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APPENDIX K
ANT IBIOT ICS IN ANIMAL FEEDS
Committee on Animal Health and the
Committee on Animal Nutrition
Board on Agriculture and Renewable Resources
National Research Council
317
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CONTENTS
EXE CUT IVE SUMMARY
CHAPTER 1 INTRODUCT ION
ClIAPTER 2 SUBTHERAPEUTIC USE OF ANTIBIOTIC S
Animal Management
Swine
Poultry
Cattle and Sheep
Amount Used and Feed Preparation
Swine
Poultry
Ruminants
Effects of Restrictions
Swine
Poultry
Ruminants
Economic Effects of a Ban on the Use of Antibiotics
Future Changes in Antibiotic Use
Alternatives
Environmental and Management Changes
Selection for Genetic Resistance in Natural
Immunity
Development of Vaccines
Adaptation of Minimal Disease Programs
Development of New Antibiotics
CHAPTER 3 EFFICACY OF ANTIBIOTICS IN ANIMAL FEEDS
Swine
Poultry
Cattle and Sheep
CHAPTER 4 RESTRICTIONS ON ANTIBIOTICS IN EUROPE
Background
Antibiotic Use
Performance
Resistance
CHAPTER 5 EFFECTS ON ANIMAL DISEASE OF
SUBTHERAPEUTIC USE OF ANTIBIOTICS
319
321
325
328
328
328
331
332
332
332
333
336
338
338
338
339
339
341
343
344
345
345
345
346
347
347
350
350
354
354
355
357
357
360
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320
CHAPTER 6 THERAPEUT IC USE OF ANT IBIOT ICS
Background
Control and Regulation
Epidemiological Considerations
CHAPTER 7 VOIDS IN KNOWLEDGE AND SUGGESTED RESEARCH
Effect of Tetracycline Feeding on Animal Therapy
Poult ry and Swine
Cattle
Relation of Antibiotic Feeding to Human Health
Mechanisms of Action of Antibiotics in Growth
Promot ion
REFERENCES
363
363
366
366
368
368
368
369
370
370
372
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EXECUTIVE SUMMARY
The food-producing animal and poultry industries have under-
gone a dramatic change that began around 1950. What was an ex-
tensive industry became extremely intensive: units increased in
animal concentration, both physically and numerically. Utiliza-
tion of the beneficial responses of feed-additive antibiotics in
improved growth and feed efficiency developed concurrently with
the intensification of the animal industry. It has been proposed
that feed-additive antibiotic usage was an integral part of this
revolution in animal-production technology. It is estimated, at
present, that 40 percent of the antibiotics produced are used for
feed additives. Estimates allocate 0.5 million kg to the cattle
industry, 1.0 million kg to poultry, 1.4 million kg to swine, and
0.4 million kg to other animals such as companion animals.
The animal producer can obtain antibiotics in the form of
balanced
the feed-manufacturing industry. The producer also has access
to and can purchase antibiotic products from farm and veterinary
supply centers. Administration of antibiotics in the drinking
water is becoming increasingly important in both poultry and
swine production.
.
supplements and premixes that are processed and sold by
Feedlot systems for beef cattle and sheep would not change
if low-level antibiotic feedings were not permitted, but it is
likely that disease problems and therapeutic use of antibiotics
would increase.
The discontinuance of low-level (5 to 10 g/ton) usage of
penicillin and tetracyclines would have little effect on the
- ~ the elimination of higher levels
(100 to 200 g/ton) would make it very difficult to control bac-
terial disease in young chickens and turkeys. If all tetracy-
clines and penicillin were banned as feed additives for poultry,
the effective alternative antibiotics and sulfa drugs would
likely maintain present production and efficiency standards.
However, the problem of selective pressure for some multiple
~ ~ ~ ~ ~ by plasmids may still persist
DoultrY industry. However.
antibiotic resistance mediated
with alternative antimicrobials.
321
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322
If only tetracyclines and penicillin were banned as feed-
additive antibiotics for swine, there would be little if any
effect on swine productivity or efficiency. There are other
promising antibacterial agents that could serve the industry well.
If subtherapeutic use of feed additive antibiotics is banned,
future changes in disease control will include preventing exposure
to infectious agents, treatment of disease after an outbreak has
occurred, and control of infectious disease by immunological means.
Preventing exposure to infectious agents will be extremely diffi-
cult and will result in a slowing down of animal production.
Post-outbreak treatment has had variable effectiveness, but would
certainly be less effective than the present use of subtherapeutic
levels of antibiotics. The control of infectious disease by immun-
ological means would be an ideal way to safeguard against subclini-
cal infection. However, thus far there has been limited success
in protecting animals against bacterial pathogens that affect the
intestinal and respiratory tracts.
Antibiotics have been effective in improving the rate and
efficiency of gain in swine, cattle, and poultry. The responses
in poultry and swine are generally greater in younger animals than
in those reaching the end of the growing-finishing period. There
is some evidence that the improved farrowing rate of swine is asso-
ciated with the use of antibiotics. Responses in cattle have not
been as great as those in swine and poultry. Improvement in rate
of gain and feed efficiency in cattle has averaged about 5 percent.
Evidence indicates that the effectiveness of antibiotics has not
decreased over time.
Antibiotics in feed have also been used in animal production
in Europe since 1953. The British have monitored microbial resist-
ance to antibiotics and have conducted some basic and applied re-
search concerning this aspect. Although the use of antibiotics in
the United Kingdom has been restricted as a result of the Report of
the Joint Committee on the Use of Antibiotics in Animal Husbandary
and Veterinary Medicine (referred to in this report as the Swann
Report; Swann et al. 1969), the total tonnage used in animal pro-
duction in 1975 was at an all-time high. Although the amount used
in animals was only about 15 percent of the total usage, the ratio
of the human population to the livestock population receiving anti-
biotics is substantially higher than in the United States.
Ingestion of antibiotics results in the development of resist-
ance in bacteria such as in the E. cold and Salmonella species. The
resistance appears to be related to usage patterns. British research
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323
has shown that resistance persists longer following long-term
use, compared to short-term use. There is strong evidence that
development of resistant strains of bacteria in humans is closely
related to antibiotics used in humans. No concrete evidence has
been reported in the United Kingdom showing that antibiotic re-
sistance has decreased since cne
use has decreased.
Swann Report, or that antibiotic
The wise use of antibiotics is not a substitute for, but
a complement to, good sanitation and husbandry practices. Ex-
tensive use of low-level antibiotics in feeds has brought about
concern for potential harmful effects due to development of
resistant strains of organisms in host animals that might cam-
promise animal as well as human health. Drug resistance in
bacteria was observed soon after the introduction of antibiotics.
Antibiotics have been used extensively in animal feeds for nearly
30 years. Questions and discussions concerned with the potential
human health hazards from subtherapeutic antibiotic feeding to
animals have been aired for nearly 30 years. Yet, it is difficult
- ~ - ~ ran he Tori hi .~n~r; fist lv
to cite human health problems that ~ rid
to meat animals fed antibiotics or that can be associated with
contact with animals fed low levels of antibiotics. There have
been incidents of salmoneDlosis in humans involving antibiotic-
resistant strains of animal origin but there is no evidence of
any relation to low-level antibiotic feeding.
Surveys of the use of drugs for therapeutic purposes indi-
cate that antibacterial agents account for almost 50 percent of
drugs used by practicing veterinarians. In vitro testing has
sometimes been questioned in that infections associated with
organisms that seem to be resistant In vitro are quite respon-
sive to antibacterial therapy In viva in clinical use.
Scattered reports, published and unpublished, attribute
failure in drug therapy to low-level antibiotic feeding. Others
claim continued effectiveness of drugs previously fed for long
periods at subtherapeutic levels. Carefully controlled studies
exploring possible relationships between antibiotic feeding and
subsequent drug effectiveness are needed.
Critical experimental studies on the effect of low-level
antibiotic feeding on animal therapy and human health are de-
finitely needed. It is proposed that studies be conducted in
the following areas:
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324
1. Does
Feeding of Tetracycline and Penicillin Compro
mise Animal Therapy?--This research should be done with swine,
poultry, and cattle. In swine and poultry, conditions should be
closely controlled. In cattle it would seem essential that re-
search be conducted in commercial-type feedlots.
2. The Relationship of Antibiotic Feeding to Human Health--
Although these studies are very complex and time-consuming, it
is important that some effort be started in this direction. The
incidence of disease-resistant organisms could be determined in
humans in industries in which the workers have close contact with
animals and animal products and with people who work in industries
that have no contact with animals or animal products. Also the
incidence of disease and the effectiveness of therapy should be
studied. Some information might be obtained by surveys of exist-
ing information.
3. Mechanisms of Action of Antibiotics in Growth Promotion--
Current evidence strongly suggests that the growth-promoting
effect from low-level feeding of antibacterial compounds is not
solely related to disease prevention. Knowledge of the mechanisms
involved is a vital missing link. If known, the study of other
means of eliciting a similar response would become feasible. Thus
such new knowledge would offer the potential for eliminating some
or all of the current reasons for using feeding levels of antibac-
terial drugs.
,
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CHAPTER 1
INTRODUCTION
The use of subtherapeutic levels of penicillin and the tetra-
cyclines in animal feeds has raised the question of the effects of
such practices on human health. The Food and Drug Administration
(FDA) has proposed a ban on certain antibiotics at subtherapeutic
levels in feed because of the potential for compromising the health
of humans. A large segment of the regulated industry, including
fanners and ranchers, has contended that in nearly 30 years of use,
antibiotics at subtherapeutic levels in animals have not compro
mised human or animal health or influenced the therapy of human
disease.
The FDA has contracted with the Assembly of Life Sciences,
National Academy of Sciences, for a review and evaluation of human
health effects of antibiotics in animal feeds. The Committee to
Study Human Health Effects of Subtherapeutic Antibiotic Use in
Animal Feeds has been appointed to:
1. study the human health effects of subtherapeutic use of
penicillin and tetracyclines (chlortetracycline and oxytetracy-
cline) in animal feeds;
2. review and analyze published and unpublished epidemiolog-
ical and other data as necessary to assess the human health conse-
quences of the subtherapeutic use of penicillin and tetracyclines
in animal feeds; and
3. assess the scientific feasibility of additional epidemio-
logical studies, and, if needed, to make recommendations about the
kind of research necessary, its estimated cost and time requirements,
and possible mechanisms to be used to conduct such studies.
Under the teems of the contract, subtherapeutic levels are
defined as use of the agent at levels of 200 g/ton or less, and/or
use of the agent for 2 weeks or longer. Animal feeds include milk
replacers, medicated blocks, and liquid feeds.
The Committee has requested the Board on Agriculture and
Renewable Resources (BARR) to prepare a critical review/position
paper on certain aspects of the problem. The following list of
questions to be answered was submitted to the BARR (the Chapter
325
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326
numbers after each question refer to the chapter in this report
that discusses the question):
1. How effective are antibiotics--especially penicillin
and tetracycline--in animal feeds? (Chapter 3)
2. Would animal husbandry methods change if antibiotics
were eliminated, or if penicillin and tetracyclines were removed?
(Chapter 2)
3. Does animal disease decrease as a result of use of
antibiotics and would there be an increase in therapeutic use of
antibiotics if subtherapeutic use was discontinued? (Chapter 2)
4. What do the data from European countries show with re-
spect to animal health and nutrition where antibiotics have
been restricted? Has the restriction of subtherapeutic use led
to increased therapeutic use, thus cancelling the benefits of
restriction? (Chapter 4)
ter 2
5. Is it likely that there would be a black market? (Chap-
2)
6. How much therapeutic use is there and has it caused
resistance problems? What is the evidence that therapeutic use of
penicillin and tetracyclines contributes to resistance and possible
health effects? (Chapter 6)
7. What epidemiological studies exist that would be valuable
for the committee to consider? Are there epidemiological studies
that should be carried out? (Chapter 6)
8. What amounts of penicillin and tetracyclines are used
subtherapeutically? (Chapter 2)
9. What amounts of penicillin and tetracyclines are used
therapeutically? (Chapter 6)
10. How are animal feeds prepared and how are the antibiotics
used in animal feeds mixed and used by farmers or feedlot operators?
(Chapter 2)
11. How are antibiotics for therapeutic use in animals regu-
lated? Do veterinarians have guidelines or antibiotic audits?
(Chapter 6)
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327
12. Has therapeutic efficacy been compromised by the use
of subtherapeutic levels of antibiotics in animal feeds? Are
resistant infections more prevalent in animals? (Chapters 5, 6)
13. Critically review the documentation for increase in
resistance, pathogenicity, and increase in numbers-of pathogens
after use of subtherapeutic antibiotics. (Chapters 5, 6)
BARR asked its Committees on Animal Nutrition and Animal
Health to set up a panel of their members and outside consul-
tants to address these questions. The Panel met on June 11 and
July 2 to 3, 1979, and prepared the statement that follows that
addresses the 13 questions.
The panel is indebted to Enriqueta C. Bond and Roy Widdus,
of the Division of Medical Sciences, for providing published
research documents on the subject, and to Philip Ross and
Selma P. Baron for their advice and guidance in the preparation
of the report.
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366
the relative importance of the human as a source of resistant orga-
nisms in animals or of animals as a source of resistant organisms
in man. Furthermore, it would be impossible at the present time to
say whether the resistant organisms arose as a result of subthera-
peutic antibiotic feeding, prophylactic use, or therapeutic use for
the treatment of a specific disease outbreak.
CONTROL AND REGULAT ION
Control and regulation of the therapeutic use of antibiotic
drugs is under the purview of the FDA, particularly the Bureau of
Veterinary Medicine and the Bureau of Foods. Control is exercised
through the mechanism of the New Animal Drug Application (NADA).
Once approval is granted and the drug is marketed, therapeutic use
by veterinarians and in some cases by livestock producers follows.
Such usage is based on the indications of the drug; the experience
of the practitioner; and the inherent constraints of the dosage,
route of administration, and the residue or withdrawal times. In
the overwhelming majority of cases care is taken to observe the
requirements of proper withdrawal times for either milk or meat.
Frog time to time, the question of auditing antibiotic drug
usage arises, primarily within the setting of human hospitals.
Other than in an institutional setting, the auditing of drug usage
would be very time consuming, costly, and difficult to control.
EPIDEMIOLOGICAL CONSIDERATIONS
There is general agreement that the use of antibiotics in
both animals and humans leads to increased frequency of antibiotic
resistance. Furthermore, there is little doubt that resistance
can be transferred through plasmids from certain resistant micro-
organisms to others that were originally sensitive. These in turn
have been shown to be transmissible to other animals and, in iso-
lated cases, to humans (Levy et al. 1976 a,b; Hirsh 1977~. This
resistance transfer or infectious drug resistance has led on the
part of some individuals, to the fear that resistant strains could
be transferred to other animals and humans, thereby creating a
reservoir of pathogens, which when involved in clinical infections,
would be unresponsive to antibiotic treatment. While such fears
may seem to be a logical extension of current knowledge regarding
resistance, there is practically no information on the extent to
which this is happening, nor is it clear in the case of the few
such instances known whether they were due to low-level antibiotic
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367
feeding, therapeutic use of antibiotics in domestic animals (in-
cluding companion and pet animals), or therapeutic or prophylactic
use of antibiotic drugs in human beings. These vexing questions are
not easily resolved, particularly in view of the fact that both
humans and animals often share the same pathogens.
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CHAPTER 7
VOIDS IN KNOWLEDGE AND SUGGESTED RESEARCH
Although voluminous research has been conducted regarding the
effects of feeding antibiotics on performance, research has been
very limited in certain other areas. Research results have shown
that resistance of microorganisms exists in animals fed antibiotics
and that this resistance can be transferred (Lipton 1977 a,b; Smith
1977a). However, there is inconclusive evidence that the use of
antibiotics as growth promotants compromises therapy of humans and
-animals. Few well-designed experiments have been reported, and
clearly there is a need for well-designed intensive investigations
of this important issue.
The main objectives of the proposed research to fill in the
primary voids concerning antibiotics are to determine: (a) if the
feeding of tetracyclines and penicillin compromise animal therapy,
(b) the relation of antibiotic feeding to human health, and (c) the
mechanism of action of antibiotics in growth promotion.
It is suggested that the research described in the following
pages be undertaken.
EFFECT OF TETRACYCL INK FEEDING ON ANIMAL THERAPY
Poultry and Swine
The possibility that administration of subtherapeutic levels
of antibiotics may compromise therapy has not been adequately in-
vestigated. Most previous studies have given negative results with
respect to this question, but according to the FDA (U.S. DHEW/FDA
1978) experiments generally were poorly designed. Carefully planned
and controlled experiments conducted with poultry and swine should
be conducted to attempt to answer this question with organisms such
as Salmonella typhimurium. This organism should be used in these
animals to determine whether development of resistant organisms will
compromise treatment of a severe infection in the species. Chicks
and swine should be inoculated with S. typhimurium to induce a low-
level, nonlethal infection, and be fed diets with and without tetra-
cycline. After a few weeks the animals will be challenged with an
inoculum calculated to cause a severe infection resulting in con-
siderable mortality. This inoculum should be isolated from animals
368
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369
fed antibiotic and should be documented to contain antibiotic-
resistant organisms. The effectiveness of therapeutic levels
of tetracyclines and other antibiotics against this infection
should be determined. To avoid the problem of possible develop-
ment of immunity, animals unexposed to the organism should also
be inoculated with the dose to cause a severe infection, and the
effectiveness of antibiotic therapy in these animals should also
be investigated. Careful laboratory work to monitor development
of antibiotic-resistant organisms in the animals and immunity
development would be needed.
Cattle
Cattle in commercial feedlots should be studied that (a) have
not received antibiotics; (b) have received a high level of anti-
biotic during the first 3 to 4 weeks, followed by a low level
during the remainder of the period on feed; and (c) have received a
high level of antibiotic during the first 3 to 4 weeks, followed by
withdrawal of the drug. Comparisons should be made of tetracycline
therapy on sick animals from the lots on the various treatments.
Response to therapy should also be monitored by the number of ani-
mals treated, the length of stay in the sick pens, and mortality.
Measurements should also include antibiotic susceptibility of orga-
nisms in treated animals and samples of healthy animals from all
lots at periodic intervals.
This type of experiment will need to be performed in coopera-
tion with university or USDA scientists and feedlots. It would be
ideal for most of the feedlots to be in the California and Arizona
area where antibiotics are not normally used. However, it would be
important that some feedlots, at least those that are treated, be
located in the Colorado or Kansas area, where a continuous level of
feeding of tetracyclines is routinely practiced. It will be essen-
tial that the cooperating feedlots use only tetracycline as the
subtherapeutic and therapeutic drug. It will be essential to reim-
burse the feedlots for death losses above the normal mortality rate
caused by the experimental treatments. Also, some compensation will
have to be made for the extra labor involved in handling the cattle,
such as monitoring the normal animals for antibiotic-resistant orga-
nisms. The organisms used to monitor resistance will likely be a
common species of Salmonella and E. colt.
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370
RELATION OF ANTIBIOTIC FEEDING TO HUMAN HEALTH
The information which would be required to answer the con-
troversial question will necessitate investigations of staggering
complexity and cost. It is likely that broad-based studies will
involve monitoring of health-related problems among human popula-
tions involved in and isolated from low-level antibiotic feed
programs. Of course, when studying people involved with animals
and animal products, animal health should also be monitored.
Baselines must also be established by determining the history of
the subjects with regard to antibiotic exposure and the suscepti-
bility of the microflora species to antibiotics.
Recent experiments with animals have shown that randomly
selected individuals already carry some resistant enteric micro-
organisms. It may be necessary to study respiratory bacterial
flora instead of, or in addition to, the changes or lack of
changes in susceptibility by species over a period of time and
the nature of any disease episode particularly if suggestive of
microbial etiology. The susceptibility of any agent thought to
be involved would have to be established and the success of anti-
microbial therapy determined clinically and microbiologically.
The logistics and mechanics of this type of study will be extremely
demanding in time and labor. Some aspects, especially those in-
volving humans, would require several years, a large population,
or both, for the collection of adequate data. If the microflora
present at the onset is already predominantly resistant to the
antimicrobials of interest, this study would be pointless.
MECHANISMS OF ACTION OF ANTIBIOTICS IN GROWTH PROMOTION
Growth promotion from the low-level feeding of antibiotics
refers to an improvement in both rate of gain and efficiency of
feed conversion. Improvement normally occurs in both measures of
performance but not necessarily to the same degree. In view of
known factors that influence rate and efficiency of gain, anti-
biotic action affecting each measure of performance should prove
to be, at least in some respects, different.
The different chemical nature, adsorbability, and bacterial
spectrum of growth promoting antibiotics suggest that the mode of
action in growth promotion cannot be the same for all of the anti-
biotics that have proven efficacious. There is also good evidence
that antibiotic action affecting growth in the different species
is not entirely from the same mode of action. Factors involved are
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371
the complex mechanisms related to disease, feed intake, digestion,
absorption, and metabolism of nutrients, as well as antibiotic
effects on enteric flora and the systemic bacterial population.
In swine, frequent measurement of rate and efficiency of gain
in control and antibiotic-fed animals reveals that a response to
the antibiotic is not consistent but occurs only occasionally, and
for what is usually a short period of time. Such an effect over
an extended period promotes average performance above controls.
In view of this important temporary effect, studies are sug-
gested in which short-term performance measurements (feed intake
and rate of gain) are correlated with similar short-term measure-
ments related to the microbiology and biochemistry of the different
physiological systems in control versus responding animals. In-
testinal cannulation to permit sampling of ingesta at different
points in the tract, together with simultaneous blood measurements,
are needed for such an approach.
Experiments designed to uncover mechanisms related to the
growth-promo/ant effect might provide a means of exploiting these
mechanisms other than by the use of feeding levels of antibacter-
ial compounds.
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372
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Representative terms from entire chapter:
feed additives
