#152 
 
Evaluating the Safety of Antimicrobial 
New Animal Drugs with Regard to their 
Microbiological Effects on Bacteria of 
Human Health Concern 
 
Guidance for Industry 
 
Draft Guidance 
 
This guidance document is being distributed for comment purposes only. 
 
This version of the guidance replaces the version made available October 2003, revising criteria 
and providing an updated ranking of medically important antimicrobials, updated data tables, 
and revised definitions.  Note  in January 2023, a typo was corrected in criteria 2 on page 25. 
 
Submit comments on this draft guidance by the date provided in the Federal Register notice 
announcing the availability of the draft guidance.  Submit electronic comments to 
https://www.regulations.gov.  Submit written comments to the Dockets Management Staff (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  20852.  All 
comments should be identified with docket number FDA-1998-D-0038. 
 
For further information regarding this document, contact Ruby Singh, Center for Veterinary 
Medicine (HFV-157), Food and Drug Administration, 7500 Standish Place, Rockville MD 20855, 
240-402-0784, email: ruby.singh@fda.hhs.gov. 
 
Additional copies of this draft guidance document may be requested from the Policy and 
Regulations Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7500 
Standish Place, Rockville MD 20855, and may be viewed on the Internet at 
https://www.fda.gov/animal-veterinary, https://www.fda.gov/regulatory-information/search-fda-
guidance-documents, or http://www.regulations.gov. 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
January 2023 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
Table of Contents 
 
I.  Introduction ......................................................................................................................... 1 
II.  Scope of Guidance Document ............................................................................................ 1 
III.  Risk Analysis Methodology ................................................................................................ 3 
A.  Background ................................................................................................................... 3 
B.  Data sources/data quality ............................................................................................. 4 
IV.  Hazard Characterization .................................................................................................... 5 
A.  Drug-specific information ............................................................................................ 5 
B.  Bacterial resistance information .................................................................................. 6 
C.  Data gaps and emerging science .................................................................................. 6 
V.  Qualitative Risk Assessment .............................................................................................. 6 
A.  Release Assessment ....................................................................................................... 7 
B.  Exposure Assessment .................................................................................................. 11 
C.  Consequence Assessment ........................................................................................... 16 
D.  Risk Estimation ........................................................................................................... 17 
VI.  Risk Management Considerations................................................................................... 19 
VII.  Application of Risk Management Strategies .................................................................. 21 
VIII.  Summary of Microbial Food Safety Assessment Process .............................................. 22 
IX.  Glossary ............................................................................................................................. 23 
Appendix A .................................................................................................................................... 25 
 
i  Contains Nonbinding Recommendations 
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Evaluating the Safety of Antimicrobial New Animal Drugs with 
Regard to their Microbiological Effects on Bacteria of Human 
Health Concern 
 
Draft Guidance for Industry 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and 
is not binding on FDA or the public.  You can use an alternative approach if it satisfies the 
requirements of the applicable statutes and regulations.  To discuss an alternative approach, 
contact the FDA staff responsible for this guidance as listed on the title page. 
 
I.  Introduction 
Prior to approving an antimicrobial new animal drug application, FDA must determine that the 
drug is safe and effective for its intended use in the animal.  The Agency must also determine that 
the antimicrobial drug intended for use in food-producing animals is safe with regard to human 
health (21 CFR 514.1(b)(8)).  FDA considers an antimicrobial new animal drug to be safe if it 
concludes that there is reasonable certainty of no harm to human health from the proposed use of 
the drug in food-producing animals.  This document provides guidance for industry to evaluate 
potential microbiological effects of antimicrobial new animal drugs on bacteria of human health 
concern as part of the new animal drug application process. 
 
This guidance document outlines a risk assessment approach to evaluate the microbial food safety 
risks1 posed by antimicrobial new animal drugs.  Within the context of risk assessment, many 
possible mechanisms to address the development of antimicrobial resistance resulting from the 
use of antimicrobial new animal drugs in food-producing animals are available to the sponsor.  
Alternative processes that may be more appropriate to a sponsors drug and its intended 
conditions of use may be used to characterize the microbial food safety of that drug. 
 
FDAs guidance documents do not establish legally enforceable responsibilities.  Instead, 
guidances describe the Agencys current thinking on a topic and should be viewed only as 
guidance, unless specific regulatory or statutory requirements are cited.  The use of the word 
should in Agency guidances means that something is suggested or recommended, but not 
required. 
 
II.  Scope of Guidance Document 
As part of the pre-approval safety evaluation process, FDA intends to consider the potential 
impact on human health of all uses of all classes of antimicrobial new animal drugs intended for 
 
1 Risk: The probability that treatment of human illness caused by the hazardous agent is compromised through 
decreased or loss of effectiveness of the human antimicrobial drug/class of interest.  
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use in food-producing animals.  This document outlines a risk assessment method that considers 
the effects of the transmission of antimicrobial resistant foodborne bacteria of human health 
concern through the consumption of animal-derived food products.  Although FDAs primary 
focus will be foodborne pathogens and their resistance determinants, other 
(enteric/gastrointestinal) bacteria may be considered when deemed necessary.   
 
FDA has provided further clarification regarding microbial food safety considerations that should 
be addressed for the investigational new animal drugs or new animal drugs covered by the 
guidance described herein.  This document focuses on the concern that the use of antimicrobial2 
new animal drugs in food-producing animals3 will result in the emergence and selection of 
antimicrobial resistant foodborne bacteria (the hazardous agent4) which can adversely impact 
human health.  
 
NOTE: This guidance describes the importance of antimicrobial resistance as a 
human food safety endpoint.  For more details on FDAs approach to the pre-
approval evaluation of human food safety please refer to FDAs GFI #3, General 
Principles for Evaluating the Human Food Safety of New Animal Drugs Used in 
Food-Producing Animals.5 
 
This risk assessment approach is recommended for the evaluation of applications submitted for all 
antimicrobial new animal drugs in food-producing animals.  Sponsors of applications described 
below are encouraged to consult with FDA to decide if the risk assessment approach is suitable 
for their application.  
 
1.  Certain supplemental New Animal Drug Applications (NADAs):  Microbial food 
safety information is not typically 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 re-evaluation of certain safety or effectiveness data in the 
parent application. 
2.  NADAs for antimicrobial drug combinations:  Microbial food safety information would 
ordinarily not be needed for antimicrobial drug combinations as defined in Section 512(d) 
 
2 Antimicrobial: For the purposes of this guidance document, refers broadly to drugs with activity against a variety of 
microorganisms including bacteria, viruses, fungi, and parasites.  Antimicrobial drugs that have specific activity 
against bacteria are referred to as antibacterial or antibiotic drugs.  The broader term antimicrobial, is used in this 
document and includes reference to drugs with activity against bacteria including antibacterials and antibiotics. 
3 See section XI.C.4. Food-Producing Animals in Guidance for Industry #61, Special Considerations, Incentives, 
and Programs to Support the Approval of New Animal Drugs for Minor Uses and for Minor Species, for examples 
of food-producing animals. 
4 Hazardous Agent: For the purposes of this guidance document, refers to antimicrobial resistant foodborne bacteria 
that are in or on a food-producing animal as a consequence of the proposed use of the antimicrobial drug in animals, 
thereby constituting the hazard. 
5 https://www.fda.gov/media/70028/download 
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of the Act (21 U. S. C. 360b(d)).  Microbial food safety would typically be addressed as 
part of the NADAs for the individual antimicrobial drugs that comprise the combination.  
However, information or data may be requested for certain types of antimicrobial drug 
combinations. 
3.  Abbreviated (generic) NADAs:  Microbial food safety information would not be needed 
for abbreviated new animal drug applications (ANADAs) filed under section 512(b)(2) of 
the FD&C Act for generic copies of approved antimicrobial new animal drugs and 
combinations.   
III.  Risk Analysis Methodology 
This guidance document outlines a risk assessment method and describes its application as a 
process to evaluate human food safety with respect to the potential microbiological effects of 
antimicrobial new animal drugs on foodborne bacteria of human health concern.  The sponsor of 
an antimicrobial new animal drug may use this guidance and the methodology described herein to 
conduct a qualitative risk assessment as part of the pre-approval safety evaluation of a new animal 
drug.  It is important to note that the sponsor is free to demonstrate the safety of their proposed 
drug product in other ways.   
 
FDAs current thinking on a qualitative approach for risk assessment is described in this 
guidance.  FDA does not intend to exclude quantitative risk assessment in favor of a qualitative 
process.  Further, FDA encourages sponsors to seek data and modeling approaches that can best 
refine and improve the approach and assumptions incorporated in this risk assessment process. 
 
If the sponsor elects to use this or a similar process, FDA recommends the assessment be 
submitted to an investigational new animal drug (INAD) file with supporting data as a component 
of the Human Food Safety technical section or it may be included in the NADA as part of the 
sponsors submission under 21 CFR 514.1(b)(8).  The results of this risk assessment can help to 
estimate the overall risk, allowing 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 application to denial.  The remainder of the document provides 
guidance on this risk assessment method. 
A.  Background 
The risk assessment process described in this guidance document is comprised of a 
hazard characterization,6 a release assessment, an exposure assessment, a consequence 
assessment, and a risk estimation (see Figure 1).  The risk estimation integrates the 
components of the risk assessment into an overall conclusion, providing a qualitative 
indication of the potential risk to human health of the proposed use of the antimicrobial 
 
6 Hazard Characterization: For the purposes of this guidance document, it is the process by which one may identify 
the hazardous agent and the conditions that influence the occurrence of the hazard.  This is based upon use in food 
animals, drug-specific information, bacteria/resistance determinant information, and the methodology for the 
determination of resistant or susceptible bacteria. 
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new animal drug.  FDA then uses the overall risk estimation ranking, along with other 
relevant data and information submitted in support of the NADA, to determine whether 
the drug is approvable under specific risk management conditions. 
Figure 1:  Components of a qualitative antimicrobial resistance risk assessment 
HAZARD CHARACTERIZATION
QUALITATIVE RISK ASSESSMENT
CONSEQUENCE 
RELEASE  EXPOSURE  ASSESSMENT
ASSESSMENT ASSESSMENT
Probability that human exposure to 
Probability that resistant  Probability for humans to  resistant bacteria results in an 
bacteria are present in  ingest bacteria in question  adverse health consequence due to 
target animal as a  from the relevant food  the use of medically or not 
medically important antimicrobials. 
consequence of drug use  commodity (rank as LOW, 
(For medically important, drug is 
(rank as LOW, MEDIUM or  MEDIUM or HIGH) ranked as IMPORTANT, HIGHLY 
HIGH) IMPORTANT or CRITICALLY 
IMPORTANT)
RISK ESTIMATION
Overall risk estimation is based on integration of RELEASE, EXPOSURE and CONSQUENCE 
assessments (rank as LOW, MEDIUM or HIGH)
 
FDAs primary concern is the potential for decreased or lost effectiveness of 
antimicrobial drugs in humans as a consequence of human exposure to resistant bacteria 
in or on food derived from treated animals.  FDA is concerned about a range of adverse 
effects that foodborne antimicrobial-resistant bacteria may have on human health.  These 
effects can include, but are not limited to, increased duration of illness, treatment failure, 
and loss of therapeutic options.  Due to difficulties associated with measuring the loss of 
effectiveness, the risk assessment process described in this guidance document results in 
a risk estimation of the probability of a hazard occurring. 
 
B.  Data sources/data quality 
A variety of materials may be used to support a microbial food safety assessment.  These 
materials should meet FDA standards for data used to support an approval.  Sponsors 
may consider: 
 
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1.  Generating necessary data through the conduct of prospective studies.  Sponsors 
should follow the requirements outlined in 21 CFR part 58 Good Laboratory 
Practices for conducting non-clinical laboratory studies.  Any deviations should 
be noted in the final study report.  
2.  Submission of current and relevant literature (including peer reviewed, published 
literature).  FDA recommends that sponsors refer to draft revised GFI #106, The 
Use of Published Literature in Support of New Animal Drug Approvals, for 
guidance regarding use of published literature.7  
IV.  Hazard Characterization 
Sponsors may choose to first characterize the hazard and the conditions that influence the 
occurrence of that hazard.  It is recommended that this hazard characterization be submitted to the 
FDA as a stand-alone document.  This submission will enable the sponsor and the FDA to 
determine the information and data that should be included in a complete microbial food safety 
risk assessment.  In addition, based on the hazard characterization contents and findings, it may 
be determined, in certain cases, that completion of a risk assessment is not necessary. 
 
FDA recommends that sponsors address the hazard characterization step of the risk assessment by 
submitting information regarding the chemical, biochemical, microbiological, and physical 
properties of the antimicrobial new animal drug that bear on characterizing the downstream 
effects of the drug.  This information may include, but should not be limited to: 
 
A.  Drug-specific information 
Chemical name and structure 
1.  Class of antimicrobial drug (e.g., macrolide) 
2.  Mechanism (e.g., protein synthesis inhibitor) and type of action (i.e., bactericidal 
vs. bacteriostatic) 
3.  Spectrum of activity (e.g., gram positive, gram negative, or both) 
4.  Standardized antimicrobial susceptibility testing methodology and specific 
susceptibility data (i.e., minimum inhibitory concentration (MIC) and minimum 
bactericidal concentration (MBC) data pertinent to the appropriate bacteria of 
human health concern).  FDA recommends that if the sponsor does not use 
standardized susceptibility test methods, the sponsor should include a detailed 
description of the antimicrobial susceptibility testing method(s) used and the 
reason(s) for the needed change.  The methods should include the quality control 
organism(s), the dilution scheme used, and the source for the interpretive criteria. 
The methods and interpretive criteria may include citations of relevant laboratory 
standards such as the Clinical and Laboratory Standards Institute (CLSI)8 or 
 
7 https://www.fda.gov/media/70056/download (April 2022).  When final, this guidance will represent FDAs current 
thinking on this topic. 
8 https://clsi.org  
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guidelines and interpretive charts made available by the European Committee on 
Antimicrobial Susceptibility Testing (EUCAST).9  Additional guidance on 
susceptibility testing may be obtained from other recognized sources. 
5.  Relative importance of the drug to human medicine (see Appendix A).   
B.  Bacterial resistance information 
Taking into account the target animal species to be treated with the drug, the conditions 
of intended use of the drug in animals, 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 consequences. 
2.  Known resistance determinants or mechanisms associated with the antimicrobial 
drug(s)/class(es) of interest.  FDA recommends that information describing 
phenotypic and genotypic similarities with resistance determinants in other 
foodborne bacteria of human concern be identified.  
C.  Data gaps and emerging science 
The sponsor or FDA may identify data gaps and areas of emerging science that may be 
relevant to the microbial food safety assessment for the proposed conditions of use. 
 
V.  Qualitative Risk Assessment 
NOTE: After submission and review of the hazard characterization, and prior to completing the 
risk assessment, the sponsor may wish to consult with FDA regarding recommendations on 
additional information to complete the risk assessment. 
 
The risk assessment approach is comprised of a release assessment, an exposure assessment, a 
consequence assessment, and a risk estimation (refer to Figure 1). 
 
FDA recommends that sponsors adapt and expand their risk assessment to accommodate the 
unique relationships that may exist among an antimicrobial new animal drug, affected bacteria, 
proposed condition(s) of use, and other parameters that potentially affect human health.  The 
assessment process outlined below will result in an overall estimate of the level of concern (risk 
estimation) associated with the emergence or selection of resistant bacteria as a consequence of 
the proposed use of the drug in animals.  This process may help guide the selection of appropriate 
risk management steps. 
 
NOTE: FDA intends to determine, when possible, the appropriate conditions of use or other risk 
management steps based on its review and consideration of the new animal drug application as a 
whole, including any risk assessment submitted by the sponsor as part of the application. 
 
 
9 https://www.eucast.org/ 
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A.  Release Assessment 
 
The release assessment estimates the probability that the proposed use of the 
antimicrobial new animal drug in food-producing animals will result in the emergence 
or selection of resistant bacteria in the animal hazard.  It describes those factors related 
to the antimicrobial new animal drug and its use in animals that contribute to the 
emergence of resistant bacteria and their acquisition of resistance determinants (i.e., 
release of the hazardous agent) in the animal.  The release assessment should also 
qualitatively estimate the probability that release of the hazardous agent would occur. 
1.  Defining the boundaries of the release assessment 
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 the animal-derived food is sampled.  
 
For the purposes of this guidance, FDA is focused on the food-producing animal as 
the source of human exposure to the hazardous agent.  Human exposure to the 
hazardous agent should be addressed in the exposure assessment. 
2.  Factors that may be considered in the release assessment 
A number of relevant factors are suggested for consideration in completing the 
release assessment.  These factors include items that are also considered as part of 
the hazard characterization step described earlier.   
 
NOTE: Following submission of the hazard characterization, the sponsor may wish 
to consult with FDA to determine the specific factors most relevant to the proposed 
conditions of use of the antimicrobial new animal drug in question.  
 
To address specific considerations relevant to the drug and its proposed conditions of 
use, the sponsor or FDA may consider factors not listed below.  FDA recommends 
all factors be clearly defined and supported. The relative significance of any 
particular factor may vary depending on the specific antimicrobial new animal drug 
application under consideration; therefore, when determining the overall release 
assessment ranking, certain factors may carry greater weight than other factors.  
Other factors may also be relevant. FDA recommends that factors considered in the 
release assessment include the following.   
a.  Product description:   
  Product formulation (active and inactive ingredients) 
  Information regarding proposed conditions of use including: 
  Desired marketing status (level of veterinary oversight (i.e.,   
prescription, veterinary feed directive, over-the-counter 
(OTC))  
  Projected market share (important for supplements)  
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  Dosage regimen [dose, duration, route of administration (e.g., 
injection, in feed, in water)]  
  Proposed product indication  
  Intended target animal class10 
  Proposed withdrawal time 
b.  Drug substance description: 
  Class of antimicrobial drug (e.g., macrolide) 
  Chemical name, CAS number, and structure 
c.    Mechanism and type of antimicrobial action: 
  Specifics regarding antimicrobial mechanisms (e.g., protein synthesis 
inhibitor) 
  Type of action (e.g., bactericidal action vs. bacteriostatic) 
d.  Spectrum of activity: 
  General information (e.g., is active against gram positive, gram 
negative, or both) 
  Specific susceptibility data (e.g., minimum inhibitory concentration 
(MIC) and minimum bactericidal concentration (MBC) data pertinent 
to food- borne bacteria of human concern)   
e.    The pharmacokinetics/pharmacodynamics of the drug: 
  Absorption, distribution, metabolism, and elimination of the drug in 
the target animal 
  Information and data on, or an estimation of, the active antimicrobial 
drug in colonic contents  
  Additional effects such as first-exposure effects, post-antibiotic 
effects, sub-MIC effects, etc. 
  Pharmacodynamics, such as concentration- and/or time-dependent 
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:   
 
10 For more details, please see GFI #191, Changes to Approved NADAs  New NADAs vs. Category II 
Supplemental NADAs (August 2020).  https://www.fda.gov/media/70423/download 
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  Known mechanism(s) of resistance in animal and human pathogens 
(e.g., antimicrobial inactivation, alteration of the drug target, reduced 
uptake, efflux of the antimicrobial, etc.) 
  Location of resistance determinants (e.g., plasmid-mediated vs. 
chromosomal; present on transposons, integrons, or phages) 
  Information and data supporting how resistance determinant(s) lead 
to non-wild type or clinically resistant phenotypes 
g.  Occurrence and rate of transfer of resistance determinants:   
FDA recommends that the sponsor provide information regarding whether 
resistance determinants are transferable and, if so, at what rate.  Relevant 
questions may include, but not limited to: 
  Can resistance determinants be transferred among bacteria by 
transformation, transduction, conjugation, or transposition?  If so, at 
what rate? 
  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 
under the proposed conditions of use.  Relevant information and/or data may 
include: 
  Other antimicrobials that may co-select for resistance. 
  Cross resistance to other antimicrobials approved in veterinary and 
human medicine. 
  Consideration of the extent of use of the proposed product (e.g., 
defined duration of use; individual animals 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 and/or related 
drugs in target pathogens and commensal intestinal bacteria.   This may be 
obtained from newly generated proprietary data, or existing sources of data, 
such as National Antimicrobial Resistance Monitoring System (NARMS) 
data,11 current literature, or other surveillance sources such as the National 
Animal Health Monitoring System (NAHMS).12  If baseline data are not 
 
11 NARMS| FDA 
12 NAHMS | USDA APHIS 
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available for the proposed antimicrobial drug, sponsors may wish to consult 
with FDA regarding collection or generation of such data.   
j.  Other factors relevant to the release assessment:   
This could include the generation of new, prospective information or data 
relating to the prevalence and rate of resistance development, including 
changes in resistance in foodborne bacteria of human health concern during, 
and after treatment under proposed conditions of use from in-situ or in-vivo 
studies. Of particular interest is resistance information relative to the 
proposed withdrawal time after which animals would be presented for 
slaughter.  
3.  Release assessment summary 
FDA recommends that the sponsor qualitatively characterize all factors relevant to 
the release assessment based on supporting information.  We recommend that this 
characterization include an estimate of whether each factor would have a low, 
medium, or high likelihood of favoring resistance emergence.  For example, the 
spectrum of activity of the drug might be ranked high for favoring resistance 
emergence or selection if the drug readily selects for mutations conferring resistance; 
in contrast, pharmacodynamics might be ranked low with regard to impact on 
resistance if the drug did not enter the target animal intestinal tract at concentrations 
shown to promote resistance development, etc.  These rankings would then be 
integrated into an overall release assessment ranking of low, medium, or high.  FDA 
recommends that the sponsor provide a detailed discussion of their conclusions, as 
well as present their conclusions in summary format (see Table 1). 
 
NOTE: If sufficient information or data regarding a factor is unavailable or was not 
generated for the assessment, the most conservative estimate (high) should be 
assumed.  
 
Table 1.  Table to collate and summarize interpretations of examples of relevant 
factors to the release assessment 
Extent to which relevant factors favor 
Relevant parameters  emergence of resistance  Release 2 
(H, M, L) 
(Comments/conclusions regarding factors) 
Mechanism of activity     
Spectrum of activity     
Pharmacokinetics     
Pharmacodynamics     
Resistance mechanism(s)     
Resistance transfer     
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Extent to which relevant factors favor 
Relevant parameters  emergence of resistance  Release 2 
(H, M, L) 
(Comments/conclusions regarding factors) 
Selection pressure 
Other factors 1 
1 Other factors may be identified that are thought to be of importance to the evaluation, i.e., data from 
whole genome sequencing or metagenomics analysis.  After submission of the hazard characterization, 
the sponsor may wish to consult with FDA regarding additional factors prior to completing the 
assessment. 
2 Potential for favoring release of resistant bacteria in ranking terms of low, medium, or high. 
4. Release assessment conclusion
The outcome of the release assessment is intended to estimate the probability that
resistant bacteria will emerge or be selected for as a consequence of the proposed use
in animals.  FDA recommends that the sponsor use conclusions obtained from
assessing all relevant factors in Table 1 to determine an overall qualitative ranking of
low, medium, or high probability for the release assessment.
B. Exposure Assessment
The exposure assessment describes the likelihood of human exposure to foodborne
bacteria of human health concern through particular exposure pathways, in this case
animal-derived food products.  The exposure assessment provides a qualitative estimate
of the probability of this exposure occurring.
The division of the qualitative risk 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 into
the exposure assessment component.
FDA recognizes that there are many factors that may affect bacteria of human health
concern 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 believes the probability that bacteria of human
health concern are present in or on the animal at slaughter may be used as an estimate of
the likelihood of human exposure to that bacterial species in the food commodity
derived from that animal.
FDA recognizes that human exposure to foodborne antimicrobial resistant bacteria is
complex, and often involves contributions from other sources of exposure (e.g., direct
contact between animals and humans, introduction of resistant bacteria into the
environment, etc.).  However, FDA believes that, during the pre-approval process,
evaluating microbial food safety relative to the primary exposure pathway (i.e.,
foodborne pathway) is the best way to qualitatively assess the risk of antimicrobial drug
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use in food-producing animals.  Uncertainties regarding the contribution of other 
exposure pathways may be considered during the development of appropriate risk 
management strategies. 
 
1.  Factors to consider in the exposure assessment 
The exposure assessment is independent of the proposed conditions of use of the 
antimicrobial drug.  It may be estimated by considering the relative amount of 
relevant bacterial contamination of the food product and the relative quantity of the 
food product consumed by humans.  While it is acknowledged that other factors such 
as food preparation practices can affect exposure, the two prior considerations are 
intended to provide a qualitative indication of the probability of human exposure to 
foodborne bacteria of human health concern.  Appropriate current survey data of 
both food commodity consumption (Table 2) and contamination (Tables 3 and 4) 
may be submitted to support a qualitative ranking of the probability of human 
exposure to the given bacteria via a particular food commodity. 
 
FDA recommends that sponsors derive the exposure assessment ranking by 
integrating the ranking of the probability of human exposure (through food) to the 
bacteria in question with the ranking of consumption of the animal-derived food 
commodity.  The qualitative probability should be expressed in terms of low, 
medium, or high as discussed below.  
2.  Example process for the estimation of exposure to the hazardous agent 
NOTE: The specific information provided in the tables in this section is for 
illustrative purposes only.  Sponsors may reference a variety of data sources which 
best characterize human exposure to bacteria of human health concern via animal-
derived foods.  FDA recommends that sponsors reference the most reliable, current 
data available at the time that the assessment for their product is conducted. 
 
FDA believes that the concept of qualitatively ranking bacterial contamination in the 
manner described is consistent with the overall risk assessment process outlined.  
The incidence of carcass contamination is a relevant factor in 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 
contamination qualitatively as low, medium, or high. 
 
Food commodity consumption:  As an example of food commodity consumption 
data, per capita meat consumption data are provided in Table 2.13  FDA 
 
13 Food Availability (Per Capita) Data System.  The ERS Food Availability (Per Capita) Data System (FADS) 
includes three distinct but related data series on food and nutrient availability for consumption: food availability data, 
 
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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 2 are illustrative 
and represent relative rankings of consumption of the commodities listed. 
 
Table 2.  Example per capita consumption data for red meats, poultry, fish and 
shellfish. 
Pounds per capita  Pounds per capita 
Commodity  consumption 1  consumption 1  Qualitative ranking 2 
(2018)  (2019) 
Beef 3  54.6  55.4  High 
Chicken  65.2  67.0  High 
Pork  47.4  48.8  High 
Fish and  
Shellfish 3  15.0  15.0  Medium 
(fresh) 
Turkey  12.8  12.6  Medium 
Lamb/mutton  0.8  0.8  Low 
Veal  0.2  0.2  Low 
1 From USDA Economic Research Service (USDA ERS  Food Availability (Per Capita) Data System 
Boneless, trimmed (edible) weight. 
2 Qualitative ranking based on relative proportion of the total per capita consumption of meat that is 
attributable to each of the individual meat commodities. 
3 Some portion of these consumption weights may be attributable to imported products.  Sponsors should 
consider this in their risk assessment. 
 
Food commodity contamination:  FDA recommends that the sponsor reference 
food commodity contamination data when completing the risk assessment for their 
product.  The most recent information should be used for the assessment.  The 
relative qualitative ranking of the level of contamination among various food 
commodities, low (< 5%), medium (5 to 25%), high (> 25%) is a general ranking, 
proposed here for illustrative purposes only, and may be subject to modification to 
more appropriately reflect the most current data.  For illustrative purposes, Tables 3 
and 4 present Salmonella and Campylobacter contamination rates in various animal-
derived food commodities.   
 
For illustrative purposes, Tables 3 and 4 present Salmonella and Campylobacter 
contamination rates in various animal-derived food commodities. 
 
loss-adjusted food availability data, and nutrient availability data.  These data serve as proxies for actual consumption 
at the national level. 
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Table 3.  Prevalence of Salmonella contamination of various animal-derived food 
commodities and qualitative contamination rankings.1 
% Positive  % Positive  % Positive 
and/or  and/or  and/or  Qualitative 
Commodity  Product type 
Prevalence 2  Prevalence 3  Prevalence 3  Ranking 3 
(2018)  (2019)  (2020) 
Ground Turkey 
25.41  22.28  18.34 
(comminuted) 
Raw Turkey  Medium 
 
Whole 
0.48  0.35  0.93 
Carcasses 
 
Ground 
 
Chicken  37.83  31.21  23.70 
 
(comminuted) 
 
  Whole 
4.25  3.59  3.38 
Raw  carcasses 
Medium 
Chicken 
Quarter/Half 
  11.83  8.99  9.68 
Carcasses 
 
Parts: 
 
legs/breasts/  12.84  8.36  7.15 
 
wings 
N/A for 
Cuts  10.62  CY19  6.43 
FY20: 6.75 
Raw Pork  High 
N/A for 
Comminuted  19.83  CY19  28.56 
FY20: 29.62 
Raw Ground  3.89  2.20  2.20 
Raw Beef  Low 
Manufacturing 
2.09  1.52  1.78 
Trim 
1 Data are derived from FSIS Data: Sampling Project Results 04012020_03312021 (usda.gov). 
2 These calculations are made using the same calculation as prevalence. FSIS is not labeling these calculations 
prevalence because the data may not meet the statistical criteria for prevalence. If FSIS determines that the data do meet 
the statistical criteria, the calculation will be updated. 
3 Relative qualitative ranking of the level of contamination among various food commodities, low (< 5%), medium (5 to 
25%), high (> 25%), is a general ranking, proposed here for illustrative purposes only, and may be subject to 
modification to more appropriately reflect the most current Calendar Year (CY) data. 
 
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Table 4.  Prevalence of Campylobacter contamination of various animal-derived food 
commodities and qualitative contamination rankings. 1 
% Positive  % Positive  % Positive 
and/or  and/or  and/or  Qualitative 
Commodity 2,  5  Product type 
Prevalence 3  Prevalence 3  Prevalence 3  Ranking 4 
(2018)  (2019)  (2020) 
Ground 
Turkey  2.71  2.64  1.33  Low 
Raw Turkey  (comminuted) 
Whole 
2.46  2.14  1.64  Low 
Carcasses 
Ground 
  Chicken  6.74  4.90  4.20  Low 
  (comminuted) 
 
Whole 
  29.50  20.55  17.99  Medium 
Carcasses 
Raw Chicken 
Quarter/Half 
  30.00  34.88  40.32  High 
Carcasses 
 
  Parts: 
  legs/breasts/  26.26  17.73  16.34  Medium 
wings 
1 Data are derived from FSIS Data: Sampling Project Results 04012020_03312021 (usda.gov). 
2 Since 2008, retail ground beef and pork were not sampled for Campylobacter due to low isolation; however, 
Campylobacter must still be considered a hazardous agent.  If the drug in question is being proposed for cattle or 
swine, then Campylobacter must be considered in the hazard characterization or risk assessment prepared in support 
of the drug.  
3 These calculations are made using the same calculation as prevalence.  FSIS is not labeling these calculations 
prevalence because the data may not meet the statistical criteria for prevalence.  If FSIS determines that the data do 
meet the statistical criteria, the calculation will be updated.  
4 Relative qualitative ranking of the level of contamination among various food commodities, low (< 5%), medium (5 
to 25%), high (> 25%), is a general ranking, proposed here for illustrative purposes only, and may be subject to 
modification based on the most current Calendar Year (CY) data. 
5 Due to data gaps for raw pork and beef, sponsors should consider other sources of data.  For example, cecal data 
collected by NARMS could be used to inform prevalence of Campylobacter contamination in these product types.  
https://www.fda.gov/animal-veterinary/antimicrobial-resistance/national-antimicrobial-resistance-monitoring-system 
 
 
 
 
 
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3.  Exposure assessment summary:  Ranking human exposure to foodborne bacteria 
Table 5 describes a possible process to estimate the probability of human exposure 
to the hazardous agent through consumption of animal-derived food commodities. 
 
Table 5:  Example to rank, qualitatively, the probability of human 
exposure to a given bacteria in a given food commodity. 
Amount of food  Amount of food commodity being consumed 
commodity 
contamination  High  Medium  Low 
High  H  H  M 
Medium  H  M  L 
Low  M  L  L 
 
4.  Exposure assessment conclusion  
The outcome of the exposure assessment is intended to estimate the probability that 
humans will be exposed to the hazardous agent through consumption of animal-
derived food commodities.  FDA recommends that the sponsor use the outcome of 
the integration process described in Table 5 to reach an overall qualitative rank of a 
low, medium, or high probability of human exposure to the hazard. 
 
C.  Consequence Assessment 
The consequence assessment describes the relationship between specified exposures to a 
hazardous agent and the consequences of those exposures (the hazard).  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 medical importance of the antimicrobial drug in question. 
 
While antimicrobial drugs are important for the treatment of infectious diseases in 
humans, some may be the sole, or one of limited therapies available to treat serious 
bacterial infections; thus, these antimicrobial drugs are believed to be of greater 
importance to human medicine (Figure 2).  Therefore, it is assumed that the human 
health consequences associated with resistance to drugs of greater importance are more 
significant than the consequences associated with resistance to drugs of lesser 
importance.  A more in-depth characterization of the potential human health impact 
based on the importance of all antimicrobial drugs, including those that are not 
medically important is illustrated in Figure 2 below:    
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Figure 2: Characterization of the potential hazard based on Medical Importance 
antimicrobial drug designation 
All Classes of 
Antimicrobials
Medically Importanta NOImT pMoerdtaicnatblly 
Critically  Highly  Do not meet criteria 
Important  Important Important to be rankedc
Potential Human Health Impact 
Highest Lowest
a Medically Important: Antimicrobial drugs that meet the criteria (as defined in Table A1, Appendix A) for 
a critically important, highly important, or important antimicrobial drug.  See Table 6 for example risk 
estimation outcomes. 
b Not Medically Important: Antimicrobial drugs that do not meet the criteria (as defined in Table A1, 
Appendix A) for a critically important, highly important, or important antimicrobial drug.  Please contact 
FDA for information and/or data needed to address microbial food safety concerns.  
c See criteria and listing of antimicrobials in Table A1, Appendix A. 
Figure 2 illustrates the concept that the greater the medical importance, the greater the risk to 
human health and that this gradient of risk on human health spans across both medically 
important and not medically important drugs.  
FDA recommends sponsors refer to Appendix A to assess the importance in human medicine of 
the drug or antimicrobial class in question and propose a human medical importance ranking to be 
expressed as important, highly important, or critically important.  For antimicrobial drugs 
considered not medically important, FDA recommends that sponsors consult with the Agency to 
determine if a qualitative risk assessment is needed.  Information available that may describe any 
potential risk to human health will be considered, along with outcomes of the release and 
exposure to derive an overall risk estimation as described below.  
 
D.  Risk Estimation 
The risk estimation integrates the results from the release, exposure, and consequence 
assessments into an overall estimate associated with the proposed conditions of use of 
the drug.  The risk estimation (low, medium, or high risk) represents the potential for 
human health to be adversely impacted by the selection or emergence of antimicrobial 
resistant foodborne bacteria associated with the use of the drug in food-producing 
animals. 
 
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The risk estimation describes the overall estimate of the risk associated with the 
proposed use of the drug in the target food-producing animals following the integration 
of the release assessment, exposure assessment and consequence assessment.  The risk 
rankings represent the relative potential for human health to be adversely impacted by 
the emergence of the hazardous agent associated with the use of the drug in food-
producing animals. 
 
Table 6 summarizes how integrating the results of the release, exposure, and 
consequence assessments can be used to arrive at a single risk estimation.  These 
estimations provide an initial assessment of the risk to human health.  
 
Table 6.  Possible risk estimation outcomes for Medically Important 
antimicrobials based on the integration of the RELEASE, EXPOSURE, 
and CONSEQUENCE assessment rankings.  
Release  Exposure  Consequence  Risk Estimation* 
low  low  important  low 
low  medium  important  low 
medium  low  important  low 
low  low  highly important  low 
low  high  important  medium 
high  low  important  medium 
medium  medium  important  medium 
medium  high  important  medium 
high  medium  important  medium 
high  high  important  medium 
low  medium  highly important  medium 
low  high  highly important  medium 
medium  medium  highly important  medium 
medium  low  highly important  medium 
medium  high  highly important  medium 
high  low  highly important  medium 
high  medium  highly important  medium 
low  low  critically important  high 
high  high  highly important  high 
low  medium  critically important  high 
medium  low  critically important  high 
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Release  Exposure  Consequence  Risk Estimation* 
low  high  critically important  high 
high  low  critically important  high 
medium  medium  critically important  high 
medium  high  critically important  high 
high  medium  critically important  high 
high  high  critically important  high 
* Risk estimation could be refined based on additional information and/or data.   
As illustrated in Figure 2 above, FDA believes the higher the medical importance of the drug, the 
greater the potential human health impact of resistance emergence.  Since the scope of this 
guidance is to address risk to humans from foodborne hazards, FDA believes the risk assessment 
methodology outlined throughout this guidance could allow sponsors to mitigate the risk.  This 
may be particularly relevant for some critically important drugs for which FDA will further 
consider if the drug (class) is used in human medicine to treat foodborne illness.  To this end, 
refinement of the risk estimation may be appropriate for specific cases after considering 
additional information and data.  
   
VI.  Risk Management Considerations  
Possible risk management steps range from denying approval of a drug application to approving 
the application under certain use conditions (as described in Table 8) aimed at mitigating human 
health risks stemming from potential antimicrobial resistance development. 
 
A.  Drug approval under safe conditions of use:  Approval of the use of a drug, assuming 
all other NADA technical sections have been satisfied, is a possible outcome of an overall 
safety evaluation that includes the qualitative antimicrobial resistance risk assessment 
process described above. 
 
Note:  Drugs estimated to be of high risk with regard to potential human 
health impact would typically warrant more restricted use conditions (e.g., 
injectable products intended for use in individual animals).  Drugs estimated 
to be of lower risk would typically warrant less restricted use conditions (e.g., 
products administered in feed or drinking water that are intended for use in 
groups of animals). 
 
B.  Denying approval of a drug application:  Section 512(d) of the FD&C Act, and 
regulations promulgated thereunder (see 21 CFR 514.111), provide possible grounds for 
denying the approval of a new animal drug application.  The statutory grounds for denying 
approval include results of tests that show the drug is unsafe, or 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. 
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C.  The following represent relevant risk management steps or conditions of use that may be 
appropriate based on the outcome of the qualitative antimicrobial resistance risk 
assessment process (see Table 8 below). 
 
1.  Marketing status limitations:  Antimicrobial drugs approved for use in animals 
may be marketed as prescription, as veterinary feed directive products, or as OTC.  
FDA believes that for medically important and some not medically important 
antimicrobial drugs, veterinary supervision is critical to ensuring judicious and safe 
use of the antimicrobial drug; therefore, such drugs might be approved for limited 
use by, or under the supervision of, a licensed veterinarian.   
 
2.  Extralabel 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, then 
extralabel use may be prohibited according to the procedures described in 21 CFR 
part 530. 
 
3.  Extent-of-use limitations:  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 7 presents a process to integrate administration and duration of 
use of an antimicrobial drug into a qualitative ranking for extent of use. 
 
Table 7:  Example ranking (low, medium, high) of extent of use in 
animals based on duration of use and population of target animals. 
Intended administration to: 
Duration of use *  individual  select groups or  flocks or herds 
animals  pens of animals  of animals 
Short 
L 1  M 2  H 3 
(<6 days) 
Medium 
L  M  H 
(6-21 days) 
Long 
M  H  H 
(>21 days) 
1 Low, 2 Medium, and 3 High extent of use 
* Duration of use will be revised on a case-by-case basis in light of, but not limited 
to, animal species, disease risk period, and animal management husbandry 
practices, etc. 
 
Administration to groups or pens of animals is defined as administration to a 
segregated group of animals within a building, house, or feedlot, whereas 
administration to flocks or herds of animals is defined as administration to all 
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animals within a building, house, or feedlot.  Sponsors may use another definition 
of these terms that is more reflective of contemporary animal husbandry and 
management practices. 
 
4.  Post-approval monitoring:  Antimicrobial new animal drugs intended for use in 
food-producing animals will be monitored through a post-approval process, such 
as NARMS.  
 
5.  Advisory input:  When making an approval decision regarding certain 
antimicrobial drugs, FDA may choose to consult with experts within and beyond 
the Agency to discuss the application. 
 
FDA believes that animal drugs may be approvable if, after evaluating all 
supporting information, FDA can conclude that there is a reasonable certainty of 
no harm to human health when the drug is approved under specific use restrictions.   
 
FDA believes that for animal drugs with a high risk estimation, a determination of 
approvability would be made on a case-by-case basis and based on a review of the 
entire application.  FDAs concerns associated with drugs estimated to pose a high 
risk to human health may be mitigated through the introduction of risk 
management steps that minimize resistance emergence or selection associated with 
any adverse impact on human health. 
 
FDA believes that the interpretation of the medium risk estimation 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).  Therefore, it is consistent to conclude that a finding of reasonable certainty 
of no harm might be reached for such drugs when use conditions are 
intermediately restrictive.  
  
FDA believes that antimicrobial drugs with a low risk estimation may be 
considered approvable if, after evaluating all supporting information, FDA can 
conclude that there is a reasonable certainty of no harm to human health when the 
drug is approved under specific use restrictions.  Such a determination would be 
made on a case-by-case basis and based on a review of the entire application. 
   
VII. Application of Risk Management Strategies 
The integration process outlined above in Table 6 results in an estimation of the risk that the use 
of an antimicrobial new animal drug will adversely impact human health.  The outcome of the 
risk estimation (low, medium, or high risk) can be used to help identify steps necessary to manage 
the risks associated with the proposed conditions of use for an antimicrobial new animal drug.  
 
Examples of risk management steps for all antimicrobials approvals, and how these steps might 
be applied to manage the estimated level of risk are provided in Table 8.  Table 8 illustrates how 
the risk estimation (low, medium, or high) outcome aligns with possible risk management 
strategies.   
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Table 8.  Examples of risk management actions based on the outcome of the 
risk estimation (low, medium, high).  
Category 3  Category 2  Category 1 
  (Risk estimation:  (Risk estimation:  (Risk estimation: 
 Low)  Medium)  High) 
 
Marketing 
OTC/VFD/Rx  VFD/Rx  Rx 
Status 1 
 
 
Extralabel Use 
Unlikely  In some cases  In some cases 
Prohibition 
 
 
Extent of Use 
High, Medium  Medium, Low  Low 
Limitations 2 
 
Post-approval   
Monitoring   In certain cases  Yes  Yes 
(e.g., NARMS)   
1 Over-the-counter (OTC), Veterinary Feed Directive (VFD), Prescription (Rx)  
2 See Table 7  
 
The conditions listed for a given drug category in Table 8 are intended to provide an example of 
the conditions of use or limitations that FDA might expect to be associated with a drug product 
based on its risk estimation outcome.  However, FDAs final determination of the approvability of 
antimicrobial new animal drug applications will depend on a consideration of all information 
available for the drug application in question, including, as needed, consultation with additional 
experts.   
 
FDA may determine that a proposed drug product can be approved under alternative use 
conditions/limitations if the sponsor provides adequate information to support the safety of the 
drug under those conditions. 
 
VIII. Summary of Microbial Food Safety Assessment Process 
FDA recommends that sponsors choosing to use this process prepare a hazard characterization 
(see section IV. Hazard Characterization) for FDA review.  After review of the hazard 
characterization, FDA and the sponsor may discuss whether a risk assessment needs to be 
completed and, if so, what information is recommended for completion of the risk assessment.  
Sponsor should then prepare the risk assessment and submit it to FDA for review. 
 
Following review, FDA will determine the risk estimation and associated risk management steps 
applicable to the proposed conditions of use for the antimicrobial new animal drug.  However, 
before preparing any microbial food safety package, FDA recommends that the sponsor contact 
the Division of Human Food Safety to determine the sequence of steps appropriate for their 
particular application. 
 
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IX.  Glossary 
Antimicrobial resistance:  The ability of a bacterium (either due to intrinsic or acquired, 
chromosomal or plasmid mediated, genetic resistance determinants) to multiply or persist in the 
presence of an increased level of an antimicrobial agent relative to the susceptible counterpart of 
the same species. 
 
Consequence assessment:  The consequence assessment describes the relationship between 
specified exposures to a 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 hazardous agent through foodborne exposure pathways.  The exposure assessment should 
estimate qualitatively the probability of this exposure to bacteria of human health concern through 
food-related pathways. 
 
Food-producing Animals:  See section XI.C.4. Food-Producing Animals in Guidance for 
Industry #61, Special Considerations, Incentives, and Programs to Support the Approval of New 
Animal Drugs for Minor Uses and for Minor Species, for examples of food-producing animals. 
 
Hazard:  A bacterial foodborne illness, attributable to an animal-derived food commodity, for 
which clinical treatment has been adversely impacted by antimicrobial resistance development 
due to the proposed use of the antimicrobial drug/class of interest in that food animal.  
 
Hazardous Agent:  Antimicrobial resistant foodborne bacteria that are in or on a food-producing 
animal as a consequence of the proposed use of the antimicrobial drug in animals, thereby 
constituting the hazard. 
 
Hazard characterization:  The process by which one may identify the hazardous agent and the 
conditions that influence the occurrence of the hazard.  This is based upon use in food animals, 
drug-specific information, bacteria and/or resistant determinant information, and the methodology 
for the determination of resistant or susceptible bacteria. 
 
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 and their acquisition of 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 the animal-
derived food is collected. 
 
Risk:  The probability that treatment of human illness caused by the hazardous agent is 
compromised through decreased or loss of effectiveness of the human antimicrobial drug/class of 
interest.  
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Risk estimation:  The overall estimate of the risk associated with the proposed use of the drug in 
the target food-producing animals following the integration of the release assessment, exposure 
assessment and consequence assessment.  The risk rankings represent the relative potential for 
human health to be adversely impacted by the emergence of the hazardous agent associated with 
the use of the drug in food-producing animals. 
 
 
 
 
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Appendix A 
Criteria for Ranking of Antimicrobial Drugs According to their Importance in Human 
Medicine 
 
Ranking process:  
Using the criteria listed below, antimicrobial drugs would be ranked as critically important, 
highly important, or important according to their therapeutic importance in human medicine.  
These ranking criteria focus on the utility of the drugs to treat human bacterial infections, 
including consideration of the seriousness of those infections, and the availability of alternative 
treatment options.  Assessment of availability of alternative treatment options includes the 
spectrum of activity of the drug, approved indications and its use clinically, toxicity of the 
drug/drug class, prevalence and type of resistance, and ability to dose in certain patient 
populations.  The assignment of a ranking to a given antimicrobial drug or antimicrobial drug 
class would depend upon the degree to which one of the factors described below is applicable to 
the drug in question.  Note that certain antimicrobial drugs might not meet any of the criteria and 
would not be considered medically important at this time.   
 
Criteria considered in ranking process:  
In developing the criteria for ranking antimicrobial drugs with regard to their importance in 
human medicine, FDA considered broad issues associated with the effectiveness of antimicrobial 
drugs in human medicine, and factors influencing the development of antimicrobial resistance, 
including the availability of therapies, from different classes of antimicrobial drugs to treat 
serious and non-serious human infections,14 and the uniqueness of the mechanisms of action, 
including, for example, the ease with which resistance develops and is transferred among 
organisms.  The criteria described in this document are not limited to foodborne risks, and more 
broadly consider issues impacting the importance of various antimicrobials for human therapy.  It 
is important that any criteria for medical importance also consider other, non-foodborne exposure 
pathways that may impact the potential of the antimicrobial drug to select for antimicrobial 
resistance and adversely affect human health.    
 
Human Medical Importance Ranking Criteria: 
The following criteria for ranking antimicrobial drugs according to relative human medical 
importance are listed from most to least important, i.e., criterion 1 is the most important. 
 
1.  Drugs from an antimicrobial class that are the sole or one of limited available therapies 
used to treat serious bacterial infections in humans.  
2.  Drugs from an antimicrobial class that are NOT the sole or one of limited available 
therapies to treat serious bacterial infections in humans; that is, drugs from more than a few 
antimicrobial classes are available. 
 
14 Please see GFI, Industry Expedited Programs for Serious ConditionsDrugs and Biologics (May 2014), 
https://www.fda.gov/media/119293/download; 21 CFR 312.300(b).  
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OR  
Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans 
and are the sole or one of limited available therapies.  
 
3.  Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans 
and are NOT the sole or one of limited available therapies; that is, drugs from more than a 
few antimicrobial classes are available.  
 
Importance rankings would be defined as follows: 
Critically important:   
Antimicrobial drugs that meet criterion 1. 
 
Highly important:     
Antimicrobial drugs that meet criterion 2. 
 
Important:   
Antimicrobial drugs that do not meet EITHER criteria 1 or 2 but meet criterion 3.  
 
 Ranking of Antimicrobial Drugs According to Their Utility in Human Medicine: 
Table A1 provides a revised ranking of antimicrobial drugs according to their utility for 
therapeutic use in human medicine.  This table reflects the medical importance rankings that 
would result from the application of the ranking criteria described in this draft guidance if they 
were later to be adopted and finalized.  Applying these same criteria, Table A2 provides examples 
of medically important antimicrobial drugs approved for use in human and/or veterinary 
medicine, and Table A3 provides examples of not medically important antimicrobial drugs. 
 
Periodic Assessment of Rankings: 
As stated above, development of new antimicrobial drugs for human therapy, the emergence or 
re-emergence of diseases in humans, and changes in prescribing practices, are among the many 
factors that may cause antimicrobial importance rankings to change over time; thus, it is 
appropriate to periodically reassess the list of medical importance rankings to align with 
contemporary science and current human clinical practices.  
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Table A1:  Ranking of Antimicrobial Drugs According to their Therapeutic Use in Human Medicine 
Ranking Criterion 2 
Drug/Drug Class  Ranking 1  Comments 3 
1  2  3 
Penicillins 
H  X  Preferred therapy for syphilis. 
Natural Penicillins 
Penicillins  One of available therapies for serious infections due to methicillin-
H  X 
Penicillinase-stable Penicillins  susceptible Staphylococcus aureus. 
Penicillins  One of available therapies for serious infections due to gram-
H  X 
Carboxypenicillins  negative bacteria including Pseudomonas aeruginosa. 
Penicillins  One of available therapies for serious infections due to gram-
H  X 
Ureidopenicillins  negative bacteria including P. aeruginosa.
One of limited available therapies for serious infections due to 
Penicillins 
C  X  Listeria monocytogenes in adults and children, and Group B 
Aminopenicillins 
Streptococcus in neonates.
-lactam/-lactamase  One of limited available therapies for serious infections due to beta 
C  X 
Inhibitor Combinations  lactamase producing gram-negative bacteria.
1 Ranking: 
CRITICALLY IMPORTANT (C): Antimicrobial drugs that meet CRITERION 1; 
HIGHLY IMPORTANT (H): Antimicrobial drugs that meet CRITERION 2;  
IMPORTANT (I): Antimicrobial drugs that meet CRITERION 3  
2 Ranking Criteria: 
1. Drugs from an antimicrobial class that are the sole or one of limited available therapies used to treat serious bacterial infections in humans.
2. Drugs from an antimicrobial class that are NOT the sole or one of limited available therapies to treat serious bacterial infections in humans; that is, drugs
from more than a few antimicrobial classes are available.
OR 
Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans and are the sole or one of limited available therapies.
3. Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans and are NOT the sole or one of limited available therapies; that
is, drugs from more than few antimicrobial classes are available.
3 Comments: This column explains the rationale for the ranking as it pertains to the clinical use of the drug/drug class in the treatment of bacterial infections 
and is not intended to describe all clinical uses of the drug/drug class. 
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Ranking Criterion 2 
Drug/Drug Class  Ranking 1  Comments 3 
1  2  3 
Used to treat non-serious infections for which drugs from more 
H  X  than a few antimicrobial classes are available. One exception is 
Cephalosporins 
cefazolin which is considered highly important and is the only 
1st Generation 
parenterally administered option used to treat serious infections 
I  X 
due to methicillin-susceptible S. aureus.
Cephalosporins  One of available therapies for serious infections due to 
H  X 
2nd Generation  S.aureus, Haemophilus influenzae, Escherichia coli.
One of limited available therapies for serious infections due to 
Cephalosporins 
gram-negative and gram-positive bacteria (certain drugs), 
All other cephalosporins not  C  X 
including Neisseria spp., P. aeruginosa, S. aureus, Streptococcus 
considered 1st or 2nd generations 
pneumoniae. 
One of limited available therapies for serious infections caused by 
gram-negative bacteria, including those due to multidrug resistant 
Aminoglycosides  C  X 
isolates, Yersinia pestis and Francisella tularensis; one of limited 
available inhaled therapies for cystic fibrosis. 
Antimycobacterials  
(drugs solely used to treat  One of limited available therapies for treatment of tuberculosis or 
C  X 
tuberculosis or other  other mycobacterial diseases. 
mycobacterial diseases) 
1 Ranking: 
CRITICALLY IMPORTANT (C): Antimicrobial drugs that meet CRITERION 1; 
HIGHLY IMPORTANT (H): Antimicrobial drugs that meet CRITERION 2;  
IMPORTANT (I): Antimicrobial drugs that meet CRITERION 3  
2 Ranking Criteria: 
1. Drugs from an antimicrobial class that are the sole or one of limited available therapies used to treat serious bacterial infections in humans.
2. Drugs from an antimicrobial class that are NOT the sole or one of limited available therapies to treat serious bacterial infections in humans; that is, drugs
from more than a few antimicrobial classes are available.
OR 
Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans and are the sole or one of limited available therapies.
3. Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans and are NOT the sole or one of limited available therapies; that
is, drugs from more than few antimicrobial classes are available.
3 Comments: This column explains the rationale for the ranking as it pertains to the clinical use of the drug/drug class in the treatment of bacterial infections 
and is not intended to describe all clinical uses of the drug/drug class. 
28  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
 
Ranking Criterion 2 
Drug/Drug Class  Ranking 1  Comments 3 
1  2  3 
One of limited available therapies for serious infections due to 
Carbapenems  C  X      gram-negative bacteria, including those due to extended spectrum 
beta lactamase producing organisms.  
One of available therapies for pelvic inflammatory disease in the 
Cephamycins  H    X   
inpatient setting. 
One of limited available therapies for serious infections due to 
Quinolones   C  X      gram-negative bacteria including diarrheal pathogens, Y. pestis 
and prophylaxis against inhalational anthrax. 
One of limited available therapies for some serious infections due 
Fosfomycin  C  X     
to resistant gram-negative bacteria.  
One of limited available therapies for serious infections due to 
methicillin-resistant S. aureus (MRSA); oral vancomycin is one of 
Glycopeptides  C  X     
the few available therapies for infections due to Clostridioides 
difficile. 
One of available therapies for of serious infections due to Group A 
Lincosamides  H    X   
streptococci and S. aureus.  
Lipoglycopeptides  H    X    One of available therapies for serious infections due to MRSA. 
One of limited available therapies for serious infections due to 
Lipopeptides  C  X     
MRSA and some vancomycin-resistant enterococci (VRE). 
1 Ranking: 
CRITICALLY IMPORTANT (C): Antimicrobial drugs that meet CRITERION 1;  
HIGHLY IMPORTANT (H): Antimicrobial drugs that meet CRITERION 2;  
IMPORTANT (I): Antimicrobial drugs that meet CRITERION 3  
2 Ranking Criteria:  
1. Drugs from an antimicrobial class that are the sole or one of limited available therapies used to treat serious bacterial infections in humans.  
2. Drugs from an antimicrobial class that are NOT the sole or one of limited available therapies to treat serious bacterial infections in humans; that is, drugs 
from more than a few antimicrobial classes are available. 
OR  
Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans and are the sole or one of limited available therapies.  
3. Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans and are NOT the sole or one of limited available therapies; that 
is, drugs from more than few antimicrobial classes are available. 
3 Comments: This column explains the rationale for the ranking as it pertains to the clinical use of the drug/drug class in the treatment of bacterial infections 
and is not intended to describe all clinical uses of the drug/drug class. 
29 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
 
Ranking Criterion 2 
Drug/Drug Class  Ranking 1  Comments 3 
1  2  3 
One of limited available therapies for serious infections due to C. 
difficile (fidaxomicin), Campylobacter jejuni. One of limited 
Macrolides  
C  X      available therapies as part of a combination regimen for 
 
nontuberculous mycobacteria, and infections due to Helicobacter 
pylori. 
Methenamine  I      X  Drugs from more than a few antimicrobial classes are available. 
One of limited available therapies for serious infections due to 
gram-negative bacteria including those due to metallo-beta 
Monobactams  C  X     
lactamase producing isolates; one of limited available inhaled 
therapies for cystic fibrosis. 
One of limited available therapies for uncomplicated urinary tract 
Nitrofurans  H    X   
infections. 
One of available therapies for serious infections due to C. difficile 
Nitroimidazoles  H    X   
and other anaerobic infections. 
One of limited available therapies for serious infections due to 
Oxazolidinones  C  X     
MRSA and VRE. 
One of available therapies for serious infections due to Rickettsiae, 
Phenicols  H    X    Salmonella spp. when other agents are contraindicated or 
ineffective. 
One of available therapies for of infections due to S. pneumoniae, 
Pleuromutilins  H    X    H. influenzae, M. pneumoniae (including macrolide-resistant 
strains). 
1 Ranking: 
CRITICALLY IMPORTANT (C): Antimicrobial drugs that meet CRITERION 1;  
HIGHLY IMPORTANT (H): Antimicrobial drugs that meet CRITERION 2;  
IMPORTANT (I): Antimicrobial drugs that meet CRITERION 3  
2 Ranking Criteria:  
1. Drugs from an antimicrobial class that are the sole or one of limited available therapies used to treat serious bacterial infections in humans.  
2. Drugs from an antimicrobial class that are NOT the sole or one of limited available therapies to treat serious bacterial infections in humans; that is, drugs 
from more than a few antimicrobial classes are available. 
OR  
Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans and are the sole or one of limited available therapies.  
3. Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans and are NOT the sole or one of limited available therapies; that 
is, drugs from more than few antimicrobial classes are available. 
3 Comments: This column explains the rationale for the ranking as it pertains to the clinical use of the drug/drug class in the treatment of bacterial infections 
and is not intended to describe all clinical uses of the drug/drug class. 
 
30 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
 
 
Ranking Criterion 2 
Drug/Drug Class  Ranking 1  Comments 3 
1  2  3 
One of limited available therapies for serious infections 
Polymyxins  C  X      due to gram negative bacteria, including P. aeruginosa 
and Acinetobacter baumannii. 
One of limited available therapies as part of combination 
therapy for infections due to M. tuberculosis, some 
Rifamycins  C  X     
serious MRSA infections and infections due to Brucella 
spp. 
One of the available therapies for treatment of serious 
Streptogramins  H    X   
infections due to S. aureus or Streptococcus pyogenes. 
Critically important tetracyclines include doxycycline 
(drug of choice for serious infections due to Rickettsiae 
C  X     
spp.) and omadacycline, eravacycline, and tigecycline 
(as they are less affected by some tetracycline 
Tetracyclines 
resistance mechanisms and may be one of the limited 
available therapies for some serious infections).  
H    X   
Highly important tetracyclines include tetracycline, 
minocycline, oxytetracycline, and chlortetracycline. 
Trimethoprim-Sulfamethoxazole is one of limited 
C  X      available therapies for serious infections due to Nocardia 
Sulfonamides, dihydrofolate 
species, L. monocytogenes. 
reductase inhibitors, and 
Sulfonamides are used to treat non-serious infections 
combinations 
I      X  for which drugs from more than a few antimicrobial 
classes are available. 
1 Ranking: 
CRITICALLY IMPORTANT (C): Antimicrobial drugs that meet CRITERION 1;  
HIGHLY IMPORTANT (H): Antimicrobial drugs that meet CRITERION 2;  
IMPORTANT (I): Antimicrobial drugs that meet CRITERION 3  
2 Ranking Criteria:  
1. Drugs from an antimicrobial class that are the sole or one of limited available therapies used to treat serious bacterial infections in humans.  
2. Drugs from an antimicrobial class that are NOT the sole or one of limited available therapies to treat serious bacterial infections in humans; that is, drugs 
from more than a few antimicrobial classes are available. 
OR  
Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans and are the sole or one of limited available therapies.  
3. Drugs from an antimicrobial class used to treat non-serious bacterial infections in humans and are NOT the sole or one of limited available therapies; that 
is, drugs from more than few antimicrobial classes are available. 
3 Comments: This column explains the rationale for the ranking as it pertains to the clinical use of the drug/drug class in the treatment of bacterial infections 
and is not intended to describe all clinical uses of the drug/drug class.
31 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
TABLE A2. Examples of Medically Important Antimicrobial Drugs Approved for Use 
in Human and/or Veterinary Medicine 1  
DRUG PRODUCT 
Veterinary 
DRUG/DRUG CLASS 
Human  Food-producing 
Companion Animals 3 
Animals 2 
Penicillins   Penicillin G 
Penicillin  Penicillin G 
Natural Penicillins  Penicillin V 
Penicillins  Dicloxacillin 
Naficillin 
Penicillinase-stable  Naficillin  Dicloxacillin 
Hetacillin 
Penicillins  Oxacillin 
Penicillins  Carbenicillin 4 
NONE APPROVED  Ticarcillin 
Carboxypenicillins  Ticarcillin 4 
Penicillins 
Piperacillin  NONE APPROVED  NONE APPROVED 
Ureidopenicillins 
Penicillins  Amoxicillin  Ampicillin 
Ampicillin 
Aminopenicillins  Ampicillin  Amoxicillin 
Amoxicillin-clavulanic 
acid 
Ampicillin-sulbactam 
Piperacillin-
tazobactam 
-lactam/- Ceftolozane-
Amoxicillin-clavulanic 
lactamase Inhibitor  tazobactam  NONE APPROVED 
acid 
Combinations  Ceftazidime-
avibactam 
Meropenem-
vaborbactam 
Imipenem-cilastatin-
relebactam 
Cephalosporins   Cefazolin  Cephalexin 
Cephapirin 
1st Generation  Cephalexin  Cefadroxil 
Cefamandole 
Cephalosporins  
Cefprozil  NONE APPROVED  NONE APPROVED 
2nd Generation 
Cefuroxime 
Cefixime 
Ceftibuten 
Cephalosporins  Cefpodoxime 
All other  Cefotaxime  Ceftiofur 
cephalosporins not  Ceftazidime  Ceftiofur  Cefovecin 
considered 1st or 2nd  Ceftriaxone  Cefpodoxime 
generations  Cefepime 
Ceftaroline 
Cefiderocol 
32 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
DRUG PRODUCT 
Veterinary 
DRUG/DRUG CLASS 
Human  Food-producing 
Companion Animals 3 
Animals 2 
Amikacin 
Gentamicin 
Neomycin  Amikacin 
Tobramycin 
Streptomycin  Gentamicin 
Aminoglycosides  Kanamycin 
Apramycin  Kanamycin 
Streptomycin 
Gentamicin  Neomycin 
Neomycin 
Plazomicin 
Isoniazid 
Pyrazinamide 
Antimycobacterials  Ethambutol  NONE APPROVED  NONE APPROVED 
Bedaquiline 
Pretomanid 
Imipenem 
Carbapenems  Meropenem  NONE APPROVED  NONE APPROVED 
Ertapenem 
Cefotetan 
Cephamycins  NONE APPROVED  NONE APPROVED 
Cefoxitin 
Ciprofloxacin  Difloxacin 
Ofloxacin  Enrofloxacin 
Enrofloxacin 
Quinolones  Levofloxacin  Marbofloxacin 
Danofloxacin 
Moxifloxacin  Orbifloxacin 
Delafloxacin  Pradofloxacin 
Fosfomycins  Fosfomycin  NONE APPROVED  NONE APPROVED 
Glycopeptides  Vancomycin  NONE APPROVED  NONE APPROVED 
Clindamycin  Lincomycin  Clindamycin 
Lincosamides 
Lincomycin  Pirlimycin  Lincomycin 
Telavancin 
Lipoglycopeptides  Dalbavancin  NONE APPROVED  NONE APPROVED 
Oritavancin 
Lipopeptides  Daptomycin  NONE APPROVED  NONE APPROVED 
Tilmicosin 
Erythromycin 
Tulathromycin 
Azithromycin 
Macrolides  Tylosin  Erythromycin 
Clarithromycin 
Tylvalosin 
Fidaxomycin 
Oleandomycin 
Methenamine  Methenamine  NONE APPROVED  Methenamine 
Monobactams  Aztreonam  NONE APPROVED  NONE APPROVED 
Nitrofurans  Nitrofurantoin  NONE APPROVED  Nitrofurazone 
Metronidazole 
Tinidazole 
Nitroimidazoles  NONE APPROVED  NONE APPROVED 
Secnidazole 
Benznidazole 
33 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
DRUG PRODUCT 
Veterinary 
DRUG/DRUG CLASS 
Human  Food-producing 
Companion Animals 3 
Animals 2 
Linezolid 
Oxazolidinones  NONE APPROVED  NONE APPROVED 
Tedizolid 
Chloramphenicol 
Phenicols  Chloramphenicol  Florfenicol 
Florfenicol 
Valnemulin 
Pleuromutilins  Lefamulin  NONE APPROVED 
Tiamulin 
Colistin 
Polymyxins  Colistin 5  Polymyxin B 
Polymyxin B 
Rifampin 
Rifamycins  Rifabutin  NONE APPROVED  NONE APPROVED 
Rifaximin 
Dalfopristin/ 
Streptogramins  Virginiamycin  NONE APPROVED 
quinupristin 
Tetracycline 
Minocycline 
Chlortetracycline  Oxytetracycline 
Doxycycline 
Tetracyclines  Oxytetracycline  Tetracycline 
Omadacycline 
Tetracycline  Doxycycline 
Eravacycline 
Tigecycline 
Sulfadimethoxine  Sulfamethazine 
Sulfonamides  Sulfadiazine 
Sulfamethazine  Sulfadimethoxine 
  Trimethoprim/ 
Trimethoprim/  Trimethoprim/  Sulfadimethoxine/  sulfadiazine 
sulfamethoxazole  sulfamethoxazole  ormetoprim  Sulfadimethoxine/ 
  ormetoprim 
1 These are examples of drug products approved for use in human and/or veterinary medicine at this time and does 
not include a listing of every approved product. For a comprehensive listing of approved drug products please refer 
to the following:  
For human drugs: https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm;  
For veterinary drugs: https://animaldrugsatfda.fda.gov/adafda/views/#/search  
2 Drugs listed are approved for use in certain food-producing animal species.  Examples of food-producing animals 
include cattle, swine, chickens, turkeys, sheep, goats, fish (excluding ornamental and aquarium fish) and other 
aquatic animal species, gamebirds and wildlife raised or harvested for food, and honeybees. 
3 Drugs listed are approved for use in certain companion animal species. Examples of companion animals include 
dogs, cats, and horses. 
4 Withdrawn 
5 Colistin (Colistimethate sodium) is approved but has never been marketed in the U.S. for use in food-producing 
animals.   
 
34 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
 
TABLE A3. Examples of Antimicrobial Drugs that are NOT MEDICALLY 
IMPORTANT 
DRUG PRODUCT 
DRUG CLASS  Veterinary 
Human 
(food-producing animals) 
Polypeptides  Bacitracin  Bacitracin 
Orthosomycins  NONE APPROVED  Avilamycin 
Aminocoumarins  NONE APPROVED  Novobiocin 
Ionophores  NONE APPROVED  Narasin 
Phosphoglycolipids  NONE APPROVED  Bambermycin 
Quinoxalines  NONE APPROVED  Carbadox 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
35