Salmonella, Non-Typhoidal Species (S. Choleraesuis, S. Enteritidis, S. Hadar, S. Typhimurium)

Salmonella infection of man and animals continues to be a distressing health problem worldwide. Far from disappearing, the incidence in developing countries may be much higher than expected. Salmonella are widely dispersed in nature, including the gastrointestinal tracts of domesticated and wild mammals, reptiles, birds, and insects. They are both commensals and pathogens that cause a broad spectrum of diseases in man and animals. There are over 2,500 serotypes of Salmonella, as defined by the somatic and flagellar antigens. Some Salmonella serotypes, such as Typhi and Paratyphi are highly adapted to humans and have no other known natural hosts. Others, such as Typhimurium and Enteritidis, have a broad host range and can infect a wide variety of animal hosts. These non-typhoid Salmonella can cause protean manifestations in humans, including acute gastroenteritis, bacteremia, and extraintestinal localized infections involving many organs. The widespread distribution of Salmonella in the environment, their increasing prevalence in the global food chain, and their virulence and adaptability result in an enormous medical, public health, and economic impact worldwide.

MICROBIOLOGY

Salmonella is named for the pathologist Salmon who first isolated Salmonella choleraesuis from porcine intestine. Salmonella is a genus of the family Enterobacteriaceae (29). The nomenclature of Salmonella has been changed many times and still remains unstable. Before 1983 the existence of multiple Salmonella species was taxonomically accepted. As a result of further experiments indicating a high degree of DNA similarity, all Salmonella isolates were classified into a single species, S. choleraesuis (19,29). The species S. choleraesuis can be subclassified into seven subgroups based on DNA similarity and host range. Subgroup I contains almost all the serotypes pathogenic for humans, except for rare human infections with group IIIa and IIIb formally designated S. arizonae (60).

In 1999, Euzéby proposed to designate “Salmonella enterica” as a “neotype species” and replace the type species of the genus Salmonella from S. choleraesuis to S. enterica (28). There are now two species recognized in the genus Salmonella: S. enterica (six subspecies) and S. bongori (one subspecies). Members of the seven subspecies can be serotyped into one of the more than 2,500 different serotypes. This system of nomenclature has become accepted for use by the World Health Organization (WHO) and in publications of the American Society for Microbiology.

The antigenic classification or serotyping of Salmonella used today is a result of years of study of antibody interactions with bacterial surface antigens by Kauffman and White in the 1920s and 1940s. Three kinds of surface antigens determine the organisms’ reaction to specific antisera. These surface antigens are made accessible to antibody after the organisms are treated in various ways. Antibodies to the somatic or polysaccharide O antigen can be used to agglutinate the bacteria in a slide agglutination test. After treatment with formaldehyde, antibodies to the flagellar or H antigen can be used to agglutinate the organism in a tube agglutination test. Specific serotypes are defined as a result of complex antigen variability. This resulted in the identification of over 2,500 Salmonella serotypes, the majority of which are named for the city where they were defined (48). Most variability noted in the O antigen that is composed of chains of oligosaccharides attached to a core oligosaccharide linked covalently to lipid A. This structure comprises the bacterial lipopolysaccharide (LPS). Hence, most serotypes have unique LPS structure.

Certain Salmonella serotypes are associated with specific clinical syndromes (60) (Table 1). Although extensive serotyping of all surface antigens can be used for formal identification, most laboratories perform a few simple agglutination reactions to define specific O antigens into serogroups, designating groups A, B, C1, C2, D, and E Salmonella (60). Although this grouping system is useful in epidemiologic studies and can be used clinically to confirm genus identification, it cannot quickly identify whether the organism is likely to cause enteric fever, because considerable cross-reactivity among serogroups occurs. For example, S. Infantis, which typically causes gastroenteritis, and S. Choleraesuis, a prominent cause of invasive infections, are both group C1. Similarly another common cause of gastroenteritis, S. Enteritidis, and S. Typhi, which causes enteric fever, are both group D. Both biochemical and serologic determinations are required to define the specific Salmonella serotypes.

EPIDEMIOLOGY

In many countries the incidence of human Salmonella infection has increased markedly over the years. During the last few decades S. Enteritidis and S. Typhimurium have emerged as the two predominant serotypes in most western countries. In the United States, each year non-typhoid Salmonella affect approximately 2-3 million persons, and cause 500-2,000 deaths (2). In 2000, the two most common serotypes isolated from human sources wereS. Typhimurium and S. Enteritidis (8). The 1995 global survey conducted by WHO showed that the global pandemic of S. Enteritidis has continued to occur in recent years. The frequent occurrence of this serotype in chickens suggests that poultry may be an important reservoir. S. Typhimurium is among the most prevalent serotypes in Europe and America and of growing importance in Southeast Asia, Africa, and the Western Pacific. S. Typhimurium can be found among a large number of different animal reservoirs. S. Choleraesuis is an infrequent serotype isolated from human sources in North America (8). However, the epidemiological pattern differs greatly in Asian countries. In Thailand, during 1988-1993, S. Choleraesuis represented the tenth most common serotype that caused salmonellosis in humans (3). This highly invasive serotype is of particular concern in Taiwan, as among the common Salmonella serotypes isolated from human sources, it was ranked the 2nd in an epidemiological survey (11). Some studies demonstrated that most of the S. Choleraesuis isolates from humans and swine exhibited the same or similar DNA fingerprints, indicating that human infections were acquired from pigs (15,69). The cross-infection may arise as a result of the contamination of food or water source by the organism. It is also speculated that the habit of eating pig offal by the local population significantly contributed to the high prevalence of S. Choleraesuis infection in the locality. Different serotypes in one country can be of global importance because of travel and animal and food product trade. Knowledge about the occurrence and epidemiology of different serotypes in different countries and geographic regions may assist in the recognition and tracing of new emerging pathogens.

Infection with non-typhoid Salmonella reflects ingestion of food or water contaminated with these organisms. The number of bacteria that must be ingested to cause symptomatic disease in healthy adults is 106 to 108 non-typhoid Salmonella organisms. In infants and persons with certain underlying conditions, a smaller inoculum can produce diseases, so that direct person-to-person transmission, although uncommon, sometimes occurs. Nursery outbreaks are a result of neonatal susceptibility to low numbers of Salmonella. After infection, Salmonella is excreted in feces for a median of 5 weeks. In young children, the excretion is prolonged. In older children and adults, Salmonella excretion lasting more than 8 weeks after infection is uncommon.

CLINICAL MANIFESTATIONS

Several distinct clinical syndromes can develop in humans infected with non-typhoid Salmonella, depending on host factors and the specific serotype involved.

Acute Enteritis

The most common clinical presentation of salmonellosis is acute enteritis. After an incubation period of 6-72 hr (mean, 24 hr), there is an abrupt onset of nausea, vomiting, and crampy abdominal pain primarily in the periumbilical area and right lower quadrant, followed by mild to severe watery diarrhea and sometimes by diarrhea containing blood and mucus. Fever affects about 70% of patients. Abdominal examination reveals some tenderness. The stool typically contains a moderate number of polymorphonuclear leukocytes and occult blood. Mild leukocytosis may be detected. Symptoms subside within 2-7 days in healthy children, and fatalities are rare.

In certain high-risk groups, the course of Salmonella enteritis may be more complicated. Neonates, young infants, and children with primary or secondary immune deficiency may have symptoms persisting for several weeks. In patients with inflammatory bowel diseases, especially active ulcerative colitis, Salmonella enteritis may cause invasion of the bowel with rapid development of toxic megacolon, systemic toxicity, and death.

Bacteremia

In contrast to adults who usually are immunologically impaired and develop Salmonella bacteremia in the absence of diarrhea, the majority of children have no predisposing risk factors and develop bacteremia as a complication of acute enteritis (41). Transient bacteremia during non-typhoid Salmonella gastroenteritis is believed to occur in approximately 5% of patients. Salmonella bacteremia is associated with fever, chills, and often with a toxic appearance. Bacteremia has been documented, however, in afebrile, well-appearing children, including neonates (occult bacteremia). Patients with certain underlying conditions, such as malignancies, collagen vascular diseases, inflammatory bowel diseases, and AIDS, are at increased risk of bacteremia, which may lead to extraintestinal infection. In patients with AIDS, septicemia often recurs despite antibiotic therapy, often with a negative stool culture for Salmonella and sometimes with no identifiable focus of infection (56). Adults with persistent bacteremia may have endocarditis, arteritis, or an infected aortic aneurysm.

Certain serotypes of Salmonella, i.e. S. Choleraesuis and S. Dublin, show much higher predilection for causing bacteremia in humans (9,11,62). These serotypes rapidly invade the bloodstream with little or no intestinal involvement. In Taiwan, S. Choleraesuis exhibits the highest degree of invasiveness (measured in terms of invasion index = no. of extra-intestinal isolates/total isolates), followed by S. Dublin and S. Enteritidis (9,11,62). In England and Wales, while the highest numbers of bloodstream isolates were from infections caused by S. Typhimurium and S. Enteritidis, the highest incidence of sepsis, also based on the invasion index of each individual serotype, was attributable to infections with S. Choleraesuis, S. Dublin, and S. Virchow (62). A recent retrospective analysis of adult cases with S. Choleraesuis bacteremia showed that most of the patients had obvious risk factors for salmonellosis, including malignancy, liver cirrhosis, systemic lupus erythematosus, and previous use of corticosteroid (9). It was also notable that 21% of the bacteremic patients subsequently developed focal infections, including septic arthritis, pneumonia, peritonitis, and cutaneous abscess (9). Such phenomenon reflects both the tenacity of the organism and comorbidities of the adult patients who develop bacteremia.

Extraintestinal Focal Infections

After salmonellae have entered the bloodstream, they have a unique capability to metastasize and cause a focal suppurative infection of almost any organ. Sites of pre-existing abnormalities are often involved. Extraintestinal infections are most common in the first 3 months of life, in those with sickle cell disease, and in those who have had prior gastrointestinal surgery (52). The most common focal infections involve the skeletal system, meninges, and intravascular sites. Salmonella is a common cause of osteomyelitis in patients with sickle cell disease. Salmonella osteomyelitis and septic arthritis also occur at sites of previous trauma or skeletal prosthesis. Reactive arthritis may follow Salmonella enteritis, usually in adolescents with the HLA-B27 antigen. Meningitis occurs about 100 times less frequently than bacteremia. Although meningitis can occur at any age, the peak incidence is in infancy (52). Patients may present with no fever and minimal symptoms, or rapid deterioration, and neurologic sequelae despite appropriate antibiotic therapy.

A feared complication of Salmonella bacteremia in adults is the development of infectious endarteritis (also known as infectious aortitis or mycotic aneurysm). Most of the patients with mycotic aneurysm due to Salmonellahave pre-existing atherosclerotic disease at the site of subsequently infected aneurysm (18,39). In a series of patients with bacteremia due to Salmonella, 25% of those >50 years of age developed an endothelial infection (18,39). This reflects the ability of Salmonella, which have been reported to invade normal arterial intima, to cause endothelial infection in the presence of atherosclerosis (18). The predominance of older patients with or without hypertension among patients with Salmonella aortitis is likely due to the increased incidence of atherosclerosis and intimal damage in these patients. Recently, Salmonella bacteremia has been noted in patients with HIV infection; however, aortitis rarely occurs in these patients because they are relatively younger and without the above risk factors (43). Unfortunately, most of the data on risk factors were from anecdotal reports or retrospective reviews, and consequently, the precise risk factors remain unclear.

In a review of 140 cases of aortitis due to Salmonella reported in the literature since 1948, the most common site of infection is the abdominal aorta, more precisely its infrarenal portion (45,55). The most common clinical features consisted of fever, abdominal pain, and/or back pain, the latter of which may be related to the site of involvement (45,55). Computed tomographic scan with contrast enhancement is considered the method of choice to diagnose mycotic aneurysm because of its ability to detect early changes in the arterial wall and the periaortic tissue (45,55). Magnetic resonance imaging (MRI), on the other hand, provides the safest and most accurate technique for diagnosis. The use of MRI angiography has particular appeal for diagnosing mycotic aneurysm in that it is entirely noninvasive and does not require the use of intravenous contrast materials or ionizing radiation. MRI angiography produces images in the transverse, sagittal, and coronal planes, which display the entire thoracic or abdominal aorta in one plane. The availability of these multiple views facilitates the diagnosis of mycotic aneurysm and determination of its extent and in many cases reveals the presence of branch vessel involvement (14).

In recent literature reviews of Salmonella aortitis, the serotypes most commonly isolated were (in order) S. Typhimurium, S. Enteritidis, and S. Choleraesuis (14,45,55). Interestingly, the reports of relatively high incidence of S. Choleraesuis infection came mostly from Taiwan (14,39). In Taiwan, S. Choleraesuis was the second most common serotype among all Salmonella serotypes isolated, and of these serotypes, it showed the highest ability to cause extra-intestinal infections (14,39). The high virulence of S. Choleraesuis to humans as well as its high prevalence may have contributed to the high incidence of endovascular infection caused by this organism in Taiwan (14,39).

LABORATORY DIAGNOSIS

The diagnosis of salmonellosis requires bacteriologic isolation of the organisms from appropriate clinical specimens. A wide range of media has been used for this purpose. All contain selective agents to inhibit different components of the gastrointestinal flora. These compounds are intended to inhibit the normal fecal flora, but may inhibit the pathogens to some extent. Thus there is a balance between selection and diagnostic yields. Bile salts will select for organisms that inhabit the bowel. More selective still is sodium desoxycholate, found in xylose lysine desoxycholate (XLD) agar, or desoxycholate citrate agar (DCA).

The next stage in the diagnostic process is the use of biochemical screening tests to distinguish them from Proteus colonies, which have similar appearances. These fermentation reactions utilize combination media such as Kligler iron agar, triple sugar agar, or Kohn’s tubes. Commercially produced kits also detect the characteristic activity of preformed enzymes (API ZYM). Organisms giving characteristic reactions are then subjected to full biochemical and serological identification. The biochemical tests include sugar fermentation tests, decarboxylation and dehydrogenation reactions and hydrogen sulphide production. Serological identification of Salmonella without biochemical confirmation is unreliable, because of the many cross-reactions with commensal gut flora. Full serological typing of Salmonella is only indicated for the identification and investigation of outbreaks.

PATHOGENESIS

Salmonella is a gastrointestinal pathogen that can penetrate into the intestinal barrier and function as intracellular pathogens within phagocytic cells. There are three types of diseases caused by Salmonella species in humans, and all occur by variations of the infection route described below. S. Typhi is the causative agent of typhoid fever. Enteritis, commonly known as food poisoning, is caused by many other non-typhoidal Salmonella serotypes, including S. Typhimurium and S. Enteritidis. S. Choleraesuis is the prototype of invasive Salmonella. These bacteria proceed through the intestinal epithelium, enter the blood, and disseminate throughout the body.

Salmonellosis in animals used for human consumption continues to be of worldwide significance, with both host adapted and broad host range serotypes being of considerable importance. Disease in animals is manifested in three forms, namely enteritis, septicemia and abortion. However, serotypes such as S. Enteriditis do not cause diseases, yet pose a significant risk to humans due to consumption of contaminated animal products. The most common serotype associated with cattle is S. Typhimurium and it typically causes enteritis resulting in watery feces containing mucous and blood. In some cases, this ultimately will result in death due to dehydration and loss of electrolytes. Most pathology is associated with the ileum, jejunum and colon, although the ileum appears to be the preferred site of colonization and invasion. Once the organism passes into the lamina propria and is taken up by macrophages, it can then spread systemically to other organs.

Salmonella organisms are considered facultative intracellular parasites with most infections arising from oral ingestion of tainted food or water. In the small intestine Salmonella species penetrate the intestinal mucosa, usually at Peyer's patches. These bacteria cause the microvilli of M cells to disappear, and the bacteria enter into a membrane bound inclusion of this epithelial cell. The intracellular bacteria can then pass through these cells to the opposite surface, and also trigger M cell lysis. Cells of the reticuloendothelial system then ingest the Salmonella, but at least with macrophages, do not readily kill the bacteria. CD18-positive cells also appear to play a role in intestinal penetration (64). In systemic infections such as typhoid fever, infected macrophages then migrate to the intestinal lymph nodes where Salmonella replicate before escaping these cells and entering the blood to disseminate throughout the body. Polymorphonuclear neutrophils (PMNs) kill Salmonella, and it is thought that these cells, and activated macrophages, control bacterial growth effectively. During enteritis, there is significant localized intestinal inflammation, including neutrophil infiltration, and fluid accumulation (70).

Salmonella invade host cells and survive intracellularly as a central part of their pathogenesis, a process that can be easily modelled in vitro in tissue culture cells. Following initial contact of a bacterium with the mammalian cell surface, several events occur (30). Host cell signal transduction cascades are activated, a marked rearrangement in actin-containing cytoskeleton occurs, and polymerized actin is required for Salmonella invasion. This appears to be mediated by the small GTP-binding protein CDC42. Membrane ruffling and macropinocytosis are also stimulated in the immediate vicinity of the invading organisms. Salmonella are engulfed by the actin driven membrane ruffles and are rapidly internalized within a vacuole. Several bacterial loci have been identified that are involved in Salmonella invasion (31). These genes are primarily clustered at the Salmonella pathogenicity island-1 (SPI-1) on the bacterial genome, although several SPI-1 secreted effectors are scattered around the chromosome. SPI-1 encodes several factors, including a type III secretory apparatus that mediates export of specific effector proteins into the host cell. These translocated effectors are involved in triggering host signal transduction pathways and mediating invasion of Salmonella into host cells by redirecting actin polymerization. Mutations in bacterial invasion genes (SPI-1) moderately decrease Salmonella virulence when delivered orally but not systemically in the murine model, but play a critical role in bovine gastroenteritis. On the other hand the SPI-2 type III secretion system is essential for systemic salmonellosis. SPI-2 is a 40-kb pathogenicity island found in S. enterica, but not in E. coli K12 (36). Mutations in the type III secretion systems genes cause the loss of survival in phagocytic cells, and are essential for virulence in the murine model (37).

Salmonella affects the expression of many epithelial and macrophage genes. Several studies have shown that proinflammatory cytokines and chemokines are activated. Microarray experiments have been used to confirm and extend these studies, determining that several other cytokines are induced, as are signalling molecules and transcriptional activators, in addition to finding several other changes in genes previously not implicated in pathogenesis (27,50).

Most studies of S. Typhimurium pathogenesis employ a well-characterized mouse infection model which closely mimics typhoid fever in humans. The bacteria penetrate the intestinal barrier and migrate to the lymph nodes and then to the liver and spleen where they proliferate (49). Importantly, this is a systemic disease and diarrheal symptoms are not seen. At early infection times (3 days) there is a rapid influx of PMNs at the infection foci, while at later times these are replaced by macrophages (classic inflammation). In both the liver and spleen, S. Typhimurium resides inside these cells (49,51) and triggers extensive apoptosis of macrophages, but not other cell types. The increasing availability of knockout mice and other reagents, as well as its similarity to typhoid fever continue to make the murine model attractive to study systemic infectious processes of salmonellosis.

SUSCEPTIBILITY IN VITRO AND IN VIVO

Global Increase of Antimicrobial Resistance

Since the end of the last century, a worldwide increase of antimicrobial resistance in non-typhoid Salmonella has been documented (57). Although S. Enteritidis remains relatively susceptible to various antimicrobial agents, high resistance rates to some traditional antibiotics have been reported for S. Typhimurium, S. Choleraesuis, and other serotypes (Table 2). The spread of a distinct multidrug-resistant S. Typhimurium strain, phage type 104 (DT104), (resistant to five antimicrobial agents: ampicillin, chloramphenicol, streptomycin, sulfonamide, and tetracycline) may have contributed greatly to such an increase (44). On the other hand, although resistance to newer antibiotics, such as extended-spectrum cephalosporins and fluoroquinolones, remains low, outbreaks or sporadic cases of infections caused by Salmonella organisms with resistance to these antibiotics have been increasingly reported over the past decade (24,57).

Since 2000, an epidemic clone of S. Choleraesuis that is resistant to multiple antibiotics, including ciprofloxacin, has emerged and widely spread in Taiwan (15,16). A clinical isolate of S. Choleraesuis simultaneously resistant to both ceftriaxone and ciprofloxacin was first found in Taiwan in 2002 (13). The occurrence and dissemination of such multi-drug resistant S. Choleraesuis have posed a serious threat to the public health in Taiwan (69).

Mechanism of Antimicrobial Resistance

Being a member of the family Enterobacteriaceae, Salmonella organisms are able to develop antimicrobial resistance through mechanisms similar to those expressed by other enterobacteria. These mechanisms include the production of hydrolytic enzymes to destroy the antibiotics in the surrounding environment, mutations in the specific target genes to escape from the action of antibiotics, decreased outer membrane permeability to prevent the antibiotics from entering the bacterial cell itself, and active efflux systems to exclude antibiotics before they become effective.

Resistance mechanisms against extended-spectrum cephalosporins are mainly due to the production of extended-spectrum cephalosporinases by the resistant bacteria. A variety of such enzymes have been described inSalmonella, and the majority belong to cefotaxime-hydrolyzing β-lactamases (CTX-M types) or CMY-2 AmpC β-lactamase that could hydrolyze cephalosporins as well as cephamycins (4,13,24,58,59,66,69). The genes encoding these extended-spectrum cephalosporinases could be carried by conjugative plasmids (4,13,34,58,65,67,69), transposons (65), or integrons (34,65). These mobile genetic elements could spread, under selective pressure, horizontally between enteric organisms (58,67). Genotyping and plasmid analysis indicated that both clonal dissemination and horizontal transfer of resistance genes, such as blaCMY-2, may contribute to the spread of the resistance determinant (66). Identical blaCMY-2-carrying plasmids have been found in Salmonella isolates with distinct chromosomal DNA patterns (66), while genetically related Salmonella isolates could harbor unrelated blaCMY-2-carrying plasmids (69). Moreover, the spread of blaCMY-2 among Salmonella isolates also could occur through the mobilization of non-conjugative plasmids that carry the resistance gene (13).

The mechanisms for Salmonella isolates to develop fluoroquinolone resistance involve mutations in the quinolone resistance-determining regions (QRDRs) of the DNA gyrase genes, active efflux, and decreased outer membrane permeability (17). The most frequently observed point mutations of the gyrA gene in fluoroquinolone-resistant Salmonella are the amino acid changes at serine-83 to phenylalanine, tyrosine, alanine, or at aspartic acid-87 to glycine, asparagine, or tyrosine (17). Mutations in the gyrB (25,32), parC (13,25), and parE (25) genes have all been found in fluoroquinolone-resistant Salmonella. Recent reports indicated that an AcrAB-TolC efflux system and its regulatory genes, marRAB and soxRS, also participate in the resistance to fluoroquinolones in Salmonella (33,47).

High-level resistance (MIC, ≥32 µg/mL) to fluoroquinolones can be reached when the individual mechanism described above appears step by step (33), although the active efflux seems to play a major role in Salmonella. When the acrB gene was inactivated, resistance levels to fluoroquinolones significantly reduced even though multiple target gene mutations are present (5). A recently identified efflux pump inhibitor, Phe-Arg-naphthylamide (MC207,110), exhibits an efficient inhibitory effect to the efflux system and was considered a promising therapeutic agent in combination therapy with fluoroquinolones to treat multi-drug resistant Salmonella infections (5). However, the use of such efflux pump inhibitors in the clinical setting needs further evaluation.

Laboratory Detection of Antimicrobial Resistance

Similar to other enteric bacteria, phenotypic examination of antimicrobial resistance in Salmonella is performed using standard methods suggested by the National Committee for Clinical Laboratory Standards (NCCLS) or now the Clinical and Laboratory Standards Institute (CLSI). Although many reports have demonstrated the production of extended-spectrum cephalosporinases among Salmonella serotypes, NCCLS guidelines have not suggested the routine screening for the production of extended-spectrum β-lactamases among these bacteria. Failure to identify drug-resistant Salmonella organisms might affect the treatment outcome of patients with invasive salmonellosis. Similarly, Salmonella with reduced fluoroquinolone susceptibility may not be detected by the standard disc diffusion method using the current NCCLS criteria (44). However, treatment by fluoroquinolones on extraintestinal infections caused by such Salmonella is relatively poorer, compared to infections caused by the susceptible strains (44). It is now known that nalidixic acid – the prototypic quinolone – is a good predictor for the reduced susceptibility to fluoroquinolones in Salmonella (35). Therefore, NCCLS has recommended in the 2003 guidelines that nalidixic acid may be used to detect such reduced susceptibility to fluoroquinolones in isolates recovered from patients with extraintestinal Salmonella infections.

ANTIMICROBIAL THERAPY

Gastrointestinal Infections

Anticrobial therapy is usually not indicated for non-toxic immunocompetent patients. Gastroenteritis caused by non-typhoid Salmonella is a self-limiting disease and treatment should consist mainly of replenishing liquids and electrolytes. A study performed on uncomplicated non-typhoid Salmonella gastroenteritis in children comparing the usefulness of oral azithromycin 10 mg/kg/day, cefixime 10 mg/kg/day, or no antibiotics for 5 days showed that no benefits were obtained with antibiotic treatment (12). This was confirmed by a meta-analysis, which showed no evidence of any clinical benefit of antibiotic therapy in otherwise healthy children and adults with non-severe Salmonella gastroenteritis. Antibiotics appear to prolong Salmonella shedding from stools at the convalescent stage (54). Antibiotics apparently eradicate gastrointestinal flora that protects the gastrointestinal tract.

However, although the risk of developing bacteremia is low (< 5% of all patients), certain patients, such as young infants < 3 months old, patients with toxic appearance and suspected extraintestinal infection, immunocompromised patients, and patients with severe colitis would benefit from empirical antibiotic treatment (38).

Empirical treatment consists of administering an oral or intravenous antibiotic for 48-72 h, or until the fever remits and the culture becomes negative. The choice of the antibiotic depends on the characteristics of patients, the susceptibility pattern of the strain and the clinical condition (Table 3). Options include ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones or third-generation cephalosporins, depending on the results of in vitrosusceptibility testing or the prevalence of known resistant strains in a specific geographical area. In a 2003 study, children admitted to the hospitals with gastroenteritis, some infected by resistant strains, ceftriaxone was the best therapeutic option (10). Although the fluoroquinolones are not recommended in children, they may be used in serious infections if there is no other alternative treatment available. In infections caused by susceptible organisms, treatment with an oral fluoroquinolone, trimethoprim-sulfamethoxazole or amoxicillin is recommended.

Extraintestinal Infections

Bacteremia should be treated with third-generation cephalosporins or fluoroquinolones, taking into account the in vitro activity of these compounds against Salmonella. In cases of high-grade bacteremia (positivity of > 50% of the three blood cultures), the existence of endovascular infection should be investigated. If such lesions are confirmed, treatment with third-generation cephalosporins should be given for 6 weeks, and in some cases, surgery would be indicated. Less experience in treating these conditions with fluoroquinolones has been obtained, although therapeutic failures have been described associated with nalidixic acid-resistant strains. In the case of low-grade bacteremia, treatment should be given for 10-14 days.

In patients with AIDS experiencing their first episode of bacteremia, intravenous antibiotic treatment for 1-2 weeks is indicated, followed by the administration of an oral fluoroquinolone for 4 weeks in order to eradicate the organism and reduce the risk of recurrence. Patients who relapse should be given prolonged treatment with trimethoprim-sulfamethoxazole or fluoroquinolones, depending on the antibiotic susceptibility of the isolate (40).Zidovudine has been reported to be active against this pathogen and patients given this drug as part of their antiretroviral therapy are better protected against recurrence (7).

Focal infections due to Salmonella may be found at different locations and their cure depends on the degree of penetration of the antibiotic at the site of the infection (46). In general, 2-4 weeks of antibiotic therapy is recommended (depending on the site) and if possible, drainage or surgical removal of the lesions should be performed. In cases of chronic osteomyelitis, abscesses, and urinary or biliary tract abnormality, surgical interventions may be required in addition to prolonged antibiotic therapy in order to eradicate the bacteria.

Recently, treatment of extraintestinal salmonellosis with ciprofloxacin has been questioned if the strains are nalidixic acid - resistant in vitro. A growing body of clinical and microbiological evidence indicates that such nalidixic acid - resistant Salmonella infections exhibit a decreased clinical response to fluoroquinolones, with subsequent therapeutic failure despite being susceptible in vitro by NCCLS criteria for quinolones. Therefore, short-course fluoroquinolone therapy should be avoided in extra-intestinal infections caused by nalidixic acid - resistant strains (1,21,68).

Involvement of the central nervous system results in a high mortality (>50%). The treatment of choice is high-dose ceftriaxone, as this drug penetrates the blood-brain barrier. For meningitis, antibiotic treatment should be continued for 4-6 weeks, in order to prevent relapse. Urinary tract infections due to Salmonella may be secondary to bacteremia and should be treated with drugs with high renal excretion, such as trimethoprim-sulfamethoxazole or fluoroquinolones.

Many antibiotics can be shown to have excellent in vitro activity but are clinically ineffective. Thus the aminoglycosides, polymyxins, and tetracyclines should not be used for systemic Salmonella infection despite their in vitro activity. There is limited evidence that large intravenous doses of some first- or second-generation cephalosporins have therapeutic value. These drugs should be considered only as possibly useful.

Reactive arthritis and undifferentiated oligoarthritis occur in some patients and are postinfectious complications of gastroenteritis caused by this pathogen. In such cases, long-term ciprofloxacin treatment has not been proven to be beneficial (53).

ADJUNCTIVE THERAPY

Surgical drainage is indicated for localized Salmonella infections. Mycotic aneurysm, the most severe form of extraintestinal non-typhoid Salmonella infection, was almost uniformly fatal in early days; however, publications of case reports and series revealed that early surgical intervention greatly increased survival (14,45,55). Most surgeons consider the excision of an infected vessel with extra-anatomic vascular reconstruction to be the surgery of choice for abdominal mycotic aneurysm (61). In addition, a prolonged course of antibiotics for 6 weeks or longer is indicated (14,45,55). A review of 136 evaluable cases seen from 1948 through 1999 found a 62% survival rate for all patients treated with combined surgical and medical therapy (14,45,55). This improved survival was apparently due to the use of advanced diagnostic techniques, surgery, and antimicrobial therapy.

ENDPOINTS FOR MONITORING THERAPY

Complete recovery is the rule in healthy children who develop Salmonella gastroenteritis, so monitoring for resolution of symptoms is usually sufficient. Young infants and immunocompromised patients often have systemic involvement, a prolonged course, and extraintestinal foci. So, objective parameters should be monitored including fever and white blood cell count. Children with sickle cell disease and osteomyelitis must receive at least 6 weeks of antibiotic treatment. Patients with HIV infection and salmonellosis need long-term oral suppressive therapy, in addition to the standard intravenous antibiotic treatment. The response of the infection to antibiotics in these patients is less predictable and relapses are not uncommon.

VACCINES

Non-typhoid Salmonella causing gastroenteritis in humans are most often transmitted through the food chain by contamination of poultry and eggs, pork procedures, beef and dairy products, and increasingly in the US by vegetables and fruits that are irrigated in the globally dispersed truck farm with Salmonella-contaminated water (42). The theoretical efficacy of vaccines which prevent the infection and colonization of animals with Salmonella is uncertain. The difficulty is that most Salmonella serotypes colonizing the animal species that are passed to humans are normal flora for these animals. The design of any vaccine to block colonization of or infection by “normal flora” is a difficult task.

There are a number of licensed live attenuated Salmonella vaccines for poultry, swine, and cattle. Most of these vaccine strains are auxotrophic for chorismic acid biosynthesis (the aro mutants), which have deletions in genes encoding adenylate cyclase (cya) or cyclic 3’, 5’-adenosine monophosphate receptor protein (crp) (22,23). All of these mutants are attenuated, yet highly immunogenic in animal models. Some of these vaccines have been used extensively to control Salmonella infection in domestic animals. However, the efficacy of vaccination of these animals in reducing Salmonella transmission through the food chain to humans is unknown.

PREVENTION OR INFECTION CONTROL MEASURES

General

Reservoirs for non-typhoid Salmonella organisms include a wide range of domestic and wild animals, such as cattle, poultry, swine, rodents, and pets like iguanas, turtles, dogs, cats, chicks, and ducklings. In humans infected with Salmonella, the excretion of bacteria can last throughout the course of infection and as a temporary carrier state for months. The mode of transmission may include ingestion of the organisms in food derived from infected animals or contaminated by feces of an infected animal or person. The source may be contaminated meat, poultry, eggs, milk, and their products, as well as water, fruits and vegetables. Preventive measures therefore should include the education of food handlers about hand hygiene, refrigerating foods in small portions, thoroughly cooking all foodstuffs, avoiding recontamination of cooked food, and maintaining a sanitary kitchen to prevent from contamination by rodents and insects. The public should be educated about the importance of consuming well-cooked food. Adequate Salmonella control programs should be established for feed control, vector control, and other sanitary measures in the animal husbandry.

Infection Control

For hospitalized patients with salmonellosis, enteric precautions in handling feces and contaminated clothing and bed linen are required. Proper handwashing should be stressed. Terminal cleaning is required when the patient has discharged. Symptomatic individuals must be excluded from food handling and from direct care of patients. Permission to return to work in handling food or in patient care generally requires at least two consecutive negative stool cultures for Salmonella collected not less than 24 hours apart; if antibiotics have been given, the initial culture should be taken at least 48 hours after the last dose.

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Tables

Table 1. Representative serogroups and serotypes of non-typhoid Salmonella and their associated clinical disease syndromes.

Serogroup	Representative Serotype	Major Clinical Syndromes
A	S. Paratyphi A	Enteric fever, focal organ involvement
B	S. Heidelberg	Bacteremia or gastroenteritis
B	S. Paratyphi B	Enteric fever or gastroenteritis
B	S. Typhimurium	Gastroenteritis
C	S. Choleraesuis	Bacteremia
C	S. Newport	Gastroenteritis
C	S. Paratyphi C	Enteric fever
D	S. Dublin	Bacteremia
D	S. Enteritidis	Gastroenteritis
D	S. Typhi	Enteric fever, focal organ involvement

Table 2. Antimicrobial resistance in nontyphoid Salmonella isolates from human sources according to some recent publications.

Country	Year of study	Salmonellaserotypes	No. of isolates	Resistance (%)						Reference
				Any antibiotics	AM	C	SXT	CIP	CRO/CTX
France	1997	S. Typhimurium	992	N/A	73	56	9	N/A	N/A	(6)
		S. Enteritidis	800	N/A	7	4	3	N/A	N/A
		S. Hadar	141	N/A	72	0	8	N/A	N/A
Spain	2001	Unspecified	1051	73	45	26	14	0.6	0.2	(20)
		S. Typhimurium	284	N/A	80	73	19	1	1
		S. Enteritidis	385	N/A	23	0	1	0	0
		S. Hadar	101	N/A	70	1	5	1	1
USA	1996-2001	Unspecified	7370	39	18	10	2	0.1	1	(63)
Turkey	2000-2002	S. Typhimurium	215	88	82	80	3	0	0.5	(26)
		S. Enteritidis	296	34	16	9	1	0.3	0
Taiwan	2003	Unspecified	675	69	44	49	31	8	1.5	(59)
		S. Choleraesuis	67	98	91	91	88	69	1.5
Taiwan	2004	Unspecified	600	N/A	N/A	N/A	N/A	8	3	(69)
		S. Choleraesuis	45	N/A	N/A	N/A	N/A	84	18

Abbreviations: AM, ampicillin; C, chloramphenicol, SXT, trimethoprim-sulfamethoxazole; CIP, ciprofloxacin; CRO/CTX, ceftriaxone or cefotaxime; N/A, data not available.

Table 3.  Recommended Antimicrobial Therapy for Non-Typhoid Salmonella Infection

Infections	Recommendations
Enteric infection	Not recommended routinely, but if severe or patient is < 3 months or > 50 years old or has prostheses, valvular heart disease, severe atherosclerosis, malignancy, or uremia: trimethoprim-sulfamethoxazolea or ciprofloxacinb or ceftriaxonec for 3-5 days or until the patient becomes afebrile; for immunocompromised patients, 14 days or longer if relapsing.
Bacteremia	Bacteremia not involving vascular structures should be treated with 10 to 14 days with ceftriaxonec or ciprofloxacind or ampicilline.  For patients with HIV infection, 1 to 2 weeks of intravenous antimicrobial therapy followed by 4 weeks of oral fluoroquinolone therapyb should be administered; long-term suppressive therapy with an oral fluoroquinolone needed for patients who relapse following 6 weeks of antimicrobial therapy.
Extraintestinal focal infection	Patients with bone and joint infection need 4-6 weeks therapy with either ceftriaxonec or ciprofloxacind. Patients with meningitis should be treated with ceftriaxonef for 4 weeks or longer. Surgery along with 6-8 weeks of ampicilline or ceftriaxonec is recommended to treat endovascular infection (mycotic aneurysm).

^a 160 and 800 mg po twice daily (pediatric dose: 5 and 25 mg/kg/dose twice daily).

^b 500-750 mg po twice daily.

^c 2 gm iv daily in 1-2 divided doses (pediatric dose: 50-75 mg/kg/day in 1-2 divided doses).

^d 400 mg iv twice daily. Fluoroquinolones not yet approved for pediatric use in Salmonella infection.

^e 2 gm iv four to six times daily (pediatric dose: 100-200 mg/kg/day in 4 divided doses).

^f 4 gm iv daily in 1-2 divided doses (pediatric dose: 100 mg/kg/day in 1-2 divided doses).

Chen PL, et al.  Non-typhoidal Salmonella bacteraemia in elderly patients: an increased risk for endovascular infections, osteomyelitis and mortality.  Epidemiol Infect 2012;140:2037-2044.

Littman RJ.  The plague of Athens: epidemiology and paleopathology.  Mt Sinai J Med 2009;76:456-67.

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