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

Filing 26

DECLARATION of Max Kahn 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)(Sorenson, Jennifer)

EXHIBIT A
TO DECLARATION OF
MAX KAHN

AMERICAN ACADEMY OF PEDIATRICS

TECHNICAL REPORT
Katherine M. Shea MD, MPH, and the Committee on Environmental Health and
Committee on Infectious Diseases

Nontherapeutic Use of Antimicrobial Agents in
Animal Agriculture: Implications for Pediatrics
ABSTRACT. Antimicrobial resistance is widespread.
Overuse or misuse of antimicrobial agents in veterinary
and human medicine is responsible for increasing the
crisis of resistance to antimicrobial agents. The American
Academy of Pediatrics, in conjunction with the US Public
Health Service, has begun to address this problem by
disseminating policies on the judicious use of antimicrobial agents in humans. Between 40% and 80% of the
antimicrobial agents used in the United States each year
are used in food animals; many are identical or very
similar to drugs used in humans. Most of this use involves the addition of low doses of antimicrobial agents
to the feed of healthy animals over prolonged periods to
promote growth and increase feed efficiency or at a range
of doses to prevent disease. These nontherapeutic uses
contribute to resistance and create health dangers for
humans. This report will describe how antimicrobial
agents are used in animal agriculture and review the
mechanisms by which such uses contribute to resistance
in human pathogens. Although therapeutic use of antimicrobial agents in agriculture clearly contributes to the
development of resistance, this report will concentrate on
nontherapeutic uses in healthy animals. Pediatrics 2004;
114:862–868; antibiotic, antimicrobial, resistance, child,
infant, agriculture, foodborne, epidemiology.
ABBREVIATIONS. NARMS, National Antimicrobial Resistance
Monitoring System; VRE, vancomycin-resistant enterococci; Q-D,
quinupristin-dalfopristin.

ANTIMICROBIAL USE IN ANIMAL FEEDS
Rationale for Use

I

n livestock and poultry production, antimicrobial
agents are used therapeutically, prophylactically,
and to promote growth and improve feed efficiency.1 Therapeutic use in clinically ill animals involves using curative doses of antimicrobial agents
for a relatively short period of time. However, antimicrobial agents used for acute illness may be delivered not just to sick individuals but to the entire
group of animals to which the sick individuals belong. Many therapeutic antimicrobial agents are administered in water to animals raised in large num-

The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account
individual circumstances, may be appropriate.
DOI: 10.1542/peds.2004-1233
PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Academy of Pediatrics.

862

PEDIATRICS Vol. 114 No. 3 September 2004

bers under industrial conditions, which may result in
individual animals or birds receiving inadequate
doses. The nature of swine and poultry production
makes it difficult to treat individual animals; if a few
birds show signs of clinical illness, the entire house
(10 000 –30 000 birds) is treated. Of the wide variety
of agents approved for therapeutic use in animals,
many are identical or similar to drugs used in human
medicine2 (Table 1). Only some require a veterinarian’s prescription. Although the therapeutic uses of
antimicrobial agents in agriculture have significant
impact on the development of resistant organisms,
they are not the focus of this report.
Antimicrobial agents are also used in animal production to promote growth, primarily by enhancing
feed efficiency; the mechanism of action is not
known. When used for this purpose, low doses of
antimicrobial agents are added to the feed of healthy
animals for much of their life span. In addition,
prophylactic antimicrobial agents are used to control
the dissemination of clinically diagnosed infectious
diseases identified within a group of animals or to
prevent an infectious disease that has not yet been
clinically diagnosed.1 Prophylactic antimicrobial
agents may be used at either low doses or therapeutic doses. These uses generate selection pressure on
microbial populations that is similar to growth-promotion use and will be discussed under the common
term “nontherapeutic use” to denote their use in
healthy animals. Prophylactic antimicrobial agents
are used to prevent diseases common to animals
grown under industrial conditions.1 Feed efficiency
refers to the ability to grow animals faster with less
food. This results in shorter time to slaughter at less
expense to the producer, improving profits and decreasing consumer costs.3 Addition of subtherapeutic doses of antimicrobial agents to feed also results
in bigger animals, an effect known as growth promotion.
Scope of Use

Manufacturers and users of antimicrobial agents
are not required to report data on production or use
for human or food-animal applications. Annual production estimates range from 35 million4 to 50 million5 pounds per year. The major nonhuman use of
antimicrobial agents is in food-animal production.
The Institute of Medicine estimates that 40% of an-

TABLE 1.

Major Antimicrobial Agent Classes Approved for Nontherapeutic Use in Animals

Antimicrobial Class
Aminoglycoside
␤-Lactam (penicillin)

␤-Lactam (cephalosporin)
Ionophore
Lincosamide
Macrolide
Polypeptide
Streptogramin
Sulfonamide
Tetracycline
Other
Bambermycins
Carbadox
Novobiocin
Spectinomycin

Species

Prophylaxis

Beef cattle, poultry, swine
Swine
Fowl, poultry
Poultry, swine

Yes
Yes

No
Yes

Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

No
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Yes
Yes
Yes
Yes

Beef cattle, goats, poultry, sheep, swine
Beef cattle, dairy cows, fowl, poultry, sheep,
swine
Beef cattle, dairy cows, poultry, sheep, swine
Beef cattle, fowl, goats, poultry, rabbits, sheep
Poultry, swine
Beef cattle, poultry, swine
Fowl, poultry, swine
Beef cattle, poultry, swine
Beef cattle, poultry, swine
Beef cattle, dairy cows, fowl, honey bees,
poultry, sheep, swine

Growth Promotion

Yes
Yes
No
No

Source: US General Accounting Office. The Agricultural Use of Antibiotics and Its Implications for Human Health. Washington, DC: General
Accounting Office; 1999. Publication no. GAO-RCED 99 –74

nual antimicrobial use in the United States is veterinary, and approximately three fourths of this use is
categorized as nontherapeutic “supplements” in
food animals.5 Other estimates of nontherapeutic use
in livestock are as high as 78%4 of the total annual
use of antimicrobial agents in the United States.
EVIDENCE OF SELECTION FOR ANTIMICROBIAL
RESISTANCE ATTRIBUTABLE TO AGRICULTURAL
USES OF ANTIMICROBIAL AGENTS

One of the most efficient ways to select for resistance genes in bacteria is to expose bacteria chronically to low doses of broad-spectrum antimicrobial
agents. Levy et al6 examined the effect of low-dose
tetracycline in feed on the intestinal flora of chickens.
Chickens were divided into experimental and control groups; the experimental group received feed
containing oxytetracycline at concentrations similar
to those used for therapy or prophylaxis; the control
group received feed without oxytetracycline. The
baseline resistance to tetracycline was generally less
than 10%, with many samples exhibiting less than
0.1% resistance. Within 36 hours, resistance began to
increase, and after 2 weeks, 90% of the chickens in
the experimental group were excreting bacteria that
were 100% resistant to tetracycline. Chickens in the
control group did not exhibit an increase in resistant
organisms during this same time period. Although
the chickens were exposed only to tetracycline, multidrug resistance developed (to tetracycline, sulfonamides, streptomycin, ampicillin, and carbenicillin)
through plasmid transfer. By 12 weeks, almost two
thirds of the chickens in the experimental group
excreted organisms resistant to tetracycline and at
least 1 additional antimicrobial agent, and more than
one quarter were resistant to 4 antimicrobial agents
(tetracycline, ampicillin, streptomycin, and carbenicillin). Over time, chickens in the control group, despite isolation in different pens, also developed resistance, although at lower levels. One third of
chickens in the control group were excreting more
than 50% resistant organisms after 4 months. Transfer of resistance to humans also occurred, although

more slowly and at lower levels than in the controlgroup chickens. Within 6 months, more than 30% of
fecal samples from farm dwellers contained more
than 80% tetracycline-resistant bacteria versus 6.8%
from control neighbors (P Ͻ .001). A 4-drug resistance pattern was found in farm families corresponding to that of the experimental-group chickens but
was not found in neighborhood controls. Six months
after the removal of all tetracycline feed from the
farm, no tetracycline-resistant organisms were isolated from stool samples in 8 of 10 farm dwellers
tested. This experiment demonstrated that resistance
can develop quickly in the presence of antimicrobial
pressure, that single-drug resistance becomes multidrug resistance, that resistance spreads beyond individuals exposed to the antimicrobial agent to other
members of their species within the environment
and to humans living and working on the farm, and
that stopping feed supplementation with oxytetracycline leads to decreased incidence of resistance.
MECHANISMS OF SPREAD OF RESISTANT
BACTERIA TO HUMANS

When animals become colonized with resistant organisms, these organisms can eventually reach humans through the food chain, direct contact, or contamination of water or crops from animal excreta.7
Increasingly, food animals are raised in large numbers under close confinement, transported in large
groups to slaughter, and processed very rapidly.8
These stressful conditions cause increased bacterial
shedding and inevitable contamination of hide, carcass,9 and meat10 with fecal bacteria. Dissemination
of resistant pathogens via the food chain is facilitated
further by centralized food processing and packaging, particularly of ground meat products, and broad
distribution through food wholesalers and retail
chains.11 Farmers, farm workers, and farm families6
as well as casual visitors12 are at risk of infection with
resistant organisms.
Environmental reservoirs may also contribute to
the movement of resistance genes. Active antimicrobial agents have been detected in water near animal
AMERICAN ACADEMY OF PEDIATRICS

863

waste lagoons,13 surface waters, and river sediments,14 giving rise to concerns that environmental
contamination with antimicrobial agents from agricultural and human use could present microbial populations with selective pressure, stimulate horizontal
gene transfer, and amplify the number and variety of
organisms that are resistant to antimicrobial agents.
Supporting this concern, investigators recently found
resistance genes identical to those found in swine
waste lagoons in groundwater and soil microbes
hundreds of meters downstream.15
Finally, there may also be direct human exposure
to antimicrobial agents. Because many antimicrobial
agents used in food-animal production can be obtained without a veterinarian’s prescription, they are
available for direct purchase and are often manually
added to feed or water at farm level. This may be
another pathway leading to development of resistance in occupationally exposed individuals, their
families, and neighbors.6
EFFECT ON TREATMENT OF INFECTIONS IN
CHILDREN

This section of the report reviews evidence that
links agricultural use of antimicrobial agents to disease in infants and children for 2 major foodborne
pathogens, Campylobacter species and Salmonella species, and for the opportunistic pathogen Enterococcus
species.
Campylobacter Species

Campylobacter organisms cause approximately 2.5
million cases of foodborne illness annually in the
United States and are the leading cause of bacterial
foodborne illness.16 The incidence of Campylobacter
infections in infants younger than 1 year is twice that
in the general population (54.1 vs 21.7 per 100 000
population).17 Almost 20% of all reported cases of
Campylobacter infections occur in children younger
than 10 years.18
Erythromycin or another macrolide is the drug of
choice for Campylobacter infections in infants and
children; fluoroquinolones and tetracyclines are used
frequently in adults. Antimicrobial resistance in
Campylobacter species is an increasing problem.19
Currently, macrolide resistance in human isolates of
Campylobacter jejuni, the species causing 90% of human infections, is stable and usually less than 5%.19
Campylobacter coli, which causes approximately 10%
of human infections, has a much higher resistance
rate, reaching 70%.20 The major reservoirs are poultry for C jejuni and turkeys and swine for C coli.21
Differences in resistance rates may reflect differences
in the use of antimicrobial agents.20 Erythromycin
and tetracyclines are approved for use in food-producing animals for therapeutic and growth-promotion purposes.
Fluoroquinolone resistance in Campylobacter species demonstrates the links among agricultural use of
antimicrobial agents, selection of resistance, and dissemination of resistant infections through the food
chain. Fluoroquinolones were approved for use by
prescription in diseased poultry flocks in the United
States in 1995.22 In Minnesota between 1996 and
864

1998, infections in humans caused by fluoroquinolone-resistant organisms increased, parallel with the
prevalence of retail domestic chicken products contaminated with fluoroquinolone-resistant organisms.
Data from the National Antimicrobial Resistance
Monitoring System (NARMS) demonstrate that fluoroquinolone resistance among Campylobacter isolates from humans began to increase nationwide in
the late 1990s, from 13% in 1997 to 20.5% in 1999.23 A
1999 survey of grocery store chicken found that 44%
of samples were contaminated with Campylobacter
species; 24% of the isolates were resistant to ciprofloxacin, and 32% were resistant to nalidixic acid.24
Increasing resistance is even more worrisome, because data suggest that strains of resistant Campylobacter species may be more virulent than sensitive
strains. In a case-control telephone study, investigators found that untreated patients with fluoroquinolone-resistant Campylobacter infection had an average of 12 days of diarrhea versus 6 days in patients
with sensitive strains (P ϭ .02).25 For patients who
were treated with fluoroquinolones, the duration of
diarrhea was significantly longer in those infected
with resistant versus sensitive strains (8 vs 6 days
[P ϭ .02]).
Salmonella Species

Nontyphoidal Salmonella organisms cause 1.4 million illnesses annually, 95% of which are thought
to be foodborne.16 It is estimated that 600 deaths
occur annually from Salmonella infections, primarily
among the elderly and very young.16 More than one
third of all cases occur in children younger than 10
years,18 and the incidence in children younger than 1
year is 10 times higher than in the general population
(128.9 vs 12.4 per 100 000).17 Ten percent of blood
and central nervous system infections caused by Salmonella species as reported to the Centers for Disease
Control and Prevention occur in children younger
than 1 year.26 Children of all ages with chronic conditions such as sickle cell anemia are at high risk of
serious complications from infections with Salmonella
species.27
The dissemination of resistant Salmonella infections
through the food chain is well documented. A 6-state
outbreak of plasmid-mediated, multidrug-resistant
Salmonella newport infection attributed to consumption of contaminated beef was traced back to a feedlot that used nontherapeutic doses of chlortetracycline as a growth promoter in feed.28 Investigators
found the outbreak organism in isolates from both
animals and humans on an adjacent dairy farm. An
increased risk of illness caused by a resistant strain
was observed in patients who were taking antimicrobial agents for other infections (odds ratio, 51.3; P ϭ
.001), suggesting that asymptomatic carriage was
converted to symptomatic infection by the use of
antimicrobial agents. Of 3 children younger than 10
years, 2 had received antimicrobial agents before
onset of their illness.
Neonatal infections caused by Salmonella species
also have been attributed to indirect exposure to
foodborne sources. Bezanson et al29 described a plasmid-mediated, 6-drug–resistant strain of Salmonella

NONTHERAPEUTIC ANTIMICROBIAL AGENTS IN ANIMAL AGRICULTURE

serotype Typhimurium acquired asymptomatically
by a pregnant woman from raw milk and passed to
her infant at birth. The infant became ill within 24
hours with septicemia and meningitis. Three to 4
days later, several other infants in the newborn nursery developed diarrhea with the same resistant organism. In another newborn nursery outbreak, Salmonella heidelberg resistant to chloramphenicol,
sulfamethoxazole, and tetracycline caused bloody diarrhea in 3 infants.30 The index case was a term
infant born by cesarean delivery after 18 hours of
ruptured membranes. The mother was a farmer’s
daughter who, until shortly before delivery, had
been working with new calves from a herd containing several sick calves.
The treatment of Salmonella infections, especially in
young children, has become increasingly difficult because of antimicrobial resistance. In the early 1980s,
the prevalence of multidrug-resistant Salmonella species began to increase and by 1995 had reached 19%
in the United States.31 Some strains, particularly Salmonella serotype Typhimurium DT104, cause invasive disease that frequently requires treatment but
may be resistant to 5 or more classes of antimicrobial
agents.32,33 Currently, extended-spectrum cephalosporins have become the preferred drugs for empiric
treatment in pediatrics, and fluoroquinolones are
preferred in adults. The efficacy of these drugs may
now be threatened. In 1999, Molbak et al34 described
an outbreak in Denmark of Salmonella serotype Typhimurium DT104 resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, tetracycline,
and quinolones, linked by molecular fingerprinting
(the process of identifying unique clones by DNA
typing) to 2 swine herds. Two patients died in this
outbreak, and therapeutic failure was considered related to antimicrobial resistance. Of 4 children, 1 was
an infant who was hospitalized and treated with
cefotaxime. Fey et al35 reported on a child from Nebraska who became infected with Salmonella serotype
Typhimurium DT104 resistant to ampicillin, chloramphenicol, tetracycline, sulfisoxazole, kanamycin,
streptomycin, several classes of cephalosporins, aztreonam, cefoxitin, gentamicin, and tobramycin. An
analysis of recent NARMS data revealed that 77% of
patients with culture-proven ceftriaxone-resistant
Salmonella infection between 1997 and 1998 were
younger than 18 years and that the prevalence of
ceftriaxone-resistant human isolates increased fivefold from 0.1% in 1996 to 0.5% in 1999.36 Human
isolates of Salmonella species resistant to 8 or more
agents increased almost sevenfold from 0.3% in
1996% to 2% in 1999. Decreased susceptibility to
fluoroquinolones may also be emerging. According
to NARMS data, the prevalence of resistance to ciprofloxacin among Salmonella isolates increased from
0.4% in 1996 to 1% in 1999.
Major reservoirs for Salmonella infection are food
animals, including poultry, cattle, and swine. Nontherapeutic antimicrobial agents are routinely used,
particularly in swine. One survey of 825 retail samples of raw chicken, turkey, pork, and beef revealed
an overall rate of 3% contamination with Salmonella
species.37 White et al38 recently reported that 20% of

retail ground meat samples were contaminated with
Salmonella species; 80% of these samples were resistant to at least 1 antimicrobial agent, 53% were resistant to at least 3 antimicrobial agents, and 16% were
resistant to ceftriaxone.
Enterococci

Enterococci are normal flora in food animals, domesticated animals, wild animals, and humans. In
the 1990s, vancomycin-resistant enterococci (VRE)
became common bacterial pathogens responsible for
an increasing number of nosocomial infection in the
United States, including in children.39 Hospitalized
and seriously ill children are increasingly affected.40,41 Patterns in the prevalence of VRE infection
have developed differently in the United States and
Europe, helping to elucidate the links between use of
antimicrobial agents in animals and resistance in
humans. Whereas the epidemic of VRE infection in
the United States seems related to the large increase
in vancomycin use in human medicine,42 the increased incidence of VRE infection in Europe seems
to be attributable to the use of antimicrobial agents in
animals. Vancomycin has not been used widely in
Europe in human medicine, but avoparcin, a related
glycopeptide, has been used as a growth promoter
for decades.43 Avoparcin selects for cross resistance
to vancomycin when used in farm animals.44,45 In the
United States, VRE is rarely cultured from healthy
individuals in the community,46 but it is often isolated from healthy community members in Europe.47
In Europe, VRE can also be cultured from healthy
poultry, pigs,48 ponies, and dogs49; uncooked
chicken meat50 and minced pork; and raw sewage
from urban and rural locations.51 Molecular fingerprinting of these isolates shows much higher heterogeneity in European isolates compared with US
isolates, suggesting that the prevalence of VRE in
Europe is a response of multiple enterococcal populations to the presence of avoparcin in a variety of
host species and locations.
Recent reports from the United States, however,
suggest a strong and emerging link between VRE
and agricultural use of antimicrobial agents. In response to the epidemic of VRE infection, quinupristin-dalfopristin (Q-D) was licensed for use in 1999 by
the US Food and Drug Administration as treatment
for highly resistant strains. Q-D is a streptogramin, a
class of antimicrobials not used previously in humans because of unacceptable toxicity.52 Virginiamycin is a related streptogramin that has been used in
the United States as a growth promoter for poultry,
swine, and cattle since 1974.53 In a recent study, 58%
of 407 retail chicken samples and 1% of human stool
samples were found to harbor Q-D-resistant enterococci 1 year before its release for human use, and
humans were also found to carry resistant organisms
without previous exposure to Q-D.54 This suggests
that ingestion of resistant enterococci in retail meats
resulted in colonization of the human gut by these
foodborne pathogens; such colonization of the gut of
humans has been documented for up to 14 days after
ingestion.55 It also demonstrates the potential risks of
using antimicrobial agents thought not to be imporAMERICAN ACADEMY OF PEDIATRICS

865

tant to human medicine as growth promoters. As
antimicrobial resistance increases, it is likely that
more veterinary agents may be modified for human
use. If resistance has already developed in animal
populations, however, the period of their efficacy in
human disease may be quite limited.

Martha Linet, MD
National Cancer Institute
Walter Rogan, MD
National Institute of Environmental Health
Sciences
Staff
Paul Spire

EUROPEAN EXPERIENCE

Sweden led Europe in banning antimicrobial
growth promoters in 1986.56 The ban in Sweden has
resulted in decreased use of antimicrobial agents in
food animals and, accompanied by improved animal
husbandry practices, sustained productivity and
profitability of the industry.57 Denmark, which has a
more industrialized animal production system similar to that in the United States, instituted a voluntary
ban on antimicrobial growth promoters in 1998. Denmark has had a similar decrease in antimicrobial use
and decreased prevalence of resistant organisms in
food animals without loss of productivity or profitability.58
CONCLUSIONS

Resistance to antimicrobial agents is an increasing
and serious problem. Judicious use of antimicrobial
agents in humans will address only approximately
50% of use and will be insufficient to curb the accelerating upward trend in resistance. The largest nonhuman use of antimicrobial agents is in food-animal
production, and most of this is in healthy animals to
increase growth or prevent diseases. Evidence now
exists that these uses of antimicrobial agents in foodproducing animals have a direct negative impact on
human health and multiple impacts on the selection
and dissemination of resistance genes in animals and
the environment. Children are at increased risk of
acquiring many of these infections with resistant bacteria and are at great risk of severe complications if
they become infected. Improved surveillance and
continued documentation will elucidate the magnitude of the impact that these uses have on public
health in general and children’s health in particular.
Committee on Environmental Health, 2003–2004
Michael W. Shannon, MD, MPH, Chairperson
Dana Best, MD, MPH
Helen J. Binns, MD, MPH
Christine L. Johnson, MD
Janice J. Kim, MD, MPH, PhD
Lynnette J. Mazur, MD, MPH
David W. Reynolds, MD
James R. Roberts, MD, MPH
William B. Weil, Jr, MD
Past Committee Members
Katherine M. Shea, MD, MPH
Sophie J. Balk, MD
Past Chairperson
Liaisons
Robert H. Johnson, MD
Agency for Toxic Substances and Disease Registry/
Centers for Disease Control and Prevention
Elizabeth Blackburn, RN
US Environmental Protection Agency
866

Committee on Infectious Diseases, 2003–2004
Margaret B. Rennels, MD, Chairperson
Carol J. Baker, MD
Robert S. Baltimore, MD
Joseph A. Bocchini, Jr, MD
Penelope H. Dennehy, MD
Robert W. Frenck, Jr, MD
Caroline B. Hall, MD
Sarah S. Long, MD
Julia A. McMillan, MD
H. Cody Meissner, MD
Keith R. Powell, MD
Lorry G. Rubin, MD
Thomas N. Saari, MD
Past Committee Members
Jon S. Abramson, MD
Past Chairperson
Gary D. Overturf, MD
Liaisons
Joanne Embree, MD
Canadian Paediatric Society
Marc A. Fischer, MD
Centers for Disease Control and Prevention
Bruce G. Gellin, MD, MPH
National Vaccine Program Office
Martin Mahoney, MD, PhD
American Academy of Family Physicians
Mamodikoe Makhene, MD
National Institutes of Health
Walter A. Orenstein, MD
Centers for Disease Control and Prevention
Douglas R. Pratt, MD
Food and Drug Administration
Jeffrey R. Starke, MD
American Thoracic Society
Jack Swanson, MD
Practice Action Group
Consultant
Edgar O. Ledbetter, MD
Ex Officio
Larry K. Pickering, MD
Red Book Editor
Staff
Martha Cook, MS
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