Henrik C' Wegener

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Veterinary Issues Contributing to Antimicrobial
Resistance

• Henrik C. Wegener
• WHO Collaborating Centre
• Danish Veterinary Institute
• Copenhagen, Denmark

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Antimicrobials use in animals

• Therapy
• treatement of disorders or disease
• Prophylaxis
• administration of antibiotics in advance of
  symptomatic disease e.g. medicated early weaning
• Growth promotion
• antibiotics used as feed additives with the
  purpose to increases feed efficiency or growth
  rate

3
Share of antimicrobials used for humans and
animals respectively in the USA and in the EU
USA
NEED FOR ACCURATE AND PUBLICLY AVAILABLE DATA!
Source UCS 2000
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Monitoring of Consumption

• WHO consultation on the Methods and Principles
  for the Monitoring of Antimicrobial Usage in Food
  Animal Production for the Protection of Public
  Health. 10-13 September 2001, Oslo, Norway.
• With the participation of FAO and OIE.
• Main recommendations
• Countries should establish a national monitoring
  programme for the usage of antimicrobial agents
  in food animals.
• Countries should have a regulatory approval and
  control system for antimicrobial agents and
  products containing antimicrobial agents.
• Data should be collected on the amount of each
  antimicrobial agent and these data should be
  reported in kilograms of active ingredient in an
  annual basis.
• Antimicrobial usage data should be linked with
  data on antimicrobial resistance, to enable
  timely corrective action. The recommendations of
  this meeting will be published soon.

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Selection and spread of antimicrobial resistance
in the farm-to-fork chain
Wild fauna Environment
(Natural Antimicrobials, Animal manure)

• Low doses
• Long duration
• Mass medication
• Prophylactic use

• Therapeutic use
• High dose/short term
• Clinical disease

Selective pressures favoring antibiotic
resistance development
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• AMR in FBP priority area of public health concern
• Identifies a number of specific public health
  hazards
• Recommends
• Monitoring of antimicrobial resistance in food
  animals and food of animal origin
• Risk Assessment
• Risk management at the primary food production
  level Prudent use of antimicrobials

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Public Health Concerns (I)Human pathogenic
bacteria spreading from animal reservoirs

• Current main concerns Resistance emerging to
  commonly used empiric therapies for acute GI
  tract infections
• Salmonella
• Fluoroquinolone-resistance
• 3rd gen. Cephalosporin-resistance
• Campylobacter
• Fluoroquinolone-resistance
• Macrolide-resistance

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• Objectives
• Identify links between spread and emergence of QL
  resistance in foodborne bacteria and human
  infection
• Recommendations on research agenda to assist in
  risk assessment
• Conclusion
• Campylobacter Salmonella a cause for concern
  but need for further research

WHO/EMC/ZOO/97.4 Distr. General English only
Quinolone Use in Food Animals and Potential
Public Health Impact
Report of a WHO Meeting Geneva, 2-5 June 1998
Division for Emerging and other Communicable
Diseases Surveillance and Control World Health
Organization
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Quinolone-resistant Salmonella Typhimurium DT104
(UK)
November 93 Enrofloxacin licensed for animal use
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Excess mortality associated with resistant
Salmonella Typhimurium infections

• The study comprised 2.047 patients registered
  between Jan. 1995 and Oct. 1999 - 2 year
  observation period
• A reference group of 20.456 persons were included
• Infections with penta- or quinolone resistant
  salmonella had increased mortality rates compared
  to infections with sensitive strains
• Resistant Sensitive
• Penta resistant (DT104) 4.8 (6.9) 2.1 (2.6)
• Quinolone resistant 10.2 (9.9) 2.1 (2.8)
• figures in parentheses not corrected for other
  diagnoses

Helms, Molbak et al., submitted
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Global trends in Campylobacter quinolone
resistance
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Public Health Concerns (II)Exchange of
resistant commensal bacteria and opportunistic
pathogens between animals and humans

• Current main concerns Resistance to important
  last resort antimicrobials for G nosocomial
  infections
• Enterococcus faecium
• Vancomycin-resistance
• Synercid-resistance
• Resistance moving from E. faecium to S. aureus
  a.o. in animals or in humans

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Usage of growth promotants in animals and
occurrence of resistant Enterococcal infections
in humans

• E. faecium causes serious life threatening
  infections in immunocompromised patients
• Vancomycin and synercid are drugs of choice
• E. faecium has an animal reservoir
• E. faecium in animals develop resistance to
  vancomycin and synercid due to the use of
  avoparcin and virginiamycin as growth promoters
• Is there a link between the animal reservoir and
  resistant nosocomial infections in humans?

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Evidence of VRE transfer from animals to humans

• VRE in food-animals (EU)
• Poultry 59
• Swine 29
• (DANMAP 97)
• VRE in food stuffs (EU)
• Poultry 16-40
• Pork 15-38
• (Wegener et al. 1997)
• VRE in the community
• EU (5)
• USA (0)
• (Goosens, 1997, Coque et al. 1996)

• VRE from animals can colonize humans
• (Blom et al. ICAAC 2000)
• Identical or closely related strains of VRE in
  animals, food and humans
• (Kruse et al. 1995, Boogard et al. 1997, Hammerum
  et al. 2000, Willems et al. 2000)
• Identical vancomycin resistance genes in animals
  and humans
• (Jensen et al. 1998)

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Synercid resistant E. faecium

• Synercid resistant E. faecium occurring in
  food-animals, food and humans in the community in
  USA and Europe
• Identical strains in humans and animals
• Identical genes, vat(D) and vat(E), in humans and
  animals
• Vat(D) located on a transposable genetic element
• Virginiamycin banned in the EU (99)
• QRA initiated by US-FDA

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WHO Global Principles

• Pre-licensing evaluation including consideration
  for resistance
• Obligatory prescription for all antimicrobials
  used for disease control
• National systems to monitor antimicrobial usage
  in food animals
• Monitoring of resistance and timely corrective
  actions
• Guidelines for veterinarians to reduce overuse
  and misuse
• Termination or rapid phasing out of antimicrobial
  growth promoters

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History of banning AGPs in the EU

• 1986, Sweden banned the use of all AGPs due to
  concerns about resistance
• 1995, the Danish MoA banned the glycopeptide AGP
  avoparcin
• 1997, avoparcin was suspended in EU
• 1998, a second growth promoter virginiamycin, a
  streptogramin, was banned in Denmark

• 1998, Danish poultry producers voluntarily
  stopped using AGPs
• July 1999, 4 growth promoters were suspended in
  EU spiramycin, tylosin, bacitracin and
  virginiamycin
• 2001, a proposal by the EU Commission to phase
  out all AGPs before end of 2006
• Autumn 2002, to be discussed and approved by the
  EU Council of Ministers

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Voluntary stop of all AGP usage in Denmark

• The producers were concerned about
• Decreased productivity
• Increased morbidity and mortality
• Increase in the No. of Salmonella infected herds
• Increased therapeutic consumption of
  antimicrobials

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Trends in the occurrence of resistance to
Vancomycin and Synercid among E. faecium from
broilers and pigs and the consumption of
Avoparcin and Virginiamycin in Denmark
Source DANMAP 99
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VRE in healthy and hospitalized humans following
prohibition of avoparcin as a growth promoter
NL
DE
BE
Klare et al., 1997 van den Bogaard et al.
2000 Ieven et al. 2001
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Experiences with broiler and pig productivity

• Finishers and growers No or a very limited
  effect of the withdrawal of AGPs
• Weaned pigs In some herds problems with post
  weaning diarrhea decrease in daily weight gain
  and increase in post weaning mortality

• Kg broilers produced per m2 and mortality were
  not affected by the withdrawal of AGPs
• The feed conversion ratio increased only
  marginally with 0.016 kg feed/kg broiler
• Cost of feed increase equivalent to costs saved
  on AGP

Retail prizes of broiler meat and pork has not
increased
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Total consumption of antimicrobials for food
animals in Denmark 1990-2000
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General and voluntary veterinary treatment
guidelines

• Use resistance surveillance data to rank
  antimicrobials according to efficacy
• Priority given to narrow spectrum antimicrobials
• Priority given to older classes of antimicrobials
• Include all diseases commonly presenting in
  clinical practice

Van den bogaard, 1993
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Danish treatment guidelines - fatteners and
slaughter pigs
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The pecuniary issue - vested interests

• In most countries, veterinarians acquire a major
  part of their income from the sale of medicines
• In the UK gt40 of the veterinarians income come
  from the sale of drugs - primarily antimicrobials
• In the Phillipines it is up to 100
• In Denmark it is lt5

WHO, 2000 If the evidence exists, appropriate
countermeasures should be taken to ensure prudent
use
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Restricting access to certain antimicrobials -
New Danish veterinary medicines regulation

• Flouroquinolones can only be prescribed if the
  need has been justified by diagnostic testing
  (AMR testing)
• Prescription must be approved by the district
  veterinary officer
• Flouroquinolones must be administered by the
  veterinarian him-/herself

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DANMAP - resistance monitoring logistics
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DANMAP - Data on Consumption of Antimicrobials in
Food Animals (Vetstat)

For each transaction Farm code Animal
species Age group Date Name of drug Quantity of
drug Reason for prescribing
85
Danish Medicines Agency
15
VETSTAT (Danish Zoonosis Centre)
Medicated animal feed
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Conclusions

• Bacterial infections spreading from animals to
  man via food has become increasingly difficult to
  cure due to resistance development, and the trend
  persists
• Integrated antimicrobial resistance monitoring
  programs should be established to support timely
  intervention by detecting new and emerging
  resistance problems relating to animals and food
• Monitoring of antimicrobials usage in animals
  (and humans) is an essential tool to detect and
  reduce misuse and overuse of antimicrobials in
  food animals
• In most countries with intensive animal
  production systems the use of antimicrobials in
  food animals can be reduced by more than 50 with
  no, or only very minor effects, on productivity
  and animal health

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Safe Food for All
Thank you for your attention!