associated’ MRSA
 Colistin resistant (mcr-1) Enterobacteriaceae
 Carbapenem resistant Enterobacteriaceae

14. ESBL and CRE resistant Enterobacteriaceae
• Extended spectrum beta-lactamase (ESBL)
– Resistance to penicillins and cephalosporins
– Initial links to poultry and invasive human isolates
– WGS studies indicate ‘phylogenetically distinct’ isolates
• Carbapenem resistance (CRE)
– Resistance to penicillins, cephalosporins, carbapenems
– Emergence of untreatable Gram negative infections
– e.g., Klebsiella pneumoniae, E. coli
• Use of last resort Abx, e.g. colistin
14

15. Colistin (polymyxin E)
• Polymyxin antibiotic effective against most
gram negative bacteria
• High toxicity in humans (kidney)
– Sparsely used in human medicine
– ‘Last resort’ option from MDR bacteria
• Resistance rare in human bacteria
– Primarily chromosomal (no HGT)
• Widely used in livestock in Asia and the EU
– Companion animals

16. Colistin resistant E. coli in China
Liu et al (2015)
• High prevalence of mcr-1 gene in E coli and
Klebsiella pneumoniae from pigs and poultry
in China (20 – 25%)
• Novel gene encoded on a plasmid and highly
transferable in vitro
• Subsequently found in many countries and
types of samples, including US swine
• Retrospective: 10% of samples positive in
German pigs in 2011-2012 (25% of farms)

17. Why does the mcr-1 gene matter?
• ‘There may be a vicious synergy of AMU in
animals and in humans, whereby resistant
bacteria that spill over to humans from
livestock can ignite a blaze of resistant
pathogens when medical AMU is high’
• ‘Elevated AMU on the farm can rapidly
amplify resistance among human pathogens
that find their way into livestock’
17
Price et al., 2015, PNAS 112:5554

18. Why does the mcr-1 gene matter?
• Colistin a 'last-line' drug against MDR Gram
negative pathogens (CRE)
• Colistin sparsely used in humans globally, but
widely used in animals in many countries
– 12,000 tons globally in 2015
• mcr-1 reported in: (Al-Tawfiq et al, 2017)
– Humans in 29 countries
– Environmental samples in 4 countries
– Animals in 28 countries
• Studies implicating food of animal origin
18

19. • “Pigs can host MDR strains with accumulated
plasmid-mediated resistance against several
last-line antibiotics”
• Fishing expeditions?
– 7,850 fecal E. coli from 2,160 pigs
– Screened with selective media with meropenem
– 2 isolates positive for blaOXA-181
• One of them positive for mcr-1

20. ST398 ‘Livestock associated’ MRSA
Generally accepted ‘facts’
• First recognized in Netherlands in 2004
• High exposure risk for people with animal contact
– 20-50% vs. ~ 0.5 - 2% in general populations
• Human clinical cases reported, some serious
– Serious infections rare in healthy livestock workers
– Several deaths (~10 in > 10 years) in medically
compromised people
– Low risk of exposure for the general public

21. LA-MRSA in the USA
• Prevalence relatively low in US swine
– ST398, ST5, ST9 (Smith 2013, Sun 2015)
• ST398 MRSA carriage same (2-3%) in people
in Iowa exposed vs. not to pigs (Wardyn, 2015)
• Study of human laboratories in IA (Nair, 2016)
– LA-MRSA found in 0.24% of MRSA cases
– LA-MSSA ~ 1% of S. aureus infections
• UMASH pilot study - Fairmont Hospital, MN
– 2 of 91 clinical S. aureus isolates ST398/t034

22. Human health impact of
MRSA CC398 in
Denmark
Jan Dahl
DVM, chief advisor
Danish Agriculture & Food Council

23. Incident human cases
Infections and screening
0
500
1000
1500
2000
2500
3000
3500
4000
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Total MRSA CC398

24. 0
500
1000
1500
2000
2500
3000
3500
4000
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Total MRSA CC398
Screening of people with pig contact
Incident human cases
Infections and screening

25. Incident human ST398 MRSA infections
(no pig contact) vs. herd prevalence
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0
20
40
60
80
100
120
2009 2010 2011 2012 2013 2014 2015 2016 2017
Herdprevalence
Humanclinicalincidence
Incidence in patients Herd prevalence

26. S. aureus bacteremias in Denmark
Total, total MRSA, MRSA CC398
0
500
1000
1500
2000
2500
2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Annualnumberofbacteremias
Total Staph Total MRSA MRSA CC398

27. MRSA bacteremias in Denmark
Total MRSA, MRSA CC398
0
10
20
30
40
50
60
70
2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017
prog
Annualnumberofbacteremias
Total MRSA MRSA CC398
~0.2% of S. aureus bacteremias

28. LA-MRSA summary
• Politically radioactive
• National situation can change rapidly
• Denmark is ‘worst case scenario’
– Dense swine and human populations
– `100% MRSA prevalence among herds
• Exposure very common in swine workers
– Disease very rare
• Public health impact remains small
– Estimated 0.6 deaths, 45 lost work days annually

29. Looking forward
• Increasing scrutiny of antibiotic use in food
animals will not go away
• More ‘issue management’ in response to
descriptive findings of AMR genes/bacteria in
food animals and retail products
– Mostly without direct links to public health impact
• Proactive approaches to ensure customers
and critics of ‘appropriate uses’
• Get on board the ‘antibiotic stewardship’ train