\# 152

Guidance for Industry

Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to
Their Microbiological Effects on Bacteria of Human Health Concern

### DRAFT GUIDANCE

####### This guidance document is being distributed for comment purposes only.

This draft document discusses a recommended approach for assessing the
safety of antimicrobial new animal drugs with regard to their
microbiological effects on bacteria of human health concern.

Comments and suggestions regarding this document should be sent to the
Dockets Management Branch (HFA 305), Food and Drug Administration, 5630
Fishers Lane, Room 1061, Rockville, MD 20852. All comments should be
identified with the Docket No. 98D-1146. Submit electronic comments to
<http://www.accessdata.fda.gov/scripts/oc/dockets/commentdocket.cfm>.

Direct questions regarding this document to William T. Flynn, (HFV-2),
Center for Veterinary Medicine, Food and Drug Administration, 7519
Standish Place, Rockville, MD 20855, 301-827-4514, e-mail:
wflynn@cvm.fda.gov.

Additional copies of this draft guidance document may be requested from
the Communications Staff (HFV-12), Center for Veterinary Medicine, Food
and Drug Administration, 7519 Standish Place, Rockville, MD 20855 and
may be viewed on the Internet at <http://www.fda.gov/cvm>*.*

**U.S. Department of Health and Human Services\
Food and Drug Administration\
Center for Veterinary Medicine\
September 6, 2002**

## **Table of Contents**

I. [Introduction](#Introduction) 1

II\. [Scope of Guidance](#Scope_of_guidance) 3

III\. [Risk Analysis Methodology](#Risk_analysis_methodology) 6

IV\. [Hazard Identification](#Hazard_Identification) 9

V. [Qualitative Antimicrobial Resistance Risk
Assessment](#v.-qualitative-antimicrobial-resistance-risk-assessment) 11

> A. [Release Assessment](#Release_Assessment) 11

B. [Exposure Assessment](#Exposure_Assessment) 16

> C. [Consequence Assessment](#Consequence_Assessment) 19
>
> D. [Risk Estimation](#Risk_Estimation) 19

VI\. [Antimicrobial Resistance Risk Management
Considerations](#vi.-antimicrobial-resistance-risk-management-considerations)
22

> [Glossary](#glossary) 28
>
> [Appendix A](#Appendix_A): Ranking of antimicrobial drugs according to
> their importance in human medicine 31
>
> [Appendix
> B](#appendix-b-human-exposure-to-bacteria-of-human-health-concern-via-animal-derived-foods):
> Human exposure to certain zoonotic pathogens through consumption of
> animal-derived foods 42
>
> [Appendix
> C](#appendix-c-re-evaluating-the-safety-of-currently-approved-antimicrobial-new-animal-drugs):
> Re-evaluating the safety of currently approved antimicrobial new
> animal drugs 45
>
> [References](#references) 47

Evaluating the Safety of Antimicrobial New Animal Drugs With Regard to
Their Microbiological Effects on Bacteria of Human Health Concern

***This document represents the Agency's current thinking on a
recommended approach for assessing the safety of antimicrobial new
animal drugs with regard to their microbiological effects on bacteria of
human health concern. It does not create or confer any rights for or on
any person and does not operate to bind the Food and Drug Administration
(FDA) or the public. An alternate approach may be used as long as it
satisfies the requirements of applicable statutes and regulations.***

**I.** []{#Introduction .anchor}**[Introduction]{.smallcaps}**

> Food-producing animals are administered antimicrobial drugs for
> therapeutic, preventive, and production purposes. 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 both commensal and
> pathogenic bacteria that may be transferred to humans by consumption
> of contaminated food products.^1,2,3,4^ With the use of antimicrobial
> drugs in food-producing animals, these bacteria may become resistant
> to drugs that may also be used to treat human illness, potentially
> making human illnesses more difficult to treat.^5,6,7,8^ In addition,
> bacteria pathogenic to humans can acquire resistance traits from
> non-pathogenic bacteria originating in food-producing animals by
> mechanisms that allow the exchange of their genetic material in the
> human gastrointestinal tract.^9,10^
>
> Antimicrobial resistance is a complex phenomenon. The selection of
> antimicrobial resistant bacterial populations occurs as a consequence
> of the combined impact of antimicrobial drug use in humans, animals,
> and plants (or other agricultural settings). As a consequence, the
> human health impact specifically due to the use of antimicrobial drugs
> in food-producing animals is difficult to assess precisely.
> Antimicrobial drug resistance has been linked to resistance against
> non-related antimicrobial drug classes, disinfectants, and other
> compounds such as heavy metals.^11,12^ The use of unrelated drugs can
> result in the co-selection of multiple drug resistance when resistance
> determinants (genes) for unrelated drugs are linked. Additionally,
> since certain mechanisms of resistance affect more than one class of
> antimicrobial drug (cross-resistance), the use of one particular
> antimicrobial drug may confer resistance to multiple drugs.^11,13,14^
>
> FDA published as a draft document on November 18, 1998 (63 FR 64094),
> and as a final document on December 17, 1999 (64 FR 70715), the
> guidance entitled \"Consideration of the Human Health Impact of the
> Microbial Effects of Antimicrobial New Animal Drugs Intended for Use
> in Food-Producing Animals\" (Guidance #78). This guidance document
> signaled a policy change with regard to the safety evaluation of
> antimicrobial new animal drugs. Although FDA had considered previously
> the microbiological effects of certain uses of antimicrobial drugs (21
> CFR 558.15), Guidance #78 stated FDA's intention to consider the
> potential human health impact of the microbiological effects
> associated with all uses of all classes of antimicrobial new animal
> drugs intended for use in food-producing animals. The specific
> microbiological effects considered in Guidance #78 included 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.
>
> On January 6, 1999, the FDA announced (64 FR 887) the availability of
> the discussion document entitled "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" (Framework Document). The Framework Document discussed
> possible strategies for managing the potential risks associated with
> the use of antimicrobial drugs in food-producing animals. These
> strategies included: 1) revision of the pre-approval safety assessment
> for antimicrobial resistance for new animal drug applications to
> assess all uses; 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. FDA has considered all comments from
> stakeholders related to the Framework Document in the process of
> developing the draft guidance discussed herein.
>
> Prior to approving an antimicrobial new animal drug application, FDA
> must determine that the drug is safe and effective. For antimicrobial
> drugs intended for use in food-producing animals, the Agency must
> determine specifically that such drug use is safe with regard to human
> health. FDA considers the drug to be "safe" if it concludes that there
> is reasonable certainty of no harm to human health from the use of the
> proposed new animal drug in food-producing animals. This draft
> guidance document provides guidance for industry on one possible
> process for evaluating potential microbiological effects of such drugs
> as part of the new animal drug application process.
>
> Consistent with the Framework Document, FDA also intends to
> re-evaluate the potential microbiological effects of antimicrobial
> drug products currently approved for use in food-producing animals and
> for which antimicrobial resistance concerns were not previously
> considered. The agency intends to re-evaluate such products using a
> risk analysis process similar to that described in this document for
> evaluating drugs prior to approval. Appendix C provides a general
> description of that process.

**II. [Scope of Guidance Document]{.smallcaps}**[]{#Scope_of_guidance
.anchor}

> FDA explained previously in Guidance #78 that it intended to consider,
> as part of the pre-approval safety evaluation process, the potential
> human health impact of the microbiological effects associated with all
> uses of all classes of antimicrobial new animal drugs intended for use
> in food-producing animals. Further clarification is provided below
> regarding which microbiological effects should be considered and which
> investigational new animal drugs (INADs) or new animal drug
> applications (NADAs) are covered by the guidance described herein.

A. Microbiological effects of animal drugs:

1.  Antimicrobial resistance: The primary focus of this guidance is to
    address the concern that the use of antimicrobial new animal drugs
    in food-producing animals will cause resistance determinants or
    resistant bacteria to emerge and to impact human health adversely.

2.  Other microbiological effects:

> a\. Pathogen load effects: Antimicrobial new animal drugs administered
> to food-producing animals may affect the bacterial populations present
> in animal intestinal tracts. These effects may include changes in the
> number of bacteria that are human pathogens (pathogen load). Although
> this potential microbiological effect of antimicrobial drugs has been
> acknowledged, there is no scientific consensus regarding the relevance
> of the effect or regarding methodologies for how such an effect could
> be measured.
>
> As a consequence, FDA convened its Veterinary Medicine Advisory
> Committee (VMAC) in January 2002 to obtain recommendations with regard
> to potential antimicrobial drug effects on pathogen load. The majority
> of the committee members concluded that the scientific evidence
> presented indicates that there is little to no public health
> significance associated with pathogen load with regard to
> antimicrobial drug use. The committee recommended that pathogen load
> studies not be included as part of the pre-approval drug process for
> either sub-therapeutic or therapeutic drugs. After considering the
> committee recommendations and other relevant scientific information,
> the FDA has concluded that, at this time, specific information
> regarding potential antimicrobial drug effects on pathogen load should
> not be included in the pre-approval new animal drug evaluation
> process. Therefore, pathogen load is not considered within the scope
> of this draft guidance document.
>
> b\. Effects of drug residues on human intestinal microflora:
> Antimicrobial drug residues present in food from food-producing
> animals may cause adverse effects on the ecology of the intestinal
> microflora of consumers.^15,16^ As a result of this concern, FDA
> published a guidance document on January 30, 1996 (61 FR 3043),
> entitled "Microbiological Testing of Antimicrobial Drug Residues in
> Food" (Guidance #52). This guidance document stated that the agency
> would consider antimicrobial activity when establishing tolerances for
> antimicrobial new animal drugs.
>
> Based on the availability of new information, FDA revised the 1996
> guidance and published a new draft guidance for industry (also
> referred to as Guidance #52) on December 27, 2001 (66 FR 66910)
> entitled "Assessment of the Effects of Antimicrobial Drug Residues
> from Food of Animal Origin on the Human Intestinal Flora."
>
> B. New animal drugs covered by this guidance:

The FDA believes that human exposure through the ingestion of resistant
bacteria from animal-derived foods represents the most significant
pathway for human exposure to resistance determinants (or resistant
bacteria) that have emerged as a consequence of antimicrobial drug use
in animals. Therefore, FDA's strategies for managing antimicrobial
resistance concerns are focused currently on those antimicrobial new
animal drugs that are intended for use in food-producing animals. As
stated in Guidance #78, this focus includes all uses of antimicrobial
new animal drugs in food‑producing animals.

C. Antimicrobial NADAs for food-producing animals that may not be
subject to this guidance:

There are certain categories or types of antimicrobial new animal drug
applications for which additional information may not be needed
regarding the microbiological effects outlined above. Such antimicrobial
new animal drug applications may include the following:

> 1\. Certain supplemental NADAs: Microbiological safety information
> typically is not needed for Category I supplemental NADAs (21 CFR
> 514.106(b)(1)). These supplements ordinarily do not require a
> reevaluation of any of the safety or effectiveness data in the parent
> application. However, information may be needed for certain Category
> II supplemental NADAs (21 CFR 514.106(b)(2)). These supplements may
> require a reevaluation of certain safety or effectiveness data in the
> parent application.
>
> 2\. NADAs for minor species or minor uses: Safety information
> regarding potential microbiological effects would ordinarily not be
> needed for NADAs for minor species or minor uses when there is an
> existing approval for the new animal drug in a major species. However,
> in certain circumstances information may be requested for drug
> applications for minor species or minor uses.
>
> 3\. NADAs for antimicrobial drug combinations: Safety information
> regarding potential microbiological effects would ordinarily not be
> needed for antimicrobial drug combinations as defined in Section
> 512(d) of the Act (21 U. S. C. 360b(d)), as amended by the Animal Drug
> Availability Act (ADAA) of 1996. Safety with regard to potential
> microbiological effects would be addressed typically as part of the
> NADAs for the individual antimicrobial drugs that comprise the
> combination. However, in certain circumstances information may be
> requested for drug applications for antimicrobial drug combinations.
>
> 4\. Generic (abbreviated) NADAs: Microbiological safety information is
> usually not needed for abbreviated new animal drug applications
> (ANADAs) for generic antimicrobial drugs, but may be needed for
> supplemental applications seeking innovative extensions to the
> conditions of use approved for the pioneer product.
>
> 5\. Other: Drug sponsors should consult with FDA to determine if
> information regarding potential microbiological effects is needed for
> their particular new animal drug application.

**[III. Risk Analysis
Methodology]{.smallcaps}**[]{#Risk_analysis_methodology .anchor}

# This guidance document outlines a risk analysis methodology and describes its application as a process for evaluating antimicrobial resistance concerns as part of the overall pre-approval safety evaluation of a new animal drug. The new animal drug sponsor may use this guidance and the methodology described to conduct a qualitative risk assessment as part of the safety evaluation of its proposed drug product. There are many factors that are included in a safety evaluation of a new animal drug. This guidance only addresses one way to evaluate human food safety with respect to the potential microbiological effects of antimicrobial drugs on bacteria of human health concern. Other considerations (i.e., potential toxicity, residues, etc.) are also evaluated as part of the overall human food safety evaluation. The sponsor is also free to demonstrate the safety of its proposed drug product in other ways. If the sponsor elects to use this process, the assessment should be submitted to the INAD file with supporting data as a component of the Human Food Safety technical section or be included in the NADA as part of the sponsor's submission under 21 CFR 514.1(b)(8). The results of this risk assessment can help to determine an overall estimate of risk to allow an informed risk management decision. Evaluation of all available information submitted in support of the NADA may result in actions ranging from approval of the new animal drug to denial of the new animal drug application. The remainder of the document provides guidance on this risk analysis methodology.

A. Background:

The risk analysis methodology outlined in this document is based on the
methodology described by the Office of International Epizootics (OIE) Ad
Hoc Group on Antimicrobial Resistance.^17^ The risk analysis methodology
described in the OIE document is tailored to address antimicrobial
resistance in animals and includes hazard identification, risk
assessment, risk management, and risk communication. Although it differs
somewhat organizationally, the OIE approach includes similar steps to
describe the risk assessment process as the risk analysis paradigm
described by the National Academy of Science/National Research Council
(NAS/NRC).^18^

The risk assessment process is comprised of a release assessment,
exposure assessment, consequence assessment, and risk estimation (See
Figure 1). The risk estimation integrates the components of the risk
assessment into an overall conclusion that provides a qualitative
indication of the potential risk of the proposed antimicrobial new
animal drug to human health. The overall risk estimation ranking is then
used by FDA, along with other relevant data and information submitted in
support of the NADA, to determine whether the drug might be approvable
under specific risk management conditions.

![](media/image1.wmf)**Figure 1.** Components of a qualitative
antimicrobial resistance risk assessment

B. Definitions:

1\. Hazard: The hazard is defined as human illness that is caused by a
specified antimicrobial-resistant bacteria, is attributable to a
specified animal-derived food commodity, and is treated with the human
antimicrobial drug of interest.

2\. Hazardous agent: The hazardous agent is the antimicrobial-resistant
bacteria or resistance determinant(s) of human health significance that
arises in a food-producing animal as a consequence of animal uses of
antimicrobial new animal drugs. A resistance determinant is a gene that,
through either activation, mutation, or external acquisition, provides a
bacterium with the necessary biochemical mechanism to survive in the
presence of an antimicrobial drug that would otherwise result in the
death or inhibition of a susceptible bacterium.

> The antimicrobial resistance determinant(s) may be carried on
> chromosomal or on extra-chromosomal DNA of pathogenic or commensal
> bacteria. For example, the resistance determinants of interest in this
> guidance include those expressed in human pathogens (e.g.,
> *Salmonella*, *Campylobacter*) or determinants that are expressed in
> commensal bacteria (e.g., *E. coli*, *Enterococcus* spp.).

3\. Risk: FDA's overriding concern is that the effectiveness of
antimicrobial drugs is decreased or lost in humans as a consequence of
human exposure to resistant bacteria (or resistance determinants)
resulting from the use of antimicrobial drugs in food-producing animals.

> Loss of antimicrobial drug effectiveness, as it is referred to here,
> is a general concept that might encompass a range of deleterious
> effects (e.g., increased duration of illness, treatment failure, loss
> of therapeutic options, etc.) that antimicrobial resistance
> determinants might have on human health. Due to the difficulties
> associated with measuring loss of effectiveness, the risk assessment
> process described here uses a more readily understood and estimated
> health effect endpoint.
>
> To that end, we define the risk as the probability that human illness
> is caused by a specified antimicrobial resistant bacteria, is
> attributable to a specified animal-derived food commodity, and is
> treated with the human antimicrobial drug of interest.

C. Data sources/data quality:

The data supporting the risk analysis may come from published
literature. FDA recommends that drug sponsors refer to Guidance for
Industry #106, "The Use of Published Literature in Support of New Animal
Drug Approval" for guidance regarding use of published literature. If
data are not readily available from published literature or previously
conducted studies, sponsors may consider generating necessary data
through the conduct of prospective studies. Drug sponsors should refer
to 21 CFR 58 for requirements related to Good Laboratory Practices for
conducting non-clinical laboratory studies.

**IV. [Hazard Identification]{.smallcaps}**[]{#Hazard_Identification
.anchor}

> Prior to initiating the risk assessment, the sponsor that elects to
> use this process should identify the hazard and the conditions that
> influence the occurrence of that hazard.
>
> As previously defined, the hazard is human illness that is caused by a
> specified antimicrobial-resistant bacteria, is attributable to a
> specified animal-derived food commodity, and is treated with the human
> antimicrobial drug of interest.
>
> FDA recommends that the hazard identification step of the risk
> assessment include the following information regarding the chemical,
> biochemical, and physical properties of the drug that bear on
> characterizing the downstream effects of the drug:

#### A. Drug-specific information:

FDA recommends that the sponsor provide information regarding the
proposed antimicrobial drug substance that includes:

1.  Chemical name and structure

2.  Class of antimicrobial drug (e.g., macrolide)

3.  Mechanism (e.g., protein synthesis inhibitor) and type of action
    (i.e., bactericidal vs. bacteriostatic)

4.  Spectrum of activity (i.e., Gram-positive, Gram-negative, broad,
    etc.)

5.  Specific susceptibility data (i.e., minimum inhibitory
    concentrations (MIC) and minimum bactericidal concentration (MBC)
    data pertinent to pathogens/commensals in question)

Additional guidance on susceptibility testing may be obtained from
recognized sources, if available, such as the NCCLS M37-A2 document
"Development of In Vitro Susceptibility Testing Criteria and Quality
Control Parameters for Veterinary Antimicrobial Agents; Approved
Guideline -- Second Edition". The M37-A2 document describes the data
needed for selection of appropriate interpretive standards and provides
quality control guidance for new veterinary antimicrobial agents.

6.  Relative importance of the drug to human medicine. Knowledge
    regarding the relative importance of the drug to human medicine may
    be important for interpreting the significance of certain
    information included in the risk assessment. Refer to human medical
    importance ranking in Appendix A.

(Note: The human importance ranking will also be incorporated in the
consequence assessment component of the risk assessment described
below.)

#### B. Bacteria/resistance determinants information:

Considering the target animal species and the antimicrobial properties
of the drug in question, FDA recommends that the sponsor identify:

1.  Bacterial species and strains for which resistance acquisition has
    potential human health consequence.

2.  Resistance determinants with human health significance that may be
    selected for and maintained as a consequence of the animal drug use.
    It is recommended that information be included that describes any
    phenotypic and genetic homologies with resistance determinants in
    other bacteria of human concern.

#### C. Antimicrobial susceptibility testing methodology:

FDA recommends that the sponsor include the antimicrobial susceptibility
testing methodology for the bacterial isolates of concern. The methods
may include citations, if available, of relevant laboratory standards
such as the National Committee on Clinical Laboratory Standards (NCCLS).
Additional guidance on susceptibility testing may be obtained from
recognized sources such as the NCCLS M37-A2 document "*Development of In
Vitro Susceptibility Testing Criteria and Quality Control Parameters for
Veterinary Antimicrobial Agents; Approved Guideline---Second Edition*".
The M37-A2 document describes the data needed for selection of
appropriate interpretative standards and provides quality control
guidance for new veterinary antimicrobial agents. Also, refer to NCCLS
M31-A2 document "*Performance Standards for Antimicrobial Disk and
Dilution Susceptibility Tests for Bacteria Isolated from Animals;
Approved Standard ---Second Edition*." The M31-A2 document provides the
currently recommended techniques for antimicrobial agent disk and
dilution susceptibility testing, criteria for quality control testing,
and interpretive criteria for veterinary use.

#### D. Data gaps and emerging science:

FDA recommends that the sponsor attempt to identify data gaps and areas
where additional information may affect current determinations.

# **V. [Qualitative Antimicrobial Resistance Risk Assessment]{.smallcaps}**

#### Based on the hazard, as specifically defined in the Hazard Identification step, the sponsor of the new animal drug electing to use this process should complete a qualitative antimicrobial resistance risk assessment and submit this assessment to FDA for review. The assessment process outlined below adapts the OIE methodology to provide a mechanism for conducting a qualitative pre-approval drug risk assessment. The assessment process described below is intended to organize and integrate an array of relevant information and provide a general method describing how this information may be interpreted. The risk assessment process is comprised of a release assessment, exposure assessment, consequence assessment, and risk estimation (refer to Figure 1).

#### This assessment process is presented in a simplified format. Sponsors are expected to adapt and expand their risk assessment protocol to accommodate unique interrelationships that may exist between a new antimicrobial drug, affected microbe(s), proposed condition(s) of use and other parameters potentially impacting human health. The assessment process outlined below is intended to result in an overall estimation of the level of concern associated with the development of antimicrobial resistance as a consequence of the proposed use of the drug in animals. This process may help guide the selection of appropriate risk management steps. 

#### FDA intends to determine the appropriate use conditions or other risk management steps based on its review of the risk assessment and consideration of the new animal drug application as a whole.

A.  []{#Release_Assessment .anchor}Release Assessment:

The release assessment describes the probability that factors related to
the antimicrobial new animal drug and its use in animals will result in
the emergence of resistant bacteria or resistance determinants in the
animal.

1\. Defining the boundaries of the release assessment:

> The release assessment should characterize the source of the defined
> hazardous agent. For the purposes of this guidance, FDA is focusing on
> the food-producing animal as a source of human exposure to the
> hazardous agent.
>
> The boundaries of the release assessment span from the point the
> antimicrobial new animal drug is administered to the food-producing
> animal, to the point the animal is presented for slaughter or
> animal-derived food is collected.
>
> Human exposure to that hazardous agent should be addressed in the
> exposure assessment.
>
> 2\. Factors to consider in release assessment:
>
> For the purposes of this risk assessment, a number of relevant factors
> are suggested for consideration in completing the release assessment.
> These factors include factors considered as part of the hazard
> identification. The sponsor may wish to consult with FDA to determine
> the specific factors that are most relevant to the new animal drug in
> question. The sponsor or FDA may consider different factors to take
> into account any specific considerations pertinent to the drug and its
> proposed conditions of use. The relative significance of any
> particular factor among all factors pertinent to the release
> assessment may vary depending on the specific new animal drug under
> consideration. Therefore, certain factors may carry greater weight
> than other factors when determining the overall release assessment
> ranking. FDA recommends that the pertinent factors considered in the
> release assessment include, but not be limited to, the following:
>
> a\. Product description: FDA recommends that the sponsor provide
> information regarding the proposed drug product that includes:

-   Product formulation (active and inactive ingredients)

-   Information regarding proposed conditions of use including:

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-   Route of administration (i.e., injection, water, feed)

-   Dosing regimen

-   Proposed product indication

-   Intended target animal species

> b\. Drug substance description: FDA recommends that the sponsor
> provide information regarding the proposed antimicrobial drug
> substance that includes:

-   Class of antimicrobial drug (e.g., macrolide)

-   Chemical name, CAS number, and structure

> c\. Mechanism and type of action: FDA recommends that the sponsor
> provide information regarding the mechanism of antimicrobial activity
> that includes:

-   Specifics known regarding antimicrobial mechanisms (e.g., protein
    synthesis inhibitor)

-   Type of action (i.e., bactericidal action vs. bacteriostatic)

> d\. Spectrum of activity: FDA recommends that the sponsor provide
> information regarding spectrum of activity that includes:

-   General data (i.e., is activity Gram-positive, Gram-negative, broad,
    etc.)

-   Specific susceptibility data (i.e., minimum inhibitory concentration
    (MIC) and minimum bactericidal concentration (MBC) data pertinent to
    pathogens/commensals in question). As stated before, refer to
    appropriate NCCLS documents.

> e\. The pharmacokinetics/pharmacodynamics of the drug: FDA recommends
> that the sponsor provide relevant information regarding such factors
> as:

-   absorption, distribution, metabolism, and elimination of the drug in
    the target animal

-   antimicrobial drug activity in colonic contents at different
    treatment and post-treatment time points

-   first-exposure effects, post-antibiotic effects, etc.

> f\. Resistance mechanisms and genetics: FDA recommends that the
> sponsor provide information regarding the mechanism(s) and genetic
> basis of resistance development that includes:

-   Known mechanism(s) for resistance (e.g., antimicrobial inactivation,
    alteration of the drug target, reduced uptake, efflux of the
    antimicrobial drug, etc.)

-   Location of resistance determinants (e.g., plasmid-mediated vs.
    chromosomal; present on transposon, integron, or phage)

g\. Occurrence and rate of transfer of resistance determinants: FDA
recommends that the sponsor provide information to help characterize
whether resistance determinants are transferable and, if so, at what
rate. Relevant questions may include:

-   Can resistance determinants be transferred among bacteria by
    transformation, transduction, conjugation, or transposition?

-   If resistance occurs by point mutation, at what rate do the point
    mutations occur?

> h\. Resistance selection pressures: FDA recommends that the sponsor
> provide information to help characterize the relative magnitude of
> selection pressure for resistance that may exist for the particular
> drug use in question. Pertinent information may include:

-   Information known regarding other antimicrobials that may co-select
    for resistance

-   Information known regarding cross resistance to other antimicrobial
    drugs approved in veterinary and human medicine

-   Consideration of the extent of use of the proposed product (e.g.,
    duration of administration; individual vs. small groups vs.
    flocks/herds)

i\. Baseline prevalence of resistance: FDA recommends that the sponsor
provide available epidemiological data outlining the existing prevalence
of resistance to the drug in target pathogens and commensal gut flora.
This may be obtained from National Antimicrobial Resistance Monitoring
System (NARMS) data, current literature, or other sources. If baseline
data is not available for their proposed antimicrobial drug, sponsors
may wish to consult with FDA regarding the generation of such data.

> j\. Other information relevant to the release assessment:
>
> Relevant additional information relating to the rate of resistance
> development and decline after treatment may include:

-   Information or studies to characterize the rate of resistance
    development in bacteria of human health concern.

-   Information or studies to characterize the decline of resistance in
    bacteria of human health concern following cessation of therapy. Of
    particular interest is information relative to the interval up to
    the earliest time point (post-drug administration) at which animals
    would be presented for slaughter.

3\. Summarizing the Release Assessment:

> FDA recommends that the sponsor characterize qualitatively all factors
> relevant to the release assessment based on supporting information. It
> is recommended that this characterization estimate whether each factor
> would have a high likelihood of favoring resistance emergence, have a
> low likelihood of favoring resistance emergence, or have an
> intermediate impact on resistance emergence. For example, the spectrum
> of activity of the drug might be ranked high for favoring resistance
> emergence if the new animal drug in question displays a broad spectrum
> of activity towards multiple organisms. Conversely, pharmacodynamics
> might be ranked low with regard to impact on resistance if the same
> drug did not enter the target animal intestinal tract at
> concentrations shown to have an effect on resistance development. FDA
> recommends that the sponsor provide a detailed discussion of the
> conclusions as well as present the conclusions in summary format (See
> Table 1 as an example).
>
> **Note:** If sufficient information regarding a factor is not
> available or has not been generated for the assessment, the most
> conservative significance of the particular factor may be assumed.
> That is, the factor would be assumed to have a high likelihood of
> contributing to resistance emergence.

4\. Release Assessment conclusion:

The outcome of the release assessment is intended to estimate the
probability that resistant bacteria or resistance determinants will
occur in animals as a consequence of the proposed drug use in animals.
FDA recommends that the sponsor use the conclusions obtained from
assessing all relevant factors to derive an overall qualitative ranking
for the release assessment. This overall conclusion may be expressed in
terms of there being a low, medium, or high probability of release of
the hazardous agent.

> **Table 1.** Table for collating and summarizing interpretation of
> relevant factors considered in completing release assessment

+--------------------------+-------------------------------------------+
| **\                      | # **Extent to which rele                  |
| Relevant parameters**    | vant factors favor resistance emergence** |
+--------------------------+-------------------------------------------+
|                          | **Comments/conclusions regarding          |
|                          | factors**                                 |
+--------------------------+-------------------------------------------+
| **Mechanism of           |                                           |
| activity**               |                                           |
+--------------------------+-------------------------------------------+
| **Spectrum of activity** |                                           |
+--------------------------+-------------------------------------------+
| **Pharmacokinetics**     |                                           |
+--------------------------+-------------------------------------------+
| **Pharmacodynamics**     |                                           |
+--------------------------+-------------------------------------------+
| **Resistance             |                                           |
| mechanism(s)**           |                                           |
+--------------------------+-------------------------------------------+
| **Resistance transfer**  |                                           |
+--------------------------+-------------------------------------------+
| **Selection pressure**   |                                           |
+--------------------------+-------------------------------------------+
| **Other factors^1^**     |                                           |
+--------------------------+-------------------------------------------+

^1^Other parameters may be identified in certain cases that are believed
to be of particular importance to the evaluation. The sponsor may wish
to consult with FDA regarding additional parameters prior to completing
the assessment (e.g., in product development meetings).

B.  []{#Exposure_Assessment .anchor}Exposure Assessment:

The exposure assessment describes the likelihood of human exposure to
the hazardous agent through particular exposure pathways. The exposure
assessment should provide a qualitative estimate of the probability of
this exposure occurring. The hazardous agent is defined as the
antimicrobial resistance determinant(s) of human health significance
that arises in a food-producing animal as a consequence of animal uses
of antimicrobial new animal drugs. The division of traditional exposure
assessment into "release" and "exposure" components effectively produces
a natural placement of animal and animal treatment factors into the
"release assessment component" and food-chain and human factors within
the "exposure assessment component."

1\. Current focus of exposure assessment:

At this time, assessing human exposure to the hazardous agent should
focus on food-related pathways. FDA believes that human exposure through
the ingestion of resistant bacteria from animal-derived foods represents
the most significant demonstrable pathway for human exposure to
resistant bacteria or resistance determinants as a consequence of drug
use in food-producing animals.

FDA recognizes that human exposure to antimicrobial resistant bacteria
(or resistance determinants) is complex and often involves the
contributions from other sources of exposure (e.g., human/animal direct
contact, introduction of resistant bacteria and resistance determinants
into the environment). However, FDA believes that evaluating drug safety
relative to the most significant exposure pathway (i.e., food-borne
pathway) is the best way to assess qualitatively the risk of
antimicrobial drug use in food-producing animals. Uncertainties
regarding the contribution of other potential pathways of exposure may
be considered during the development of appropriate risk management
strategies.

2\. Factors to consider in exposure assessment:

> The exposure assessment may be accomplished by integrating information
> that characterizes:

a\. The probability for humans to be exposed to given bacteria via a
particular food commodity.

> This factor is independent of drug use in animals and may be estimated
> by considerations of 1) the probability of contamination of food
> product by the bacteria of interest and, 2) the per capita consumption
> of the food commodity. While it is acknowledged that other factors
> such as food preparation practices can affect exposure, the above two
> considerations can provide a qualitative indication of the magnitude
> of the probability of human exposure. Survey data of both food
> commodity contamination and per capita consumption may be submitted to
> support a qualitative ranking of the probability of human exposure to
> the given bacteria via a particular food commodity. Refer to Appendix
> B for examples of how such information may be integrated.

b\. Probability that bacteria of interest (to which humans are exposed)
are resistant to particular antimicrobial drug or possess associated
resistance determinants.

> FDA recommends that the sponsor rank qualitatively (i.e., low, medium,
> high) this probability by one of the following methods:
>
> \(1\) Base the ranking on specific and current susceptibility data on
> bacterial isolates obtained from animal-derived food commodities
>
> Since this represents a more direct measure, use of this type of
> information is recommended when available. This information may be
> available, for example, in a case where the same or related drug has
> already been approved in animals and has been in use under similar
> conditions.
>
> ***OR***

(2) Base the ranking on the conclusions of the release assessment

> When susceptibility data as described in (1) above are not available,
> the conclusions derived from the release assessment may be applied
> here as an indicator of the probability of resistance associated with
> the animal-derived food.
>
> The release assessment characterized the probability that the bacteria
> of concern in/on the animal when presented for slaughter would be
> resistant or carry resistance determinants (as a consequence of drug
> use). It is recognized that there are many factors that may affect the
> bacteria of interest between the time animals are presented for
> slaughter (or the animal-derived food is collected) and the time the
> final food product is consumed. For the purposes of this qualitative
> risk assessment, FDA assumes that the probability that bacteria in the
> animal at slaughter will be resistant may be used as an estimate of
> the probability that the same bacterial species would be resistant in
> the food commodity derived from that animal.
>
> 3\. Summarizing the Exposure Assessment:
>
> FDA recommends that the sponsor integrate the two key factors cited
> above (i.e., probability of exposure to the bacteria and probability
> that bacteria are resistant) to characterize the probability of human
> exposure to the identified hazardous agent(s).
>
> That is, FDA recommends that the sponsor derive the exposure
> assessment ranking by integrating the ranking for the probability of
> human exposure (through food) to the bacteria in question with the
> probability that the bacteria will be resistant to the drug in
> question. This integration may be accomplished through the use of
> Table B4 in Appendix B and Table 2 below.
>
> **Table 2.** Process for characterizing the probability of human
> exposure to the identified hazardous agent (i.e., specified resistant
> bacteria or resistance determinants).

+----------------+---------------+---------------+--------------------+
|                | ###           |               |                    |
|                | Probability o |               |                    |
|                | f human expos |               |                    |
|                | ure to the ha |               |                    |
|                | zardous agent |               |                    |
+----------------+---------------+---------------+--------------------+
|                | ##            |               |                    |
|                | # Probability |               |                    |
|                |  of human exp |               |                    |
|                | osure to give |               |                    |
|                | n bacteria^2^ |               |                    |
+----------------+---------------+---------------+--------------------+
| **Probability  | **High**      | **Medium**    | **Low**            |
| that bacteria  |               |               |                    |
| of interest    |               |               |                    |
| are            |               |               |                    |
| resistant^1^** |               |               |                    |
+----------------+---------------+---------------+--------------------+
| **High**       | H             | ## H          | M                  |
+----------------+---------------+---------------+--------------------+
| **Medium**     | H             | M             | L                  |
+----------------+---------------+---------------+--------------------+
| **Low**        | M             | L             | L                  |
+----------------+---------------+---------------+--------------------+

> ^1^May be based on susceptibility data on bacterial isolates from food
> commodity or on the outcome of the Release Assessment
>
> ^2^Ranking from Table B4 in Appendix B
>
> 4\. Exposure Assessment conclusion:
>
> The exposure assessment ranking may be expressed as low, medium, or
> high probability of human exposure to the hazardous agent.
>
> C. []{#Consequence_Assessment .anchor}Consequence Assessment
>
> The consequence assessment describes the relationship between
> specified exposures to a biological agent (the hazardous agent) and
> the consequences of those exposures. For the purposes of this risk
> assessment, FDA believes that the potential human health consequences
> of exposure to the defined hazardous agent may be estimated
> qualitatively by considering the human medical importance of the
> antimicrobial drug in question.

Certain antimicrobial drugs are considered to be of greater importance
to human medical therapy than other antimicrobial drugs. Therefore, it
is assumed that the human health consequences of human illness due to
antimicrobial resistant bacteria are more significant if the resistance
is to a drug that is important for treating disease in humans.

The sponsor should refer to Appendix A of this document for information
related to assessing the importance of the drug in question for human
medicine. FDA recommends that the consequence assessment conclusion be
based on the human medical importance ranking and be expressed as a
high, medium, or low ranking.

D.  []{#Risk_Estimation .anchor}Risk estimation:

> The risk estimation integrates the results from the release
> assessment, exposure assessment, and consequence assessment to produce
> an overall estimate of the risk. All three elements of the risk
> assessment process are important contributing factors and should be
> integrated and considered as a whole when assessing the risk.
>
> FDA recommends that the risk estimation process rank drugs as low,
> medium, or high risk. The risk rankings represent the relative
> potential for human health to be adversely impacted by the emergence
> of antimicrobial resistance associated with the use of the drug in
> animals.
>
> Table 3 provides a method for integrating the possible outcomes of the
> release, exposure, and consequence assessments into a single risk
> estimation ranking. The distribution of risk estimation rankings
> listed in Table 3 is intended to provide an initial indication as to
> how the rankings may be integrated. Further refinement of the risk
> estimation ranking may be necessary for specific cases based on
> available information. The following provides the Agency's rationale
> for the risk estimation rankings provided in Table 3.
>
> 1\. A risk estimation ranking of *low:*
>
> Drugs ranked low for risk estimation include those ranked low for all
> three components of the risk assessment as well as those ranked low
> for two components and medium for the third component. FDA believes
> that a single medium ranking when the other two risk assessment
> components are ranked low should not increase substantially the
> overall level of risk. Therefore, combinations involving two low ranks
> and one medium are consistent with an overall risk estimation ranking
> of low.
>
> 2\. A risk estimation ranking of *high:*
>
> Drugs ranked high for risk estimation include those ranked high for
> all three components of the risk assessment as well as those ranked
> high for two components and medium for the third component. FDA
> believes that a single medium ranking when the other two risk
> assessment components are ranked high should not decrease
> substantially the overall level of risk. Therefore, combinations
> involving two high ranks and one medium are consistent with an overall
> risk estimation ranking of high.
>
> 3\. A risk estimation ranking of *medium:*
>
> As listed in Table 3, the largest number of possible risk estimation
> outcomes is assigned the medium ranking. Drugs ranked medium for risk
> estimation include those drugs ranked medium for all three risk
> assessment components as well as those ranked high for one, medium for
> another, and low for the third component. FDA considers these
> combinations to represent a medium overall risk due to the
> intermediate nature of the three rankings considered collectively.
>
> The drugs assigned a medium ranking in Table 3 also include drugs with
> risk assessment outcomes that include a number of combinations of
> high, medium and low rankings. These combinations do not fit obviously
> into either the low or high risk overall rankings. Therefore, these
> combinations are also included among those that are considered of
> medium risk overall.
>
> 4\. Refining risk estimation rankings:
>
> Although applicable to all risk estimation rankings, medium risk
> estimation rankings in particular, may be subject to further
> refinement based on a consideration of all factors relevant to the
> specific case in question. For example, certain drugs ranked medium
> based on Table 3 may ultimately be assigned a high or low ranking if
> factors are identified that warrant that the risk ranking be modulated
> up or down. A consideration of certain factors specific to the case in
> question may warrant the assignment of greater (or lesser) weight to
> one of the components of the risk assessment. Such a modification in
> the weight or contribution of the release, exposure, or consequence
> assessments may result in a change in the overall risk estimation
> ranking.
>
> **Table 3.** Provisional risk estimation rankings based on the
> integration of the release, exposure, and consequence assessment
> rankings

+-----------------+-----------------+----------------+-----------------+
| **Release**     | ### Exposure    | #              | ###             |
|                 |                 | ## Consequence | Risk Estimation |
+-----------------+-----------------+----------------+-----------------+
| low             | low             | low            | low             |
+-----------------+-----------------+----------------+-----------------+
| low             | low             | medium         | low             |
+-----------------+-----------------+----------------+-----------------+
| low             | medium          | low            | low             |
+-----------------+-----------------+----------------+-----------------+
| medium          | low             | low            | low             |
+-----------------+-----------------+----------------+-----------------+
| low             | low             | high           | medium          |
+-----------------+-----------------+----------------+-----------------+
| low             | medium          | medium         | medium          |
+-----------------+-----------------+----------------+-----------------+
| low             | medium          | high           | medium          |
+-----------------+-----------------+----------------+-----------------+
| low             | high            | low            | medium          |
+-----------------+-----------------+----------------+-----------------+
| low             | high            | medium         | medium          |
+-----------------+-----------------+----------------+-----------------+
| low             | high            | high           | medium          |
+-----------------+-----------------+----------------+-----------------+
| medium          | medium          | low            | medium          |
+-----------------+-----------------+----------------+-----------------+
| medium          | medium          | medium         | medium          |
+-----------------+-----------------+----------------+-----------------+
| medium          | medium          | high           | medium          |
+-----------------+-----------------+----------------+-----------------+
| medium          | low             | high           | medium          |
+-----------------+-----------------+----------------+-----------------+
| medium          | low             | medium         | medium          |
+-----------------+-----------------+----------------+-----------------+
| medium          | high            | low            | medium          |
+-----------------+-----------------+----------------+-----------------+
| medium          | high            | medium         | medium          |
+-----------------+-----------------+----------------+-----------------+
| high            | low             | low            | medium          |
+-----------------+-----------------+----------------+-----------------+
| high            | low             | medium         | medium          |
+-----------------+-----------------+----------------+-----------------+
| high            | low             | high           | medium          |
+-----------------+-----------------+----------------+-----------------+
| high            | medium          | low            | medium          |
+-----------------+-----------------+----------------+-----------------+
| high            | medium          | medium         | medium          |
+-----------------+-----------------+----------------+-----------------+
| high            | high            | low            | medium          |
+-----------------+-----------------+----------------+-----------------+
| medium          | high            | high           | high            |
+-----------------+-----------------+----------------+-----------------+
| high            | medium          | High           | high            |
+-----------------+-----------------+----------------+-----------------+
| high            | high            | medium         | high            |
+-----------------+-----------------+----------------+-----------------+
| high            | high            | high           | high            |
+-----------------+-----------------+----------------+-----------------+

######## **VI. [Antimicrobial Resistance Risk Management Considerations]{.smallcaps}** {#vi.-antimicrobial-resistance-risk-management-considerations .unnumbered}

The qualitative antimicrobial resistance risk assessment process
provides for the ranking of proposed antimicrobial new animal drugs with
regard to the level of risk that their use will cause an adverse impact
on human health. All elements of the risk assessment process (i.e.,
release, exposure, and consequence assessments) should be integrated and
considered as a whole when assessing the risk. This integration process,
described previously as the risk estimation, qualitatively assigns a
high, medium, or low risk ranking to the proposed new animal drug. This
risk ranking can be used to help identify the steps necessary to manage
the risks associated with the approval of a given antimicrobial drug.

> This section of the guidance describes various risk management steps
> and outlines how these steps might be applied to manage the specified
> level of risk. Table 5 below creates three categories (i.e., Category
> 1, 2, and 3) for antimicrobial new animal drugs intended for use in
> food-producing animals. These categories associate the drug risk
> ranking (i.e., high, medium, or low risk) with a set of possible risk
> management strategies.

Antimicrobial new animal drugs that are ranked as high risk might only
be considered approvable under the limited set of conditions outlined
for Category 1 drugs. The basis for concluding that a drug should be
ranked as high risk include such factors as 1) a moderate to high
probability that antimicrobial resistance would emerge in the animal in
association with the proposed drug use (release assessment), 2) a
moderate to high probability that humans would be exposed to
antimicrobial-resistant bacteria or associated resistance determinants
through food (exposure assessment), and 3) the finding that the
potential consequences of exposure to human health would be moderate to
high. In addition, to reach a finding of high risk overall, two of the
three major components of the risk assessment would have been ranked
high and the third component ranked medium. As previously discussed, FDA
believes that a single medium ranking when the other two risk assessment
components are ranked high should not substantially decrease the overall
level of risk. Therefore, combinations involving two high ranks and one
medium are consistent with an overall risk estimation ranking of high.

FDA believes that the NADA for certain antimicrobial drugs ranked as
high risk might still be considered approvable if FDA can conclude that
after evaluating all supporting information there is a reasonable
certainty of no harm when the drug is approved under specific use
conditions (e.g., such as those outlined for Category 1 drugs). Such a
determination would be made on a case-by-case basis and on a review of
the entire application. Although drugs in this category may include
those that are moderately or highly important to human medicine, FDA
believes that there may be some circumstances where the proposed
conditions of use outlined for Category 1 drugs might be determined to
be sufficiently restrictive to minimize resistance emergence in the
animal and thereby prevent the effect of resistance on human health.

FDA believes that the NADA for certain antimicrobial drugs ranked as low
risk might be considered approvable if FDA can conclude that after
evaluating all supporting information there is a reasonable certainty of
no harm when the drug is approved under specific use conditions (e.g.,
such as those outlined for Category 3 drugs). For a drug to be ranked as
low risk overall, two of three major components of the risk assessment
would have been ranked as low and the third component ranked moderate.
FDA believes that a single medium ranking when the other two risk
assessment components are ranked low should not substantially increase
the overall level of risk. Therefore, combinations involving two low
ranks and one medium are consistent with an overall risk estimation
ranking of low.

A finding of low risk indicates that the probability of human exposure
to resistance is low and the potential human health consequence (if
exposure to resistance did occur) is also low. A finding of low risk
might also be reached when the potential human health consequence is
medium, but only when the potential for human exposure to the resistance
is low. Alternatively, the potential for exposure to resistance might be
medium, but only when the potential human health consequence is low.

FDA believes that the NADA for certain antimicrobial drugs ranked as
medium risk might be considered approvable if FDA can conclude that
after evaluating all supporting information there is a reasonable
certainty of no harm when the drug is approved under specific use
conditions (e.g., such as those outlined for Category 2 drugs).
Interpreting the medium risk category of drugs is more complex than the
other categories, since the conclusions for the various risk assessment
components are potentially more disparate (i.e., ranging from low to
high). However, FDA believes it is appropriate to conclude that drugs in
this category are associated with a level of risk that is intermediate
between the high and low risk category drugs. Therefore, it is
consistent to conclude that a finding of reasonably certainty of no harm
might be reached for such drugs when use conditions are intermediately
restrictive.

As described below, the possible risk management steps range from
denying the approval of a drug application (i.e., the drug is unsafe or
not shown to be safe) to approving the application under various use
conditions that assure the safety of the product.

A.  Denying approval of a drug application: The Federal Food, Drug, and
    Cosmetic Act (FFDCA), Sec. 512(d), and regulations promulgated
    thereunder (see 21 CFR 514.111), provides possible grounds for
    denying the approval of a new animal drug application. The statutory
    grounds for denying approval include the results of tests that show
    the drug is unsafe or the determination that there is insufficient
    information as to whether the drug is safe. Consequently, denying
    the approval of an antimicrobial drug application is one possible
    outcome of an overall safety evaluation which could include the
    Qualitative Antimicrobial Resistance Risk Assessment process
    described above.

B.  Drug approval under safe conditions of use: If there are no grounds
    (as provided for by statute and regulation as described above) for
    denying the approval of a new animal drug application, FDA will
    approve the use of the drug under those conditions for which safety
    and effectiveness has been demonstrated.

Therefore, use conditions may be approved that are considered consistent
with assuring the safety (i.e., with reasonable certainty of no harm) of
a given drug in a given category of concern. Drugs considered to be of
high concern (with regard to potential human health impact) would
typically be associated with more restricted use conditions. Drugs
considered to be of lower concern would typically be associated with
less restricted use conditions in food-producing animals.

C. The following represent relevant risk management steps or conditions
that may be appropriate based on the outcome of the Qualitative
Antimicrobial Resistance Risk Assessment process.

1.  Marketing status limitations: Antimicrobial drugs approved for use
    in animals may be marketed as prescription (Rx), over-the-counter
    (OTC), or veterinary feed directive (VFD) products. FDA believes
    that for certain antimicrobial drugs in particular, veterinary
    supervision is critical to assuring the judicious and safe use of
    the antimicrobial drug. Therefore, such drugs might be approved for
    limited use by, or under the supervision of, a veterinarian. For
    other antimicrobial drugs, the requirement for veterinary
    supervision may not be warranted.

2.  Extra-label use prohibition: As provided under 21 CFR 530.21(a)(2),
    FDA may prohibit the extralabel use of an approved new animal drug
    or class of drugs in food-producing animals if FDA determines that
    "the extralabel use of the drug or class of drugs presents a risk to
    the public health." If significant concerns exist regarding
    assurance of drug safety in light of potential extralabel use,
    extralabel use may be prohibited according to the procedures
    described in 21 CFR 530.

3.  Extent-of-use limitations: It is recognized that how antimicrobial
    drugs are used may influence the rate and extent to which resistance
    emerges. In general, it is believed that increasing the extent to
    which an antimicrobial drug is used will increase selection
    pressures for resistance. FDA believes that "extent of use" is an
    important factor to consider when determining safe conditions of use
    for an antimicrobial new animal drug. Table 4 integrates method and
    duration of administration of an antimicrobial drug into a
    qualitative ranking for "extent of use".

> **Table 4:** Ranking (L, M, H) of extent of antimicrobial drug use in
> animals based on duration and method of administration

  ---------------- ---------------- ------------------- -------------------
  Duration of use  Intended                             
                   administration                       
                   to:                                  

                   individual       select groups or    flocks or herds of
                   animals          pens of animals^1^  animals^2^

  **Short**\       **L**^3^         **M**^4^            **H**^5^
  (\<6 days)                                            

  **Medium**\      **L**            **M**               **H**
  (6-21 days)                                           

  **Long\          **M**            **H**               **H**
  **(\>21 days)                                         
  ---------------- ---------------- ------------------- -------------------

> ^1^Administration to select groups/pens of animals involves the
> delivery of drug to a specific segregated subset of animals within a
> confinement facility (e.g., administration to a subset of animals
> within a building, house, feedlot, etc.).
>
> ^2^Administration to flocks/herds of animals involves the delivery of
> drug to all animals within a confinement facility (e.g.,
> administration to all animals within a building, house, feedlot,
> etc.).
>
> ^3^Low, ^4^Medium, and ^5^High extent of use
>
> D. The following activities are additional important risk management
> steps associated with the approval of antimicrobial new animal drugs
> in food-producing animals.

1.  Post-approval monitoring: Antimicrobial new animal drugs intended
    for use in food-producing animals are subject to monitoring through
    the National Antimicrobial Resistance Monitoring System (NARMS).

2.  Advisory committee review: When making an approval decision
    regarding a Category 1 or select Category 2 drugs, FDA may choose to
    convene an advisory committee to discuss the application.

E. Application of risk management strategies:

The antimicrobial resistance risk assessment described in this guidance
document is intended to characterize qualitatively the human health risk
associated with the proposed use of a given antimicrobial drug in
food-producing animals.

The final step of the risk assessment (i.e., risk estimation) integrates
the components of the assessment into a low, medium, or high ranking of
the probability of the risk occurring. The risk management strategies
discussed in this section of the document are categorized into three
levels of concern (i.e., Category 1, 2, or 3). In general, Category 1
includes those drugs ranked "high" in the risk estimation, Category 2
includes those ranked "medium", and Category 3 includes those ranked as
"low." However, certain cases may warrant alternative categorization.

Table 5 summarizes potential risk management steps that FDA recommends
be considered by the sponsor in proposing use conditions for an
antimicrobial drug in a given Category of concern. As illustrated in
Table 5, drugs in Category 1 are associated with a high risk ranking and
would typically be subject to the most restricted use conditions.
Category 3 drugs have a low risk ranking and would typically be subject
to the least limitations. Category 2 drugs, ranked intermediate for risk
to human health, would typically be subject to limitations that are
intermediate between those of Categories 1 and 3.

**Note:** Category 2 drugs (as described in Table 5) include several
approval conditions that may or may not be applied to all drugs in the
category. For example, the table indicates that restrictions limiting
extra-label use may be considered for certain Category 2 drugs. FDA may
consider applying more restrictive risk management steps to those
Category 2 (medium risk) drugs that are ranked "high" for consequence
assessment *and* ranked "high" for release *or* exposure assessment (see
Table 3).

The conditions listed for a given drug category in Table 5 are intended
to provide an indication of the conditions of use or limitations that
FDA might expect to be associated with a drug product in that category.
However, FDA's final determination as to the approvability of specific
new animal drug applications will depend on a consideration of all
information available for the specific drug application in question. FDA
may determine that a proposed drug product can be approved under
alternative use conditions/limitations proposed by the sponsor if the
sponsor provides adequate information to support the safety of the drug
under those conditions.

> **Table 5.** Examples of potential risk management steps associated
> with the approval of antimicrobial new animal drugs in food-producing
> animals based on the level of concern (1, 2, or 3) as estimated by a
> qualitative antimicrobial resistance risk assessment.

  ---------------- ------------------ ------------------ ------------------
                   **Category of                         
                   concern**                             

  **Approval       **Category 1**     **Category 2**     **Category 3**
  conditions**                                           

  Marketing        Rx                 Rx/VFD             Rx/VFD/OTC
  Status^1^                                              

  Extra-label use  No ELU             Restricted in some ELU permitted
  (ELU)                               cases^3^           

  Extent of use^2^ Low                Low, medium        Low, medium, high

  Post-approval    NARMS              NARMS              NARMS
  monitoring                                             

  Advisory         Yes                In certain         No
  committee review                    cases^3^           
  considered                                             
  ---------------- ------------------ ------------------ ------------------

> ^1^Prescription (Rx), Veterinary Feed Directive (VFD),
> Over-the-counter (OTC)
>
> ^2^See Table 4 for characterization of extent of use
>
> ^3^These risk management steps may be appropriate for certain Category
> 2 drugs that were ranked high for consequence assessment **and**
> ranked "high" for release **or** exposure assessment.

### Glossary

**Antibiotic**: Class of substances produced by microorganisms that can
kill or inhibit the growth of some groups of microorganisms. In this
document the term is meant to refer to chemicals active against bacteria
and is used interchangeably with the term antimicrobial.

**Antimicrobial:** Class of substances that can kill or inhibit the
growth of some groups of microorganisms. In this document the term is
meant to refer to chemicals active against bacteria and is used
interchangeably with the term antibiotic.

**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.

**Broad-spectrum antibiotic**: An antibiotic effective against a large
number of bacterial species; generally describes antibiotics effective
against both Gram-positive and Gram-negative bacteria.

**Commensal bacteria:** Bacteria that live continuously on or in certain
parts of the body without causing disease under normal circumstances.

**Consequence assessment:** The consequence assessment describes the
relationship between specified exposures to a biological agent (the
hazardous agent) and the consequences of those exposures. For the
purposes of this risk assessment, FDA has decided that the potential
human health consequences of exposure to the defined hazardous agent may
be estimated qualitatively by considering the human medical importance
of the antimicrobial drug in question.

**Exposure assessment:** The exposure assessment describes the
likelihood of human exposure to the released hazardous agent (resistant
determinant\[s\]) through particular exposure pathways. The exposure
assessment should estimate qualitatively the probability of this
exposure occurring. At this time, assessing human exposure to the
hazardous agent will focus on food-related pathways. FDA has decided
that human exposure through the ingestion of resistant bacteria from
animal-derived foods represents a significant demonstrable pathway for
human exposure to resistant bacteria or resistance determinants as
consequence of drug use in food-producing animals.

**Extra-label:** Extra-label use means actual use or intended use of a
drug in an animal in a manner that is not in accordance with the
approved labeling. This includes, but is not limited to, use in species
not listed in the labeling, use for indications (disease or other
conditions) not listed in the labeling, use at dosage levels,
frequencies, or routes of administration other than those stated in the
labeling, and deviation from the labeled withdrawal time based on these
different uses.

**Foodborne pathogens:** Infectious organisms associated with
food-producing animals that can cause disease in humans (e.g.,
*Salmonella, Campylobacter, E. coli* O157:H7).

**Food-producing animals:** Animals reared for the production of meat or
other food products (e.g., eggs, milk).

**Gram-negative bacteria:** Bacteria with a cell wall with a
structurally distinct outer membrane layer and less peptidoglycan in
their cell wall than gram-positive bacteria. Because of the outer layer,
they do not retain crystal violet-iodine complex and are thus
decolorized by alcohol or acetone enabling them to be counterstained.

**Gram-positive bacteria:** Bacteria with a predominantly peptidoglycan
cell wall. They retain crystal violet-iodine complex when treated with
alcohol or acetone and appear deep blue under the microscope.

**Hazard:** The hazard is defined as human illness that is caused by a
specified antimicrobial-resistant bacteria, is attributable to a
specified animal-derived food commodity, and is treated with the human
antimicrobial drug of interest.

**Hazardous agent:** The hazardous agent is the antimicrobial resistance
determinant(s) of human health significance that arises in a
food-producing animal as a consequence of animal uses of antimicrobial
new animal drugs.

#### **Hazard identification**: The process by which one may identify the hazard and the conditions that influence the occurrence of that hazard. This is based upon drug-specific information, bacteria/resistance determinant information, and the methodology for the determination of "resistant" or "susceptible" bacteria.

**Microflora:** The populations of bacteria normally present in the
intestine, body openings, and on the skin.

**Minimum inhibitory concentration (MIC)**: The lowest concentration of
an antimicrobial agent, 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.

**Plasmid:** A piece of extrachromosomal DNA much smaller than the
bacterial chromosome, usually covalently closed circular molecules.
Plasmids exist in the cytoplasm independently of the chromosome and
control their own replication.

**Release assessment:** The release assessment should describe those
factors related to the antimicrobial new animal drug and its use in
animals that contribute to the emergence of resistant bacteria or
resistance determinants (i.e., release of the hazardous agent) in the
animal. The release assessment should also estimate qualitatively the
probability that release of the hazardous agent would occur. For the
purposes of this assessment process, the boundaries of the release
assessment span from the point the antimicrobial new animal drug is
administered to the food-producing animal, to the point the animal is
presented for slaughter or animal-derived food is collected.

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

**Resistance determinant:** A gene that, through either activation,
mutation, or external acquisition, provides a bacterium with the
necessary biochemical mechanism to survive in the presence of an
antimicrobial drug that would otherwise result in the death or
inhibition of a susceptible bacterium.

**Risk:** The probability that human illness is caused by a specified
antimicrobial resistant bacteria, is attributable to a specified
animal-derived food commodity, and is treated with the human
antimicrobial drug of interest.

**Risk analysis methodology:** The risk analysis methodology described
includes hazard identification, risk assessment, risk management, and
risk communication.

**Risk assessment:** The risk assessment process is comprised of a
release assessment, exposure assessment, consequence assessment, and
risk estimation.

**Risk estimate:** The risk estimation integrates the components of the
risk assessment into an overall conclusion. For the purposes of this
document, the risk estimation provides a qualitative indication of the
potential risk to human health of a proposed antimicrobial new animal
drug. The risk estimation is used for determining appropriate risk
management steps.

**Risk management:** The process of identifying, selecting and
implementing measures that can be applied to reduce the level of risk.

**Transposon:** A small mobile DNA element that carries one or several
genes, plus genes encoding for its own transposition between various
locations in the bacterial genome.

**Veterinary Feed Directive (VFD)**: A veterinary feed directive is a
written statement that authorizes the client (the owner of the animal or
animals or other caretaker) to obtain and use animal feed containing a
VFD drug to treat their animals only in accordance with the FDA-approved
directions for use. The VFD category of medicated feeds was created by
the Animal Drug Availability Act of 1996 to provide an alternative to
prescription status for certain therapeutic animal pharmaceuticals for
use in feed.

**Zoonotic disease:** An infectious disease that is transmissible under
normal conditions between animals and humans.

**Appendix A**[]{#Appendix_A .anchor}

###### **Ranking of antimicrobial drugs according to their importance in human medicine**

**Objective:** This appendix describes a process for ranking
antimicrobial drugs with regard to their relative importance in human
medicine. This ranking should be considered when completing the *hazard
identification* and the *consequence assessment* portions of the
qualitative risk assessment outlined in this guidance document. The
general criteria for determining the importance ranking are outlined and
a preliminary listing of various antimicrobial drugs and assigned
rankings is provided.

**Ranking process:** Based on a consideration of the factors described
below, specific antimicrobial drugs or classes of drugs should be ranked
as to whether they are of high, medium, or low importance to human
medical therapy. The assignment of a high, medium, or low ranking to a
given drug or class of drugs is dependent upon the degree to which any
one or more of the factors described below is applicable to the drug in
question. Table A1 lists antimicrobial drugs and drug classes and
suggests a preliminary human importance ranking based on a consideration
of the factors described below.

**Note:** Table A1 does not necessarily include all antimicrobial drugs
or drug classes. The development of new drugs for human therapy, the
emergence of diseases in humans, or changes in prescribing practices,
etc., are among the factors that may cause the importance rankings to
change over time. Therefore, it is important that rankings provided in
Table A1 be reassessed to confirm that the ranking is consistent with
current circumstances. The sponsor may wish to consult with FDA
regarding the ranking relevant to their proposed drug at the time the
assessment is being completed. New information available may be
considered that would alter the ranking listed in this document.

**Factors considered in ranking process:** In developing criteria for
ranking antimicrobial drugs with regard to their importance in human
medicine, broad issues associated with the efficacy of drugs in human
medicine and factors influencing the development of antimicrobial
resistance were considered. Specific factors considered when determining
importance include the types of infections treated, the availability of
alternative therapies, the uniqueness of the mechanism of action, the
ease with which resistance develops and is transferred between
organisms, how broadly the agent is used in humans, and the usefulness
of the drug in foodborne infections. Note that multiple factors may be
applicable to some products, illustrating their considerable importance
to human medicine.

# **Factors related to drug efficacy**

1\. **Sole or limited available therapy:** Antimicrobial drugs that are
the only approved therapy or one of only a few approved therapies
available to treat certain very serious human infections are
particularly important in human medicine.

Examples include:

-   vancomycin and linezolid in the treatment of certain serious
    infections such as endocarditis, osteomyelitis, or pneumonia caused
    by methicillin-resistant *Staphylococcus aureus* (MRSA).

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-   dalfopristin/quinupristin and linezolid in the treatment of serious
    bloodstream infections caused by vancomycin-resistant enterococcus
    (VRE) species.

FDA believes that these products should be considered of "high"
importance until such time as widespread resistance in humans precludes
their use or other suitable alternative agents become available.

2\. **Therapy of choice:** There are many more drugs that are not the
sole therapy for a disease but are still the preferred choice for
therapy for a given infection. Many of these situations are quite
important in the management of disease in human medicine.

These drugs would include those that are central to the treatment of
conditions of high morbidity and/or mortality or that are important to
public health. An antimicrobial drug may be central to the treatment of
a given infection because of efficacy alone, because of a combination of
efficacy and tolerability, or because experience with the drug has made
it the standard of care for the condition in question. Some drugs have
added importance due to their broad use in human medicine. Examples of
such drugs are presented below:

-   erythromycin for the treatment of pneumonia caused by *Legionella
    pneumophila*.

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-   ceftriaxone or cefotaxime for the empirical treatment of bacterial
    meningitis.

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```
-   rifampin for post-exposure prophylaxis of invasive disease caused by
    *Neisseria meningitidis*.

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-   streptomycin for tuberculosis.

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-   cefazolin for prophylaxis of post-operative wound infections.

3\. **Spectrum of activity of particular importance:** Drugs may also be
of importance due to the spectrum of their antimicrobial activity. For
instance, the drug may be useful in the treatment of infections due to
important, resistant Gram-positive infections. Examples include:

-   vancomycin for methicillin resistant *S. aureus* (MRSA).

-   dalfopristin/quinupristin for vancomycin resistant enterococcus
    (VRE).

-   beta-lactamase inhibitor combinations for penicillinase or
    cephalosporinase-producing pathogens.

Drugs useful in the treatment of infections due to important, resistant
Gram-negative infections including:

-   aminoglycosides and fluoroquinolones for treatment of *Pseudomonas
    aeruginosa* infections.

4\. **Important oral therapy:** The ability to treat serious infections
either wholly or in part with oral therapy is quite important in human
medicine. This allows for easy outpatient therapy in situations where a
patient might otherwise require parenteral and possibly inpatient
therapy to complete a full course of treatment. Drug examples include:

-   oral erythromycin or azithromycin for infections due to
    *Legionella*.

-   fluoroquinolones and trimethoprim-sulfamethoxazole for a variety of
    infections.

Drugs in the above situations will often be considered of "high"
importance. They may on occasion be considered of "medium" importance
depending upon the infections treated and the availability of
alternatives.

# 5. **Important for treating foodborne infections:** Foodborne pathogens offer the most direct link between infection or colonization in animals and infection in humans. Not only are these organisms important for the morbidity they may produce but they offer the opportunity for transmission of resistance elements from animals to humans. The possibility also exists for the transmission of resistance elements within humans and animals from the pathogenic bacteria to other organisms. Therefore, the importance of the drug in treating foodborne infections is an important component of determining its importance for human medicine particularly in the setting of veterinary drug development. These products should typically be considered of "high" importance. This category would include drugs that are the sole or primary treatment for serious foodborne infection. Examples include:

-   quinolones in the treatment of multi-drug resistant *Salmonella*
    infections

-   expanded-spectrum cephalosporins in the treatment of invasive
    *Salmonella* infections

Other drugs may be useful for treatment of foodborne infections, however
the disease may not be as severe and/or there are other options for
treatment. Such products might be considered either of "high" or
"medium" importance. An examples includes:

-   trimethopim-sulfamethoxazole for some *Salmonella* and *Shigella*
    infections.

6\. **Drug with unique mechanism of action:** The mechanism of action of
antimicrobials involves the interaction of the drug with specific target
molecules within the target organism. The targets of currently approved
antimicrobials include inhibition of specific steps in cell membrane
function, or cell wall, protein, or nucleic acid synthesis. The
development of an antimicrobial with a new and unique mechanism of
action unlike that in previously approved drugs is important to the
medical community. This is especially true if resistance to the new
antimicrobial is unknown. Limiting the development of such drugs for
uses outside of human medicine may be one of the tools to limit the
emergence of antimicrobial resistance. Examples include:

-   linezolid inhibition of protein synthesis at an earlier step than
    other currently approved antimicrobial agents

> The designation of a unique mechanism is not expected to last
> indefinitely. For example, when norfloxacin became the first approved
> fluoroquinolone, its mechanism of action was considered novel. The
> mechanism of action of new fluoroquinolones may not be considered
> novel.
>
> However, drugs may have the same target but increased affinity for
> that target which may still render them unique and valuable in human
> medicine. For instance, all fluoroquinolones target cellular
> topoisomerases, including both DNA gyrase and topoisomerase IV. Older
> quinolones preferentially target DNA gyrase. Newer quinolones have
> more balanced affinity for both DNA gyrase and topoisomerase IV. This
> means that unlike the situation with older quinolones, multiple
> mutations in the genes coding for both topoisomerases might be
> required before a significant loss of drug activity would occur for
> newer quinolones.

Initial compounds in a class with a unique mechanism might receive a
"high" importance designation. The importance of mechanism on such a
designation may be reassessed when multiple products in that class are
on the market or when organisms demonstrate significant increases in the
rate of antimicrobial resistance in human disease.

### Factors related to resistance development

7\. **Cross resistance within drug class:** The development of new
antimicrobial drugs that are not susceptible to the resistance
mechanisms of prior generations of antimicrobial drugs of the same class
has been important in preserving options for antimicrobial therapy in
humans. Ideally, the development of new drugs within a class of
antimicrobials would not encourage the development of antimicrobial
resistance to prior generations of antimicrobials in the same class.

> Unfortunately, resistance to newer members of a drug class often
> predicts resistance to older agents in that class. For example, Gram
> negative bacteria resistant to streptomycin (an earlier
> aminoglycoside) would not predict resistance to gentamicin or amikacin
> (relatively newer aminoglycosides). However, gentamicin or amikacin
> resistance often predicts resistance to streptomycin. A similar
> pattern can be seen with cefazolin (a first generation cephalosporin)
> and ceftriaxone (a third generation agent). Cefazolin resistant
> organisms are often still susceptible to ceftriaxone, while most
> ceftriaxone resistant organisms are cefazolin resistant.
>
> "Higher generation" or "extended spectrum" products in such classes
> might be expected to have a designation of "high" importance. The
> categorization of initial products in a class would depend upon the
> particular characteristics of the drug and its use in specific human
> infections. They could be in any category.
>
> **Note**: If cross-resistance is known to exist between drugs of
> differing importance ranking, the drug in question should typically be
> ranked according to the highest level of importance among the drugs
> being compared.

8\. **Cross resistance across drug classes:** The development of new
antimicrobial drugs that are not susceptible to the resistance
mechanisms of other classes of antimicrobials are an essential component
in preserving our capability to treat resistant infections in humans.
Ideally, the development of new antimicrobials in a class of
antimicrobials should not encourage the development of antimicrobial
resistance to other classes of antimicrobials. Achieving this goal has
not been easy.

> Unfortunately, resistance to one class of antimicrobials is often
> linked to resistance in another class. For example, in Gram negative
> bacteria resistant to beta-lactam antibiotics, the mechanism of
> resistance is often inactivation of the drug by a beta-lactamase found
> on extra-chromosomal elements, e.g., plasmids. Such plasmids may also
> possess resistance genes to other classes of antibiotics (sulfa drugs,
> chloramphenicol, etc.). On the other hand, development of resistance
> to the quinolones occurs via chromosomal mutation of genes encoding
> efflux or for the cellular topoisomerases that are the target site for
> this class of drugs. Although a recent report described
> plasmid-mediated quinolone resistance, chromosomal mutations
> conferring resistance to quinolones have not been shown to be
> transferable to other pathogens at the present time^19^. Therefore,
> antimicrobial drugs that do not confer resistance to other classes of
> antimicrobial drugs are expected to be considered of greater
> importance to human medicine.
>
> **Note**: If cross-resistance is known to exist between drug classes
> of differing importance ranking, the drug class in question should
> typically be ranked according to the highest level of importance among
> the drug classes involved.

9\. **Ease of transmissibility of resistance:** The dissemination of
resistant determinants via plasmids and transposons is a critical factor
in the assessment of the importance of antimicrobials to human medicine.
Transmission of resistance may be considered low (relative difficulty of
transmission from one organism to another) or high (relative ease of
transmission from one organism to another). For the purposes of this
guidance, transmissibility of resistance can be defined as follows:

-   Low = intrinsic resistance (outer membrane impermeability) or change
    in target site that is non-transmissible. An example would be
    fluoroquinolone resistance due to mutation of *gyr A*. or *par C*
    (topoisomerase IV) or overexpression of chromosomal efflux pumps.

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```
-   High = single or multi-drug resistance that is transmissible. One
    example would be macrolide-lincosamide-streptogramin (MLS)
    resistance, which confers resistance to macrolides, lincosamides,
    and streptogramin B classes of antibiotics. This form of resistance
    has been shown to be transmissible on plasmids and transposons.
    Plasma mediated ß-lactamases are another example.

> Low transmissibility of resistance is clearly more desirable in
> preserving the usefulness of an antibiotic in human medicine. Products
> that demonstrate this low transmissibility of resistance are more
> likely to be ranked of high importance, although a final determination
> would take into account other characteristics mentioned in this
> document.

10\. **Cross-resistance between drugs used in animals and drugs used in
humans:**\
In circumstances in which a drug proposed for use in animals is not used
in human medicine, but is known to be cross-resistant with a drug that
is used in human medicine, the animal drug should typically be assigned
the importance ranking of that human drug.

> Avoparcin is an example of this scenario. While this drug is not used
> in human medicine, it belongs to the same class as vancomycin, and
> resistance to avoparcin could predict resistance to vancomycin. If
> cross-resistance to avoparcin and vancomycin is demonstrated, one
> should consider designating avoparcin as a highly important drug as
> one would vancomycin.

**Table A1.** Ranking of antimicrobial drugs/drug classes based on the
identified relevant factors

<table>
<colgroup>
<col style="width: 21%" />
<col style="width: 6%" />
<col style="width: 4%" />
<col style="width: 5%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 5%" />
</colgroup>
<thead>
<tr class="header">
<th><strong>Drug class/drug</strong></th>
<th><blockquote>
<p><strong>Human importance rank</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>Sole Therapy</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>Drug of Choice</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>Active for resistant Gram Positives</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>Active for resistant Gram Negatives</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>Oral Therapy</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>Treats Foodborne Infection</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>Unique Mechanism</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>No Cross Resistance within Class</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>No Cross Resistance Across Classes</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>Low ease of transmissibility of resistance</strong></p>
</blockquote></th>
<th><blockquote>
<p><strong>Serious Infection</strong></p>
</blockquote></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><strong>Natural penicillins</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Benzathine penicillin G</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Penicillin G</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Penicillin V</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Penicillinase-Resistant Penicillins</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Cloxacillin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Dicloxacillin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Nafcillin</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Oxacillin</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td><strong>Antipseudomonal Penicillins</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Carbenicillin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Mezlocillin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Pipercillin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Pipercillin/tazobactam</td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Ticarcillin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Ticarcillin/Clavulanate</td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td><strong>Aminopenicillins</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Amoxicillin</td>
<td></td>
<td></td>
<td></td>
<td>?</td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Ampicillin</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Ampicillin/Sulbactam</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td><strong>1st Generation Cephalosporins</strong></td>
<td>M</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Cefazolin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Cefadroxil</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Cephalexin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Cephradine</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>2nd Generation Cephalosporins</strong></td>
<td>M</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Cefaclor</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Cefaclor-CD</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Cefamandole</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Cefonacid</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Cefprozil</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Cefuroxime</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Lorcacarbef</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>3rd Generation Cephalosporins</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Cefdinir</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Cefixime</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Cefoperazone</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Cefotaxime</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Cefpodoxime</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Ceftazidime</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Ceftibuten</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Ceftizoxme</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Ceftriaxone</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td><strong>4th Generation Cephalosporins</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Cefepime</td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td><strong>Cephamycins</strong></td>
<td>M</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Cefotetan</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Cefoxitin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td><strong>Carbapenems</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Imipenem</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Meropenem</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td><strong>Monobactams</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Aztreonam</td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>Quinolones</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Cinoxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Nalidixic Acid</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Oxolinic Acid</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Pipemidic Acid</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Fluoroquinolones</strong></td>
<td>H</td>
<td></td>
<td>x</td>
<td>x</td>
<td>x</td>
<td>x</td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td>x</td>
</tr>
<tr class="even">
<td>Ciprofloxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Enoxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Gatifloxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Grepafloxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Levofloxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Lomefloxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Moxifloxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Norfloxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Ofloxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Sparfloxacin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td><strong>Aminoglycosides</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Amikacin</td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td>x+</td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Gentamicin</td>
<td>M</td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Kanamycin</td>
<td>L</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Neomycin</td>
<td>L</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Netilmicin</td>
<td>M</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Spectinomycin</td>
<td>M</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Streptomycin</td>
<td>H</td>
<td></td>
<td>x</td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Tobramycin</td>
<td>H</td>
<td>x</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td><strong>Macrolides</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Azithromycin</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Clarithromycin</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Erythromycin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td><strong>Ketolides</strong></td>
<td>H</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Telithromycin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Tetracyclines</strong></td>
<td>M</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Chlortetracycline</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Demeclocycline</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Doxycycline</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Minocycline</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Tetracycline</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td><strong>Glycopeptides</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Oritavancin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Teicoplanin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Vancomycin</td>
<td></td>
<td>x</td>
<td>x</td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td><strong>Streptogramins</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Dalfopristin/<br />
quinupristin</td>
<td></td>
<td>x</td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td><strong>Oxazolidones</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Linezolid</td>
<td></td>
<td>x</td>
<td></td>
<td>x</td>
<td></td>
<td>x</td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td><strong>Rifamycins</strong></td>
<td>H</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Rifabutin</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Rifampin</td>
<td></td>
<td></td>
<td>x</td>
<td>x</td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td><strong>Other</strong></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Bacitracin</td>
<td>L</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Chloramphenicol</td>
<td>M</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Clindamycin</td>
<td>M</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Isoniazid</td>
<td>H</td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="odd">
<td>Metronidazole</td>
<td>H</td>
<td></td>
<td>x</td>
<td></td>
<td>x</td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Polymyxin B</td>
<td>L</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Pyrazinamide</td>
<td>H</td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
<tr class="even">
<td>Trimethoprim/<br />
sulfamethoxazole</td>
<td>H</td>
<td></td>
<td>x</td>
<td>x</td>
<td></td>
<td>x</td>
<td>x</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>x</td>
</tr>
</tbody>
</table>

## **Appendix B**** Human exposure to bacteria of human health concern via animal-derived foods**

The exposure assessment component of the qualitative antimicrobial
resistance risk assessment described in this document includes
consideration of consumption patterns in the U.S. population and the
prevailing contamination levels in the various animal-derived food
commodities. Below are example data sets of these two types of
information. The specific information provided is for illustrative
purposes. FDA recommends that the sponsor reference data that is most
current at the time that the assessment for their product is being
conducted.

**Per capita meat consumption:** Per capita meat consumption data are
provided in Table B1. The data presented are for the year 2000 and are
published by the USDA Economic Research Service. FDA recommends that the
sponsor reference this type of information when completing the risk
assessment for their product. The most recent available information
should be used for the assessment. The qualitative rankings provided in
Table B1 are provisional and represent relative rankings of consumption
of the commodities listed for the year 2000.

**Food commodity contamination:** Prevalence data for *Salmonella* and
*Campylobacter* in various animal-derived food commodities are provided
in Tables B2 and B3, respectively. FDA recommends that the sponsor
reference this type of information when completing the risk assessment
for their product. The most recent available information should be used
for the assessment. The qualitative rankings provided in Tables B2 and
B3 are provisional and represent relative rankings of contamination of
the commodities listed.

FDA believes that the concept of qualitatively ranking bacterial
contamination in the manner described is consistent with the overall
risk assessment process outlined. In addition, FDA believes that the
incidence of carcass contamination is a relevant factor for estimating
the probability of human exposure to foodborne bacteria. For the
purposes of this risk assessment, FDA assumes that a high incidence of
carcass contamination is more likely to lead to human exposure through
food than a low incidence of carcass contamination. Based on this
assumption, FDA believes that it is appropriate to rank qualitatively
contamination as low, medium, or high.

The specific criteria for assigning low, medium, or high contamination
rankings are provided in footnotes to Tables B2 and B3. These rankings
are based primarily on the most recent USDA/FSIS *Salmonella*
contamination data cited in Table B2. FDA acknowledges that the calendar
year 2001 contamination data listed in Table B2 indicate that all listed
food commodities are below their respective *Salmonella* performance
standards (i.e., baseline prevalence). For the purposes of the
assessment process outlined here, FDA has decided to base the criterion
for "high" contamination on the highest level of contamination reported
for *Salmonella* in 2001. Therefore, a prevalence of contamination of
greater than 25 percent is considered a "high" level of contamination.
The medium and low contamination rankings are bracketed at 5 to 25
percent and less than 5 percent, respectively. For consistency, the same
ranking criteria may be applied to other bacteria such as
*Campylobacter* as described in Table B3.

**Ranking human exposure to foodborne pathogen:** Table B4 describes a
process for integrating the qualitative rankings for food commodity
consumption and food commodity contamination into a single human
exposure ranking.

**Table B1.** Per capita consumption data for red meats, poultry, fish
and shellfish for the year 2000

+--------------------+-------------------------+-----------------------+
| ### Commodity      | Per capita              | Qualitative           |
|                    | consumption\*\          | ranking\*\*           |
|                    | (pounds per capita per  |                       |
|                    | year)                   |                       |
+--------------------+-------------------------+-----------------------+
| ## Beef            | 64.4                    | High                  |
+--------------------+-------------------------+-----------------------+
| Veal               | 0.6                     | Low                   |
+--------------------+-------------------------+-----------------------+
| Pork               | 47.7                    | High                  |
+--------------------+-------------------------+-----------------------+
| Lamb and mutton    | 0.8                     | Low                   |
+--------------------+-------------------------+-----------------------+
| Chicken            | 52.9                    | High                  |
+--------------------+-------------------------+-----------------------+
| Turkey             | 13.6                    | Medium                |
+--------------------+-------------------------+-----------------------+
| Fish and shellfish | 15.2                    | Medium                |
+--------------------+-------------------------+-----------------------+
| Total meat         | 195.2                   |                       |
+--------------------+-------------------------+-----------------------+

\*From USDA Economic Research Service^20^; Boneless, trimmed (edible)
weight.

\*\*Qualitative ranking based on relative proportion of the total per
capita consumption of meat that is attributable to each of the
individual meat commodities.

**Table B2.** Prevalence of *Salmonella* contamination of various
animal-derived food commodities and provisional qualitative
contamination rankings

  ---------------- ---------------- ------------------- -------------------
  Commodity        Baseline         Calendar Year 2001  Qualitative
                   prevalence       Prevalence (%)^1,2^ ranking^3^
                   (%)^1^                               

  Broilers         20.0             11.9                Medium

  Market hog       8.7              3.8                 Low

  Cows/bulls       2.7              2.4                 Low

  Steer/Heifer     1.0              0.6                 Low

  Ground Beef      7.5              2.8                 Low

  Ground Chicken   44.6             19.5                Medium

  Ground Turkey    49.9             26.2                High
  ---------------- ---------------- ------------------- -------------------

^1^As reported in the USDA/FSIS "Progress Report on *Salmonella* Testing
of Raw Meat and Poultry Products, 1998-2001"^21^

^2^Prevalence data for CY 2001 for all size slaughter establishments and
establishments that produce raw ground product

^3^Relative qualitative ranking of the level of contamination among
various food commodities; Low (\< 5%), Medium (5 -- 25%), High (\> 25%)

**Table B3.** Prevalence of *Campylobacter* contamination of various
animal-derived food commodities and provisional qualitative
contamination rankings

  ---------------------- ----------------------- ------------------------
  Commodity              Prevalence (%)^1^       Qualitative ranking^2^

  Broilers               88                      High

  Turkeys                90                      High

  Market hog             32                      High

  Cows/bulls             1                       Low

  Steer/Heifer           4                       Low

  Ground Beef            0                       Low

  Ground Chicken         60                      High

  Ground Turkey          25                      Medium
  ---------------------- ----------------------- ------------------------

^1^Data from national surveys conducted between 1992 -- 1997.^22-29^

^2^Relative qualitative ranking of the level of contamination among
various food commodities; Low (\< 5%), Medium (5 -- 25%), High (\> 25%)

**Table B4.** Possible process for ranking qualitatively the probability
of human exposure to a given bacteria in a given food commodity

+------------------+----------------+-----------------+---------------+
|                  | ### Proba      |                 |               |
|                  | bility of huma |                 |               |
|                  | n exposure to  |                 |               |
|                  | given bacteria |                 |               |
+------------------+----------------+-----------------+---------------+
|                  | per capita     |                 |               |
|                  | consumption of |                 |               |
|                  | the food       |                 |               |
|                  | commodity      |                 |               |
+------------------+----------------+-----------------+---------------+
| Probability of   | **High**       | **Medium**      | **Low**       |
| food commodity   |                |                 |               |
| contamination    |                |                 |               |
+------------------+----------------+-----------------+---------------+
| **High**         | H              | H               | M             |
+------------------+----------------+-----------------+---------------+
| **Medium**       | H              | M               | L             |
+------------------+----------------+-----------------+---------------+
| **Low**          | M              | L               | L             |
+------------------+----------------+-----------------+---------------+

## **Appendix C**** Re-evaluating the safety of currently approved antimicrobial new animal drugs**

I. Objective: FDA intends to re-evaluate the safety of antimicrobial
drug products currently approved for use in food-producing animals and
for which antimicrobial resistance concerns were not previously
considered as described in either Guidance for Industry #78 or the
current guidance. This Appendix provides a description of the type of
process that FDA intends to use to complete this re-evaluation.

II. Prioritization: To use available resources most effectively, FDA
    intends to prioritize its efforts to re-evaluate currently approved
    products. An outline of how this process may be prioritized is
    described below.

```{=html}
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```
A.  Resolve any currently pending regulatory actions (e.g., pending
    notices of opportunity for a hearing) initiated due to human health
    concerns associated with antimicrobial resistance.

B.  Re-evaluate products currently approved for use in food-producing
    animals that are ranked "high" with regard to their importance for
    human medicine and are considered "high" due to their importance for
    treating foodborne disease in humans (see Appendix A for ranking
    process).

C.  Re-evaluate the other products currently approved for use in
    food-producing animals that are ranked "high" with regard to
    importance for human medicine.

D.  Re-evaluate products currently approved for use in food-producing
    animals that are ranked "medium" with regard to importance for human
    medicine.

E.  Consider re-evaluation of products currently approved for use in
    food-producing animals that are ranked "low" with regard to
    importance for human medicine.

```{=html}
<!-- -->
```
III. Re-evaluation process: The process of re-evaluating approved
     antimicrobial new animal drugs may include such elements as the
     following:

```{=html}
<!-- -->
```
A.  The general concepts of the risk analysis methodology described in
    this document for the pre-approval evaluation of antimicrobial new
    animal drugs may be applied to the process for re-evaluating
    currently approved products.

B.  FDA may conduct an initial assessment to determine if the safety of
    the approved product (when used under currently approved use
    conditions) is brought into question. Based on this assessment, FDA
    may determine that the drug, under certain use conditions is unsafe
    or no longer shown to be safe, or that certain use restrictions
    should be applied in order for that drug to continue to be
    considered safe. In some cases, FDA may propose to withdraw the
    approval of certain drug uses (e.g., certain conditions of use of a
    product, use in certain animal species, etc.).

C. In the course of conducting the re-evaluation of all currently
available information relevant to the NADA(s) in question, FDA may
identify additional information that is needed to evaluate safety.

IV. Risk management: FDA intends to apply the same basic risk management
    strategies outlined for the pre-approval assessment process in the
    re-evaluation of approved antimicrobial new animal drugs. FDA
    believes these strategies are appropriate for managing antimicrobial
    resistance in association with the use of all antimicrobial drugs
    used in food-producing animals. Based on the assessed risk to human
    health, FDA actions may:

```{=html}
<!-- -->
```
A.  Restrict products currently available over-the-counter (OTC) to
    prescription or veterinary feed directive use. FDA believes that
    only those drug products that are of low concern with regard to
    potential impact on human health may be available OTC.

B.  Prohibit extra-label use for certain drug products. In particular,
    FDA believes that drugs that are of high concern with regard to
    potential impact on human health may be prohibited from extra-label
    use.

C.  Limit the extent of use of certain antimicrobial drug products,
    particularly those that are considered to be of high concern with
    regard to potential impact on human health. For example, whole
    herd/flock administration or continuous administration of such drug
    products may not be considered appropriate.

D.  Initiate process to withdraw approval of drug product/use condition
    of concern.

### References

1\. Witte W. 1998. Medical consequences of antibiotic use in
agriculture. Science 279:996-997.

2\. White, D.G., S. Zhao, R. Sudler, S. Ayers, S. Friedman, S. Chen,
P.F. McDermott, S. McDermott, D.D. Wagner, and ,J. Meng. 2001. Isolation
and characterization of antimicrobial resistant *Salmonella* isolated
from retail ground meats. N. Eng. J. Med. 345:1147-1154.

3\. McEwen S.A., P.J. Fedorka-Cray. 2002. Antimicrobial use and
resistance in animals. Clin. Infect. Dis. 34 (Suppl 3):S93-S106.

4\. Ribot, E.M., R.K. Wierzba, F.J. Angulo, and T.J. Barrett. 2002.
*Salmonella enterica* serotype Typhimurium DT104 isolated from humans,
United States, 1985, 1990, and 1995. Emerg. Infect. Dis. 8:387-391.

5\. Tollefson L, Altekruse SF, Potter ME. 1997. Therapeutic antibiotics
in animal feeds and antibiotic resistance. Rev. Sci. Tech. 16:709-715.

6\. McDermott, P.F., S.M. Bodeis, L.L. English, D.G. White, R.D. Walker,
S. Zhao, S. Simjee, and D.D. Wagner. 2002. The use of fluoroquinolones
in chickens rapidly selects for ciprofloxacin resistance in
*Campylobacter jejuni*. J. Infect. Dis. 185:837-840.

7\. National Academy of Sciences Committee on Drug Use in Food Animals.
1999. The use of drugs in food animals: Benefits and risks. National
Academy Press, Washington D.C.

8\. Dunne, E.F., P.D. Fey, P. Kludt, et al. 2000. Emergence of
domestically acquired ceftriaxone-resistant *Salmonella* infections
associated with AmpC β-lactamases. JAMA 284:3151-3156.

9\. Witte, W. 2000. Ecological impact of antibiotic use in animals on
different complex microflora: environment. Int. J. Antimicrob. Agents.
14:321-325.

10\. Swartz, M.N. 2002. Human diseases caused by foodborne pathogens of
animal origin. Clin. Infect. Dis. 34(Suppl 3):S111-S122.

11\. Summers, A.O. 2002. Generally overlooked fundamentals of bacterial
genetics and ecology. Clin. Infect. Dis. 34(Suppl 3):S85-S92.

12\. Salyers, A.A., and C.F. Amiable-Cuevas. 1997. Why are antibiotic
resistance genes so resistant to elimination? Antimicrob. Agents
Chemother. 41:2321-2325.

13\. P.F McDermott, S. Zhao, D.D. Wagner, S. Simjee, R.D. Walker, and
D.G. White. 2002. The food safety perspective of antibiotic resistance.
Anim. Biotechnol. 13:71-84.

14\. Levy, S.B. 2002. The 2000 Garrod lecture. Factors impacting on the
problem of antibiotic resistance. J. Antimicrob. Chemother. 49:25-30.

15\. Woodward. K.N. 1998. The use of microbiological end-points in the
safety evaluation and elaboration of maximum residue limits for
veterinary drugs intended for use in food producing animals. J. Vet.
Pharmacol. Ther. 21:47-53.

16\. Paige, J.C., L. Tollefson, M.A. Miller. 1999. Health implications
of residues of veterinary drugs and chemicals in animal tissues. Vet.
Clin. North Am. Food Anim. Pract. 15:31-43.

17. Vose, et al. Antimicrobial resistance: risk analysis methodology for
    the potential impact on public health of antimicrobial resistant
    bacteria of animal origin. In: Review of Science and Technology.
    Vol. 20(3), 811-827. Office of International Epizootics. Paris, 2001

18\. Committee on the Institutional Means for Assessment of Risks to
Public Health,\
Commission on Life Sciences, and National Research Council. 1983. Risk
Assessment in the Federal Government: Managing the Process. National
Academy Press, Washington, D.C.

19\. Tran, J.H. and G.A. Jacoby. 2002. Mechanism of plasmid-mediated
quinolone resistance. Proc. Nat. Acad. Sci. 99:5638-5642.

20\. United States Department of Agriculture, Economic Research Service,
Food Consumption Data System, See
<http://www.ers.usda.gov/data/foodconsumption/>

21\. United States Department of Agriculture, Food Safety and Inspection
Service, Progress Report on *Salmonella* Testing of Raw Meat and Poultry
Products, 1998-2001. \[available at
<http://www.fsis.usda.gov/OPHS/haccp/salm4year.htm>\].

22\. 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. \[available at
[[http://www.fsis.usda.gov/OPHS/baseline/contents.htm]{.underline}](http://www.fsis.usda.gov/OPHS/baseline/contents.htm)\].

23\. 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. \[available at
[[http://www.fsis.usda.gov/OPHS/baseline/contents.htm]{.underline}](http://www.fsis.usda.gov/OPHS/baseline/contents.htm)\].

24\. 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. \[available at
[[http://www.fsis.usda.gov/OPHS/baseline/contents.htm]{.underline}](http://www.fsis.usda.gov/OPHS/baseline/contents.htm)\].

25\. 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. \[available at
[[http://www.fsis.usda.gov/OPHS/baseline/contents.htm]{.underline}](http://www.fsis.usda.gov/OPHS/baseline/contents.htm)\].

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

27\. 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%5D>.

28\. 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%5D>.

29\. United States Department of Agriculture- National Agricultural
Statistics Service, Agricultural Statistics Board. Poultry Slaughter
data. Unpublished data. personal communication, J. Lange.