Significance and Sources of Antimicrobial-Resistant Nontyphoidal Salmonella
Infections in Humans in the United States: The Need for Prudent Use
of Antimicrobial Agents, Including Restricted Use of Fluoroquinalones,
in Food Animals
Table of Contents
- Abstract
- Introduction
- Clinical Significance of Antimicrobial-resistant
Salmonellae
- Epidemiology of Antimicrobial-resistant Pathogens,
Including Salmonella
- Sources of Antimicrobial-resistant Salmonella
Infections
- Carriage Rates
- Infectious Dose
- Outbreak Investigations
- Sporadic Case-Control Studies
- Molecular "Fingerprinting"
- Emergence of Usual Strains in Humans
- Sources of Antimicrobial-resistant Salmonella
Infections
- Trace Backs of Selected Foodborne
Disease Outbreaks
- Emergence of Salmonella Typhimurium
DT104 R-type ACSSuT with Decreased Susceptibility to Fluoroquinolones
in the United Kingdom
- Comparison of Patterns of Antimicrobial
Resistance Patterns of Salmonella Isolates from Humans
and Animals
- Comparison Patterns of Antimicrobial
Usage in Humans and Animals with Antimicrobial Resistance Patterns
Among Humans and Animals
- Human Health Risks of Fluoroquinolone Use in
Food Animals
- Need for Prudent use of Antimicrobial Agents in
Food Animals
- References
Abstract
Human Salmonella infections are common; most infections are
self-limiting but severe disease may occur. Fluoroquinolones and third-generation
cephalosporins are the drugs-of-choice for invasive Salmonella
infections in humans. Little correlation is noted between the antimicrobial
resistance patterns of isolates collected from persons with Salmonella
infections and antimicrobial agents used for the treatment of Salmonella
infections in humans. Direct evidence is available which demonstrates
that antimicrobial resistant Salmonella results from the use
of antimicrobial agents in food animals and these antimicrobial resistant
Salmonella are subsequently transmitted to humans. Because
of the adverse health consequences in humans and animals associated
with the increasing prevalence of antimicrobial resistant Salmonella,
there is an urgent need to emphasize non-antimicrobial strategies,
such as improved sanitation and hygiene, to develop guidelines for
the prudent usage of antimicrobial agents, and to restrict the use
of fluoroquinolones in food animals.
Introduction
Much of the discussion about the adverse human health effects associated
with the veterinary use of antimicrobial agents has been clouded by
confusion surrounding the clinical significance and sources of antimicrobial-resistant
nontyphoidal Salmonella infections in humans (Institute of
Medicine, 1989; U.S. Congress, Office of Technology and Assessment,
1995). This issue needs to be revisited in the light of the recent
discussions concerning the public health implications of veterinary
use of fluoroquinolones (Anonymous, 1994; Beam, 1994), a class of
antimicrobials essential for the treatment of several life-threatening
infections in humans (Wilcox and Spencer, 1992; Conte, 1995). Because
of these public health concerns, the Food and Drug Administration
prohibited the extra-label use of fluoroquinolones in food animals
in the United States in August, 1997. Two fluoroquinolones, enrofloxacin
and sarafloxacin, are approved, however, for use in poultry in the
United States.
To address the human health implications of the veterinary use of
fluoroquinolones, we reviewed the medical literature and data available
at the Centers for Disease Control and Prevention (CDC) about the
epidemiology of human i infections. In this report, we discuss the
clinical significance of antimicrobial-resistant Salmonella
infections in humans, the epidemiology of antimicrobial-resistant
pathogens including Salmonella, the sources of Salmonella
(including antimicrobial-resistant Salmonella) infections in
humans, the causes and consequences of development of antimicrobial-resistant
Salmonella, and suggest necessary actions to protect the public's
health.
Clinical Significance of Antimicrobial-resistant
Salmonellae
Salmonellosis results in considerable human morbidity in the United
States. Although most human Salmonella infections result in
a mild, self-limiting gastrointestinal illness characterized by diarrhea,
fever and abdominal cramps, the infection can spread to the bloodstream,
meningeal linings of the brain, or other deep tissue sites, leading
to a severe and occasionally fatal illness. Each year, there are an
estimated two to four million human Salmonella infections in the United
States (Chalker and Blaser, 1988; Council for Agricultural Science
and Technology, 1994), causing an estimated 80,000 to 160,000 persons
to seek medical attention. Clinical specimens collected from some
of the persons who have sought medical attention result in approximately
40,000 culture-confirmed cases a year reported to CDC (Hargrett-Bean
et al., 1988; Centers for Disease Control and Prevention: Salmonella
Surveillance, 1996). Each year in the United States, an estimated
8,000 to 18,000 persons are hospitalized and 500 persons die of Salmonella
infections (Cohen and Tauxe, 1986).
Antimicrobial agents are not essential for the treatment of most
Salmonella infections which manifest as uncomplicated gastroenteritis
because such infections usually are self-limiting, and treatment may
prolong the carrier state, and may result in the emergence of a resistant
infection in the treated person (Wilcox and Spencer, 1992; Conte,
1995). Antimicrobial agents are, however, commonly prescribed for
persons with Salmonella infections who seek medical attention. In
surveys conducted by CDC in 1990 (Lee et al., 1994) and 1995,
40% of persons with Salmonella infections who sought medical
attention were treated with antimicrobial agents. Ciprofloxacin, a
fluoroquinolone antimicrobial agent, was the most commonly prescribed
antimicrobial agent for Salmonella infections. Ciprofloxacin,
which became available for oral use in humans in the United States
in 1988, was used by approximately 25% of persons who received antimicrobial
agents in the 1990 survey and 33% in the 1995 survey, suggesting that
>100,000 persons with Salmonella infections have been treated
with ciprofloxacin in the past 10 years in the United States (between
2-3 million prescriptions of ciprofloxacin are dispensed annually,
for a variety of conditions, in the United States).
In contrast to patients with uncomplicated gastroenteritis, effective
antimicrobial agents are essential for the treatment of patients with
bacteremia, meningitis, or other extra intestinal Salmonella
infections (Wilcox and Spencer, 1992; Conte, 1995). In approximately
six percent of the culture-confirmed cases reported to CDC, Salmonella
is isolated from specimens collected from extra-intestinal sites -
usually from blood (Hargrett-Bean et al., 1988; Centers for
Disease Control and Prevention: Salmonella Surveillance, 1996).
Since approximately 40,000 culture-confirmed cases are reported to
CDC each year, effective antimicrobial agents are critical and may
be life-saving for at least 2,400 persons a year in the United States.
Unfortunately, the selection of antimicrobial agents for the treatment
of invasive infections has become increasingly restricted due to increasing
antimicrobial resistance among Salmonella isolates.
In the past, chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole
were used to treat Salmonella infections (Riley et al.,
1984; McDonald et al., 1987; Lee et al., 1994). However, among
1,272 randomly selected Salmonella isolates from humans tested at
CDC in the National Antimicrobial Resistance Monitoring System in
1996, 21% were resistant to ampicillin, 10% to chloramphenicol, and
4% to trimethoprim-sulfamethoxazole. (Centers for Disease Control
and Prevention. CDC/FDA/USDA National Antimicrobial Monitoring System
1996 Annual Report). In contrast, almost all of the Salmonella
isolates tested at CDC have been susceptible to fluoroquinolones and
third-generation cephalosporins (Centers for Disease Control and Prevention.
CDC/FDA/USDA National Antimicrobial Monitoring System 1996 Annual
Report; Herikstad et al., 1997a; Herikstad et al.,
1997b). For this reason, and because of the favorable pharmacodynamic
properties of these antimicrobial agents, fluoroquinolones and third-generation
cephalosporins are the drugs-of-choice for the treatment of invasive
Salmonella infections in adults and children, respectively.
Should Salmonella develop antimicrobial resistance to these
two antimicrobial agents, suitable alternative antimicrobial agents
are not currently available and adverse human health consequences,
including prolonged hospitalizations and increased frequency of treatment
failures, which may result in deaths, are expected.
While reviewing the clinical significance of antimicrobial-resistant
Salmonella infections, it is useful to evaluate the correlation
between the antimicrobial agents used to treat persons with Salmonella
infections and antimicrobial-resistance among human Salmonella
isolates. Information provided from surveys conducted by CDC within
selected counties in the United States in 1985 (McDonald et al.,
1987), 1990 (Lee et al., 1994) and 1995 indicates that the
proportion of persons with a Salmonella infection receiving
an antimicrobial agent who were treated with ampicillin declined from
60% in 1985 to 5% in 1995, while the proportion of isolates resistant
to ampicillin steadily increased. The proportion of persons treated
with trimethoprim-sulfamethozone, in contrast, remained constant while
trimethoprim-sulfamethozone resistance increased slightly. Most significantly,
the proportion of patients with salmonellosis treated with ciprofloxacin
or extended-spectrum cephalosporins markedly increased without an
emergence of resistance to either of these antimicrobial agents among
human Salmonella isolates.
The continued susceptibility of human Salmonella isolates
to fluoroquinolones and extended-spectrum cephalosporins was confirmed
in over 4,000 isolates in 1995 (Herikstad et al., 1997a;
Herikstad et al., 1997b) and 1,200 isolates in 1996
(Centers for Disease Control and Prevention. CDC/FDA/USDA National
Antimicrobial Monitoring System 1996 Annual Report). Taken together,
these data suggest there is little correlation between the antimicrobial
agents used in persons with Salmonella infections and development
of antimicrobial resistance among human Salmonella isolates.
If human antimicrobial use is not associated with the increasing antimicrobial
resistance seen among Salmonella isolates, what is causing
the increasing prevalence of antimicrobial-resistance observed among
Salmonella isolates? Prior to addressing that question, it
is useful to review the epidemiology of antimicrobial-resistant pathogens.
Epidemiology of Antimicrobial-resistant Pathogens,
Including Salmonella
Antimicrobial agents are used to treat microbial infections in humans,
plants and animals; they are given prophylactically to healthy humans,
plants and animals to prevent infections, and they are given in low
doses to food animals to improve their growth rate and feed conversion.
There is a preponderance of evidence that the use of antimicrobial
agents, at subtherapuetic or therapeutic concentrations, results in
antimicrobial resistance. However, in order for an antimicrobial-resistant
pathogen to have a public health consequence, there must be both usage
of the antimicrobial agent and dissemination of the resistant pathogen.
The role of dissemination can be illustrated by observing the consequences
of using fluoroquinolones for the treatment of three different infections:
methicillin-resistant Staphylococcus aureus (MRSA) in
humans, Salmonella in humans, and Salmonella in food
animals. Fluoroquinolones have been widely used in the United States
for the treatment of human MRSA and Salmonella infections,
but since they have not been widely used for the treatment of Salmonella
infections in food animals in this country, this latter instance will
be described using events which have occurred in the United Kingdom
(it is reasonable to assume such events would occur in the United
States under similar conditions of fluoroquinolone usage).
The emergence of human MRSA infections in hospitals in the United
States is a major public health concern (Panlilio et al., 1992).
When the first fluoroquinolone (ciprofloxacin) was approved in the
United States for human use there was optimism that ciprofloxacin,
which was highly effective against MRSA, might lessen the public health
impact of MRSA infections. Shortly after the approval of ciprofloxacin,
it became widely used for the treatment of human MRSA infections.
With the widespread usage, human infections with ciprofloxacin-resistant
MRSA rapidly emerged in the United States; by 1991-1992, 85% of MRSA
isolates from hospitals in the National Nosocomial Infection Surveillance
System were resistant to ciprofloxacin (Coronado et al., 1995).
The rapid emergence of ciprofloxacin-resistance MRSA is clearly related
to both the increased use of ciprofloxacin in humans and the efficiency
of dissemination, via person-to-person transmission, of ciprofloxacin-resistant
MRSA in hospitals.
As indicated earlier, ciprofloxacin has also been widely used for
the treatment of Salmonella infections in humans. Because antimicrobial-resistance
follows antimicrobial usage, Salmonella with decreased susceptibility
to ciprofloxacin may have developed in persons with salmonellosis
who were treated with ciprofloxacin, however, because person-to-person
transmission of Salmonella is rare, Salmonella with
decreased susceptibility to ciprofloxacin has not been disseminated
in the United States. This is in sharp contrast to the situation in
the United Kingdom, where a fluoroquinolone (enrofloxacin) has been
widely used in food animals following its approval for veterinary
use in 1993. Following the approval of enrofloxacin for veterinary
use in the United Kingdom, decreased susceptibility to fluoroquinolones
(Minimum Inhibitor Concentration [MIC] >0.25) rapidly emerged among
human Salmonella isolates, particularly among isolates of multiply-resistant
S. serotype Typhimurium DT104 which were resistant to ampicillin,
chloramphenicol, streptomycin, sulfonamides, and tetracycline (R-type
ACSSuT). DT014 R-type ACSSuT has emerged as the second most common
strain of Salmonella isolated from humans. In 1993, none of
the DT104 R-type ACSSuT isolates had a decreased susceptibility to
fluoroquinolones; by 1996, 14% had a decreased susceptibility (Threfall
et al., 1997). A parallel rapid emergence of decreased susceptibility
to fluoroquinolones, as indicated by antimicrobial resistance to nalidixic
acid (resistance nalidixic acid, a quinolone, indicates decreased
susceptibility to fluoroquinolones) has been observed among animal
S. Typhimurium DT104 R-type ACSSuT isolates at the central
veterinary diagnositic laboratory in the United Kingdom.
Sources of Antimicrobial-resistant Salmonella
Infections
Salmonella live in the intestines of mammals, birds and reptiles.
Once shed into the environment in the feces of infected animals, Salmonella
may survive for long periods in water, soil, and on or within foods.
Although Salmonella infections occur commonly in humans, person-to-person
transmission of Salmonella is uncommon in the United States.
In less developed countries, in contrast, person-to-person transmission
may be the source for a greater proportion of human Salmonella
infections and nosocomial sources of antimicrobial-resistant Salmonella
have been identified (Cherubin, 1981). Historically, before the development
of hospital infection control procedures in the United States, nosocomial
outbreaks of salmonellosis with person-to-person transmission, particularly
in newborn nurseries, were not infrequent (Tauxe, 1986).
Most human Salmonella infections in the United States occur from
the ingestion of contaminated food and many of these foods are foods
of animal origin. Direct fecal-oral transmission following contact
with animal feces is another, less common, source of human salmonellosis.
At least six lines of evidence can be presented which, taken together,
demonstrate that foods of animal origin are the dominant source of
human salmonellosis, and suggest that person-to-person transmission
is an uncommon source of human salmonellosis in the United States.
1. Carriage Rates
Although the prevalence varies, Salmonella is frequently isolated
from the feces of food animals, companion animals, and wild animals.
In longitudinal studies, some animals may excrete Salmonella
for long periods of time. For example, many birds, including poultry,
are infected with Salmonella and shed the organism in their
feces (an estimated 20% of retail packages of poultry are contaminated
with Salmonella). Fecal excretion of Salmonella by humans,
in contrast, is relatively uncommon among apparently healthy individuals
and is fairly short-lived among persons with salmonellosis. A review
of several surveys of stool specimens from apparently healthy persons
found a median carriage rate of Salmonella of 0.15% (Buchwald
and Blaser, 1988). A review of several outbreak investigations determined
the median duration of excretion by persons with salmonellosis to
be about four weeks (Chalker and Blaser, 1988).
2. Infectious Dose
Volunteer studies among healthy adults suggest that a large oral
infectious dose of Salmonella (>106 organisms) given in
water usually is necessary to cause infection in a high proportion
of recipients (McCullough and Eisele, 1951). These observations are
supported by the relative low frequency of secondary illness within
households in which a primary culture-confirmed case is identified
and the rarity of day-care center outbreaks of salmonellosis; such
settings commonly result in person-to-person transmission of enteric
pathogens with low infectious doses (e.g., Shigella and Escherichia
coli O157). The infrequent occurrence of secondary infections
of salmonellosis and day-care center associated outbreaks suggest
that person-to-person transmission of Salmonella occurs infrequently.
3. Outbreak Investigations
Although outbreaks only represent a fraction of the cases of Salmonella
infections which occur, much insight into the epidemiology of salmonellosis
has been provided through investigations of outbreaks. Most outbreak
investigations are conducted by state or local health departments
who report foodborne disease outbreaks to CDC as part of the Foodborne
Disease Outbreak Surveillance System (Bean et al., 1996). A
small number of investigations are conducted each year by CDC in collaboration
with state and local health departments.
Between 1988 and 1992, an average of 110 outbreaks of Salmonella
were reported each year to CDC (Bean et al., 1996).
Sixty percent of these outbreaks were caused by Salmonella
serotype Enteritidis and most of these were attributed to eating undercooked
eggs. Many of these egg-associated outbreaks were traced back to their
farm of origin and it was demonstrated that infected hens were the
source of the outbreak. Among outbreaks caused by Salmonella
serotypes other than Enteritidis, a variety of food items were implicated,
particularly other foods of animal origin. A small number of fresh
fruits and vegetables were also implicated. A few of these outbreaks
were traced back to their farm of origin. Although some outbreaks
involved infected food handlers, rather than being evidence of person-to-person
transmission of Salmonella, in most cases, the food handlers
probably became infected because they also ate the contaminated foods.
Taken together, outbreak investigations demonstrate that foods, particularly
foods of animal origin, are an important source of Salmonella
infections in humans.
4. Sporadic Case-Control Studies
Further evidence that foods of animal origin are associated with
many human Salmonella infections is provided from investigations
of persons with sporadic Salmonella infections (infections
that were not recognized to be associated with an outbreak). Few such
investigations have been reported, however, perhaps because investigations
of sporadic infections are less likely to implicate a common source
because several sources may be involved.
Case-control studies of sporadic cases of Salmonella Enteritidis
were conducted in New York in 1989 (Morse et al., 1994), California
in 1994 (Passaro et al., 1996), and Utah in 1995 (Centers for
Disease Control and Prevention. EPI-AID 96-16, July 1996). These studies
each demonstrated that eating raw or undercooked eggs was the most
important risk factor for acquiring infections. Case-control studies
of sporadic Salmonella cases involving serotypes other than
Enteritidis include an investigation in Switzerland in 1996 of infections
caused by a variety of serotypes which implicated eggs as the most
important sources of infections (Schmind et al., 1996), California
in 1984 of infections again caused by a variety of serotypes which
implicated poultry (Kass et al., 1992), California in
1985 of Salmonella Dublin which implicated raw milk (Richwald
et al., 1988), and a study of Salmonella Typhimurium
and Enteritidis infections in Minnesota in 1989 and 1990 which found
eggs as the most important source for both infections (Hedberg et
al., 1993).
5. Molecular "Fingerprinting"
After identification of the particular Salmonella serotype,
several procedures (e.g., phage typing, pulsed-field gel electrophoresis,
plasmid profiling, ribotyping) may be used to further differentiate
Salmonella isolates (Threfall et al., 1994). Such subtyping
techniques may be useful in epidemiological investigations to support
or refute the postulated source of the outbreak. For example, in the
18 outbreaks of Salmonella Enteritidis in 1990 and 1991 in
which eggs were implicated as the source, trace backs and environmental
investigations on the implicated farms led to the detection of the
human outbreak strain of S. Enteritidis, as determined by phage
type, from the environment (100%) and from internal organs (88%) of
implicated flocks strongly suggesting that the implicated farms were
the sources of the outbreaks (Altekruse et al., 1993). Another
example is provided from Denmark where phage-typing, and plasmid profiling
of Salmonella Typhimurium isolates from human and animal
sources showed some animal strains and human strains to be indistinguishable
and concluded that spread of the strains from animals to humans was
the most probable explanation (Seyfarth et al., 1997).
6. Emergence of Usual Strains in Humans
Monitoring of human Salmonella surveillance data, when supported
by serotyping and perhaps additional subtyping techniques, can enable
the detection of the emergence of a unusual strains of Salmonella.
Possible sources for an increased number of an unusual strain of Salmonella
among human isolates may sometimes be indicated by the emergence of
the same unusual strain among isolates from animals, foods, and other
sources. When such investigations have been conducted, often the source
of the increase has been traced to foods of animal origin.
For example, beginning in 1969 there was a marked increase in human
isolates of Salmonella Agona detected in the United
States and several other countries. Salmonella Agona
had not been isolated in the United States before 1969, but by 1972
it was the eighth most common serotype isolated from humans in the
United States (Glynn et al., in press). Field investigations
and surveillance data determined Peruvian fish meal fed to chicken
to be the source of the infections. Critical to the investigation
was the identification of Salmonella Agona from Peruvian
fish meal in routine surveillance sampling of fish meal in 1970 (Clark
et al, 1973).
The widespread geographic distribution of unusual strains also supports
a limited role for person-to-person transmission of Salmonella
in the developed world. For example, the almost simultaneous emergence
in the United States and Europe of Salmonella Agona,
and more recently an indistinguishable clone of multi-drug-resistant
Salmonella Typhimurium DT104 R-type ACSSuT (Glynn et
al., in press), suggests transmission via the contamination of
a widely distributed vehicle, such as food, rather than infected persons.
Although comparisons between human and animal Salmonella surveillance
data are useful in investigating the epidemiology of salmonellosis,
such comparison should consider the specimen collection practices
inherent in the submission of specimens to clinical laboratories within
each surveillance system. For example, for both human and animal isolates,
the specimens submitted to the clinical laboratories usually are collected
from ill individuals. Since the serotypes of Salmonella in
ill animals and in foods of animal origin, which come from apparently
healthy animals, are likely to be different, crude comparisons of
the "top ten" Salmonella serotypes in humans and
in animals can lead to the erroneous conclusion that Salmonella
serotypes which are common in certain animals (e.g., Salmonella
serotype Cholerasuis in swine) and rare in humans are nonpathogenic
to humans. Thus, comparisons of the most common serotypes in certain
animals and humans can not be used to conclude that food animals are
not the most common sources of certain serotypes.
Sources of Antimicrobial-resistant Salmonella
Infections
Since most human Salmonella infections in the United States
are acquired from ingestion of contaminated foods, and because most
stool specimens which yield Salmonella (including antimicrobial-resistant
Salmonella) are obtained from patients before the patient takes
antimicrobial agents (if the patient takes antimicrobial agents),
it follows that most antimicrobial-resistant Salmonella infections
are acquired from ingestion of foods contaminated with antimicrobial-resistant
Salmonella. Another, less common, source of antimicrobial-resistant
Salmonella is direct fecal-oral transmission following contact
with animal feces. Strong supporting evidence that, in the United
States, persons infected with antimicrobial-resistant Salmonella
rarely obtain their infection from other infected persons is provided
by the inability to identify fluoroquinolone-resistant among 4,000
Salmonella isolates in 1995 - since ciprofloxacin is widely
used for the treatment of patients with salmonellosis, it is reasonable
to assume the fluoroquinolone-resistant Salmonella emerged
in the intestinal tract of some of the individuals infected with Salmonella
who received ciprofloxacin, however, transmission to other persons
must be rare because no domestically acquired resistant infections
were detected.
If antimicrobial-resistant Salmonella infections are acquired
from the ingestion of foods contaminated with antimicrobial-resistant
Salmonella, what causes the emergence and increasing prevalence
of antimicrobial-resistant Salmonella? The emergence and increasing
prevalence of antimicrobial resistant Salmonella is the direct
result of antimicrobial agents usage. In the United States, antimicrobial
agents are mostly used in humans, animals and on plants. Since human
usage in the United States has little impact on resistance among Salmonella,
and because most persons infected with antimicrobial-resistant Salmonella
do not have a history of recent international travel (Riley et
al., 1984; McDonald et al., 1987; Lee et al., 1994)
and few antimicrobial agents are used on plants, the only likely cause
for the emergence and increasing prevalence of antimicrobial-resistant
Salmonella in the United States is the use of antimicrobial
agents in animals, predominately food animals. Four lines of evidence
support the conclusion that most antimicrobial-resistance among Salmonella
isolates in humans results from the use of antimicrobial agents in
food animals.
1. Trace Backs of Selected Foodborne Disease
Outbreaks
Several outbreak investigations of antimicrobial-resistant Salmonella
infections in humans have combined epidemiologic fieldwork and laboratory
subtyping techniques to trace back antimicrobial-resistant Salmonella
through the food distribution system to farms, and antimicrobial use
on the farms was found to be associated with the antimicrobial resistance
(Holmberg et al., 1984; Lyons et al., 1985; Tack et
al., 1985; Spika et al., 1987). In one investigation, hamburgers
contaminated with antimicrobial-resistant Salmonella were traced,
using a unique plasmid profile, from supermarkets, through meat processing,
to well beef cattle which had been feed subtherapuetic antimicrobial
agents (Holmberg et al., 1984). In another investigation, approximately
1,000 persons were infected by hamburger contaminated with antimicrobial-resistant
Salmonella serotype Newport with an unusual marker - chloramphenicol
resistance. Chloramphenicol-resistant S. Newport was traced from ill
persons, through processing, to dairy cattle on farms where chloramphenicol
had been used (Spika et al., 1987). Although such investigations
provide considerable insight into the complexity of Salmonella
transmission, they suffer from the limitations of epidemiology studies.
However, when combined with other lines of evidence, such investigations
illustrate the potential human health consequences of the use of antimicrobial
agents on farms.
2. Emergence of Salmonella Typhimurium
DT104 R-type ACSSuT with Decreased Susceptibility to Fluoroquinolones
in the United Kingdom
The continued emergence of S. Typhimurium DT104 with
decreased susceptibility to fluoroquinolones in humans in the United
Kingdom provides increasingly strong evidence that antimicrobial-resistance
among Salmonella isolates in humans results from the use of
antimicrobial agents in food animals. Decreased susceptibility to
fluoroquinolones among human Salmonella isolates was rare in
the United Kingdom prior to 1993, despite the widespread use of ciprofloxacin
in humans since 1987. As previously mentioned, following the 1993
approval and widespread use of enrofloxacin in veterinary medicine,
human Salmonella isolates (and animal isolates) with decreased
susceptibility to ciprofloxacin rapidly emerged beginning in 1994
(Threfall et al., 1997).
3. Comparison of Patterns of Antimicrobial
Resistance Patterns of Salmonella Isolates from Humans and
Animals
If veterinary use of antimicrobial agents is responsible for the
development of antimicrobial resistant Salmonella in animals
which may be transmitted to humans, then the patterns of antimicrobial
resistance observed among Salmonella isolates collected from
healthy animals and humans should be similar. These similarities become
most evident when focusing on a serotype of Salmonella in humans
which are predominately derived from a single animal source. For example,
human infections with S. serotype Heidelberg are often
associated with eating undercooked chicken. Resistance patterns of
S. Heidelberg isolates from humans and healthy chickens are
similar.
4. Comparison Patterns of Antimicrobial
Usage in Humans and Animals with Antimicrobial Resistance Patterns
Among Humans and Animals
Although limited data is available on antimicrobial agent usage (subtherapuetic
and therapeutic) in food animals, the available data suggests that
the patterns of antimicrobial agent usage in food animals are similar
to the spectrum of antimicrobial resistance observed among Salmonella
isolates from food animals and humans. In contrast, the patterns of
antimicrobial agent usage in humans are dissimilar to the spectrum
of antimicrobial resistance observed in humans.
Human Health Risks of Fluoroquinolone Use in Food
Animals
With the recognition that foods of animal origin are the source of
most human Salmonella infections (and most antimicrobial-resistant
Salmonella infections), and that most antimicrobial resistance
among Salmonella isolates in the United States is caused by
the use of antimicrobial agents in food animals, it is possible to
evaluate the potential human health consequences of unrestricted veterinary
use of fluoroquinolones in the United States using the human health
risks model developed by the Institute of Medicine in 1988 (Institute
of Medicine, 1989). Each year in the United States, most of the approximately
2,400 persons with life-threatening invasive Salmonella infections
are treated with fluoroquinolones, of whom (although the isolates
are susceptible to fluoroquinolones) approximately 500 die. Fluoroquinolones
may therefore be life-saving for approximately 1,900 persons each
year in the United States. If widespread fluoroquinolone resistance
were to emerge among Salmonella isolates in the United States,
evidence presented in this review demonstrates that this resistance
would be the direct result of fluoroquinolone use in food animals.
Because few persons have had fluoroquinolone-resistant Salmonella
infections, the clinical significance of fluoroquinolone-resistant
is not precisely known, however, because other antimicrobial treatment
options are limited, treatment failures and serious outcomes, including
deaths, would be expected. If 10% of Salmonella isolates in
the United States were fluoroquinolone-resistant, and 10% of persons
with invasive fluoroquinolone -resistant infections were to die, fluoroquinolone
usage in food animals, which is currently limited to use in poultry,
under such a scenario, would result in 19 deaths each year.
Need for Prudent Use of Antimicrobial Agents
in Food Animals
The emergence and increasing prevalence of antimicrobial-resistant
Salmonella complicates the treatment of Salmonella infections
in humans and animals. For example, few antimicrobial agents are available
for the treatment of Salmonella Typhimurium DT104 R-type ACSSuT
which becomes resistant to trimethoprim and fluoroquinolones. The
increasing prevalence of antimicrobial resistance among Salmonella
isolates, and the potential emergence of fluoroquinolone-resistant
infections with adverse human health consequences, demonstrates the
urgent need to develop strategies to reduce antimicrobial agent usage
in food animals. Since antimicrobial agent usage can be reduced through
the implementation of non-antimicrobial means of controlling infectious
diseases, such as improved hygiene and sanitation, such efforts, which
will minimize development of antimicrobial resistance and dissemination
of antimicrobial-resistant pathogens, should be emphasized (Helmuth
and Protz, 1997). Efforts should also be taken to ensure that antimicrobial
agents are used prudently in food animals - prudent usage of antimicrobial
agents maximizes the therapeutic effect of the antimicrobial agent
and minimizes the development of antimicrobial resistance.
Since subtherapuetic (growth promoter) uses of antimicrobial agents
do not exert a therapeutic effect, such uses are non-prudent and should
be replaced by non-antimicrobial methods of growth promotion. Because
of the particular contribution of subtherapeutic use of penicillin
and tetracycline in the development and dissemination of antimicrobial
resistant Salmonella, the subtherapuetic use of penicillin
and tetracycline should be terminated (World Health Organization,
Division of Emerging and Other Communicable Diseases Surveillance
and Control, 1997). Because fluoroquinolones are a vital class of
antimicrobial agents for the treatment of potentially life-threatening
Salmonella infections in humans, and widespread usage of fluoroquinolones
in food animals will lead to rapid emergence and dissemination of
resistance to humans with adverse health consequences, the use of
fluoroquinolones in food animals should be restricted, particularly
until validated guidelines for the prudent use of antimicrobial agents
in food animals have been implemented and certified.
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