Antibiotic Use in Agriculture:
Background and Legislation
Geoffrey S. Becker
Specialist in Agricultural Policy
January 7, 2010
Congressional Research Service
7-5700
www.crs.gov
R40739
CRS Report for Congress
P
repared for Members and Committees of Congress
Antibiotic Use in Agriculture: Background and Legislation
Summary
Public health experts have expressed concern about an increase in antibiotic resistance among
sick patients. Such resistance has been linked to a number of causes, such as overuse of
antibiotics by medical professionals and their patients, and their wide use for nontherapeutic
(essentially nonmedical) purposes in food animals. Agricultural producers administer antibiotics
in feed for some types of food-producing animals not only to treat and prevent diseases, but also
to encourage growth and efficient use of feed rations. Some argue that nontherapeutic uses should
be severely constrained and/or limited to drugs not associated with human medical treatments.
Others oppose this approach, arguing that many animal production operations would not be
commercially viable (and that the animals’ health could be compromised) without the drugs’
routine use, and/or that the linkage between such use and antimicrobial resistance lacks a strong
scientific basis.
In the 111th Congress, companion bills (H.R. 1549, S. 619) have been introduced that would
phase out the nontherapeutic use in food animals of seven specific classes of antibiotic drugs that
can also be used to treat or prevent diseases and infections in humans. While not directly
endorsing the bills, a top official of the U.S. Food and Drug Administration (FDA), which
regulates animal drugs under the Federal Food, Drug, and Cosmetic Act, recommended in July
2009 that the phase-out of nontherapeutic uses of animal antibiotics be considered.
Some supporters of the bills have urged that they be incorporated into other pending legislation
(for example, H.R. 2749, a food safety bill approved in June 2009 by the House Energy and
Commerce Committee). Others, including some members of the House Agriculture Committee,
have expressed strong opposition to the antibiotics bills and their inclusion in any food safety
legislation.
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Antibiotic Use in Agriculture: Background and Legislation
Contents
At Issue....................................................................................................................................... 1
Current Legislative Proposals...................................................................................................... 1
Administration Views.................................................................................................................. 2
Use of Antibiotics in Agriculture ................................................................................................. 3
Types of Use ......................................................................................................................... 3
Amount of Use...................................................................................................................... 5
Public Health Concerns ............................................................................................................... 6
Regulatory Approach ................................................................................................................ 10
Tables
Table 1. Examples of Antibiotics Commonly Used in Animals .................................................... 4
Contacts
Author Contact Information ...................................................................................................... 12
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Antibiotic Use in Agriculture: Background and Legislation
At Issue
Increased resistance of microbial pathogens to the various antimicrobial drugs developed to treat
them is a widely recognized public health problem.1 Most scientific and public health experts
agree that the problem is linked to a number of causes, including over-prescription of
antimicrobial drugs by medical practitioners, their misuse by patients, releases into the
environment, and—at the root of all of these reasons—the ability of the pathogens themselves to
evolve and adapt rapidly.
Another reason for resistance can be the use of antimicrobials or, more specifically, antibiotics, in
food-producing animals. However, stakeholders disagree on the extent of agriculture’s
contribution to the problem and on the strength of scientific evidence of such a linkage.
A number of bills have been introduced in recent years aimed at curtailing agricultural uses of
medically significant antibiotics, but none have been enacted. The issue is again being debated in
the 111th Congress, where new bills (H.R. 1549, S. 619) are pending. Top officials of the U.S.
Food and Drug Administration (FDA) weighed in on the debate in July 2009 by expressing
support in concept for phasing out nontherapeutic (essentially, nonmedical) uses of antimicrobials
in food animal production. Whether a bill will advance beyond the hearing stages remains to be
seen, however; many, including those with large agricultural constituencies, oppose these bills.
Current Legislative Proposals
Companion bills to restrict the use of medically significant antibiotics in food animals were
introduced in the House and Senate on March 17, 2009, as H.R. 1549 by Representative
Slaughter and S. 619 by Senator Reid (for Senator Kennedy). These bills, the Preservation of
Antibiotics for Medical Treatment Act of 2009 (PAMTA), are similar in title and purpose to bills
introduced but not enacted in the 110th Congress (H.R. 962, S. 549), the 109th Congress (H.R.
2562, S. 742), the 108th Congress (H.R. 2932, S. 1460), and the 107th Congress (H.R. 3804, S.
2508).
The currently pending bills (H.R. 1549, S. 619) would amend the key FDA authorizing law—the
Federal Food, Drug, and Cosmetic Act (FFDCA, 21 U.S.C. 301 et seq.)—to require the Secretary
of Health and Human Services (HHS, under which FDA is located) to withdraw, within two
years, the approval of any “nontherapeutic use” in food-producing animals of a “critical
antimicrobial animal drug.” Such action would be required unless the Secretary determines, in
writing, that the holder of an approved application (i.e., the drug’s sponsor) has demonstrated, or
a risk analysis has found, “that there is a reasonable certainty of no harm to human health due to
the development of antimicrobial resistance that is attributable in whole or in part to the
nontherapeutic use of the drug.” The HHS Secretary also would be required to refuse a new
application for a critical antimicrobial animal drug if the sponsor failed to demonstrate the same
“reasonable certainty” standard.
1 The term “antimicrobial” refers broadly to drugs that act against a variety of microorganisms, including bacteria,
viruses, fungi, and parasites. The term “antibiotic,” or “antibacterial,” refers to a drug that is used to treat infections
caused by bacteria. Antibiotics are, therefore, types of antimicrobial drugs. The issues discussed in this report involve
principally, but not exclusively, antibiotic drugs. The terms “antibiotic” and “antimicrobial” are often used
interchangeably in policy discussions, and in this report.
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The bills would define a “critical antimicrobial animal drug” to be one that “is intended for use in
food-producing animals” and is composed wholly or partly of “any kind of penicillin,
tetracycline, macrolide, lincosamide, streptogramin, aminoglycoside, or sulfonamide,” or “any
other drug or derivative of a drug that is used in humans or intended for use in humans to treat or
prevent disease or infection caused by microorganisms.”
With respect to such drugs, the bills would define the term “nontherapeutic use” as “any use of
the drug as a feed or water additive for an animal in the absence of any clinical sign of disease in
the animal for growth promotion, feed efficiency, weight gain, routine disease prevention, or
other routine purpose.”
H.R. 1549 was the subject of a hearing in the House Rules Committee.2 Neither the House nor the
Senate version otherwise advanced during the first session of the 111th Congress. Supporters have
considered seeking to attach the bills to pending food safety or health reform legislation, but have
not done so at this time.3
Another antimicrobial resistance bill, the “Strategies to Address Antimicrobial Resistance Act”
(STAAR, H.R. 2400, introduced May 13, 2009, by Representative Matheson), takes a different
approach to the issue of antimicrobial resistance. H.R. 2400 would apply broadly to all
antimicrobials and to a variety of uses, including in human health care, not just to antimicrobials
used in food animals. The bill, which had been introduced in the 110th Congress as H.R. 3697,
would establish an Antimicrobial Resistance Office within the HHS Secretary’s office as well as a
public health advisory board to channel advice and expertise on the issue, and would reauthorize
a number of antimicrobial resistance programs authorized in a previous law that have since
expired, among other things.4 The bill has not advanced.
Administration Views
The Obama Administration has not taken a position on the PAMTA or STAAR bills, but HHS
officials have suggested that a phase-out of the use of antimicrobials for growth promotion and/or
feed efficiency may be considered. “Eliminating these uses will not compromise the safety of
food,” an FDA official told Congress in July 2009. Noting that the agency’s current statutory
authority for withdrawing a new animal drug approval “is very burdensome,” he stated that any
proposed legislation should “facilitate the timely removal of nonjudicious uses of antimicrobial
drugs in food-producing animals.”5
At the same time, he added, FDA believes that some antimicrobial uses for disease prevention
“are necessary and judicious to relieve or avoid animal suffering and death.” However, he noted a
2 U.S. Congress, House Committee on Rules,
H.R. 1549—Preservation of Antibiotics for Medical Treatment Act of
2009, 111th Cong., 1st sess., July 13, 2009.
3 See, for example, Ben Moscovitch, “Lawmaker, Stakeholders Try Rallying Support for Animal Antibiotic Ban,”
FDA
Week, December 4, 2009.
4 This paragraph is based in part on material in a CRS congressional distribution memo, “Comparison of Selected Bills
in the 110th Congress Regarding Animal Drug Use and Antimicrobial Resistance,” dated June 9, 2008, by Sarah A.
Lister, Specialist in Public Health and Epidemiology.
5 Joshua M. Sharfstein, FDA Principal Deputy Commissioner of Food and Drugs, July 13, 2009, testimony before the
House Committee on Rules; and Linda Tollefson, FDA Assistant Commissioner for Science, June 28, 2008, testimony
before the Senate Committee on Health, Education, Labor, and Pensions.
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number of factors that should be considered in weighing the need for such a use and stated that
“FDA also believes that the use of medications for prevention and control should be under the
supervision of a veterinarian.”6 In practical terms, this would mean that animal antimicrobials that
are currently available over the counter would no longer be, although whether a prescription
would be needed in all situations remains unclear.7
Use of Antibiotics in Agriculture8
Types of Use
Antibiotics are used in food-producing animals for three major reasons, according to HHS’s
Centers for Disease Control and Prevention (CDC).9 First, they are used in high doses for short
periods of time to treat sick animals. Second, they are used—also in high doses for short periods
of time—to prevent diseases during times when animals may be more susceptible to infections
(for example, after weaning, or during transport). This use “usually involves treating a whole herd
or flock, which increases the likelihood of selecting for organisms that are resistant to the
antibiotic.” Finally, “antibiotics are commonly given in the feed at low doses for long periods to
promote the growth of cattle, poultry, and swine. In the 1950s studies showed that animals given
low doses of antibiotics gained more weight for a given amount of feed than untreated animals.
Exactly how this occurs is still greatly unknown.”10
Animal drugs may be administered either by injecting them directly or by mixing them into feed
and water. The latter method may be viewed as more efficient when treating large groups of
animals, and it is the only feasible approach for some species such as poultry and fish.11
Citing USDA survey data from 1999, McEwen and Fedorka-Cray observed that approximately
83% of feedlots administered at least one antibiotic for disease prevention or growth promotion,
including control of liver abscesses, accelerated weight gain, and prevention of respiratory
disease outbreaks. Other feedlot uses were for a variety of individual animal or group treatments
such as for diarrhea and pneumonia. Cow-calf producers, however, used antimicrobials relatively
little. Milk replacers to feed veal calves could contain antimicrobials for disease prevention;
6 Sharfstein testimony.
7 See, for example, “New Administration First to Let FDA Take Strict Stance on Antibiotics,”
FDA Week, July 24,
2009. Some antimicrobials approved for use in food animals may be purchased over the counter by producers. Other
require greater oversight, including veterinary prescriptions with varying requirements, depending on the drug, its
intended use, and stipulations associated with its approval.
8 Portions of this report are adapted from out-of-print CRS Report RL30814,
Antibiotic Resistance: An Emerging
Public Health Issue, by Donna U. Vogt and Brian A. Jackson. Another source is Government Accountability Office
(GAO, then called the General Accounting Office),
Antibiotic Resistance: Federal Agencies Need to Better Focus
Efforts to Address Risk to Humans from Antibiotic Use in Animals (GAO-04-490), April 2004.
9 Antibiotics also are used in plant agriculture, primarily sprayed in orchards as a prophylactic treatment for diseases.
Although use data are somewhat limited, this use appears to be limited. Source: Anne K. Vidaver, “Uses of
Antimicrobials in Plant Agriculture,”
Clinical Infectious Diseases, 2002:34, Supplement 3, pp. S107-S110.
10 CDC, “Antibiotic Resistance 101,” posted on its web page, “Get Smart: Know When Antibiotics Work on the Farm,”
at http://www.cdc.gov/narms/get_smart.htm.
11 Scott A. McEwen and Paula J. Fedorka-Cray, “Antimicrobial Use and Resistance in Animals,”
Clinical Infectious
Diseases, 2002:34, Supplement 3, pp. S93-S106.
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lactating dairy cattle could receive antimicrobial injections to treat or prevent mastitis. Poultry
were administered antimicrobials to treat, control, or prevent a number of problematic diseases
such as necrotic enteritis (an intestinal infection) and
E. coli infections; several types were also
approved and widely used mainly for growth promotion and feed efficiency in broilers, egg
layers, and turkeys. For swine, antimicrobial use was mainly in feed at relatively low
concentrations for growth promotion or disease prevention, particularly after weaning. Swine
received antimicrobials either individually or in feed to treat or prevent pneumonia, bacterial
diarrhea caused by such organisms as
E. coli and
Clostridium perfringens, swine dysentery, and
ileitis.12
Table 1. Examples of Antibiotics Commonly Used in Animals
(feedlot cattle, swine, broiler chickens)
Antibiotic Class
Animal Use
Human Medicine Importance
Cephalosporin (3rd gen.)
disease treatment in cattle and swine
critical
Fluoroquinoline
disease treatment in cattle
critical
Penicillins
disease treatment in cattle; growth, disease
high
treatment in swine
Macrolide
disease treatment and prevention in cattle; growth,
critical
disease treatment and prevention in swine
Phenicol
disease treatment and prevention in cattle
not
Sulfonamide growth
in
swine
not
Tetracycline
disease treatment and prevention in cattle; growth,
high
disease treatment and prevention in swine
Lincosamide
disease treatment in swine
high
Pleuromutilin growth
in
swine
not
Polypeptide
growth in swine; growth promotion, disease
not
prevention in chickens
Streptogramin
growth, disease prevention in chickens
high
Carbadox growth
in
swine
not
Bambermycin
growth, disease prevention in chickens
not
Source: Adapted from GAO,
Antibiotic Resistance: Federal Agencies Need to Better Focus Efforts to Address Risk to
Humans from Antibiotic Use in Animals, Appendix V. Rankings of human medicine importance are GAO’s, based on
FDA determinations.
Notes: With regard to human medicine importance, FDA ranks antibiotics as “critical y important” (“critical” in
the above table), “highly important” (“high” in the table), or “important.” The ranking is based on five criteria
from the most important (it is used in treating pathogens that cause foodborne disease) to the least important
(there is difficulty in transmitting resistance across genera and species). See the discussion under “Regulatory
Approach” later in this report.
Long-term, low-dose treatments may serve as a prophylactic against diseases, particularly where
animals are housed in large groups in close confinement facilities. Such facilities are very widely
12 McEwen and Fedorka-Cray.
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used in commercial swine, poultry, and egg production and are increasingly being adopted in the
dairy and beef cattle industries. On the one hand, animal confinement facilities provide for closer
and more cost-effective management of animals, protection from the elements and predators, and
increased biosecurity (protection from outside pathogens, whether unintentionally or intentionally
introduced). On the other hand, the concentrated nature of such agricultural operations means that
a disease, if it occurs, can spread rapidly and become quickly devastating—increasing the need to
rely on antibiotics as a preventive measure.
Antibiotics work by interfering with some part of the necessary biological mechanisms of
bacteria to kill them directly or to halt their growth. They are broadly divided into classes based
on their chemical structures and modes of action. Classes include a “lead” antibiotic as initially
discovered, and modified versions of it, including improvements designed to overcome
developing resistance to it. (See
Table 1.) After penicillin was first clinically tried in the 1930s
(and mass-produced in the 1940s), antibiotic development and usage in both animal and human
populations, generally of the same types of drugs, grew steadily. By the 1950s antibiotics came
into even wider use as livestock growth promoters.13
Amount of Use
Reliable data on total U.S. antibiotic use do not appear to be publicly available. A 2001 report by
the Union of Concerned Scientists (UCS), a science-based advocacy organization, stated that 24.6
million pounds of antibiotics were used for nontherapeutic purposes in food animals annually.
The organization asserted that this represented 70% of all antibiotics produced in the United
States in one year.14 Others including the Animal Health Institute (AHI), which represents
companies that market animal drugs and other animal health products, counter that the UCS
figures are based on questionable assumptions and estimates (in part, because no publicly reliable
data appear to have been developed). Also, the UCS counts in the total such substances as
ionophores, which are used as growth promoters in animals but have never been used in human
medicine, AHI has noted.15
UCS includes disease prevention in its definition of nontherapeutic use along with growth
promotion. Others have taken issue with this definition. The American Veterinary Medical
Association (AVMA) has argued: “The term ‘non-therapeutic’ has no meaning in federal
regulation or common usage. The FDA approves antimicrobials for four purposes: disease
treatment, disease prevention, disease control, and growth promotion/feed efficiency. The FDA
does not approve antimicrobials for ‘non-therapeutic’ uses.”16 The last AHI survey of its members
reported that 87% of the antibiotics used in all animals (including nonfood animals such as pets)
were for disease treatment, control, and prevention.17 A policy statement on antibiotic usage by
the American Public Health Association (APHA) asserts that as much as 40% of all antibiotics
13 CDC, “Landmarks in Antibiotic Use,” posted on its web page, “Get Smart: Know When Antibiotics Work on the
Farm,” at http://www.cdc.gov/narms/get_smart.htm.
14 Union of Concerned Scientists,
Hogging It: Estimates of Antimicrobial Abuse in Livestock, January 2001.
15 AHI, e-mail communication, July 20, 2009.
16 Christine Hoang, DVM, MPH, AVMA, September 25, 2008, testimony before the House Agriculture Subcommittee
on Livestock, Dairy, and Poultry.
17 AHI, e-mail communication, July 20, 2009.
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used in the United States are added into feeds to promote efficient growth, but no source is
provided for this figure.18
Seeking more useful data, lawmakers included a provision in the Animal Drug User Fee
Amendments of 2008 that requires drug sponsors to submit an annual report to the HHS Secretary
for each approved antimicrobial drug that is sold or distributed for use in food-producing animals.
The annual report must contain such details as the amount of the active ingredient and the
quantities distributed domestically and exported. The Secretary is required to make summaries of
the information available to the public. The first annual report for currently approved antibiotics
must be submitted no later than March 31, 2010.19
Citing data inadequacies, Representative Slaughter on September 21, 2009, asked the
Government Accountability Office (GAO) to examine these questions:
• What data exist on the types and quantities of antibiotics used in food animals
and on the purposes for which they are used?
• What further data do USDA, FDA, and CDC believe are needed to assess and
mitigate the risks to humans from antibiotic use in animals and what efforts are
underway or are needed to collect these data?
• To what extent is USDA monitoring food animals and meat for the emergence of
antibiotic-resistant strains of pathogens, such as
E. coli,
Campylobacter,
Salmonella, and
Listeria?
• How effectively is FDA overseeing industry compliance with currently approved
animal antibiotics and uses for these antibiotics?
• What is FDA’s plan and time frame for reevaluating the antibiotics (and antibiotic
uses) that it has approved for animals?
• What efforts have USDA, FDA, and CDC taken to assess the human health risks
related to antibiotic use in animals, and what have the assessments shown?20
Public Health Concerns
Approximately 2 million people acquire bacterial infections each year in U.S. hospitals alone.
Approximately 90,000 die as a result, and 63,000, or 70%, of these deaths are from infections
resistant to one or more antimicrobial drugs.21 Antimicrobial resistance is a natural phenomenon
associated with use of antimicrobial drugs and began to be recognized soon after penicillin was
18 APHA, “Antibiotic Resistance Fact Sheet,” accessed July 21, 2009, at http://www.apha.org/advocacy/reports/facts/
advocacyfactantibiotic.htm.
19 Section 105 of P.L. 110-316, signed into law August 14, 2008. Other proposals in the 110th Congress would have
provided for more extensive data requirements. See CRS Report RL34459,
Animal Drug User Fee Programs, by Sarah
A. Lister.
20 The letter was posted on the Representative’s website and accessed September 30, 2009, at
http://www.louise.house.gov/index.php?option=com_content&view=article&id=1306:slaughter-asks-gao-for-
additional-data-on-antibiotic-use-in-animals&catid=41:press-releases&Itemid=109. See also the discussion in the next
section on the work of the existing National Antimicrobial Resistance Monitoring System for Enteric Bacteria.
21 Sharfstein testimony; Tollefson testimony.
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first used. However, strains that acquire an ability to survive a drug and to multiply have been
subject to wider scientific study.22 According to the CDC:
Bacteria become resistant to antibiotics through several mechanisms. Through their ability to
share genetic information, bacteria can transfer resistant genes to one another. Some bacteria
develop the ability to neutralize an antibiotic before it can do them harm, others can rapidly pump
the antibiotic out, and still others can change the antibiotic attack site so it cannot affect the
function of the bacteria. In addition, bacteria that were at one time susceptible to an antibiotic can
acquire resistance through mutation of their genetic material or by acquiring pieces of DNA that
code for the resistance properties from other bacteria. The DNA that codes for resistance can be
grouped in a single easily transferable package called a plasmid. Bacteria can become resistant to
many antimicrobial agents because they can acquire multiple antibiotic resistant plasmids.23
Antimicrobial use in animals has contributed to the emergence of antimicrobial-resistant
microorganisms but is by no means the only cause. Many scientists believe that the misuse and
overuse of antimicrobials in human medicine have greatly accelerated antimicrobial resistance.
Physicians may prescribe the drugs too frequently or for the wrong reasons (e.g., prescribing
antibiotics to treat viral infections, which do not respond to the drugs). Patients may not complete
their prescribed courses of an antimicrobial, making it more likely the surviving microbes will
develop resistance.24 Sometimes, antimicrobials are used as preventive measures, for example,
before surgeries to ward off infections or prior to travel to avert traveler’s diarrhea. Hospital
medical staff appear to contribute to resistance through improper sanitary practices like
inadequate hand washing or instrument cleaning.
Another route of resistance is the release of antibiotics into the environment (e.g., through runoff
from farm waste). Studies have found that some pharmaceuticals, including antibiotics, are not
completely used in human or other animal bodies and can be passed into the sewage system,
where treatment does not break them down completely. Significant concentrations of certain
drugs have been reported in drinking water, for example. Testimony presented in 2008 to a Senate
committee cited several studies that found antimicrobial-resistant bacteria in groundwater
sampled near hog farms.25
Many foodborne bacteria that can cause disease in humans, such as
Salmonella,
Campylobacter,
and strains of
E. coli including O157:H7, are found in the intestinal tracts of healthy food-
producing animals like swine, poultry, and cattle. According to FDA, “When an animal is treated
with an antimicrobial drug, a selective pressure is applied to all bacteria exposed to the drug.
Bacteria that are sensitive to the antimicrobial are killed or put at a competitive disadvantage,
while bacteria that have the ability to resist the antimicrobial have an advantage and are able to
grow more rapidly than the more susceptible bacteria.”26 Resistant bacteria can then be
transferred to the human population through either direct contact with the animals or through
22 See, for example, J. F. Acar and G. Moulin, “Antimicrobial resistance at farm level,”
Rev. sci. tech. Off. int. Epiz.,
2006, 25(2), 775-792.
23 CDC, “Antibiotic Resistance 101.”
24 Sharfstein testimony.
25 Jay P. Graham, Research Fellow at the Johns Hopkins Bloomberg School of Public Health, June 28, 2008 testimony
before the Senate Health, Education, Labor, and Pensions Committee.
26 FDA, Center for Veterinary Medicine (CVM),
Judicious Use of Antimicrobials for Swine Veterinarians, and
Judicious Use of Antimicrobials for Poultry Veterinarians, http://www.fda.gov/AnimalVeterinary/SafetyHealth/
AntimicrobialResistance/default.htm.
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consumption of improperly handled food from them. FDA “believes that human exposure through
the ingestion of antimicrobial resistant bacteria from animal-derived foods represents the most
significant pathway for human exposure to bacteria that have emerged or been selected as a
consequence of antimicrobial drug use in animals.”27
According to FDA, an estimated 80% of the estimated 2.5 million annual human cases of illness
from campylobacteriosis are foodborne, and 95% of the 1.4 million annual human cases from
non-typhoidal salmonellosis are foodborne. When the bacteria are also resistant to antimicrobial
drugs, public health can be compromised. For example, despite regulatory restrictions on the use
of two FDA-approved fluoroquinolone products, ciprofloxacin-resistant
Campylobacter were
found in 20% of retail chicken product samples. Further, molecular subtyping showed an
association between resistant strains of bacteria found in chicken products and in human cases of
campylobacteriosis.28
In 1996 the CDC began a new effort to collect antimicrobial resistance data in collaboration with
FDA and the U.S. Department of Agriculture (USDA). The effort, the National Antimicrobial
Resistance Monitoring System (NARMS) for Enteric Bacteria, is charged with monitoring
antimicrobial resistance among foodborne bacteria isolated from humans. The most recent
published report includes surveillance data for 2006 for clinical non-Typhi
Salmonella,
Salmonella ser. Typhi,
Shigella,
Campylobacter, and
E. coli O157 isolates.29 The NARMS
reported that:
• 19.6% (160 out of 816) of
Campylobacter isolates were resistant to the
fluoroquinolone ciprofloxacin, compared with 12.9% (28 out of 217) in 1997;
• 2.7% (60 out of 2,184) of non-Typhi
Salmonella isolates were resistant to the
quinolone nalidixic acid, compared with 0.4% (5 out of 1,324) in 1996;
• 3.6% (79 out of 2,184) of non-Typhi
Salmonella isolates were resistant to the
third-generation cephalosporin ceftiofur, compared with 0.2% (2 out of 1,324) in
1996;
• 54.0% (175 out of 324) of
Salmonella ser. Typhi isolates were resistant to the
quinolone nalidixic acid, compared with 19.2% (32 out of 167) in 1999.
FDA has observed that “[d]efinitive answers about the safety of antimicrobial use in animals
remain scientifically challenging, but more information is accumulating that raises concerns about
food safety.” The agency also cited earlier studies from the Netherlands, the United Kingdom, and
Spain indicating temporal relationships between ciprafloxin-resistant
Campylobacter and
approval of fluoroquinolones for food-producing animals, for example.30
27 FDA,
Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on
Bacteria of Human Health Concern, Guidance for Industry #152, October 23, 2003, p. 3.
28
Judicious Use of Antimicrobials for Swine Veterinarians, and
Judicious Use of Antimicrobials for Poultry
Veterinarians. In 2005, FDA withdrew its approval of Baytril, a fluoroquinolone related to the human drug Cipro, in
poultry (which it first proposed to do in 2000), after it concluded that the drug played a role in promoting antibiotic
resistance among
Campylobacter infections in humans. See http://www.fda.gov/AnimalVeterinary/SafetyHealth/
RecallsWithdrawals/ucm042004.htm.
29 Data can be accessed at http://www.cdc.gov/NARMS/.
30
Judicious Use of Antimicrobials for Swine Veterinarians, and
Judicious Use of Antimicrobials for Poultry
Veterinarians.
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Others believe that the scientific evidence regarding the relationship between animal antibiotics
use and human health risk is subject to differing interpretations. The AVMA, while
acknowledging the need for prudent use of such drugs, has called such evidence “limited and
conflicting.”31 The organization and others argue that leveling a ban on those now in use,
particularly before conducting additional studies and risk-based evaluations, would be detrimental
to both animal and human health.
The AVMA and others have pointed to the experience in Europe, where the European Union (EU)
phased out antimicrobials for animal growth promotion as of January 1, 2006.32 Among EU
members, Denmark implemented a voluntary ban on the use of antimicrobials for growth
promotion in 1998 and a mandatory ban in 2000. This ban, which was not extended to the use of
these drugs for control and treatment of disease, “has not resulted in significant reduction of
antibiotic resistance patterns in humans. It has, however, resulted in an increase in disease and
death in swine herds and an increase in the use of antimicrobials for therapeutic uses in swine
herds that discontinued the use of antibiotic growth promoters,” according to the AVMA.33
Such observations are based on data published in annual reports on the antimicrobial situation by
the Danish government.34 Others have offered differing interpretations of the data. The Pew
Environment Group reported that an updated assessment of the impacts of Denmark’s ban shows
that although therapeutic use of antibiotics increased slightly after the ban, it has leveled off since
2003, and total antibiotic consumption has decreased significantly. The assessment also shows
limited if any long-term effects on overall productivity in the swine herd, and a decrease in
antimicrobial resistance has followed reduced use.35
Meanwhile, the United States is participating with other member countries in a Codex
Alimentarius Commission Ad Hoc Intergovernmental Task Force on Antimicrobial Resistance
aimed at helping to develop guidelines to assess human health risks associated with the presence
of antimicrobial resistant agents transmitted through food and feed. Codex, which established the
task force in 2006, is the international standards body for food safety. The United States in
September 2009 submitted its comments on proposed draft guidelines to be discussed at an
October 2009 task force meeting in Korea.36
31 AVMA, “Judicious Therapeutic Use of Antimicrobials,” accessed July 21, 2009, at http://www.avma.org/issues/jtua/
default.asp.
32 This phase-out is delineated under Article 11 of European Parliament and Council Regulation No. 1831/2003, on
additives for use in animal nutrition, at http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=
OJ:L:2003:268:0029:0043:EN:PDF.
33 Lyle Vogel, DVM, MPH, DACVM, AVMA, June 24, 2008, testimony before the Senate Health, Education, Labor,
and Pensions Committee.
34 The most recent report is DANMAP 2007—Use of antimicrobial agents and occurrence of antimicrobial resistance in
bacteria from food animals, foods and humans in Denmark. DANMAP is the Danish acronym for the Danish Integrated
Antimicrobial Resistance Monitoring and Research Programme. The annual reports can be accessed at
http://www.danmap.org/.
35 Robert P. Martin, Senior Officer of the Pew Environment Group and former Executive Director of the Pew
Commission on Industrial Farm Animal Production, July 13, 2009 testimony before the House Rules Committee.
Martin’s testimony states that these new findings recently had been presented to a producers conference in Kansas by a
Danish health official and would be published later in 2009 in the Journal of the AVMA.
36 For information and links, see the FSIS September 9, 2009, news release “Public Meeting to Address Agenda Items
for the 3rd Session of the Codex Ad Hoc Intergovernmental Task Force on Antimicrobial Resistance,” at
http://www.fsis.usda.gov/News_&_Events/NR_090909_01/index.asp.
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Antibiotic Use in Agriculture: Background and Legislation
Regulatory Approach
The FDA’s Center for Veterinary Medicine (CVM) is responsible for regulating the manufacture
and distribution of drugs and food additives for all animals, including food animals, under
authority of the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended.37 CVM approves
new animal drugs, using criteria similar to those in the approval process for human medicines,
with the intent of ensuring their safety and effectiveness.
Generally, animal drug approval, including for antimicrobials, is conducted under two processes.
The first process involves the submission by the drug’s manufacturer or sponsor of an application
for an investigational new animal drug (INAD) exemption to conduct pre-approval clinical trials.
The second process is the new animal drug application (NADA) review. The review includes the
evaluation not only of its safety and effectiveness for the intended animal, but also, for a food
animal, its safety to humans who might consume food from the animal. Among the required tests
for an animal drug not required for a human one is how much time is necessary for drug residues
to leave the animal’s body (withdrawal time), to ensure that antibiotic residues are not in food
products made from it. A new animal drug product cannot be marketed without NADA
approval.38
The FDA issued in October 2003 a guidance document reflecting its “current thinking” regarding
its assessment of the safety to humans of antimicrobial animal drugs.39
Evaluating the Safety of
Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of
Human Health Concern (Guidance #152) focuses specifically on food safety, and in particular on
the risk that foodborne pathogens that contaminate these products will be resistant to
antimicrobial drugs that were used in the food-producing animal. The guidance does not address
other effects of antimicrobial animal drug use, such as from environmental runoff, or the question
of antimicrobial residues that may be present in the food products. The latter hazard is addressed
in several other FDA guidance documents.
An assessment of the potential public health effects of the use of antimicrobial animal drugs is
challenging in at least three ways. First, drug sponsors cannot readily explore potential public
health effects of animal drugs through premarket clinical trials, as the trials are not conducted on
humans. Second, antimicrobial resistance is a hazard that sometimes develops only after an
antimicrobial drug is approved and becomes widely used; it is not necessarily a hazard that exists
and can be studied during the approval process. Third, the causal pathways by which uses of an
antimicrobial animal drug may lead to antimicrobial resistance in microbial pathogens, and
thereby cause or worsen human illness, are often poorly understood, or may be difficult to
document because relevant data are not available. Guidance #152 is the agency’s effort to clarify,
for drug sponsors, its approach to these challenges, using qualitative risk assessment.
37 Primary authority is at FFDCA § 512 [21 U.S.C. 360(b)].
38 FFDCA § 512(d), regarding review of animal drug applications, provides grounds for denying approval, including
tests that show the drug is unsafe, or the determination that there is insufficient information as to whether the drug is
safe. Applicable regulations are at 21 CFR 514.1(b)(8). For a fuller explanation of the approval process, see Appendix
B of CRS Report RL34459,
Animal Drug User Fee Programs, by Sarah A. Lister.
39The following discussion of Guidance #152 is adapted from material prepared in 2008 by Sarah A. Lister, CRS
Specialist in Public Health and Epidemiology. The guidance document can be viewed at this FDA web page:
http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/
UCM052519.pdf.
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Antibiotic Use in Agriculture: Background and Legislation
Guidance #152 provides a step-wise approach that comports with international standards.40 First,
FDA recommends that drug sponsors submit a hazard characterization, providing basic
information about the drug, its uses and mechanisms of action, mechanisms for the emergence of
resistance in target and non-target microbes, the importance of the drug in human medicine, the
state of scientific information and knowledge gaps about the drug and antimicrobial resistance,
and related information. Based on the hazard characterization, FDA could potentially (1) provide
more specific guidance regarding the conduct of the subsequent risk assessment; (2) determine
that a risk assessment was not necessary to demonstrate the drug’s safety; or (3) determine that
such a demonstration was not likely to be made, and that the application was not likely to
succeed.
Next, the three steps in the qualitative risk assessment are (1) a
release assessment to estimate 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; (2) an
exposure
assessment of the likelihood of human exposure to foodborne bacteria of human health concern
through particular exposure pathways, in this case through foods of animal origin; and (3) a
consequence assessment regarding the importance of the antimicrobial animal drug or its analogs
in human medicine, though a sponsor may use alternate data if it believes it to be more current or
otherwise superior. This process yields an FDA ranking of each antimicrobial drug according to
its importance in human medicine, as “critically important,” “highly important,” or “important.”
Outputs are then to be integrated into an overall risk estimation, using a matrix provided in the
guidance. The risk estimation would yield an overall assessment of the public health risk
associated with the proposed conditions of use of the drug, ranked as high (Category I), medium
(Category II), or low (Category III).
Guidance #152 says that an advisory committee may be convened to evaluate the applications of
Category I and selected Category II antimicrobial animal drugs. The guidance then lays out a risk
management strategy for approved antimicrobial animal drugs, noting that even a Category I
classification would not necessarily result in the denial of approval, but would likely require
appropriate (and perhaps more stringent) risk management steps. These steps may include
limiting the conditions, including duration, of use; requiring veterinary supervision (versus, for
example, over-the-counter marketing); prohibiting extra-label uses;41 and postmarket monitoring
of microbial resistance to the drug, possibly through NARMS.
After Guidance #152 was published, FDA convened its Veterinary Medicine Advisory Committee
(VMAC) in September 2006 to consider an application for cefquinome, an antibiotic to be used in
beef cattle. The drug’s sponsor presented its risk assessment according to the guidance,
concluding that the proposed uses placed the drug in Category II (medium risk), and
recommending that the drug be approved, with certain postmarket risk management steps. The
40 FDA cites a 2001 method for antimicrobial risk analysis published by the Office of International Epizootics (OIE),
the international animal health standard-setting and harmonization organization, of which the United States is a
member.
41 “Extra-label use,” which is similar to “off-label use” of drugs in humans, is defined by FDA (at 21 C.F.R. 530) as
“[a]ctual use or intended use of a drug in an animal in a manner that is not in accordance with the approved labeling.
This includes, but is not limited to, use in species not listed in the labeling, use for indications (disease and other
conditions) not listed in the labeling, use at dosage levels, frequencies, or routes of administration other than those
stated in the labeling, and deviation from labeled withdrawal time based on these different uses.” Such use is by
definition a prescription drug use, and is only permitted within the scope of a valid veterinarian-client-patient
relationship. Extra-label use is limited to circumstances when the health of an animal is threatened by failure to treat;
therefore, extra-label use to enhance production is prohibited.
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Antibiotic Use in Agriculture: Background and Legislation
VMAC instead voted against approving the drug. FDA, which does not have to abide by the
committee’s recommendation, had not approved the drug as of December 2009.
The trajectory of the cefquinome application highlights the challenging and evolving regulatory
approach to the safety of antimicrobial animal drugs. The drug’s sponsor reached a conclusion of
medium risk using guidance that it called conservative, leaning toward greater safety when
evidence was insufficient. Consumer representatives asserted that the guidance should have given
the drug a higher consequence risk ranking, which would have yielded a higher overall risk
ranking.42 Industry representatives asserted that members of the committee strayed from the
methodical constraints of the guidance in reaching their individual conclusions.
The FDA also has developed a series of species-specific educational materials for veterinarians
based on 15 AVMA-developed “Guidelines for the Judicious Therapeutic Use of Antimicrobials.”
These guidelines range from employing where possible non-drug preventive strategies such as
appropriate husbandry and hygiene to using the narrowest-spectrum antimicrobials whenever
appropriate.43 At its annual meeting on July 10, 2009, the AVMA House of Delegates reportedly
voted to create a steering committee to reassess its policy regarding judicious use, a process that
could take a year to complete.44
Author Contact Information
Geoffrey S. Becker
Specialist in Agricultural Policy
gbecker@crs.loc.gov, 7-7287
42 Martin of the Pew Environment Group stated in his House testimony that most animal antibiotics in nontherapeutic
use were approved before the FDA began considering the resistance question, and that the agency has not established a
schedule for reviewing existing approvals, even though Guidance #152 notes the importance of doing so.
43 For details see http://www.fda.gov/AnimalVeterinary/SafetyHealth/AntimicrobialResistance/
JudiciousUseofAntimicrobials/default.htm.
44 “AVMA votes to reassess antimicrobial policy,”
Food Chemical News, July 27, 2009.
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