Antimicrobial use in agriculture – resistance from both society and microbes
FarmSmart Agricultural ConferenceUniversity of Guelph, Guelph, Ontario
Tim McAllisterPrincipal Research ScientistLethbridge Research Centre
Agriculture andAgri-Food Canada
Agriculture etAgroalimentaire Canada
Source: WHO, 2014
May 2016: UK commissioned a review on AMR by Jim O’Neill
In nearer term, expect GDP to be reduced by 0.5% by 2020, and 1.4% by 2030
Nature: doi:10.1038/nature.2014.15135
Holmes et al., 2015
Holmes et al., 2015
Global consumption in livestock in 228 countries (mg/10 km2 pixel)
2010 2030 ‐ 63,151 tons in 2010‐ Increase by 67% in 2030
Increased demand for livestock products in middle‐income countries
Resulting shift to large‐scale farms
Van Boeckl et al., 2015
Posterior distributions for estimates of antimicrobial consumption in cattle, chickens, and pigs in OECD countries
Thomas P. Van Boeckel et al. PNAS 2015;112:5649-5654
©2015 by National Academy of Sciences
45 mg kg‐1148 mg kg‐1
172 mg kg‐1
Resistance genes are ubiquitous and ancient
Bhuller et al., 2012 D’Costa et al., 2011
Lechuguilla Cave, New MexicoRegion isolated for 4M years
Permafrost sediment
Microbial war
Antibiotic use heightens resistance
Schmieder and Edwards, 2012Chait et al., 2012
Void in antibiotic development pipeline
Use of antibiotics
Linton, A.H. (1977) and Irwin, R. (2007)
Elanco Animal Health
ribosomesribosomes
DHFDHF
THFTHF
PABA
cell wall synthesis & integrity
bacitracincarbapenemscephalosporinsD-cycloserinemonobactamspenicillinsvancomycin
translation (protein synthesis)50s inhibitors: 30s inhibitors:erythromycin tetracyclinechloramphenicol streptomycinclindamycin spectinomycinlincomycin kanamycin
gentamycin
folic acid metabolism
trimethoprimsulfonamide
DNA replicationnalidixic acidquinolones DNA synthesis
metronidizole
transcriptionrifampicin
cytoplasmicmembrane
polymyxins
chromosomalDNA
chromosomalDNA
mRNAmRNA
Antibiotic classes (cellular target)
antibioticalteringenzyme
antibioticalteringenzyme
antibioticdegrading enzyme
antibioticdegrading enzyme
antibiotic
antibiotic
antibioticantibioticresistancegenes
chromosomal DNAchromosomal DNA
plasmidDNA
plasmidDNAantibiotic
efflux pump
antibioticefflux pump
Adapted from Levy & Marshall, 2004
Elanco Animal Health
Importance in treating serious human infections
CATEGORYI I VI I I I I
Preferred optionfor serious
infections and limited or no treatment alternatives available
Preferred option for serious infections, alternatives available
Not a preferred option for serious
infections,
Not a preferred option, not used
in human medicine
SWINE FEEDAntibiotic RankVirginiamycin IILincomycin IITilmicosin IITylosin phosphate IIChlortetracycline , sulfamethazine and procaine penicillin
II/III
Lincomycin and Spectinomycin II/IIITylosin phosphate and Sulfamethazine
II/III
Zinc bacitracin and procaine penicillin
II/III
Bacitracin methylene disalicylate
III
Bacitracins IIIChlortetracycline IIIOxytetracycline IIIIonophores IV
POULTRY FEEDAntibiotic RankVirginiamycin IIErythromycin thiocyanate IIHygromycin B IIPenicillin from Procaine penicillin
II
Zinc bacitracin and Procaine Penicillin
II
Bacitracins IIIChlortetracycline IIIOxytetracycline IIIBambermycins IVIonophores IV
CATTLE FEEDAntibiotic RankTylosin phosphate IIOxytetracycline hydrochloride and Neomycin sulphate
II/III
Bacitracins IIIChlortetracycline IIIChlortetracycline and Sulfamethazine
III
Oxytetracycline IIIIonophores IV
Antibiotics approved for animal feed, ranked by importance to humans
Rankings according to Health Canadacriteria
I0.03%
II15.35%
II/III13.05%
III42.33%
IV29.24%
Source: CIPARS report, 2008
Ranked by importance to human medicine (I‐IV)
ANIMALS
Source: Cameron and McAllister, 2016
McAllister and Topp 2015; Animal Frontiers
Natural | ConventionalCommercialbroiler farms
Waste WaterTreatmentInfluent
Waste WaterTreatmentEffluent
Clinical Bacterial Isolates
Alberta Health Region
Catch basins
Retail meat
Irrigated soilsmanure
Natural |ConventionalPork production
Surface WaterWetlands &
Creeks
Natural |ConventionalBeef production
sewagedrinking water
crops
common antibioticsmeat distribution
manurewater runoff
ANTIMICROBIALRESISTANCECONTINUUM
E. coli, enterococci, Salmonella,Campylobacter, metagenomic DNA
E. coli, enterococci, Pasteurellaceae,metagenomic DNA
E. coli, enterococci
E. coli, enterococci
E. coli, enterococci,metagenomic DNA
E. coli, enterococci,metagenomic DNAE. coli, enterococci,
Salmonella,metagenomic DNA
McAllister et al., unpublished
Alberta HealthRegion
Clinical BacterialIsolates
Catch basins
Surface WaterWetlands &
CreeksBeef production
Fecalcomposite
sewagedrinking water
crops
common antibioticsmeat distribution
manurewater runoff
ANTIMICROBIALRESISTANCECONTINUUM
Enterococci diversity is niche‐specific
n=2,192
n=113
n=209
n=429
Waste WaterTreatmentInfluent
Waste WaterTreatmentEffluent
n=141
Antimicrobial resistance determinant (ARD) sequences were sourced from 3 databases
ResfinderCenter for Genomic Epidemiology
2,202 ARDs
ARG‐ANNOTUniversité Aix‐Marseille, Marseille, France
1,686 ARDs
CARDMcMaster University
2,696 ARDs
Master, non‐redundant database3,111 ARDs
Databases exist, but are they • comprehensive? • up‐to‐date?• accurate? • complete?
Noyes et al. 2016 e‐life
AMR Prevalence
(McAllister ‐ Morley lab unpublished)
(McAllister – Morley lab unpublished data)
Catch Basin Fecal Composite
(McAllister – Morley lab unpublished data)
What are the next steps?• Optimize antimicrobial use through reduction in misuse.
• Benchmark actual antimicrobial use.
• More rapid and accurate diagnostics (next generation sequencing).
• Better understanding of transmission, dissemination through enhanced surveillance.
• Multiple linkages with other antimicrobial resistant genes
• Linkages with virulence factors
• Phylogenetic profile, density and distribution of human pathogens.
Dar et al., 2015
RESEARCHStudy the kinds & flow of resistance (genes) and zoonotic potential of
microbes
MANAGEMENTConsider livestock production practices to reduce use and potential impact on human
medicine
SURVEILLANCEMonitor the emergence of
resistance (genes) and potential for transfer between livestock –
the environment – and consumer products
DEVELOPMENT OF ALTERNATIVES
Design/test therapeutic approaches against veterinary or zoonotic
diseases
Take Home Point
Microbes are masters of adaptation
Oct. 15, 2012: Health Canada Recalls Antibacterial hand soap –Pseudomonas aeruginosa
Dr. Rahat ZaheerDr. Ed ToppDr. Trevor AlexanderDr. Sheryl GowDr. Patrick BoerlinDr. Frank LarneyDr. Srinivas SuraShaun CookDr. Cassidy KlimaAlicia BeukersRuth BarbeiriAnimal handling staffDr. Ron ReadDr. Deirdre ChurchDr. Sylvia ChecklyDr. Calvin BookerDr. Sherry HannonDr. Paul Morley
Agriculture andAgri-Food Canada
Agriculture etAgroalimentaire Canada
Dr. Kim Stanford
2016
Questions?