A 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
Food and Drug Administration Center for Veterinary Medicine
Table of Contents
I.
Statement of Purpose
II.
Introduction
III.
Current Regulatory Approach
IV.
A Framework for Evaluating and Assuring the Microbial
Safety of Proposed Uses of Antimicrobials in Food-Producing Animals
- Pathogen Load
- Resistance
- Importance of Antimicrobial Drugs for Human Medicine
- Category I Drugs
- Category II Drugs
- Category III Drugs
- Evaluating the Potential Exposure of Humans
- High Potential Human Exposure
- Medium Potential Human Exposure
- Low Potential Human Exposure
- Microbial Safety
- Category I Drugs (I/H, I/M, I/L)
- Category II Drugs (II/H, II/M, II/L)
- Category III Drugs (III/H, III/M, III/L)
V. References
Evidence of increasing resistance to antimicrobial drug treatment in
bacteria that infect humans has raised questions about the role that
antimicrobial drug use in food-producing animals plays in the emergence
of antimicrobial drug resistant bacteria. Scientists generally agree
that the development of resistant bacteria that cause human infections
that are not foodborne primarily results from the use of antimicrobial
drugs in humans. (7). FDA, along with other agencies and groups, is
actively working to find ways to encourage the prudent use of antimicrobials
in human medicine to help address the significant contribution of human
use to antimicrobial resistance. The framework set out in this document,
however, focuses only on the issue of use of antimicrobial drugs in
food-producing animals, which is of key importance in the development
of resistance in foodborne pathogens and may be important in some non-foodborne
infections.
FDA is charged with the regulatory responsibility of ensuring that the
use of antimicrobial drugs in food-producing animals does not result
in adverse health consequences to humans. FDA also recognizes that the
use of antimicrobial drugs in food-producing animals is important in
helping to promote animal health and helping to provide an abundant
and affordable supply of meat, milk, and eggs. However, FDA's primary
public health goal must be to protect the public health by preserving
the long-term effectiveness of antimicrobial drugs for treating diseases
of humans.
FDA is undertaking an extensive process to evaluate issues related to
the use of antimicrobial drugs in both humans and animals and develop
policies that protect the public health. With regard to antimicrobial
uses in animals, as a first step, on November 18, 1998, FDA made available
to the public a draft guidance document, "Evaluation of the Human
Health Impact of the Microbial Effects of Antimicrobial New Animal Drugs
Intended for Use in Food-Producing Animals." (3). That draft guidance
announced that FDA believes that evaluating the human health impact
of the microbial effects associated with all uses of all antimicrobial
new animal drugs in food-producing animals is necessary. The draft guidance
provides that in assessing the human health impact of such uses, two
separate but related factors should be evaluated: 1) the quantity of
antimicrobial drug resistant enteric bacteria formed in the animal's
intestinal tract following exposure to the antimicrobial new animal
drug (resistance); and 2) changes in the number of enteric bacteria
in the animal's intestinal tract that cause human illness (pathogen
load).1
This document is the second step in the agency's consideration of issues
related to use of antimicrobial drugs in food-producing animals. The
document sets out a conceptual risk-based framework for evaluating the
microbial safety of antimicrobials drugs intended for use in food-producing
animals. FDA is making this document available to the public as a vehicle
to initiate discussions with the scientific community and other interested
parties on the agency's thinking about appropriate underlying concepts
to be used to develop policies protective of the public health. Thus,
FDA is seeking comments on whether the concepts set out in this document,
if implemented, will accomplish the agency's goal of protecting the
public health by ensuring that significant human antimicrobial therapies
are not lost due to use of antimicrobials in food-producing animals,
while providing for the safe use of antimicrobials in food-producing
animals. The agency is also seeking input on important areas of scientific
complexity identified in this document.2
Antimicrobial drugs
are products that affect bacteria by inhibiting their growth or by killing
them outright. Antimicrobial drugs are used to treat bacterial diseases
in humans, and since their discovery have prevented countless deaths
worldwide. In animals, these drugs are used to control, prevent, and
treat infection, and to enhance animal growth and feed efficiency. Since
the 1950's, when use in animal production became widespread, the use
of antimicrobials has enhanced production efficiencies that have contributed
to the availability of a reasonably-priced and plentiful food supply.
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1 Enteric bacteria in animals represent a special risk for causing
human illness and for inducing resistance in bacteria in humans because
they are the bacteria most likely to contaminate a food product and
then be ingested.
2. After evaluating input on the framework, the agency will take appropriate
procedural steps to develop and implement any resulting policies.
That bacteria could select for and develop resistance to antimicrobial
drugs became apparent soon after the first antimicrobial drug, penicillin,
was widely used. Antimicrobial use promotes antimicrobial resistance
mainly by selecting for resistant bacteria(5). When an antimicrobial
drug is used to treat an infection, the bacteria most sensitive to the
drug die or are inhibited. Those bacteria that have, or acquire, the
ability to resist the antimicrobial persist and replace the sensitive
bacteria. If these bacteria are disease-causing (pathogenic) in humans,
they may directly cause disease resistant to treatment (2, 5, 8).
In addition, bacteria can become resistant indirectly when resistance
traits are passed on from other bacteria by mechanisms which allow the
exchange of their genetic material. In this way, resistance can be transferred
between nonpathogenic and pathogenic bacteria and from bacteria that
usually inhabit the gastrointestinal tract of animals to those that
infect humans (16).
When antimicrobial drugs are administered to food-producing animals,
they can thus promote the emergence of resistance in bacteria that may
not be pathogenic to the animal, but are pathogenic to humans (6, 7,
9, 20). For example, Salmonella, Campylobacter, and E. coli
O157 are common and can exist in the intestinal flora of various
food-producing animals without causing disease. However, all three bacteria
can cause severe foodborne illness in humans. If, when using an antimicrobial
in a food-producing animal, resistance occurs in such bacteria, and
the resistant bacteria are then ingested by and cause an illness in
a consumer who needs treatment, that treatment may be compromised if
the pathogenic bacteria are resistant to the drug used for treatment
(8). The link between antimicrobial resistance in such foodborne pathogenic
bacteria and use of antimicrobials in food-producing animals has been
demonstrated in a number of studies (10, 11, 12, 13). For foodborne
pathogens, especially for those such as Salmonella that are rarely
transferred from person to person in the United States and, therefore,
for which human use of antimicrobials is unlikely to be a significant
contributor to development of antimicrobial resistance, the most likely
source of most antimicrobial resistance is use of antimicrobials in
food-producing animals.
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3 Soon after the feeding of antimicrobials to animals became
popular, scientists expressed concern about the effect of this practice
on bacterial resistance (1, 18). In 1969, a report (1) that some bacteria
were capable of transferring their antimicrobial resistance to other
bacteria via the transfer of extra-chromosomal material called R-plasmids
increased the concern that the use of subtherapeutic levels of antimicrobials
in animal feed (e.g., for growth promotion) would promote the the spread
of drug resistance from bacteria in animals to bacteria in humans and
thereby compromise human drug therapy.
The use of antimicrobial drugs in food-producing animals can also promote antimicrobial resistance in bacteria that ordinarily are not human pathogens. In some circumstances (e.g., in hospitalized or immunocompromised individuals), some of these bacteria may directly cause infections in humans (4, 15). Alternatively, the bacterial resistancegene(s) can be transferred to pathogenic bacteria in the human gastrointestinal tract or in the environment and these newly-resistant bacteria may then cause human infections in the immunocompromised host. One example of resistance in ordinarily nonpathogenic bacteria is the case of vancomycin resistant enterococci (VRE). Patients with bloodstream infections due to VRE may have higher rates of persistent bloodstream infections resistant to treatment and a higher frequency of adverse outcomes, including death, when compared to patients whose enterococcal infections are sensitive to vancomycin (17).Epidemiological evidence has raised concern that the development of vancomycin resistant enterococci in humans in Europe may have been related in part to the induction of cross resistance to vancomycin due to food animal use of the related glycopeptide antibiotic, avoparcin (9, 14, 22, 25).
As stated in the November 18, 1998, draft guidance, in addition to the
issue of antimicrobial resistance, the agency believes that it needs
to evaluate the effect of the use of antimicrobials in food-producing
animals on pathogen load. Generally, antimicrobial drug therapy in animals
cures clinical infections by reducing the level of specific pathogens.
However, this therapy may also disturb the normal intestinal microbial
ecosystem in the animal, resulting in an increase in the bacteria that
can cause human infections or prolonging the duration of the carrier
state of such bacteria (pathogen load). Animals carrying increased amounts
of pathogens at the time of slaughter present an increased risk for
contamination of food and resulting human illness.
III.
Current Regulatory Approach
Currently, the agency
requires that applicants for over-the-counter uses of antimicrobials
intended to be administered to food-producing animals in feed for more
than 14 days (generally, for growth promotion rather than as therapies
to prevent or treat disease) submit, as part of their safety data, results
of preapproval studies intended to detect the development of antimicrobial
resistance in enteric bacteria from treated animals. This approach for
assuring the microbial safety for humans of food-producing animal uses
of antimicrobial drugs was closely scrutinized as recently as 1995,
when FDA approved two fluoroquinolone products for therapeutic use in
poultry in the United States. Significant attention was focused on FDA's
approval of these products (even though they were intended for therapeutic
use in animals), because fluoroquinolones, which have been used in human
medicine since 1980, are very important for human therapy.4 FDA
approved these products for poultry use after having taken the issue
of approvability of fluoroquinolones for use in food-producing animals
to a panel of experts comprising FDA's Center for Veterinary Medicine
Advisory Committee and the Center for Drug Evaluation and Research's
Anti-Infective Drugs Advisory Committee. The panel supported several
restrictions on the use of this class of drugs in food-producing animals
to minimize the risks related to the development of resistant bacteria
in animals. In accordance with the advisory committee recommendations,
two fluoroquinolone poultry products were approved in 1995 under prescription
status and for therapeutic purposes only. In addition, as a result of
the advisory committee recommendations, FDA established in 1996 the
National Antimicrobial Resistance Monitoring System (NARMS) to prospectively
monitor changes in antimicrobial susceptibilities of selected enteric
bacteria of animals that can cause disease in humans. Finally, FDA also
issued an order to prohibit all extra-label use of fluoroquinolones
in animals, which became effective in August 1997. These restrictions
and conditions were put in place to assure that resistance to fluoroquinolones
did not develop in bacteria that are transferred from poultry to humans,
and that if a trend towards resistance were to develop, the agency would
be able to detect such a trend at an early stage.
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4 Fluoroquinolones are considered to be one of the most valuable
antimicrobial drug classes available to treat human infections because
of their spectrum of activity, pharmacodynamics, safety and ease of
administration. This class of drugs is effective against a wide range
of human diseases and is used in both treatment and prophylaxis of bacterial
infections. Fluoroquinolones have been particularly important in the
treatment of foodborne infections often resistant to other antimicrobials.
Recent reports from the scientific and public health communities, however,
have rekindled concerns, both domestically and internationally, about
the relationship between the approval of fluoroquinolones for therapeutic
use in food-producing animals and the development of fluoroquinolone
resistance in Campylobacter, a food borne human pathogen, and
the increase in humans of fluoroquinolone resistant Campylobacter
infections. The approval of these drugs in food-producing animals in
the Netherlands (10), the United Kingdom (24) and Spain (19) temporally
preceded increases in resistance in Campylobacter or Salmonella
isolates. Moreover, despite the conditions and restrictions placed on
the use of the two approved poultry products in the United States, there
have been recent reports of an increase in fluoroquinolone resistance
in Campylobacter spp. in poultry in the United States (23). In
addition, an association has been noted between fluoroquinolone resistance
in Salmonella Typhimurium DT-104 and the approval and use of
a fluoroquinolone for veterinary therapeutic use in the U.K. (21, 20,
24). Because of such information concerning the development of resistant
bacteria following therapeutic use of drugs in food-producing animals,
the agency believes that it needs to better address the development
of bacterial resistance as part of the safety determination for antimicrobial
new animal drugs used for therapeutic purposes.
FDA believes that the recent data concerning the transfer of fluoroquinolone
resistant foodborne pathogens through the food supply and the in
vitro and epidemiologic data supporting the possibility of resistance
transfer in or mediated by other pathogens (e.g. vancomycin resistant
enterococci) establish that, in order to protect the public health,
previously accepted assumptions concerning the impact of therapeutic
animal uses of antimicrobial drugs on human health must be reexamined.
As previously stated, the agency took the first step by issuing the
November 18, 1998 draft guidance. If the draft guidance is implemented,
the agency recognizes that its current approach does not include all
the elements necessary for evaluation of such complex issues. The agency
has developed the concepts set out in the framework discussed below
as a possible approach for evaluation of the complex public health issues
related to the use of antimicrobial drugs in food-producing animals.
IV.
A Framework for Evaluating and Assuring the Microbial Safety of Proposed
Uses of Antimicrobials In Food-Producing Animals
This framework represents FDA's preliminary informed consideration of how to evaluate and minimize the potential human health effects of uses of antimicrobial drugs in food-producing animals. As set out in the November 18 draft guidance (Appendix A), FDA believes that microbial safety includes both pathogen load and resistance concerns. To address these concerns, this framework includes five components:
1) assessing the effect of proposed uses on human pathogen load;
2) assessing the safety of proposed animal uses of drugs according to
their (or related drugs) importance in human medicine and the potential
human exposure to resistant bacteria acquired from food-producing animals
that are human pathogens or that can transfer their resistance to human
pathogens;
3) assessing pre-approval data showing that the level of resistance
transfer from proposed uses of drugs, if any, will be safe;
4) establishing "resistance" and "monitoring" thresholds
to ensure that approved uses do not result in resistance development
in animals or transfer to humans above the established levels; and
5) establishing post-approval studies and monitoring.
FDA believes that a system with these five components would allow the
agency to best accomplish its goals of preserving antimicrobial drugs
for use in both humans and animals. 5
_________________________
5 FDA anticipates that the framework, if finalized and implemented,
will be part of the approval of new animal drug applications, and as
resources permit, will also be used for reviews of existing approved
uses of antimicrobials for
food-producing animals.
As discussed earlier in this document, the agency has explained the
importance of evaluating pathogen load at the time of slaughter in its
November 18, 1998 draft guidance. The manner in which the pathogen load
evaluation would relate to other parts of the framework is discussed
later in the document.
With respect to resistance, the agency believes that the evaluation of the human health impact of the development of resistant bacteria from antimicrobial drugs used in food-producing animals depends primarily on the following two factors:
1) The importance of the drug or drug class in human medicine; and
2) The potential human exposure to resistant bacteria acquired from
food-producing animals that are human pathogens or that can transfer
their resistance to human pathogens.
Based on an evaluation of these two factors, FDA believes that proposed
uses of antimicrobials in food-producing animals can be placed into
one of three main categories based on the importance of the drug or
drug class in human medicine and then into one of three sub-categories
determined by the potential human exposure, directly or indirectly,
to resistant human pathogenic bacteria. FDA believes that these categories
would aid the agency in evaluating the potential microbial human health
impact of the use of the antimicrobial drug in food-producing animals,
that is, the likely impact of the animal use of the antimicrobial drug
on the long term availability of safe and effective antimicrobial drugs
to treat human disease. 6
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6 The agency discusses below, under C. Microbial Safety, an approach
for dealing with antimicrobials whose categorization of importance in
human medicine is based upon treatment of human non-enteric pathogens
to which transfer of resistance from animal enteric bacteria would appear
not to be biologically plausible.
A. Importance of Antimicrobial Drugs for Human Medicine
While recognizing that the importance of antimicrobial drugs for human
medicine represents a continuum, in order to develop a rational and
workable regulatory scheme, the agency is considering dividing antimicrobial
drugs into three categories based on their unique or relative importance
to human medicine. The agency realizes that the categorization will
have to be flexible because new antimicrobials will be developed and
the importance of existing therapies may change over time due to new
medical needs and shifting patterns of antimicrobial resistance.7
Despite these issues, FDA believes that it is crucial to determine the
importance of an antimicrobial in human medicine before it can determine
what effect the development of resistance to that drug from food-producing
animal use will have on human health. The agency recognizes that obtaining
public input will be important in developing the criteria for categorizing
drugs as to their importance in human medicine.
_________________________
7 For example, if Campylobacter becomes increasingly resistant
to quinolones, and erythromycin becomes the only effective drug to treat
Campylobacter, the importance of erythromycin for human medicine
may increase such that it would move to a higher category. Similarly,
future development of human uses of an antimicrobial that currently
is used only in animals would result in a reevaluation of that durg's
importance in human medicine.
Antimicrobial drugs would be considered to be in Category I if they
or drugs in the same class meet any of the following criteria:
1) Essential for treatment of a serious or life threatening disease
in humans (conditions of high morbidity or mortality) for which there
is no satisfactory alternative therapy.
2) Important for the treatment of foodborne diseases in humans where
resistance to alternative antimicrobial drugs (e.g., Category II drugs)
may limit therapeutic options (recognizing the special risks of both
resistance development in, and transmission to, humans of foodborne
pathogens).
3) The drug is a member of a class of drugs for which the mechanism
of action and/or the nature of resistance-induction is unique, resistance
to the antimicrobial drug is rare among human pathogen(s), and the drug
holds potential for long term therapy in human medicine.
In addition, any antimicrobial that can induce or select for cross-resistance
to a Category I drug would be considered a Category I drug. Similarly,
if an antimicrobial is not used in human medicine, and if it could be
demonstrated to the agency's satisfaction that it does not induce cross-resistance
to any antimicrobials in the same class used in human medicine that
are Category I, then it would not be considered a Category I drug.
The following are examples of types of drugs that would be included
in Category I:
1) Quinolones for serious infections caused by multi-drug resistant
Salmonella spp. (resistant to Category II drugs). Quinolones
are often the primary treatment for salmonellosis, which in the U.S.
generally is food borne. Quinolones are also the drugs of choice and
alternative therapies for many life-threatening resistant gram negative
infections.
2) Vancomycin for serious infections (e.g., sepsis, pneumonia, endocarditis)
caused by methicillin resistant S. aureus, and ampicillin resistant
enterococci. Vancomycin is the only well proven treatment drug available
to treat serious infections with these organisms.
3) Dalfopristin/quinupristin (Synercid) for vancomycin-resistant enterococcal
infections. Additionally, Synercid has an unique mechanism of action.
It was presented to an FDA Advisory Committee in February 1988.
4) Third generation cephalosporins used to treat foodborne infections
(e.g., ceftriaxone for Salmonellosis in children).
Antimicrobial drugs would be considered to be in Category II if they
do not meet any of the criteria for Category I and they or drugs in
the same class meet the following criterion:
They are drugs of choice or important in the treatment of a potentially
serious disease, whether food borne or otherwise, but satisfactory alternative
therapy exists.
In addition, any antimicrobial that can induce or select for cross-resistance
to a Category II drug would be considered a Category II drug. Similarly,
if an antimicrobial is not used in human medicine, and if it could be
demonstrated to the agency's satisfaction that it does not induce cross-resistance
to any antimicrobials in the same class used in human medicine that
are Category II, then it would not be considered a Category II drug.
The following are examples of types of drugs that would be included
in Category II:
1) Ampicillin for treatment of infections due to Listeria monocytogenes.
The disease is life threatening; however, alternative therapies are
available (e.g., trimethoprim-sulfamethoxasole).
2) Cephalosporins not in Category I which do not induce cross resistance
to those in Category I; beta lactams and beta lactamase inhibitor combinations
because they represent both drugs of choice and alternative therapies
for many life threatening gram negative infections.
3) Erythromycin for treatment of Campylobacter infections.
4) Trimethoprim-sulfamethosaxole for treatment of a wide range of serious
enteric infections including susceptible Salmonella and Shigella
infections.
Antimicrobial drugs would be considered to be in Category III if they
do not meet the criteria for Category I or Category II and they or drugs
in the same class meet any of the following criteria:
1) They have little or no use in human medicine.
2) They are not the drug of first choice or a significant alternative
for treating human infections including food borne infections.
The following are examples of type of drugs that would be included in
Category III:
1) Ionophores (e.g., monensin) which currently have no usage in human
medicine
2) The polymixins (e.g., Polymixin B and colistin) since they have significant
toxicities and have been supplanted by other drugs for virtually all
human use.
B. Evaluating the Potential Exposure of
Humans
FDA believes that the effects of antimicrobial resistance transfer from
animals to humans are determined by a complex chain of events which
includes: the ability of the drug to induce resistance in bacteria;
the likelihood that use in food-producing animals will promote such
resistance; the likelihood that any resistant bacteria in or on the
animal will then be transferred to humans; and the likelihood that such
transfer will result in loss of availability of human antimicrobial
therapies.
FDA believes that information concerning these events can be used to
categorize the likelihood of human exposure to resistant human pathogens
from a proposed use of an antimicrobial in a food-producing animal into
High (H), Medium, (M) or Low (L) categories. FDA believes that the following
are the kinds of factors that should be considered when classifying
the potential exposure of humans to resistant human pathogens ultimately
resulting from use of an antimicrobial in food-producing animals:
Drug attributes(e.g., mechanism and rate of resistance induction, induction of cross-resistance to other related or unrelated drugs, activity spectrum);
Product use
(e.g., dose, duration and route of treatment, number of animals treated, duration of time between last treatment and potential human impact, animal species [including general patterns of human consumption]); and
Potential human contact
(e.g., microorganisms of concern, animal management practices, manure management practices, environmental contamination, food processing).
FDA anticipates that, with different uses, the relative contributions
of factors to the likelihood of human exposure may vary. For example,
under certain circumstances, treatment of only a low percentage of a
species population with an antimicrobial may result in exposure of large
numbers of humans to resistant human pathogens. Although treatment of
a low number of animals might seem, at first, to be a medium or even
a low potential human exposure, the proposed species to be treated,
the frequency and extent with which that species is colonized by human
pathogens, and the frequency of resistance induction associated with
the antimicrobial could actually result in the proposed use being considered
to pose a high human exposure. Thus, a low risk with respect to one
of the factors listed above or even a low incidence of resistance in
an animal population cannot, by itself, assure a low human exposure.
Similarly, circumstances could occur where an antimicrobial is used
widely in animals but the potential human exposure is low because the
antimicrobial cannot induce resistance transferable to potential human
pathogens treated by that antimicrobial. In short, if such a sub-categorization
system is implemented, FDA believes that it will be complex and that
the sub-categories will need to be determined on a product- use by product-
use basis.
The examples and discussion that follow illustrate how these factors
might be assessed to determine whether potential human exposure is High,
Medium, or Low. FDA requests comment on the factors that the agency
has set out with respect to evaluating potential human exposure.
1. High Potential Human Exposure
EXAMPLE: An antimicrobial drug which induces significant cross-resistance
to an antimicrobial used in human medicine is used for improved growth
or feed efficiency in cattle, swine, and poultry.
FDA believes that animal drug uses like this one are most likely to
result in high potential human exposure (H). Some antimicrobial drugs
used for improved growth and feed efficiency are administered in feed
throughout the life of the animal on a flock or herd wide basis. For
such drugs, a significant percent of the animal population could be
expected to be medicated since use of the drug would have a positive
effect on growth or feed efficiency in all animals as opposed to antimicrobials
intended for therapeutic purposes, when use of the drug would only have
a positive effect on exposed or infected animals. Moreover, some of
these species have significant baseline incidence of colonization with
human foodborne pathogens, making resistance induction likely. However,
FDA recognizes that it may be possible that antimicrobial drugs used
for improved growth and feed efficiency may not pose a high human exposure
risk, if the treated species has a low incidence of colonization with
human foodborne pathogens and routine processing conditions reduce this
incidence further.
2. Medium Potential Human Exposure
EXAMPLE: An antimicrobial drug administered in drinking water ad libitum is used for 7 days to treat E. coli infections in a herd of swine and the drug has been shown, in vitro, to induce resistance to an antimicrobial used in humans to treat foodborne pathogens such as Salmonella species. This drug is administered to all of the animals in the herd in the production class that is susceptible to the disease when a disease outbreak occurs. However, outbreaks occur in only a small fraction of the herds brought to market.
FDA believes that, typically, drugs intended for use for the control,
prevention, mitigation, or treatment of disease conditions where use
duration is between 6 and 21 days would tend to result in a medium potential
human (M) exposure. However, if the proposed species to be treated has
a significant baseline incidence of colonization with human foodborne
pathogens, making resistance induction in a human pathogen more likely,
the proposed use could be considered a high potential human (H) exposure.
3. Low Potential Human Exposure
EXAMPLE: An antimicrobial drug used for individual treatment of short
duration, where the disease requires treatment of only a small percentage
of the animals in a flock or herd.
FDA believes that treatments of individual animals for short duration
(e.g., less than 6 days) would tend to result in a low potential human
(L) exposure. While a given drug might have attributes leading to a
high potential to induce resistance, both the proposed short-term usage
and the limited potential for human contact generally
suggest a low potential human (L) exposure.
As described above, proposed antimicrobial drug usages in food-producing
animals would be placed into two categories according to two factors
(importance to human medicine and potential human exposure to resistant
bacteria acquired from food-producing animals that are human pathogens
or that can transfer their resistance to human pathogens). The two categorizations
would then be combined to determine what actions would be considered
necessary to assure the safe use of the drug.
The agency recognizes that there will be some antimicrobials whose categorization
of their importance in human medicine would be based upon treatment
of non-enteric pathogens. The agency recognizes that in this setting,
certain uses of antimicrobials in food-producing animals would not be
expected to lead to development of resistance that could be transferred
from the animal's intestinal bacteria to those human non-enteric pathogens.
For example, a drug's human importance category might be based primarily
upon its use to treat a respiratory pathogen of humans which is not
present in the gastrointestinal tract of animals. Given our current
understanding of mechanisms of resistance, FDA believes that, generally,
it would not appear biologically plausible for resistance to be transferred
from animal enteric pathogens to the human respiratory pathogen. The
agency believes that if the case can be made that such circumstances
exist for a particular animal use, it would be appropriate to handle
such a drug according to the criteria below for a Category III drug
for purposes of pre- and post- market requirements pertaining to antimicrobial
resistance. The agency seeks comment on this point, including input
on the information that would be needed to support such an action.
1. Category I Drugs: (I/H, I/M, I/L)
Resistance
Threshold: For Category I drugs, FDA believes that human exposure
to resistant bacteria from animals must be avoided or extensively minimized
to assure that these drugs remain effective for treating human disease.
The agency believes that it may be possible in certain cases to define
a level of resistant bacteria in animals that would result in no or
insignificant transfer of resistance to human pathogens. The agency
believes that this level of resistant bacteria in animals would need
to be determined for each antimicrobial prior to approval, and may vary
depending on the human or animal pathogen of concern. The agency welcomes
information and data that would support the establishment of safe resistance
thresholds in animals for Category I drugs. However, in the absence
of adequate data and other information to identify and support the safety
to humans of any level of resistance increase in animals, the agency
believes that any such increase would not be shown to be safe. The agency
recognizes that, as part of this process, sufficiently sensitive tests
would need to be available that have been shown to be able to detect
whether any such increase occurs.
The agency is considering whether, in certain cases, defining resistance
thresholds based on data from human isolates showing decreasing in
vitro susceptibility or increasing resistance may provide the most
sensitive methodology to detect an emerging resistance problem. The
agency requests comments on whether and when it would be appropriate
to set resistance thresholds on human data, animal data, or both.
Monitoring Threshold: For all Category I drugs, if
a resistance threshold can be established, the agency would establish
monitoring thresholds for resistance development in animals to guide
the post approval monitoring programs for these products. The monitoring
thresholds would be established so that they would serve as an early
warning system signaling when loss of susceptibility or resistance prevalence
is approaching a level of concern.
FDA believes that the monitoring threshold would serve to signal that
further epidemiological investigation by the drug sponsor would be warranted
to assess why a loss of susceptibility or an increase in resistance
was occurring at an unexpected rate and whether there were ways to mitigate
the loss of susceptibility or increasing resistance trend. If mitigation
was not successful, and resistance or loss of susceptibility continued
to increase such that it reached the resistance threshold, withdrawal
of the drug for the use(s) of concern from the marketplace would be
warranted.
The agency notes that the ability to set scientifically- based resistance
and monitoring thresholds depends on at least two factors: 1) the ability
to demonstrate that a particular resistance threshold is adequately
protective of the public health, and 2) the ability to detect when the
resistance and monitoring thresholds are reached. In the absence of
either factor, the agency presumably would not be able to approve new
uses of antimicrobials in food-producing animals when such approval
is dependent upon setting and monitoring such thresholds.
Pre-approval studies: For all Category I drugs,
pre-approval studies to address antimicrobial resistance would be necessary
to characterize the nature of resistance development. FDA believes that
studies in the target animal would need to assess the rate and extent
of resistance development in enteric bacteria of concern. FDA also believes
that it would be appropriate to evaluate mitigation measures, including
withdrawal periods, to determine their effect on decreasing the rate
and extent of resistance development. If a drug sponsor intends to market
a product for multiple indications and demonstrates that the highest
exposure scenario is safe, FDA may reconsider the need for additional
studies to demonstrate the safety of the lower exposure uses.
For all Category I/H and some Category I/M drugs, pre-approval studies
to address pathogen load would also be necessary. For other Category
I/M and all Category I/L drugs, pathogen load studies would not be necessary.
Changes in pathogen load are generally related to the pathogen, the
antimicrobial involved, the duration of antimicrobial therapy and the
time between cessation of therapy and slaughter of the animal. Antimicrobial
products used for a short duration generally do not disturb the normal
intestinal microflora and thus generally do not cause an overgrowth
of bacterial pathogens. Therefore, pathogen load studies for Category
I/L drugs would not be necessary.
Antimicrobial products in the medium exposure category, i.e., those
used for longer duration, may disturb the intestinal microflora and
cause an overgrowth of bacterial pathogens. If there is a long inherent
withdrawal time between treatment and slaughter of the animal, the normal
intestinal microflora generally recover, and pathogen load is reduced
prior to slaughter. Therefore, whether pathogen load studies would be
needed for a Category I/M drug would need to be determined on a case
by case basis.
Antimicrobial products in the high exposure group, i.e., long duration
of use, would probably disturb the intestinal microflora and favor the
increase in bacterial pathogens. Since products in this category generally
would be used in a large number of animals, the amount of time required
for the pathogen load to decrease would need to be determined in order
to ensure that human exposure to foodborne pathogens is minimized. Therefore,
for all Category I/H drugs, pathogen load studies would be necessary.
Post-approval Studies and Monitoring: FDA believes
that on-farm studies to monitor antimicrobial resistance prevalence
by the sponsor would be necessary to ensure that resistance thresholds
are not exceeded after approval. FDA believes that on-farm collection
of information on resistance prevalence and associated risk factors
would be necessary so that the agency and drug sponsor could monitor
for established monitoring and resistance thresholds, and so that intervention
and mitigation strategies could be investigated and initiated in a timely
fashion. Data generated through these studies, in addition to other
scientific data, would provide a critical early warning system for detecting
and evaluating the emergence of resistance to antimicrobials under field
conditions. FDA believes that the collection of this on-farm information
could be addressed from a drug-specific approach or from a broad national
on-farm program.
In addition, FDA would monitor resistance through the National Antimicrobial
Resistance Monitoring System (NARMS). As noted earlier, NARMS, established
in January 1996 and funded by the FDA, is a joint surveillance effort
by the CVM, the Centers for Disease Control and Prevention, and the
U.S. Department of Agriculture to prospectively monitor changes in antimicrobial
susceptibilities of zoonotic enteric pathogens from human and animal
clinical specimens from healthy farm animals, and from carcasses of
food-producing animals at slaughter.
Reporting: FDA believes that more detailed drug sales
information (e.g., submitted by state, species, dosage form, season
when applicable, calendar year, and containing an estimate of active
units sold) would be necessary to be submitted as part of the drug experience
report. This information would allow more direct correlation between
loss of susceptibility or increasing resistance trends observed in NARMS
or on-farm monitoring programs with the actual use of both individual
drugs and drug classes. FDA notes that this information would also allow
more effective implementation and assessment of any intervention or
mitigation strategies to be initiated in response to findings of decreased
susceptibility or increasing resistance trends over time.
FDA requests comment on whether these concepts are appropriate for assessing
and assuring the safety of the use of Category I drugs in food-producing
animals.
2. Category II Drugs (II/H, II/M, II/L)
Resistance Threshold: For Category II drugs, the agency believes that a defined level of increased resistance in humans due to use of the drug in food-producing animals could safely occur because there will be other safe and effective drugs available to treat human infections. However, FDA believes that the resistance thresholds would vary depending on many factors, including how many satisfactory alternatives to the drug exist, how much resistance exists to each alternative, and the human pathogen of concern. Moreover, due to the wide range of drugs that fall into Category II and due to the wide range of infections that these drugs treat, FDA notes that, for some Category II drugs (e.g., drugs of choice for life-threatening infections and drugs used for serious infections where pre-existing levels of resistance are low), the allowable increase of resistance in humans would likely be extremely low.
Resistance thresholds in animals would need to be determined for all
Category II drugs. While the agency believes that some level of resistance
transfer from animals to humans due to use of a Category II drug in
animals may be shown to be safe, it does not have data and information
currently that would enable it to establish such levels.
As stated under Category I above, the agency is considering whether,
in certain cases, defining resistance thresholds based on data from
human isolates showing decreasing in vitro susceptibility or increasing
resistance may provide the most sensitive methodology to detect an emerging
resistance problem. The agency request comments on whether and when
it would be appropriate for Category II drugs to set resistance thresholds
on human data, animal data, or both.
Monitoring Threshold: Monitoring thresholds
for resistance development in animals would need to be determined for
all Category II/H and some Category II/M drugs to guide the post approval
monitoring programs for these products. For other Category II/M and
all Category II/L drugs, the agency believes that monitoring thresholds
would not need to be determined because of lesser potential human exposure.
Monitoring thresholds would be established so that they would serve
as an early warning system for when loss of susceptibility or resistance
prevalence is approaching a level of concern. FDA also believes that
the monitoring threshold would serve to signal that further epidemiological
investigation by the drug sponsor would be warranted to assess why a
loss of susceptibility or an increase in resistance was occurring at
an unexpected rate and whether there were ways to mitigate the loss
of susceptibility or increasing resistance trend. If mitigation was
not successful, and resistance or loss of susceptibility continued to
increase such that it reached the resistance threshold, withdrawal of
the drug for the use(s) of concern from the marketplace would be warranted.
Preapproval Studies: For all Category II drugs,
the agency believes that pre-approval studies to address antimicrobial
resistance would be necessary. For all Category II/H and some Category
II/M drugs, pre-approval studies to address pathogen load would also
be necessary. For other Category II/M and all Category II/L drugs, pathogen
load studies would not be necessary, as explained for Category I drugs.
Post-approval Studies and Monitoring: FDA believes that,
for those Category II drugs with resistance and monitoring thresholds
(all Category II/H and some Category II/M drugs), on-farm studies to
monitor antimicrobial resistance prevalence by the sponsor would be
necessary to ensure that resistance thresholds were not exceeded after
approval. For all Category II drugs, including those that would not
require on-farm studies by sponsors, FDA would monitor resistance through
NARMS. If NARMS data indicated that unexpected or unacceptable resistance
was emerging, FDA could reevaluate on-going post approval studies, order
other studies to be conducted, or institute other appropriate actions.
Reporting: For Category II drugs, FDA believes
that more detailed drug sales information (e.g., submitted by state,
species, dosage form, season when applicable, calendar year, and containing
an estimate of active units sold) would be necessary to be submitted
as part of the drug experience report. This information would allow
more direct correlation between loss of susceptibility or increasing
resistance trends observed in NARMS or on-farm monitoring programs with
the actual use of both individual drugs and drug classes. FDA notes
that this information would allow more effective implementation and
assessment of any intervention or mitigation strategies to be initiated
in response to findings of decreased susceptibility or changes in increases
in resistance trends over time.
FDA requests comment on whether these concepts are appropriate for assessing
and assuring the safety of the use of Category II drugs in food-producing
animals.
3. Category III Drugs (III/H, III/M, III/L)
Resistance Threshold: For all antimicrobial drugs in Category III (III/H, III/M, III/L), the agency believes that resistance transfer from animals to humans would have no effect on the availability of effective antimicrobial drugs to treat human diseases. Thus, FDA believes that establishing resistance thresholds in animals would not be necessary to assure human safety.
Monitoring
Threshold: FDA believes that it would not be necessary
to establish monitoring thresholds for Category III drugs.
Pre-Approval Studies: FDA anticipates that pre-approval studies to address antimicrobial resistance would not be necessary to assess safety for humans other than those that could be needed to demonstrate that the drugs do not induce cross resistance to any Category I or Category II antimicrobial drugs. However, with respect to pathogen load, FDA believes that pre-approval studies would be necessary for Category III/H drugs and some Category III/M drugs. For other Category III/M and Category III/L drugs, pathogen load studies would not be needed, as explained for Category I drugs.
Post-Approval
Studies and Monitoring: FDA does not think that on-farm
studies of antimicrobial resistance by the sponsor would be necessary
for any Category III drugs. However, resistance would be monitored through
NARMS. Specific on-farm investigations could become necessary if data
from NARMS indicated an unexpected or unacceptable emerging trend of
increasing resistance.
Reporting:
As with the other classes of drugs, for Category III drugs, FDA believes that more detailed drug sales information (e.g., submitted by state, species, dosage form, season when applicable, calendar year, and containing an estimate of active units sold) would be necessary to be submitted as part of the drug experience report.
FDA requests comment on whether these concepts are appropriate for assessing
and assuring the safety of the use of Category III drugs in food-producing
animals.
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[Source: www.fda.gov/cvm/index/vmac/antimi18.html]