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and antibiotic resistance
ab a c a
Shu-Kee Eng , Priyia Pusparajah , Nurul-Syakima Ab Mutalib , Hooi-Leng Ser , Kok-Gan
d a
Chan & Learn-Han Lee
a
Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Selangor Darul
Ehsan, Bandar Sunway, Malaysia
b
School of Science, Monash University, Selangor Darul Ehsan, Bandar Sunway, Malaysia
c
UKM Medical Centre, UKM Medical Molecular Biology Institute (UMBI), Bandar Tun Razak,
Cheras, Kuala Lumpur 56000, Malaysia
d
Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of
Science, University of Malaya, Kuala Lumpur, Malaysia
Published online: 09 Jun 2015.

To cite this article: Shu-Kee Eng, Priyia Pusparajah, Nurul-Syakima Ab Mutalib, Hooi-Leng Ser, Kok-Gan Chan & Learn-Han Lee
(2015): Salmonella: A review on pathogenesis, epidemiology and antibiotic resistance, Frontiers in Life Science

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 Frontiers in Life Science, 2015
http://dx.doi.org/10.1080/21553769.2015.1051243

Salmonella: A review on pathogenesis, epidemiology and antibiotic resistance

Shu-Kee Enga,b , Priyia Pusparajaha , Nurul-Syakima Ab Mutalibc , Hooi-Leng Sera , Kok-Gan Chand and Learn-Han Leea∗
a Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Selangor Darul Ehsan, Bandar Sunway, Malaysia; b School
of Science, Monash University, Selangor Darul Ehsan, Bandar Sunway, Malaysia; c UKM Medical Centre, UKM Medical Molecular
Biology Institute (UMBI), Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; d Division of Genetics and Molecular Biology,
Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
(Received 20 October 2014; accepted 11 May 2015 )

Salmonella is one of the most frequently isolated foodborne pathogens. It is a major worldwide public health concern,
accounting for 93.8 million foodborne illnesses and 155,000 deaths per year. To date, over 2500 Salmonella serotypes have
been identified and more than half of them belong to Salmonella enterica subsp. enterica, which accounts for the majority
of Salmonella infections in humans. Salmonella infections that involve invasive serotypes are often life threatening, neces-
sitating appropriate and effective antibiotic therapy. The emergence of multi-drug-resistant (MDR) Salmonella serotypes is
having a great impact on the efficacy of antibiotic treatment, and an increasing prevalence of MDR strains may lead to an
Downloaded by [Learn-Han Lee] at 00:47 10 June 2015

increase in mortality rates of Salmonella infections. Epidemiological studies indicate that MDR Salmonella serotypes are
more virulent than susceptible strains, as reflected by increased severity and more prolonged disease in patients infected by
MDR strains. Preventive measures have been proposed to eliminate the spread of Salmonella infection. While the main-
tenance of effective food hygiene and water sanitation remain the cornerstones, additional measures such as restriction of
indiscriminate use of antibiotics in food animals are important. This review provides an overview of Salmonella infection,
and discusses the nomenclature, pathogenesis, clinical manifestations, epidemiology and antibiotic resistance of Salmonella.
Keywords: Salmonella; multi-drug resistance; enteric fever; foodborne

Introduction uncooked animal food products. The slaughtering pro-

Salmonella infection remains a major public health con-
cern worldwide, contributing to the economic burden of
both industrialized and underdeveloped countries through
the costs associated with surveillance, prevention and treat-
ment of disease (Crump et al. 2004). Gastroenteritis is
the most common manifestation of Salmonella infection
worldwide, followed by bacteraemia and enteric fever
(Majowicz et al. 2010) (Figure 1). Salmonella is a rod-
shaped, Gram-negative facultative anaerobe that belongs
to the family Enterobacteriaceae (Barlow & Hall 2002).
Within the genus Salmonella, around 2600 serotypes have
been identified with the use of the standard Kauffman–
White scheme and most of these serotypes have the ability
to adapt within a variety of animal hosts, including humans
(Allerberger et al. 2003). Salmonella and Campylobac-
ter are the most frequently isolated foodborne pathogens,
and are predominantly found in poultry, eggs and dairy
products (Silva et al. 2011). Other food sources that are
involved in the transmission of Salmonella include fresh
fruits and vegetables (Pui et al. 2011). In general, food
animals such as swine, poultry and cattle are the prime
sources of Salmonella infections. The major dissemina-
tion routes of the pathogens involve trade in animals and
cess of food animals at abattoirs is considered one of
the important sources of organ and carcass contamination
with Salmonella (Gillespie et al. 2005). The emergence
of antibiotic-resistant foodborne pathogens has raised the
concern of the public as these pathogens are more virulent,
causing an increase in the mortality rate of infected patients
(Chiu et al. 2002).
Classification and nomenclature
Salmonella was first discovered and isolated from the
intestines of pigs infected with classical swine fever, by
Theobald Smith in 1855. The bacterial strain was named
after Dr Daniel Elmer Salmon, an American pathologist
who worked with Smith. The nomenclature of Salmonella
is controversial and still evolving. Currently, the Cen-
ters for Disease Control and Prevention (CDC) uses the
nomenclatural system of Salmonella recommended by the
World Health Organization (WHO) Collaborating Cen-
tre (Popoff et al. 2003). According to this system, the
genus Salmonella is classified into two species, Salmonella
enterica (type species) and Salmonella bongori, based on
differences in their 16S rRNA sequence analysis. The type

*Corresponding author. Emails: lee.learn.han@monash.edu; leelearnhan@yahoo.com

© 2015 Taylor & Francis

 2 S.-K. Eng et al.
Figure 1. Incidence rate of enteric fever and gastroenteritis in different regions around the world.
Downloaded by [Learn-Han Lee] at 00:47 10 June 2015
species, S. enterica, can be further classified into six
subspecies based on their genomic relatedness and bio-
chemical properties (Reeves et al. 1989). The subspecies
are denoted with roman numerals: I, S. enterica subsp.
enterica; II, S. enterica subsp. salamae; IIIa, S. enterica
subsp. arizonae; IIIb, S. enterica subsp. diarizonae; IV,
S. enterica subsp. houtenae; and VI, S. enterica subsp.
indica. Among all the subspecies of Salmonella, S. enter-
ica subsp. enterica (I) is found predominantly in mammals
and contributes approximately 99% of Salmonella infec-
tions in humans and warm-blooded animals. In contrast,
the other five Salmonella subspecies and S. bongori are
found mainly in the environment and also in cold-blooded
animals, and hence are rare in humans (Brenner et al.
2000).
In addition to the classification of subspecies based
on phylogeny, Kauffman and White developed a scheme
to further classify Salmonella by serotype based on three
major antigenic determinants: somatic (O), capsular (K)
and flagellar (H) (Brenner et al. 2000). The heat-stable
somatic O antigen is the oligosaccharide component of
lipopolysaccharide located at the outer bacterial mem-
brane. A specific serotype of Salmonella can express more
than one O antigen on its surface (Hu & Kopecko 2003).
The heat-labile H antigens are found in the bacterial flag-
ella and are involved in the activation of host immune
responses. Most Salmonella spp. contain two distinct genes
that encode for the flagellar proteins; these bacteria have
the special ability of expressing only one protein at a time
and are, therefore, called diphasic (phase I and II). Each
serotype expresses specific phase I H antigens which are
responsible for its immunological identity, whereas phase
II antigens are non-specific antigens that can be shared by
many serotypes (McQuiston et al. 2008). The surface K
antigens are heat-sensitive polysaccharides located at the
bacterial capsular surface and are the least common anti-
gens found in the serotypes of Salmonella. Virulence (Vi)
antigens, a special subtype of K antigen, are found only in
three pathogenic serotypes: Paratyphi C, Dublin and Typhi.
A formal identification of a specific serotype can be car-
ried out by comprehensive serotyping of all the antigenic
determinants of the bacterium. However, most clinical
laboratories prefer to conduct simple agglutination reac-
tions to antibodies or antisera specific to the somatic O
antigens with the intention of grouping Salmonellae into
six serogroups, designated A, B, C1, C2, D and E. This
grouping system provides valuable information for epi-
demiological studies and allows genus identification of
Salmonella infections (Wattiau et al. 2011). To date, over
2500 serotypes have been identified; more than 50% of
these serotypes belong to S. enterica subsp. enterica, which
accounts for most of the Salmonella infections in humans
(Guibourdenche et al. 2010). The term ‘serovar’, which
is synonymous to serotype, is commonly used in the lit-
erature. Although the species name ‘Salmonella enterica’
has been adopted by the CDC and WHO for years, it
has not been accepted officially by the Judicial Commis-
sion. Therefore, the naming of a particular Salmonella
serotype usually omits the subspecies; Salmonella enterica
subspecies enterica serotype Typhi, for example, is short-
ened to Salmonella ser. Typhi or S. Typhi in the literature
(Brenner et al. 2000).
Pathogenesis
The severity of Salmonella infections in humans varies
depending on the serotype involved and the health status of
the human host. Children below the age of 5 years, elderly
people and patients with immunosuppression are more sus-
ceptible to Salmonella infection than healthy individuals.
 Frontiers in Life Science
Almost all strains of Salmonella are pathogenic as they
have the ability to invade, replicate and survive in human
host cells, resulting in potentially fatal disease.
Salmonella displays a remarkable characteristic during
its invasion of non-phagocytic human host cells (Hansen-
Wester et al. 2002) whereby it actually induces its own
phagocytosis in order to gain access to the host cell. The
remarkable genetics underlying this ingenious strategy is
found in Salmonella pathogenicity islands (SPIs), gene
clusters located at the large chromosomal DNA region and
encoding for the structures involved in the invasion pro-
cess (Grassl & Finlay 2008). When the bacteria enter the
digestive tract via contaminated water or food, they tend
to penetrate the epithelial cells lining the intestinal wall.
SPIs encode for type III secretion systems, multi-channel
proteins that allow Salmonella to inject its effectors across
the intestinal epithelial cell membrane into the cytoplasm.
The bacterial effectors then activate the signal transduction
pathway and trigger reconstruction of the actin cytoskele-
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ton of the host cell, resulting in the outward extension or
ruffle of the epithelial cell membrane to engulf the bacte-
ria. The morphology of the membrane ruffle resembles the
process of phagocytosis (Takaya et al. 2003).
The ability of Salmonella strains to persist in the host
cell is crucial for pathogenesis, as strains lacking this abil-
ity are non-virulent (Bakowski et al. 2008). Following the
engulfment of Salmonella into the host cell, the bacterium
is encased in a membrane compartment called a vacuole,
which is composed of the host cell membrane. Under nor-
mal circumstances, the presence of the bacterial foreign
body would activate the host cell immune response, result-
ing in the fusion of the lysosomes and the secretion of
digesting enzymes to degrade the intracellular bacteria.
However, Salmonella uses the type III secretion system
to inject other effector proteins into the vacuole, causing
the alteration of the compartment structure. The remod-
elled vacuole blocks the fusion of the lysosomes and this
permits the intracellular survival and replication of the bac-
teria within the host cells. The capability of the bacteria to
survive within macrophages allows them to be carried in
the reticuloendothelial system (RES) (Monack et al. 2004).
Clinical manifestations
Based on the clinical patterns in human salmonellosis,
Salmonella strains can be grouped into typhoid Salmonella
and non-typhoid Salmonella (NTS). In human infec-
tions, the four different clinical manifestations are enteric
fever, gastroenteritis, bacteraemia and other extraintesti-
nal complications, and chronic carrier state (Sheorey &
Darby 2008).
Enteric fever
Salmonella Typhi is the aetiological agent of typhoid
fever, while paratyphoid fever is caused by S. Paratyphi
3
A, B and C. Since the clinical symptoms of paratyphoid
fever are indistinguishable from typhoid fever, the term
‘enteric fever’ is used collectively for both fevers, and
both S. Typhi and S. Paratyphi are referred as typhoid
Salmonella (Connor & Schwartz 2005). Humans are the
sole reservoir for the two strains of typhoid Salmonella.
The organisms are transmitted via the ingestion of food or
water contaminated with the waste of infected individu-
als. Enteric fever is characterized by an incubation period
of one week or more, with prodomal symptoms such as
headache, abdominal pain and diarrhoea (or constipation),
followed by the onset of fever (Bhan et al. 2005). Diarrhoea
is more commonly observed in children, whereas patients
with immunosuppression are more likely to develop con-
stipation (Thielman & Guerrant 2004). During the illness,
enteric fever displays a specific fever pattern with an ini-
tial low-grade fever ( > 37.5°C to 38.2°C) which slowly
develops to high-grade fever ( > 38.2°C to 41.5°C) in the
second week. If the patient is left untreated, fever can per-
sist for a month or more (Patel et al. 2010). Besides fever,
infected patients may also develop myalgia, bradycardia,
hepatomegaly (enlarged liver), splenomegaly (enlarged
spleen), and rose spots on their chest and abdomen
(Kuvandik et al. 2009). In endemic regions, approximately
15% of the infected patients develop gastrointestinal com-
plications which include pancreatitis, hepatitis and chole-
cystitis. Haemorrhage is one of the most severe gastroin-
testinal complications that occur as a result of perforation
of Peyer’s patches, lymphatic nodules located at the ter-
minal ileum, resulting in bloody diarrhoea. On top of that,
the ability of typhoid Salmonella to survive and persist in
the RES results in relapse in approximately 10% of the
infected patients (Parry et al. 2002).
Gastroenteritis
Salmonella strains other than S. Typhi and S. Paratyphi are
referred to as NTS, and are predominantly found in animal
reservoirs. NTS infections are characterized by gastroen-
teritis or ‘stomach flu’, an inflammatory condition of the
gastrointestinal tract which is accompanied by symptoms
such as non-bloody diarrhoea, vomiting, nausea, headache,
abdominal cramps and myalgias. Symptoms such as hep-
atomegaly and splenomegaly are less commonly observed
in patients infected with NTS (Hohmann 2001). Com-
pared to typhoid infections, NTS infections have a shorter
incubation period (6–12 h) and the symptoms are usually
self-limiting and last only for 10 days or less (Crump
et al. 2008). Gastrointestinal complications of NTS infec-
tions include cholecystitis, pancreatitis and appendicitis,
while the perforation of the terminal ileum has no associa-
tion with NTS infections (Hohmann 2001). Infants, young
children, elderly people and immunocompromised patients
are highly susceptible to NTS infections and develop
more severe symptoms than normal individuals (Scallan
et al. 2011).
 4 S.-K. Eng et al.
Bacteraemia and other extraintestinal complications
Salmonella bacteraemia is a condition whereby the bac-
teria enter the bloodstream after invading the intesti-
nal barrier. Almost all the serotypes of Salmonella can
cause bacteraemia, while S. Dublin and S. Cholearaesuis
are two invasive strains that are highly associated with
the manifestations of bacteraemia (Woods et al. 2008).
Similar to enteric fever, high fever is the characteris-
tic symptom of bacteraemia, but without the formation
of rose spots as observed in patients with enteric fever.
In severe conditions, the immune response triggered by
bacteraemia can lead to septic shock, with a high mor-
tality rate. The clinical manifestation of bacteraemia is
more commonly seen in NTS infections than in typhoid
Salmonella infections. The difference in the clinical mani-
festation is believed to be associated with the presence of
the spv (Salmonella plasmid virulence) gene in NTS which
causes non-typhoidal bacteraemia, based on genetic anal-
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ysis (Guiney & Fierer 2011). Although the mechanism of
the gene to enhance the virulence traits of NTS remains
unclear, expression of the gene is required to prolong apop-
totic cell death and this may allow the bacteria to persist
in the host cells for a longer period (Gulig et al. 1993).
Approximately 5% of patients infected with NTS develop
bacteraemia and, in some cases, extraintestinal compli-
cations occur, with the lung being the most commonly
compromised organ. Other extraintestinal complications
include cellulitis, urinary tract infections, pneumonia,
endocarditis and meningitis (Shimoni et al. 1999; Arii
et al. 2002).
Chronic carrier state
The status of chronic carrier is defined as the shedding
of bacteria in stools for more than a year after the acute
stage of Salmonella infection. Since humans are the only
reservoir of typhoid Salmonella, carriers of S. Typhi and
S. Paratyphi are responsible for the spreading of enteric
fever in endemic regions, as the common transmission
route is the ingestion of water or food contaminated with
the faeces of chronic carriers (Bhan et al. 2005). About
4% of patients with enteric fever, predominantly infants,
elderly people and women, may become chronic carriers
(Gonzalez-Escobedo et al. 2011). In contrast, the carrier
state of NTS is less frequent, with an occurrence rate of
0.1% in patients with non-typhoidal salmonellosis. This is
because the primary reservoir of NTS is animals, instead
of humans (Hohmann 2001).
Epidemiology
NTS infections, which cause self-limited illness, are the
most common Salmonella infections and occur worldwide.
In contrast, enteric fever, caused by typhoid Salmonella,
is associated with a high morbidity and mortality rate and
occurs predominantly in underdeveloped countries (Hardy
2004).
Epidemiology for enteric fever
In 2000, the incidence of enteric fever was estimated to
be 22 million cases resulting in 200,000 deaths worldwide,
predominantly in underdeveloped countries (Crump et al.
2004). The incidence and mortality rate of enteric fever
vary from region to region, but the mortality rate can be
as high as 7% in spite of antibiotic therapy.
Enteric fever is endemic in many regions of the African
and Asian continents as well as countries such as in
Europe, South and Central America, and the Middle East.
The incidence of enteric fever in the USA and some Euro-
pean countries is low, with the total number of Salmonella
cases being less than 10 per 100,000 annually. Most of
the cases reported in these countries are related to travel,
with the disease being imported by foreigners or travellers
returning from Africa, India or Pakistan (Molbak et al.
2002; Cooke et al. 2007). Israel has a very low incidence
of enteric fever and this has further reduced from 0.42
to 0.23 cases per 100,000 from 1995 to 2003. However,
the pattern of the causative organism reflects an increasing
number of cases of S. Paratyphi, with this organism being
isolated from 57.4% of the patients reported with enteric
fever in Israel (Meltzer et al. 2006). This appears to match
the worldwide increase in infection caused by S. Paraty-
phi, especially in Asian countries in which these strains
are responsible for more than 50% of the incidence of
enteric fever (Woods et al. 2006). The increase in S. Paraty-
phi infection raises concern over the effectiveness of the
typhoid fever vaccines in use and highlights the need for
more extensive epidemiological study of the pathogen.
Many Asian countries, including China, India, Viet-
nam, Pakistan and Indonesia, have high incidence rates
of enteric fever, exceeding 100 cases per 100,000 popu-
lation annually. Compared to other Asian countries, Pak-
istan and India have the highest incidence rates of 451.7
cases and 214.2 cases per 100,000 population, respectively
(Ochiai et al. 2008). The incidence of enteric fever reported
worldwide is actually more of an estimate as investi-
gations of enteric fever are usually conducted on large
outbreaks while isolated cases are often underreported.
In many developing countries, especially in sub-Saharan
Africa, the limited diagnostic resources and proper surveil-
lance tools result in poor characterization of the burden of
enteric fever.
In endemic regions, enteric fever occurs more fre-
quently in infants, preschool and school-age children. Epi-
demiological studies for the past few years show that the
annual incidence of enteric fever among children below 5
years old was approximately 25 per 100,000 population in
China and Vietnam, while the incidence in India and Pak-
istan reached up to 450 per 100,000 annually (Mweu &
English 2008).
 Frontiers in Life Science 5

Epidemiology for non-typhoid Salmonella infections
Gastroenteritis is the most common Salmonella infection
worldwide, accounting for 93.8 million cases which result
in 155,000 deaths per year (Majowicz et al. 2010). Based
on data for 2001–2005 provided by SalmSurv (a foodborne
disease surveillance network supported by WHO), the most
common isolated serotype responsible for NTS infections
worldwide was S. Enteriditis (65%). This was followed
by S. Typhimurium and S. Newport, which contributed
12% and 4% of the clinical isolates, respectively (Galanis
et al. 2006). Salmonella Enteriditis was the most common
serotype in Asia, Latin America and Europe, accounting
for 38%, 31% and 87% of the clinical isolates, respec-
tively. In Africa, S. Enteriditis and S. Typhimurium were
the two most common serotypes reported, occurrring in
26% and 25% of the isolates, respectively. In contrast to the
countries mentioned previously, S. Typhimurium (29%)
was most frequently reported in clinical isolates in North
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(HIV)-infected patients, and these invasive strains confer
a mortality rate up to 25% (Gordon et al. 2008). In con-
trast, the invasive disease caused by NTS is less frequently
reported in Asia (Khan et al. 2010).
In the USA, data provided by the Foodborne Diseases
Active Surveillance Network (FoodNet) show that NTS
infections were most commonly reported in that region,
with an incidence of 17.6 cases per 100,000 population
annually, and these organisms have been reported as being
the largest contributor to death statistics (39%) among all
foodborne pathogens (Barton Behravesh et al. 2011). As
mentioned by CDC, the most recent outbreak (2010) in the
USA involved the contamination of eggs by S. Enteriditis,
resulting in 1939 cases of NTS infections across 16 states.
Some common factors associated with the Salmonella
outbreaks include incomplete cooking of food products,
improper storage and direct contact with raw ingredients
(Lynch et al. 2006). The food products that are pre-
dominantly associated with the outbreaks include animal

America, followed by S. Enteriditis (21%) (Galanis et al.

2006).
In spite of improvements in hygiene and sanitation,
the incidence of NTS infections continues to increase,
creating a burden in both industrialized and underdevel-
oped countries (Majowicz et al. 2010). The incidence of
NTS-associated disease is estimated to cause 690 cases
per 100,000 population in Europe while the incidence of
NTS infection in Israel is around 100 cases per 100,000
annually (Weinberger & Keller 2005). Invasive NTS is
endemic in underdeveloped countries, especially in sub-
Saharan Africa, with high occurrence rates in children
below 3 years old and human immunodeficiency virus
products such as milk, poultry and eggs, as well as food
products such as chocolate and peanut butter (Table 1).
Unlike typhoid Salmonella, animals are the major
reservoir of NTS. The transmission of NTS infection to
humans can occur through the ingestion of food or water
contaminated with infected animals’ waste, direct contact
with infected animals or consumption of infected food ani-
mals. The worldwide incidence rate of NTS infection is
high as the strains can be found naturally in the environ-
ment and in both domestic and wild animals including
cats, dogs, amphibians, reptiles and rodents. The diver-
sity of possible reservoirs of infection results in significant

Table 1. Selected major outbreaks of Salmonella spp. from 2002 to 2014.

No. of cases
Year Serovar reported Food source Country Remarks Reference

2014 Salmonella Infantis, 300 Live poultry USA 80% of the reported ill CDC (2012)
S. Newport or S. Hadar people had contact with
live poultry a week
before the illness began
2012 Salmonella Bareilly and 425 Raw yellowfin tuna USA Present in the frozen raw CDC (2013)
S. Nchanga yellowfin tuna product
known as Nakaochi
Scrape
2010 Salmonella Montevideo 272 Red and black USA Found in the pepper added CDC (2010)
pepper/ to the meats
Italian-style
meats
2007 Salmonella Tennessee 628 Peanut butter USA Found in the environmen- CDC (2007)
tal samples collected
from the plant
2005 Salmonella Oranienburg 126 Alfalfa Australia Alfalfa at a production OzFoodNet (2006)
facility
2002 Salmonella Oranienburg 439 Chocolate Germany S. Oranienburg isolated Werber et al. (2005)
from chocolate (high
fat content) displayed
a higher level of heat
resistance
 6 S.-K. Eng et al.
challenges for public health authorities to control the
infections (Swanson et al. 2007; Dione et al. 2011).
Antibiotic resistance
The emergence of antimicrobial resistance in Salmonella
strains is a serious health problem worldwide (Chiu et al.
2002). In the early 1960s, the first incidence of Salmonella
resistance to a single antibiotic, namely chloramphenicol,
was reported (Montville & Matthews 2008). Since then, the
frequency of isolation of Salmonella strains with resistance
towards one or more antimicrobial agents has increased
in many countries, including the USA, the UK and Saudi
Arabia (Yoke-Kqueen et al. 2008). Antimicrobial agents
such as ampicillin, chloramphenicol and trimethoprim–
sulfamethoxazole are used as the traditional first line treat-
ments for Salmonella infections. Salmonella spp. resis-
tant towards these agents are referred to as multi-drug
resistant (MDR).
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For many years, the phenotypic trait of MDR was
widely distributed among S. Typhi and, at a lower rate,
among S. Paratyphi (Rowe et al. 1997). Africa and Asia are
two continents with a high isolation frequency of S. Typhi
displaying MDR phenotype. In a surveillance study con-
ducted in five Asian countries, India, Pakistan and Vietnam
had higher rates of MDR isolates of S. Typhi than Indone-
sia and China (Ochiai et al. 2008). Other reports present
similar data, with a high rate of MDR isolates of S. Typhi
in Pakistan, India, Nepal and Vietnam, while in China,
Indonesia and Laos the incidence rate of MDR S. Typhi
is relatively low (Chuang et al. 2009).
With the emergence of resistance towards tradi-
tional antibiotics, fluoroquinolones and extended-spectrum
cephalosporins have been introduced as the antimicrobial
agents of choice in treating MDR S. Typhi (Sood et al.
1999). However, reports show an increase in the number
of cases with typhoid Salmonella developing resistance
towards fluoroquinolones. In countries with a higher inci-
dence of MDR isolates, S. Paratyphi displays a higher
level of resistance towards fluoroquinolones compared to
S. Typhi (Hasan et al. 2008). Nalidixic acid resistance,
which is used as an indicator of reduced susceptibility of
ciprofloxacin and other fluoroquinolones, is displayed by
isolates from Pakistan, India and Vietnam, with high inci-
dence rates of 59%, 57% and 44%, respectively (Ochiai
et al. 2008).
As for NTS, the number of strains developing MDR
phenotype has increased in many countries since the first
emergence of MDR S. Typhimurium DT104 strains in
1990 (Helms et al. 2005). Based on data from 2005 to
2006 presented by the National Antimicrobial Resistance
Monitoring System (NARMS), 84% of clinical isolates
of NTS displayed MDR phenotype and 4.1% of the iso-
lates had reduced susceptibility to cephalosporins in the
USA. NARMS presented data (from 1996–2007) which
are more comprehensive, reporting the emergence of NTS
isolates that are resistant to nalidixic acid and ceftriaxone.
This phenomenon has raised concern among public health
authorities regarding both clinical management and pre-
vention of the infection (Crump et al. 2011). A surveillance
study on 135,000 clinical isolates of NTS was conducted
in Europe from 2000 to 2004, and the data showed that
15% of the isolates displayed MDR phenotype and 20% of
the isolates were resistant to nalidixic acid (Meakins et al.
2008).
Spread of resistance
The emergence of Salmonella with antimicrobial resistance
is mainly promoted by the use of antibiotics in animal
feed to promote the growth of food animals, and in veteri-
nary medicine to treat bacterial infections in those animals
(Hyeon et al. 2011). This poses a high risk of zoonotic
disease with the transmission of MDR Salmonella strains
from animals to humans via the ingestion of food or water
contaminated with the animals’ faeces, direct contact or
the consumption of infected food animals (Holmberg et al.
1984). Moreover, MDR Salmonella strains were found in
some exotic pet animals such as tortoises and turtles, as
well as their water environment, and this could result in a
higher risk of zoonotic infections in humans through direct
contact with these animals (Trust & Bartlett 1979; Shane
et al. 1990).
Mechanisms of resistance
Studies show that the serotypes of Salmonella displaying
MDR phenotype have the ability to generate various types
of hybrid plasmids. The majority of the gene cassettes
located within these plasmids consist of resistance genes
that confer the antimicrobial resistance property of the
serotypes against traditional antibiotics such as chloram-
phenicol, tetracycline, ampicillin and streptomycin (Guerra
et al. 2001, 2002). The emergence of Salmonella serotypes
with reduced ciprofloxacin susceptibility is a result of chro-
mosomal mutation at the quinolone resistance-determining
regions of the gyrA gene (Chiu et al. 2002). Some
serotypes of Salmonella have begun to develop resis-
tance towards broad-spectrum cephalosporins as a result
of mutated genes that encode for extended-spectrum β-
lactamases, hydrolysing antibiotics with β-lactam rings
such as cephalosporin and cephamycins (Carattoli et al.
2002).
Clinical relevance
The development of multi-drug resistance in the serotypes
of Salmonella has a significant impact on the antibiotic
treatment of Salmonella infections. Infections that involve
the invasive serotypes are often life threatening and require
effective antibiotic treatment. Quinolones and third gener-
ation cephalosporins have been the antibiotics of choice
 Frontiers in Life Science
in treating infections with MDR Salmonella (Karon et al.
2007). However, the emergence of Salmonella serotypes
resistant to quinolones and cephalosporin poses a new
challenge in treating infected patients, and the lack of an
effective antibiotic therapy may lead to an increase in the
morbidity and mortality rates.
The emergence of MDR Salmonella has also resulted
in the increased severity of bacterial infections in humans
and animals. Epidemiological studies show that MDR
Salmonella strains cause more severe or prolonged syn-
dromes than susceptible strains, implying that the MDR
strains are more virulent than the susceptible ones (Travers
& Barza 2002). Data show that patients infected with MDR
Salmonella strains are more ill and septic at the onset of the
disease, and the illness is typically accompanied by high
fever, enlargement of the spleen and liver, and abdominal
swelling (Buch et al. 1994).
Downloaded by [Learn-Han Lee] at 00:47 10 June 2015
Prevention
Contaminated water or food is the major transmission
route of enteric fever. Historically, the USA and West-
ern Europe were endemic for enteric fever; however, the
incidence of Salmonella infection decreased significantly
with proper food and water sanitation, pasteurization of
milk and other dairy products, and elimination of the use
of human faeces in food production. A decrease in the
incidence of Salmonella infections was observed in Latin
America in parallel with the introduction of sanitation mea-
sures (Crump et al. 2004). At present, preventive measures
for enteric fever concentrate on access to safe water and
food, proper sanitation and the use of typhoid vaccines.
Ensuring the safety of water for consumption is the
main goal for the elimination of possible transmission
routes of typhoid Salmonella as well as NTS. This impor-
tant measure has been successfully achieved in industri-
alized countries, such as in Europe and the USA, but not
in developing and underdeveloped countries (Clasen et al.
2007). Besides water, Salmonella spp. can be found in a
variety of foods, predominantly in poultry, eggs and dairy
products. Proper handling and cooking of food are mea-
sures proposed to eradicate the bacterial contamination of
food. In many countries, food irradiation has been greatly
promoted owing to its effectiveness in reducing the risk
of food contamination. Approved by several public health
agencies, including the WHO and CDC, the technology of
food irradiation is only partially utilized in some areas in
Europe and the USA because of the risk of radioactivity
(Osterholm & Norgan 2004). Vaccination is an effective
measure in preventing enteric fever. Inactive parenteral
and oral live attenuated vaccines are the two types of vac-
cine currently approved for the prevention of enteric fever.
However, these licensed vaccines are limited to infants
and they are not effective in preventing infections caused
by S. Paratyphi and NTS (Lin et al. 2001). As for NTS,
one effective measure is to restrict the inappropriate use
7
of antibiotics in food animals and their feed (Talbot et al.
2006).
Conclusion
Salmonella infection remains a distressing public health
concern worldwide. The genetic make-up of the
Salmonella strains permits their adaptation in various envi-
ronments, including human, animal and non-animal hosts.
This increases the difficulty in eliminating the bacteria.
Moreover, the emergence of MDR Salmonella strains
poses a great challenge in terms of effective treatment
of the infections caused by these strains. Several preven-
tive measures have been proposed to stop the spread of
Salmonella infection, and the restriction of indiscriminate
use of antibiotics in food animals is by far one of the most
effective measures.
Two vaccines have been approved for the prevention
for enteric fever, but no licensed vaccines are available for
S. Paratyphi and NTS infection. Further research on the
development of vaccines for all Salmonella strains may
potentially result in great benefits for affected countries.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by a University of Malaya grant for
high impact research (UM-MOHE HIR Nature Microbiome grant
no. H-50001-A000027) awarded to K-GC and external industry
grants from Biotek Abadi Sdn Bhd (vote no. GBA-808138 and
GBA-808813) awarded to L-HL.
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