**An Approach for Establishing Thresholds in Association with the Use of
Antimicrobial Drugs in Food-Producing Animals**

##### A Discussion Document

###### **FDA Center for Veterinary Medicine**

###### **December 19, 2000**

**[Table of Contents]{.smallcaps}**

# I. Executive Summary

# II. Introduction

## A. NARMS

## B. Pathogen Reduction Programs

## C. Framework Document

> D. Judicious Use of Antimicrobial Drugs

## E. Research Initiatives

## F. Alternatives to Antimicrobial Drugs

## III. Threshold Concept Background

## IV. An Approach for Establishing Thresholds

### A. Overview

#### **Figure 1:** Overview of the approach for establishing thresholds

### B. Pre-Approval Microbiological Safety Assessment

#### **Figure 2:** Summary of type of data for input into a pre-approval Microbiological Safety Assessment

### C. Establishment of Thresholds

#### 1. Overview

#### 2. Setting Human Health Thresholds

#### 3. Establishing Resistance Thresholds

##### Description of Model for Deriving Resistance Thresholds

1)  Uncertainty distributions

2)  Measurable human health impact

3)  Measurable level of exposure

> b\. Calculating Resistance Thresholds

###### **Figure 3:** Relationship between measurable levels and thresholds

##### c. Two Alternative Methods for Deriving Resistance Thresholds

##### 1) Maximum human health impact method of establishing resistance threshold

##### 2) Current human health impact method of establishing resistance threshold

##### d. Summary of Establishing Resistance Thresholds

###### **Table 1:** Types of data and information that may be needed in a risk assessment model

###### **Figure 4:** The proportionality relationship between human health impact and resistance among animal isolates showing current and maximum human health impact estimates

#### D. Risk Management Considerations

#### Setting Thresholds for Multiple Species

> F. Reassessment of Thresholds

### G. Regulatory Options for Approved Products

# V. Glossary

# VI. References

# Appendix 1: Example Calculation of Thresholds by Method 1

VIII\. Appendix 2: Risk Management Considerations

# [Executive Summary]{.smallcaps}

The Center for Veterinary Medicine (CVM) is charged with the regulatory
responsibility of ensuring that the use of antimicrobial drugs in
food-producing animals does not result in adverse health consequences to
humans. The selection of antimicrobial resistant bacterial populations
is a consequence of exposure to antimicrobial agents and can occur from
human, animal, and agricultural uses. Food animals are administered
antimicrobial drugs for therapeutic, preventive, and production
purposes. The use of antimicrobial drugs in food-producing animals is
necessary to maintain their health and welfare. However, food-producing
animals can become reservoirs of bacteria capable of being transferred
in or on food. Food carrying resistant bacterial pathogens can cause
illness in people consuming the food or contribute to the human
reservoir of resistant bacteria. The use of antimicrobial drugs in
food-producing animals may cause bacterial pathogens to become resistant
to drugs that may also be used to treat human illness, potentially
making human illness more difficult to treat.

CVM recognizes that minimizing the emergence of antimicrobial-resistant
bacteria in animals and their subsequent spread to humans through the
food supply is a complex problem requiring a coordinated multifaceted
approach. Accordingly, CVM has expended considerable effort to identify
and support those programs and activities that will reduce the risk to
the public. Where mitigation strategies were identified that lie outside
the regulatory authority of CVM, support has been enlisted from other
Federal agencies, international agencies dedicated to public and animal
health, and stakeholder organizations. CVM believes that, taken
together, these steps will have a substantial impact in controlling the
emergence and spread of resistant bacteria from animals to humans
through the food supply.

Despite these preemptive measures, there may occur situations in which
the approved use of an antimicrobial drug in animals gives rise to
resistant bacteria that in turn pose a risk to human health. In these
situations, and as an added measure of human health protection, CVM is
considering the establishment of regulatory thresholds intended to
arrest the further emergence of resistant foodborne pathogens. As
required by the Federal Food, Drug, and Cosmetic Act (FFDCA), CVM has
applied the reasonable certainty of no harm standard to human safety
considerations associated with the use of antimicrobial drugs in
food-producing animals. CVM believes that implementation of an approach
as outlined in this paper could be consistent with this standard, but is
exploring the impact of the approach under the current standard, whether
modifications to the approach or an alternative approach could also meet
the standard, or whether legislative change to the standard should be
considered.

This discussion document describes a possible approach to the
establishment and use of thresholds. The approach describes two types of
thresholds, a human health threshold and a resistance threshold. The
human health threshold is the unacceptable prevalence of infections in
humans that are treated with the antimicrobial drug of concern, are
associated with bacteria resistant to the drug of concern, and for which
the resistance is attributable to the use of an antimicrobial drug in
animals. Based on the current safety standard, the \"unacceptable
prevalence\" is considered that level at which there is no longer
reasonable certainty that there is no harm to human health. The human
health thresholds discussed in this document focus on enteric or
systemic illness in humans. The resistance threshold is the maximum
allowable prevalence of resistant bacteria isolated from animal-derived
food, that is, the level of such resistant bacteria at which there would
still be reasonable certainty that the human health threshold would not
be crossed. The resistance threshold is derived through an
epidemiology-based model that relates the prevalence of resistant
bacteria in food to an impact on either enteric illness (EI) or systemic
illness (SI) in humans. The scope and complexity of the implementation
and use of thresholds is described with the intent to stimulate
constructive discussion.

If this threshold approach is implemented, when post-approval
surveillance indicates that bacterial susceptibility to specific
antimicrobial drugs is decreasing, the prevalence of resistant bacteria
is increasing, or that the prevalence of resistant bacteria has exceeded
the resistance threshold level, a range of actions may be taken. For
example, if changes are observed, but the resistance threshold has not
been reached, voluntary mitigation strategies by groups such as the
pharmaceutical industry, food animal production groups, and the
veterinary community (e.g., education, labeling changes, use
restrictions, etc.) may be implemented to curtail further loss of
susceptibility. However, if surveillance data indicate that the
resistance threshold has been exceeded, CVM would initiate procedures to
withdraw from the label any animal species that has reached or exceeded
its threshold.

# Introduction

The Center for Veterinary Medicine (CVM) is charged with the regulatory
responsibility of ensuring that the use of antimicrobial drugs in
food-producing animals does not result in adverse health consequences to
humans. Food animals are administered antimicrobial drugs for
therapeutic, preventive, and production purposes. CVM recognizes that
the use of antimicrobial drugs in food-producing animals is important in
helping to promote animal health, welfare, and productivity. However,
food-producing animals can serve as reservoirs of pathogenic bacteria
that may be transferred to humans by consumption of contaminated food
products. With the use of antimicrobial drugs in food-producing animals,
these bacterial pathogens may become resistant to drugs that may also be
used to treat human illness, potentially making human illnesses more
difficult to treat. In addition, bacteria pathogenic to humans can
acquire resistance traits from non-pathogenic bacteria originating in
food animals by mechanisms that allow the exchange of their genetic
material in the human gastrointestinal tract.

Antimicrobial resistance is a complex human health issue with multiple
contributing factors. The selection of antimicrobial resistant bacterial
populations is a consequence of exposure to antimicrobial drugs and can
occur from human, animal, and agricultural uses. Recently implemented
food safety monitoring programs are still developing in response to the
evolving needs of agencies such as the FDA. As a consequence, the human
health impact due to the use of antimicrobial drugs in food-producing
animals can be difficult to assess. It requires the ability to attribute
human health impacts (in whole or in part) to the domestic (i.e., U.S.)
use of antimicrobial drugs in animals. This association is complicated
by other sources of resistance, including the use of the same or similar
antimicrobial drugs in human medicine, people contracting resistant
bacterial infections while traveling outside of the United States,
illness in people consuming imported foods or foods from imported
animals, and epidemics of multi-drug resistant pathogens. Antimicrobial
drug resistance has been linked to resistance against other
antimicrobial drug classes, disinfectants, and other compounds such as
heavy metals. The use of unrelated drugs can result in the co-selection
of multiple drug resistance. Additionally, cross-drug resistance occurs
from the use of a particular antimicrobial drug when the mechanism of
resistance affects more than one class of antimicrobial drug.

CVM recognizes that minimizing the emergence of antimicrobial-resistant
bacteria in animals and their subsequent spread to humans through the
food supply is a complex problem requiring a coordinated multifaceted
approach. Accordingly, CVM has expended considerable effort to identify
and support those programs and activities that will reduce the risk to
the public. Where mitigation strategies were identified that lie outside
the regulatory authority of CVM, additional support has been enlisted
from other Federal agencies, international agencies dedicated to public
and animal health, and stakeholder organizations. The CVM strategy for
addressing antimicrobial resistance is one component of more broad
reaching strategies being developed at the Agency level by the Food and
Drug Administration and at the interagency level in the form of the
Public Health Action Plan to Combat Antimicrobial Resistance.^1^ Copies
of this plan are available at
<http://www.cdc.gov/drugresistance/actionplan/>.

It is important to understand the legal framework within which CVM must
operate. For a new animal drug to be approved for use in food animals,
the sponsor must demonstrate to CVM that there is reasonable certainty
that no harm to human health will result from the proposed use of the
drug. Therefore, since the standard to be met is reasonable certainty
rather than absolute certainty, the sponsor does not have to demonstrate
zero risk. CVM believes that the presence of antimicrobial resistant
human pathogens in or on animal-derived food as a consequence of
antimicrobial drug use in animals is a safety concern that is subject to
the reasonable certainty of no harm standard.

This discussion document does not attempt to define the minimum criteria
for what would constitute "harm". However, as described in this
document, the relevant human health concern is considered to be an
unacceptable increase in the prevalence of human infections that are
treated with the antimicrobial drug of concern and that are caused by
bacteria resistant to that drug due to the use of an antimicrobial drug
in animals. Based on the current safety standard, an \"unacceptable
increase\" is considered that level at which there is no longer
reasonable certainty that there is no harm to human health.

CVM recognizes that meeting this standard is difficult, and may have
significant impact on the availability of drugs to treat animal illness.
CVM wishes to foster debate on the best policies and science to meet the
reasonable certainty of no harm standard, as well as on the implications
to animal health of meeting the statutorily-required standard. CVM
recognizes that there are times in which the allowed use of an approved
antimicrobial drug leads to the development of resistance in pathogens
in food from animals treated with the drug. In those circumstances, the
agency needs a way by which it and the sponsor know when a level of
resistance has been reached that violates the standard of reasonable
certainty of no harm, that is, when the use of the animal drug is no
longer shown to be safe. That is the goal of the approach for
establishing thresholds described in this document.

The CVM strategy that includes a number of contributing components,
described in brief below, is a regulatory approach that CVM believes is
protective of the human health. The threshold concept provides an added
measure of human health protection by establishing a clearly defined
point at which CVM would initiate procedures for withdrawing the
approval of a particular antimicrobial drug use in animals. This action
would be triggered in the event that the approved use of the drug in
animals is found to give rise to resistant bacteria that in turn present
an unacceptable risk to human health. As noted above, CVM is required by
the FFDCA to apply the reasonable certainty of no harm standard to human
safety considerations associated with the use of antimicrobial drugs in
food-producing animals. CVM believes that implementation of an approach
as outlined in this paper could be consistent with this standard, but is
exploring the impact of the approach under the current standard, whether
modifications to the approach or an alternative approach could also meet
the standard, or whether legislative change to the standard should be
considered. The threshold concept is but one component of a multifaceted
approach for assuring that the use of antimicrobial drugs in
food-producing animals is safe with regard to human health. The various
components of this multifaceted strategy are briefly described below.

**National Antimicrobial Resistance Monitoring System (NARMS)**

CVM believes that the safety assessment of antimicrobial drugs must
include monitoring for the development of resistance. Monitoring is done
through the National Antimicrobial Resistance Monitoring System (NARMS).

NARMS was initiated in l996 as a collaboration between the FDA, the
Centers for Disease Control, National Center for Infectious Diseases
(CDC), the United States Department of Agriculture Agricultural Research
Service, and Food Safety and Inspection Service. NARMS monitors
development of antimicrobial resistance of zoonotic enteric pathogens
from human and animal clinical specimens, from healthy farm animals, and
from carcasses of food-producing animals at slaughter.^2^ NARMS current
partners include 17 state and local public health laboratories and 8
veterinary sentinel sites. Its purpose is to prospectively monitor the
antimicrobial resistance of human, animal, and animal product isolates
of selected enteric bacteria.

Concerns associated with the approval of antibiotics important to human
medical therapy for use in food animals was the driving force for the
development of NARMS. Prior to NARMS there was no antibiotic resistance
surveillance system that was national in scope, continuous, and that
monitored within the same system resistance development among isolates
from both humans in the community setting and from animals.

The goals of NARMS are to provide descriptive data on the extent and
temporal trends of antimicrobial susceptibility in enteric organisms
from the human and animal populations; provide timely information to
veterinarians and physicians; prolong the life span of approved drugs by
promoting the prudent use of antimicrobial agents; identify areas for
more detailed investigation; and guide research on antimicrobial
resistance. The majority of the animal isolates are obtained from raw
product collected from federally inspected slaughter and processing
plants. The human isolates are collected from state health department
partners. The seventeen NARMS sites (CA, CT, CO, FL, GA, KS, Los Angeles
County, MA, MD, MN, NJ, New York City, NY, OR, TN, WA, and WV) represent
100 million people, or approximately one‑third of the U.S. population.

Since 1996, NARMS has conducted surveillance for antimicrobial
resistance among isolates of non‑typhoidal *Salmonella* and *Escherichia
coli* O157:H7. In 1997, surveillance was expanded to include human
isolates of *Campylobacter*. Currently, NARMS surveillance also includes
*enterococci* isolated from human stool samples and animal products,
*Campylobacter* isolated from animal products, as well as human isolates
of *Shigella* and *Salmonella* Typhi.

Isolates are tested for susceptibility using minimum inhibitory
concentrations, or MICs. *Salmonella*, *Shigella* and *E. coli* are
tested with Sensititre (Trek Diagnostics, Westlake OH) a semi‑automated
system, for susceptibility to 17 antimicrobial agents. *Campylobacter*
isolates are tested using the E‑test system (AB Biodisk, Solna Sweden)
for susceptibility to 8 antimicrobial agents. *Enterococci* isolates are
identified to species level and tested by Sensititre and microbroth
dilution for susceptibility to 27 antimicrobial agents. Results are
entered into a SAS database for analysis.

Since 1996, NARMS has provided data that have been used to initiate
field investigations of outbreaks of illness marked by a pathogen which
displayed an unusual antimicrobial resistance pattern, provided the data
for a risk assessment of the human health impact of fluoroquinolone use
in poultry, stimulated research in molecular characteristics of
resistance emergence and transfer, improved our knowledge of risk
factors associated with the development of an antimicrobial‑resistant
infection, and triggered broader research projects of prudent
antimicrobial use in animals and the role of the environment in the
emergence and spread of antimicrobial resistance.

# The NARMS program continues to expand by adding new test sites, bacterial pathogens and antimicrobial drugs for evaluation. Plans are currently underway to include the resistance profiles of enteric pathogens isolated from a wide variety of retail foods. This dynamic, national monitoring system will be an integral part of the threshold monitoring process.

# Pathogen Reduction Programs

Recently implemented food safety programs such as USDA's pathogen
reduction program are critical contributors to CVM's overall strategy
for managing human health risks associated with resistant foodborne
pathogens. The USDA program that is based on the principles of Hazard
Analysis and Critical Control Point (HACCP) appears to be having a
positive effect on reducing the overall incidence of foodborne
pathogens. However, surveillance data indicate that pathogens continue
to be present on animal-derived food products.^3^ CVM recognizes the
importance of this program in that reducing the incidence of pathogens
on food will reduce human exposure and, in turn, reduce the incidence of
foodborne related human illness. Any gains achieved in reducing the
overall incidence of foodborne disease will serve to reduce the
potential human health impact experienced as a consequence of foodborne
disease that is associated with a resistant pathogen. CVM also
recognizes that the USDA pathogen reduction program is essential in that
it serves as a critical source of isolates for the NARMS program. This
collaboration between agencies is critical to the success of the
program.

**Framework Document**

CVM announced with the publication of Guidance for Industry #78,
\"Consideration of the Human Health Impact of the Microbial Effects of
Antimicrobial New Animal Drugs Intended for Use in Food-Producing
Animals\", a regulatory change with regard to the safety evaluation of
antimicrobial drugs.^4^ Although CVM had previously considered such
effects for certain uses of antimicrobial drugs, the guidance stated
CVM's intention to consider the potential human health impact of the
microbial effects associated with all uses of all classes of
antimicrobial new animal drugs intended for use in food-producing
animals. The microbial effects of concern include the impact of
antimicrobial drug use in animals on the rate and extent of resistance
emergence and on the quantity of bacteria in animals that are pathogenic
to humans.

Given that the regulatory approach then in use did not adequately
address these concerns, CVM outlined in a 1998 discussion document
titled, "Proposed Framework For Evaluating And Assuring The Human Safety
Of The Microbial Effects Of Antimicrobial New Animal Drugs Intended For
Use In Food-Producing Animals" (i.e., the Framework Document) several
coordinated strategies to the management of risk associated with
antimicrobial use in food-producing animals.^5^ The Framework Document
discussed both pre-approval and post-approval approaches. The strategies
include: 1) revision of the pre-approval safety assessment for
antimicrobial resistance for new animal drug applications to assess all
uses for microbial safety; 2) categorization of antimicrobial drugs
based upon the importance of the drug for human medicine; 3)
post-approval monitoring for the development of antimicrobial drug
resistance; 4) the collection of food animal drug use data; and 5) the
establishment of regulatory thresholds.

*Drug categorization*: A key component of the Framework Document is the
concept of categorizing antimicrobial drugs according to their
importance for treating disease in humans. The Framework Document
discusses three categories with the most important drugs being
considered Category I. CVM believes that this categorization process is
an integral part of a safety assessment in that it provides some initial
indication of the potential human health impact resulting from treatment
failure due to resistance. The categorization process also focuses the
greatest level of attention on those antimicrobial drugs of greatest
importance to human medical therapy. As outlined in the Framework
Document, pre-approval and post-approval requirements would likely be
greatest for those antimicrobial drugs that are highly important for
treating disease in humans. As a consequence, greater emphasis would
likely be placed on developing drugs for animal use that are of lower
importance for human therapy.

*Pre-approval Assessment of antimicrobial drugs*: As noted previously,
CVM announced with Guidance for Industry #78 its intentions to include
in its safety evaluation of all antimicrobial drugs intended for use in
food-producing animals a consideration of the potential human health
impact associated with the emergence of antimicrobial resistance. CVM
has held discussions on the subject of using pre-approval study
information to characterize safety in terms of the rate and extent of
resistance development in food-producing animals (i.e., public workshop
held February 22-24, 2000). The transcripts of the February 22-24, 2000,
public meeting and copies of the speaker presentations are available at
<http://www.fda.gov/cvm/antimicrobial/oldmeet.htm>. Such studies would
be used to provide CVM with information to assess whether antimicrobial
susceptibility changes of human health concern would occur, or would
occur at an unacceptable rate. The Center intends to issue further
guidance on this aspect of a microbiological safety assessment in the
future. The current document discusses the type of data that may be
provided as part of an assessment of the microbiological safety of an
unapproved antimicrobial new animal drug.

During the evaluation of antimicrobial drugs prior to their approval,
CVM considers all available relevant information pertaining to food
safety including the potential of the drug to promote the emergence or
spread of resistant food borne pathogens. Traditionally, where there was
concern, CVM relied on restrictive measures as a means of managing risk.
Such restrictions included limiting the sale and distribution to
prescription only channels, specifying a dose or dose range sufficiently
large to minimize the emergence of resistant pathogens, specifying the
conditions under which the drug could be used, and prohibiting extra
label use when deemed appropriate

CVM can only approve drugs for food animals which, in its best judgment,
meet the standard of reasonable certainty of no harm. With respect to
antimicrobial resistance, CVM would not approve a drug intended for use
in food animals if it had reason to believe that the approval would lead
in a relatively short period of time, to development of antimicrobial
resistance at a level that would pose a risk to human health such that
it would preclude a finding of reasonable certainty of no harm.
Unfortunately, unlike chemical residues which are evaluated for their
toxic properties using a battery of well-established animal and
laboratory methods, CVM is aware of no such predictive models to
estimate with precision the rate and extent of bacterial resistance that
may emerge from the use of antimicrobial drugs in food animals.

*Thresholds:* FDA can only approve drugs for use in food animals for
which the sponsor has established, among other things, that there is a
reasonable certainty that no harm attributable to use of the drug will
come to people from eating food from the animal species administered the
drug according to approved label conditions. The agency recognizes that
there can be no absolute certainty that use of the drugs will not
ultimately lead to adverse human health effects. Therefore, as an added
safeguard to protect human health in the event that resistance among
bacterial isolates in humans results from the use of a drug in food
animals, CVM is considering the establishment of resistance thresholds.
Through the establishment of resistance thresholds, CVM hopes to define
predetermined endpoints which, if reached, would indicate that the
antimicrobial drug is no longer shown to be safe for use in a given food
animal species. The threshold, therefore, would serve as the regulatory
trigger for initiating immediate withdrawal from the label of the animal
species that has reached its resistance threshold, recognizing that
actually accomplishing such withdrawal takes time because of due process
requirements, and that antimicrobial resistance may continue to increase
during that time.

Although the overall concept is the same, it should be noted that the
threshold approach outlined in this document differs from that initially
proposed in the Framework Document. A description of how the approach
discussed in this document differs from that in the Framework Document
is provided later in the *Threshold Concept Background*.

*Drug use information*: CVM currently requires the submission of certain
drug sales information as part of the annual drug experience report for
approved drug products. The Framework Document identified the need for
the pharmaceutical industry to submit more detailed antimicrobial drug
sales information as part of its annual report. CVM believes that this
additional information is needed to monitor drug use patterns in
relation to the antimicrobial susceptibility data being monitored
through the NARMS program. The ability to correlate use patterns with
changing antimicrobial susceptibility would allow implementation and
assessment of intervention or mitigation strategies. CVM is moving
forward on developing new requirements for antimicrobial drug use
information through a notice and comment rule-making process.

# Judicious Use of Antimicrobial Drugs

Antimicrobial resistance is of concern when the same or related
antimicrobial drugs are used in both animal agriculture and in human
medicine. Guidelines for the judicious use of antimicrobial drugs have
recently been prepared by the American Veterinary Medical Association
(AVMA) and provide guidance to veterinary practitioners on ways to
maximize the efficacy of antimicrobial drugs, while minimizing the
development of antimicrobial resistance.^6^ Initiatives are also
underway in many producer associations to develop similar guidelines and
/ or recommendations. CVM has participated with a number of these
organizations in developing these principles and has provided support
for developing educational materials. CVM has also provided support for
several ongoing studies to evaluate the impact of judicious use
practices on the emergence of antimicrobial resistance.

# Research Initiatives

CVM recognizes that additional research is needed on the relationship
between antimicrobial use in food animals and the associated human
health impact related to antimicrobial resistant bacteria. The
importance of the issue and the need for interagency collaboration is
highlighted in the Draft Public Health Action Plan to Combat
Antimicrobial Resistance.^1^ Copies of the draft are available at
<http://www.cdc.gov/drugresistance/actionplan/>.

CVM has initiated its own intramural and collaborative research efforts
to investigate factors associated with development, dissemination, and
persistence of bacterial antibiotic resistance in both the animal
production environment and food supply. Microbiologists from CVM's
Office of Research are currently conducting or are participating in
projects specifically targeted to gathering data on such issues as: (1)
the current background level of bacterial antibiotic resistance in
retail animal-derived food products; (2) the development and persistence
of bacterial antibiotic resistance from aquaculture and animal
production environments; (3) characterization of mechanisms of
resistance dissemination and transfer among pathogenic and commensal
bacteria associated with food-producing animals and aquaculture
environments; (4) determining the roles that animal feeds and feed
commodities play in the dissemination of antibiotic resistance and
pathogen carriage; and (5) co-selection of antibiotic resistance
phenotypes associated with the use of sanitizers and other antimicrobial
drugs in animals. In addition, CVM is a contributing laboratory to CDC's
PulseNet molecular fingerprinting network involved in the molecular
epidemiology of foodborne outbreaks. The CVM laboratory provides the
only source of data on animal-associated bacterial pathogens into the
PulseNet system.

In addition to the intramural research, CVM also collaborates in
extramural research grants and funds extramural research activities
through cooperative agreements. This extramural research is designed to
complement and augment the intramural research program. Six of the
projects are designed to elucidate the prevalence and risk factors
associated with the dissemination of antibiotic resistant *Salmonella,
E. coli* O157:H7, and enterococci within the animal production
environment. Another study seeks to adapt and validate for use in the
animal production environment microbial detection methods developed for
human food.

# Alternatives to antimicrobial drugs

CVM is interested in evaluating products that may be considered
alternatives to antimicrobial drugs. As an example, CVM approved the
first competitive exclusion product in 1999 \"for the early
establishment of intestinal microflora in chickens to reduce
*Salmonella* colonization.\" CVM would support the development of other
products that would have a positive human health impact. In addition,
CVM acknowledges the importance of continued advances in vaccine
development and other management practices that may reduce reliance on
the use of antimicrobial drugs in food-producing animals.

# Threshold Concept Background

This discussion document describes a possible approach for establishing
thresholds as a means of assuring the safe use of antimicrobial drugs in
food-producing animals complimentary to the approval process itself.
Such thresholds are intended to provide an added measure of protection
should the emergence of antimicrobial resistance as a consequence of
antimicrobial drug use in food-producing animals pose an unacceptable
risk to human health, that is, that there was no longer reasonable
certainty that no human health harm would result from an approved use of
the drug. This document provides a detailed technical description of the
proposed methodology for the purpose of stimulating discussion at an
upcoming scientific public meeting.

The current document provides a more detailed discussion of the
threshold concept introduced in the Framework Document and describes a
possible approach for establishing thresholds. It should be noted that
the approach outlined in this document differs from that initially
proposed in the Framework Document. The Framework Document discussed two
thresholds, a resistance threshold and a monitoring threshold, that
would be established prior to the approval of a new animal antimicrobial
drug for use in food-producing animals. The resistance threshold was
described as the upper limit for the level of resistant bacteria that
can be transferred from animals to consumers and still be considered
safe for the consumer. Exceeding the resistance threshold was considered
to represent an unacceptable human health risk. The monitoring threshold
was described as a level of resistance for the food animal species that
would allow industry to monitor the development of resistance to the
antimicrobial and identify when intervention and mitigation programs
should be implemented. Exceeding the monitoring threshold was considered
to represent an early warning signal of resistance development.

The approach outlined in this document also proposes the establishment
of two types of thresholds, a human health threshold and a resistance
threshold. The human health threshold described in this document
represents the unacceptable prevalence of infections in humans that are
treated with the antimicrobial drug of concern, are associated with
bacteria resistant to the drug of concern, and for which the resistance
is attributable (in whole or in part) to the use of an antimicrobial
drug in animals. Based on the current safety standard, the
\"unacceptable prevalence\" is considered that level at which there is
no longer reasonable certainty that there is no harm to human health.

The resistance threshold described in this document is the maximum
allowable level of resistance prevalence in bacteria isolated from the
food animal that does not pose an unacceptable risk to human health.
This resistance threshold is derived through an epidemiology-based model
that describes the relationship between the human health threshold and
resistance levels in animals. Therefore, exceeding a resistance
threshold would be considered a level of resistance at which there is no
longer reasonable certainty that there is no harm to human health.

The approach described in this paper does not include the establishment
of \"monitoring thresholds\" as an early warning system. However, given
that the proposed resistance threshold is based on a measurable endpoint
in animals, CVM believes that resistance thresholds will allow industry
to monitor the development of resistance to the antimicrobial and
identify when intervention and mitigation programs should be
implemented. A monitoring system that utilizes thresholds, such as that
described in this document, would provide a timely warning of the
emergence of bacterial resistance among pathogens of human health
concern. At this time, the approach included in this discussion paper
addresses the establishment of thresholds for foodborne pathogens only.
However, CVM intends to apply a similar risk-based approach to the
establishment of resistance thresholds for non-pathogenic bacteria such
as enterococci. CVM is in the process of developing a risk assessment on
enterococci that should be helpful in further refining an approach to
establishing thresholds for non-pathogenic bacteria.

CVM believes that resistance thresholds would need to be determined for
certain antimicrobial products prior to approval. CVM envisions that
resistance thresholds will 1) encourage industry participation in
monitoring for the development of resistance to an antimicrobial
product; 2) identify when intervention and mitigation programs might be
implemented by the pharmaceutical industry, producer organizations, or
CVM; 3) identify when procedures should be initiated by CVM to withdraw
from the label the approval of a particular food animal species; and 4)
assist in prolonging the effectiveness of antimicrobial drugs in humans
and food animals. If it is determined that resistance thresholds do not
have to be established for certain drugs or drug classes, it may also
help the pharmaceutical industry to target classes of drugs for
development for animal use.

# [An Approach for Establishing Thresholds]{.smallcaps}

# Overview

The approach outlined in this document discusses the establishment of
two types of thresholds for certain antimicrobial products intended for
use in food-producing animals. The first type of threshold, referred to
as the human health threshold (T(x)), is the unacceptable prevalence of
infections in humans that are treated with the antimicrobial drug of
concern, are associated with bacteria resistant to the drug of concern,
and for which the resistance is attributable (in whole or in part) to
the use of an antimicrobial drug in animals. These human health
thresholds specifically focus on the incremental effects on existing
enteric illness or systemic illness in humans as a consequence of the
causative bacteria being resistant to the antimicrobial drug the
affected persons are expected to receive. Based on the current safety
standard, the \"unacceptable prevalence\" is considered that level at
which there is no longer reasonable certainty that there is no harm to
human health.

The second type of threshold discussed is referred to as the resistance
threshold. The resistance threshold (t(x)) is the maximum allowable
prevalence of resistant bacteria isolated from animal-derived food that
does not pose an unacceptable risk to human health. The resistance
threshold is derived through an epidemiology-based model that relates
the prevalence of resistant bacteria in food to an impact (as described
above) on either enteric illness (EI) or systemic illness (SI) in
humans. Isolates are defined as resistant if their minimum inhibitory
concentration (MIC) reaches or exceeds the resistance breakpoint
established for the related drug used in human medicine. Therefore, a
resistance threshold (i.e., prevalence of resistance in animals) would
be established for a particular antimicrobial drug in animals that
correlates to the human health threshold. If changes in susceptibility
or changes in the prevalence of resistance among animal isolates are
observed via monitoring, but a resistance threshold is not exceeded,
voluntary mitigating actions may be implemented. However, if a
resistance threshold were exceeded, this would be considered a level of
resistance at which there is no longer reasonable certainty that there
is no harm to human health. .

This document outlines an approach for assessing when the establishment
of thresholds would be needed for the approval of an antimicrobial drug
in animals. This determination could be made through the completion of a
Microbiological Safety Assessment by the animal drug sponsor. Through
this process, it may be determined that the proposed antimicrobial
product does not pose a human health concern and, therefore, the
establishment of resistance thresholds would not be needed prior to
approval in a food-producing animal.

If the Microbiological Safety Assessment concludes that establishment of
resistance thresholds are necessary for approval, this document
describes an epidemiology-based model that could be used to derive such
thresholds. The epidemiology-based model is intended to relate the
prevalence of resistant bacteria in food to an impact on either enteric
illness (EI) or systemic illness (SI) in humans. This document outlines
two alternative methods by which the resistance thresholds could be
derived. The determination of which method to use would be driven by
data availability. Although the two methods presented are very similar
in concept, one method uses an estimate of the maximum human health
impact in its calculations (i.e., makes assumption that all human cases
attributed to animal species were due to bacteria resistant to drug of
concern), whereas, the second method uses current human health impact
information (i.e., uses current data to determine proportion of
animal-related human cases that were due to bacteria resistant to drug
of concern). The advantage of using the maximum possible human health
impact is that it permits calculation of the resistance threshold (t(x))
without the data required for the second method.

Following the establishment of the resistance thresholds and subsequent
approval of the antimicrobial new animal drug, the pertinent bacterial
pathogen(s) (for which thresholds were established) would be monitored
post-approval with regard to susceptibility to the related drug of
importance to human medicine. As discussed above, observed shifts in
susceptibility (that do not exceed the resistance threshold) may trigger
certain voluntary actions. However, if the prevalence of resistance
exceeds the threshold, CVM would initiate procedures to withdraw from
the label any animal species that has reached or exceeded its threshold.
An overall outline of this approach for establishing thresholds is
presented in Figure 1.

![](media/image1.wmf)

![](media/image1.wmf)**Pre-approval Microbiological Safety Assessment**

As outlined in Guidance for Industry #78, \"Consideration of the Human
Health Impact of the Microbial Effects of Antimicrobial New Animal Drugs
Intended for Use in Food-Producing Animals\", CVM intends to consider
the potential human health impact of the microbial effects associated
with all uses of all classes of antimicrobial new animal drugs intended
for use in food-producing animals.^4^ CVM believes that consideration of
this concern may be facilitated by a Microbiological Safety Assessment.
Such an assessment would collect and organize all pertinent data and
information relevant to the potential human health impact associated
with the proposed antimicrobial drug use in animals. Data, provided by
the drug sponsor, that may be necessary for this evaluation may include,
but are not limited to:

-   Information regarding the proposed conditions of use of the product
    that would help characterize the potential for human exposure to
    zoonotic enteric bacteria associated with the treated animal.

-   Baseline prevalence of appropriate zoonotic enteric bacteria in the
    target animal species and in humans.

-   Baseline susceptibility of appropriate zoonotic enteric bacteria to
    the relevant drug used in human medicine obtained from animal
    isolates and human community isolates.

-   Information to determine the level of concern for the proposed
    animal drug use as it may impact human medicine.

-   Antimicrobial susceptibility breakpoints for the relevant human
    drugs in the appropriate zoonotic enteric bacteria.

-   Pharmacokinetic and pharmacodynamic information for the new animal
    drug in the food animal.

-   Information regarding the mechanism of action and mechanism(s) of
    resistance.

The information included in the Microbiological Safety Assessment may be
used to evaluate the potential human health impact associated with the
proposed use and may be used to make a determination as to whether it
was necessary to establish a resistance threshold at the time of
approval. CVM anticipates that a resistance threshold would likely be
required for those drugs considered highly important to human medicine.
For those antibiotics that are not used in human medicine and are not
cross-resistant to drugs used in human medicine, a resistance threshold
may not be required. The extent to which thresholds should be
established for the other drugs, and how those thresholds might be set,
are issues that require further discussion.

CVM also believes that the Microbiological Safety Assessment would help
to guide the establishment of the appropriate post-approval surveillance
criteria for the proposed product. As noted above, CVM envisions that
all proposed uses of antimicrobial drugs in food animals would be
required to undergo this assessment. The information provided in this
assessment may be used to make a determination as to whether
post-approval surveillance is warranted, and if so, what should be the
appropriate criteria for such surveillance.

![](media/image1.wmf)

![](media/image1.wmf)**Establishment of Thresholds**

**Overview**

This section contains two subsections. The first subsection, Setting
Human Health Thresholds, discusses the concept of setting human health
thresholds. The human health threshold is defined as the unacceptable
prevalence of infections in humans that are treated with the
antimicrobial drug of concern, are associated with bacteria resistant to
the drug of concern, and for which the resistance is attributable (in
whole or in part) to the use of an antimicrobial drug in animals.

The second subsection, Establishing Resistance Thresholds, describes an
epidemiology-based model that is used to derive resistance thresholds.
The resistance threshold (referred to later in this document as t(x)) is
the maximum allowable prevalence of resistant bacteria isolated from
animal-derived food that does not pose an unacceptable risk to human
health. The resistance threshold is derived through an
epidemiology-based model that relates the prevalence of resistant
bacteria in food to a particular impact on either enteric illness (EI)
or systemic illness (SI) in humans.

The association between the human health and the resistance thresholds
is based on certain epidemiological information. In particular, an
association is made between the annual prevalence of people affected by
enteric or systemic foodborne-related illness and the quantity of food
animal commodity containing resistant bacteria to which the population
was exposed during the year. The calculations provided in the following
sections demonstrate that the threshold of material can be reduced to an
expression of the threshold prevalence of resistance among bacterial
isolates from the food animal commodity. The resistance threshold is
that prevalence associated with a particular preset human health
threshold. A resistance threshold can be set to correspond to a
measurable human health impact, or through safety factors (see Appendix
2) to avoid any human health impact.

# Setting Human Health Thresholds

There is a wide spectrum of potential human health impacts associated
with treatment failure due to antimicrobial resistance. This document
focuses on foodborne-related enteric or systemic illness in humans and
the potential associated incremental health impact experienced as a
consequence of antimicrobial resistance in the causative bacteria. CVM
considers that enteric and systemic illnesses are possible endpoints
that could be used in the regulation of the antimicrobial animal drug.

1\. **Threshold for impact on enteric illness:** In a given year, a
certain proportion of the U.S. population will experience enteric
foodborne illness and will be treated with an antimicrobial drug. Some
cases may be due to bacteria that are resistant to the drug
administered. Therefore, the threshold for impact on enteric illness is
defined as the unacceptable prevalence of cases of enteric illness in
the U.S. population that are treated with the antimicrobial drug of
concern, are associated with bacteria resistant to the drug of concern,
and for which the resistance is attributable (in whole or in part) to
the use of an antimicrobial drug in animals. Such cases would be
expected to experience decreased or loss of effectiveness of their
antimicrobial drug treatment.

2.  **Threshold for impact on systemic illness:** In a given year, a
    certain proportion of the U.S. population will experience systemic
    foodborne illness and will be treated with an antimicrobial drug.
    Some cases may be due to bacteria that are resistant to the drug
    administered. Therefore, the threshold prevalence of cases of
    systemic illness impacted is defined as the unacceptable prevalence
    of cases of systemic illness in the U.S. population that are treated
    with the antimicrobial drug of concern, are associated with bacteria
    resistant to the drug of concern, and for which the resistance is
    attributable (in whole or in part) to the use of an antimicrobial
    drug in animals. Such cases would be expected to experience
    decreased or loss of effectiveness of their antimicrobial drug
    treatment.

The symbol T(EI) is used for the human health threshold for enteric
illness. The symbol T(SI) is used for the human health threshold for
systemic illness. A symbol of T(x) may be used to represent the human
health threshold without specifying a particular end point such as
enteric illness or systemic disease.

The threshold concept is one component of a multi-pronged strategy for
managing antimicrobial resistance. As stated previously, CVM has issued
guidance (Guidance for Industry #78) indicating that the safety
evaluation of new animal drug applications for antimicrobial drugs for
food-producing animals should include a consideration of the potential
impact of antimicrobial resistance on human health. CVM believes that
thresholds provide a mechanism for taking appropriate action should
post-approval monitoring efforts indicate that an antimicrobial drug
used in animals is no longer shown to be safe. Implementation of a
threshold concept, such as that discussed in this document, necessitates
that a certain human health impact(s) be identified as a means of
monitoring the continued safety of antimicrobial drug use in animals.
Based on current safety standards, such thresholds would be used to
indicate the point at which there is no longer reasonable certainty that
there is no harm to human health.

CVM anticipates considerable discussion regarding the selection of the
appropriate human health impacts to measure and establishment of the
unacceptable threshold prevalence for that human health impact. This
document is intended to stimulate discussion on these points. CVM seeks
further input on setting human health thresholds.

# Establishing Resistance Thresholds

**Description of Model for Deriving Resistance Thresholds**

**Model proportionality factor (k-res):** The basis for determining a
resistance threshold is a modeled rate or proportionality factor, k-res.
This factor links a measurable level of human health impact (H(x)) to a
quantity of animal-derived food (Q) containing bacteria resistant to an
antimicrobial drug of interest. The factor, k-res, is a key component of
the approach outlined for deriving resistance thresholds in that it is
intended to approximate the relationship between exposure to resistant
bacteria (i.e., Q) and some effect on human health (i.e., H). The
ability to calculate k-res is dependent on the availability of data to
derive values for the parameters H and Q. If such data are not available
(e.g., in the case of a new drug where no resistance has been
documented), some other means of approximating k-res would be necessary.
This may include applying the k-res factor derived for other
drug/bacteria situations.

As noted above, the factor, k-res, attempts to link drug-related human
health effects to exposure to animal-derived food containing bacteria
resistant to that drug. Therefore, when considering data to derive the
factor, k-res, it should be noted that, based on current safety
standards, existing information relevant to drug-related human health
effects must not preclude a determination of reasonable certainty of no
harm.

**Uncertainty distributions:** Point estimates of quantities will be
discussed in the process of explaining the data and the steps used to
calculate resistance thresholds. It should be noted, however, that the
resistance thresholds derived from the model would have attendant
uncertainty distributions. The 95^th^ percentile of the distribution of
the estimated number of people affected and the associated prevalence of
resistance in animals could be used rather than the mean of the
distribution. Alternatively, the 5^th^ percentile of the distribution of
the resistance threshold derived from the model could be used.

**Measurable human health impact (H(x)):** As discussed in this
document, a measurable human health impact (H(x)) represents the current
measured prevalence of infections in humans that are treated with the
antimicrobial drug of concern, are associated with bacteria resistant to
the drug of concern, and for which the resistance is attributable (in
whole or in part) to the use of an antimicrobial drug in animals.
Additionally, exposure is associated with meat containing drug-resistant
bacteria whose resistance was attributed to the use of antimicrobial
drugs in the food animal species that produced the meat.

One way to estimate the prevalence of people impacted (H(x)) is as
follows:

H(x) = estimate of the total prevalence of cases of disease\
×\
proportion of total cases due to exposure to animal-derived food
commodity\
×\
proportion of cases with resistance attributed to animal-derived food
commodity\
×\
proportion of cases expected to be treated with the antimicrobial drug
of interest

The estimated total prevalence of cases is determined annually for
foodborne pathogens in FoodNet, Foodborne Diseases Active Surveillance
Network, by the CDC. Periodically, the CDC also conducts case-control
studies and surveys that provide more detailed information. Such
information includes the prevalence of people impacted by infections
caused by drug-resistant bacteria for which they sought care and
received an antibiotic to which the bacteria were resistant. In the case
of antimicrobial drugs for which transmission of resistance from animals
to humans would primarily be expected to occur through foodborne
pathogens, resistance thresholds would be established only for a few
bacteria, perhaps *Campylobacter* and *Salmonella*. CDC provides annual
estimates of the total number of campylobacteriosis and salmonellosis
cases in the U.S. With attention focused mainly on a few foodborne
pathogens, it will be possible to develop estimates of the proportion of
all cases and from this, the number of cases, attributable to various
animal species. Scientific panels may also be useful in determining
estimates for parameters that are difficult to measure directly. These
estimates would need to be reviewed periodically. Once in place, the
estimates would be used during the pre-approval process in the
establishment of resistance thresholds using one of the approaches
described in the following sections.

It should be noted that the current measurable level of human health
impact (H(x)) must be lower than the human health threshold (T(x))
which, as stated earlier in this document, is the level at which there
is no longer a reasonably certainty of no harm to humans.

**Measurable level of exposure (Q):** This document describes a
measurable level of exposure as the number of pounds of a particular
food animal commodity containing drug-resistant bacteria.

While number of pounds of product containing resistant bacteria may be
the most practical way to discuss the measurable level of exposure,
Table 1 illustrates that the quantity is not measured directly. Instead,
a measurable quantity to which the population is exposed (Q) would
typically be a product of several terms. The total number of pounds of
food animal commodity consumed is known from USDA records. The portion
of the total number of pounds containing any of the bacteria of interest
is estimated from the USDA data. The prevalence of antimicrobial
resistance among bacterial isolates is determined through the NARMS
program.

Therefore, Q could be estimated as follows:

Q = total pounds of product consumed\
×\
proportion of sampled pounds containing bacteria\
×\
proportion of samples from which resistant bacteria are isolated

**Calculating Resistance Thresholds**

The proportionality relationship between the measurable human health
impact (H(x)) and the associated observable exposure (Q) is expressed,

> H(x) = \[k-res\] \* Q. (Equation 1)

Now, assuming all underlying factors in the system modeled remain stable
over the period of interest, this relationship is considered stable over
that period. During such a stable period, the relationship allows a
linear prediction of the prevalence of people impacted from the quantity
of food animal commodity containing resistant drug-resistant bacteria to
which the population is exposed. If the level of exposure associated
with the human health threshold, T(x), is designated Q~t~(x), it is also
true that for the specific threshold values, T(x) and Q~t~(x),

> T(x) = \[k-res\] \* Q~t~ (x). (Equation 2)

Taking equations (1.) and (2.) in combination it follows that,

![](media/image2.wmf) (Equation 3)

This relationship permits solution for a resistance threshold t(x),
expressed as the prevalence of resistance among isolates from samples of
the food commodity containing the bacteria of interest. A resistance
threshold (t(x)) is associated with a set human health threshold value
(T(x)), given measurable values of impact H(x), and proportion of all
isolates from food samples from which resistant isolates are obtained
(h). To illustrate as in Equation 3 above, write:

![](media/image3.wmf)

and

![](media/image4.wmf)

Then when the total weight in pounds and proportion contaminated with
bacteria are cancelled from both sides in Equation 3, it can be seen
that the solution for the resistance threshold specified in terms of
prevalence of resistance is:

> $t(x) = \frac{T(x) \times \text{ h}}{H(x)}$ (Equation 4)

We would consider using the prevalence of carcasses from which resistant
bacteria are isolated at slaughter (or from products at retail for
situations in which slaughter data will not be collected).

The essential strategy of the proposed quantitative approach outlined
above is illustrated in Figure 3. There are four quantities represented
here:

-   H(x) -- The current measured prevalence of infections in humans that
    are treated with the antimicrobial drug of concern, are associated
    with bacteria resistant to the drug of concern, and for which the
    resistance is attributable (in whole or in part) to the use of an
    antimicrobial drug in animals.

-   h -- A consistent measure of the current prevalence of
    animal-derived foods containing resistant bacteria.

-   T(x) -- The unacceptable prevalence of infections in humans that are
    treated with the antimicrobial drug of concern, are associated with
    bacteria resistant to the drug of concern, and for which the
    resistance is attributable (in whole or in part) to the use of an
    antimicrobial drug in animals.

-   t(x) -- The resistance threshold (t(x)) is the maximum allowable
    prevalence of resistant bacteria isolated from animal-derived food
    that does not pose an unacceptable risk to the human health.

![](media/image1.wmf)**Figure 3:** Diagram illustrating the relationship
between human health thresholds, resistance thresholds, measured levels
of resistance in animals, and measured impacts in human health. A
measured level of resistance (1.) is linked to a measured human health
impact (2.) by Equation 1 through \[k-res\], based on an
epidemiology-based model. The human health threshold (3.) is linked
through \[k-res\] to the resistance threshold (4.). After approval the
measured prevalence of resistance (h) is compared to the resistance
threshold \[t(x)\] set prior to approval. The measurable human health
impact \[H(x)\] is compared to the set human health threshold \[T(x)\]
level for confirmation. The relationship between observable human health
impact and observable prevalence of resistance is examined to determine
if \[k-res\] needs to be adjusted.

**Two Alternative Methods for Deriving Resistance Thresholds**

Two methods are described in the following sections for using the
proposed epidemiology-based model for deriving resistance thresholds.
The methods differ mainly in the amount of data required to perform the
calculations to establish the resistance thresholds. Coincident
differences in assumptions are required.

**Method 1: *Maximum Human Health Impact Method of Establishing t(x)***

In the case of antimicrobial drugs for which transmission of resistance
from animals to humans would primarily be expected to occur through food
borne pathogens, resistance thresholds would likely be established for
*Campylobacter* and *Salmonella*. *Campylobacter* and *Salmonella* are
commonly isolated from food animals at slaughter^7-14^ and represent the
predominant bacterial pathogens isolated from cases of enteric illness
for those pathogens under surveillance in FoodNet^15^. CDC provides
annual estimates of the total prevalence of cases of campylobacteriosis
and salmonellosis in the U.S. in FoodNet reports. To use Method 1, it is
necessary to know the total prevalence of cases of illness in humans
attributable to the animal species of interest. The total prevalence of
illness is multiplied by the attributable fraction to determine the
prevalence of cases attributed to the animal species. The assumption is
made that when there are no resistant bacterial isolates among isolates
from a given animal species, no human cases with resistant bacteria are
attributable to that animal species. Similarly, the assumption is made
that when all isolates from an animal species are resistant; all human
cases attributable to that animal species will be caused by resistant
bacteria.

This maximum prevalence of cases with resistant infections is multiplied
by the fraction of those cases expected to be treated with the
antimicrobial drug of concern to yield the maximum human health impact
that would be expected if 100 percent of the animal isolates are
resistant. A line drawn between these two points, the zero value and the
prevalence of cases attributable to the animal species who would be
given the antimicrobial drug of interest, is a first approximation of
the relationship between the human health impact and the prevalence of
resistance among isolates from the food animal commodity of interest.
The maximum prevalence of cases who were given the antimicrobial drug to
which the bacteria causing their infections are resistant constitutes a
measurable health impact (H(x)), denoted H~max~(x). Its associated value
of prevalence of resistance among isolates in the animal species is h
= 1. As mentioned in the previous section, these two values and the set
value T(x) may now be used to solve for the resistance threshold (t(x))
in the animal species:

> $t(x) = \frac{T(x)}{H\text{max}(x)}$ (Equation 5)

Note that this method implies that the prevalence of resistance among
isolates in the food animal commodity is the same as the prevalence of
resistance among isolates from people with illness attributed to the
food animal commodity. This method is quite simple to apply and
beneficial in the situation where there are little data on resistance in
the food animal, such as when a novel animal drug is in the review
process. This method assumes that the likelihood of the pathogen to
cause an infection in humans is the same for susceptible and resistant
strains. It also assumes that the distribution of the total numbers of
bacteria that are found on units of a food-animal commodity is the same
regardless of the prevalence of resistance among the bacteria. An
example calculation using Method 1 is provided in Appendix 1.

**Method 2: *Current Human Health Impact Method of Establishing t(x)***

Calculating t(x) by Method 2 requires data on the prevalence of cases
with disease caused by resistant bacteria for which resistance is
attributable to use of an antimicrobial drug in a food animal species,
and on the prevalence of resistance among isolates from the food animal
commodity of interest. This prevalence is not estimated under the
current surveillance system, which estimates only the total prevalence
of cases caused by each pathogen. The total prevalence must then be
translated into the prevalence of cases caused by resistant bacteria
attributable to the food animal commodity by applying an estimated
proportion of resistant cases among all cases attributable to the food
animal commodity. Until the prevalence of cases caused by resistant
pathogens attributable to the food animal commodity is estimated
directly, Method 2 requires the data required by Method 1 plus an
estimate of the proportion of cases with resistant bacteria attributable
to the food animal commodity. Despite the additional data requirements,
Method 2 has an advantage over Method 1 because it assumes linearity
only over a narrow range around the current estimate rather than over
the entire range from 0 to 100% resistance prevalence in the isolates
from the food animal commodity.

The current human health impact is an estimation of the prevalence in
the U.S. population of some particular health effect in the current
year. The two prevalences offered for consideration in this document
are:

1\. **Current impact on enteric illness**: In any given year, a certain
proportion of the U.S. population will experience enteric foodborne
illness and will be treated with an antimicrobial drug. Some cases may
be due to bacteria that are resistant to the drug administered. The
current impact on enteric illness is defined as the current prevalence
of cases of enteric illness in the U.S. population that are treated with
the antimicrobial drug of concern, are associated with bacteria
resistant to the drug of concern, and for which the resistance is
attributable (in whole or in part) to the use of an antimicrobial drug
in animals. Such cases are expected to experience decreased or loss of
effectiveness of their antimicrobial drug treatment.

2\. **Current impact on systemic illness**: In any given year, a certain
proportion of the U.S. population will experience systemic foodborne
illness and will be treated with an antimicrobial drug. Some cases may
be due to bacteria that are resistant to the drug administered. The
current impact on systemic illness is defined as the current prevalence
of cases of systemic illness in the U.S. population that are treated
with the antimicrobial drug of concern, are associated with bacteria
resistant to the drug of concern, and for which the resistance is
attributable (in whole or in part) to the use of an antimicrobial drug
in animals. Such cases are expected to experience decreased or loss of
effectiveness of their antimicrobial drug treatment.

Just as was the case for each threshold prevalence where there is an
associated expected human health impact T(x), there is a current human
health impact estimate associated with each current prevalence. These
are the values H(x) introduced in the section above entitled,
**Description of Model for Deriving Resistance Thresholds**. Risk
managers compare estimates of the current prevalences with the threshold
prevalences, or the corresponding values of H(x) to T(x), to determine
whether an unacceptable human health risk has been or is about to be
reached. The following offers some suggestions on how these values could
be determined and then how the resistance threshold is calculated.

***Calculating Resistance Thresholds Using Current Impacts***

This measure of risk (H(x)) will normally be the most easily estimated
impact, since it will usually be the most frequent human health effect.

H(x) = current total prevalence of people with illness (x = EI or SI)\
×\
the attributable fraction for the food animal species\
×\
current prevalence of resistance in cases attributed to food animal
commodity\
×\
proportion expected to receive antimicrobial drug of concern

Assuming the current prevalence of resistance in cases attributed to
food animal commodity is known, the resistance threshold associated with
the human health threshold is calculated as follows:

$$$t(x) = \frac{T(x) \times \text{ h}}{H(x)}$ (Equation 6)

***Summary of Establishing Resistance Thresholds***

A resistance threshold set under the approach in this document would be
established prior to the approval of certain antimicrobial products for
use in food-producing animals. As discussed above, the resistance
threshold would be linked to the human health threshold through a
proportionality relationship between a measurable human health impact
and the exposure to food animal product containing resistant bacteria
associated with that human impact. The graph shown in Figure 4
illustrates that the maximum human health impact and the current human
health impact are two conveniently understood points among the many
possible points that comprise the relationship between human health
impact and resistance among animal isolates.

This document describes two methods for using a model to derive
resistance thresholds. The availability of data partially dictates how
estimates for required quantities are derived. Table 1 lists the type of
information used in the model and compares the information needed for
the two methods described.

The benefit of using Method 1, the maximum health impact method, is that
it permits calculation of t(x) without requiring data on the prevalence
of resistance in cases attributed to the food animal commodity. This
would be particularly useful in situations where a product is the first
new animal drug in its class. In such situations, there presumably would
be no data on the prevalence of resistance to the drug in the food
animal commodity attributable to animal drug use at the time of the
review of the new animal drug application. Method 1 derives the
resistance threshold by making the assumption that all human cases of
foodborne disease attributed to the food animal species would be due to
bacteria resistant to the drug of concern. The advantage of using Method
2, the current health impact method, is that it allows CVM to adjust the
calculation of k-res from that based on the assumptions in Method 1.
That is, Method 2 uses current data to determine the proportion of
animal-related human cases that would be due to bacteria resistant to
the drug of concern. Of course, in such situations, approvals for new
uses could only occur in circumstances in which the existence of
animal-related human cases due to bacteria resistant to the drug of
concern would not preclude approval of such drug for additional uses.

The 5^th^ percentile of the uncertainty distributions for the modeled
resistance threshold would be more protective of human health than would
be the mean of the distribution. See Appendix 1 for example calculations
of resistance thresholds for individual animal species and extensions to
multiple species as discussed later in this document. The example
calculations are not modeled values. They are presented to illustrate
the logic used in modeling resistance thresholds.

![](media/image3.wmf)

> **Figure 4:** Indicates the proportional relationship between human
> health impact (H(x)) and resistance among animal isolates (h) showing
> current and maximum human health impact (H~max~(x))estimates. The
> expected maximum impact used in Method 1 is the prevalence of
> infections in humans that are treated with the antimicrobial drug of
> concern, are associated with bacteria resistant to the drug of
> concern, and for which the resistance is attributable to the use of an
> antimicrobial drug in animals. It is called the maximum impact because
> it is calculated assuming all disease cases attributable to the animal
> species are resistant. A line connects the maximum to (0,0) and
> \[k-res\] is the slope of that line. Using Method 2, the ratio of the
> current human impact (y-axis) to the prevalence of resistance among
> food animal product associated with the current human impact (x-axis)
> is \[k-res\].

**Table 1.** Types of data and information that may be needed in the
epidemiology-based model. Data and sources are listed for example
purposes and are not intended to be an exhaustive list.

+--------------------------------------------------+---------+---------+
| ## Data to support human health impact estimate  | ## M    | ## M    |
|                                                  | ethod 1 | ethod 2 |
+--------------------------------------------------+---------+---------+
| U.S. population (denominator for determining     | Yes^1^  | Yes     |
| prevalences)                                     |         |         |
+--------------------------------------------------+---------+---------+
| FoodNet (or other sample) population             | No      | Yes     |
+--------------------------------------------------+---------+---------+
| Observed cases enteric/systemic disease in the   | No      | Yes     |
| sampled population                               |         |         |
+--------------------------------------------------+---------+---------+
| Prevalence of culture confirmed cases reportable | Yes     | No^2a^  |
| to health department (enteric and systemic) in   |         |         |
| US                                               |         |         |
+--------------------------------------------------+---------+---------+
| Prevalence of culture confirmed resistant cases  | No      | Yes^3^  |
| reportable to health department (enteric and     |         |         |
| systemic) in U.S.                                |         |         |
+--------------------------------------------------+---------+---------+
| Proportion of enteric/systemic disease cases     | Yes     | Yes     |
| attributable to the animal species               |         |         |
+--------------------------------------------------+---------+---------+
| Proportion of enteric/systemic disease cases     | No      | Yes^2b^ |
| attributed to the animal species and resistant   |         |         |
| to the antimicrobial drug under study            |         |         |
+--------------------------------------------------+---------+---------+
| Proportion of persons with enteric/systemic      | Yes     | Yes     |
| disease that seek care and are treated with the  |         |         |
| antimicrobial drug under study                   |         |         |
+--------------------------------------------------+---------+---------+
| ## Data to support exposure estimate             | ##      | ##      |
+--------------------------------------------------+---------+---------+
| Total prevalence of bacteria among the animal    | No      | No      |
| product samples                                  |         |         |
+--------------------------------------------------+---------+---------+
| Prevalence of antibiotic resistant bacteria      | No      | No      |
| among bacteria collected from contaminated       |         |         |
| animal product samples                           |         |         |
+--------------------------------------------------+---------+---------+
| Estimated prevalence of antibiotic-resistant     | No      | Yes     |
| bacteria in animal product                       |         |         |
+--------------------------------------------------+---------+---------+
| Consumption of animal product from domestically  | No      | No      |
| reared animals, per capita (lbs.) in U.S.^4^     |         |         |
+--------------------------------------------------+---------+---------+
| Total consumption of animal product from         | No      | No      |
| domestically reared animals in U.S. (lbs.)^4^    |         |         |
+--------------------------------------------------+---------+---------+
| Total consumption of animal product from         | No      | No      |
| domestically reared animals contaminated with    |         |         |
| antibiotic resistant bacteria in U.S. (lbs.)^4^  |         |         |
+--------------------------------------------------+---------+---------+

1.  "Yes" indicates the value is necessary for calculating a resistance
    threshold by the given method.

2.  Information estimated by the current surveillance system.

3.  If this information were estimated by the surveillance system, this
    line would supplant the line containing 2b.

4.  Note: Although consumption data are not needed, changes in
    consumption will alter the value of \[k-res\], as indicated between
    Equations 3 and 4.

**Risk Management Considerations**

After assessing the risk, there may be circumstances where additional
factors need to be considered in order to make a decision as to how to
manage the risk identified. Such factors may include a consideration of
sub-populations that may be at greater risk than the general population.
In addition, consideration may be given to the level of uncertainty
inherent in the evaluation of the risk. Such uncertainty may be
addressed through the application of various safety factors. Also,
safety factors could be applied to the model in order that thresholds be
set to correspond to a level to preclude a measurable human health
impact. These examples of risk management considerations are described
in Appendix 2 of this document to stimulate further discussion.

**Setting thresholds for multiple food animal species**

The approach set out in the document would allow CVM to consider a
number of options including the relative contribution to the human
health impact from each animal commodity group. CVM believes that there
needs to be significant discussion for setting thresholds when a
particular antimicrobial drug is or potentially will be approved in more
than one food animal species.

One possible approach is to set resistance thresholds based on the
relative contribution to human health by each food animal commodity. If
an antimicrobial is to be used in multiple species, it may be necessary
to provide each animal industry with its own resistance threshold. CVM
believes that the use of a specific antimicrobial in animals constitutes
the decision option against which the human health risk should be
measured. This means that whatever human health thresholds are
determined, the risk should be shared among the animal species for which
the antimicrobial has been approved such that the combined human health
impact from all antimicrobial drug use in food animals will not exceed
T(x). This leads to the restriction that for number of species (n),

$\sum_{i = 1}^{n}{a_{i}\lbrack t_{i}(x)\text{*k-res}_{i}\rbrack} \leq T(x)$
(Equation 8)

where a~i~ is the multiplier used to allocate a portion of the
resistance threshold to species i.

A readily calculable method for distributing the allowable risk among
species would be to allocate the risk in proportion to the weight of
consumable food product contributed by each animal species. The
resistance thresholds derived for each animal species (based on that
species\' contribution to the human health impact) would be divided by
the number of species. In this case a~i~ is 1/n. See Appendix 1 for
example calculations of resistance thresholds for multiple species.

Alternatives to this approach would be to share the human health impact
equally among all species or to allocate the resistance threshold in
proportion to the species contribution to human disease.

Once these human health thresholds are set by species, one needs to
determine a measure that estimates the relative proportion of foodborne
disease that each species contributes. The model can then determine what
the resistance threshold would be for that species to match its human
health threshold. If any commodity group exceeds the resistance
threshold, CVM would initiate procedures to withdraw from the label the
animal species that has reached or exceeded its threshold.

Pharmaceutical companies may seek approval for a new antimicrobial one
species at a time. Following the above philosophy, seeking approval for
a second, third, etc. species would necessitate reducing the level of
resistance allowed in those species already approved.

In the event that it proves impossible to distinguish the proportion of
foodborne disease contributed by each species, it would be necessary to
monitor the total human health impact and relate that directly to the
human thresholds, withdrawing the product globally should the human
health threshold be reached.

**Reassessment of Thresholds**

CVM anticipates that after the approval of a new antimicrobial drug for
use in food-producing animals, it will periodically reassess the
established threshold to account for new information and data. Data
collected through the NARMS program and from other sources after
approval will allow a more accurate determination of a resistance
threshold for a particular use of an antimicrobial drug. Reconsideration
of an established resistance threshold would also be appropriate given
changes in the use of the antimicrobial drug or related antimicrobial
drug in human medicine, changes in the pathogenicity or virulence of
resistant bacteria, changes in hygienic practices leading to greater or
fewer foodborne illnesses, changes in consumption patterns of
animal-derived foods, and emergence of new foodborne pathogens.

**Regulatory Options for Approved Products**

CVM envisions the codification of the resistance threshold as part of
the approval of a new animal drug application. If the resistance
threshold was determined to have been exceeded prior to approval, the
new animal drug application would not be approved. The basis for this
codification is that the continued use of the new animal drug, when the
resistance threshold has been exceeded, contributes to the loss of
effectiveness of important human antimicrobial therapies and, as such,
causes the use of the new animal drug to be no longer shown to be safe.

If, after antimicrobial drug approval, shifts in susceptibility are
observed via the post-approval monitoring program (and the resistance
threshold has not been exceeded) voluntary action may be initiated to
mitigate further loss of susceptibility. However, if the resistance
threshold was found to have been exceeded, CVM would initiate procedures
to withdraw from the label any animal species that has reached or
exceeded its threshold. This process would not preclude the agency from
taking any regulatory steps at any time if human health is at risk
because of the use of a new animal drug.

**[Glossary]{.smallcaps}**

**ADI -** Acceptable Daily Intake. Quantity of the new animal drug that
may safely be consumed in the human diet daily for a lifetime.

**Breakpoints** - Specific values, expressed relative to terms such as
Minimum Inhibitory Concentrations (MICs), or zones of inhibition (which
can be correlated with MICs using appropriate statistical methods),
which categorize bacteria as clinically susceptible, intermediate or
resistant.

***Campylobacter* Risk Assessment** - The first probabilistic risk
assessment undertaken by the Center for Veterinary Medicine which
estimated the human health impact of drug resistant Campylobacter
resulting from fluoroquinolone use in poultry. Available at
<http://www.fda.gov/cvm/antimicrobial/Risk_asses.pdf>.

**Current impact on enteric illness**: In any given year, a certain
proportion of the U.S. population will experience enteric foodborne
illness and will be treated with an antimicrobial drug. Some cases may
be due to bacteria that are resistant to the drug administered. The
current impact on enteric illness is defined as the current prevalence
of cases of enteric illness in the U.S. population that are treated with
the antimicrobial drug of concern, are associated with bacteria
resistant to the drug of concern, and for which the resistance is
attributable (in whole or in part) to the use of an antimicrobial drug
in animals. Such cases are expected to experience decreased or loss of
effectiveness of their antimicrobial drug treatment.

**Current impact on systemic illness**: In any given year, a certain
proportion of the U.S. population will experience systemic foodborne
illness and will be treated with an antimicrobial drug. Some cases may
be due to bacteria that are resistant to the drug administered. The
current impact on systemic illness is defined as the current prevalence
of cases of systemic illness in the U.S. population that are treated
with the antimicrobial drug of concern, are associated with bacteria
resistant to the drug of concern, and for which the resistance is
attributable (in whole or in part) to the use of an antimicrobial drug
in animals. Such cases are expected to experience decreased or loss of
effectiveness of their antimicrobial drug treatment.

**Drug characterization factor (DCF)** - An additional factor to
multiply the estimated human health impact of an antimicrobial drug to
compensate for the loss of an important human drug therapy. Criteria
will be established.

**Framework Document** - A December 1998 draft document by the Center
for Veterinary Medicine that outlines a range of potential regulatory
issues affecting antimicrobial drugs to be used in food-producing
animals. These issues include pre- and post-approval studies, the
significance of the drug to human medicine and regulatory thresholds
(See page 1 onto 2). The document is issue oriented and has not resulted
in Center guidance at this time. . Available at
<http://www.fda.gov/cvm/index/vmac/antimi18.html>.

**Human Health Threshold** - The unacceptable prevalence of infections
in humans that are treated with the antimicrobial drug of concern, are
associated with bacteria resistant to the drug of concern, and for which
the resistance is attributable (in whole or in part) to the use of an
antimicrobial drug in animals. Human health thresholds specifically
focus on the incremental effects on enteric illness or systemic illness
in humans as a consequence of the causative bacteria being resistant to
the antimicrobial drug the affected persons are expected to receive.
Based on current safety standards, the \"unacceptable prevalence\" is
considered that level at which there is no longer reasonable certainty
that there is no harm to human health.

**K-res** - A proportionality constant relating the nominal mean number
of cases of illness due to drug resistant bacteria attributable to a
particular food-animal species to the estimated amount of food product
(derived from given food animal species) consumed that contains
drug-resistant bacteria.

**h** - A consistent measure of the current prevalence of animal-derived
foods containing resistant bacteria.

**H(EI)** - The current level of human health impact of enteric illness
resulting from the current level of material containing drug-resistant
bacteria.

**H~max~(x)** - The maximum level of human health impact resulting from
the use of an antimicrobial drug in food producing animals causing 100%
resistance to a human antimicrobial drug, given current prescription
practices in human medicine.

**H(SI)** - The current level of human health impact of systemic illness
given the current level of material containing drug resistant bacteria.

**H(x)** - The current measured prevalence of infections in humans that
are treated with the antimicrobial drug of concern, are associated with
bacteria resistant to the drug of concern, and for which the resistance
is attributable to the use of an antimicrobial drug in animals (where x
= EI or SI).

**Minimum inhibitory concentration (MIC)** - The lowest concentration of
an antimicrobial drug, expressed in µg/ml or mg/L that, under defined
*in-vitro* conditions prevents the growth of bacteria within a defined
period of time.

**Minimum inhibitory concentration (MIC) distribution** - The range of
MICs for a given population of organisms when tested against a specific
antimicrobial drug under defined *in-vitro* conditions

**Mitigation Programs** - Actions initiated by CVM, the sponsor, or
other groups to alleviate the concern for unacceptable human health
impacts resulting from the use of the antimicrobial drug in food
animals. These actions may include a wide range of activities such as
education, changes in animal production practices, changes to the animal
drug label, or initiation of procedures to withdraw the animal drug
product.

**Model Adjustment Factor (MAF)** - A factor to multiply risk estimates
to compensate for uncertainty in the model. This may be similar to the
uncertainty multipliers commonly used in unit risk estimates from
laboratory animals to derive an acceptable daily intake. Criteria and
experience will be developed as the Center considers using such factors.

**Monitoring** - The collection of specific data used for regulatory
purposes

**NADA** - New Animal Drug Application

**NARMS -** National Antimicrobial Resistance Monitoring Program.
Available at http://www.cdc.gov/ncidod/dbmd/narms/

**Q -** Quantity of product containing bacteria resistant to an
antimicrobial of interest.

**Resistance** - A characteristic of a bacterial strain in which it is
not inhibited by the usually achievable systemic concentrations of an
antimicrobial agent with normal dosing schedules and/or falls in the
range where specific mechanisms are likely (e.g., beta-lactamases), and
clinical efficacy has not been reliable in treatment studies.

**Resistance Threshold** - The resistance threshold (t(x)) is the
maximum allowable prevalence of resistant bacteria isolated from
animal-derived food that does not pose an unacceptable risk to human
health. The resistance threshold is derived through an
epidemiology-based model that relates the prevalence of resistant
bacteria in food to an impact on either enteric illness (EI) or systemic
illness (SI) in humans.

Exceeding a resistance threshold would be considered a level of
resistance at which there is no longer reasonable certainty that there
is no harm to human health. For the purposes of this definition,
bacteria are considered resistant if their minimum inhibitory
concentration (MIC) reaches or exceeds the resistance breakpoint
established for the related drug used in human medicine.

**Surveillance** - The close and vigilant review of data coming from a
system used for regulatory purposes.

**Susceptible** - A characteristic of a bacterial strain in which it is
inhibited by the usually achievable systemic concentrations of an
antimicrobial agent with normal dosing schedules and/or falls in the
range where specific mechanisms are not likely (e.g., beta-lactamases),
and clinical efficacy has been reliable in treatment studies.

**Threshold for impact on enteric illness:** In a given year, a certain
proportion of the U.S. population will experience enteric foodborne
illness and will be treated with an antimicrobial drug. Some cases may
be due to bacteria that are resistant to the drug administered.
Therefore, the threshold for impact on enteric illness is defined as the
unacceptable prevalence of cases of enteric illness in the U.S.
population that are treated with the antimicrobial drug of concern, are
associated with bacteria resistant to the drug of concern, and for which
the resistance is attributable (in whole or in part) to the use of an
antimicrobial drug in animals. Such cases are expected to experience
decreased or loss of effectiveness of their antimicrobial drug
treatment.

**Threshold for impact on systemic illness:** In a given year, a certain
proportion of the U.S. population will experience systemic foodborne
illness and will be treated with an antimicrobial drug. Some cases may
be due to bacteria that are resistant to the drug administered.
Therefore, the threshold prevalence of cases of systemic illness
impacted is defined as the unacceptable prevalence of cases of systemic
illness in the U.S. population that are treated with the antimicrobial
drug of concern, are associated with bacteria resistant to the drug of
concern, and for which the resistance is attributable (in whole or in
part) to the use of an antimicrobial drug in animals. Such cases are
expected to experience decreased or loss of effectiveness of their
antimicrobial drug treatment.

**t(EI)** - The resistance threshold for enteric illness. It is the
maximum allowable prevalence of resistant bacteria isolated from
animal-derived food that does not cause an unacceptable impact on
enteric illness in humans.

**t(SI)** - The resistance threshold for systemic illness in humans. It
is the maximum allowable prevalence of resistant bacteria isolated from
animal-derived food that does not cause an unacceptable impact on
systemic illness in humans.

**t(x)** - The generic resistance threshold (i.e., a resistance
threshold derived in relation to a human health impact, x (where x = EI
or SI). See above for complete definition of **Resistance Threshold**.

**T(EI)** - The human health threshold for enteric illness.

**T(SI)** - The human health threshold for systemic illness.

**T(x)** - The generic form of the human health threshold, for x={EI or
SI}.

**[References]{.smallcaps}**

1\. FDA, \"Public Health Action Plan to Combat Antimicrobial
Resistance,\" June 22, 2000 (65 FR 38832). Available at
<http://www.cdc.gov/drugresistance/actionplan/>.

2.  Tollefson, L., Angulo, F. and Cray, P. National Surveillance for
    Antibiotic Resistance in Zoonotic Enteric Pathogens. (In) Hunt, E.,
    and Tollefson, L. The Veterinary Clinics of North America, Food
    Animal Practice Microbial Food Borne Pathogens. March 1998. W.B.
    Saunders Co. Philadelphia, 14(1); 141-150.

3.  CDC Preliminary FoodNet Data on the Incidence of Foodborne
    Illnesses - Selected Sites, United States, 1999. MMWR. March 17,
    2000 / 49(10); 201-5. Available at
    <http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/mm4910a1.htm>.

4.  FDA, \"Guidance for Industry: Consideration of the Human Health
    Impact of the Microbial Effects of Antimicrobial New Animal Drugs
    Intended for Use in Food-Producing Animals (GFI #78),\" 64 FR 72083
    and 72084, December 23, 1999. Available at
    <http://www.fda.gov/cvm/guidance/guidad78.html>.

5.  FDA, \"Proposed Framework For Evaluating And Assuring The Human
    Safety Of The Microbial Effects Of Antimicrobial New Animal Drugs
    Intended For Use In Food-Producing Animals,\" January 6, 1999 (64 FR
    887). Available at
    <http://www.fda.gov/cvm/index/vmac/antimi18.html>.

6\. AVMA. Judicious Antimicrobial-Use Principles, Related Proposals
Approved by Board. JAVMA 214(2): p167-8

7\. United States Department of Agriculture, Food Safety and Inspection
Service, Science and Technology Microbiology Division, April 1996
Nationwide Broiler Chicken Microbiological Baseline Data Collection
Program, July 1994-June 1995. \[available at
<http://www.fsis.usda.gov/OPHS/baseline/contents.htm> \] .

8\. United States Department of Agriculture, Food Safety and Inspection
Service, Science and Technology Microbiology Division, February 1996
Nationwide Beef Microbiological Baseline Data Collection Program: Cows
and Bulls, December 1993-November 1994. \[available at
<http://www.fsis.usda.gov/OPHS/baseline/contents.htm> \].

9.  United States Department of Agriculture Food Safety and Inspection
    Service, Science and Technology Microbiology Division, January 1994
    Nationwide Beef Microbiological Baseline Data Collection Program:
    Steers and Heifers, October 1992- September 1993. \[available at
    <http://www.fsis.usda.gov/OPHS/baseline/contents.htm> \].

10\. United States Department of Agriculture Food Safety and Inspection
Service, Science and Technology, Microbiology Division, April 1996
Nationwide Federal Plant Raw Ground Beef Microbiological Survey, August
1993- March 1994. \[available at
<http://www.fsis.usda.gov/OPHS/baseline/contents.htm> \].

11\. United States Department of Agriculture, Food Safety and Inspection
Service, Science and Technology Microbiology Division, June 1996
Nationwide Pork Microbiological Baseline Data Collection Program: Market
Hogs, April 1995-March 1996. \[available at
<http://www.fsis.usda.gov/OPHS/baseline/contents.htm>\].

12\. United States Department of Agriculture, Food Safety and Inspection
Service, Science and Technology Microbiology Division, May 1996
Nationwide Raw Ground Chicken Microbiological Survey.

13\. United States Department of Agriculture, Food Safety and Inspection
Service, Science and Technology, Microbiology Division, May 1996
Nationwide Raw Ground Turkey Microbiological Survey. \[available at
<http://www.fsis.usda.gov/OPHS/baseline/contents.htm> \].

14\. United States Department of Agriculture, Food Safety and Inspection
Service, Science and Technology, Office of Public Health and Science,
Microbiology Division, August 1998 Nationwide Young Turkey
Microbiological Baseline Data Collection Program, August 1996-July 1997,
\[available at <http://www.fsis.usda.gov/OPHS/baseline/contents.htm> \].

15\. Centers for Disease Control and Prevention. FoodNet CDC/FSIS/FDA
Foodborne Diseases Active Surveillance Network. CDC's Emerging
Infections Program. 1998 Surveillance Results. Preliminary Report.
Atlanta, Georgia.

**Appendix 1**

**Example Calculation of Thresholds t(EI) by Method 1**

Assume that the current estimated prevalence of an enteric illness
caused by animal-derived food is 6.67 cases per 1000 people in the U.S.
annually.

Assume that 10 percent of the cases are treated with the antimicrobial
drug of concern such that:

H~max~(EI) = 6.67\*10^-3^ \* 0.10 = 6.67\*10^-4^

Assume that the antimicrobial drug of concern is approved for use in
four food animal species and that each species is responsible for
causing a proportion of total enteric illness cases such that: Species
*A* causes 60 percent of the cases, Species *B* causes 20 percent of the
cases, Species *C* causes 15 percent of the cases, and Species *D* cause
5 percent of the cases.

For any given human health threshold (T(EI) expressed as a prevalence),
a resistance threshold (t(EI) expressed as percent) can be calculated
for each species according to the formula:

t~i~(EI) = [T(EI)\*a~i~\*]{.underline} 100%

H~max~(EI) \* S~i~

Where:

a~i~ = 1/n where n is the number of food animal species for which the
antimicrobial drug is approved. In this example, n=4 such that a~i~ =
0.25.

S~i~ is fraction of the total number of food borne cases caused by the
food animal species of concern such that:

S~A~ = 0.60

S~B~ = 0.20

S~C~ = 0.15

S~D~ = 0.05

**Appendix 2**

> **Risk Management Considerations**

**Consideration of sub-populations**

If an identifiable sub-population (e.g., certain immuno-compromised
people) bears a significantly greater proportion of the risk than the
general population it seems appropriate that they should be the focus of
protective measures. However, this is provided that the defined
sub-population is not able to avoid or manage the risk and receives no
significant direct benefits from exposure to the risk that are greater
than the population in general. One could argue that these people are
shouldering the risk for the entire population and that they should not
have to be exposed to any risk imposed on them by the population as a
whole that is greater than the population accepts upon itself.

In that case, the current prevalence estimates for enteric illness (EI)
and systemic illness (SI) that will be compared with the threshold
prevalences for these potential impacts would be modified as follows:

**Sub-population current** prevalence **(EI)** = Expected cases of
enteric illness in sub-population due to resistance in the year and
treated with the antimicrobial drug of concern / Size of sub-population.

**Sub-population current** prevalence **(SI)** = Expected cases of
systemic illness in sub-population due to resistance in the year and
treated with the antimicrobial drug of concern / Size of sub-population.

For any identified sub-populations, these threshold levels would replace
the three population risk estimates (since they will always be more
stringent), and used together to determine whether an unacceptable human
health impact has or is likely to be reached by comparing them with the
threshold prevalences for enteric illness (EI) and systemic illness
(SI).

**Adjusting the current risk estimate for statistical uncertainty and
model uncertainty**

***Compensating for statistical uncertainty***

Models used to estimate current levels of human health impact should
account for statistical uncertainty. The resultant estimates therefore
have uncertainty distributions that reflect the degree to which one
cannot be sure about the true value because of the small amount of data.
Picking the 95^th^ percentile of these estimates, or any other
appropriately high percentile, as the measure of the risk is a
conservative action because it evaluates the risk at a value that we are
95% (for example) statistically certain the true value lies below.

This approach has the limitation that it only considers the uncertainty
due to inference about some measure from a set of data. Any inference is
based on a mathematical model. Statistical analysis cannot take into
account any inaccuracies arising from a mismatch between the model
assumptions used to create the mathematics of the model and physical
reality. The model uncertainty can be separately accounted for by
multiplying the risk estimates by a 'model adjustment factor' described
below.

***Compensating for model uncertainty***

CVM recognizes that the epidemiology-based model set out in this
document may overestimate or underestimate the impact of the animal drug
on antimicrobial bacterial resistance and changes in human health. A
model adjustment factor (MAF) intended to be applied to provide
adjustments for unquantified factors may need to be applied to the
results of the model to address this concern. CVM will need to develop
criteria for the application of this uncertainty factor.

***Compensating for potential loss of efficacy of an important drug***

CVM recognizes that the epidemiology-based model set out in this
document may not address the importance of the drug in human medicine. A
drug categorization factor (DCF) may need to be applied to the results
of the model to address this concern. CVM will need to develop criteria
for the application of this uncertainty factor.

**Resistance Threshold Safety Factor**

The resistance threshold described in this document is the maximum
allowable level of resistance prevalence in bacteria isolated from the
food animal that does not pose an unacceptable risk to human health.
This resistance threshold is derived through an epidemiology-based model
that describes the relationship between the human health threshold and
resistance levels in animals, and presumably could contain some safety
factor to minimize the likelihood of the human health threshold ever
being reached. Further discussion is needed regarding the development
and application of such a safety factor.