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CHAPTER 1
THE USE OF ANT IMICROBIAL A(;ENTS1
The discovery of the first selective antimicrobial agent
approximately four decades ago was a major milestone in the his-
tory of medicine and human health. The subsequent development of
antimicrobial therapy largely centered on the search for drugs with
effectiveness against microbial species that were not susceptible
to drugs then in use.
These powerful new drugs have been shown to save lives when
used to treat some severe infections and to reduce the burden of
illness when used prophylactically in certain clinical situations
(Utz, Appendix A). Since antibiotics] are isolated from microorga-
nisms, strains of some microbial species have predictably evolved
the capacity to inactivate them or became impermeable to them, i.e.,
these strains have developed resistance to these antibiotics. Re-
sistance to synthetic antimicrobial agents arises from the variation
normally displayed by individual microorganisms within species.
Thus, the consequence of expanded use of antimicrobial drugs has
been an increased prevalence of resistant organisms resulting from
the selection process. In certain places, such as hospitals, contact
between individuals has facilitated the spread of these resistant
bacteria.
Consequently, researchers sought agents that were active
against strains in which resistance had become prevalent. The ex-
panding array of antimicrobials, particularly antibiotics, provided
alternatives in most cases. But control of infections is sometimes
delayed if the resistance of the infecting organism is not recognized
immediately, and physicians may need to use drugs that are more toxic,
more expensive, or less effective than those that would be selected
if the infecting organisms were not resistant (Utz, Appendix A).
Trends in the antimicrobial resistance patterns of a number of
clinically important pathogens have been reviewed by Finland (1979)
and Stollenman (1978~. The prevalence of multiply ant~microbial-
resistant Staphylococcus aureus increased until 1960 but subsequently
declined in association with a change in phage types. Recently,
strains of Streptococcus pneumonias with multiple resistance
have been found in a number of countries. Strains of Haemophilus
An antibiotic is a chemical substance produced by microorganisms
that has the capacity at low concentrations to inhibit the growth
of or to destroy bacteria and other microorganisms. An antimicro-
bial is any agent that destroys microorganisms or suppresses their
multiplication or growth.
1
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influenzas producing f-lactamase and occasional strains with
resistance to chloramphenicol have also been observed, as have
strains of Neisseria gonorrhoeae producing plasmid-mediated
S-lactamase. Other changes are noted by Finland (1979~.
Differences in resistance encountered in certain pathogens
of humans are often observed in separated geographical areas
(Finland, 1979), in different hospitals (O'Brien, Appendix I),
or in local outbreaks, e.g., of chloramphenicol-resistant strains
of Salmonella typhi in Vietnam and Mexico (Finland, 1979~. The
committee could find no comparable assessments of the trends in
resistance to antimicrobials that might have occurred in the
major pathogens of food animals over the last three decades.
The prevalence of clinically significant antimicrobial-
resistant bacterial strains correlates with the increasing use
of antimicrobial agents in the course of clinical practice
(Finland, 1955a,b,c; 1979~.
The necessity for therapeutic use of antimicrobial agents in
the treatment of overt disease in animals has not been questioned.
However, the continuous use of subtherapeutic levels of antimicro-
bials in animal feeds for growth promotion, improvement of feed
efficiency, and disease prophylaxis has been criticized as posing
dangers to human health by making an important quantitative con-
tribution to the pool of antimicrobial-resistant bacteria that may
be transferred to the human population. Possible "qualitative"
effects of the selection pressure imposed by subtherapeutic usage
on resistance profiles or transfer mechanisms are discussed below
and by O'Brien (Appendix I).
For regulatory purposes, the Food and Drug Administration
(FDA) defines subtherapeutic use as the administration of doses
less than or equal to 200 g of antimicrobial per ton of feed for
2 weeks or longer. However, the FDA has approved the marketing
of some antimicrobial agents for use at levels below 200 g/ton to
treat certain diseases (Animal Health Institute, 1979~. There-
fore, the current definition of subtherapeutic use in animal feeds
encompasses certain uses that are therapeutic in intent in addi-
tion to those for prophylaxis and the improvement of growth and
efficiency of feed conversion.
In the hope of preserving the effectiveness of the antimicro-
bial agents that are important in the therapy of human diseases,
some governments (e.g., the United Kingdom) have regulated the use
of these agents as growth promotants in animal feeds (Swann et al.,
1969~. Antimicrobials used to treat humans are still approved in
those countries for use in animals on veterinary prescription.
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Similar actions have been under cons iteration in many other coun-
tries, including the United States. Since penicillin and the
tetracyclines are effective and widely used in the therapy of human
disease, the FDA has proposed restriction of their subtherapeutic
use in animal feeds.
This committee has attempted to determine if human health is
affected by the subtherapeutic use of antimicrobials in animal
feeds and to ascertain what additional information is needed to
make a more definitive determination.
NATURE OF THE SELECTION PRESSURE IMPOSED BY ANTIMICROBIALS
. .
It is important to distinguish between the effects of an anti-
microbial drug on a single ant~microbial-sensitive microbial strain
and the effects on a heterogeneous mixture of species or strains.
When antimicrobial drugs are brought into contact with multiplying
susceptible microorganisms, the organisms are generally inhibited
from multiplying further or are killed. When the susceptible orga-
nisms constitute a portion of the total microbial flora that is
exposed to the drugs, the elimination of the susceptible organisms
is generally followed by some degree of compensatory multiplication
of the more resistant or nonsusceptible strains. Such a shift in
the composition of the enteric flora may facilitate infection by a
pathogen (Seelig, 1966~.
Another important consideration in the evaluation of possible
effects on human health is the possibility of "qualitative" as well
as quantitative changes i n resistance brought about by the continuing
selection pressure exerted by subtherapeutic levels of antimicrobials
in animal feeds. To date, most research has been focused on quan-
titative changes, i.e., changes in the prevalence of resistance,
primarily because techniques to study qualitative changes have
only recently been developed. Qualitative changes could include
the development of new combinations of resistance genes, combina-
tion with genes for other characteristics, e.g., toxins, the spread
of such plasmids to new hosts and, possibly most seriously, the
evolution of more efficient, wider host-range transfer mechanisms.
The evidence for such changes is discussed by Jacoby and Low
(Appendix C). The implications of this "molecular epidemiology of
plasmids" are considered by O'Brien (Appendix I). Another change
that could be regarded as qualitative is the shift in the composition
of the gastrointestinal flora under the selection pressure of sub-
therapeutic dosages of antimicrobials. This shift will produce
changes in the interactions of the flora components with each other
and with the host. Little is known about the composition of the
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gastrointestinal flora in either humans or animals, especially the
anaerobic components (Savage, Appendix D). Therefore, because of
the lack of data and methodology to carry out _ -viva experiments,
it is not possible to assess the significance for human health of
such shifts.
Investigators who have studied resistance in the gastroin-
testinal flora of humans or animals have generally observed changes
in the prevalence of R factors in E. cold or its close relative
Salmonella because these organisms are easy to culture and manipu-
late and because they can be pervasive pathogens in both humans and
animals. The significance of resistance in these two species may
not be the sate since their "ecology" is different. This is dis-
cussed briefly in the next section.
A thorough assessment of the significance for human health of
various uses of antimicrobials requires knowledge of the consequences
of the selection pressures imposed by intermittent, therapeutic doses
versus subtherapeutic continuous feeding and of different routes of
administration. Unfortunately, there are insufficient data comparing
These regimens. Such data would have been of invaluable assistance
to the committee during its deliberations.
MECHANISMS AND TRANSFER OF RESISTANCE
In most instances bacterial resistance to antimicrobial agents
is conferred by extrachromosomal genetic elements called plasmids.
Those conferring resistance are called R factors or R plasmids
(Jacoby and Low, Appendix C). These plasmids are widely distri-
buted among bacterial species, including those that are pathogenic
in humans and animals. Some plasmids transfer between species of
different genera.
Two general types of R plasmids have been identified on the
basis of their transmissibility characteristics:
Large R plasmids harbor approximately 100 genes and are trans-
missible to other cells by a process called conjugation or bacterial
mating. Approximately 25 plasmid genes code for functions that are
required for transmissibility, several other genes code for repli-
cation functions, and from four to six genes generally code for
resistance to antimicrobials. The f unctions of other genes on the
larger R plasmids have not been identified.
Small R plasmids usually harbor approximately 10 genes. These
plasmids do not carry the genes for transmissibility and are not
transmissible when by themselves. However, a transmissible plasmid
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may sometimes mediate the transfer of an otherwise untransmiss-
ible one when present simultaneously in the same cell.
Some pairs of R plasmids cannot coexist stably in the same
host cell, a phenomenon referred to as incompatibility. This
simple criterion has enabled investigators to differentiate R plas-
mids into more than 40 incompatibility groups. The mechanism of
incompatibility is not yet understood. It may be related to the
control of plasmid replication.
Different R plasmids may represent a group of genetic elements
of diverse origin. However, even if located on plasmids in different
incompatibility groups, the genes that confer resistance to specific
antimicrobials are very similar. This may be explained by recent
observations that certain antimicrobial resistance genes are located
on segments of DNA (transposons) that may spontaneously translocate
from one plasmid to another, thereby disseminating the resistance
genera) among various plasmids (Kleckner, 1977~. Factors that pro-
mote or inhibit the transfer of R factors In viva are not completely
understood (Jacoby and Low, Appendix C).
The biochemical mechanisms of resistance are known in most
instances. R plasmids confer resistance to antimicrobials either
by encoding for enzymes that chemically modify and thus inactivate
the agent, by specifying a substitute metabolic enzyme that is
insensitive to the agent, or by specifying a decrease in cell
permeability to the agent. All three types of resistance mecha-
nisms may be determined by the same plasmid, whether transmissible
or nontransmissible. Thus, R plasmids are endowed with genes that
increase the probability of survival of host cells in the presence
of combinations of antimicrobials. The continued spread among bac-
teria of resistance to more than one antimicrobial and the further
acquisition of additional resistance genes by individual R plasmids
results from the selection pressure imposed by the use of antimicro-
bials.
A number of factors affect the transfer rate+ of plasmids
between species, e.g., the frequency with which R enteric bacteria
come into contact with other bacteria and the environment in which
they meet. The logistics of transfer of bacteria from animals to
humans and of interbacterial transfer of plasmids may be different
for different organisms. Salmonellae are generally infrequent,
abnormal components of the flora of animals and humans, but when
present they occur in enormous numbers that increase the potential
for transfer at such times. _ coli, compared to the anaerobic
flora, usually constitute a numerically small proportion of the
gastrointestinal flora of animals and humans, but its continuous
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presence (Savage, Appendix D) offers a different potential for
transfer.
Bacterial genetic aspects of drug resistance have been
reviewed by Jacoby and Low (Appendix C). The dissemination of
drug-resistance genes among diverse bacterial genera is also dis-
cussed by these authors as well as by O'Brien (Appendix I). The
epidemiology of plasmid transfer has not been studied in suffi-
cient detail.
Whatever motivation lies behind the use of antimicrobial
agents in any specific situation, the consequences will be the
same. Administration of an antimicrobial will result in a selec-
tion pressure favoring an increase in the prevalence of resistant
organisms.
THE USE OF ANTIMICROBIALS IN HUMAN MEDICINE
The use of antimicrobials in both hospitalized and ambulatory
patients is extensive. Kunin (1979) reported that between 23% to
37.8% of hospitalized individuals receive them. Finkel (1978)
estimated from dispensed prescription data and FDA certification
records that approximately 190 million prescriptions for the major
ant~microbials were filled for ambulatory patients in the United
States in 1977. This is nearly one course of treatment per year
for each person in the United States and includes approximately
43 million prescriptions for tetracycline.
The consequences resulting from the administration of anti-
microbials to humans have been examined by Finland (1979~. Hartley
and Richmond (1975) reported that oral intake of tetracycline leads
to the emergence of a predominantly tetracycline-resistant coliform
gastrointestinal flora within 48 hours in those treated. The excre-
tion of resistant organisms continues at least 10 days after the
treatment is terminated (Richmond, 1975~.
A complete evaluation of the increased prevalence of resistance
to antimicrobials would require consideration of not only the contri-
butions from subtherapeutic and therapeutic use in animals but also
the extent to which these agents are administered to humans. Richmond
and Linton ( 1980) studied the use of tetracyclines in the County
of Avon in England and its possible relation to the excreti on of
tetracycline-resistant bacteria. They estimated that one in 130
individuals in the county carried a large proportion of tetracycline-
resistant organisms in their alimentary tracts. Examination of swabs
from sewers in predominantly residential areas of Bristol (in Avon)
(Lipton _ al., 1974) indicated that approximately 3% of the isolated
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coliforms were resistant to tetracycline. Richmond and Linton
(1980) concluded that, . . . there hardly seems a need to
postulate a veterinary source for the resistant coliforms encoun-
tered in the human population. This is not to say that resistant
_ cold of animal and poultry origin cannot reach the human popu-
lation: clearly they can and do (Lipton et al., 1977~. And some
resistant salmonellae of animal origin certainly seem to have
caused serious human epidemic disease (Anderson, 1968[b]~. But
whether the use of antibiotics in the animal and poultry rearing
industries has a major quantitative impact must be question-
able; . . ."
The approach adopted by Linton and Richmond is necessarily
indirect and requires a number of approximations and assumptions.
Although no similar studies have been conducted in the United
States, the data reported by Kunin (1979) and Finkel (1978) on
prescriptions in this country indicate that the administration of
antimicrobials to humans is widespread.
THE USE OF ANTIMICROBIALS IN AGRICULTURE
The livestock and poultry industry has undergone dramatic
changes since 1950. Operations that were extensive became more
intensive. There were increases in the size of facilities, the
number of animals reared, and a move toward centralization.
Socioeconomic changes, as well as advances in biomedical sciences,
nutrition, engineering, and management, have all contributed to
this evolution.
Shortly after anthmicrobials had been discovered and their
therapeutic use in humans and animals had begun, investigators
J earned that the addition of antimicrobials to animal feed was
effective in growth promotion, improvement of feed conversion,
prophylaxis, and treatment of certain diseases. These effects
of antimicrobials are especially useful when animals are stressed
either by intensive husbandry practices or shipment.
The use of antibiotics (and most probably sulfonamides) in
animal husbandry has steadily increased since 1950 as has animal
production (Table 1~. In 1978 approximately 48% of the antibiotics
produced were designated for addition to animal feeds or for other
(minor) uses (U.S. International Trade Commission, 1979~. The
motivation for such use and the economic consequences of restrict-
ing subtherapeutic concentrations of antimicrobials in feed have
been dealt with in reports by the National Academy of Sciences
Board on Agriculture and Renewable Resources (BARR, Appendix K)
and the U.S. Department of Agriculture (1978~.
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TABLE 1
Antibiotic Production from 1950 to 1978 (millions of kg~a~b
Medicinal Use in Added to Animal Feed and
Year Total Humans and Animals Other Applications
1978 11.66 6.08 5.58
1977 10.48 6.35 4.58
1976 9.30 4. 72 4.54
1975 8. 30 4. 26 4.04
19 74 9.30 5.99 3. 36
1973 9.43 5.72 3.72
1972 7.53 4.45 3.08
1971 8.12 4.90 3.22
1970 7.67 4.35 3.31
1969 5. 99 3. 36 2.63
1968 4.67 2. 72 1.95
1967 4.29 2.36 1.91
1966 4.40 2.45 1. 91
1965 3.40 2.13 1.27
1964 2. 95 1.77 1. 18
1963 3.04 1.91 1.13
19 62 2. 86 1.81 1.04
1961 2.31 1.50 0.82
1960 2.13 1.36 0.77
1959 1.68 1.04 0.64
1958 1.59 1.18 0.41
1957 1.47 1.08 0.39
1956 1.24 0.89 0.35
1955 0.95 0.71 0.24
1954 1.05 0.83 0.22
1953 0.94 0.74 0. 2C
1952 0.79 0.67 0. 12
1951 O. 69 0.58 0.11
1950 0.39 0. 39 Mentioned, but no figure
Data extracted from reports of the U. S.
~ 1951-1979) .
bValues exclude production of sulfonamides.
In te rna t tonal Tr ade Commi s sio n
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The mechanisms by which antimicrobials improve growth and
the efficiency of feed conversion are not fully understood.
Some suggested effects include modification of host metabolism,
nutrient sparing or alteration of nutrient absorption, and selec-
tive activity against microorganisms (BARR, Appendix K).
Total amounts used and patterns of usage, which vary with
species and geographic location, are described in reports by BARR
(Appendix K) and the Animal Health Institute (1979~. Information
on the total amount of specific antimicrobials administered for
each application listed above does not appear to be available.
Certain antimicrobials (streptomycin, tetracyclines, peni-
cillin) are also used to control plant pathogens. Although this
application might also have consequences for human health, the
amounts used are much smaller (Goodman, Appendix B).
The addition of subtherapeutic amounts of antimicrobials to
animal feeds continues to be of concern because of its implica-
tions for human health and because some believe that this use is
unessential. In the United States therapeutic concentrations of
drugs are given to livestock extensively, with or without veteri-
nary prescription. Treated animals are not always isolated from
untreated ones, and animal-to-animal transfer of Rob organisms is
known to occur (Levy, 1978~. Since most herds and flocks receive
antimicrobials somewhere in the production chain either for growth
promotion, prophylaxis, or therapy, it is difficult to identify
slaughtered livestock that have not been given antimicrobials or
have not been exposed to animals that had.
DEF INITION OF HUMAN HEALTH HAZARD
The difficulty of determining whether human health is
affected by the subtherapeutic use of antimicrobials in feeds is
compounded by the diversity of opinions concerning the definition
of a hazard to human health. Some view an increase in the pool
of antimicrobial-resistant bacteria or an increase in Salmonella
shedding by food animals as a source of danger. Others maintain
that a significant hazard to health exists only if antimicrobial-
resistant organisms can be shown to be transmitted to animal hand-
lers or to meat processors. Others attach importance only to the
passage of resistant microorganisms to meat consumers. Still
others view these circumstances as unrealized, potential hazards.
These scientists insist that incremental morbidity and, perhaps,
excess mortality that can reasonably be attributed to resistant
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organisms resulting from subtherapeutic use of antimicrobials
must be documented before risk to human health from this cause
can be substantiated. This divergence of opinion was reflected
in the committee itself.
There are no data from which to predict quantitatively the
change in the morbidity and mortality of humans that might result
from an increased prevalence of resistant bacteria in animals
or from the transfer of these organisms to humans. Although a
measurable risk to human health cannot be ascribed to these phe-
nonema, they remain plausible potential hazards since some of the
individual steps in the transmission chain to humans have been
independently demonstrated but not quantified (see Chapter 3~.
An increased prevalence of resistant bacteria may result from
the administration of both therapeutic and subtherapeutic levels
of antimicrobials to animals and human beings. Thus, the question
is raised whether antimicrobials used subtherapeutically in the
meat industry add measurably to the carriage of resistant organisms,
the incidence of clinical illness, or the number of complications
resulting from antimicrobial resistance in the treatment of diseases.
The committee could find little relevant information on the relative
selection pressures for antimicrobial resistance exerted by continu-
ous low-dose feeding versus intermittent higher, therapeutic doses.
This subject is examined later in this report.
Other possible hazards to health (also discussed below) re-
ceived committee attention but were eliminated from further deliber-
ations because they were not central to the major issue or because
there was insufficient information.
Katz (Appendix E) prepared for committee consideration an
assessment of the potential hazards to humans presented by resi-
dues of antimicrobials in livestock and poultry meat products.
Surveys have shown that slaughtered animals may contain residues
of penicillin or tetracycline that probably resulted from inade-
quate withdrawal times or large dosages (Huber, 1971~. More recent
surveys (Katz, Appendix E; Mussman, 1975; USDA, 1979) indicate that
the residues resulting from penicillin or tetracycline used as feed
additives were generally below the limits currently permitted by
the FDA. Residues of tetracyclines were undetectable in animals
slaughtered 1 to 5 days after withdrawal of antimicrobial-containing
feed. The small amounts of these residues in the muscle tissues of
animals do not survive normal food preparation because of heat in-
activation during cooking (Katz, Appendix E).
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Katz (Appendix E) reported that there has been concern that
the therapeutic use of penicillin has resulted in significant
residues. However, he noted that current regulations governing
the subtherapeutic use of penicillin as a feed additive appear to
result in very low or infrequent residues in meat.
Katz concluded, "It is doubtful that antibiotic residues
or their degradation products will provide any selective pressure
on enteric bacteria contaminating the carcasses of animals." The
committee concurs with this assessment. It believes that further
studies of the effect on human health resulting from penicillin
and tetracycline residues in meat would not elucidate the hazard
from subtherapeutic levels of antimicrobials in animal feeds.
The committee also viewed an assessment of the immunological
consequences to humans resulting from penicillin and tetracycline
residues in livestock and poultry meat products (Adkinson, Appendix
J). Although pertinent information is limited, the committee con-
curs with Adkinson's conclusion that "there is little reason to
believe that foodstuffs obtained from animals fattened with anti-
biotic-supplemented feed impose a significant risk to human health
by contributing to antib~otic-induced allergic reactions."
Adkinson indicated that further investigations in several
areas could provide information that would be useful in clinical
situations. However, the committee believes that immunological
problems arising from the use of antimicrobials in animal feeds
are not a serious health risk for the general population.
In attempting to define the possible hazards to human health,
the committee wished to know how the acquisition of antimicrobial
resistance affected the virulence of pathogens infecting humans
and animals. Since limited conclusive information appeared to be
available (Jacoby and Low, Appendix C), the committee decided not
to review this topic in depth.
Representative terms from entire chapter:
antimicrobial agents
