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OCR for page 35
CHAPTER 4
STUDY POSSIBILITIES
The committee considered ways to remedy deficiencies in the
information that has been used to support claims that the subther-
apeutic use of antimicrobials in animal feeds creates a hazard to
the health of humans. The studies suggested in this chapter are
not to be interpreted as proposals of work that would provide a
sufficient basis for an acceptable quantitative assessment of any
risk to human health since the remaining gaps in knowledge would
still have to be bridged by conjecture or speculation.
~ ~ Rather, the
committee believes these studies to be the most fruitful approaches
to quantifying some of the stages in the chain of events from which
health hazards might result (see Chapter 2) so that speculations
concerning such hazards may be more firmly based.
Study 1 should identify relative contributions of subthera-
peutic and therapeutic antimicrobial regimens to the emergence of
resistant enteric flora in animals. Studies 2 and 3 are designed
to assess the extent to which carriage by humans of bacteria
having R factors is associated with meat consumption or occupational
exposure to bacteria from animals in abattoirs. Study 4 addresses
the relationships between carriage of or occupational exposure to
Rib organisms and increased morbidity from urinary tract infections.
Each proposal points out the limitations of the study and indicates
what conclusions can be drawn from the data to be collected. Before
these studies commence more detailed protocols should be evaluated
by groups of individuals with expertise in the disciplines that
are relevant to each study.
STUDY 1--THE EFFECTS OF SUBTHERAPEUTIC AND THERAPEUTIC DOSES OF
ANTIMICROBIALS ON THE PREVALENCE OF R+ ENTERIC ORGANISMS IN ANIMALS
.
In this study, the relationship between the appearance of
resistant Enterobacteriaceae and the pattern and dose of antimicro-
bials used in the feed of food animals or otherwise administered to
them could be examined. The proportion of E. colt, salmonellae, and
other Enterobacteriaceae carrying R plasmids should be measured in
beef cattle,
~ / . . ~. . ~
hogs, and chickens before, during, and after they are
red anchor created with various doses of tetracycline at growth pro-
motional, prophylactic, and/ or therapeutic levels. This study will
clarify the contribution of subtherapeutic and therapeutic dosing
regimens to the emergence of resistant enteric flora in animals.
35
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36
Experimental Study Design
The committee regards the ability to obtain animals +th
a very low, preferably zero, incidence and proportion of R en-
teric bacteria in their gut flora as central to the usefulness
of this study. Alternative strategies, which could be adopted
if it proves impossible to meet this criterion, are discussed
under Interpretation of Results.
Within each animal species, individual animals not pre-
viously exposed to ant~microbials should be allocated randomly
to pens, and the pens should be assigned randomly to treatment
groups, each of which contains more than one pen of animals.
The number of animals in each pen and the number of pens may
differ along the three animal species and should be specified
so that the samples are of sufficient size for investigators
to detect meaningful differences in the proportions of animals
carrying tetracycline-resistant organisms among the various
treatment groups.
Prior to random allocation, several fecal samples should
be collected from each animal to establish the baseline for
total flora, for the prevalence of R+ organisms, and for the rate
at which such pathogens as Salmonella are shed. Fecal specimens
should be examined for a short period after penning in order to
monitor exchange of bacteria among animals in each pen. Speci-
mens should be examined at regular intervals thereafter to moni-
tor the changes occurring during the feeding period. Bacterio-
logical procedures should be determined on the advice of persons
with expertise in the field of veterinary microbiology.
Animals should be divided into treatment groups as follows:
1. No antimicrobials. These animals should be given no
antimicrobials of any sort during the feeding period.
2. Subtherapeutic levels of tetracyclines. These animals
should receive tetracyclines for a period similar to
that during which the antimicrobials are administered
during typical rearing conditions for that species.
Three dose levels should be given to different groups:
a. A level no greater than the minimum regarded as
necessary to elicit growth promotion or more effi-
cient feed conversion.
b. The usual level of antimicrobials fed to the particu-
lar animal species for growth promotion, improvement
of feed conversion, and disease prophylaxis.
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37
c. A level substantially above the usual feeding level
but not above regulatory definition of a maximum
subtherapeutic dose.
3. Therapeutic doses of tetracycline. These animals should
not receive subtherapeutic antimicrobials. A simulated
typical course of tetracycline therapy should be adminis-
tered to the group at a specified time during the feeding
period in accordance with accepted veterinary practices for
the test species. If it is decided that tetracycline should
be given to only some animals in the group, this must be
recorded.
4. Subtherapeutic plus therapeutic doses of tetracyclines.
These animals should be fed the usual subtherapeutic levels
(2b) of tetracycline during the entire feeding period and
should be treated with a simulated therapeutic course of
tetracycline, thus combining 2b and 3 above.
In the event of sickness requiring the use of therapeutic doses
of antimicrobials in any treatment group, all animals judged (on
predetermined criteria) to be sick should be permanently removed
from the experiment and from contact with the remaining test
animals and should be treated as indicated by prudent veterinary
practice.
Antimicrobials should be discontinued in all animals prior to
slaughter at the time designated by current regulations to en-
sure that residual levels do not exceed those permitted in
carcasses. Monitoring of R+ bacteria should be continued in
some animals for a period after the animals +onmally would have
been slaughtered to observe all changes in R prevalence after
antimicrobials are withdrawn.
Design of data acquisition. The design of the quantitative
culture techniques should enable investigators to detect a
biologically important difference in the number of tetracy-
cline-resistant organisms in fecal specimens from the various
treatment groups. These techniques should be designed by per-
sons with expertise in microbiology and in biostatistics as it
relates to the analysis of microbiological data. The protocols
and analytical methods should be specified in advance.
Data to be collected:
1. The number of animals in each group carrying Enterobacteria-
ceae with R factors mediating tetracycline resistance should
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38
2.
be recorded. For each stool specimen, the Enterobacteria-
ceae should be enumerated and serotyped, and the percentage
carrying R factors mediating resistance to tetracycline
should be ascertained by quantitative culture techniques.
Salmonellae shed by each animal should be enumerated and
serotyped.
3. The weight of each animal should be recorded at the beginning,
at the end, and at regular intervals during the experiment.
Feed should be analyzed chemically for a range of antimi-
crobials prior to use to avoid contamination and to ensure
that the desired levels of tetracycline are achieved when
supplementation is intended. Contaminated feed should be
discarded to avoid the selection (by antimicrobial agents
other than tetracycline) of organisms carrying plasmids on
which resistance to tetracycline is linked to other resis-
tances. The feed consumed in each pen should be recorded,
and the consumption of antimicrobials by individual animals
should be calculated.
Site conditions: One or more sites, such as an agriculture ex-
per~ment station or veterinary college, should be selected. They
should enable investigators to meet the following criteria:
1. Test animals should be me intained in a controlled experi-
mental environment, but they should be handled in a manner
that simulates current growing and finishing practices
before marketing.
2. The sites should contain isolation facilities to prevent
transfer of bacteria among pens. Different personnel will
be needed for each pen to prevent cross-infection between
pens.
3.
Direct veterinary supervision during the course of the
experiment should be available.
There should be local slaughtering facilities in which
the bacteriological characteristics of carcasses produced
during this experiment can be monitored.
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39
Observational Studies
These studies require the cooperation of commercial operations
that use antimicrobials in a pattern similar to some or all of those
used in the experimental study design described above. Fecal samples
and feed samples should be collected, and the feeding history and
weight gains of the animals throughout the feeding period should be
recorded. Fecal samples should be analyzed microbiologically with
the same methods that were proposed in the experimental study design.
The data obtained from these groups should be analyzed in a manner
that will enable investigators to compare the appearance of R+
organisms in these groups to that of the groups in the experimental
study design.
Costs
The numbers of animals used in the following calculations are for
illustrative purposes only. They should not be interpreted as the
committee's recommendation for quantities needed to obtain statisti-
cally meaningful results. Investigators should determine the number
to be used in accordance with the principles indicated in the study
design outlined above. Animals should be observed past the usual mar-
keting time in order to assess the full consequences of antimicrobial
withdrawal on the microbial flora. The costs of acquiring specimens
are included under Veterinary Supervision estimates. Partial costs
may be recovered by sale of the animals.
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40
EXPERIMENTAL STUDY: BOVINES
-
Costs are based on six groups of 20 animals.
Purchase of Animals:
In order to acquire animals with known antimicrobial expo-
sure histories, it may be necessary to pay more than the
going market rate, which varies with time.
Acquisition of 120 400-lb calves at approximately $1.25/lb will
cost:
120 x 400 lb x $1.25/lb
Feed and Care Costs:
120 x 240 days x $5.00/day
Veterinary Supervision (2 h/day):
2 h x 240 days x $30/h
Animal Husbandry: Total Direct Cost =
=- $ 60,000
= 144,000
- 14,400
Laboratory Services (based on one specimen/animal every 3 days):
80 specimens/animal x 120 animals
x $25/specimen
Total Direct Costs
Overhead (estimated 50%)
$218,400
240,000
458,400
229,200
BOVINES, TOTAL COST
$687,600
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41
EXPERIMENTAL STUDY: SWINE
-
Costs are based on s~x groups of 20 animals.
Purchase of Animals:
Acquisition of 120 specific pathogen-free animals
mately 4 weeks old, will cost:
120 x $180/an~mal
Feed and Care Costs:
120 x 180 days x $2.00/day
Veterinary Supervision (2 h/day):
180 days x 2 h x $30/h
Animal Husbandry: Total Direct Cost =
, approxi
= $ 21,600
= 43,200
= 10,800
Laboratory Services (based on one specimen/animaI every 3 days):
60 specimens/animal x 120
animals x $25/specimen
Total Direct Costs
Overhead (estimated 50%)
SWINE, TOTAL COST
$75, 600
180,000
$255, 600
127,800
$383, 400
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42
EXPERIMENTAL STUDY: CHICKENS
Costs are based on six groups of 50 chickens.
Purchase of Animals:
Acquisition of 300 specific pathogen-free chicks will cost:
300 x $15
Purchase cost may be lower if chicks are
reared from eggs rather than obtained
already hatched.
Feed and Care Costs:
300 chickens x $0.50/day x 100 days
Veterinary Supervision (2 h/day):
100 days x 2 in/day x $30/h
Anima1 Husbandry: Total Direc t Cost
= $ 4,500
= 15,000
= 6,000
=
Laboratory Services (based on one specimen/animal every 3 days ):
34 speci~nens/animal x 300 animals
x $2 5/specimen
Total Direc t Cost
Overhead ~ estimated 50%)
s
CHICKENS, TOTAL COST
$ 25,500
255,QOO
280,500
140,250
$420,750
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43
TOTAL COSTS - STUDY PROPOSAL 1: EXPERI~:NTAL STUDY
Bovines
Swine
Chickens
$687, 600
383, 400
420, 7 50
$1, 491, 750
Any costs recovered from the sale of the animals could be returned
to the contractor.
OBSERVATIONAL STUDY
Cost for the observational study will be dependent upon the arrange-
ments that can be made with those commercial concerns willing to
cooperate in the study and the sizes of the groups to be observed.
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44
Interpretation of Results
There are a number of possible results from this study:
Animals receiving antimicrobials may have no greater preva-
lence of R+ organisms and no more Salmonella with pathogenicity
for humans than animals not receiving antimicrobials. This is an
unlikely result, given data to the contrary. However, if such a
result did occur, there would be no evidence to indicate that the
subtherapeutic use of antimicrobials might affect human health.
The prevalence of R+ organisms or Salmonella with pathogeni-
city for humans may be similar in animals on subtherapeutic regi-
mens of antimicrobials and those on therapeutic regimens, and these
prevalences might be greater than that in the untreated animals.
In this instance there would be no evidence to indicate that sub-
therapeutic use of antimicrobials increases the possible hazard to
humans over that from the therapeutic use of antimicrobials.
If the prevalence of either R+ organisms or of pathogenic
Salmonella resulting from the subtherapeutic use of antimicro-
bials significantly exceeds that from therapeutic use, then one
still cannot infer that the subtherapeutic use of antimicrobials
represents a definite risk of human disease. Further studies would
be required to measure the effects on human health resulting from
increased prevalence in animals of R+ organisms or of Salmonella
with pathogenicity for humans.
If animals with al low initial prevalence of R+ enteric orga
~ obtained, the study ~-
nisms cannot be o DEainea ~ Ene scuay snouts De moored to Determine
if the feeding of strictly monitored antimicrobial-free feed results
in a decline in R+ prevalence.
The validity of such conclusions depends upon the degree to
which the experimental conditions, antimicrobial regimens, etc.,
actually parallel production practices. This can be ascertained
by including the observational study in the overall design.
STUDY 2--STUDIES OF VEGETARIANS AND NONVEGETARIANS
This study would measure the extent to which carriage of
bacteria with R factors is associated with meat consumption. It
begins with the hypothesis that consumption of meat contaminated
with antimicrobial-resistant bacteria from animals would result in
meat-eaters having a higher prevalence of antimicrobial-resistant
enteric bacteria than do vegetarians. Two related studies are
described in Chapter 3.
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45
Study Design
Groups of vegetarians and nonvegetarians should be compared
for prevalence of resistant Enterobacteriaceae in their fecal
flora. The groups must be carefully controlled for factors such
as antimicrobial usage, age, socioeconomic status, family size,
age of children, and pets. Seventh Day Adventists and Mormons
would provide two convenient study groups. In this study the pre-
valence of R+ factors is monitored by the use of resistance to
tetracycline because of its likely frequency in the population and
its therapeutic significance. Moreover, it is the subject of the
proposed restrictions by the Food and Drug Administration (FDA).
Data to be Collected
.
The number of persons in each group carrying Enterobacteria-
ceae with R factors mediating resistance to tetracycline should
be determined. The sample size should be sufficiently large for
investigators to identify a meaningful difference, if it exists,
in the rate of colonization by organisms with resistance to tetra-
cycline.
The percentage of Enterobacteriaceae that carry R factors
mediating resistance to tetracycline in each fecal specimen
should be ascertained by quantitative culture techniques. These
techniques should be designed to detect a biologically important
difference in the prevalence of tetracycline resistance factors
in stool specimens obtained from the groups being compared.
Costs
A preliminary survey should be conducted to ascertain approx-
imate prevalence rates of R+ carriage. A pilot study of 100 vege-
tarians and 100 nonvegetarians would cost approximately $100,000 for
epidemiological and laboratory services. The size and desirability
of the full survey should be decided on the basis of the results of
the preliminary survey.
Interpretation of Results
If the prevalence of organisms with R factors is the same in
vegetarians as in meat-eaters, there would be no support from this
study for the belief that either the therapeutic or subther+peutic
use of antimicrobials in animals affects human health via R orga-
nisms on or in meat.
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46
If meat-eaters have a greater prevalence of R+ bacteria
than do vegetarians, it is possible to infer that the excess of
antimicrobial-resistant bacteria is associated with the ingestion
of meat, but it is not possible to differentiate between the
effects of subtherapeutic and therapeutic uses of ant~microbials
in meat sources. Other confounding variables would include the
handling of meat products and contamination of cooking utensils +
or work surfaces. If meat-eating is associated with a greater R
prevalence, then further studies would be needed to determine if
the excess of R+ organisms results in excess morbidity or mor-
tality or complicates the treatment of diseases and to determine
the influence on R+ prevalence of other aspects of diet.
STUDY 3--STUDIES OF ABATTOIR WORKERS, THEIR FAMILIES, AND
NEIGHBORHOOD CONTROLS
This study would measure the extent to which occupational
exposure of humans to bacteria from animals is associated with
carriage by humans of bacteria with R factors. Secondarily, it
would gauge the spread of these bacteria or R factors among
humans who are-in close contact with one another.
Abattoir workers are exposed to large numbers of bacteria
frog animals but are not exposed to antimicrobial-containing
feeds. Consequently, they are exposed to the organisms (which
are likely to be resistant in animals fed antimicrobials), but
unlike farm workers they are not exposed to dusts containing
antimicrobials that might be ingested or inhaled, thereby exerting
a selective pressure favoring resistant enteric or respiratory
tract bacteria. Thus, abattoir workers can be used productively
to evaluate the propensity of bacteria from animals to colonize
humans and to study the secondary spread of such bacteria and/or
R factors via contact spread to family members. If secondary
spread occurs, family members would be expected to have an inter-
mediate but increased R factor carriage rate compared to controls.
Study Design
Groups of abattoir workers involved in the processing of
poultry, pork, and cattle, their household contacts, and+neighbor-
hood controls should be compared for the prevalence of R Entero-
bacteriaceae in their stool flora. The groups must be carefully
controlled for factors such as antimicrobial usage, age, socio-
economic status, family size, age of children, and household pets.
In this study the prevalence of R factors is monitored by the use
of resistance to tetracycline as a marker for the same reasons
given under Study 2.
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47
Data to be Collected
The number of persons in each group carrying Enterobacteria-
ceae with R factors mediating resistance to tetracycline should be
determined. The population groups studied should be large enough
to provide a high probability for identifying a meaningful differ-
ence, if one exists, in the carriage rate for the tetracycline
resistance factor. Information on the task performed by the abat-
toir workers should be collected in order to determine their
potential for exposure to enteric organisms.
For each stool specimen, quantitative culture techniques
should be used to determine the percentage of Enterobacteriaceae
that carry R factors mediating resistance to tetracycline. These
techniques should be designed to detect a biologically important
difference in prevalence.
Costs
A preliminary survey should be conducted to ascertain approxi-
mate prevalence rate& of R+ carriage. The rates found in such a
survey would determine the size and desirability of a full survey.
A pilot study of 100 abattoir workers and 100 controls would cost
approximately $100,000 for epidemiological and laboratory services.
The size and desirability of the full survey should be decided on
the basis of the results of the preliminary survey.
Interpretation of Results
.
By comparing rates at which R+ bacteria are carried by abattoir
workers with those of their families and neighborhood controls, one
can determine if any association exists between occupational exposure
to bacteria from animals and an increased prevalence of R factors in
the human enteric flora. Such comparisons would also allow one to
evaluate spread of R factors among humans in close contact with one
another.
If the prevalence of organisms with R factors is the same in
abattoir workers and controls, this study would provide no support
for the belief that resistant bacteria, resulting from either the
therapeutic or subtherapeutic use of antimicrobials in animals,
significantly affects the flora or health of humans.
It would not be possible to attribute a greater prevalence in
the abattoir workers solely or in part to the subtherapeutic use of
antimicrobials in feeds. Further studies would be needed to determine
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48
if any observed excess of R+ organisms in abattoir workers resulted
in excess morbidity or mortality or in complications in the treat-
ment of diseases.
RATIONALE FOR CONDUCTING STUDIES OF MORBIDITY AND MORTALITY
IN HUMANS
The three studies described above are intended to serve as
indicators of the development and transfer of resistant enteric
organisms. If there is no indication of an important association
between the exposure of animals to either subtherapeutic or thera-
peutic levels of antimicrobials and the development of resistant
enteric organisms, or if exposure to bacteria from animals fails
to influence the flora of humans, the possibility of detrimental
effects on human health would not be sufficiently well established
to justify widespread changes in the current use of antimicrobials
throughout the meat industry. If either the vegetarian study or
the abattoir study indicates that the carriage of resistant orga-
nisms by humans is associated with meat consumption or occupational
exposure to bacteria from animals, more extensive evaluations of
morbidity and mortality would be justified. One possible study is
detailed below.
STUDY 4--COMPARISON OF CONTROLS WITH SUBJECTS WITH URINARY TRACT
INFECTION
Laboratory screening services frequently discover urinary
tract infections (UTI) by culturing urine samples obtained from
women during routine medical examinations. These screenings can be
linked with other microbiological tests to determine the existence
of an association between R+ Enterobacteriaceae in stool flora and
the occurrence of primary UTI and to ascertain the proportion of
primary UTI infection that is caused by antimicrobial-resistant
Enterobacteriaceae. Brumfitt et al. (1971) have conducted a small
study of these topics.
Study Design
If the results of Studies l, 2, and 3 indicate that more
extensive evaluations of morbidity and mortality are necessary,
the committee recommends that a screening for primary UTI be con-
ducted on 5,000 females who work in the meat processing industry
(e.g., in poultry dressing plants) and who thus are exposed to
high levels of antimicrobial-resistant bacteria. If the screening
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49
can be conducted in a processing plant that can provide reliable
data concerning the antimicrobials received by the birds that
are processed, the antimicrobial-resistant profiles of the flora
of the poultry carcasses should be compared with those of the
isolates from humans. Such additional sampling would add to the
costs of the study but would provide exceedingly useful corrobor-
ative information. In conjunction with the screening of meat
processors, an equally large group of controls should be studied,
e.g., the 9,000 women in East Boston, Massachusetts first studied
by Kass (1978) could be resurveyed. These surveys would enable
investigators to compare female meat processors who have bacteri-
uria with similarly infected women in an urban setting far removed
from contact with livestock and to match cases and controls for age,
race, parity, and antimicrobial history.
Participating screening services should use uniform procedures
and criteria to detect UTI's. New cases should be asked to return
for a confirmatory urinary culture, at which time a rectal swab
should be obtained to determine the carriage of R+ Enterobacteria-
ceae.
Women who have not received antimicrobials during the preced-
ing calendar year should then be matched with control (non-UTI)
women of comparable age, race, parity, and negative antimicrobial
history as determined by the screening service. For each stool
specimen from a case or control, all Enterobacteriaceae should be
serotyped and the percentage with R factors should be ascertained
by quantitative culture techniques. The number of cases and con-
trols required to discriminate between no association and a meaning-
ful difference at acceptably low probabilities for error must be
specified in a detailed protocol. The control population of 9,000
should yield approximately 150 cases of bacteriuria, approximately
100-120 of which will be infected with E. cold (Kass, 1978~.
The role of resistance selected by the therapeutic use of
antimicrobials in humans should be rigorously investigated and
controlled in this study. Even a negative result with a large
group would enable investigators to estimate the upper bound of
the risk to human health.
All confirmed cases of UTI should be studied in the following
manner.
1. Each isolated infecting strain should be tested for
antimicrobial susceptibility patterns, type distribution, and
plasmid DNA sequence homology.
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mine:
50
2. Each patient should be sent a questionnaire to deter
Basic demographic data
Basic household composition
Identification of infection as a sporadic case or part of
an outbreak
Occupation of patient, spouse, and household contacts
Outcome of illness--expense in terms of workdays
lost, medical expenses, etc.
Present health status of subject
Antimicrobial history of subject and household
members and pets during past 2 years
Hospitalization history of subject during past
2 years
Major illness of subject and household members
during past 2 years
Patients with UTI characterized by bacteria with resistance
to antimicrobials should be compared with patients with UTI
characterized only by antimicrobial-sensitive bacteria to deters
mine whether there are differences in antimicrobial history, in
exposure to animals or carcasses that had been in contact with
antimicrobials, or in exposure to feeds containing antimicrobials.
Interpretation of Results
If women with resistant enteric flora have a relatively high
risk of a UTI compared to those without resistant fecal flora,
the prevalence of R+ fecal flora among new cases should be greater
than that among comparable controls. The observation of such an +
association would favor the interpretation that the carriage of R
organisms, from whatever source, is indicative of an elevated risk
of UTI. An insignificant association would indicate that the pre-
sence of R+ enteric flora does not make an important contribution
to this form of morbidity. This study would be sensitive to a
differential virulence between resistant and susceptible enteric
flora causing UTI's, but it would not elucidate the contribution of
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51
the subtherapeutic use of antimicrobials in animal feeds to this
cause of illness. Whatever the results of this study, they would
not provide justification for drawing general conclusions about
the likely changes in the virulence of other pathogens gaining
resistance to antimicrobials.
The comparison of UTI prevalence between groups with high and
low exposure to R+ enteric organisms would provide some indication
of the amount of primary UTI that is attributable to an occupational
exposure. With a sufficiently large control group and high risk +
groups in proximity to animals or carcasses with high levels of R
organisms, a positive result would enable some conclusions to be
drawn about total antimicrobial use in animals and UTI in humans
caused by antimicrobial-resistant bacteria. No conclusion could
be drawn about the relative contribution of subtherapeutic use to
the increased morbidity.
Costs
If such a study were conducted over 2 years, which would allow
time for training of personnel and analyzing results, an estimated
$150,000 per year would be required. If the study were spread over
3 years, the total annual cost would be reduced by approximately
15%. If the information concerning the ant~microbials received by
poultry passing through the processing plant can be obtained and the
flora of the carcass is subsequently sampled, then add~tional~costs
will be incurred.
Representative terms from entire chapter:
occupational exposure
