Version July 2025
INTRODUCTION —
Salmonellae are motile gram-negative bacilli that infect or colonize a wide range of hosts.
Salmonellae cause a broad range of human infection, including [1]:
●Enteric fever (systemic illness with fever and abdominal symptoms)
●Gastroenteritis
●Bacteremia and endovascular infection
●Focal metastatic infections such as osteomyelitis or abscess
●An asymptomatic chronic carrier state
Enteric fever is caused by Salmonella Typhi and Salmonella Paratyphi. These infections are discussed separately. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis" and "Enteric (typhoid and paratyphoid) fever: Treatment and prevention".)
Other Salmonella serotypes are known collectively as nontyphoidal salmonellae. The epidemiology, trends in antimicrobial resistance, microbiology, and pathogenesis of these organisms will be reviewed here. The clinical features and treatment of illness due to nontyphoidal salmonellae are discussed separately. (See "Nontyphoidal Salmonella: Gastrointestinal infection and asymptomatic carriage" and "Nontyphoidal Salmonella bacteremia and extraintestinal infection".)
EPIDEMIOLOGY
Geographic distribution
●Worldwide – Nontyphoidal salmonellae are a major cause of diarrhea worldwide. The global burden of nontyphoidal Salmonella gastroenteritis has been estimated at about 94 million cases (mostly foodborne) and 155,000 deaths yearly [2].
The burden of nontyphoidal Salmonella gastroenteritis appears to be particularly high in Asia; as an example, the incidence in east Asia was estimated to be 4 cases per 100 persons with over 88,000 associated deaths in 2006 [2-4].
The incidence of nontyphoidal Salmonella bacteremia is discussed in detail elsewhere. (See "Nontyphoidal Salmonella bacteremia and extraintestinal infection", section on 'Epidemiology'.)
●United States – Salmonella is one of the most common bacterial causes of foodborne illness in the United States. Conservative estimates suggest that there are about 1.4 million Salmonella infections in the United States per year, which result in approximately 25,000 hospitalizations and 420 deaths [5]. These estimates are an extrapolation from the number of reported cases, which represent a fraction of the true incidence since many cases are not diagnosed. There are an estimated 39 cases of undocumented salmonellosis for each culture-confirmed case [6].
•Outbreaks – Updated information on outbreaks may be found on websites maintained by the United States Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration.
Foodborne Salmonella outbreaks can be widespread. Between 2016 and 2021 in the United States, there were 186 foodborne disease outbreaks spanning multiple states; approximately 65 percent were caused by Salmonella [7,8].
Some important outbreaks from the past several years include Salmonella Sundsvall and Salmonella Oranienburg associated with cantaloupes (230 cases in 2023), S. Oranienburg associated with onions (over 650 cases in 2021), S. Newport associated with onions (1127 cases in 2020), S. Enteritidis associated with peaches (101 cases in 2020), S. Javiana associated with cut fruit (165 cases in 2019), multidrug-resistant S. Reading associated with raw turkey products (358 cases), and S. Infantis associated with raw chicken products (129 cases in 2018).
Salmonella outbreaks may occur more frequently than typically recognized [9]. Because certain serotypes may be associated with particular food or animal sources, evaluating for the presence of multiple serotypes (if resources permit) can help focus the investigation on potential outbreak sources.
•Surveillance – Salmonella is the second most commonly isolated bacterial pathogen evaluated through the FoodNet survey, a collaborative active surveillance program involving 10 state public health departments and covering approximately 15 percent of the United States population. The most commonly identified serotypes of Salmonella are S. Enteritidis, S. Newport, S. Typhimurium, S. Javiana, and S. Infantis [8]. S. Infantis infections are increasing and linked to chickens; S. Typhimurium infections are decreasing, which may be linked to poultry vaccination.
Salmonellosis rates differ by region [10]. In some FoodNet sites, decreases in rates of salmonellosis may have been a result of on-farm control measures, better refrigeration, consumer education, and better food handling in restaurants and homes.
Transmission — Primary modes of transmission include foodborne and animal contact. Less commonly, person-to-person transmission may also occur.
●Foodborne infection – Nontyphoidal salmonellae are a common cause of foodborne outbreaks (table 1). Salmonellae are associated with animal reservoirs and, therefore, with animal- and plant-based agricultural products [11-13].
•Poultry, eggs, and egg products – Poultry or egg consumption confer risk for nontyphoidal Salmonella infection [14,15]. Salmonellae can be passed transovarially from chickens to intact shell eggs [16]. Thus, infection can be transmitted via intact eggs. The frequency of S. Enteritidis-contaminated eggs is difficult to estimate since the rate depends on the level of colonization among hens and the timing of egg production with respect to infection acquisition [12]. On average, in the United States, the frequency of contamination is 1 in 20,000 eggs [17].
Pooling of large numbers of eggs can result in contamination of food products that may be broadly distributed, with potential to transmit infection to thousands. As an example, a nationwide outbreak of 224,000 cases of S. Enteritidis infection resulted from ice cream manufactured in one state and distributed widely [18]. The putative source of contamination was tankers, which transported ice cream base but previously had been used to carry liquid eggs.
•Other foods or dietary supplements – Nontyphoidal salmonellae have also been associated with fresh produce, meat (including ground beef as well as dog food), fish, shellfish (eg, frozen shrimp), milk, nut butters and vegan nut-based cheese, spices, flour, salt, and other foods, as well as contaminated water [19-38]. Novel food sources of Salmonella infection, including frog legs and sugar cane, are continuously being identified [39]. Contamination can occur at many points along the food processing pathway, which, in resource-abundant settings, has become increasingly industrialized, centralized, and global in scope.
Unregulated herbal products can also become contaminated. As an example, kratom, an herb that is used in self-treatment of opioid withdrawal, was associated with a 2018 multistate outbreak that involved several different brands of the product and several different serotypes of Salmonella, prompting a mandatory recall of all kratom products [40,41].
•Infant formula – Among infants, Salmonella infections have been associated with concentrated liquid infant formula, perhaps related to the storage and handling of opened cans of concentrated formula [42]; outbreaks of salmonellosis also have been linked to consumption of powdered infant formula [43-45].
Case control studies in infants have suggested that breastfeeding protects against acquisition of Salmonella infection in infancy [42,46]. (See "Infant benefits of breastfeeding", section on 'Prevention of illnesses while breastfeeding'.)
•Water – Water supplies are contaminated at lower levels than food, resulting in lower attack rates and longer incubation periods in waterborne outbreaks. It is more common for contaminated irrigation water to contaminate food than for water to transmit disease [47].
●Animal contact
•Reptiles and amphibians – Transmission of Salmonella can occur from contact with reptiles and amphibians (eg, snakes, lizards, turtles, iguanas, frogs) [42,48-55]. In one outbreak of Salmonella Poona associated with pet turtles, 40 percent of the cases occurred in patients younger than one year old (and presumably unlikely to handle the animals), highlighting the possible role of indirect transmission [53]. Turtles under four inches have been banned by the Public Health Service Act and the U.S. Food & Drug Administration (FDA) since 1975 because of the augmented risk of salmonella from small turtles that are more easily handled, put into mouths, etc [56]. (See "Zoonoses: Animals other than dogs and cats", section on 'Salmonella and other gastrointestinal pathogens'.)
In the United States, the Centers for Disease Control and Prevention (CDC) recommends that children under five years of age and immunocompromised patients avoid contact with reptiles [50,57,58]. The risk of Salmonella infection after reptile exposure can be reduced by washing hands with soap and water after handling reptiles and keeping the reptiles away from food-preparation areas [51].
•Live poultry – Transmission of Salmonella can occur from contact with live poultry including chicks and ducklings [59,60]. The potential impact of risk associated with live poultry purchased as pets or for backyard flocks is quite large, as approximately 50 million live poultry are sold through mail-order hatcheries in the United States annually. The CDC recommends that live poultry should not be kept inside the house, particularly in areas where food or drink is prepared or served. Hands should be washed with soap and water after touching live poultry or their environment, and children under five years of age and immunocompromised patients should avoid handling live poultry, including chicks and ducks.
•Other animals – Transmission of Salmonella can occur from contact with cats and dogs [61], other pets (hamsters, mice, rats, and hedgehogs) [62-64], as well as pet foods [65,66].
In addition to infection from pets, there have been multiple outbreaks of enteric disease associated with animal exposure in public settings, such as county fairs, farms, and petting zoos. In a review of 55 such outbreaks, Salmonella species accounted for 22 percent [67]. Wild songbirds, birdfeeders, and urban birds have also been linked to human transmission [68,69].
●Person-to-person – The possibility of person-to-person transmission was demonstrated in a report of infections in two hospitalized patients with identical Salmonella isolates and a phlebotomist who had drawn their blood three days before illness onset of illness [70]. In addition, an outbreak of salmonellosis thought to be transmitted through person-to-person spread or contact with contaminated surfaces has also been described [71].
Risk factors — Host factors that predispose to severe Salmonella infection are summarized in the table (table 2). These include:
●Extremes of age – Salmonellosis is most problematic in people over 60 years of age and in infants. In a study of the FoodNet survey results from 1996 through 1999, the incidence of invasive Salmonella infection (isolation of the organism from blood, cerebrospinal fluid, peritoneal fluid, or bone and joint) was 0.9 cases per 100,000 persons, with the highest incidence among infants younger than one year old (7.8 cases per 100,000 persons) [72-74].
In the United States surveillance in 2022, data from 10 geographically states showed that of 177,000 infections, 26 percent of patients were hospitalized and less than 1 percent died [75]. Most deaths occur in older patients with comorbid illnesses.
●Impaired immunity – A variety of host defense alterations result in increased susceptibility to infection with Salmonella spp. These include impaired cellular immunity due to advanced human immunodeficiency virus (HIV) infection, corticosteroid use or malignancy, and alteration in the intestinal flora due to prior antibiotic therapy [76-83]. These conditions may result in more severe initial infection and more serious sequelae such as bacteremia, metastatic foci of infection, or prolonged infection.
●Reduced gastric acidity – The infectious dose is lower in patients with clinical conditions associated with a reduction in gastric acidity, such as neonates [84], patients with achlorhydric states [85], patients who have undergone gastric surgery [86,87], and patients taking antacids or H2 blockers [74,87-89]. Iron overload syndromes (eg, from transfusions or hemochromatosis) may augment the risk of Salmonella infection.
●Antecedent antibiotic use – Antecedent antibiotic use confers increased risk for salmonellosis [90]. It can reduce the infectious dose necessary to cause disease, by diminishing the protective indigenous flora.
In an outbreak of multidrug-resistant S. Typhimurium enteritis, antibiotic use was more frequent among infected patients than controls (30 versus 6 percent) [24]. A similar association was observed in an outbreak of illness due to Salmonella Havana (30 versus 13 percent); the association persisted even when controlled for the presence of underlying illness or immunosuppression [79].
Patients at increased risk for invasive disease are discussed further separately. (See "Nontyphoidal Salmonella: Gastrointestinal infection and asymptomatic carriage", section on 'High risk for invasive disease' and "Nontyphoidal Salmonella bacteremia and extraintestinal infection", section on 'Outcomes'.)
ANTIMICROBIAL RESISTANCE
●In the United States
•Resistance rates – Rates of antibiotic resistance in Salmonella are an area of significant concern. United States surveillance data from 2004 to 2018 showed that 20 percent of nontyphoidal Salmonella were resistant to at least one antibiotic (ampicillin, azithromycin, ceftriaxone, ciprofloxacin, or trimethoprim-sulfamethoxazole) [91]. Acquisition of resistant strains appears to be a marker of more severe illness, although this relationship is not necessarily causal [92]. Of Salmonella isolates associated with illness due to animal contact or pet food between 2015 and 2018, 19 percent were resistant to at least one antibiotic and 10 percent were resistant to three or more antibiotics [93].
•Surveillance – In the United States, the National Antimicrobial Resistance Monitoring Systems (NARMS): Enteric Bacteria is a collaboration among the United States Centers for Disease Control and Prevention (CDC), U.S. Food and Drug Administration (FDA), and United States Department of Agriculture (USDA) that monitors antimicrobial resistance in enteric bacteria, including Salmonella spp. As clinical labs are using more culture-independent techniques, which do not provide antimicrobial resistance results, to identify enteric pathogens, national drug resistance surveillance programs are of increasing importance. The NARMS website has the most current information on resistance reports in the United States. European data can be viewed online at the European Food Safety Authority website.
Clinically important patterns in antimicrobial resistance from these sites include the following:
-About 8.6 percent of nontyphoidal Salmonella strains in the United States are nalidixic acid-resistant and 0.5 percent are resistant to ciprofloxacin [94].
-Approximately 3.5 percent of non-typhoidal Salmonella isolates in the United States are resistant to ceftriaxone [94]. Resistance prevalence varies by source and serotype.
●Outside the United States
•In Europe, 16.7 percent of strains are nalidixic acid-resistant, 13.5 percent are resistant to ciprofloxacin [95], and 1.8 percent are resistant to cefotaxime [95].
•In East Asia, higher minimum inhibitory concentrations (MICs) to fluoroquinolones and resistance carried on conjugative plasmids (which are transferrable to other gram-negative bacteria) appear to be emerging [96].
●Multidrug resistance – In 2022, the CDC issued a report regarding infection with multidrug-resistant Salmonella Newport among travelers to Mexico [97,98]. Most isolates are susceptible to ceftriaxone but resistant to ampicillin, ciprofloxacin, and trimethoprim-sulfamethoxazole. Azithromycin may not be effective for treating this strain and should be used with caution; clinical breakpoints for resistance have not been established for this drug. However, most isolates carry a macrolide resistance gene and show an elevated minimum inhibitory concentration (>32 mcg/mL) on laboratory testing.
●Extended-spectrum beta-lactamases – Extended-spectrum beta-lactamase (ESBL) genes are emerging in salmonellae in all areas, and certain serotypes may be more likely to support specific plasmids or resistance-encoding genetic elements [99,100]. The Clinical and Laboratory Standards Institute (CLSI) has altered break points that define susceptibility of Enterobacteriaceae (including Salmonellae) to third generation cephalosporins, in part, to simplify recognition of strains potentially bearing beta-lactamase resistance elements by non-reference laboratories that do not routinely perform more sophisticated testing directed at identifying these enzymes [101]. The revised breakpoints eliminate the need to perform ESBL screening and confirmatory tests for treatment decisions. Laboratories are implementing these changes slowly, so reports may have varying definitions of resistance to these important clinical agents.
Carbapenemase production in nontyphoidal Salmonellae is rare but has been reported [102,103].
MICROBIOLOGY —
Salmonellae are gram-negative, facultatively anaerobic Enterobacteriaceae.
Nomenclature and identification
●Nomenclature – The genus Salmonella consists of two species, Salmonella enterica and Salmonella bongori. Salmonella enterica is further divided into six different subspecies.
Most clinically important Salmonellae are formally classified within a single subspecies, Salmonella enterica, subspecies enterica [104]. Familiar organisms such as Salmonella Typhi, Salmonella Choleraesuis, Salmonella Enteritidis, and Salmonella Typhimurium, are now individual serotypes of this single subspecies; previously they were believed to represent separate species based upon antigenic structures, host range, and biochemical characteristics. Many laboratories continue to report names recognizable to clinicians, such as Salmonella enterica serovar typhi.
●Identification – Salmonellae are relatively easy to identify in the clinical microbiology laboratory [105]. Salmonellae grow under both aerobic and anaerobic conditions. They are oxidase negative and virtually all are lactose negative (white on MacConkey agar plates). Fewer than 1 percent of Salmonellae are lactose-positive, which can rarely cause difficulties in identification. Most Salmonellae produce hydrogen sulfide, which is easily detected on the selective indicator plates used for plating stool specimens, such as Hektoen agar (colonies appear light greenish with black centers) or Salmonella-Shigella agar (colonies appear white with black centers).
Most laboratories identify Salmonellae by a combination of antigenic and biochemical reactions. Suspicious colonies are agglutinated using antisera directed against specific O (lipopolysaccharide) and H (flagellar) antigens that allow identification of the serogroup. Only S. Typhi, S. Paratyphi C, and some strains of Salmonella Dublin and Citrobacter freundii possess the Vi capsular polysaccharide antigen [106], which can be rapidly detected by slide agglutination studies.
Serogroups and serotypes
●Serogroups
•Definition – The approximately 2500 serotypes of Salmonella can be characterized by three major antigens: the somatic O antigen, the flagellar H antigen, and the surface Vi antigen.
The somatic O antigen is derived from the lipopolysaccharide cell wall component; it is used by clinical laboratories to divide Salmonella into serogroups A, B, C1, C2, D, and E (table 3). Some laboratories do not perform serogrouping; the required reagents and expertise for performing these tests are increasingly difficult to find.
•Limitations – The serogroups cannot be used to distinguish enteric fever-causing strains from gastroenteritis-causing strains; group D contains both Salmonella Enteritidis (which most frequently causes gastroenteritis but may occasionally cause a 'typhoidal' illness with bacteremia) and S. Typhi (which causes enteric fever), while group B contains Salmonella Typhimurium as well as some strains of S. Paratyphi. In addition, cross-reactivity can occur between serogroups.
●Serotypes
•Correlation with clinical illness – Serotyping is more specific than serogrouping and usually is performed at state or reference laboratories. Increasingly, public health laboratories are using genomic techniques to identify specific serotypes and track outbreaks [107,108].
The host specificity of different Salmonella serotypes often determines the nature of the clinical illness.
-Enteric fever – The serotypes that cause enteric fever are frequently not associated with diarrheal symptoms; however, patients with enteric fever may have transient diarrhea prior to onset of fever.
Enteric fever is caused by S. Typhi and S. Paratyphi. These strains are highly adapted to humans and do not colonize or cause disease in animals; rarely S. Paratyphi has been associated with domestic animals (see "Pathogenesis of enteric (typhoid and paratyphoid) fever").
-Gastroenteritis – S. Enteritidis and S. Typhimurium have broad host ranges and may produce colonization or gastroenteritis in humans, mice, and fowl.
These serotypes are most frequently associated with gastroenteritis in humans due to large reservoirs in domestic animals. Salmonella Choleraesuis (adapted for swine) and Salmonella Dublin (adapted for cattle) are associated with human septicemia and metastatic foci of infection, but are uncommon causes of gastroenteritis [109]. Salmonella Gallinarum-pullorum (adapted for fowl) causes relatively transient illness in humans in the setting of ingestion of large inocula.
•Correlation with epidemiology – Cases of human salmonellosis are almost entirely limited to the serotypes of Salmonella enterica, subspecies enterica; the top five serotypes responsible for human disease are S. Enteritidis, S. Typhimurium, S. Infantis, S. Stanley, and S. Newport. Most human infections due to non-enterica subspecies develop in adults with weakened immune systems [110].
Infectious dose — Data on the number of Salmonella organisms required for clinical illness have been obtained from studies on human volunteers and outbreaks [111]. Large inocula (>104 organisms) produce higher rates of illness after shorter incubation periods, compared with small inocula (≤103 organisms). Asymptomatic excretion may occur after ingestion of small inocula; however, even very small inocula (5 to 100 organisms) may cause disease in susceptible hosts. The infectious dose necessary to cause disease may be lower in settings of antibiotic use and diminished gastric acid. (See 'Risk factors' above.)
PATHOGENESIS —
A number of factors related both to the pathogen and the host influence the pathogenesis of Salmonella gastroenteritis (figure 1).
●Host factors – Host factors that defend against Salmonella infection include the acidic environment of the stomach and the normal intestinal microbial flora.
•Pathogen interaction with enteric host defenses – Ingested microorganisms must traverse the acidic barrier of the stomach to establish enteric infection (table 2). Salmonella survive poorly at the very low pH encountered in the stomach, but exhibit increased tolerance if exposed to a moderately acidic environment (pH 4 to 5). The organism's ability to adapt to low pH has been called the acid tolerance response [112].
Salmonella must also withstand an array of other enteric defenses including bile salts, pancreatic enzymes, Paneth cell antimicrobial peptides [113], and secretory IgA [114]. In addition, Salmonellae must compete with the normal intestinal microbial flora.
•Pathogen interaction with host intestinal flora – Normal intestinal microbial flora prevent pathogen transmission (known as colonization resistance), as well as facilitate pathogen clearance. Colonization resistance likely represents a combination of the physical, chemical, metabolic and microbiological features of a diverse, healthy gut flora maintained by a fiber-rich, unprocessed diet.
These principles of colonization resistance and pathogen clearance were illustrated by a study in which mice with low complexity gut flora failed to clear S. Typhimurium from the gut lumen; pathogen clearance was achieved by transferring a normal complex microbiota [115]. Similarly, in another study, two immunocompromised patients with relapsing Salmonella infantis infection were cured with prolonged ertapenem followed by encapsulated fecal transplant, suggesting that repopulation of the gut microbiome may be effective for clearing persistent Salmonella [116].
Some data suggests that Enterococcus may decrease the risk of invasive disease from Salmonella. In a chicken model, animals fed an Enterococcus-rich diet had lower inflammatory markers and mortality, and higher body weight [117]. Similarly, a combination probiotic containing Lactobacillus salivarius and Enterococcus faecium has been shown to reduce the rate of Salmonella colonization in chickens [118].
Fermented foods may confer some protection against Salmonella. In a study of mabisi (a traditional Zambian fermented milk product), longer duration of fermentation correlated with levels of nontyphoidal Salmonella [119]. In addition, fermented blueberry juice and kefir (a fermented milk drink containing multiple probiotic organisms, lactic acid, and bacteriocins) have been shown to have antimicrobial properties in vitro against Salmonella [120].
●Adherence and invasion – Salmonellae adhere to and invade the gastrointestinal tract and submucosal lymphoid system through several different mechanisms. Bacterial entry into and survival within host cells are facilitated by multiple virulence factors.
•Adherence – Adherence is mediated by multiple genes. Fimbriae are very important in adhering to and adapting to a eukaryotic cell surface [121]; several fimbrial operons may facilitate adherence [122]. Biofilms may play a role as well [121]. The invasion operon (inv) can also induce adherence [123].
•Invasion – Invasion may be achieved by several mechanisms:
-Salmonella can selectively attach to specialized epithelial cells overlying Peyer's patches in the colon known as M (microfold) cells. These cells are an important portal of entry into the submucosal lymphoid system [124]. M cells are highly endocytic and can rapidly transfer material from their luminal side to their basal side, where the T cells and antigen-presenting cells reside, ready to elicit an immune response.
-Columnar epithelial cells may also be an important common portal of entry for Salmonella, particularly since they greatly outnumber the M cells [125].
-Salmonellae can induce nonphagocytic cells such as enterocytes to internalize them. This process of bacterial-mediated endocytosis has been studied extensively in vitro and appears to be important in the pathogenesis of Salmonella gastroenteritis [126,127].
-Invasion can occur via the "lumen sampling" dendritic cells that intercalate between epithelial cells by extending protrusions into the gut.
-Numerous small foci of solitary intestinal lymphoid tissues (SILTs) with a strong inflammatory response can be found in the murine small intestine; Salmonella can be observed within these SILTs at early stages of infection, and the SILTs may act as portals of entry [128].
Following invasion into the cell, the bacteria remain within a modified phagosome known as the Salmonella-containing vacuole (SCV), within which they survive and replicate.
●Shedding and persistence
•Shedding – The mechanisms of persistent Salmonella fecal shedding are complex.
Mutations in global regulators (especially the BarA/SirA virulence regulatory pathway) have been found in specimens from humans with persistent Salmonella infection [129]. These mutations appear to facilitate shedding even though they result in decreased expression of virulence genes, attenuated pathogenicity and a weaker host immune response.
•Persistence – Some non-replicating Salmonella display a reversible, antibiotic-tolerant phenotype; they can persist following antibiotic treatment and then revert to growth phase. Research on Salmonella growth and survival during antibiotic treatment has shown that antibiotic killing correlated with single-cell division rates, such that non-dividing Salmonella had the highest survival rates but were rare [130]. Most surviving bacteria were from the more common moderately growing, partially tolerant Salmonella.
In the gallbladder, Salmonella can undergo genetic changes resulting in biofilm-producing isolates with improved persistence, especially in the presence of gallstones [131].
●Pathogenicity islands – Two Salmonella "pathogenicity islands" (SPI) have been identified, termed SPI-1 and SPI-2 [132-137]. Both SPIs encode multiple virulence factors, including Type III secretions systems (TTSS). These TTSSs facilitate bacterial entry, replication within cells, and target cell transcriptional reprogramming via effector proteins that are highly conserved across different serotypes but have enough differences to explain some variation in clinical presentations. The TTSS creates a hypodermic needle-like apparatus and injects proteins into the cells, facilitating uptake of the bacteria into those cells.
●Inflammatory response mechanisms
•Neutrophil migration – Virulent strains of Salmonella can induce migration of subepithelial neutrophils across polarized epithelial cells in vitro [138]. In human S. Typhimurium-induced colitis, there is substantial neutrophil infiltration into the intestine; it is uncertain whether this is due to effectors from Salmonella or innate inflammation pathways triggered by pathogen recognition receptors on cells in the lamina propria [139].
It has been hypothesized that the paracellular traffic of neutrophils induces diarrhea by causing paracellular fluid and electrolyte fluxes. This is supported by the observation that strains which do not usually cause enteritis, such as S. Typhi and S. gallinarum, also do not induce neutrophil transmigration [140].
•Lipid A – Lipid A is the biologically active component of lipopolysaccharide (LPS) found in the cell wall of Salmonella and other gram-negative bacteria. Lipid A is toxic to mammalian cells and is a potent immunomodulator.
Certain features of the lipid A in Salmonella may correlate with virulence or activation of host inflammation [141,142]. Lipid A induces toll-like receptor 4 (TLR4)-mediated responses, which are important for host defense against Salmonella infection, and modifications in lipid A as part of Salmonella's adaptation to host environments reduce this signaling [143].
•Enterotoxins – Enterotoxins may play a role in Salmonella gastroenteritis. An enterotoxin, encoded by the stn gene and antigenically similar to cholera toxin, has been identified [144-146]. While many Salmonellae carry the stn gene, only a fraction express this gene [147].
●Survival within phagocytes – Salmonellae persist within the reticuloendothelial system. Macrophages may be the main cell type to support bacterial growth in vivo, and this growth is regulated by both the host and the Salmonella [148,149]. The ability of Salmonella to survive within macrophages contributes to dissemination of the microorganism from the submucosa to the circulation and the reticuloendothelial system.
●Role of virulence plasmids – Nontyphoidal Salmonellae carry a variety of virulence plasmids [150]. A highly conserved 8 kilobase region of DNA contained within these plasmids has been associated with the ability to induce bacteremia and persist within the reticuloendothelial system [150,151]. Plasmid borne genes may also affect host immune responses, for example by attenuating T cell proliferation [152].
HOST EFFECTS —
The innate immune system, cell-mediated immunity, and humoral immunity all play important roles in limiting Salmonella infection.
●Immune response – Components of the immune response include innate immunity, cell-mediated immunity, and humoral immunity.
•Innate immune system – The innate immune system plays a critical role in the initial response to Salmonella infection. It may be the determining factor in whether the infection is subclinical or more aggressive. The importance of macrophages and polymorphonuclear (PMN) leukocyte response to Salmonella has been well described; depressed PMN function is associated with increased risk for Salmonella infection in humans. Conditions associated with depressed PMN function include sickle cell anemia [80], malaria [82,153], schistosomiasis [154], and histoplasmosis [155].
•Cell-mediated immunity – Cell-mediated immunity plays an important role in clearing infection and protecting against subsequent Salmonella infection. Clinical vigilance in the diagnosis and management of Salmonella infections should be increased in patients with cellular immunosuppression. As an example, infection is more severe and prolonged in patients with depressed cellular immunity due to glucocorticoids [156], HIV/AIDS [76,77,157], and malignancy [78]. In one study including 249 cases of bacteremia among patients with HIV infection, nontyphoidal Salmonella was the second most frequent bacterial isolate (14 percent of cases) [158].
•Humoral immunity – The importance of the humoral response in containing Salmonella infection is illustrated by vaccination studies with S. Typhi. In a trial of the oral live-attenuated typhoid vaccine Ty21a, bacterial 16S rRNA pyrosequencing was employed to evaluate whether oral immunization resulted in alterations of the intestinal microbiota and whether a given microbiota composition is associated with defined S. Typhi-specific immunological responses [159]. No discernible perturbations of the bacterial assemblage were found after vaccine administration. Among individuals able to mount a humoral response, no differences in microbial composition, diversity, or temporal stability were observed; however, individuals displaying broader (multiphasic) cell mediated immune responses harbored more diverse, complex communities.
Development of vaccines against non-typhoidal Salmonellae has been hampered by concern about inducing the post-infectious inflammatory syndromes associated with GI infection, such as reactive arthritis.
●Salmonella and bowel disease – There have been some reports of a higher incidence of inflammatory bowel disease after Salmonella infection; this may be due to shifts in the intestinal microbiome, alterations in the intestinal immune response, or alteration of the epithelial barrier.
However, Salmonella infection has not been conclusively associated with increased risk for inflammatory bowel disease [160]. In a review of 20,471 patients with Campylobacter or nontyphoidal Salmonella infections between 2000 and 2015 in Great Britain, less than 2 percent of patients developed sequelae within 12 months of infection, most commonly irritable bowel syndrome [161]
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient education: Salmonella infection (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology
•Geographic distribution – Nontyphoidal salmonellae are a major cause of diarrhea worldwide. In the United States there are at least 1.4 million Salmonella infections per year, which result in approximately 25,000 hospitalizations and 420 deaths. (See 'Geographic distribution' above.)
•Transmission – Primary modes of transmission include foodborne and animal contact. Salmonella outbreaks have been commonly associated with poultry and eggs; many other food products, including fresh produce, have also been implicated in infections and outbreaks. Contact with reptiles and live poultry are also sources of Salmonella infection. (See 'Transmission' above.)
•Risk factors – Host factors that predispose to severe Salmonella infection are summarized in the table (table 2). These include extremes of age (age >60 years and infants), impaired immunity, reduced gastric acidity, and antecedent antibiotic use. (See 'Risk factors' above.)
●Antibiotic resistance – Rates of antibiotic resistance in Salmonella are an area of significant concern; 16 percent of nontyphoidal Salmonella in the United States are resistant to at least one antibiotic, and approximately 2 percent are resistant to at least three antibiotics. (See 'Antimicrobial resistance' above.)
●Microbiology – Salmonellae are gram-negative, facultatively anaerobic Enterobacteriaceae. Most clinically important Salmonellae are classified within a single subspecies: Salmonella enterica, subspecies enterica.
•Serogroups and serotypes – Salmonella may be serogrouped based on the O antigen derived from the lipopolysaccharide cell wall component (table 3). However, serogroups cannot be used to distinguish enteric fever-causing strains from gastroenteritis-causing strains.
Serotyping is more specific than serogrouping and usually is performed at reference laboratories for outbreak tracking.
●Pathogenesis – Salmonellae adhere to and invade the gastrointestinal tract several different mechanisms. The ability of Salmonella to survive within macrophages contributes to the dissemination of the microorganism from the submucosa to the circulation and the reticuloendothelial system. The host immune response plays an important role in clearing and protecting against subsequent infection. (See 'Pathogenesis' above.)
