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U.S. Department of Health and Human Services

Animal & Veterinary

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Complexities with Developing a Threshold Approach

SLIDE 1: COMPLEXITIES WITH DEVELOPING A THRESHOLD APPROACH

 

SLIDE 2: ANTIBIOTICS ARE A SPECIAL CLASS OF DRUGS

  • THEY ARE SOCIETAL
  • THEY AFFECT THE ENVIRONMENT

 

SLIDE 3: ANIMAL TO HUMAN TRANSFER OF RESISTANT BACTERIA

  • Direct routes of human exposure
    • Contact with animals
    • Ingestion of contaminated food
  • Indirect routes of exposure: environmental
    • Soil
    • Water

 

SLIDE 4: ANTIBIOTICS ENTER THE ECOSYSTEM

  • Any antibiotic use contributes to a broad resistance gene pool
  • Transfer of resistance increases complexity
    • Among species
    • Among pathogens and commensals

 

SLIDE 5: GENETIC LINKAGE

  • Antibiotic resistance genes are linked
    • on plasmids, transposons, integrons
    • Long term use of a single drug selects for multidrug resistance

 

SLIDE 6: EXPOSURE TIME

  • Exposure time stabilizes resistance genotype.
    • increases the fitness of the plasmid and host organism (Lenski et al., 1994)
    • increases the fitness of the resistant organism
  • Mathematical modeling suggests a sigmoidal rise in resistance over exposure time (Austin et al., 1999)

 

SLIDE 7: Relationship of Dose and Time to Resistance Frequency

A graphic image describing the relationship of Dose and Time to Resistance Frequency

 

SLIDE 8: ANTIBIOTIC USE IN ANIMALS: GENERAL CONSIDERATIONS

  • Local use has global impact
  • Antibiotics persist and act in the environment
  • Resistance selected by a single drug is spread in tandem with other resistances
  • Resistance is stabilized by longer drug exposure

 

SLIDE 9: CVM’s RISK MANAGEMENT

  • Supports WHO’s general principles for antibiotic resistance containment
    • Minimizing negative public health impact of animal antibiotic use
    • Providing for safe, effective use in veterinary medicine
  • CVM has taken and proposed important steps to meeting the complex challenge
    • Surveillance
    • Risk assessment
    • Proposed threshold approach to manage the risk

 

SLIDE 10: HUMAN HEALTH EFFECTS OF ANIMAL USE?

  • Does antibiotic use in animals select for specific resistances?
  • Does human exposure occur only directly?
  • Is the resistance frequency in animal samples mathematically related to human health impact in a linear way?

 

SLIDE 11: CHALLENGES ASSOCIATED WITH THE STRATEGY

  • Choice of surveillance targets must be continually refined and expanded
  • Risk assessment is an indirect method
  • Ecological impact is difficult to assess
  • Risk Thresholds depend on first defining a specific Human Health Threshold

 

SLIDE 12: THE THRESHOLD APPROACH

  • An important first step to preserve the efficacy of these crucial drugs
  • “The quality of risk analysis will improve as the quality of input improves. As we learn more about biology, chemistry, physics, and demography, we can make progressively better assessments of the risks involved.”
    • Science and Judgment in Risk Assessment. National Research Council. 1994

 

SLIDE 13: RECOMMENDATIONS

  • Focus first on absolute change in resistance frequency
  • Set thresholds as conservatively as possible
    • Specific to drug and organism of concern
    • Specific to genetic basis of resistance transfer
  • Consider incorporation of sentinel surveillance data
  • Make risk management an iterative process
    • Consider non-linear models
    • Make models drug-bug specific

 

SLIDE 14: PRUDENT ANTIBIOTIC USE

  • Remove use of antibiotics as growth promoters, when the drug class is also used in humans (WHO global principle for animal resistance containment, 2000)
  • Carefully consider consequences of growth promotant use even if drugs are not currently used in human medicine
  • Discourage treatment of long duration

 

SLIDE 15: ONGOING CHALLENGES

  • The challenges involved suggest
    • Continued and expanded surveillance
    • Continued reassessment of the threshold model
    • Continued involvement of all stakeholders
      • Advocacy groups, Industry, Research Institutions
  • The Alliance for the Prudent Use of Antibiotics (APUA) is contributing to the effort with
    • FAAIR: Facts about Antibiotics in Animals and their Impact on Resistance
    • ROAR: Reservoirs of Antibiotic Resistance