Natural Resources Defense Council, Inc. et al v. United States Food and Drug Administration et al

Filing 33

DECLARATION of Jennifer A. Sorenson in Support re: 19 MOTION for Summary Judgment.. Document filed by Center For Science In The Public Interest, Food Animal Concerns Trust, Natural Resources Defense Council, Inc., Public Citizen, Inc., Union Of Concerned Scientists, Inc.. (Attachments: # 1 Exhibit A, # 2 Exhibit B, # 3 Exhibit C, # 4 Exhibit D, # 5 Exhibit E, # 6 Exhibit F, # 7 Exhibit G, # 8 Exhibit H, # 9 Exhibit I, # 10 Exhibit J, # 11 Exhibit K, # 12 Exhibit L, # 13 Exhibit M, # 14 Exhibit N, # 15 Exhibit O, # 16 Exhibit P, # 17 Exhibit Q, # 18 Exhibit R, # 19 Exhibit S, # 20 Exhibit T, # 21 Exhibit U, # 22 Exhibit V, # 23 Exhibit W, # 24 Exhibit X, # 25 Exhibit Y, # 26 Exhibit Z, # 27 Exhibit AA, # 28 Exhibit BB, # 29 Exhibit CC, # 30 Exhibit DD)(Sorenson, Jennifer)

EXHIBIT I
TO DECLARATION OF
JENNIFER A. SORENSON
1999 Citizen Petition

THE U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION

Petition to Rescind Approvals of the
Subtherapeutic Uses in Livestock of
Antibiotics Used in (or Related to Those
Used in) Human Medicine

)
)
)
)
...)

Docket No.

Submitted by the

Center for Science in the Public Interest
Environmental Defense Fund
Food Animal Concerns Trust
Public Citizen’s Health Research Group
Union of Concerned Scientists
March 9, 1999

Table of Contents

I.

Action Requested.......... .......... ...................... ...................... ........... .......... ........... .........1

II.

Executive Summary ...... .......... ...................... ...................... ........... .......... ........... .........2

III. Introduction ................. .......... ...................... ...................... ........... .......... ........... .........4
IV. Statement of Factual Grounds.. ...................... ...................... ........... .......... ........... .........5
A. Policy Background.. .......... ...................... ...................... ........... .......... ........... .........5
B. Scientific Background ........ ...................... ...................... ........... .......... ........... .........9
1. Subtherapeutic antibiotics are used widely in livestock.... .......... ........... .......10
2. Subtherapeutic antibiotic use in livestock leads to the selection of
antibiotic resistance ... ...................... ...................... ........... .......... ........... .......11
................. .......... ......................
3. Antibiotic-resistant bacteria can be transferred between animals
and between animals and people ....... ...................... ........... .......... ........... .......13
4. Antibiotic-resistant bacteria may transfer resistance genes to other
bacteria .......... .......... ...................... ...................... ........... .......... ........... .......16
5. Subtherapeutic antibiotic use may select for multi-drug-resistant bacteria
that can cause infections that are difficult to treat..... ........... .......... ........... .......18
6. Subtherapeutic antibiotic use jeopardizes therapeutic options in
veterinary and human medicine ......... ...................... ........... .......... ........... .......20
7. Subtherapeutic use of antibiotics reduces the effectiveness of new
human-use antibiotics, jeopardizing human health .... ........... .......... ........... .......22
8. Decreasing subtherapeutic uses of antibiotics on farms can reduce
the prevalence of antibiotic-resistant bacteria and does not adversely
affect animal health.... ...................... ...................... ........... .......... ........... .......23
C. Expert committees and leading scientists support a phase out of
subtherapeutic antibiotic use in livestock ......... ...................... ........... .......... ........... .......25

ii

V. Statement of Legal Grounds ....... ...................... ...................... ........... .......... ........... .......27
A. The FDA has legal authority to withdraw the approval of new animal
drug applications that are unsafe ..................... ...................... ........... .......... ........... .......27
B. The FDA has asserted its authority to consider the public-health impact of antibiotic
resistance when regulating the use of antimicrobial drugs in livestock. .......... ....... 29
C. In light of recent evidence, Congress’ directive to the FDA to suspend
proceedings for the withdrawals of NADAs for penicillin and tetracyclines
in animal feed pending additional studies is moot.................... ........... .......... ........... .......32
D. The FDA should adopt policies consistent with the current international
trend of phasing out the subtherapeutic use of medically important antibiotics ....... 34
VI. Economic Impact.......... .......... ...................... ...................... ........... .......... ........... .......35
VII. Environmental Impact... .......... ...................... ...................... ........... .......... ........... .......38
.......... ...................... ...................... ...........
VIII. Conclusion.. ................. .......... ...................... ...................... ........... .......... ........... .......38
IX. Certification ................. .......... ...................... ...................... ........... .......... ....... 39

iii

March 3, 1999

Dockets Management Branch
Food and Drug Administration
5630 Fishers Lane
Room 10-61
Rockville, MD 20852

Citizen Petition
I. Action Requested
The Center for Science in the Public Interest (CSPI)1, Environmental Defense Fund (EDF)2,
Food Animal Concerns Trust (FACT)3, Public Citizen’s Health Research Group4and Union of
Concerned Scientists (UCS)5 submit this petition under § 512(e) of the Federal Food, Drug, and
Cosmetic Act (FDCA) to request the Commissioner to rescind approvals for subtherapeutic uses in

1

The Center for Science in the Public Interest is a nonprofit organization based in
Washington, D.C., that has been working to improve the public’s health since 1971. CSPI is
supported largely by its one million subscribers to Nutrition Action Healthletter.
2

The Environmental Defense Fund, a leading national, New York-based nonprofit
organization, represents 300,000 members. EDF links science, economics, and law to create
innovative, equitable, and economically viable solutions to today's environmental problems.
3

Food Animal Concerns Trust is a nonprofit organization that advocates for animal
husbandry methods that will improve the safety of meat, milk, and eggs.
4

Public Citizen’s Health Research Group is a research-based health-advocacy group that
devotes a majority of its time to examining the safety of drugs, medical devices, and health-care
practices.
5

The Union of Concerned Scientists, established in 1969, is an independent, nonprofit
organization dedicated to advancing responsible public policies in areas where technology plays a
critical role.
1

livestock of any antibiotic6 used in (or related to those used in) human medicine. The ban should
include subtherapeutic applications of such medically important antibiotics as penicillin, tetracyclines,
erythromycin, lincomycin, tylosin, and virginiamycin, as well as other antibiotics used in (or related
to those used in) human medicine for growth promotion, improved feed efficiency, and disease
prevention.

II. Executive Summary
Shortly after the discovery and widespread introduction of antibiotics into medical practice
50 years ago, scientists observed that bacteria could develop resistance to them. The more
antibiotics are used, the more rapidly resistance develops. When such resistance develops, bacterial
growth is no longer stopped by the antibiotic, and, thus, the antibiotic is no longer capable of treating
or curing the disease. Antibiotic resistance can transform infections from easy to treat to illnesses
that require prolonged treatments, necessitate lengthy hospitalizations, or cause death.
Since the 1950s, farmers have been using antibiotics as a production tool in raising livestock.
They add antibiotics to livestock feed to counteract the effects of crowded living conditions and
poor hygiene. In the U.S., as much as one third of all antibiotics produced are added to feed each
year. Such use causes the development of antibiotic resistance among foodborne pathogens that can
sicken people who consume tainted meat or touch infected animals. It also can result in antibiotic
resistance in nonpathogenic bacteria. Those bacteria may transfer their resistance genes to diseasecausing bacteria, resulting in antibiotic-resistant infections in people.

6

For the purpose of this petition, the term antibiotic is used interchangeably with
antimicrobial.
2

This petition summarizes the scientific evidence that agricultural uses of antibiotics cause the
development of antibiotic resistance in human pathogens. Recent data show that more bacteria are
becoming resistant to one, or sometimes several, antibiotics. For example, the prevalence of
resistance to five antibiotics among a particular strain of Salmonella has increased from 0.6 percent
in 1979 to 34 percent in 1996.
This petition calls upon the Food and Drug Administration (FDA) to rescind approvals of
certain agricultural uses of antibiotics when such uses endanger human health. Specifically, the FDA
should not allow an antibiotic to be used as a livestock feed additive if that antibiotic is used in (or
related to one used in) human medicine. That position is supported by the World Health
Organization, the Centers for Disease Control and Prevention, the American Public Health
Association, the Association of State and Territorial Health Officials, the Natural Resources Defense
Council, the American Medical Women’s Association, and other organizations.
The FDA has the legal authority and responsibility to ensure that the use of antibiotics in
livestock does not endanger human health. In the 1970s it proposed rescinding the approvals of
penicillin and tetracycline as feed additives because of the human-health risk associated with such
use, but that proposal was never finalized.
In 1998, the FDA proposed a new framework for approving antibiotics for livestock designed
to ensure that the agency consider whether such use would cause antibiotic resistance and, therefore,
pose a threat to public health. The FDA’s action on this issue reaffirms its statutory authority to
ensure that agricultural uses do not jeopardize human health by increasing antibiotic resistance.
However, the framework falls short by not adequately addressing existing uses of antibiotics. In

3

order to be truly protective, the FDA must rescind already-approved uses of medically important
antibiotics in livestock feed, in order to protect those invaluable drugs.

III. Introduction
Subtherapeutic levels of antibiotics are used by the cattle, swine, and poultry industries to
promote growth and reduce the costs of raising livestock. Unfortunately, that use fosters antibiotic
resistance in bacteria which can be transmitted to humans -- via the food supply or through direct
contact with livestock or manure.7 If a person is infected by pathogenic antibiotic-resistant bacteria,
antibiotic treatment could be ineffective, thereby jeopardizing human health.
The subtherapeutic use of antibiotics also leads to increased levels of antibiotic resistance in
animal pathogens on the farm. That resistance endangers livestock because it makes the antibiotics
less useful for treating common animal infections. Consequently, veterinarians and animal-drug
manufacturers are pushing for new approvals of antibiotics for use in animals that
are essential for treating human diseases. The use of those antibiotics on farms may compromise
their effectiveness in human medicine. Reducing nonessential uses of antibiotics in livestock and
improving hygiene conditions and husbandry methods on farms would likely result in lower levels of
antibiotic-resistant bacteria in farm animals, healthier animals, and reduced need for new, medically
essential antibiotics to treat livestock infections.

7

While subtherapeutic antibiotic uses contribute to antibiotic resistance, so do medical and
other agricultural uses. The FDA and other agencies need to identify and reduce other problematic
agricultural and medical uses of antibiotics. See CSPI report (Center for Science in the Public
Interest. Protecting the Crown Jewels of Medicine: A Strategic Plan to Preserve the Effectiveness
of Antibiotics. Washington, D.C.: CSPI; 1998.)
4

Although the exact contribution of agricultural subtherapeutic uses of antibiotics to human
health problems is not known, there is wide agreement among experts around the world that they do
result in adverse human-health consequences. The Food and Drug Administration (FDA) should
take action before the problem reaches crisis proportions. It is intolerable that people (and livestock)
should be sick for longer periods of time or die, simply because agribusiness thinks it might reduce its
operating costs.

IV. Statement of Factual Grounds
A. Policy Background
Subtherapeutic use of antibiotics is the administration of those drugs at a dosage less than is
necessary and/or for a period of time longer than is necessary to treat an infection. The FDA defines
subtherapeutic use as the use of antibiotics in livestock for more than 14 days. Antibiotics are used
subtherapeutically in raising poultry, cattle, and swine and are estimated to account for as much as 80
percent of the antibiotics used in agriculture.8
The mechanisms by which antibiotics promote growth are not well understood. Researchers
have hypothesized that antibiotics improve feed-conversion efficiency. That improvement may be
because antibiotics suppress low-level infections that result from confinement farming, infections
which, if untreated, inhibit animal growth. Antibiotics have little or no benefit when good
management practices are followed.

8

Levy, S., The Antibiotic Paradox: How Miracle Drugs are Destroying the Miracle. New
York (NY): Plenum Publishing Corporation; 1992: pp. 137-156 [hereinafter Levy, The Antibiotic
Paradox, 1992].
5

The subtherapeutic agricultural use of antibiotics used in (or related to other antibiotics used
in) human medicine poses a significant public-health hazard. Those antibiotics include penicillin,
tetracyclines, and erythromycin, as well as tylosin and lincomycin (both are related to erythromycin)
and virginiamycin (related to Synercid).
Soon after it became routine to add antibiotics to animal feed in the 1950s, health officials in
the U.S. and abroad became concerned that long-term treatment of livestock with low doses of
antibiotics could endanger human health.9 In the 1970s, the FDA itself proposed rules to revoke the
then-permitted subtherapeutic uses of penicillin and tetracyclines.10,11,12,13 At that time, the FDA also
proposed that all antibiotics that are used in human medicine only be used in animals for short-term
therapeutic uses prescribed by a veterinarian (unless the drug’s sponsor submitted data that
demonstrated that subtherapeutic use would not jeopardize human health). In 1978, Congress
directed the FDA to hold such actions in abeyance until additional studies were completed by the
National Academy of Sciences.

9

Levy, The Antibiotic Paradox, 1992 pp. 137-156.

10

U.S. Food and Drug Administration. Proposed statement of policy. Antibiotics and
sulfonamide drugs in animal feeds. Federal Register 1972; 37: 2444-2445.
11

U.S. Food and Drug Administration. Statement of policy and interpretation regarding
animal drugs and medicated feeds. Antibiotic and sulfonamide drugs in the feed of animals. Federal
Register 1973; 38: 9811-9814.
12

U.S. Food and Drug Administration. Notice of opportunity for hearing. Penicillincontaining premixes; Opportunity for hearing. Federal Register 1977; 42: 43772-43793.
13

U.S. Food and Drug Administration. Notice of opportunity for hearing. Tetracycline
(chlortetracycline and oxytetracycline)-containing premixes; Opportunity for hearing. Federal
Register 1977; 42: 56264-56289.
6

In 1984, the nonprofit Natural Resources Defense Council (NRDC) petitioned the
Department of Health and Human Services (DHHS) to ban the subtherapeutic use of penicillin and
tetracyclines in animal feed.14 The petition was based largely on two new studies. One study
showed that antibiotic-resistance genes in bacteria infecting humans were identical to those found in
bacteria infecting animals. The other study showed that subtherapeutic use of antibiotics in cattle
was linked to an outbreak of antibiotic-resistant Salmonella in people who ate hamburger.15,16
The petitioners claimed that the subtherapeutic use of penicillin and tetracyclines in animal
feed posed an “imminent hazard” to human health and should be banned. The DHHS denied the
petition on the basis that the NRDC failed to establish that the continued subtherapeutic use of
penicillin and tetracyclines in animal feed posed an imminent hazard to the public’s health that
warranted immediate suspension of their approval.17,18 At that time, the FDA could have initiated

14

Natural Resources Defense Council, Petition to Suspend New Animal Drug Applications
for Subtherapeutic Uses of Penicillin and the Tetracyclines in Animal Feed. Docket No. 84P-0399,
1984.
15

O’Brien, T.F., Hopkins, J.D., Gilleece, E.S., Medeiros, A.A., Kent, R.L., Blackburn, B.O.,
Holmes, M.B., Reardon, J.P., Vergeront, J.M., Schell, W.L., Christenson, E., Bissett, M.L., and
Morse, E.V., Molecular epidemiology of antibiotic resistance in Salmonella from animals and human
beings in the United States. New England Journal of Medicine 1982; 307: 1-6.
16

Holmberg, S.D., Osterholm, M.T., Senger, K.A., and Cohen, M.L., Drug-resistant
Salmonella from animals fed antimicrobials. New England Journal of Medicine 1984; 311: 617-622
[hereinafter Holmberg, 1984].
17

The “imminent hazard” standard places a high burden of proof on the petitioner and
requires that, without direct evidence of imminent and quantitative harm to human health, such a
petition will be denied. We do not rely on such authority in this petition.
18

United States Department of Health and Human Services, Decision of the secretary
denying petition to suspend new animal drug applications for subtherapeutic uses of penicillin and the
tetracyclines in animal feed, Docket number 84P-0399, November 19, 1985 [hereinafter DHHS
petition denial, 1985].
7

steps to withdraw the approvals by claiming that new scientific evidence demonstrated that such uses
were no longer safe, but it did not do so.
Since the 1985 ruling on the NRDC petition, sufficient scientific evidence has been published
to demonstrate clearly that subtherapeutic use of antibiotics used in (or related to those used in)
human medicine jeopardizes human health. Below we discuss that new evidence, as well as some of
the older evidence. Moreover, in the past several years, numerous scientists and professional
organizations, including the Centers for Disease Control and Prevention (CDC), the World Health
Organization (WHO), and the World Veterinary Association (WVA), have urged that antibiotics that
are used in humans, or that select for resistance to antibiotics use in humans, should not be used
subtherapeutically in livestock.19,20,21 A recent United Kingdom House of Lords report called for a
voluntary phasing out, or if necessary, a ban of the subtherapeutic use in livestock of antibiotics that
are used in (or related to those used in) human medicine.22 Even a recent report of the National
Academy of Sciences’ National Research Council (NAS-NRC), acknowledged that agricultural uses
of antibiotics pose a risk to the public health.23,24 Thus, the FDA should take action now to rescind
19

Glynn, M.K., Bopp, C., Dewitt, W., Dabney, P., Mokhtar, M., Angulo, F.J., Emergence of
multidrug-resistant Salmonella enterica serotype typhimurium DT104 infections in the United States.
New England Journal of Medicine 1998; 338: 1333-1338 [hereinafter Glynn, 1998].
20

World Health Organization, The Medical Impact of the Use of Antimicrobials in Food
Animals, Report of a WHO Meeting; 1997 October 13-17; Berlin, Germany [hereinafter WHO
meeting, 1997].
21

World Veterinary Association, Antibiotics Should Not Be Used As Growth Promotants.
Press release, Sept. 9, 1998 at <http://www.worldvet.org/press27.htm>.
22

House of Lords, Resistance to Antibiotics and Other Antimicrobial Agents: Seventh
Report of the Select Committee on Science and Technology, United Kingdom; 1998.
23

That report was prepared by a panel that did not include a single public-health official (but
did included several people associated with drug companies and agricultural interests).
8

approvals for subtherapeutic uses in livestock of any antibiotic used in (or related to those used in)
human medicine.

B. Scientific Background
Bacteria have the capacity to develop defense mechanisms against antibiotics and become
resistant to the drugs’ effects. When such resistance develops, bacteria are no longer killed by the
antibiotic, and, thus, the antibiotic is no longer capable of treating or curing the disease. The more
an antibiotic is used, the greater the selective pressure, and the more likely it is that natural selection
will foster the growth of bacteria that evade the effects of the antibiotic.
Natural selection plays a key role in the development of antibiotic resistance. Most bacteria
die or their growth is inhibited when exposed to antibiotics to which they are sensitive (not resistant).
The death of sensitive bacteria leaves more space and nutrients available for the surviving resistant
bacteria, allowing the resistant bacteria to multiply freely.
Not only can resistant bacteria proliferate after sensitive bacteria are killed off by an
antibiotic, but resistant bacteria also can transfer that resistance to other bacteria (even bacteria that
are of different genera) that have never been exposed to the antibiotic. That transfer may occur
when bacteria exchange with other bacteria either loops of DNA (plasmids) or portions of their
chromosomes that may contain antibiotic-resistant genes.25
1. Subtherapeutic antibiotics are used widely in livestock.

24

National Research Council, The Use of Drugs in Food Animals: Benefits and Risks.
Washington, D.C.: National Academy Press; 1998 [hereinafter The Use of Drugs in Food Animals,
1998].
25

Levy, The Antibiotic Paradox, 1992 pp. 71-82.
9

Subtherapeutic antibiotics are used widely and frequently in livestock in the United States. It
is estimated that more than 16 million pounds of antibiotics (about one third of all antibiotics) are
used subtherapeutically for growth promotion.26 Seventeen different agents (including antibiotics
and coccidiostats) are approved for subtherapeutic use for growth promotion and improved feed
efficiency. Of those agents, four are used in human medicine (penicillin, tetracycline, erythromycin,
and bacitracin) and three are related to those used in human medicine (lincomycin, tylosin, and
virginiamycin). Those seven antibiotics are used widely in livestock. We are not aware of any
publicly available data on how much of each antibiotic is used. The remaining 10 agents are not used
in human medicine and are not addressed in this petition.27
2. Subtherapeutic antibiotic use in livestock leads to the selection of antibiotic
resistance.
Agricultural uses of antibiotics (including subtherapeutic uses) promote the spread of
antibiotic-resistant bacteria in treated livestock.28 Those resistant bacteria can be transferred to
humans via contaminated food products or through direct or indirect contact with animals.
A number of studies show that the subtherapeutic use of antibiotics leads to the development
of antibiotic-resistant bacteria in livestock. A 1976 study showed that subtherapeutic antibiotic use
in poultry selects for antibiotic resistance in E. coli.29 The researchers inoculated a few chickens

26

Levy, S., Multidrug resistance -- A sign of the times. New England Journal of Medicine
1998; 338: 1376-1378.
27

It is impossible to determine what antimicrobials currently used in livestock will be needed
to treat antibiotic-resistant infections in people in the future. For example, Synercid, which soon will
be approved for treating deadly antibiotic-resistant infections in people, is related to the feed
additive, virginiamycin, which scientists previously thought would be too toxic to give to people. To
protect the effectiveness of future antibiotics, and to protect humans and animals from any adverse
side effects, the petitioners urge the FDA to phase out the remaining 10 antimicrobials, as
recommended by the World Health Organization.
28

Although it is impossible to evaluate the relative contribution of therapeutic and
subtherapeutic use of antibiotics to the development of antibiotic resistance, subtherapeutic uses of
antibiotics play a key role by exerting selective pressure that enables antibiotic-resistant bacteria to
flourish. In countries that have banned or decreased the subtherapeutic uses of antibiotics, resistance
levels have declined dramatically (see discussion on pp. 23-25).
29

Levy, S.B., Fitzgerald, G.B., Macone, A.B., Spread of antibiotic-resistant plasmids from
10

with tetracycline-resistant E. coli and housed them with uninoculated birds. Then, half of the
chickens were fed a tetracycline-supplemented diet. During the course of the experiment,
researchers isolated tetracycline-resistant E. coli from tetracycline-fed chickens that had not been
inoculated with those bacteria, but that had been housed with the inoculated chickens. In
comparison, researchers found no tetracycline-resistant E. coli in chickens that were housed with
inoculated birds but not fed tetracycline-supplemented feed. That suggests that the tetracycline given
in the feed provides the selective pressure that allows antibiotic-resistant strains to proliferate.
In 1983, farmers in certain parts of Germany began using a new antibiotic, nourseothricin, for
growth promotion in swine.30 Before then, nourseothricin resistance had never been observed. By
1985, nourseothricin-resistant E. coli bacteria were found in swine and in pork products.
Enterococci are a common hospital-acquired pathogen. When they are multi-drug resistant,
they are difficult to treat and sometimes fatal. In Denmark, where the subtherapeutic use of tylosin
in livestock is common, 90 percent of enterococci in pigs are resistant to tylosin.31 In contrast, in
Finland, where tylosin rarely is used subtherapeutically, only 15 percent of enterococci are tylosin
resistant.
Similarly, in the Netherlands, where avoparcin was used subtherapeutically in pigs, 39 percent
of enterococci isolated from pigs were resistant to avoparcin (and the related human-use antibiotic,

chicken to chicken and from chicken to man. Nature 1976; 260: 40-42 [hereinafter Levy, 1976].
30

Hummel, R., Tschäpe, H., Witte, W., Spread of plasmid-mediated nourseothricin resistance
due to antibiotic use in animal husbandry. Journal of Basic Microbiology 1986; 26: 461-466
[hereinafter Hummel, 1986].
31

Ministry of Agriculture, Food and Fisheries, Can We Use Less Antibiotics?, Stockholm,
Sweden; 1997 [hereinafter Can We Use Less Antibiotics? 1997].
11

vancomycin).32 In contrast, in Sweden, which banned the use of all antibiotics (including avoparcin)
as growth promoters in 1986, avoparcin- and vancomycin-resistant enterococci are not found in fecal
samples from pigs.
In northern European countries, where avoparcin is used as a growth promotant, enterococci
resistant to the related antibiotic vancomycin are common in healthy people.33,34 However, in the
U.S., where agricultural uses of avoparcin and vancomycin are not approved, vancomycin-resistant
enterococci are not found in animals or in people outside the hospital setting.35
3. Antibiotic-resistant bacteria can be transferred between animals and
between animals and people.
It has long been known that once bacteria in animals develop resistance to antibiotics, those
bacteria can be transferred to other animals and to people. As described previously (p. 11), a 1976
study showed that antibiotic-resistant bacteria can be transferred from chicken to chicken and from
chicken to people.36 Tetracycline-resistant E. coli were isolated from uninoculated chickens that
were fed tetracycline-supplemented feed and were housed with chickens inoculated with tetracycline-

32

Stobberingh, E.E., Usage of antimicrobial growth promoters in food animals poses a public
health threat. Abstract from 38th Interscience Conference on Antimicrobial Agents and
Chemotherapy, American Society for Microbiology, 1998 September 24-27; San Diego, CA.
33

Van der Auwera, P., Pensart, N., Korten, V., Murray, B., Influence of oral glycopeptides
on the faecal flora of human volunteers: selection of highly glycopeptide resistant enterococci.
Journal of Infectious Disease 1996; 173:1129-1136.
34

Schouten, M.A., Voss, A., Hoogkamp-Korstanje, J.A.A., VRE and meat [letter]. The
Lancet 1997; 349: 1258.
35

Silverman, J., Thal, L.A., Perri, M.B., Bostic, G., Zervos, M.J., Epidemiological evaluation
of antimicrobial resistance in community-acquired enterococci. Journal of Clinical Microbiology
1998; 36: 830-832.
36

Levy, 1976.
12

resistant E. coli. Additionally, those researchers isolated bacteria with the resistance plasmid from
animal handlers. A 1977 study showed that antibiotic-resistant bacteria from animals can be
transferred to people who handle raw meat.37
Salmonella, a food-borne pathogen that sickens an estimated 1.4 million and kills 500
Americans each year,38 is readily transmissible from animals to humans. In the developed world, the
majority of Salmonella infections in humans come from food, with additional cases arising from
direct contact with animals. If Salmonella bacteria carried by animals developed resistance to
antibiotics, those resistant bacteria could be transferred to humans.
A study in 1980 showed that an outbreak of antibiotic-resistant Salmonella in infants in a
hospital nursery originated from farm animals.39 A farmer’s daughter who was pregnant worked
with calves up until four days before she delivered her baby. The pregnant woman fed sick calves
from her hand in an effort to teach them to drink from a bucket. After the woman gave birth, she
had diarrhea. In addition, her baby developed diarrhea three days after he was born, as did two other
babies in the nursery. Culturing the patients and calves revealed that all were infected with
Salmonella heidelberg that was resistant to chloramphenicol, sulfamethoxazole, and tetracycline. All
three of those antibiotics are, or were previously, used in agriculture. Those cases suggest that

37

Linton, A.H., Animal to man transmission of Enterobacteriaceae. Royal Society of Health
Journal 1977; 97: 115-118.
38

Center for Disease Control and Prevention, National Center for Infectious Disease Branch,
FoodNet, 1998.
39

Lyons, R.W., Samples, C.L., DeSilva, H.N., Ross, K.A., Julian, E.M., Checko, P.J., An
epidemic of resistant Salmonella in a nursery: animal-to-human spread. Journal of the American
Medical Association 1980; 243: 546-547.
13

antibiotic-resistant Salmonella spread to a woman through direct contact with sick farm animals.
The bacteria also spread from baby to baby in the hospital setting.
An outbreak of multiple-antibiotic-resistant Salmonella typhimurium (resistant to ampicillin,
chloramphenicol, kanamycin, streptomycin, sufadiazine, and tetracycline) occurred among newborns
in a Canadian hospital in 1983.40 That outbreak was traced back to local dairy cattle which were
infected with the same strain of antibiotic-resistant bacterium. The mother of the first infant to
become sick lived on the farm with the infected cattle and drank unpasteurized milk. (The other
babies became ill three to four days later, probably from cross-contamination by nurses who cared
for them.)
A study by Holmberg, published in 1984, demonstrated animal-to-human transmission of
antibiotic-resistant Salmonella newport (resistant to ampicillin, carbenicillin, and tetracycline).41 The
genes for resistance were located on a plasmid. Eighteen patients had consumed hamburger meat
from a herd of cattle that had been fed subtherapeutic amounts of tetracycline to promote growth.
Although the suspect meat was not available for testing, all of the patients came from Minnesota,
South Dakota, and Iowa, states where the suspect meat was distributed. In addition, the only
isolation of that particular antibiotic-resistant strain in the previous year occurred in dairy cows on a
farm adjacent to the beef herd.

40

Bezanson, G.S., Khakhria, R., Bollegraaf, E., Nosocomial outbreak caused by antibioticresistant strain of Salmonella typhimurium acquired from dairy cattle. Canadian Medical
Association Journal 1983; 128: 426-427.
41

Holmberg, 1984.
14

4. Antibiotic-resistant bacteria may transfer resistance genes to other bacteria.
Using antibiotics subtherapeutically increases the prevalence of antibiotic-resistant bacteria.
Those bacteria could colonize people and pass their resistant genes to human pathogens by a process
called horizontal gene transfer.42 For example, a person might consume meat that is contaminated
with nonpathogenic bacteria. If those benign bacteria contained genes that confer antibiotic
resistance, the resistance genes could be transferred in a person’s gut from the harmless bacteria to
pathogenic bacteria.
One example of horizontal gene transfer was observed in Germany.43 In 1983, farmers in
certain parts of Germany began using a new antibiotic, nourseothricin, for growth promotion in
swine. That use quickly led to the development of nourseothricin resistance among E. coli isolated
from swine and from pork products. By 1990, nourseothricin-resistant E. coli had been passed to
farm workers, farmers’ families, citizens in the community in which nourseothricin was used, and
patients suffering from urinary tract infections. A few years later, the nourseothricin-resistance gene
was found in Shigella, a bacterium found in primates (including humans) but not in swine.44 No
nourseothricin-resistant bacteria were isolated from people or animals in other parts of Germany
where the antibiotic was not being used. The appearance of nourseothricin-resistant Shigella
indicated that the resistance moved from bacteria exposed to antibiotics on the farm to a human
pathogen.

42

Levy, The Antibiotic Paradox, 1992 pp. 78-89.

43

Hummel, 1986.

44

Tschäpe, H., The spread of plasmids as a function of bacterial adaptability. FEMS
Microbiology Ecology 1994; 15: 23-31.
15

Another example of horizontal transfer was demonstrated in the laboratory. Scientists
facilitated the transfer of an unusual tetracycline-resistance gene, tet (Q), from Prevotella rumincola
isolated from sheep to Bacteriodies fragilis, a human pathogen.45 P. rumincola is found in high
numbers in the normal gut bacteria of sheep and cattle. Although that experiment does not prove
that horizontal transfer of resistance occurs in nature, it shows that transfer is biologically possible.
Further research suggested that such transfer likely does occur in nature. The identical tet (Q) gene
was found in B. fragilis in humans and in P. rumincola isolated from animals.46 A 1992 study
showed that Staphylococcus aureus and enterococci can transfer antibiotic-resistance genes in the
laboratory setting.47 Presumably, that transfer also could happen in nature.
A fourth example that suggests that transfer of antibiotic-resistant genes can occur between
different species of bacteria comes from the U.K.48 The use of apramycin, an aminoglycoside,
caused the emergence of resistance in E. coli found in feces of treated animals. The resistant bacteria
had a unique plasmid profile and were resistant to apramycin, gentamicin (another aminoglycoside),
and hygromycin B (an antiparasitic agent used in agriculture). Resistant E. coli with the identical
45

Shoemaker, N.B., Salyers, A.A., unpublished data, cited in Speer, B.S., Shoemaker, N.B.,
Salyers, A.A., Bacterial resistance to tetracycline: mechanisms, transfer, and clinical significance.
Clinical Microbiology Reviews October 1992: 387-399.
46

Shoemaker, N.B., Wang, G., Salyers, A.A., Evidence for natural transfer of a tetracycline
resistance gene between bacteria from the human colon and bacteria from the bovine rumen. Applied
Environmental Microbiology 1992; 58: 1313-1320.
47

Noble, W.C., Virani, Z., Cree, R.G., Co-transfer of vancomycin and other resistance genes
from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus. FEMS Microbiology Letters
1992; 72: 195-198 [hereinafter Noble, 1992].
48

Johnson, A.P., Burns, L., Woodford, N., Threlfall, E.J., Naidoo, J., Cooke, E.M., George,
R.C., Gentamicin resistance in clinical isolates of Escherichia coli encoded by genes of veterinary
origin. Journal of Medical Microbiology 1994; 40: 221-226.
16

pattern of resistance were subsequently found in hospital patients. One of those patients also was
infected with Klebsiella pneumonia (a human pathogen) that had the same resistance pattern. The
resistance gene apparently was horizontally transferred between E. coli and Klebsiella pneumoniae.
5. Subtherapeutic antibiotic use may select for multi-drug-resistant bacteria
that can cause infections that are difficult to treat.
Subtherapeutic use of one antibiotic can select for bacteria that are resistant to several
antibiotics. That is because several resistance genes may be grouped together on bacterial DNA.
Use of any of the antibiotics to which the bacteria are resistant could select for resistance to all of the
antibiotics. Because they are resistant to multiple antibiotics, multi-drug-resistant infections may be
particularly difficult to treat.
Multi-drug-resistant Salmonella typhimurium, which accounts for about 10 percent of all
Salmonella infections, poses a major health concern.49 Most of those infections are caused by
Salmonella typhimurium DT104, which usually is resistant to ampicillin (a penicillin),
chloramphenicol, streptomycin, sulfonamides, and tetracycline. Since 1979, the prevalence of human
Salmonella typhimurium isolates that are resistant to those antibiotics increased from
0.6 percent to 34 percent.
Multi-drug-resistant DT104 caused an outbreak at a dairy farm in Vermont that sickened and
killed cattle and sickened nine people (one almost died) who cared for the cattle or who drank
unpasteurized milk.50 Because the infections were multi-drug resistant, physicians had difficulty

49

Glynn, 1998.

50

Friedman, C.R., Epidemic Intelligence Service Officer, Center for Disease Control and
Prevention, memo to Epidemiology Program Office, Centers for Disease Control and Prevention,
June 27, 1997.
17

finding an antibiotic that was effective against those infections. After several failed attempts,
physicians finally were able to treat the one hospitalized victim with the one class of drug to which
the DT104 strain was not resistant (and to which the patient was not allergic): fluoroquinolones.
Salmonella typhimurium DT104 also may be a particularly virulent strain of Salmonella.
Infections may be associated with greater morbidity and mortality than other Salmonella
infections.51,52 In the U.K., where DT104 is the predominant strain of Salmonella isolated from
people, a 1994 study reported that 41 percent of people who became ill with that strain required
hospitalization, and three percent died.53 In addition, in some DT104 outbreaks in the U.K., the
mortality rate among DT104-infected cattle ranges from 40 to 60 percent.54
In 1998, an outbreak in Denmark of multi-drug-resistant DT104 that also was resistant to
fluoroquinolones was traced to a herd of pigs. Among the 22 victims were several people who did
not respond to fluoroquinolone therapy. One death was indirectly attributable to treatment failure.55
6. Subtherapeutic antibiotic use jeopardizes therapeutic options in veterinary
and human medicine.

51

Wall, P.G., Morgan, D., Lamden, K., A case control study of infection with an epidemic
strain of multiresistant Salmonella typhimurium DT104 in England and Wales. Communicable
Disease Report CDR Review 1994; 4: R130-R135 [hereinafter Wall, 1994].
52

A recent study suggests that DT104 may not be more virulent than other subtypes of
Salmonella typhimurium. (Threlfall, E.J., Ward, L.R., Rowe, B., Multiresistant Salmonella
typhimurium DT104 and salmonella bacteraemia. The Lancet 1998; 352: 287-288.) This issue has
yet to be resolved.
53

Wall, 1994.

54

U.S. Department of Agriculture, Food Safety and Inspection Service, Situation
Assessment: Salmonella typhimurium DT104. December 1997 [hereinafter Situation Assessment:
Salmonella typhimurium DT104, December 1997].
55

Anonymous, Outbreak of quinolone-resistant, multiresistant Salmonella typhimurium
DT104, Denmark. Weekly Epidemiological Record 1998; 42 :327-328.
18

Subtherapeutic use of older antibiotics such as penicillin and tetracycline has rendered them
less effective in treating animal disease. Consequently, veterinarians and farmers have had to use
newer antibiotics to treat animal disease, which in turn accelerates the development of antibiotic
resistance to those newer antibiotics.
In the U.K., the use of antibiotics has fostered the emergence of multi-drug-resistant
Salmonella typhimurium DT104 that often is lethal to cattle. Because of the agricultural use of
antibiotics, multi-drug-resistant-DT104 infections are resistant to the antibiotics typically used to
treat Salmonella in cattle. As a result, to treat those infections, farmers must resort to the same
antibiotics that are used for treating human cases of invasive Salmonella: Bactrim (trimethoprimsulfamethoxazole) and fluoroquinolones. Not surprisingly, the use of Bactrim and fluoroquinolones
to treat DT104 infections in cattle is leading to the development of resistance to those drugs. In
1995, only two years after fluoroquinolones commonly were used in cattle, 16 percent of multi-drugresistant DT104 isolated from cattle were resistant to fluoroquinolones.56 From 1993 to 1996, the
proportion of DT104 isolates from cattle resistant to trimethoprim, one of the active ingredients in
Bactrim, rose from less than two percent to 24 percent in the U.K.57 If DT104 bacteria resistant to
fluoroquinolones and Bactrim were to cause bloodstream infections in humans, those infections
would be difficult to treat.

56

Hughes, J.M., Assistant Surgeon General and Director, National Center for Infectious
Diseases, letter to Stephen Sundlof, Center for Veterinary Medicine, Food and Drug Administration,
May 14, 1997.
57

Situation Assessment: Salmonella typhimurium DT104, December 1997.
19

In the U.S., where tetracycline is used subtherapeutically in livestock, tetracycline-resistance
among animal isolates of Salmonella ranges from 24 percent in cattle to 50 percent in swine.58
Because tetracycline is ineffective against many cases of Salmonella infections in livestock, other
antibiotics, such as ceftiofur (a third-generation cephalosporin), must be used. However, in children,
third-generation cephalosporins are the drugs of choice for treating invasive Salmonella infections.59
As ceftiofur is used more in animals, resistance is likely to develop, potentially leaving no
therapeutic options for those infected children.

7. Subtherapeutic use of antibiotics reduces the effectiveness of new human-use
antibiotics, jeopardizing human health.
The subtherapeutic use of antibiotics can threaten the value not only of currently available
antibiotics, but also of antibiotics that will be developed and marketed in the future.
A new class of antibiotics called streptogramins may become one of the only effective
measures against deadly bloodstream infections caused by antibiotic-resistant enterococci. Although
it has not yet been approved for use in humans, the potential value of one streptogramin -- Synercid - already has been compromised because of agricultural use of another antibiotic in the same class.
That is because resistance to one antibiotic can cause resistance to an entire class of antibiotics.
Turkeys that had been fed subtherapeutically another streptogramin, virginiamycin, harbor

58

Tollefson, L., Angulo, F.J., Fedorka-Cray, P.J. National surveillance for antibiotic
resistance in zoonotic enteric pathogens. Veterinary Clinics of North America: Food Animal
Practice 1998; 14: 141-150.
59

Fluoroquinolones can be used to treat invasive Salmonella infections in adults, but are not
approved for use in children under 18 years of age.
20

enterococci bacteria that also are resistant to Synercid.60 If people touch or consume turkey meat
that is contaminated with those streptogramin-resistant enterococci and become ill, Synercid, if and
when it is approved for human use, would be ineffective against that illness. In the U.S., Synercidresistant bacteria have not yet been found in humans. However, in Germany, where Synercid also is
not yet used in humans but where virginiamycin is used subtherapeutically in livestock, enterococci
resistant to Synercid have been detected in humans.61
The development of widespread streptogramin resistance from subtherapeutic uses of one
streptogramin, virginiamycin, also is a concern because it is possible that the gene responsible for
streptogramin resistance could be transferred from enterococci to other human pathogens, such as
Staphylococcus aureus. Gene transfer between those types of bacteria has been demonstrated in in
vitro experiments.62
Staphylococcus aureus is a leading cause of deadly hospital-acquired (nosocomial)
bloodstream infections. Staph infections are becoming increasingly resistant to all approved
antibiotics. Synercid, once approved, is expected to be an important tool for treating resistant staph
infections. If resistance to Synercid were passed from enterococci to Staphylococcus aureus due to
the subtherapeutic use of virginiamycin, Synercid might not be effective.

60

Thal, L.A., Welton, L.A., Perri, M.B., Donabedian, S., McMahon, J., Chow, J.W., Zervos,
M.J., Antimicrobial resistance in enterococci isolated from turkeys fed virginiamycin. Antimicrobial
Agents and Chemotherapy 1998; 42: 705-708.
61

Witte, W., Medical consequences of antibiotic use in agriculture. Science 1998; 279: 996997 [hereinafter Witte, 1998].
62

Noble, 1992.
21

8. Decreasing subtherapeutic uses of antibiotics on farms can reduce the
prevalence of antibiotic-resistant bacteria and does not adversely affect animal
health.
Some critics of limiting antibiotics for growth promotion have claimed that once resistance
develops, it is impossible to get rid of and that, therefore, no purpose would be served by banning
subtherapeutic uses of antibiotics.63,64 However, in countries that have banned certain subtherapeutic
uses of antibiotics, decreases in resistance to those antibiotics have occurred, thereby restoring the
effectiveness of those antibiotics to treat disease. For example, in Denmark, following a 1995 ban on
the use of avoparcin as a growth promoter, glycopeptide-resistant enterococci in Danish broiler
flocks declined from 82 percent to 12 percent.65 Although no reduction has been seen in swine, that
is likely due to the facts that: a) swine production is continuous (as compared to broilers which is allin, all-out production allowing for cleaning between flocks), and b) swine producers changed from
avoparcin to tylosin (which also selects for glycopeptide-resistant enterococci), whereas Danish
broiler producers stopped using any kind of antimicrobial growth promoters.66 In contrast, other
countries that have not banned subtherapeutic use of antibiotics, such as the U.S., have seen
continuing increases in resistance to antibiotics used subtherapeutically.67
63

Hays, V.W., Black, C.A., Antibiotics for animals: the antibiotic resistance issue. Ames, IA:
Comments from Council for Agricultural Science and Technology (CAST); 1989.
64

Gustafson, R.H., Symposium: Antibiotic residues in meat and milk: use of antibiotics in
livestock and human health concerns. Journal of Dairy Science 1991; 74: 1428-1432.
65

Danish Zoonosis Centre, DANMAP 1997. Consumption of Antimicrobial Agents and
Occurrence of Antimicrobial Resistance in Bacteria from Food Animals, Food and Humans in
Denmark. Copenhagen; 1998.
66

Wegener, H., director of Danish veterinary diagnostic laboratory, personal communication,
November 1998 [hereinafter Wegener, personal communication, 1998].
67

Glynn, 1998.
22

Critics also have claimed that animal health suffers when subtherapeutic antibiotics are not
used.68 However, improvements in animal husbandry methods can mitigate the need for
subtherapeutic use of antibiotics with no increase in animal disease. Shortly after the Swedish ban on
subtherapeutic uses of antibiotics, there was increased mortality among farm animals.69 However,
after Swedish farmers improved their animal husbandry practices, those increases disappeared.
Similarly, after the voluntary ban of growth promoters in Denmark in January 1998, disease
incidence in broilers did not increase.70

C. Expert committees and leading scientists support a phase out of subtherapeutic
antibiotic use in livestock.
Since the FDA first proposed limiting the agricultural use of subtherapeutic antibiotics in
1972 and the NRDC petition of 1984, a number of authoritative organizations have recommended,
and a number of countries have implemented, limits. One of the strongest calls for halting such uses
came from the World Health Organization in 1997. WHO concluded that excessive use of
antimicrobials, especially as growth promotants in livestock, presents a growing risk to human
health.71 The WHO recommended that:
The use of any antimicrobial agent for growth promotion in animals should be terminated if it
is: used in human therapeutics; or known to select for cross-resistance to antimicrobials used
in human medicine.

68

Animal Health Institute, Fast Facts about Antibiotics and Animals. Alexandria, VA:
Animal Health Institute; 1998.
69

Can We Use Less Antibiotics, 1997.

70

Wegener, personal communication, 1998.

71

WHO meeting, 1997.
23

Increased concerns regarding risks to public health resulting from the use of antimicrobial
growth promoters indicate that it is essential to have a systematic approach towards replacing
growth-promoting antimicrobials with safer non-antimicrobial alternatives.
Currently, most developed nations, with the notable exception of the United States and
Canada, have banned the subtherapeutic use of penicillin and tetracycline.72 In addition, in December
1998, the agricultural ministers of the European Union banned the subtherapeutic agricultural uses of
bacitracin, spiramycin, virginiamycin, and tylosin. Along with the antibiotics that already were
banned by the EU, this completed the ban of all medically important antibiotics. Prior to that ban,
Sweden banned the use of any antibiotic for growth promotion; Denmark banned the subtherapeutic
use of virginiamycin; Finland banned the subtherapeutic use of tylosin and spiramycin.73,74 To
prevent resistance to antibiotics useful in treating animal disease from developing, Finland proposed
that any antibiotic used in veterinary medicine for therapeutic purposes should not also be approved
for use as a subtherapeutic additive in feed.75
A 1998 report of the Economic and Social Committee of the European Communities also
supported limits on agricultural uses of antibiotics.76 It stated:

72

Although countries like the U.K. have banned the practice of using penicillin and
tetracycline in subtherapeutic doses by farmers, veterinarians may still prescribe antibiotics for those
purposes. It is unclear how much subtherapeutic dosing of livestock still takes place.
73

Ministry of Agriculture, Food and Fisheries, Sweden, Today We Defeat Bacteria. What
About Tomorrow? 1997 November 13; Brussels, Belgium.
74

Can We Use Less Antibiotics?, 1997.

75

Can We Use Less Antibiotics?, 1997.

76

European Communities, Opinion of the Section for Protection of the Environment, Public
Health and Consumer Affairs of the Economic and Social Committee on the Resistance to
Antibiotics as a Threat to Public Health, July 7, 1998.
24

.

The use of antibiotics should be limited to (well established) veterinary medical purposes. In
this connection, the Committee shares the view expressed by the Expert Committee at the
October 1997 WHO meeting in Berlin that “increased concerns regarding risks to public
health resulting from use of antimicrobial growth promoters indicate that it is essential to
have a systematic approach towards replacing growth promoting antimicrobials with safer,
non-antimicrobial alternatives.” In this context, the emphasis should be first and foremost on
limiting the use of antibiotics that can provoke cross-resistance to drugs that are or will
become relevant in human health care.
In February 1998, Wolfgang Witte of the Robert Koch Institute in Germany stated in a
commentary in Science: ...................
In the future, it seems desirable to refrain from using any antimicrobials for the promotion of
animal growth. As exemplified by the use of virginiamycin in animal feed and the subsequent
emergence of enterococci resistant to antibiotics, the use of any antimicrobial can lead to
unexpected consequences that limit medical choices.77
In May 1998, Stuart Levy, a Professor of Molecular Biology at Tufts University Medical

School, president of the American Society for Microbiology, and director of the Alliance for the
Prudent Use of Antibiotics, wrote in a New England Journal of Medicine editorial, that recent
findings have:
made it even clearer that the use of growth promoters affects the drug resistance of
environmental reservoirs, with direct consequences for the treatment of disease in humans
[and that] such findings led to a ban on avoparcin in the European Union countries and,
recently, on virginiamycin in Denmark.78

V. Statement of Legal Grounds
A. The FDA has legal authority to withdraw the approval of new animal drug
applications that are unsafe.
The FDCA provides in pertinent part that:
77

Witte, 1998.

78

Levy, S., Multidrug resistance -- a sign of the times. New England Journal of Medicine
1998; 338: 1376-1378.
25

The Secretary shall, after due notice and opportunity for a hearing to the applicant, issue an
order withdrawing approval of an application filed pursuant to subsection (b) with respect to
any new animal drug if the Secretary finds:
(A) that experience or scientific data show that such drug is unsafe for use under the
conditions of use upon the basis of which the application was approved; [emphasis added]
(B) that new evidence not contained in such application or not available to the Secretary
until after such application was approved, or tests by new methods, or tests by methods not
deemed reasonably applicable when such application was approved, evaluated together with
the evidence available to the Secretary when the application was approved, shows that such
drug is not shown to be safe for use under the conditions of use upon the basis of which the
application was approved . . . . 79 [emphasis added]

As used in that provision, the word “safe” in section 512, “has reference to the health of man or
animal.”80
Recently, the FDA issued a notice of availability of a guidance for industry that is directly on
point.81 The guidance relies on two statutory provisions in 21 U.S.C. § 360b(d)(2)(A) and (B) as
legal authority. Those provisions require the FDA, in determining whether an animal drug is “safe,”
to consider: (l) “the probable consumption of such drug and of any substance formed in or on food
because of the use of such drug”; and (2) “the cumulative effect in man or animal of such drug,

79

FDCA § 512(e), 21 U.S.C. § 360b(e). Implementing regulations parallel the language of
the statute. 21 C.F.R. § 514.115(b).
80

FDCA § 201(u), 21 U.S.C. § 321(u).

81

63 Fed. Reg. 64094 -95. Food and Drug Administration, Guidance for Industry:
Evaluation of the Human Health Impact of the Microbial Effects of Antimicrobial New Animal
Drugs Intended for Use in Food-Producing Animals; Availability (Nov. 18, 1998) [hereinafter FDA
Notice of Availability of Guidance to Industry, 1998].
26

taking into account any chemically or pharmacologically related substance.” In evaluating safety, the
FDA may also consider “other relevant factors.”82
The FDCA thus provides the FDA with ample authority to withdraw approval of the new
animal drug applications (NADAs) of the antibiotic uses at issue in this petition. In the past, the
FDA has used such authority to withdraw the approvals of NADAs for diethylstilbestrol (DES),83
chloramphenicol,84 and furazolidone and nitrofurazone.85 Although the withdrawals in those cases
were based on the fact that residues from the drugs would have adverse effects on humans, the
overriding principle that led to withdrawal in all of those cases is that their use in food-producing
animals was unsafe for humans.
As discussed above (pp. 9-27), the subtherapeutic use of antibiotics selects for antibiotic
resistance in bacteria in animals. Those antibiotic-resistant bacteria can infect people and make them
sick. Additionally, people can become colonized with non-pathogenic antibiotic-resistant bacteria
from animals that can pass their resistance genes to pathogenic bacteria. Leading experts in
infectious disease agree that the subtherapeutic use of antibiotics dangerously compromises the
effectiveness of approved and future antibiotics for treating infections in humans. Therefore, the
subtherapeutic agricultural use of antibiotics that are used in (or related to those used in) human
medicine is “unsafe” within the meaning of the FDCA, and the FDA should withdraw the approvals
of those uses.
82

21 U.S.C. § 360b(d)(2).

83

44 Fed. Reg. 54852 (Sept. 21, 1979).

84

51 Fed. Reg. 1367 (Jan. 13, 1986), 50 Fed. Reg. 27059 (July 1, 1985).

85

56 Fed. Reg. 41902 (Aug. 23, 1991).
27

B. The FDA has asserted its authority to consider the public-health impact of
antibiotic resistance when regulating the use of antimicrobial drugs in livestock.
In a May 4, 1998, discussion paper on antimicrobial use in food animals, Dr. Stephen
Sundlof, director of the Center for Veterinary Medicine (CVM) stated:
CVM believes it is critical that prudent use of antimicrobials be emphasized in order to
minimize the development of antimicrobial resistance and to ensure the continued efficacy
and availability of antimicrobial products for use in food producing animals.86
He defined “prudent use” as “[u]se that maximizes therapeutic effect while minimizing the
development of resistance.”87
Under Dr. Sundlof’s definition of prudent use, the subtherapeutic use of antibiotics used
medically should not be allowed. Subtherapeutic use is not prudent because it promotes the
development of antimicrobial resistance and jeopardizes the continued efficacy and availability of
antimicrobial products for medical and veterinary uses. Nontherapeutic uses of antibiotics should not
be allowed to erode the value of essential uses.
More recently, the FDA underscored the importance of antibiotic resistance by issuing in the
Federal Register a notice of availability of a guidance document.88 The notice announced the FDA’s
determination that:

86

Dr. Stephen Sundlof, director, Center for Veterinary Medicine, Food and Drug
Administration, The Issue of Antimicrobial Use in Food Animals. May 4, 1998 [hereinafter Sundlof,
May 1998].
87

Sundlof, May 1998

88

FDA Notice of Availability of Guidance to Industry, 1998
28

It is necessary to evaluate the human health impact of the microbial effects associated with all
uses of all classes of antimicrobial new animal drugs intended for use in food-producing
animals when approving such drugs.
The FDA also proposed a “Framework Document” for addressing the adverse microbial
effects of antimicrobial animal drugs.89 At the time that this petition was submitted, the “Framework
Document” was not finalized.90 Thus, the criteria for approving new antimicrobial animal drugs are
still undefined and the FDA’s approach to reviewing the safety of currently approved veterinary uses
of antibiotics is still unclear. The “Framework Document” acknowledges that the FDA will review
already-approved antibiotics only“as resources permit.” We believe that any new public-health
safeguards adopted for future antibiotic approvals must also be applied to already-approved
antibiotics.
This petition calls upon the FDA to address immediately the longstanding problem of
subtherapeutic use of antibiotics, which for decades has jeopardized the effectiveness of those drugs

89

Food and Drug Administration, Center for Veterinary Medicine, Proposed Framework for
Evaluating and Assuring the Human Safety of the Microbial Effects of Antimicrobial New Animal
Drugs For Use in Food-Producing Animals, December 9, 1998 [hereinafter FDA Framework
Document, 1998].
90

Petitioners CSPI, EDF, and UCS provided testimony at an FDA meeting on July 25, 1999,
which raised a number of concerns about the proposed Framework Document. In order to provide
adequate public-health safeguards, the framework must be applied retroactively, to antibiotics
already on the market. The process to withdraw an already-approved antimicrobial from the market
must be expeditious, in order to prevent human harm from resistance. We also are concerned about
the categorization of antibiotics in the Framework Document. Category I drugs should not be
permitted in livestock because they are vital to treating human diseases. Category II drugs (which
should include any antibiotic that is used in human medicine not in Category I , including little-used
drugs) should not be allowed for use in livestock if such use causes any increase in antibiotic
resistance. Category III drugs should include drugs that are not used in human medicine, such as
ionophores.
29

and the health of Americans. Under FDA’s proposed Framework, all of the antibiotics at issue in
this petition should be considered Category I or II drugs, because of their importance in human
medicine. Therefore, if the “Framework Document” is implemented and applied to existing
subtherapeutic uses of antibiotics, it should trigger steps to rescind approvals of those uses. If the
“Framework Document” is not implemented or not applied to existing subtherapeutic uses of
antibiotics, the FDA could initiate withdrawal proceedings immediately under current law because
the subtherapeutic uses of antibiotics at issue in this petition are not safe (See discussion pp. 9-27).

C. In light of recent evidence, Congress’ directive to the FDA to suspend proceedings
for the withdrawals of NADAs for penicillin and tetracyclines in animal feed pending
additional studies is moot.
In 1977, the FDA issued proposed notices of withdrawal for the NADAs for premixes
containing penicillin or tetracycline91 because of its concerns over the transfer of drug resistance from
animals to humans, as well as efficacy concerns. Congress, however, required that the FDA suspend
further action on those withdrawals pending further study by the National Academy of Sciences
(NAS). In particular, Congress authorized the FDA to contract with NAS “to review data on the
subject, identify data gaps, and make recommendations for further action.”92
The subsequent NAS report concluded that:
The postulated hazards to human health from the subtherapeutic use of antimicrobials in
animal feeds were neither proven nor disproven. The lack of data linking human illness with
this subtherapeutic use must not be equated with proof that the proposed hazards do not
exist.93
91

42 Fed. Reg. 56,264 (Oct. 21, 1977).

92

H.R. No. 96-1095 at 105-06 (Agriculture, Rural Development and Related Agencies
Appropriation Bill, 1981) [hereinafter H.R. No. 96-1095 Appropriations Bill, 1981].
93

National Research Council, Effects on Human Health of Subtherapeutic Use of
30

The NAS further concluded that a single comprehensive study to settle the issue was considered
technologically impractical. Nevertheless, the NAS recommended that:
future epidemiological studies . . . be carefully planned to fill gaps in our present knowledge
and especially to avoid the errors of ambiguous design and small sample size that have caused
such difficulties in interpreting the data.94
In response to NAS’ recommendations, Congress stated that the FDA would be expected to
continue to hold in abeyance any implementation of its proposal pending the final results of [research
generating new epidemiological information] and evidentiary hearings.95
In 1986, in considering another appropriations bill for the FDA, Congress concluded that:
The evidence presented to support the position that discontinuing the use of subtherapeutic
antibiotics in animal feeds would improve human health is
inconclusive . . . . The Committee is aware that the FDA is continuing to study this issue and,
therefore, will expect the FDA to consider the final reports of the several epidemiological
studies commissioned by the Animal Health Institute before the Agency takes further action
restricting the use of antibiotics in animal feeds.96
As discussed in above (pp. 9-27), in the years since Congress halted the FDA’s proposed
withdrawals of NADAs for penicillin and tetracycline, numerous studies have shown that antibiotic
use in livestock selects for antibiotic-resistant bacteria that pose a risk to human health. In addition,
a more recent NAS report, entitled The Use of Drugs in Food Animals: Benefits and Risks,
acknowledges that “there is a link between the use of antibiotics in food animals, the development of

Antimicrobials in Animal Feeds, Washington, D.C.: National Academy Press; 1980 [hereinafter
Effects on Human Health of Subtherapeutic Use of Antimicrobials in Animal Feeds, 1980].
94

Effects on Human Health of Subtherapeutic Use of Antimicrobials in Animal Feeds, 1980.

95

H.R. No. 96-1095 Appropriations Bill, 1981.

96

S. 99-137 at 116 (Agriculture, Rural Development, and Related Agencies Appropriation
31

bacterial resistance to these drugs, and human disease, although the incidence of such disease is very
low.”97
In addition, authoritative scientific bodies such as the U.S. Centers for Disease Control and
Prevention98 and the World Health Organization99 consider it a human-health risk to permit
subtherapeutic use in livestock of antibiotics that are used in (or related to those used in) human
medicine.
Congress’ concerns as to whether subtherapeutic use of antibiotics leads to human-health
risks has been satisfied by ample research. Thus, the FD should consider that Congress’ directive has
been satisfied and take the action requested in this petition.

D. The FDA should adopt policies consistent with the current international trend of
phasing out the subtherapeutic use of medically important antibiotics.
The FDA should consider any decision regarding the continued subtherapeutic use of
antibiotics in the context of international harmonization. In recent legislation, Congress concluded
that as part of the FDA’s mission, it must participate through appropriate processes with
representatives of other countries to “harmonize regulatory requirements, and achieve appropriate
reciprocal arrangements.”100 As mentioned previously (pp. 23-25), the European Union and a

Bill, 1986).
97

The Use of Drugs in Food Animals, 1998.

98

Glynn, 1998.

99

WHO meeting, 1997.

100

Food and Drug Administration Modernization Act of 1997 (FDAMA), P.L. No. 105-115,
111 Stat. 2295 (1997), codified at 21 U.S.C. § 393(b)(3).
32

number of countries have banned the subtherapeutic use of medically important antibiotics.
Prohibiting the subtherapeutic use of medically important antibiotics in the U.S. would serve to
harmonize U.S. regulatory policy with that of many other nations and help ensure that U.S. farmers
and processors have full access to global markets.

VI. Economic Impact
In a recent report, a committee of the National Academy of Sciences (NAS) attempted to
estimate the economic impact of banning subtherapeutic uses of antibiotics.101 Using data from the
industry-financed advocacy group, the Council for Agricultural Science and Technology (CAST), the
committee estimated that banning subtherapeutic uses of antibiotics could cost the average consumer
as much as 18 cents per week ($9.72 per year) in higher food costs. That estimate is based on
elimination of all subtherapeutic uses of all antibiotics, not just those antibiotics that are used in (or
related to those used in) human medicine. Additionally, CAST’s estimate assumed a certain level of
growth promotion from subtherapeutic antibiotic use that is poorly documented. In fact, in Sweden,
where antimicrobial growth promotants are not used, cattle production rates have not changed.102
Therefore, it is unclear if there will be an increase in food costs as estimated by the industry.
According to the NAS report, the farmers who would experience the largest losses due to a
ban of all antibiotics in subtherapeutic doses would be those who have the worst management

101

The Use of Drugs in Food Animals, 1998.

102

Wierup, M., Swedish University of Agricultural Sciences, Sweden, personal
communication, January 1999.
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practices.103 Subtherapeutic antibiotics have the greatest effect in animals that are under stress due
to inadequate nutrition and poor sanitation.104 One study showed that pork producers who wash
hoghouses every time a group of pigs is moved out and who grow piglets in off-site growing
facilities can reduce their antibiotic use without suffering economic hardship.105
In fact, it is possible to raise animals economically without growth-promoting antibiotics.
For example, in Sweden antibiotics are not allowed for growth promotion and are used only
sparingly for therapeutic purposes in farm animals. Swedish officials say reductions in antibiotic use
have been done cost effectively.106 In Denmark, where broiler producers stopped using growth
promoters starting in January of 1998, producers have estimated that the cost of raising a broiler has
increased by one quarter of a Danish Crown (less than four cents).107
Also, other growth promotants and/or improved management practices are commercially
viable. For instance, spokespersons for two of the leading poultry producers in the U.S., Tyson
Foods, Inc., and Perdue Farms, Inc., say that their companies do not use subtherapeutic doses of
human-use antibiotics for growth promotion because they do not consider that practice cost

103

The Use of Drugs in Food Animals, 1998.

104

Braude, R., Kon, S.K., Porter, J.W.G., Antibiotics in nutrition. Nutrition Abstracts and
Reviews 1953; 23: 473-495.
105

Dial, G.D., Wiseman, B.S., Davies, P.R., Marsh, W.E., Molitor, T.W., Morrison, R.B.,
Thawley, D.G., Strategies employed in the U.S.A. for improving the health of swine. Pig News and
Information 1992; 13(3): 111N-123N.
106

Fox, J.L., WHO experts recommend reducing antibiotic use in food animals, ASM News
1998; 64(1): 29.
107

Wegener, personal communication, 1998.
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effective.108,109 Advances in research to find alternatives to antibiotics, such as competitive exclusion
and vaccines, also may make subtherapeutic antibiotic use obsolete.
When considering the economic costs to the agriculture and animal-drug industry of banning
the subtherapeutic uses of certain antibiotics, an important consideration is the economic benefits
that a ban would create by decreasing medical expenses for treating antibiotic-resistant infections.
Antibiotic-resistant infections have been estimated to cost between $100 million and $30 billion
annually.110 The proportion that is due to subtherapeutic uses of antibiotics is unknown. What is
known is that antibiotic-resistant infections are more difficult and more costly to treat. Patients with
antibiotic-resistant infections may need to be hospitalized to receive intravenous antibiotic treatment,
may be hospitalized for longer periods of time, or may miss work due to illness.
Reducing subtherapeutic uses of antibiotics may or may not have adverse economic
consequences on drug makers and farmers. However, even if they do have some adverse
consequences, those costs would be balanced in whole or in part by reductions in health-care costs
and more importantly, by health benefits to the public.

VII. Environmental Impact

108

Fussell, L., veterinarian, Tyson Foods, Inc., personal communication, February 1998.

109

Auletta, R., attorney to Perdue Farms, Inc., personal communication, February 1998.

110

Phelps, C.E., Bug/drug resistance: sometimes less is more. Med Care 1989; 27: 194-203.
35

The proposed ban on subtherapeutic uses of medically important antibiotics likely will have
little or no adverse environmental impact. Although the industry claims that halting all
subtherapeutic uses of antibiotics might increase the amount of waste produced by animals, they
provide little, if any, evidence to support their claim. Indeed farmers may find that raising livestock
under less crowded conditions is an effective way to reduce antibiotic use. Less intensive farming
could lead to less concentrated animal waste, thereby providing an environmental benefit. In
addition, since this petition does not request a ban on all growth promotants, the action requested
here may merely result in a substitution of the type of growth promotants used, which likely will have
no net adverse environmental impact. The FDA should monitor increases in use of other
antimicrobials (or other methods) that are substituted for the banned antibiotics and ensure their
safety.
With regard to the microflora environment, ending the subtherapeutic use of certain
antibiotics in livestock would remove an unnatural pressure on bacteria that promotes the prevalence
of antibiotic resistance.

VIII. Conclusion
The FDA should ensure that agricultural uses of antibiotics do not endanger the public health
by rescinding current approvals that permit the subtherapeutic use in livestock of antibiotics that are
used in (or related to those used in) human medicine. That use of antibiotics leads to the
development of antibiotic-resistance that could cause bacterial infections that are difficult or
impossible to treat.
IX. Certification
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The undersigned certify that, to the best of their knowledge and belief, this petition includes
all information and views on which the petition relies, and that it includes representative data and
information known to the petitioners which are unfavorable to the petition.

Respectfully submitted,

________________________
Patricia B. Lieberman, Ph.D.
Staff Scientist

_______________________
Margo G. Wootan, D.Sc.
Senior Scientist

_______________________
Ilene Ringel Heller, Esq.
Senior Staff Attorney

For more information call:
Patricia Lieberman
Center for Science in the Public Interest
1875 Connecticut Avenue, NW
Suite 300
Washington, D.C. 20009
phone: [phone], ext. 342
fax: [phone]
[e-mail]

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