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OCR for page 22
CHAPTER 3
CRIT ICAL REVIEW OF THE EPIDEMIOLOG ICAL LITERATURE
Ef fects on human health resulting from the use of antimi-
crobials in animal feeds have been reviewed by distinguished
scientists in the United States and Europe. Reports prepared
by the Swann Committee (Swann et al., 1969), the Food and Drug
Administration (FDA) Task Force (FDA, 1972), the FDA Environ-
mental Impact Statement staff (FDA, 1978), the Office of
Technology Assessment (1979), and the World Health Organization
(1974, 1976, 1978) provide extensive coverage of the issues and
background information. The majority opinion expressed in each
report was that an increased prevalence of antimicrobial-resistant
organisms presents a threat to human health and that the subther-
apeutic use of antimicrobials increases the prevalence of R
organisms in animals. In all of the reports authors were not able
or did not attempt to quantitate or estimate the relative contri-
but~on of the subtherapeutic use of antimicrobials in animals to
health problems in humans caused by R+ organisms--one of the
objectives of this study. Majorities of the individuals involved
in these various studies recommended policies aimed at restricting
the subtherapeutic use of ant~microbials in animal feeds, particu-
larly for those agents used in the therapy of diseases in humans.
The therapeutic use of antimicrobials in both animals and
humans has been shown to result in an increased prevalence of
resistant bacteria (Anderson, 1968a; Finland, 1979; Mercer et al.,
1971~. Similar results have been demonstrated for subtherapeutic
use in both animals and humans (Goldberg et al., 1961; Savage,
Appendix D; Siegel, 1976; Sprunt, 1977~.
There is little evidence to indicate the quantitative contri-
butions of these usages to effects on human health attributable to
antimicrobial-resistant bacteria. The epidemiological literature
on this topic is reviewed below.
INVESTIGATIONS OF EPIDEMICS
A number of investigations of epidemics have indicated that
antimicrobial-resistant bacteria from animals can cause infections
in humans (Anderson, 1968a; Anderson and Datta, 1965; Center for
Disease Control, 1977; Fish et al., 1967; Lyons et al., 1980; Rowe
_ al., 1979; Threlfall et al., 1978a, b). Some of these epidemics,
involving Salmonella typhimurium phage type 1 (Anderson and Datta,
1965), phase type 29 (Anderson, 1968a), and phage types 204 and 193
22
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23
(Rowe _ al., 1979; Threlfall, 1978a,b), took place in the United
Kingdom. One case in Canada was also caused by S. typhimurium
(Fish _ al., 1967~. Another outbreak, which took place in
Connecticut, involved S. Heidelberg (Center for Disease Control,
1977; Lyons et al., 1980~.
In the earlier outbreaks in the United Kingdom, there was
substantial evidence indicating that the resistant bacteria were
selected by indiscriminate therapeutic use of antimicrobials in
animals (Anderson, 1968a; Anderson and Datta, 196
5~. The value
of phase typing, as it is used in the United Kingdom, is its clear
demonstration that the entire sequence of events involved in trans-
mission of R+ organisms to humans via food is possible. In the
Connecticut outbreak, the investigators demonstrated that the
reservoir of the multiply resistant Salmonella infection was likely
to have been harbored by a group of 1-week-old calves owned by one
of the ill persons. Lyons et al. (1980) indicate that these calves
had been treated by their owner for the diarrhea that they had when
brought to the owner's farm. In the Canadian case, the patient
became ill approximately 1 week after illness was observed in a cow
with which he had had direct physical contact. The cow had been
treated therapeutically with antimicrobials by the owner at the
onset of the illness. Organisms identified as S. typhimurium phase
type 10 with identical antimicrobial-resistance profiles were iso-
lated initially from the cow and later from the patient. Although
reports of these epidemics document the transfer of resistant bac-
teria from animals to humans, there are no studies to quantitate
the frequency of that occurrence.
Furthermore, not all observations have reinforced the sugges-
tion that a reservoir of resistant bacteria in animals provides the
major source of resistant bacteria in humans. In a study conducted
in Omaha, Nebraska between 1968 and 1978, Meyer and Lerman (1980)
documented the rise and fall in prevalence of resistant strains of
Shigella sonnet, which was a predominant pathogen in humans during
that period. In 1973, they observed a peak in the prevalence of
resistance to ampicillin and a similar pattern of resistance to five
other antimicrobials. There was no evidence that the use of ampi-
cillin in humans had changed during the course of the study.
Cherubin et al. (1980) reported a very similar pattern of rise
and fall of resistance to ampicillin for Salmonella typhimurium iso-
lated in New York City from 1965 to 1968. He attributed this pattern
in humans to an epidemic of a resistant strain but pointed out that
isolates from calves and other animals in New York State did not
exhibit a similar change. Calves continued to harbor ampicillin-
resistant strains at a prevalence that increased annually from 1972
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24
to 1978. Thus, there is evidence for waves of resistant enteric
flora in humans and in animals that do not correlate we th each
other or with patterns of antimicrobial usage in humans. This
suggests a substantial degree of separation of reservoirs in
humans and animals.
POPULATION SURVEYS
By conducting retrospective health surveys of farm families,
rural families with no animals, and urban families, all having
had a recent hospital admission, Smith et al. (1974) attempted to
determine whether association with farm animals was connected with
greater risk of disease. Comparing admission diagnoses, they found
no significant differences and no preponderance of antimicrobial-
resistant bacterial disease. However, since there were insufficient
numbers of subjects in the survey and the study design was not sat-
isfactory, no general conclusion can be drawn.
In other attempts to determine the possible consequences to
human health from the subtherapeutic use of antimicrobials in ani-
mal feeds, investigators have studied the relative prevalence of
antimicrobial-resistant bacteria among various groups or have
attempted to demonstrate the possibility of particular steps in the
chain connecting the antimicrobials in animal feeds to increased
carriage of R+ bacteria in humans. Discussions of many of these
studies are contained in the consultant reports to the committee
(Appendixes A-J). Those that deal with the epidemiological aspects
of the question are reviewed briefly below. Limitations on the
inferences that can be drawn from these narrow studies are detailed
in Chapter 2.
As far as the committee could determine, there ha+e been no
adequate attempts to relate an increased carriage of R organisms
to putative increased morbidity and mortality or dilemmas caused
by resistance in the treatment of infection. Thus, predictions of
the magnitude of any possible risk cannot be made from results of
studies on particular stages or steps in the transmission chain.
The prevalence of resistant enterobacteria in groups with vary-
ing exposure to domestic livestock has been investigated by Betinov]
(1972), Dorn et al. (1975), Fein et al. (1974), Linton et al. (1972),
Siegel (1976), Siegel et al. (1975), Smith and Crabb (1961), Smith
_ al. (1974), Wells and James (1973), Wiedemann and Knothe (1971),
and Woods et al. (1972~.
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25
Smith
resistance
~. . ~
al e (1974) compared the proportion of E. cold with
antimicrobials among several groups of Iowa families
and their livestock. They compared rural families with and with-
out livestock, urban families, and both urban and rural families
in which one member had recently been discharged from hospital in-
patient status. Results generally indicated that the proportion
of _ cold with resistance to four or more antimicrobials was
greatest among families with livestock, regardless of their recent
association with hospitals, and lowest among both urban and rural
groups without a recent hospital association or proximity to
livestock. These results include neither quantification of the
transfer of resistance between animals and humans nor specifica-
tion of resistance patterns. Since all livestock raised by these
families had received some antimicrobials, some members of these
families had been exposed to both the livestock fed antimicrobials
and the feed containing the antimicrobials. However, the study
does suavest that persons working with livestock that are receiving
antimicrobials do harbor more resistant E. cold than do families
not exposed to livestock.
independent of recent hospital exposures.
Unfortunately, the history of antimicrobial use by these humans
was not documented.
Comparing rural and urban dwellers in England, Linton et al.
(1972) found a much higher proportion of drug-resistant coliform
bacilli in the feces of rural adults working with livestock than
in rural adults not so employed. Urban adults harbored an inter-
mediate proportion of resistant organisms. Both urban and rural
children less than 5 years old harbored the highest proportion of
all groups tested. Although this finding suggests an association
between working with livestock and increased levels of resistant
organisms, the authors supplied no information on antimicrobial
usage in either animals or humans nor was there a comparison of
specific resistance patterns between the flora of the animals and
that of the humans exposed to them.
Dorn _ al. (1975) conducted a small study comparing the
specific resistance patterns between Missouri farm families raising
beef and hogs and their
and consuming home-raised meat and their animals. They found
significant association between resistance patterns in animals and
families who consumed home-raised meat but not between patterns in
animals and families who did not consume meat they raised. They
concluded that the exposure of humans to E. cold from animals
through consumption of meat was more plausible than mere contact
with animals as an explanation for interspecific crossover of
transferable drug resistance.
animals and between families both raising
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26
Siegel _ al. (1975) compared the proportion of antimicro-
bial-resistant colifonms in five groups of Illinois persons with
varying exposure to antimicrobials and animals fed antimicrobials.
They found that the proportion of the enteric flora with resist-
ance to antimicrobials in these groups ranked in the following
decreasing order: (1) people working on farms in contact with
farm animals receiving antimicrobials in feed, (2) people residing
on the same farms but not in contact with the animals, (3) people
treated with antimicrobial drugs, (4) untreated people residing
with treated individuals, and (5) untreated people not residing on
livestock farms. In general, groups 1, 2, and 3 had similarly high
proportions of colifonms with resistance to oxytetracyclines, dihy-
drostreptomycin, and ampicillin, group 5 had the lowest proportion,
and group 4 was usually intermediate. These results indicate that
living on farms, raising livestock fed antimicrobials, or being
treated with antimicrobials resulted in approximately equivalent
proportions of organisms with resistance to these three antimicro-
bials and that persons without direct exposure to antimicrobials
or animals fed antimicrobials have fewer resistant organisms. Since
Siegel and his colleagues presented few data concerning specific
antimicrobials used in humans or animals or specific matching re-
sistance patterns, it is not possible to evaluate the role of feed
containing subtherapeutic levels of antimicrobials in increasing
the prevalence of resistant bacteria in either animals or people.
From studies conducted in the Federal Republic of Germany,
Wiedemann and Knothe (1971) indicated that both farm workers and
city dwellers carried enterobacteria with resistance to antimicro-
bials (in some cases plasmid-med~ated), but that the proportion of
the total enterobacterial flora with resistance was higher in farm
workers. The significance of the results they obtained by comparing
the percentages of farm workers, their relatives, feed handlers,
city dwellers, slaughterhouse workers, chickens, calves, and pigs
carrying resistant Enterobacteriaceae cannot be evaluated since
the number of subjects in each category was not reported.
Each of the studies noted above suffers from various methodo-
logic deficiencies that should be avoided in future efforts. None
adequately quantitates the nature and extent of exposure to antimi-
crobials. Particularly lacking are data pertaining to those drugs
given therapeutically to the study subjects. Moreover, the studies
do not specify the type of antimicrobial given to the animals. Most
of the investigators do not adequately describe the contact between
the animals and the subjects. Since these studies are cross-sectional,
they can indicate whether an association exists between an increased
prevalence of resistant bacteria in humans and contact with animals,
or direct contact with feeds containing antimicrobials, but cannot
establish that such contacts cause the increase. In only one study
OCR for page 27
27
was there an attempt to match the specific resistance patterns
of _ cold from animals to those from exposed humans. None of
the studies adequately documents the health status of the study
subjects.
Despite their limitations, these studies lead to certain
conclusions. Animals fed antimicrobial agents for extended
periods or treated with antimicrobials develop resistant entero-
bacteria. People in close contact with those animals and their
antimicrobial-containing feed are more likely to harbor resistant
organisms in their gut flora than those without contact with
animals. Patients who have received therapeutic drugs have a sim-
ilar or even greater likelihood of carrying resistant organisms.
Children who have not personally received antimicrobials also seem
to have a high prevalence of R+ organisms in their flora for rea-
sons that are currently not clear. Future studies can be based on
the assumption that these conclusions have been reasonably well
established.
Two more surveys that deserve attention compared the preva-
lence of resistant E. cold in meat-eaters and in those who did not
eat meat. Such a comparison would indicate if eating meat from
animals that were presumed to have received antimicrobials was asso-
ciated with an increased carriage of R+ organisms. In a study by
Guinke _ al. (1970) the groups selected as meat-eaters were mili-
tary kitchen personnel and office workers; those who did not eat
meat were vegetarians and infants less than 6 months of age. Because
the groups were relatively small and not strictly comparable, the
conclusions drawn from these studies are questionable. But the
percentages of the 77 vegetarians and 87 infants yielding resistant
_ cold were not significantly lower than those in the meat-eating
groups. This study does not provide evidence that eating meat is
associated with an increased intestinal carriage of resistant coli-
fonms.
Lebek (1972) reported the distribution of R factors among E`.
cold isolated from feces of healthy and ill human subjects. The
percentages of various groups studied having R+ organisms in their
fecal flora were: hospital patients, 84% (74 of 88~; healthy nurses,
82% (82 of 100~; healthy soldiers, 51% (26 of 51~; healthy 6-9 year
olds, 65% (66 of 101~; and healthy vegetarians, 57% (16 of 28~.
The vegetarians were described as belonging to a religious c~mmun-
ity that takes no drugs and lives on a vegetarian diet," and the
children, according to their parents, had not received antimicrobial
drugs during the 2 years preceding the investigation. Although it
is difficult to determine if the groups were strictly comparable, the
results again do not support the concept that eating meat is asso-
ciated with an increased intestinal carriage of resistant colifonms.
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28
EXPERIMENTAL STUD IES
In the experimental studies described below, investigators
have examined aspects of the transfer of resistant bacterial
strains from animals to humans. By themselves these studies do
not allow quantitative prediction of risk for the general popula-
tion.
Hirsh and coworkers (Burton _ al., 1974; Hirsh et al., 1974~_ _
examined the effects of varying doses of oxytetracycline (OTC) on
colonization of the gut in humans following ingestion of resistant
E. cold of bovine origin. No differences were found in length of
time the organisms were excreted by those fed either O or 50 mg
OTC/day, but 1,000 mg/day did potentiate the establishment of tetra-
cycline-resistant E. colt.
In more direct experiments, Smith (1969) fed to a human various
doses of resistant E. cold of animal origin containing unique resist-
ance markers. The resident strains occasionally acquired resistance
from the animal donor strains but the resistance was not maintained.
In an experiment that simulated the most likely exposure to be
encountered by the general public, Linton (1977) studied five humans
who, over a period of 3 months, handled, cooked, and ingested 15
chickens that had been sampled for E. colt. One of the five subjects
was clearly colonized after handling but before eating. The coloniza-
tion was transient. As in the experiment by Smith, plasmid-mediated
resistance from E. cold in chickens was transferred to a strain of
_ cold in the original resident flora of the human host.
In "feeding" studies, highly artificial conditions are sometimes
created, e.g., huge doses are sometimes fed to a subject in a medium
such as bicarbonate. Hence, results must be extrapolated with caution.
In two more experiments, investigators attempted to determine
whether the administration of low doses of tetracycline to animals
resulted in the transfer of resistant bacteria to humans. Hirsh and
Wiger (1977) studied the fecal flora from 30 calves, 16 of which were
fed 350 mg/day of tetracycline, and from their 20 handlers. A low
level of transfer was found irrespective of whether the calves were
receiving tetracycline.
Levy and coworkers (Levy, 1978; Levy et al., 1976a,b) observed
an increased prevalence of antimicrobial-resistant intestinal bac-
teria in a farm family in contact with chickens fed tetracycline and
the tetracycline-containing feed. Later, they detected resistance
in organisms isolated from chickens not fed antimicrobials and from
farm personnel other than the family. Of particular interest was
the reversibility of the apparent selection for resistant organisms
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29
after 9 months of usage. This was indicated by the finding that
resistant organisms were not observed 6 months after discontinuance
of the supplement. Furthermore, the use of only one antimicrobial
(tetracycline) did lead to selection of strains with multiple
resistance. There were some problems with the design of this study.
More appropriate controls could have been used, and the sampling
frequencies could have been more nearly equal. Resistance patterns
reported in the earlier paper by Levy et al. (1976a) did not always
include resistance to tetracycline, the agent in the chicken feed
exerting the selection pressure.
When the results of these studies are examined together, they
suggest that supplementation of animal feeds with antimicrobials
can select for resistance in the enteric organisms of animals. This
resistance can be transferred to humans who are in contact with
these animals and their feeds or to those who handle the carcasses,
e.g., those who prepare food for cooking. The resistance profiles
selected may include resistance to agents in addition to those added
to the feed since resistance genes are often linked. In some studies
the prevalence of resistance has been shown to decline when supple-
mentation is discontinued. In other instances herds receiving feed
believed to be free of antimicrobials and with no recent history of
antimicrobial therapy have a high prevalence of R+ organisms (Smith
et al., 1974)e This may be attributable to contamination of the
feed (Siegel, 1976~. In January 1980, this topic was discussed at
a conference sponsored by the U.S. Department of Agriculture on the
contamination of feed by the sulfonamides. However, it cannot be
predicted with certainty that the overall prevalence of antimicro-
bial-resistant organisms in animals will decrease to low levels if
the subtherapeutic use of antimicrobials in feed is ended.
A large and complicated study was designed and conducted by
Siegel (1976~. He attempted to use bacteriophage typing to identify
E. cold strains so that he could follow their transfer from various
.
animal sources to humans--on the farm, in the slaughterhouse, or
in the surrounding community. Despite some methodological problems,
the study indicates that swine were the probable source of bacterial
phage types that were found in poultry and beef cattle. These phage
types were the same as those found most often in humans on farms.
Presumably, they also originated from the pigs. Some of the farm
strains that were prevalent on the carcasses were also found in
slaughterhouse workers and in the slaughterhouse. There was evi-
dence that other strains--some of which were carried by the workers
or were present in the slaughterhouse--were transferred onto the
carcasses at this point. Analysis of the flora of the consumers of
the pork products was more difficult. Although pork consumers shared
some common phage types with the workers in the slaughterhouse and
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30
on the farm, the route and extent of transfer was impossible to
measure. This type of observational study is limited in what it
can demonstrate, since it cannot indicate the direction in which
organisms transfer. Genetically marked organisms, such as those
used by Smith (1969) and Hirsh et al. (1974), might provide a
better technique for following transmission.
CASE REPORTS
Some case reports provide evidence for the transfer of plasmid-
mediated resistance under normal conditions. Petrocheilou and
coworkers (1977, 1979) described tetracycline-resistant plasmids
found in a number of E. cold strains from a woman who had received
prolonged tetracycline treatment for acne vulgaris. Her husband,
who had received no antimicrobial therapy, also harbored such strains.
The two E. cold strains were indistinguishable as were the plasmids
they carried. This observation suggests that E. cold carrying R
plasmids may spread from individuals under treatment to untreated
close contacts.
The study by Neu _ al. (1973) suggested that specific resis-
tance patterns could be transferred (in the intestines of one patient
and in the urinary tract of another) from one organism to another.
The transfer was suggested by the similar spectra of antimicrobial
resistance. Corroboration of the transfer by plasmid DNA homology
studies, such as those reported by Petrocheilou and coworkers (1977,
1979), was not attempted in the study of Neu et al. (1973~.
Brumfitt and coworkers (1971) studied urinary tract infections
caused by E. cold in patients living at home. Seven (19%) of 37 fe
male patients had infections characterized by resistant E. cold
and 23 (62%) carried some resistant E. cold in their fecal flora.
In eight patients who had predominantly resistant (> 607) E. cold
fecal flora, five had urinary tract infections characterized by
resistant E. colt. In 15 patients whose fecal flora contained a
~-
lower proportion of resistant E. cold (0-507), only one patient had
a urinary tract infection characterized by a resistant strain. From
these findings, the investigators concluded that resistant strains
of E. colt, when carried in the intestine, were neither more nor less
likely to infect the urinary tract than were nonresistant strains.
SUBTHERAPEUTIC USE IN HUMANS
The committee also examined reports pertaining to the conse-
quences of long-term administration of subtherapeutic levels of
ant~microbials to humans to learn if there were adequate data which,
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31
upon extrapolation, might allow conclusions to be drawn about the
effects on Herman health that could result from sub~herapeutic
levels of antimicrobials in animal feeds.
Goldberg et al. (1961) demonstrated that low dosages (10 mg
per day) of OTC increased the prevalence of resistant bacteria
in prison volunteers. Some subjects who did not receive OTC shed
resistant coliforms. In those individuals whose resistant bacter-
ial flora was increased by OTC, the prevalence of resistant coli-
forms returned to normal within 2 months after the OTC treatment
was stopped.
Haight and Pierce (1954) reported a study in which naval
recruits were given 250 mg of chlortetracycline or 100,000 units
of procaine penicillin per day orally for 7 weeks. Those
receiving antimicrobials gained more weight than did the controls.
There are a number of categories of infections for which anti-
microbials have been used prophylactically in humans (Utz, Appendix
A). A major use is the administration of tetracyclines to control
acne in adolescents (Schmidt et al., 1973~. Antimicrobials are also
used in the prevention of endocarditis subsequent to rheumatic fever
(McVay and Sprunt, 1953~. Valtonen et al. (1977) have described the
effects on enteric bacterial flora that result from neomycin prophy-
laxis in patients with hypercholesterolemia.
The committee examined many original research reports and a
number of review articles on the subtherapeutic use of antimicro-
bials in humans including the following. Many papers on the use of
tetracyclines to control acne have been reviewed by the American
Academy of Dermatology (1975~. Jukes (1973) described a variety of
reports on the long-term administration of antimicrobials to infant
and children or to patients with tropical sprue. Reports on the sub-
therapeutic and prophylactic use of antimicrobials in humans have
been reviewed extensively by the Council for Agricultural Science
and Technology (in press) and Pfizer, Inc. (1978~.
The subtherapeutic or prophylactic administration of antimi-
crobials to humans generally results in an increased prevalence of
resistant organisms in the recipient. Sprunt (1977) demonstrated
that this increase is lower when intermittent doses are injected
intramuscularly than when prophylaxis is administered orally. More-
over, she reported that lower doses eliminate only a small portion
of the resident flora, thereby permitting fewer resistant organisms
to survive and multiply.
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32
In most of these studies no added health risk attributable
to resistant organisms was recorded. However, the number of
individuals involved in any one study of prophylaxis was small,
and the study designs did not have as their primary objective
the detection of adverse health effects of antimicrobial use.
Thus, it is not possible to quantify the risk of infection from
resistant bacteria resulting from such antimicrobial usage. Risks
from prophylactic use are indicated in a recent report of two
patients who developed endocarditis due to resistant viridans
streptococci after undergoing oral penicillin prophylaxis subse-
quent to rheumatic fever (Parrillo et al., 1979~. How commonly
this happens is not known. Since reports of such occurrences
are rare, the committee believes that they probably occur infre-
quently.
EXPERIENCE WITH REGULATIONS IN OTHER COUNTRIES
Surveys of resistance in isolates from animals and humans
have been conducted in several countries following the institu-
tion of various regulations governing the addition of antimi-
crobials to animal feeds. The reports of these surveys should
be reviewed although they contain information that is far from
conclusive. Moreover, surveys of the prevalence of resistance
do not necessarily indicate "qualitative" changes in resistance,
e.g., new combinations of resistance, more efficient transfer
mechanisms, or a wider potential host range for a new plasmid.
In the United Kingdom the regulations recommended by the
Swann committee (Swann _ al., 1969) were implemented in 1971
although no baseline data on antimicrobial use or resistance
patterns had been collected. The development of the regulations
and their effects have been reviewed by Braude (1978), Linton et
_ . (1977), and Smith (1977~. The "Swann regulations" restricted
primarily feed supplementation with antimicrobials that have value
in the therapy of infections in humans. However, the restricted
antimicrobials have remained available through veterinary pre-
scription for use in animals. Smith (1977) reported that "in the
four years since [the 'Swann'] prohibition, the amount of tetracy-
cline-resistant _ cold in the pig population might have decreased
slightly but the incidence of pigs excreting these organisms (100%
in 1975) had not." In the United Kingdom, SoJka et al. (1977) re-
ported that from 1971 to 1974 there was no evidence of a consistent
decline in total resistance; however, they reported a small increase
in resistance to tetracycline in salmonellae isolated from animals.
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33
Since 1974, 30%-35% of the Salmonella isolates from humans in
.
the United Kingdom have been resistant to antimicrobials. Recently,
there has been a rise in multiple resistance due to a particular
prevalent phage type. In 1965, also in the United Kingdom, approx-
imately 40% of the Salmonella isolates from bovines were resistant.
By 1978 this had risen considerably: approximately 70% of the Salmo-
nella isolates from bovines were resistant (L. Ward, Central Public
Health Laboratory, United Kingdom, personal communication). Linton
_ al. (1977) and Braude (1978) point out that there is little
indication that the overall sales of antimicrobials for veterinary
use have declined as a consequence of the Swann regulations. Farm
animals may well be receiving the same amounts of antimicrobials as
in the past, ostensibly for different purposes, i.e., prophylaxis or
treatment of disease rather than for growth promotion, and possibly
by alternative routes of administration (Braude, 1978~.
Regulations developed by the European Economic Community to
control the use of antimicrobials in animal feeds came into force
in 1974. They proscribed the addition of tetracyclines to feed, a
practice that had been increasing in the Netherlands since the
1960's. Subsequent to this prohibition, a decrease in the prev-
alence of tetracycline-resistant strains of Salmonella in pigs and
~ ~ A _ (1979~. It is difficult
to attribute this decrease unequivocally to the ban on tetracyclines
as feed additives since an epidemic of one antimicrobial-resistant
phase type (505) of Salmonella typhimurium contributed greatly to
the prevalence of resistant strains in the early 1970's. It is
questionable whether the decrease in resistance to tetracv~line
after 1974 was due to the chance in regulations or to
humans was resorted by van Leeuwen et al.
=_ _ _O~ _ __ the cessation
of the epidemic of this particular resistant strain in both humans
and pigs. The prevalence of resistant strains before that epidemic
was similar to the levels after regulations came into force. A
similar decrease in resistance was not observed in isolates from
calves for which tetracycline is still used therapeutically. Phage
type 505 of S. typhimurium was not prevalent in this species. There
are no data to show if the use of tetracycline has in fact decreased
during the period studied by van Leeuwen and colleagues (1974-1978~.
In the Federal Republic of Germany, Bulling and coworkers (1973)
and Stephan et al. (1976a,b, 1977a,b) reported a decline in tetracy-
cline-resistant S. typhimurium and S. Panama in calves and pigs
since the 1974 ban. There are no comparable data on isolates from
humans in Germany nor on antimicrobial use in that country.
A specific strain of S. typhimurium (phase type 505) was a
major contributor to the resistance pattern in the Netherlands and
the Federal Republic of Germany. Since the epidemic caused by that
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34
strain has now dissipated, it remains to be seen whether the
trend of reduced prevalence of resistance will continue.
Data from Europe do not indicate whether restrictive
regulations have actually reduced or averted hazards to human
health.
CONCLUS IONS DRAWN FROM THE LITERATURE
Relatively little research on the subtherapeutic use of
antimicrobials in animal feeds and the use of antimicrobials in
animals generally is truly epidemiological.
Reports are often
based on regrettably few subjects observed for brief periods. The
findings of such research are fragmented bits of information con-
cerning isolated sections of the meat production system. Therefore,
they do little to resolve the question: does the subtherapeutic use
of antimicrobials in animal feeds relate to excessive morbidity and
mortality of humans? However, the data indicate that antimicrobial-
resistant organisms transfer from animals to humans who have been
in contact with them on farms. Moreover, abattoir workers have
been shown to harbor the same phase types as found in farm animals.
The extent of subsequent person-to-person exchange has not been
adequately determined. Furthermore, there is no evidence to prove
that resistant bacteria are more prevalent among people consuming
meat and meat products than among other groups.
There are no data linking human illness with the subtherapeu-
tic use of antimicrobials in any aspect of animal husbandry, but
the absence of information is certainly not to be equated with proof
that the proposed hazards dd not exist. For many questions pertain-
ing to the subtherapeutic use of antimicrobials, the research is
inadequate or nonexistent. The committee discussed in detail how
this situation might be remedied.
Chapter 4.
Its suggestions are contained in
Representative terms from entire chapter:
animal feeds
