Version May 2024
INTRODUCTION — Salmonellae are motile gram-negative bacilli that infect or colonize a wide range of mammalian hosts. They cause a number of characteristic clinical infections in humans, including:
●Gastroenteritis
●Enteric fever (systemic illness with fever and abdominal symptoms)
●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. The microbiology, epidemiology, clinical features, and treatment of these infections are discussed elsewhere. (See "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis" and "Enteric (typhoid and paratyphoid) fever: Treatment and prevention".)
Other Salmonella serotypes are collectively known as nontyphoidal salmonellae. The bacteriology, epidemiology, and trends in antimicrobial resistance of these organisms will be reviewed here. The pathogenesis, clinical features, and treatment of specific Salmonella syndromes are discussed separately. (See "Pathogenesis of Salmonella gastroenteritis" and "Nontyphoidal Salmonella: Gastrointestinal infection and asymptomatic carriage" and "Nontyphoidal Salmonella bacteremia and extraintestinal infection".)
MICROBIOLOGY — Salmonellae are gram-negative, facultatively anaerobic Enterobacteriaceae. The genus Salmonella consists of two species, Salmonella enterica and Salmonella bongori; the former is further divided into six different subspecies. Based upon high levels of deoxyribonucleic acid (DNA) similarity, most clinically important salmonellae are formally classified within a single subspecies, Salmonella enterica, subspecies enterica [1]. Familiar organisms such as Salmonella Typhi, Salmonella Choleraesuis, Salmonella Enteritidis, and Salmonella Typhimurium, previously believed to represent separate species based upon antigenic structures, host range, and biochemical characteristics, are now individual serotypes of this single subspecies. Many laboratories will continue to report names recognizable to clinicians such as Salmonella enterica serovar typhi or Salmonella Typhimurium. Serotype and serovar are synonymous.
Salmonellae are relatively easy to identify in the clinical microbiology laboratory [2]. 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 [3], which can be rapidly detected by slide agglutination studies.
Simple grouping based upon O antigen is usually reported initially before more complete serotyping is available. Although serogrouping may provide a clue as to the specific organism (table 1), this may not always be useful clinically. As an example, both S. Enteritidis (which most frequently causes gastroenteritis) and S. Typhi (which causes enteric fever) belong to group D; S. Enteritidis may occasionally cause a systemic "typhoidal" illness with bacteremia.
Formal serotyping is more specific than serogrouping and usually is only performed at state or reference laboratories. Public health laboratories are increasingly using genomic techniques to identify specific serotypes and to find and track outbreaks [4,5].
Salmonellosis is a reportable illness in the United States, and laboratories are required to report isolates to state authorities.
EPIDEMIOLOGY
Incidence
Globally — 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 [6].
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 [6].
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 [7]. These estimates are an extrapolation from the number of reported cases, which represent a fraction of the true incidence, as many cases are not diagnosed. There are an estimated 39 cases of undocumented salmonellosis for each culture-confirmed case [8].
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 [9]. 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.
Salmonella outbreaks due to multiple serotypes may occur more frequently than typically recognized [11]. Because certain serotypes are known to be likely associated with particular food types or animal sources, evaluating for the presence of multiple serotypes (if resources permit) can help focus the investigation on potential outbreak sources.
Modes of transmission — 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 infection — Nontyphoidal salmonellae are a common cause of foodborne outbreaks. Salmonellae are associated with animal reservoirs and, therefore, with animal- and plant-based agricultural products [12-14]. Salmonella outbreaks have been most commonly associated with poultry and eggs, although the proportion of egg-related Salmonella outbreaks declined over time and many other food products have been implicated in infections and outbreaks.
●Poultry, eggs, and egg products – Both chicken and egg consumption are risk factors for nontyphoidal Salmonella infection [15,16]. Salmonellae can be passed transovarially from chickens to intact shell eggs [17]. Thus, single, intact, normal-appearing eggs can transmit infection. The frequency of S. Enteritidis-contaminated eggs is difficult to estimate because the rate varies depending upon the level of colonization among hens in a flock and the timing of egg production with respect to acquisition of infection in the hen [13]. On average, in the United States, the frequency of contamination is 1 in 20,000 eggs [18].
Pooling of large numbers of eggs can result in contamination of food products that may be distributed nationally and potentially 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 [19]. 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, and other foods, as well as contaminated water [20-39]. Novel food sources of Salmonella infection, including frog legs and sugar cane, are continuously being identified [40]. Contamination can occur at many points along the food processing pathway, which, in resource-rich 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 [41,42].
Foodborne Salmonella outbreaks can be widespread. Between 2010 and 2014 in the United States, there were 120 foodborne disease outbreaks reported that spanned multiple states, the majority of which were caused by Salmonella [43]. Salmonella outbreaks were most commonly associated with fruits, seeded vegetables, sprouts, and nuts/seeds, but the three largest outbreaks were traced to eggs, poultry, and a raw tuna product. Reports of such foodborne Salmonella outbreaks in the United States can be found on the CDC website.
Some important outbreaks from the past several years include Salmonella Sundsvall and Salmonella Oranienburg associated with cantaloupes (230 cases in 2023), Salmonella 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), Salmonella Javiana associated with cut fruit (165 cases in 2019), multidrug-resistant Salmonella Reading associated with raw turkey products (358 cases), and Salmonella Infantis associated with raw chicken products (129 cases in 2018).
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 [44]; outbreaks of salmonellosis also have been linked to consumption of powdered infant formula [45-47]. Studies have also suggested that riding in a shopping cart with meat or poultry placed next to an infant is a risk factor for Salmonella [44]. Case control studies in infants have suggested that breastfeeding protects against acquisition of Salmonella infection in infancy [44,48]. (See "Infant benefits of breastfeeding", section on 'Prevention of illnesses while breastfeeding'.)
Animal contact — In addition to the foodborne route, transmission of Salmonella can occur from contact with reptiles and amphibians (eg, snakes, lizards, turtles, iguanas, frogs) [44,49-56], from live poultry including chicks and ducklings [57,58], from cats and dogs [59], from other pets (hamsters, mice, rats, and hedgehogs) [60-62], and from pet foods [63,64].
●Reptiles and amphibians – A case-control study conducted in 1996 and 1997 in five states in the United States estimated that reptiles and amphibians accounted for 6 percent of all human, laboratory-confirmed sporadic Salmonella infections, and 21 percent of infections in individuals under age 21 [65]. In a subsequent report from Michigan, reptile-associated salmonellosis accounted for 12 percent of cases of Salmonella infection in children ≤5 years of age between January 2001 and June 2003 [50]. Turtles were considered the probable source of many of these infections. In a study from Spain, 48 percent of pet reptiles from homes or shops carried Salmonella, and 72 percent of those were multidrug-resistant organisms [66]. Since nontyphoidal Salmonella infections are common and usually sporadic, the association with turtle exposure may not be detected [49].
In the United States, the CDC recommends that children under five years of age and immunocompromised patients avoid contact with reptiles [51,67,68]. Although there is a federal law prohibiting the sale of small turtles, turtle sales continue to occur. 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 [52]. In one outbreak of Salmonella Poona associated with pet turtles, 40 percent of the cases were younger than one year old and presumably unlikely to handle the animals, highlighting the possible role of indirect transmission [54]. CDC recommendations for turtles as pets are available on the CDC website.
●Live poultry – Live poultry (including backyard chickens) are a source of Salmonella infection that is relatively under-recognized by the general public [69]. In one study, over 75 percent of flock owners in Massachusetts considered these birds to be pets [70].
Between 2004 and 2011, 316 illnesses caused by a particular strain of Salmonella Montevideo were reported from multiple states across the United States [58]. The majority of patients were children younger than five years old, and most reported contact with live young poultry, many of which had been purchased as pets, in the week prior to the illness. Of those interviewed, only 21 percent were aware of the risk of Salmonella with the handling of live poultry, and only 7 percent were apprised of this risk on acquisition of the bird. Investigation traced the outbreak to a mail-order hatchery, which subsequently instituted control measures that decreased but did not eliminate the number of cases caused by this strain of S. Montevideo in subsequent years. Smaller outbreaks of different Salmonella species have been also been linked to handling of live poultry purchased as pets or for backyard flocks [57,71,72]. The potential impact of this risk 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 – Although other pets are rarely confirmed as the source of human salmonellosis, zoonotic transmission of gastrointestinal illnesses from sick pets may occur [59-61]. Raw pet foods and treats for companion animals may also be a hidden reservoir of Salmonella in the home [73,74].
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 [75]. Wild songbirds, birdfeeders, and urban birds have also been linked to human transmission [76,77].
Person-to-person — A report of infections with identical Salmonella isolates in two hospitalized patients who were part of a multistate outbreak and a phlebotomist who had drawn their blood three days before the onset of illness demonstrated the possibility of person-to-person transmission [78]. An outbreak of fluoroquinolone-resistant salmonellosis, thought to be transmitted through person-to-person spread or contact with contaminated surfaces, has also been described [79].
Risk for severe disease — Foodborne salmonellosis may be more severe than other foodborne infections. This was suggested in a registry-based study from Denmark that included 52,121 patients with foodborne bacterial gastroenteritis: 18 percent had infection due to nontyphoidal Salmonella spp, and 14 percent were hospitalized within 90 days of a microbiologic diagnosis [80]. The risk of invasive illness was more than sixfold higher in patients with infection due to nontyphoidal Salmonella compared with other bacterial causes of gastroenteritis.
Salmonellosis is most problematic in people over 60 and 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) [81]. Seventy-one percent of patients with invasive salmonellosis were hospitalized and approximately 5 percent died. Most deaths occurred in older patients with comorbid illnesses.
Although most nontyphoidal Salmonella infections occur in otherwise healthy individuals, 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 (table 2) [82-89]. These conditions may result in more severe initial infection and more serious sequelae such as bacteremia, metastatic foci of infection, or prolonged infection. (See "Pathogenesis of Salmonella gastroenteritis".)
Certain subtypes can also cause more severe disease than others. As an example, in a 2019 outbreak of Salmonella Dublin, a subtype associated with bacteremia, eight of nine people identified early in the outbreak warranted hospitalization, compared with a historical hospitalization rate of 20 percent [90]. S. Dublin, S. Panama, and S. Poona were found to be more invasive in a nationwide registry in the Netherlands [91]. (See "Nontyphoidal Salmonella bacteremia and extraintestinal infection".)
ANTIMICROBIAL RESISTANCE — Antimicrobial resistance is a global problem with nontyphoidal salmonellae [92-95]. There is significant geographic variability in resistance patterns, and epidemics of specific problematic strains occur worldwide.
●United States – 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), US Food and Drug Administration, and United States Department of Agriculture 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 [96]. In Europe, 16.7 percent of strains are nalidixic acid-resistant and 13.5 percent are ciprofloxacin resistant [97]. 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 [98].
•Approximately 3.5 percent of non-typhoidal Salmonella isolates in the United States are resistant to ceftriaxone [96]. Resistance prevalence varies by source and serotype. In Europe, 1.8 percent of reported isolates are resistant to cefotaxime [97].
●Multidrug resistance – In 2022, the CDC issued a report regarding infection with multidrug-resistant Salmonella Newport among travelers to Mexico [99,100]. 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 [101,102]. The Clinical and Laboratory Standards Institute 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 [103]. 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 [104,105].
●Mechanisms – Antimicrobial resistance in foodborne human pathogens is thought to be due, in part, to antibiotic overuse and development of resistance by organisms in animals. Several reports highlight the transmission of antibiotic-resistant strains of Salmonella from food animals, the need for judicious use of antimicrobial agents in both clinical practice and animal husbandry, as well as the need for ongoing surveillance of antimicrobial resistance patterns of important foodborne pathogens:
•A study from Denmark linked transmission of S. Typhimurium DT104 infections in 25 patients to a Danish swine herd [106]. Eleven patients were hospitalized, two died, and the organism had reduced susceptibility to fluoroquinolones.
•A report from Canada described a strong correlation between ceftiofur resistance in S. Heidelberg isolated from retail chicken and the incidence of ceftiofur resistance in clinical isolates from across Canada [107].
•A 2019 United States outbreak of S. Newport with decreased susceptibility to azithromycin and ciprofloxacin was linked through whole genome sequencing to beef and cheese imported from Mexico, consumption of which was epidemiologically associated with outbreak cases [108].
SUMMARY
●Salmonellae are motile gram-negative bacilli that typically are oxidase- and lactose-negative and produce hydrogen sulfide. Most clinically important salmonellae are classified as Salmonella enterica, subspecies enterica. Salmonella Typhi and Paratyphi cause enteric fever. Other Salmonella serotypes are collectively known as nontyphoidal salmonellae. (See 'Introduction' above and 'Microbiology' above.)
●Nontyphoidal salmonellae are common causes of foodborne gastroenteritis worldwide, particularly in outbreak settings. Salmonella outbreaks have been commonly associated with poultry and eggs, but many other food products, including fresh produce, other meats, nuts, and spices, as well as aquatic products, have also been implicated in infections and outbreaks. (See 'Foodborne infection' above.)
●Contact with reptiles and live poultry is an additional source of Salmonella infection and should be avoided by children younger than five years and immunocompromised patients. (See 'Animal contact' above.)
●Gastroenteritis due to nontyphoidal salmonellae is generally more severe than that due to other pathogens. Infants, individuals over 60 years old, and patients with impaired cellular immunity are at risk for severe salmonellosis (table 2). (See 'Risk for severe disease' above.)
●There is significant geographic variability in antimicrobial resistance patterns in nontyphoidal salmonellae. In the United States and Europe, rates of resistance to fluoroquinolones or third generation cephalosporins are not high but warrant close monitoring. Extended-spectrum beta-lactamase (ESBL) genes are emerging in salmonellae in some regions. (See 'Antimicrobial resistance' above.)
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