Food safety and antibiotic resistance are two aspects of the threat Salmonella
Typhimurium DT104 poses to the US. This report focuses more on the food safety aspect of
DT104 and was developed to inform Food Safety and Inspection Service (FSIS) management on
this emerging issue. The Food and Drug Administration (FDA) regulates antibiotic use and
the issue of antibiotic resistance is considered in greater detail by the Interagency
Working Group on Antimicrobial Susceptibility Monitoring chaired by FDA, Center for
Veterinary Medicine (CVM). This report is particularly concerned with DT104 as a foodborne
pathogen and the potential for mitigation of the risk from this source.
Salmonella Typhimurium DT104 (DT104) is an emerging foodborne pathogen detected in
several countries worldwide including: the United States, the United Kingdom (UK), Canada,
Germany, France, Austria, and Denmark. Of particular concern with DT104 is the presence of
a multiple antimicrobial resistance pattern (R-Type) to ampicillin, chloramphenicol,
streptomycin, sulfonamides, and tetracycline (ACSSuT). Molecular studies have demonstrated
that in this strain resistance genes are chromosomally encoded. This is important because
removal of the selective pressure from antibiotics is not expected to reverse resistance,
as it might with extrachromosomal mediated resistance. Also of concern is the increasing
trend of additional resistance of DT104 to trimethoprim and ciprofloxacin (a
fluoroquinolone) which has occurred in the UK. In the US, DT104 R-type ACSSuT has been
isolated from poultry, swine, cattle, and other domestic and wild animals. However, no
DT104 R-type ACSSuT isolates in the United States have shown resistance to trimethoprim or
In the UK, DT104 was first detected in 1984. The number of reported human isolates
increased from 259 in 1990, to 4,006 in 1996. This rapid increase in DT104 isolates
exceeds the increase in Salmonella Enteritidis cases in the previous decade, and
evidence suggests that the rate of increase is continuing. DT104 is now the second most
prevalent strain of Salmonella isolated from humans in England and Wales.
In the US, the number of sporadic Salmonella isolates from humans that were
Typhimurium did not increase dramatically between 1990 (8,510 isolates) and 1996 (9,501
isolates), but the proportion of Salmonella Typhimurium isolates that are R-type
ACSSuT increased from 9% in 1990, to 33% in 1996. Although all geographic areas had cases,
cases were more common in the west. The Centers for Disease Control and Prevention (CDC)
was involved in four outbreak investigations of S. Typhimurium R-type ACSSuT
infections, three on the west coast and one in the northeast. Each of these investigations
implicated unpasteurized dairy products. The source of DT104 in two of the outbreaks was
traced to dairy farms.
DT104 is an animal pathogen and a foodborne pathogen of humans. The mortality rate for
clinically affected cattle with this strain is reported to be 40-60% in some outbreaks in
the UK. The case fatality rate in humans may be higher than with other Salmonella
infections. In a study of 83 DT104 cases in the United Kingdom, 41% of patients were
hospitalized and 3% died. In contrast, the case-fatality rate for other nontyphoid Salmonella
infections was approximately 0.1%. In the United States, S. Typhimurium R-type
ACSSuT infections have been more likely to cause bacteremia and have been associated with
longer hospitalizations. No increase in mortality has been observed.
Recent antibiotic use in humans and animals is a predisposing factor for S.
Typhimurium DT104 infection. This has been observed in other enteric bacterial pathogens
as well. Killing the competitive gut flora may allow unrestricted growth of a pathogen. In
addition, the use of antibiotics to treat infection prolongs the carrier state of DT104 in
humans and animals. Both of these features indicate a need to educate physicians,
veterinarians, and the public about the potential adverse consequences of indiscriminate
Currently, the best prospect for minimizing human illness is a strategy of barriers to
introduction and multiplication of DT104 throughout the farm-to-table continuum. No unique
control methods are presently available for S. Typhimurium DT104 in humans or
animals because little is known about the epidemiology of DT104. Control measures that are
effective against other types of Salmonella spp. Will reduce the likelihood of
transmission of S. Typhimurium DT104.
Because of the need for a farm-to-table risk reduction strategy for DT104, an interagency
team of scientists from FSIS, CDC, APHIS, ARS, and FDA should be equipped with resources
to: 1) Facilitate studies in order to develop appropriate risk reduction measures at all
segments of the farm-to-table continuum, 2) Communicate research projects and needs to
avoid duplication and encourage collaboration, and 3) Develop a coordinated process to
investigate DT104 human and animal outbreaks from the point of illness to the source.
Food safety and antibiotic resistance are two aspects of the threat Salmonella
Typhimurium DT104 poses to the US. This report focuses more on the food safety aspect of
DT104 and was developed to inform FSIS management on this emerging issue. The Food and
Drug Administration (FDA) regulates antibiotic use and the issue of antibiotic resistance
is considered in greater detail by the Interagency Working Group on Antimicrobial
Susceptibility Monitoring chaired by FDA, Center for Veterinary Medicine (CVM). This
report is particularly concerned with DT104 as a foodborne pathogen and the potential for
mitigation of the risk from this source.
For the purpose of this report Salmonella enterica serotype Typhimurium definitive
type 104 (DT104) refers to S. Typhimurium organisms as identified by phage typing
procedures. A clone of DT104 has an antimicrobial resistance pattern (R-Type) to
ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline (ACSSuT). This
bacterial strain most commonly includes a 60 megadalton (MDa) plasmid (epidemic strain)
that does not code for antibiotic resistance. It should be noted that not all definitive
type DT104 isolates are R-type ACSSuT and not all R-type ACSSuT Salmonella
Typhimurium are definitive type 104. The relationship between S. Typhimurium,
R-type ACSSuT, and definitive type 104 needs better quantification.
Recent reports of increasing incidence of a multiple antibiotic resistant strain of S.
Typhimurium DT104 in humans and cattle have posed a major emerging public health issue of
international concern.1,2,3 Although most of the
well-known occurrences were originally reported in the UK, other European countries such
as Germany, France, Austria and Denmark have subsequently reported outbreaks.2 There is a growing emergence and concern in the US as well.3,4
A dramatic increase in the total number of human isolations of a multiple antibiotic
resistant strain of S. Typhimurium DT104 is accompanied by an emerging complexity
of multiple antibiotic resistance patterns.3, 5 A recent
study in England and Wales indicates a progressive increase in the total number of S.
Typhimurium DT104 isolations from 259 in 1990 to 4006 in 1996.6
The R-type ACSSuT pattern with resistance to ampicillin, chloramphenicol, streptomycin,
sulphonamides and tetracyclines increased from 39% of the DT104 isolates in 1990 to 98% in
1995. Further, a R-type pattern with additional resistance to trimethoprim (ACSSuTTm) that
was first reported in 1992 increased from <2% in 1993 to 24% of DT104 isolates in 1996.
A third R-type with additional resistance to ciprofloxacin (ACSSUTCp) increased from 1% in
1993 to 14% of DT104 isolates in 1996. This growing drug resistance pattern will
complicate the options available in the treatment of salmonellosis.
The S. Typhimurium DT104 R-type ACSSuT strain has an extensive
reservoir base that encompasses a wide range of species with potential to transmit
infection to humans directly and indirectly.1,7 During
the early 1990s in the UK, the prevalence of S. Typhimurium DT104 of R-type ACSSuT
increased in cattle, calves, swine, sheep and poultry (Table 1). The prevalence of this
strain increased in cattle, calves, swine and sheep, accounting for 70%, 72%, 36% and 70%
of Salmonella isolates respectively in 1995. The most dramatic increase in
prevalence for this strain occurred in poultry, which increased from 4% of Salmonella
isolates in 1993 to 52% in 1995. The Laboratory of Enteric Pathogens in the UK during
1991-1995 received 110 Salmonella isolates from cats, 78 (71%) were serotype
Typhimurium and 40 (51%) of those were DT104 R-type ACSSuT8.
|Table 1. Prevalence of S. Typhimurium DT104 in Other Countries
||Type of Animal
that are DT104(%)
|a Data from Salmonella in Livestock
Production, 1995, Ministry of Agriculture Fisheries and Food, Veterinary Laboratory
b Data from the International Workshop on Mulidrug
resistant S. Typhimurium DT104 May 1, 1997, CDC.
Retrospective evidence from banked Salmonella isolates in Washington state
indicate that S. Typhimurium DT104 R-type ACSSuT has been present in cattle in the
US since at least 1993 (personal communication, Dan Rice, Washington State University).
This strain has also been isolated from a wide variety of other animals in the US
including pig, sheep, chicken, turkey, horse, goat, emu, cat, dog, elk, mouse, coyote,
ground squirrel, raccoon, chipmunk and several species of birds.4
Currently in the US there are three sources of animal prevalence information on S.
Typhimurium DT104 R-type ACSSuT: 1) The National Antimicrobial Susceptibility Monitoring
System, 2) The National Veterinary Services Laboratories (NVSL), and 3) Washington State
University investigations. Differences related to the design of these studies must be kept
in mind when interpreting and comparing this information. None of these studies represent
solely a random sampling of Salmonella isolates from animals in the US and
therefore can not be considered representative of a national prevalence. The majority of
isolates available for testing from the NVSL and from Washington State are clinical
specimens submitted from veterinarians, thus livestock producers who are less likely to
utilize the services of a veterinarian are excluded from the database. The National
Antimicrobial Susceptibility Monitoring System has both clinical and non-clinical
isolates. Farms from which several isolates were submitted for analysis may skew the
interpretation of the data and overestimate the overall prevalence of S.
Typhimurium. The Washington State study reports data on cattle only, whereas the other two
sources include a variety of species.
All three sources tested isolates by first identifying S. Typhimurium by
serotyping. Antibiotic susceptibility testing was then performed to identify the ACSSuT
resistance pattern. Finally, S. Typhimurium isolates demonstrating R-type ACSSuT
were phage typed to identify DT104. Phage typing has not been completed for all isolates
reported. The R-type pattern ACSSuT is considered a good marker for the phage type DT104
in the US and is the test more commonly applied in the US since most laboratories are
equipped to perform it. An S. Typhimurium isolate with the ACSSuT R-type pattern is
not, however, always phage type DT104 and DT104 isolates with resistance patterns other
than R-type ACSSuT will not be detected.
The National Antimicrobial Susceptibility Monitoring System is an ongoing interagency
program to provide descriptive data on the extent and temporal trends of antimicrobial
susceptibility of Salmonella isolates from human and animal populations. The 1995
baseline study for the animal portion of this program tested 1,041 animal Salmonella
isolates for antibiotic susceptibility. The animal isolates came from healthy and ill
animals throughout the US. In 1996, the number of animal Salmonella isolates tested
was 1,922. The species distribution changed from 1995 to 1996 making comparison of results
between years difficult. Animal isolates included in this program came from multiple
sources such as NVSL, the National Animal Health Monitoring System (NAHMS), the National
Animal Disease Center, the Food Safety and Inspection Service (FSIS) the National Poultry
Improvement Plan, and research projects of collaborators.
Though the types of species and their distribution are similar from year to year, the
sources of the isolates and exact proportions of types of animals vary. Caution in making
direct year to year comparisons of the results is advised. The proportion of S.
Typhimurium isolates which were R-type ACSSuT in 1995 was 10.2% (14/137), in 1996, 10.5%
(45/427). The proportion of S. Typhimurium R-type ACSSuT isolates which are DT104
in the National Antimicrobial Susceptibility Monitoring System studies are 64% (9/14) for
1995 and 22.2% (10/45) for 1996.
The NVSL study included Salmonella isolates from various species and from
clinically ill and healthy animals submitted to NVSL from October 1996 through mid
February 1997. The proportion of S. Typhimurium R-type ACSSuT among S.
Typhimurium isolates (26%) in the study is higher than in the National Antimicrobial
Susceptibility Monitoring System 1996 study (10.5%). Possible explanations for the
differences are the inclusion of more healthy animals in the National Antimicrobial
Susceptibility Monitoring System study than in the NVSL study, differing proportions of
the various species included in the two studies, and that many samples were collected much
longer before submission in the animal segment of the National Antimicrobial
Susceptibility Monitoring System.
Washington State University investigators recognized outbreaks of salmonellosis in dairy
herds in the Pacific Northwest over the past several years associated with the R-type
ACSSuT strain of S. Typhimurium.4 In a
retrospective analysis of antibiotic resistance patterns of isolates submitted to the
diagnostic lab at Washington State University, none of 44 S. Typhimurium isolates
submitted prior to 1986 had the R-type ACSSuT. Between 1986 and 1991, 13% of 83 S.
Typhimurium isolates were identified as R-type ACSSuT and this proportion increased to 64%
of 51 isolates between 1992 and 1995. The reported annual number of animal S.
Typhimurium cases in the Pacific Northwest has not shown an increasing trend. This
possibly indicates a competitive advantage for phage type DT104 R-type ACSSuT,9 resulting in a reduction in other serotypes of Salmonella
while DT104 increased. Sixty of the isolates were phage typed and 95% (57/60) were DT104.
Additional prevalence information for S. Typhimurium DT104 in cattle will be
available in the future. NAHMS conducted a national survey of dairy operations in 1996. A
stratified random sample of dairy operations from 20 selected states that represent 83% of
US dairy cows was chosen for the study. Fecal samples were obtained from 100 farms and 100
livestock markets (cull dairy cows) and tested for Salmonella spp. including S.
Typhimurium DT104. Information was collected which will allow evaluation of herd-level and
animal-level risk factors for Salmonella shedding. In August 1997 NAHMS began
collecting fecal samples from beef cows on 200 operations across the US. These will be
cultured for the presence of Salmonella spp. including S. Typhimurium DT104.
Little information is available on the demographic distribution of the S.
Typhimurium DT104 T-type ACSSuT strain in animals other than cattle. In the UK in 1995, a
similar proportion of Salmonella isolates among calves (72%) were DT104 compared to
adult cattle (70%) (Table 1). Calves were more severely affected than adult cattle in a
case-control study conducted in the U.K.1 Investigators
in the northwest US however, have reported that clinical disease occurred predominantly in
cows in the immediate post calving period and less commonly in young calves.4 Outbreaks of DT104 in cattle in the US have occurred primarily in
dairy cattle herds with only a few incidents in beef cow-calf herds (Besser, 1997,
Workshop Minutes). In the northeast US, eight outbreaks on dairy farms of S.
Typhimurium resistant to ampicillin, chloramphenicol and tetracycline (testing did not
include sulfonamides or streptomycin) were reported from 1996 through May 1997 (personal
communication, Dr. Pat McDonough, Cornell University). Multiple age groups of cattle were
affected in these outbreaks in the northeast US.
DT104 is present in many areas of the US. Northern regions of the country, especially the
northwest, may have higher prevalences than other regions (Dan Rice, written
communication, Workshop Minutes). Whether this is due to differences in active
surveillance or real differences is unknown. In a study of cull dairy cattle at five
slaughter establishments widely separated across the United States all S.
Typhimurium DT104 were obtained from cull dairy cows at the western establishment. These
samples constituted 88.6% (31/35) of the S. Typhimurium examined from that
Seasonality has been identified as a factor in the distribution of S. Typhimurium
DT104 in cull dairy cattle. Thirty of the 31 (96.8%) S. Typhimurium identified as
DT104 were isolated during the winter sampling period.10
In a case-control study of cattle conducted in the UK, cases were more common in the
summer months, associated with the calving season, than the winter months.1
DT104 appears to cause a higher morbidity and mortality rate among infected animals
than other nontyphoid Salmonella infections.11
The mortality rate for clinically affected animals with this strain is reported to be
50-60% in some outbreaks in the UK (Workshop Minutes). In a case-control study of cattle
in the UK, a 40% case fatality rate was reported, with a higher rate among calves than
among adult animals.1 Clinical signs of DT104 in cattle
included pyrexia (fever), depression and mental dullness, decreased milk production,
anorexia, dehydration with scleral injection, increased saliva production, and diarrhea
progressing to dysentery.1 Animals may be asymptomatic
carriers of DT104 and shed large numbers of organisms for up to 18 months following an
outbreak.1, 8 Cats have been reported to shed the
organism up to 14 weeks and symptomatic cats are reported to shed large numbers of
organisms from the mouth.22
A case-control study of risk factors for S. Typhimurium DT104
infection was reported in 1996.1, 12 The study
population included all cattle herds that submitted specimens to the diagnostic laboratory
services of the Ministry of Agriculture, Fisheries, and Food Veterinary Investigation
Centres and Scottish Agricultural Colleges from May 1994 to October 1995. Statutory
reporting of all Salmonella is mandated for all food animal species and some other
species under the Zoonosis Order, 1989 and the Poultry Breeding Flocks and Hatcheries
Order, 1993. Salmonella isolates are serotyped under the Kauffman White Scheme and
phage typed according to PHLS schemes. Case herds were herds in which S.
Typhimurium DT104 R-type ACSSuT was isolated from at least one bovine on the premises.
Group B Salmonella isolated from bovines during standard diagnostic investigation
were evaluated for resistance to ampicillin, chloramphenicol, tetracycline, and
trimethoprim to identify the epidemic strain. Control herds were selected randomly from
all non-case submissions during the same time as the case herds. Data were collected via
personal interviews at the farm by Veterinary Investigation Officers. Outbreaks were more
prevalent in dairy herds than in beef herds, mixed dairy and beef herds, and calf herds.
Outbreaks were more prevalent in larger herds and during the summer which corresponds to
the calving season for dairy herds in the UK. The within-herd prevalence ranged from 0.1
to 100.0 percent, but the median prevalence was only 4%. The most frequently reported
clinical signs were watery diarrhea, anorexia, and poor condition. Exposure variables
containing two to eight levels of exposure were analyzed for association between S.
Typhimurium DT104 infection and exposure. Statistically significant risk factors were
identified using univariate and multivariable analyses. Odds ratios and 95% confidence
intervals, adjusted for two potentially confounding variables (geographic location and the
season in which the laboratory diagnosis was made), were reported. There was no indication
that herd-size was considered as a confounder.
Five of the ten risk factors that were statistically significant in the univariate
analysis were included also in the multivariable analysis (Table 2). Three additional risk
factors were statistically significant in the univariate analysis, but were excluded from
the multivariable analysis due to a high percentage of missing data points (Table 2). A
total of 42 odds ratios were reported for the 10 risk factors because multiple levels of
several risk factors were analyzed. Given that 42 odds ratios were reported, of which 5
were statistically significant, at least two of the 5 could have been significant by
|Table 2. Case-control Studies of Risk Factors for Salmonella Typhimurium
DT104 Infection in Cattle in Great Britaina
||1.14 to 177.1
|New herd additions within 14 days
preceding the index casec
||1.36 to 4.92
||1.24 to 6.29
||1.37 to 2.94
|Sick animals and difficult calvings
||1.06 to 2.16
|High feral cat densityd
||1.09 to 1.65
|Wild bird access to feed storage
||1.11 to 2.51
|Purchase cattle from dealer herdsd
||1.62 to 9.36
|a These results are from Evans, 1996
and Evans and Davies, 1996. The study included 656 cases and 505 controls.
b C.I. - confidence interval
c Results of multivariable statistical analysis
d Results of univariate statistical analysis
As with other enteric bacterial pathogens, recent antibiotic use is a risk factor for
infection with S. Typhimurium DT104. In the US, S. Typhimurium with
resistance to ampicillin, chloramphenicol and tetracycline (streptomycin and sulfonamides
were not included in resistance testing), caused three cat associated outbreaks, one in a
veterinary hospital in New York and two in veterinary hospitals in California between
1996-1997. A predisposing event in these cat outbreaks was prophylactic antibiotic therapy
(personal communication, Dr. Pat McDonough, Cornell University). Recent antibiotic use may
kill competitive gut flora allowing unrestricted growth of the pathogen.
Unique control methods are presently not available for S. Typhimurium DT104
because little is known about the epidemiology of DT104. The same methods that are
effective against other types of Salmonella spp. i.e. good production practices,
should help control harborage and transmission of DT104. These generally rely on
decreasing exposure and increasing immunity of susceptible hosts. S. Typhimurium
DT104 has been isolated from a wide range of species including livestock, companion
animals, and wildlife. The widespread distribution of DT104 makes effective controls
potentially more problematic than the control of S. Enteritidis phage type 4, which
has a reservoir mainly confined to poultry. Some of the risk factors associated with the
spread of DT104 among cattle were listed in Table 2. Further studies on the spread of
DT104 are needed.
Of particular importance from a control point of view in cattle is the role of
asymptomatic carriers. Following recovery from illness, S. Typhimurium DT104 has
been found in fecal samples of clinically normal cattle for varying periods up to 18
months.1,13 In one instance when a carrier was
introduced to another healthy group, it triggered infection leading to clinical signs in
the healthy group. Identifying clinically ill herds as a source of asymptomatic shedders
may be one beneficial control measure to minimize the spread of DT104.
Flock or herd exposure is decreased through cleaning and disinfecting premises,
controlling rodents, and minimizing contamination of feed. Cleaning and disinfecting
premises and controlling rodents are most effective in closed environments. Once
introduced, it is difficult to consistently eliminate Salmonella spp. from the
environment. Oosterom showed that reduction but not elimination of Salmonella spp.
in swine was possible through an integrated program of rodent control, cleaning and
disinfecting, and pelletizing feed.14,15
In contrast Wray reported that Salmonella spp. were isolated from the environment
of six of nine dairy farms after cleaning and disinfecting.16
The Salmonella Enteritidis Pilot Project isolated S. Enteritidis in
approximately 50% of the layer houses after cleaning and disinfecting.17
In a few cases S. Enteritidis was isolated from houses that had previously tested
negative. This project also showed that rodent control in layer houses decreased the
probability of the houses being contaminated with S. Enteritidis.
Numerous reports have shown that although animal feed is frequently contaminated with Salmonella
spp, the Salmonella spp. in feed are not necessarily the same as the Salmonella
spp. isolated from animals. Veldman described a survey of poultry feed in which 10% of 360
samples of poultry feed in the Netherlands were contaminated with Salmonella spp.18 No S. Enteritidis was isolated despite an ongoing
outbreak of S. Enteritidis in poultry flocks at the time.
Research to control salmonellosis has focused on the use of bacterins to increase
immunity. Davies reported that a killed bacterin was effective in controlling S.
Typhimurium in cattle.19 Hassan reported that a modified
live bacterin prevented infection of virulent S. Typhimurium in chickens.20 The Salmonella Enteritidis Pilot Project showed that
layer hens vaccinated with a killed S. Enteritidis bacterin were less likely to lay
S. Enteritidis contaminated eggs.
S. Typhimurium DT104 R-type ACSSuT was first detected in humans in the UK in
1984. Initially, most DT104 isolates were associated with foreign travel and few DT104
isolates were multidrug resistant. In the late 1980s, the number of human isolates of
DT104 in the United Kingdom began to increase remarkably and an increasing proportion of
the isolates were resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides,
and tetracycline (R-type ACSSuT). In the 1990s, the number of reported human isolates of
DT104 R-type ACSSuT increased from 259 in 1990, to 4,006 in 1996. This rapid increase in
DT104 R-type ACSSuT isolates exceeds the increase in S. Enteritidis cases in the
previous decade, and there is evidence that the rate of increase is continuing. By 1995, S.
Typhimurium DT104 R-type ACSSuT had become the second most commonly isolated Salmonella
from humans, second only to S. Enteritidis phage type 4. In 1996, DT104 R-type
ACSSuT accounted for more than 10% of human Salmonella isolates in the United
Kingdom, and caused an estimated 30,000-300,000 human infections.5
Of additional concern is the increasing proportion of human DT104 R-type ACSSuT isolates
which are resistant to antibiotics important in the treatment of life-threatening invasive
Salmonella infections. The proportion of DT104 isolates resistant to trimethoprim
increased from <2% in 1993 to 24% in 1996, while the proportion resistant to
ciprofloxacin increased from 1% in 1993 to 14% in 1996.
The first known human S. Typhimurium DT104 isolate was identified in Canada in
1970 (Workshop Minutes). S. Typhimurium DT104 R-type ACSSuT has been reported from
many European countries, including Denmark, Germany, France and Italy. Although precise
information on the incidence of DT104 is not available, several countries have reported
increases similar to the United Kingdom. In addition, the increase in reported S.
Typhimurium DT104 occurred at approximately the same time. Molecular studies indicate that
the organism in these additional countries is very similar, if not identical, to the
organism in the United Kingdom (personal communication, John Threlfall, PHLS, London).
Preliminary data suggests that DT104 may have emerged in the United States at
approximately the same time as in the United Kingdom. Each year in the United States,
there are an estimated 800,000 - 4 million cases of salmonellosis of which approximately
40,000 are culture-confirmed and reported to the Centers for Disease Control and
Prevention (CDC). Salmonella isolates are not routinely forwarded to CDC from state
health departments. However, special studies were conducted in selected counties in 1980,
1985, 1990, and 1995 in which all Salmonella isolates were forwarded to CDC for
antimicrobial susceptibility testing. The proportion of S. Typhimurium isolates in
the selected county studies which were R-type ACSSuT increased from 2% in 1980, to 4% in
1985, to 9% in 1990, and to 12% in 1995 (workshop minutes). The proportion of those R-type
ACSSuT which were DT104 was 0% in 1980, 25% in 1985, 50% in 1990, and 85% in 1995.
In 1995, all 50 states participated in the National Salmonella Antimicrobial
Resistance Study where they sent every tenth isolate to CDC. Twenty-eight percent
(275/976) of the S. Typhimurium isolates were R-type ACSSuT, and approximately 85%
of those isolates were DT104. Although all geographic areas had cases, cases were more
common in the west.
In 1996, isolates from 14 state and local health departments participating in the National
Antimicrobial Susceptibility Monitoring System were sent to CDC. Thirty-three percent
(110/304) of S. Typhimurium isolates were R-type ACSSuT, and approximately 85% of
those isolates were DT104. Cases were more common in the west. To date, no DT104 R-type
ACSSuT isolates in the United States have shown resistance to trimethoprim or
The clinical features associated with infection with DT104 R-type ACSSuT may be more
severe than other Salmonella infections. In a study of 83 DT104 cases in the United
Kingdom, 41% of patients were hospitalized and 3% died. In contrast, the case-fatality
rate for nontyphoid Salmonella infections is approximately 0.1%. In the United
States, S. Typhimurium R-type ACSSuT infections have been more likely to cause
bacteremia and have been associated with longer hospitalizations; further investigations
are ongoing (Workshop Minutes).
Consumption of food items contaminated with S. Typhimurium DT104 and direct
contact with infected animals are important risk factors in the transmission cycle. Often
these are foods of animal origin such as beef, pork or poultry. In a case-control study of
sporadic DT104 infections in the United Kingdom in 1993, infection was associated with
eating chicken and pork sausages.21 In 46 outbreak
investigations of DT104 infections conducted in the United Kingdom from 1992 to 1996, 78%
(n=36) of the outbreaks were attributed to foodborne transmission and 15% (n=7) were
associated with direct contact with farm animals (personal communication, Patrick Wall,
PHLS, London). A variety of food items were implicated.
Epidemiological investigations in the United States are ongoing. Preliminary analysis of a
national case-control study of sporadic S. Typhimurium R-type ACSSuT infections did
not clearly implicate specific food items. There was an association between infections and
direct contact with animals with diarrhea or visiting farms. Such contact, as in the
United Kingdom, may explain perhaps 10% of cases and represents a higher proportion of
illness associated with animal contact compared to other Salmonella infection. In
addition, a high proportion of persons infected with S. Typhimurium R-type ACSSuT
reported taking antibiotics, particularly penicillin-type antibiotics (amoxicillin,
ampicillin, etc) compared to controls, indicating the need to educate physicians and the
public about the potential adverse consequences of widespread antibiotic use among humans.
There have been five outbreaks of human illness identified in the United States (two in
California, one each in Washington, Nebraska, and Vermont). Four of these outbreaks
involved consumption of unpasteurized dairy products or contact with dairy cattle.
The presence of a large, cat population residing indoors as pets in close association with
humans could be an important epidemiological factor in the spread of this disease to
humans. Cats have been reported to shed S. Typhimurium DT104 in feces for twelve
weeks or longer after recovery from an acute illness.22
The cycle may be perpetuated in a barn setting where cats contaminate animal feeds.
The association between ill animals and S. Typhimurium DT104 infections in humans
has also been described in Washington State where a higher proportion of persons with S.
Typhimurium DT104 infections lived in counties with a large number of dairy cattle
compared to persons with other Salmonella infections. Field investigations of S.
Typhimurium DT104 outbreaks on dairy farms in Washington and New York provide anecdotal
reports that a higher proportion of these farm workers had recent diarrheal illness
compared to outbreaks of other Salmonella spp. on other dairy farms. CDC has been
involved in four outbreak investigations of S. Typhimurium R-type ACSSuT
infections, three on the west coast and one in the northeast. Each of these investigations
have implicated unpasteurized dairy products and two of the investigations have been
traced to dairy farms.
No unique control methods are presently available for S. Typhimurium DT104 in
humans because little is known about the epidemiology. Control measures that are effective
against other types of Salmonella spp. may reduce the likelihood of transmission of
S. Typhimurium DT104. Controlling Salmonella spp. in humans relies on
decreasing exposure through hygienic processing of products and proper preparation and
storage of cooked products. Specific measures include thoroughly cooking foods of animal
origin, avoiding cross contamination of other foods, avoiding consumption of unpasteurized
dairy products, and educating food handlers. Even in the absence of adequate control
methods in animals, instituting control methods at food preparation can still minimize the
number of human outbreaks.23 More research is needed on
risk factors for foodborne illness from S. Typhimurium DT104.
The following estimated numbers of US S. Typhimurium DT104 cases are based on
several assumptions that must not be over interpreted. Some data from sentinel projects,
which may not be generalizable, are extrapolated to make national assumptions. Percentages
of Salmonella surveillance isolates identified as a particular serotype or subtype
are based on small numbers that may not be stable. The following two methods provide
estimates of the S. Typhimurium DT104 burden in the US.
- US estimates of the total number of human Salmonella infections range from
800,000 to 4,000,000 per year.24 Approximately 24% of
the 4024 Salmonella isolates in the 1995 National Salmonella Antimicrobial
Resistance Study and 24% of the 39,032 Salmonella isolates reported to CDC in 1996
were S. Typhimurium. Approximately 33% of S. Typhimurium isolates are of
R-type ACSSuT. Approximately 93% of the S. Typhimurium isolates with R-type ACSSuT
are in the DT104 complex. These percentages produce a cumulative multiplier (24% * 33% *
93%) of 7.4%. Multiplying 0.074 by the 800,000 to 4,000,000 estimated Salmonella
infections per year, yields an estimated range of 59,200 to 296,000 S. Typhimurium DT104
cases per year.
- Similar estimates are obtained using a different technique. The sequential surveillance
artifact for Salmonella has been estimated at 39:1; in other words, for each
reported culture confirmed case, thirty-nine people were initially infected.25 There are approximately 10,000 culture confirmed cases of S.
Typhimurium annually. Assuming the general Salmonella artifact applies to S.
Typhimurium, and there is no a priori reason to believe otherwise, we estimate 390,000
people are infected with S. Typhimurium per year. Using the previous percentage
estimates of R-types and definitive types, an estimate of 120,000 S. Typhimurium
DT104 cases per year is obtained. This value lies within the previous range.
Cost of illness estimates are based on the number of foodborne cases and deaths, number of
cases with secondary sequela, the associated costs of medical care, lost productivity, and
other costs such as special education and residential-care costs.26
There is equivocal evidence on whether human infection with DT104 is more severe than
infection with other non-typhoidal Salmonella. A study in the UK showed that 78% of 46
outbreaks of DT104 were of foodborne origin. (personal communication, Patrick Wall, PHLS,
London) Using the above estimates, 46,000 to 231,000 foodborne cases of DT104 occur per
year. Fifty-eight to 128 of these may result in death.26
Two S. Typhimurium DT104 costs of illness estimates can be obtained:26
Using a $5 million (1995 dollars) statistical life value estimated from wage-risk studies,
the financial burden of foodborne non-typhoidal Salmonella has been estimated at
$4.8 - 12.2 billion per year. Using the above 0.074 multiplier and a $5 million (1995
dollars) statistical life value estimated from wage-risk studies, the financial burden of S.
Typhimurium DT104 infection on the US population is estimated to be $360 to 900 million
A human capital approach, increased by a willingness-to-pay multiplier, estimates the
value of a statistical life, depending on age, to range from roughly $15,000 to $1,979,000
in 1995 dollars. Using the human capital approach, the financial burden of foodborne
non-typhoidal Salmonella has been estimated at $0.9 3.5 billion per year. Using the
above 0.074 multiplier, the financial burden of S. Typhimurium DT104 infection on
the US population is estimated to be $67 to 260 million per year.
The priority rating process provides a relative public health ranking of foodborne
pathogens associated with beef at slaughter.27 Although
the following relative priority ranking applies specifically to beef, this does not imply
that beef is the primary foodborne vehicle for DT104. Epidemiologic investigations are
needed to define the major DT104 risk factors. The following assumptions were made in
completing the priority rating model to determine the relative ranking of DT104. These
assumptions are largely reflective of knowledge about Salmonella spp. in general,
not Salmonella Typhimurium DT104 in particular.
- All demographic groups susceptible to infection.
- Less than 106 estimated cases per year.
- Low current consumer concern.
- 0.5-5% case fatality rate.
- 3 - 7 day duration of infection.
- Multiple gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) likely in infected
- Moderate extra-intestinal symptoms in the general population.
- Rarely detected with current organoleptic slaughter inspection procedures.
- Agent can multiply on product to reach infectious dose.
- Moderate infectious dose (102 to 105).
- Low prevalence on carcasses (0.1 to 0.5% positive).
Using the priority rating method, S. Typhimurium DT104 ranked fifth, below the
other priority pathogens E. coli O157:H7, Salmonella spp. (excluding DT104),
Listeria monocytogenes, and Campylobacter (Table 3). This ranking places S.
Typhimurium DT104 in the upper tier of beef associated foodborne agents of concern.
|Table 3: Priority Rating for six beefborne pathogens
||Priority Rating (max=90)
|E. Coli O157:H7
|S. Typhimurium DT104
Limited information concerning the prevalence and distribution of DT104 in humans and
animals in the US is available. There are few analytic studies to date in the literature
which address risk factors and transmission of DT104 in the US. Because of the need for a
farm-to-table risk reduction strategy for DT104, an interagency team of scientists from
FSIS, CDC, APHIS, ARS, and FDA should be equipped with resources to: 1) Facilitate studies
in order to develop appropriate risk reduction measures, 2) Communicate research needs and
work in progress to avoid duplication and encourage collaboration, and 3) Develop a
coordinated process to investigate DT104 human and animal outbreaks from the point of
illness to the source to identify risk factors for the reduction of the organism at all
segments of the farm-to-table continuum.
Future research concerning S. Typhimurium DT104 in the areas of surveillance,
analytic epidemiology, microbiology and pharmacology, should address the following
- determine and monitor national incidence, prevalence and distribution of sporadic
- develop an outbreak surveillance system
- test Salmonella isolates for flouroquinolone, trimethoprim, and
- determine and monitor national prevalence and distribution of infection by species and
by clinical status
- develop an outbreak surveillance system
- conduct carcass and product testing
- test Salmonella isolates for flouroquinolone, trimethoprim, and
- Risk factor studies to determine: role of antibiotic use, behaviors associated with
infection, demographic risk factors
- Transmission studies to determine: role of specific foods in transmission, live animal
(pets, livestock) to human transmission, waterborne transmission, person-to-person
transmission, restaurant versus home transmission
- Identify and evaluate control measures: determine effectiveness of education and other
- Risk factor studies to determine: demographic risk factors; role of animal movement both
on farm and livestock markets, sales, trucks; role of antibiotics; role of farm management
- Transmission studies to determine: role of environmental contamination eg. water, feed,
sludge, rodents, wildlife; role of direct animal to animal and human to animal
transmission; watershed contamination.
- Identify and evaluate control measures: determine effectiveness of improved biosecurity,
sanitation and hygiene measures in preventing transmission; effectiveness of potential
methods to increase animal immunity (bacterins, vaccine, feed type, competitive
exclusion), quality assurance programs.
- Evaluate the effectiveness of HACCP systems in decreasing carcass contamination with
- Evaluate the effectiveness of procedures such as irradiation, carcass washing, steam
pasteurization, etc. in reducing DT104
- Standardize lab diagnostic procedures
- Examine usefulness of various subtyping techniques (PFGE, Plasmid profiles, PCR)
- Establish reference database of molecular subtyping information
- Determine specific organism characteristics such as: heat and acid tolerance, infective
dose, ecology, survivability in the environment in various media, etc.
- Evaluate potential for DT104 to acquire new resistance (in-vitro studies)
- Determine significance and role of Copenhagen variant
- Evaluate the genetic relatedness of DT104 isolates
- Evaluate the effect of antibiotic use on infection, shedding, etc.
Salmonella Typhimurium DT104 is an emerging pathogen detected in several
countries worldwide including: the United States, the United Kingdom, Canada, Germany,
France, Austria, and Denmark. Illness has been associated with the consumption of pork
sausages, chicken, unpasteurized dairy products, a brand of meat paste, and direct contact
with ill animals. Much additional information is needed about the epidemiology of DT104 in
Of particular concern with DT104 is the presence of a multiple antimicrobial resistance
pattern (R-Type) to ampicillin, chloramphenicol, streptomycin, sulfonamides, and
tetracycline (ACSSuT). Molecular studies have demonstrated that in this strain resistance
genes are chromosomally encoded. This is important because removal of the selective
pressure from antibiotics is not expected to reverse resistance, as it might with plasmid
mediated (non-chromosomal) resistance. Also of concern is the increasing additional
resistance of DT104 to trimethoprim and ciprofloxacin (a fluoroquinolone) which has
occurred in the UK. To date, no DT104 R-type ACSSuT isolates in the United States have
shown resistance to trimethoprim or ciprofloxacin.
Pathogen reduction efforts in the production segment of the farm-to-table continuum will
be difficult with DT104. DT104 has a broad reservoir base in domestic, companion, and wild
animals. A significant rate of morbidity has been observed in infected livestock and
poultry and a significant rate of mortality has been identified in cattle. Producers will
be more willing to pursue control when their livelihood is affected. On the other hand,
control efforts must be targeted to a wide range of animals. Further study is needed on
the ecology of DT104 on farms to identify effective controls.