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U.S. Department of Health and Human Services

Animal & Veterinary

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CVM Approach to the Establishment of Thresholds - General Overview

General Overview

Stephen F. Sundlof, D.V.M., Ph.D.
FDA Center for Veterinary Medicine
January 22, 2001


Threshold Concept

Regulatory thresholds first proposed in the 1999 Framework document

  • “The agency believes that it may be possible in certain cases to define a level of resistant bacteria in animals that would result in no or insignificant transfer of resistance to human pathogens.”
  • “The agency believes that this level of resistant bacteria in animals would need to be determined for each antimicrobial prior to approval, and may vary depending on the human or animal pathogen of concern.”


Why Thresholds? 

  • Unlike chemical residues which are evaluated using a battery of well established laboratory methods, no predictive models presently exist to estimate the rate and extent of bacterial resistance that may emerge from the use of antimicrobial drugs in food animals
  • In the absence of predictive models, CVM is proposing the establishment of resistance thresholds as an added safeguard to protect public health.

Deconstructing Thresholds

  • Thresholds consist of 3 interrelated parts
    • antimicrobial
    • Animal species
    • bacterial species
  • One or more thresholds may be established for a specific drug in a given animal species


Central Premise of the CVM Method

  • By understanding the dynamics of the disease itself, the impact of resistance on human health can be estimated
    • requires knowledge of  the extent to which bacteria on a given food commodity are transferred to humans and cause disease
    • by focusing on the disease rather than the specific drug, only a limited number of disease models are needed to support a wide variety of antimicrobial drugs

What the Method Does Not Require

  • predictive models that would be difficult to develop and subject to error
  • knowledge of complex dose-response relationships or minimum infective dose
  • knowledge of the effects of animal husbandry, transport, and processing on pathogen load
  • knowledge of food handling practices

What the Method Does Require 

  • Knowledge of the contribution each food animal species makes to the overall disease prevalence in humans
  • The likelihood that the patient will be treated with the antimicrobial of concern
  • All other data are captured in real time through ongoing surveillance programs


Example 1 Hmax(x)

  • 10% of all Salmonella cases can be traced back to food derived from Species A
  • If 10% of all patients with salmonellosis are treated with the antimicrobial drug of concern…
  • Up to 1% of patients may not respond to treatment when 100% of Salmonella are resistant as the result of antimicrobial drug use in Species A

Example 2 H(x)

  • Up to 1% of patients may not respond to  treatment when 100% of Salmonella are resistant as the result of antimicrobial drug use in Species A
  • But if only 2% of Salmonella from Species A are resistant to the antimicrobial…
  • The current human health impact would be 0.02% or 2 out of every 10,000 Salmonella cases


Recalculating Resistance Thresholds 

  • Resistance thresholds can be periodically adjusted to take into account changes in:
    • Food production practices
    • Food processing practices
    • Food hygiene practices
    • Food consumption
    • Physician prescribing practices


Limitations to the CVM Approach

  • The proposed approach does not deal with all of the potential issues associated with antimicrobial resistance such as:
    • Multiple drug resistance
    • Indirect transfer of resistance to non-zoonotic pathogens
  • Failure of the threshold approach to resolve all concerns is not a justification for abandonment


My hopes for this meeting

  • Reach agreement on an approach to establishing resistance thresholds
  • Our failure to reach agreement on this issue will only prolong a contentious debate which has now lasted for more than 30 years. The consequences will be equally negative for agriculture and public health.