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 ||)|| Docket No.____|
|Used in) Human Medicine||)|| |
Submitted by the
Center for Science in the Public Interest
Environmental Defense Fund
Food Animal Concerns Trust
Public Citizens Health Research Group
Union of Concerned Scientists
March 9, 1999
Table of Contents
|I. Action Requested|| |
|II. Executive Summary|| |
|III. Introduction|| |
|IV. Statement of Factual Grounds|| |
| ||A. Policy Background|| |
| ||B. Scientific Background|| |
| || || ||1. Subtherapeutic antibiotics are used widely in livestock.|| |
| || || ||2. Subtherapeutic antibiotic use in livestock leads to the selection of antibiotic resistance|
| || || ||3. Antibiotic-resistant bacteria can be transferred between animals and between animals and people|
| || || ||4. Antibiotic-resistant bacteria may transfer resistance genes to other bacteria|
| || || ||5. Subtherapeutic antibiotic use may select for multi-drug-resistant bacteria that can cause infections that are difficult to treat.|
| || || ||6. Subtherapeutic antibiotic use jeopardizes therapeutic options in veterinary and human medicine|
| || || ||7. Subtherapeutic use of antibiotics reduces the effectiveness of new human-use antibiotics, jeopardizing human health|
| || || ||8. Decreasing subtherapeutic uses of antibiotics on farms can reduce the prevalence of antibiotic-resistant bacteria and does not adversely
affect animal health|
| ||C. Expert committees and leading scientists support a phase out of subtherapeutic antibiotic use in livestock|
|V. Statement of Legal Grounds|| |
| ||A. The FDA has legal authority to withdraw the approval of new animal drug applications that are unsafe|
| ||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|
| ||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|
| ||D. The FDA should adopt policies consistent with the current international trend of phasing out the subtherapeutic use of medically important antibiotics|
|VI. Economic Impact|| |
|VII. Environmental Impact|| |
|VIII. Conclusion|| |
|IX. Certification|| |
March 3, 1999
Dockets Management Branch
Food and Drug Administration
5630 Fishers Lane
Rockville, MD 20852
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 Citizens Health Research Group(4)and
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 livestock of any antibiotic(6) 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
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 disease-causing bacteria, resulting in antibiotic-resistant
infections in people.
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 Womens Association, and other
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 FDAs 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 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.
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.
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.
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 drugs 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.
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
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
publics health that warranted immediate suspension of their approval.(17),(18) At that time, the FDA
could have initiated 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 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.
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
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 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
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, 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
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-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 farmers 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 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.
4. Antibiotic-resistant bacteria may transfer resistance genes to other
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 persons 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.
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 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 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):
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
6. Subtherapeutic antibiotic use jeopardizes therapeutic options in
veterinary and human medicine.
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 (trimethoprim-sulfamethoxazole) 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-drug-resistant 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.
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 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., Synercid-resistant 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.
8. Decreasing subtherapeutic uses of antibiotics on farms can reduce the
prevalence of antibiotic-resistant bacteria and does not adversely affect
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 all-in, 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)
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.
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:
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
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:
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
(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
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, 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.
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. Sundlofs 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
FDAs determination that:
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 FDAs 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 and the health of Americans. Under FDAs 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 tetracycline(91) 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
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 FDAs 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 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 Prevention(98) and the World Health Organization(99) 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
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 FDAs 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 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, CASTs
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
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
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
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.
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.
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.
Patricia B. Lieberman, Ph.D.
Margo G. Wootan, D.Sc.
Ilene Ringel Heller, Esq.
Senior Staff Attorney
For more information call:
Center for Science in the Public Interest
1220 L St. N.W., Suite 300
Washington, D.C. 20005
phone: (202) 332-9110, ext. 342
fax: (202) 265-4954
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 publics 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 todays 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 Citizens 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
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.
6. For the purpose of this petition, the term antibiotic is used interchangeably with
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.)
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].
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. Penicillin-containing 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.
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. OBrien, 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].
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
21. World Veterinary Association, Antibiotics Should Not Be Used As Growth Promotants. Press release, Sept. 9, 1998
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).
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
25. Levy, The Antibiotic Paradox, 1992 pp. 71-82.
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 chicken to chicken and from chicken to man. Nature 1976; 260: 40-42 [hereinafter Levy,
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].
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.
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.
40. Bezanson, G.S., Khakhria, R., Bollegraaf, E., Nosocomial outbreak caused by
antibiotic-resistant strain of Salmonella typhimurium acquired from dairy cattle. Canadian
Medical Association Journal 1983; 128: 426-427.
41. Holmberg, 1984.
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.
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.
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.
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.
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.
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.
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:
996-997 [hereinafter Witte, 1998].
62. Noble, 1992.
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.
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.
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.
77. Witte, 1998.
78. Levy, S., Multidrug resistance a sign of the times. New England Journal of Medicine
1998; 338: 1376-1378.
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].
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).
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
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.
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95. H.R. No. 96-1095 Appropriations Bill, 1981.
96. S. 99-137 at 116 (Agriculture, Rural Development, and Related Agencies
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98. Glynn, 1998.
99. WHO meeting, 1997.
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107. Wegener, personal communication, 1998.
108. Fussell, L., veterinarian, Tyson Foods, Inc., personal communication, February 1998.
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