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Salmonella: A review on pathogenesis, epidemiology and antibiotic resistance Salmonella: A review on pathogenesis, epidemiology and antibiotic resistance
Eng, Shu-Kee; Pusparajah, Priyia; Ab Mutalib, Nurul-Syakima; Ser, Hooi-Leng; Chan, Kok-Gan; Lee, Learn-Han
2015-07-03 00:00:00
Frontiers in Life Science, 2015 Vol. 8, No. 3, 284–293, http://dx.doi.org/10.1080/21553769.2015.1051243 a , b a c a d a∗ Shu-Kee Eng , Priyia Pusparajah , Nurul-Syakima Ab Mutalib , Hooi-Leng Ser , Kok-Gan Chan and Learn-Han Lee a b Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Selangor Darul Ehsan, Bandar Sunway, Malaysia; School of Science, Monash University, Selangor Darul Ehsan, Bandar Sunway, Malaysia; UKM Medical Centre, UKM Medical Molecular Biology Institute (UMBI), Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; 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 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- cess of food animals at abattoirs is considered one of cern worldwide, contributing to the economic burden of the important sources of organ and carcass contamination both industrialized and underdeveloped countries through with Salmonella (Gillespie et al. 2005). The emergence the costs associated with surveillance, prevention and treat- of antibiotic-resistant foodborne pathogens has raised the ment of disease (Crump et al. 2004). Gastroenteritis is concern of the public as these pathogens are more virulent, the most common manifestation of Salmonella infection causing an increase in the mortality rate of infected patients worldwide, followed by bacteraemia and enteric fever (Chiu et al. 2002). (Majowicz et al. 2010) (Figure 1). Salmonella is a rod- shaped, Gram-negative facultative anaerobe that belongs Classification and nomenclature to the family Enterobacteriaceae (Barlow & Hall 2002). Salmonella was first discovered and isolated from the Within the genus Salmonella, around 2600 serotypes have intestines of pigs infected with classical swine fever, by been identified with the use of the standard Kauffman– Theobald Smith in 1855. The bacterial strain was named White scheme and most of these serotypes have the ability after Dr Daniel Elmer Salmon, an American pathologist to adapt within a variety of animal hosts, including humans who worked with Smith. The nomenclature of Salmonella (Allerberger et al. 2003). Salmonella and Campylobac- is controversial and still evolving. Currently, the Cen- ter are the most frequently isolated foodborne pathogens, ters for Disease Control and Prevention (CDC) uses the and are predominantly found in poultry, eggs and dairy nomenclatural system of Salmonella recommended by the products (Silva et al. 2011). Other food sources that are World Health Organization (WHO) Collaborating Cen- involved in the transmission of Salmonella include fresh tre (Popoff et al. 2003). According to this system, the fruits and vegetables (Pui et al. 2011). In general, food genus Salmonella is classified into two species, Salmonella animals such as swine, poultry and cattle are the prime enterica (type species) and Salmonella bongori, based on sources of Salmonella infections. The major dissemina- tion routes of the pathogens involve trade in animals and differences in their 16S rRNA sequence analysis. The type *Corresponding author. Emails: lee.learn.han@monash.edu; leelearnhan@yahoo.com © 2015 Taylor & Francis Frontiers in Life Science 285 Figure 1. Incidence rate of enteric fever and gastroenteritis in different regions around the world. species, S. enterica, can be further classified into six bacterial capsular surface and are the least common anti- subspecies based on their genomic relatedness and bio- gens found in the serotypes of Salmonella. Virulence (Vi) chemical properties (Reeves et al. 1989). The subspecies antigens, a special subtype of K antigen, are found only in are denoted with roman numerals: I, S. enterica subsp. three pathogenic serotypes: Paratyphi C, Dublin and Typhi. enterica; II, S. enterica subsp. salamae;IIIa, S. enterica A formal identification of a specific serotype can be car- subsp. arizonae; IIIb, S. enterica subsp. diarizonae;IV, ried out by comprehensive serotyping of all the antigenic S. enterica subsp. houtenae; and VI, S. enterica subsp. determinants of the bacterium. However, most clinical indica. Among all the subspecies of Salmonella, S. enter- laboratories prefer to conduct simple agglutination reac- ica subsp. enterica (I) is found predominantly in mammals tions to antibodies or antisera specific to the somatic O and contributes approximately 99% of Salmonella infec- antigens with the intention of grouping Salmonellae into tions in humans and warm-blooded animals. In contrast, six serogroups, designated A, B, C1, C2, D and E. This the other five Salmonella subspecies and S. bongori are grouping system provides valuable information for epi- found mainly in the environment and also in cold-blooded demiological studies and allows genus identification of animals, and hence are rare in humans (Brenner et al. Salmonella infections (Wattiau et al. 2011). To date, over 2000). 2500 serotypes have been identified; more than 50% of In addition to the classification of subspecies based which these serotypes belong to S. enterica subsp. enterica, on phylogeny, Kauffman and White developed a scheme accounts for most of the Salmonella infections in humans to further classify Salmonella by serotype based on three (Guibourdenche et al. 2010). The term ‘serovar’, which major antigenic determinants: somatic (O), capsular (K) is synonymous to serotype, is commonly used in the lit- and flagellar (H) (Brenner et al. 2000). The heat-stable erature. Although the species name ‘Salmonella enterica’ somatic O antigen is the oligosaccharide component of has been adopted by the CDC and WHO for years, it lipopolysaccharide located at the outer bacterial mem- has not been accepted officially by the Judicial Commis- brane. A specific serotype of Salmonella can express more sion. Therefore, the naming of a particular Salmonella than one O antigen on its surface (Hu & Kopecko 2003). serotype usually omits the subspecies; Salmonella enterica The heat-labile H antigens are found in the bacterial flag- subspecies enterica serotype Typhi, for example, is short- ella and are involved in the activation of host immune ened to Salmonella ser. Typhi or S. Typhi in the literature responses. Most Salmonella spp. contain two distinct genes (Brenner et al. 2000). that encode for the flagellar proteins; these bacteria have the special ability of expressing only one protein at a time Pathogenesis and are, therefore, called diphasic (phase I and II). Each The severity of Salmonella infections in humans varies serotype expresses specific phase I H antigens which are depending on the serotype involved and the health status of responsible for its immunological identity, whereas phase the human host. Children below the age of 5 years, elderly II antigens are non-specific antigens that can be shared by people and patients with immunosuppression are more sus- many serotypes (McQuiston et al. 2008). The surface K ceptible to Salmonella infection than healthy individuals. antigens are heat-sensitive polysaccharides located at the 286 S.-K. Eng et al. Almost all strains of Salmonella are pathogenic as they A, B and C. Since the clinical symptoms of paratyphoid have the ability to invade, replicate and survive in human fever are indistinguishable from typhoid fever, the term host cells, resulting in potentially fatal disease. ‘enteric fever’ is used collectively for both fevers, and Salmonella displays a remarkable characteristic during both S. Typhi and S. Paratyphi are referred as typhoid its invasion of non-phagocytic human host cells (Hansen- Salmonella (Connor & Schwartz 2005). Humans are the Wester et al. 2002) whereby it actually induces its own sole reservoir for the two strains of typhoid Salmonella. phagocytosis in order to gain access to the host cell. The The organisms are transmitted via the ingestion of food or remarkable genetics underlying this ingenious strategy is water contaminated with the waste of infected individu- found in Salmonella pathogenicity islands (SPIs), gene als. Enteric fever is characterized by an incubation period clusters located at the large chromosomal DNA region and of one week or more, with prodomal symptoms such as encoding for the structures involved in the invasion pro- headache, abdominal pain and diarrhoea (or constipation), cess (Grassl & Finlay 2008). When the bacteria enter the followed by the onset of fever (Bhan et al. 2005). Diarrhoea digestive tract via contaminated water or food, they tend is more commonly observed in children, whereas patients to penetrate the epithelial cells lining the intestinal wall. with immunosuppression are more likely to develop con- SPIs encode for type III secretion systems, multi-channel stipation (Thielman & Guerrant 2004). During the illness, proteins that allow Salmonella to inject its effectors across enteric fever displays a specific fever pattern with an ini- the intestinal epithelial cell membrane into the cytoplasm. tial low-grade fever ( > 37.5°C to 38.2°C) which slowly The bacterial effectors then activate the signal transduction develops to high-grade fever ( > 38.2°C to 41.5°C) in the pathway and trigger reconstruction of the actin cytoskele- second week. If the patient is left untreated, fever can per- ton of the host cell, resulting in the outward extension or sist for a month or more (Patel et al. 2010). Besides fever, ruffle of the epithelial cell membrane to engulf the bacte- infected patients may also develop myalgia, bradycardia, ria. The morphology of the membrane ruffle resembles the hepatomegaly (enlarged liver), splenomegaly (enlarged process of phagocytosis (Takaya et al. 2003). spleen), and rose spots on their chest and abdomen The ability of Salmonella strains to persist in the host (Kuvandik et al. 2009). In endemic regions, approximately cell is crucial for pathogenesis, as strains lacking this abil- 15% of the infected patients develop gastrointestinal com- ity are non-virulent (Bakowski et al. 2008). Following the plications which include pancreatitis, hepatitis and chole- engulfment of Salmonella into the host cell, the bacterium cystitis. Haemorrhage is one of the most severe gastroin- is encased in a membrane compartment called a vacuole, testinal complications that occur as a result of perforation which is composed of the host cell membrane. Under nor- of Peyer’s patches, lymphatic nodules located at the ter- mal circumstances, the presence of the bacterial foreign minal ileum, resulting in bloody diarrhoea. On top of that, body would activate the host cell immune response, result- the ability of typhoid Salmonella to survive and persist in ing in the fusion of the lysosomes and the secretion of the RES results in relapse in approximately 10% of the digesting enzymes to degrade the intracellular bacteria. infected patients (Parry et al. 2002). However, Salmonella uses the type III secretion system to inject other effector proteins into the vacuole, causing Gastroenteritis the alteration of the compartment structure. The remod- Salmonella strains other than S. Typhi and S. Paratyphi are elled vacuole blocks the fusion of the lysosomes and this referred to as NTS, and are predominantly found in animal permits the intracellular survival and replication of the bac- reservoirs. NTS infections are characterized by gastroen- teria within the host cells. The capability of the bacteria to teritis or ‘stomach flu’, an inflammatory condition of the survive within macrophages allows them to be carried in gastrointestinal tract which is accompanied by symptoms the reticuloendothelial system (RES) (Monack et al. 2004). such as non-bloody diarrhoea, vomiting, nausea, headache, abdominal cramps and myalgias. Symptoms such as hep- Clinical manifestations atomegaly and splenomegaly are less commonly observed in patients infected with NTS (Hohmann 2001). Com- Based on the clinical patterns in human salmonellosis, pared to typhoid infections, NTS infections have a shorter Salmonella strains can be grouped into typhoid Salmonella incubation period (6–12 h) and the symptoms are usually and non-typhoid Salmonella (NTS). In human infec- self-limiting and last only for 10 days or less (Crump tions, the four different clinical manifestations are enteric et al. 2008). Gastrointestinal complications of NTS infec- fever, gastroenteritis, bacteraemia and other extraintesti- tions include cholecystitis, pancreatitis and appendicitis, nal complications, and chronic carrier state (Sheorey & while the perforation of the terminal ileum has no associa- Darby 2008). tion with NTS infections (Hohmann 2001). Infants, young children, elderly people and immunocompromised patients Enteric fever are highly susceptible to NTS infections and develop Salmonella Typhi is the aetiological agent of typhoid more severe symptoms than normal individuals (Scallan fever, while paratyphoid fever is caused by S. Paratyphi et al. 2011). Frontiers in Life Science 287 Bacteraemia and other extraintestinal complications occurs predominantly in underdeveloped countries (Hardy 2004). 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 Epidemiology for enteric fever cause bacteraemia, while S. Dublin and S. Cholearaesuis In 2000, the incidence of enteric fever was estimated to are two invasive strains that are highly associated with be 22 million cases resulting in 200,000 deaths worldwide, the manifestations of bacteraemia (Woods et al. 2008). predominantly in underdeveloped countries (Crump et al. Similar to enteric fever, high fever is the characteris- 2004). The incidence and mortality rate of enteric fever tic symptom of bacteraemia, but without the formation vary from region to region, but the mortality rate can be of rose spots as observed in patients with enteric fever. as high as 7% in spite of antibiotic therapy. In severe conditions, the immune response triggered by Enteric fever is endemic in many regions of the African bacteraemia can lead to septic shock, with a high mor- and Asian continents as well as countries such as in tality rate. The clinical manifestation of bacteraemia is Europe, South and Central America, and the Middle East. more commonly seen in NTS infections than in typhoid The incidence of enteric fever in the USA and some Euro- Salmonella infections. The difference in the clinical mani- pean countries is low, with the total number of Salmonella festation is believed to be associated with the presence of cases being less than 10 per 100,000 annually. Most of the spv (Salmonella plasmid virulence) gene in NTS which the cases reported in these countries are related to travel, causes non-typhoidal bacteraemia, based on genetic anal- with the disease being imported by foreigners or travellers ysis (Guiney & Fierer 2011). Although the mechanism of returning from Africa, India or Pakistan (Molbak et al. the gene to enhance the virulence traits of NTS remains 2002; Cooke et al. 2007). Israel has a very low incidence unclear, expression of the gene is required to prolong apop- of enteric fever and this has further reduced from 0.42 totic cell death and this may allow the bacteria to persist to 0.23 cases per 100,000 from 1995 to 2003. However, in the host cells for a longer period (Gulig et al. 1993). the pattern of the causative organism reflects an increasing Approximately 5% of patients infected with NTS develop number of cases of S. Paratyphi, with this organism being bacteraemia and, in some cases, extraintestinal compli- isolated from 57.4% of the patients reported with enteric cations occur, with the lung being the most commonly fever in Israel (Meltzer et al. 2006). This appears to match compromised organ. Other extraintestinal complications the worldwide increase in infection caused by S. Paraty- include cellulitis, urinary tract infections, pneumonia, phi, especially in Asian countries in which these strains endocarditis and meningitis (Shimoni et al. 1999;Arii are responsible for more than 50% of the incidence of et al. 2002). 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 Chronic carrier state more extensive epidemiological study of the pathogen. The status of chronic carrier is defined as the shedding Many Asian countries, including China, India, Viet- of bacteria in stools for more than a year after the acute nam, Pakistan and Indonesia, have high incidence rates stage of Salmonella infection. Since humans are the only of enteric fever, exceeding 100 cases per 100,000 popu- reservoir of typhoid Salmonella, carriers of S. Typhi and lation annually. Compared to other Asian countries, Pak- S. Paratyphi are responsible for the spreading of enteric istan and India have the highest incidence rates of 451.7 fever in endemic regions, as the common transmission cases and 214.2 cases per 100,000 population, respectively route is the ingestion of water or food contaminated with (Ochiai et al. 2008). The incidence of enteric fever reported the faeces of chronic carriers (Bhan et al. 2005). About worldwide is actually more of an estimate as investi- 4% of patients with enteric fever, predominantly infants, gations of enteric fever are usually conducted on large elderly people and women, may become chronic carriers outbreaks while isolated cases are often underreported. (Gonzalez-Escobedo et al. 2011). In contrast, the carrier In many developing countries, especially in sub-Saharan state of NTS is less frequent, with an occurrence rate of Africa, the limited diagnostic resources and proper surveil- 0.1% in patients with non-typhoidal salmonellosis. This is lance tools result in poor characterization of the burden of because the primary reservoir of NTS is animals, instead enteric fever. of humans (Hohmann 2001). 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 Epidemiology annual incidence of enteric fever among children below 5 NTS infections, which cause self-limited illness, are the years old was approximately 25 per 100,000 population in most common Salmonella infections and occur worldwide. China and Vietnam, while the incidence in India and Pak- In contrast, enteric fever, caused by typhoid Salmonella, istan reached up to 450 per 100,000 annually (Mweu & is associated with a high morbidity and mortality rate and English 2008). 288 S.-K. Eng et al. Epidemiology for non-typhoid Salmonella infections (HIV)-infected patients, and these invasive strains confer a mortality rate up to 25% (Gordon et al. 2008). In con- Gastroenteritis is the most common Salmonella infection trast, the invasive disease caused by NTS is less frequently worldwide, accounting for 93.8 million cases which result reported in Asia (Khan et al. 2010). in 155,000 deaths per year (Majowicz et al. 2010). Based In the USA, data provided by the Foodborne Diseases on data for 2001–2005 provided by SalmSurv (a foodborne Active Surveillance Network (FoodNet) show that NTS disease surveillance network supported by WHO), the most infections were most commonly reported in that region, common isolated serotype responsible for NTS infections with an incidence of 17.6 cases per 100,000 population worldwide was S. Enteriditis (65%). This was followed annually, and these organisms have been reported as being by S. Typhimurium and S. Newport, which contributed the largest contributor to death statistics (39%) among all 12% and 4% of the clinical isolates, respectively (Galanis foodborne pathogens (Barton Behravesh et al. 2011). As et al. 2006). Salmonella Enteriditis was the most common mentioned by CDC, the most recent outbreak (2010) in the serotype in Asia, Latin America and Europe, accounting USA involved the contamination of eggs by S. Enteriditis, for 38%, 31% and 87% of the clinical isolates, respec- resulting in 1939 cases of NTS infections across 16 states. tively. In Africa, S. Enteriditis and S. Typhimurium were Some common factors associated with the Salmonella the two most common serotypes reported, occurrring in outbreaks include incomplete cooking of food products, 26% and 25% of the isolates, respectively. In contrast to the improper storage and direct contact with raw ingredients countries mentioned previously, S. Typhimurium (29%) (Lynch et al. 2006). The food products that are pre- was most frequently reported in clinical isolates in North dominantly associated with the outbreaks include animal America, followed by S. Enteriditis (21%) (Galanis et al. products such as milk, poultry and eggs, as well as food 2006). products such as chocolate and peanut butter (Table 1). In spite of improvements in hygiene and sanitation, Unlike typhoid Salmonella, animals are the major the incidence of NTS infections continues to increase, reservoir of NTS. The transmission of NTS infection to creating a burden in both industrialized and underdevel- humans can occur through the ingestion of food or water oped countries (Majowicz et al. 2010). The incidence of contaminated with infected animals’ waste, direct contact NTS-associated disease is estimated to cause 690 cases with infected animals or consumption of infected food ani- per 100,000 population in Europe while the incidence of mals. The worldwide incidence rate of NTS infection is NTS infection in Israel is around 100 cases per 100,000 high as the strains can be found naturally in the environ- annually (Weinberger & Keller 2005). Invasive NTS is ment and in both domestic and wild animals including endemic in underdeveloped countries, especially in sub- cats, dogs, amphibians, reptiles and rodents. The diver- Saharan Africa, with high occurrence rates in children sity of possible reservoirs of infection results in significant below 3 years old and human immunodeficiency virus 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 Frontiers in Life Science 289 challenges for public health authorities to control the isolates that are resistant to nalidixic acid and ceftriaxone. infections (Swanson et al. 2007; Dione et al. 2011). 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 Antibiotic resistance study on 135,000 clinical isolates of NTS was conducted The emergence of antimicrobial resistance in Salmonella in Europe from 2000 to 2004, and the data showed that strains is a serious health problem worldwide (Chiu et al. 15% of the isolates displayed MDR phenotype and 20% of 2002). In the early 1960s, the first incidence of Salmonella the isolates were resistant to nalidixic acid (Meakins et al. resistance to a single antibiotic, namely chloramphenicol, 2008). was reported (Montville & Matthews 2008). Since then, the frequency of isolation of Salmonella strains with resistance towards one or more antimicrobial agents has increased Spread of resistance in many countries, including the USA, the UK and Saudi The emergence of Salmonella with antimicrobial resistance Arabia (Yoke-Kqueen et al. 2008). Antimicrobial agents is mainly promoted by the use of antibiotics in animal such as ampicillin, chloramphenicol and trimethoprim– feed to promote the growth of food animals, and in veteri- sulfamethoxazole are used as the traditional first line treat- nary medicine to treat bacterial infections in those animals ments for Salmonella infections. Salmonella spp. resis- (Hyeon et al. 2011). This poses a high risk of zoonotic tant towards these agents are referred to as multi-drug disease with the transmission of MDR Salmonella strains resistant (MDR). from animals to humans via the ingestion of food or water For many years, the phenotypic trait of MDR was contaminated with the animals’ faeces, direct contact or widely distributed among S. Typhi and, at a lower rate, the consumption of infected food animals (Holmberg et al. among S. Paratyphi (Rowe et al. 1997). Africa and Asia are 1984). Moreover, MDR Salmonella strains were found in two continents with a high isolation frequency of S. Typhi some exotic pet animals such as tortoises and turtles, as displaying MDR phenotype. In a surveillance study con- well as their water environment, and this could result in a ducted in five Asian countries, India, Pakistan and Vietnam higher risk of zoonotic infections in humans through direct had higher rates of MDR isolates of S. Typhi than Indone- contact with these animals (Trust & Bartlett 1979; Shane sia and China (Ochiai et al. 2008). Other reports present et al. 1990). similar data, with a high rate of MDR isolates of S. Typhi in Pakistan, India, Nepal and Vietnam, while in China, Mechanisms of resistance Indonesia and Laos the incidence rate of MDR S. Typhi is relatively low (Chuang et al. 2009). Studies show that the serotypes of Salmonella displaying With the emergence of resistance towards tradi- MDR phenotype have the ability to generate various types tional antibiotics, fluoroquinolones and extended-spectrum of hybrid plasmids. The majority of the gene cassettes cephalosporins have been introduced as the antimicrobial located within these plasmids consist of resistance genes agents of choice in treating MDR S. Typhi (Sood et al. that confer the antimicrobial resistance property of the 1999). However, reports show an increase in the number serotypes against traditional antibiotics such as chloram- of cases with typhoid Salmonella developing resistance phenicol, tetracycline, ampicillin and streptomycin (Guerra towards fluoroquinolones. In countries with a higher inci- et al. 2001, 2002). The emergence of Salmonella serotypes dence of MDR isolates, S. Paratyphi displays a higher with reduced ciprofloxacin susceptibility is a result of chro- level of resistance towards fluoroquinolones compared to mosomal mutation at the quinolone resistance-determining S. Typhi (Hasan et al. 2008). Nalidixic acid resistance, regions of the gyrA gene (Chiu et al. 2002). Some which is used as an indicator of reduced susceptibility of serotypes of Salmonella have begun to develop resis- ciprofloxacin and other fluoroquinolones, is displayed by tance towards broad-spectrum cephalosporins as a result isolates from Pakistan, India and Vietnam, with high inci- of mutated genes that encode for extended-spectrum β - dence rates of 59%, 57% and 44%, respectively (Ochiai lactamases, hydrolysing antibiotics with β -lactam rings et al. 2008). such as cephalosporin and cephamycins (Carattoli et al. As for NTS, the number of strains developing MDR 2002). phenotype has increased in many countries since the first emergence of MDR S. Typhimurium DT104 strains in Clinical relevance 1990 (Helms et al. 2005). Based on data from 2005 to 2006 presented by the National Antimicrobial Resistance The development of multi-drug resistance in the serotypes Monitoring System (NARMS), 84% of clinical isolates of Salmonella has a significant impact on the antibiotic of NTS displayed MDR phenotype and 4.1% of the iso- treatment of Salmonella infections. Infections that involve lates had reduced susceptibility to cephalosporins in the the invasive serotypes are often life threatening and require USA. NARMS presented data (from 1996–2007) which effective antibiotic treatment. Quinolones and third gener- are more comprehensive, reporting the emergence of NTS ation cephalosporins have been the antibiotics of choice 290 S.-K. Eng et al. in treating infections with MDR Salmonella (Karon et al. of antibiotics in food animals and their feed (Talbot et al. 2007). However, the emergence of Salmonella serotypes 2006). 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 Conclusion morbidity and mortality rates. Salmonella infection remains a distressing public health The emergence of MDR Salmonella has also resulted concern worldwide. The genetic make-up of the in the increased severity of bacterial infections in humans Salmonella strains permits their adaptation in various envi- and animals. Epidemiological studies show that MDR ronments, including human, animal and non-animal hosts. Salmonella strains cause more severe or prolonged syn- This increases the difficulty in eliminating the bacteria. dromes than susceptible strains, implying that the MDR Moreover, the emergence of MDR Salmonella strains strains are more virulent than the susceptible ones (Travers poses a great challenge in terms of effective treatment & Barza 2002). Data show that patients infected with MDR of the infections caused by these strains. Several preven- Salmonella strains are more ill and septic at the onset of the tive measures have been proposed to stop the spread of disease, and the illness is typically accompanied by high Salmonella infection, and the restriction of indiscriminate fever, enlargement of the spleen and liver, and abdominal use of antibiotics in food animals is by far one of the most swelling (Buch et al. 1994). effective measures. Two vaccines have been approved for the prevention Prevention for enteric fever, but no licensed vaccines are available for S. Paratyphi and NTS infection. Further research on the Contaminated water or food is the major transmission development of vaccines for all Salmonella strains may route of enteric fever. Historically, the USA and West- potentially result in great benefits for affected countries. ern Europe were endemic for enteric fever; however, the incidence of Salmonella infection decreased significantly with proper food and water sanitation, pasteurization of Disclosure statement milk and other dairy products, and elimination of the use No potential conflict of interest was reported by the authors. 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- Funding sures (Crump et al. 2004). At present, preventive measures This work was supported by a University of Malaya grant for for enteric fever concentrate on access to safe water and high impact research (UM-MOHE HIR Nature Microbiome grant food, proper sanitation and the use of typhoid vaccines. no. H-50001-A000027) awarded to K-GC and external industry Ensuring the safety of water for consumption is the grants from Biotek Abadi Sdn Bhd (vote no. GBA-808138 and main goal for the elimination of possible transmission GBA-808813) awarded to L-HL. 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 References in developing and underdeveloped countries (Clasen et al. Allerberger F, Liesegang A, Grif K, Khaschabi D, Prager R, 2007). Besides water, Salmonella spp. can be found in a Danzl J, Hock F, Ottl J, Dierich MP, Berghold C, et al. variety of foods, predominantly in poultry, eggs and dairy 2003. 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