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CHAPTER 2
MEASURING EFFECTS ON HUMAN HEALTH FROM THE SUBTHERAPEUTIC
USE OF ANTIMICROBIALS IN ANIMAL FEEDS
A complex chain of events begins with the addition of sub-
therapeutic levels of antimicrobials to animal feed, proceeds to
the selection of bacteria bearing R plasmids in the animal gut
and the transfer of these bacteria to humans (or their plasmids
into the flora of humans), and ends with possibly adverse effects
on human health.
The entire chain can be thought of as a stochastic process.
All steps of the chain are apparently possible, but have not been
quantified. For example, the extent of the normal transfer of R+
organisms between animals or between animals and humans has not
been adequately measured.
The entire length of this chain is germane to this study,
i.e., how does a change in the addition of antimicrobials to
animal feed at the beginning of the chain alter the probability
or severity of diseases or the ability to treat them at the end
of the chain?
A number of complications can arise when attempting to re-
solve this question. This is illustrated by the following series
of questions that should be addressed when treating a hospitalized
patient suffering from septicemia due to Salmonella.
1.
Is the Salmonella strain resistant to antimicrobials?
2. Is the resistance plasmid mediated?
3. Was the Salmonella resistant to drugs when the infec-
tion occurred or did it acquire resistance through
transfer of an R factor from the patientts resident
microbial flora?
4.
Did the patient acquire the Salmonella infection from
contaminated meat or from another person?
5. If the infection was acquired from meat, had the
animal received an antimicrobial?
Was the antimicrobial given to the animal for growth
promotion, for prophylaxis, or for treatment of an
illness?
12
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7.
If the Salmonella acquired resistance by it-factor
transfer from E. colt, was the resistant E. cold
selected by an antimicrobial used in previous treat-
ment or did the patient acquire a resistant E. cold
strain from another person or from ingestion of con-
taminated meat? If the resistant strain was acquired
from another person, was that person infected via
the food chain and did the food chain begin with an
animal that had received subtherapeutic doses of
antimicrobials?
Determination of the answers to all of these questions for
an individual patient is obviously very difficult and may well be
impossible.
Antimicrobial use varies greatly among producers of cattle,
swine, and poultry, within each of these subsets of the industry,
and among different parts of the country. Moreover, the distribu-
tion channels are long and complex. Consequently, a consumer may
purchase meat that was processed in a distant plant from animals
raised in a still more distant place.
The beef consumed by a household may have come from a feedlot
in which antimicrobials were used only to treat sick animals, but
its pork may have come from pigs fed tetracycline for growth promo-
tion. Even if Salmonella may be judged more likely to have come
from one source than from another, it may have acquired resistance
by plasmid transfer from E. cold derived from either source.
EPIDEMIOLOGICAL STUDIES
The definitive epidemiological study of effects related to
the subtherapeutic use of antimicrobials in animal feeds should
encompass all aspects of meat production from animal breeding to
consumption.
Methods
The committee examined the approaches that could be taken
to relate the subtherapeutic use of antimicrobials in animal feed
to the risk of increased morbidity and mortality in humans. It
then grouped these approaches into six categoriese
Cross-Sectional Studies (Population or Prevalence Sur-
veys). Total communities, random samples of a total community,
or selected subsets of a population may be identified and asked
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14
to provide answers to questions, undergo laboratory or clinical
procedures, or both. Such surveys are conducted once, and the
findings are customarily presented as prevalence ratios of a
disease or condition between populations. Differences in the
prevalence of the disease or condition in demographic subgroups
may be interpreted as reflecting differences in risk caused by
the exposure under study. Specifically-, populations that have
had considerable exposure and others with minimal exposure to
animals receiving antimicrobials via their feed could be surveyed
to determine the prevalence of some+specific conditions, e.g.,
urinary tract infection caused by R organisms. The results of
such surveys may be confounded by differences in prevalence of
some associated causal or risk factors, such as socioeconomic sta-
tus. For instance, elevated rates of diarrhea! disease in farm
workers handling feed containing antimicrobials, when compared to
rates in nonfarm groups, may be due as much to differences in
sanitation in the work and home environments as to the acquisition
of resistant pathogens from animals.
Surveys are conducted frequently because they are relatively
inexpensive and generally quite rapid. Survey data are generally
unreliable in identifying the differences between statistical asso-
ciation and cause and effect, partly because the effects of time
are difficult to incorporate into a cross-sectional survey. This
weakness presents a particular disadvantage in any situation
that changes over time.
Case-Comparison Studies. The characteristics of patients
with a disease or other condition may be compared with those of
a group of people who are free of the disease or condition, but
whose other characteristics, such as age, sex, race, and history
of exposure to therapeutic levels of ant~microbials, are similar.
The comparison subjects are often selected from the same clinical
setting in which the cases were discovered, but may be selected
from groups living in the same neighborhood or perhaps by a random
sampling of the general community. The characteristics of both
groups and the exposure to which they have been subjected are sur-
veyed retrospectively. For instance, patients with a disease be-
lieved to be attributable to resistant microorganisms can be
matched with comparison subjects. Exposure to animals, to animal
products, or to feed containing antimicrobial agents is the deter-
mined retrospectively. The efficiency of such a study may be im-
proved by careful selection of comparison subjects to match the
characteristics of the cases. The relative risk associated with
certain characteristics, such as degrees of exposure to antimicro-
bials in animal feed, may be estimated by calculating odds ratios.
Such studies may be relatively inexpensive and can be conducted
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15
rapidly, but they require careful predetermination of the char-
acteristics to be matched and investigated retrospectively. If
important variables are missed or mismatching occurs, results may
be interpreted incorrectly.
Cohort Studies. Variables related to risk of a population
or a selected subset of a population may be identified and char-
acterized, and the study group followed over time to observe new
cases of illness. For instance, generally healthy individuals with
high exposure to animal feeds containing antimicrobials, or to meat
from animals that consumed such feed, and other members of the same
community without such exposure may be followed for a year or longer.
Populations with different exposures can be examined for differences
in incidence or severity of diseases or for difficulties encountered
during their treatment. The differences in these measurements will
reflect the risk associated with the different exposures.
Cohort studies are generally considered to be the most effec-
tive approach to establishing differences in risk associated with
various conditions, but they are expensive and time-consuming.
Moreover, they require careful recordkeeping, meticulous followup of
the cohort, and attentiveness to ensure that differences in medical
care or inaccurate definitions of morbid events do not confound the
study.
Experimental Studies. After a defined study population is
-
identified and characterized, an appropriate subgroup is subjected
to an experimental procedure. The test group is then followed to
observe the effects of the procedure. The remainder of the initial
group serves as a control. Experimental studies, particularly when
the exposed group is randomly selected, are very effective in estab-
lishing the cause-and-effect relationship between the experimental
variable and the observed outcome. Thus, if it were possible to
select a large number of subjects and randomly assign them to groups
that are or are not exposed to animals fed antimicrobials or to the
products of those animals, useful information would undoubtedly
accrue.
The performance of experimental studies with humans may be
questioned on ethical grounds if there is any known or theorized
hazard of the exposure being investigated. Moreover, such con-
trolled trials are frequently very difficult to conduct because
the subjects may not adhere to the regimen to which they have been
randomly assigned. Experimental studies cannot yield definitive
information on the likelihood that similar effects would result at
similar frequencies under natural conditions.
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Investigation of Epidemics. Outbreaks of a disease may be
investigated retrospectively with epidemiological methods. Such
investigations cannot quantitate the prevalence of diseases since
only reported cases can be investigated. Nevertheless, they can
be useful in establishing a probable chain of transmission.
Case Reports/Case Series. Although not an epidemiological
method, reports of individual cases or series of cases may also
establish that a particular sequence or chain of events is possi-
ble. They cannot be used to predict the prevalence of a disease
or condition or the risk of any practice.
WHAT IS THE IDEAL STUDY?
The ideal study would start with the selection of animal-
rearing facilities marked by sharply different practices in
antimicrobial use--i.e., no use; subtherapeutic use in feeds
for improving growth and feed conversion and for prophylaxis;
intermittent therapeutic use; and both subtherapeutic and
therapeutic use. A substantial number of facilities in each
selected category should be studied to ensure that any observed
differences in flora are more likely to be related to differences
in antimicrobial use rather than to other confounding variables.
Fecal specimens should be examined from a large enough s~m-
ple of animals in each flock or herd to monitor changes in the
proportion of animals carrying Salmonella spp. and E. cold with
resistance and the percentage of these resistant organisms in
each animal's flora. Ideally, full microbiological characteriza-
tion of the flora, both aerobic and anaerobic, should be performed
for both animals and humans. Special attention should be given to
changes in those indices associated with intermittent therapeutic
applications of antimicrobials.
Similar studies should be conducted of employees, their fam-
ilies, and a comparison group of neighbors employed in other
occupations to determine whether their microflora follow patterns
like those observed in animals.
At the next several steps in the production chain--the slaught-
erhouses and wholesale and retail butcher shops--bacteriological
studies of carcasses, the work environments, employees, their fami-
lies, and their neighbors should be pursued over time to determine
whether changes in the indices of drug resistance occurring in the
production facilities can be traced through the processing plants.
The processing plants should, of course, receive meats from only
one of the specified categories of animal producers.
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17
Finally, these same investigative techniques should be used
in comparable communities where the meats and meat products are
sold, prepared, and consumed, still separated by the type of anti-
microbial use in animal feeds at their sources. Selecting c~mpar-
able communities may be difficult since many factors need to be
matched, e.g., the degree of hygiene in butcher shops. Samples
of households should be selected, and the enteric bacteria of the
family members should be characterized. The sampling would permit
community-wide estimates of the prevalence of both resistant and
susceptible Salmonella infection, as well as the prevalence of
colonization with resistant E. colt. A system of defining, identi-
fying, and recording illnesses should be established in order to
compute the rates of disease caused by Salmonella and to determine
the special problems that result from illnesses attributable to
resistant strains.
Attempts should be made to trace the spread of Salmonella
infection in these communities, identifying wherever possible
cases attributable to contact with or consumption of contaminated
meat and those due to secondary spread from person to person.
The nature of antimicrobial resistance in other pathogens
causing illness in these communities should also be investigated
to ascertain the extent to which R factors arising from therapeu-
tic and subtherapeutic antimicrobial use in animals are transferred
between microbial species and constitute a health problem.
A characterization of the R plasmids, which can be achieved by
physical, genetic, or enzyme techniques (Jacoby and Low, Appendix C;
O'Brien, Appendix I), could provide corroborative evidence of the
direction of transmission and information on qualitative changes
in resistance.
If the inquiries conducted on the breeding farms and the
feedlots reveal no differences in the prevalence of resistant
organisms in animals related to the differing use of antimicrobials,
the study could be terminated. If such differences are apparent,
further work would be needed. The second phase of the study would
determine the occupationally associated risk of acquisition of
resistant organisms and provide some information on the likelihood
of spread from these foci. The carrier rates in samples from the
neighborhoods of the abattoir workers should provide data on the
prevalence of resistant enteric bacteria in general communities, as
would the information derived from the household samples in the
third phase. The community-based studies would relate the carrier
rates in a community to the use of antimicrobials in animals and
measure the associated burden of disease (see Table 2-1~.
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TABLE 2-1
The Ideal Comprehensive Study Design
PHASE 1: BREEDING FARMS AND FEEDLOTS
Study Groups
Herds and flocks in four cate-
gories of antimicrobial use:
no antimicrobial use
subtherapeutic use only
therapeutic use only
both subtherapeutic and
therapeutic use
Animal handlers
Family members
Neighbors
Study Procedures
Bacteriological indices:
Prevalence of carriage of anti-
microbial-resistant Salmonella
spp./relative frequency of
resistant organisms in each
specimen
Prevalence of carriage of antimi-
crobial-resistant E. colt/
relative frequency of resistant
. . .
organisms In eac ~ specimen
Characterization of fecal flora
and plasmids
PHASE 2: SLAUGHTERHOUSES, PROCESSING PLANTS, AND RETAIL BUTCHER SHOPS
~ _ .
Study Groups
Carcasses
Meat handlers
Family members
Neighbors
PHASE 3: COMMUNITIES
Study Groups
-
Households selected on the basis
of probability sample
Cases of salmonellosis
Other cases of infectious
diseases caused by bacteria
Study Procedures
Bacteriological indices (as above)
Human illness caused by bacteria
Study Procedures
Bacteriological indices (as above)
Tracing of source of infection
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FEASIBILITY OF A COMPREHENSIVE STUDY
The committee reviewed methods for gathering information
on the effects of various exposures on subsequent morbidity and
mortality and for determining the specific needs for information
on the subtherapeutic use of antimicrobials in animal feeds. It
concluded that the comprehensive study described above could not
be realized or even approximated. This decision reflects a number
of facts, which are discussed below:
The use of antimicrobials differs markedly for the three major
meat animals--cattle, swine, and poultry. Moreover, for each type
of animal the use of antimicrobials varies in various parts of the
country and at different times, e.g., with seasons or weather con-
ditions. Moreover, it is often not possible to differentiate whether
the antimicrobials had been given for growth promotion, prophylaxis,
or treatment of manifest illness. In much of the industry, only
insignif icant numbers of animals have never received any antimicro-
bials, and in normal rearing and processing operations, it is not
practical to identify these animals. During shipment from breeding
farms to feedlots, groups of animals with different exposures to
antimicrobials are often combined. The likely exchange of bacteria
between animals under these circumstances further hinders the identi-
fication of the origin of any observed R+ organisms.
The processing of meats and meat products also contributes to
the mixing of meats from animals with different antimicrobial his-
tories. Cross-contamination can also occur in these processes,
e.g., via cutting boards and instruments. Currently, there is no
hope of identifying communities in which residents can purchase only
the meat of animals that had been exposed to only one regimen of
antimicrobial usage.
The diseases and conditions likely to result from resistant
microorganisms in the general population exposed to meat are rela-
tively rare. Overt diarrhea caused by Salmonella, acute urinary
tract infections in young women, and other illnesses related to
infections with enteric pathogens all have extremely low incidence
rates. Thus, any study attempting to relate an increase (po+sibly
a small increase) in morbidity or mortality to exposure to R orga-
nisms on meat (whether selected by subtherapeutic or therapeutic
antimicrobial use) would be so massive that it would probably be
unmanageable. Additionally, the chain of events linking antimi-
crobial-resistant bacteria in the animal gut to overt human infec-
tions is extraordinarily difficult to trace in any given case.
This difficulty would increase the uncertainty in the study
and jeopardize the validity of any risk estimates that might be
developed.
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ALTERNATIVES TO A COMPREHENSIVE STUDY AND THEIR DEFICIENCIES
.
Less comprehensive approaches, although more realistic, can-
not provide direct evidence of a consistent chain of causation from
subtherapeutic antimicrobial use in animal feeds to human illness.
Moreover, the fragmentary data that are available (discussed below)
not only suffer from deficiencies of method and design but also
leave gaps that can be bridged only by conjecture or speculation.
Better research may repair the former, but little can be done about
the latter. Some deficiencies of the narrower studies are listed
below:
~ Studies of the prevalence of antimicrobial-resistant
bacteria in animals cannot be used to determine the extent of the
transmission of R+ enteric organisms from animals to human popula-
tions.
~ In studies of the prevalence of R+ organisms in farm
workers, the R+ bacteria acquired directly from animals cannot
easily be distinguished from those R+ organisms resulting from the
selection pressure exerted by ingested or inhaled antimicrobials
from the feeds.
· Studies of the prevalence of resistant organisms on car-
casses or in abattoir workers do not provide direct measurements of
the extent to which these organisms are transmitted to the general
population, nor can they distinguish the effects of subtherapeutic
use from the therapeutic use of antimicrobials.
· Studies comparing the prevalence of R+ organisms in meat-
eaters and vegetarians cannot differentiate whether observed differ-
ences in the meat-eaters can be attributed to the selective pressure
for resistance exerted by the subtherapeutic use or by the therapeutic
use of antimicrobials in the animals consumed. Such studies would
also need to take into account the use of antimicrobials in the sub-
jects themselves or in persons in their immediate environment.
· Studies on the prevalence rates of R+ organisms in different
populations can only imply the causes for differences in rates.
They do not relate R+ prevalence rates to increases in morbidity,
mortality, or complications in therapy caused by resistance in the
pathogen.
The foregoing discussion makes it clear that isolated studies
on parts of the transmission chain cannot be used to quantitate the
overall effects on human health resulting from the subtherapeutic
use of antimicrobials in animal feeds.
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This committee therefore concludes that it is not possible to
conduct a feasible, comprehensive direct study of the effects on
human health arising from the subtherapeutic use of antimicrobials
in animal feeds. However, after examining some of the issues
and the research conducted to date, the committee outlined several
studies that might quantitate some of the stages in the chain of
causation on which speculation of hazard is based.
The studies are presented as an indication of what the com-
mittee believes to be the most fruitful approaches. They will not
provide a direct assessment of the effects on human health resulting
from subtherapeutic levels of antimicrobials. Chapter 4 contains
descriptions of these studies and some caveats on the interpretation
of their results.
Representative terms from entire chapter:
resistant organisms
