Salmonellosis

Last updated October 8, 2008

Agent
Pathogenesis
Epidemiology
Clinical Features
Differential Diagnosis
Laboratory Diagnosis
Treatment
Vaccines
Travel Implications
Disease Prevention and Control
References

Agent

Classification

Salmonella is a genus of the family Enterobacteriaceae and is classified into two species:

Salmonella enterica, which comprises six subspecies designated by names or Roman numerals (Roman numerals are used most commonly):

Subspecies enterica (I)
Subspecies salamae (II)
Subspecies arizonae (IIIa)
Subspecies diarizonae (IIIb)
Subspecies houtenae (IV)
Subspecies indica (VI)

Salmonella bongori, formerly known as subspecies V but now classified as a separate species (see References: Brenner 2000; CDC 2004: Salmonella surveillance: annual summary, 2003, 2005)

Members of Salmonella species can be further divided into more than 2,541 serotypes (serovars) and are classified according to their somatic (O) and flagellar (H) antigens. Additional surface (Vi) antigens and habitat also can be used to classify serotypes (see References: Bopp 2003). Formulas are derived from the Kaufmann-White scheme, which was adopted by the Centers for Disease Control and Prevention (CDC) on Jan 1, 2003 (see References: CDC 2004: Salmonella surveillance: annual summary, 2003). According to that classification scheme, all Salmonella serotypes can be designated by the following antigenic formula: subspecies [space] O antigens [colon] phase 1 H antigen [colon] phase 2 H antigens. For example, the formula for Salmonella Typhimurium is I 4,5,12:i:1,2, and the formula for Salmonella Enteritidis is I 9,12:g,m:-.
Subspecies enterica (or subspecies I) contains 1,454 serotypes and includes almost all of the serotypes pathogenic for humans.
Subspecies I serotypes are named using genus and serotype, with a few exceptions. For example, Salmonella enterica subspecies enterica serotype Typhimurium can be referred to simply as Salmonella Typhimurium. However, recently emerged monophasic strains that otherwise conform to the antigenic formula for Salmonella Typhimurium are called Salmonella I 4,5,12:i:- Serotypes from other subspecies are usually designated by a formula, with a few exceptions.

Key Microbiologic Characteristics

Salmonellae have the following characteristics:

They are gram-negative, rod shaped bacilli.
They are 2 to 3 microns by 0.4 to 0.6 microns in size.
They are non-spore-forming facultative anaerobes.
Movement is via peritrichous flagellae (except for Salmonella Gallinarum-pullorum); organisms are unique in that they typically express two (H) antigens on their flagella.
Organisms produce acid on glucose fermentation, reduce nitrates, and do not produce cytochrome oxidase.
Differential metabolism of sugars and other biochemical properties can be used to distinguish serotypes, as shown in the table below.

Differences Between the Major Subgroups of Salmonella Organisms
Property or Test	Subspecies
Property or Test	I	II	IIIa	IIIb	IV	V	VI
DNA hybridization group	1	2	3	4	5	?	?
Fermentation: Dulcitol	+	+	0	0	0	+	d
Fermentation: Lactose	0	0	d	d	0	0	d
Fermentation: Mucate	+	+	+	d	0	+	d
o-Nitrophenyl-beta-galactoside	0	d	+	+	0	+	d
Malonate utilization	0	+	+	+	0	0	0
Growth in potassium cyanide	0	0	0	0	+	+	0
Gelation hydrolysis	0	+	0	+	+	+	0
+, >90% positive; 0 <10% positive; d, 11%-89% positive. Adapted from Isenberg 2003 (see References).

Genomes of at least five strains and several virulence plasmids have been sequenced:

Salmonella Typhi strain CT18 has a 4,809,037-base pair (bp) chromosome with 4,430 open reading frames (see References: Parkhill 2001).
Salmonella Typhimurium strain LT2 has a 4,857,432-bp chromosome with 5,599 coding sequences, including 204 pseudogenes. The pseudogenes may explain this strain's host restriction to humans (see References: McClelland 2001).
Salmonella Choleraesuis strain SC-B67 has a 4,755,500-bp chromosome, a 138,742-bp plasmid (pSC138), and a 49,558-bp virulence plasmid (pSCV50). This strain is highly invasive among nontyphoidal Salmonella, usually causing sepsis or extraintestinal focal infections in humans (see References: Chiu 2005).
Salmonella enterica serovar Enteritidis P4 (isolate P125109) and a chicken restricted Salmonella enterica serovar Gallinarum (isolate 287/91) have been sequenced, and comparisons of genomic sequences provide insight into mechanisms of host and tissue adaptation (see References: Thompson 2008).
Several virulence plasmids have also been sequenced (from Salmonella Dublin, S Cholereasesuis, S Enteritidis, and S Typhimurium). Analyses of sequences suggest that these plasmids evolved from a larger plasmid into smaller ones via deletions and selected recombination events (see References: Hong 2008).

Pathogenesis

Virulence Factors

Salmonella virulence is determined by Salmonella pathogenicity islands (SPIs) that contain multiple functionally related genes whose protein products are translocated into the host (see References: Ohl 2001, Pegues 2005).
All salmonellae encode a type III secretion system within the SPI-1 (SPI-1 T3SS) that is required for bacterial-mediated endocytosis and intestinal epithelial cell invasion.

SPI-1 T3SS functions as a "molecular syringe" to facilitate transfer of bacterial proteins.
The effector proteins translocated into the host cell are unique to each pathogen and contribute to the virulence phenotype of each.
Two SPI-1 translocated proteins (SipC and SipA) promote host cell membrane ruffling and interact with the Rho family of monomeric guanosine triphosphate (GTP)-binding proteins. Tissue culture studies reveal that serotypes that have mutant SipA invade cells less efficiently.
Additional SPI-1 translocated proteins (SopE, SopE2, SopB) induce membrane ruffling and macropinocytosis. SopB also acts as an inositol polyphosphatase indirectly stimulating Rho GTPases. Combined mutation of SopB, SopE, or SopE2 reduces Salmonella invasion of epithelial cells in tissue culture models, suggesting that all three are necessary for cellular invasion.

Another island, SPI-2, encodes additional genes essential for intracellular replication and survival within the cell and for establishment of systemic infections (see References: Collier-Hyams 2002).
The PhoP/PhoQ regulatory system induces transcription of over 40 genes required for the survival of salmonellae in macrophages. In addition, a second type III secretion system encoded on SPI-2 (SPI-2 T3SS) promotes survival within macrophages.
Salmonellae also express several enzymes that inactivate reactive oxygen and nitrogen species produced by macrophages.
Virulence plasmids of Salmonella Typhimurium, S Choleraesuis, S Enteritidis, and S Dublin contain a region that promotes dissemination beyond the intestine in animal models and contributes to bacteremia in humans (see References: Fierer 1992).
Increasing resistance to multiple antibiotics represents a significant problem (see References: Su 2004, Weinberger 2005) and can be introduced to new strains by virulence plasmids (see References: Chiu 2005).

Major Mechanisms of Pathogenesis

Salmonellae avoid host defenses in the stomach and then reach the small intestine (see References: Ohl 2001, Pegues 2005). They adhere to intestinal epithelial cells by adhesive structures (fimbriae) that promote binding and invade intestinal epithelial cells to provoke gastroenteritis. The steps in the process include:

Bacterial mediated endocytosis: A highly coordinated series of interactions between proteins released by salmonellae and proteins of the host cell causes host cellular surface membrane ruffling and engulfment of bacteria in cellular vacuoles.
Neutrophil recruitment and migration: Salmonellae associated with gastroenteritis induce a secretory response in intestinal epithelium and initiate recruitment and transmigration of neutrophils into the intestinal lumen.
Epithelial cell cytokine secretion: In tissue culture models of Salmonella Enteritidis, translocation of SPI-1 proteins into intestinal epithelial cells leads to synthesis and polarized secretion of inflammatory mediators and neutrophil chemoattractants.
Fluid and electrolyte secretion: Several translocated SPI-1 proteins contribute to intestinal inflammation and fluid secretion. Intestinal inflammation likely contributes to fluid secretion and diarrhea by disrupting the epithelial barrier and increasing water flux by an exudative mechanism. Innate immune system activation also contributes to intestinal inflammation.
Systemic infection: Salmonella Typhi invades macrophages, and migration of infected macrophages to reticuloendothelial organs via the lymphatic system and blood produces systemic illness with less diarrhea (see References: Ohl 2001, Pegues 2005).

Epidemiology

Reservoirs

The main reservoirs for nontyphoidal Salmonella are animals:

Poultry
Livestock
Pets
Reptiles

Salmonella Typhi and S Paratyphi colonize only humans, so they can be acquired only from close contact with a person who has typhoid fever, from a chronic carrier, or from water or food contaminated by human feces (see References: Pegues 2005).

Modes of Transmission

Nontyphoidal Salmonella

Historically, the major mode of transmission was consumption of inadequately cooked or pasteurized foods of animal origin, such as poultry, beef (including ground beef), fish, eggs, and dairy products (including ice cream) (see References: AAP 2006, McLaughlin 2006, Seo 2006, Todd 1997).

S Enteritidis associated with consumption of inadequately cooked shell eggs has become the predominant Salmonella serotype and source of foodborne disease in the United States and several other countries (see References: CDC 2004: Salmonella surveillance: annual summary, 2003).
Contamination of raw animal products can occur during slaughter and processing. Presence of Salmonella Enteritidis has increased in broiler chicken carcasses surveyed between 2000 and 2005 in the United States and represents a source of foodborne disease in chicken and processed products (see References: Altekruse 2006). Other isolates found in turkey pot pies were responsible for a multistate outbreak in 2007 (see References: CDC 2007: Investigation of outbreak of human infections caused by Salmonella I 4,[5], 12:i:-; Mody 2008)

Over the past 10 to 15 years, Salmonella infections associated with consumption of fresh fruits and vegetables, including seeds, sprouts, spices, and herbs, have been increasingly recognized. [Add Fruits and vegetables can become contaminated with human or animal feces during growth, transport, or processing, although gaseous and aqueous ozone can reduce contamination in selected produce (see References: Bialka 2007: Efficacy of acqueous ozone; Bialka 2007: Utilization of gaseous ozone). The bacteria can grow into the plant from the roots of leafy plants such as lettuce (see References: Bernstein 2007) and within or on other plants such as tomatoes (see References: Shi 2007). Leaf age and presence of protozoans on plants also influence contamination and bacterial growth on leafy greens such as lettuce and spinach. Young (inner) lettuce leaves consistently harbored about 10-fold higher bacterial populations than middle leaves harvested from mature lettuce heads (see References: Brandl 2008, Gourabathini 2008).
Large, geographically dispersed outbreaks associated with environmental contamination of processed foods have developed as a major concern. Occasionally, spices (paprika is the one most commonly affected) (see References: Vij 2006), processed foods (eg, microwavable pot pies, infant formula) (see References: Cahill 2008, CDC 2007: Investigation of outbreak of human infections, Salmonella I 4,[5], 12:i:-), and produce can be the source of illness (see References: CDC 2007: Multistate outbreaks of Salmonella infections associated with raw tomatoes; CDC 2008: Outbreak of Salmonella serotype Saintpaul infections associated with multiple raw produce items).

Processed foods can also be contaminated during production. Peanut butter has caused outbreaks in Australia (see References: Scheil 1998) and the United States (see References: CDC 2007: Salmonellosis—outbreak investigation). Peanut butter contaminated during processing in a Georgia factory caused 628 cases in 47 states from mid-2006 through May 22, 2007 (see References: CDC 2007: Multistate outbreak of Salmonella serotype Tennessee; CDC 2007: Salmonellosis—outbreak investigation).
Powdered infant formula has been linked to at least six outbreaks in recent years (see References: Cahill 2008).
Bottled water has been a rare cause of outbreaks, most recently in 2006 (see References: Palmera-Suarez 2007).

Infected food handlers have been shown to transmit Salmonella and have been responsible for outbreaks (see References: Hedberg 1991, Medus 2006). Workers who have been ill can shed Salmonella for a median of 30 days (range, 2 days to 280 days); therefore, assessment of food-worker infection is essential for controlling outbreaks traced to restaurants (see References: Medus 2006).
As many as 90% of reptiles may be Salmonella carriers. Between 3% and 5% of all cases of salmonellosis in humans have been associated with exposure to exotic pets, especially reptiles (including pet turtles, iguanas, lizards, and snakes) (see References: CDC 2004: Salmonella surveillance: annual summary, 2003; Woodard 1997). The United States banned the sale of small turtles (carapace < 4 in. [10.2 cm]) in 1975 (see References: FDA 2005: Human health hazards), and reissued a warning because of a resurgence of turtle sales and subsequent outbreaks (see References: CDC 2008: Multistate outbreak of human Salmonella infections associated with exposure to turtles; CDC 2007: Turtle-associated salmonellosis in humans).
Pet rodents probably represent an underrecognized source of human Salmonella infection. In 2007, these animals were responsible for an outbreak of multidrug-resistant Salmonella in several states. Of 22 patients interviewed, 13 (59%) in 10 states reported exposure to pet hamsters, rats, or mice, and 2 (9%) had secondary infections (see References: Swanson 2007).
Animals in petting zoos may also serve as sources of infection, as may certain other animals, such as baby poultry (see References: CDC 2007: Three outbreaks of salmonellosis associated with baby poultry) and livestock (see References: AAP 2006).
Other modes of transmission include ingestion of contaminated water (see References: O'Reilly 2007, CDPHE 2008) and contact with contaminated dyes and medical instruments (see References: AAP 2006).

S Typhi and S Paratyphi

Unlike other Salmonella species, Salmonella Typhi and S Paratyphi are found only in humans, and infection implies contact with an infected person or consumption of contaminated food or water (see References: AAP 2006, Srikantiah 2007).
Typhoid fever is endemic in many countries and cases in the United States are usually acquired during international travel to developing regions, particularly southeast Asia and the Indian subcontinent (see References: Freedman 2006, Srikantiah 2007).

Incidence

Nontyphoidal salmonellosis—United States

An estimated 1.4 million cases of salmonellosis (with an estimated 580 fatal infections) occur annually in the United States (see References: CDC: Salmonellosis. Division of Bacterial and Mycotic Diseases 2005).
According to data obtained through the Foodborne Diseases Active Surveillance Network (FoodNet) of CDC's Emerging Infections Program, Salmonella remains the most common bacterial/parasitic enteric pathogen in the United States (see References: CDC 2004-2008: Preliminary FoodNet data on the incidence of infection with pathogens transmitted commonly through food). In 2007, 6,790 of 17,883 laboratory-confirmed infections were caused by Salmonella strains (see References: CDC 2008: Preliminary FoodNet data, 2007). The FoodNet system collects data from 10 sites across the country through active, population-based surveillance for laboratory-diagnosed illness. Although the system provides the best available estimate on the incidence of various enteric pathogens transmitted commonly through food, there are a number of limitations to the system and the data do not reflect the true incidence of infection (since many illnesses are not laboratory-confirmed). Given these caveats, the following observations on salmonellosis are available from 2003 through 2007 FoodNet reports.

The incidence rate of laboratory-confirmed Salmonella infections has remained relatively stable during the past 5 years (incidence per 100,000 population was 14.5 in 2003, 14.7 in 2004, 14.55 in 2005, 14.81 in 2006, and 14.92 in 2007). All of the recent estimates exceed the national health objective goal for 2010 of 6.8 per 100,000 persons (see References: HHS: Healthy People 2010; CDC 2007: Preliminary FoodNet data [2006]; CDC 2008: Preliminary FoodNet data [2007]).
In 2003, Salmonellae were isolated most frequently from children younger than 5, who accounted for 25% of isolates in that year. Each of the next four age categories (teens through 40s) had about 10% of isolates Numbers of cases declined among older age-groups (see References: CDC 2004: Salmonella surveillance: annual summary, 2003)
Salmonella infections in 2007 were the furthest from the national target for 2010 of any of the foodborne diseases tracked (see References: CDC 2008: Preliminary FoodNet data, [2007])..
Of the 6,299 isolates serotyped in 2007, seven types accounted for 61.6% of infections (see References: CDC 2008: Preliminary FoodNet data [2007]):

Salmonella Enteritidis (1,062 isolates; 16.9%)
S Typhimurium (1,006; 16%)
S Newport (656; 10.4%)
S I 4, [5],12:i:- (358; 5.7%)
S Javiana (347; 5.5%)
S Heidelberg (243; 3.9%)
S Montevideo (211; 3.4%)

Comparison of 2007 data with data from 2004 to 2006 shows that the incidence of individual Salmonella serovars did not decrease significantly. Among the seven most common Salmonella serotypes, the incidence of Salmonella Typhimurium and S Heidelberg infections decreased slightly, S Newport and S I 4,[5],12:i:- increased, while the others did not change significantly. Salmonella infection overall decreased 8% in 2007 compared with 1996 to 1998 baseline data (see References: CDC 2008: Preliminary FoodNet data [2007]).
The FoodNet data indicate declines in infections for several other enteric pathogens, but to sustain these declines will require additional efforts to prevent foodborne infections, reduce pathogens in food animal reservoirs, and prevent produce contamination. In particular, the decline of serotypes associated with food-animal production and the increase in a wide variety of other serotypes suggest that an increased proportion of Salmonella infections may be due to contaminated produce.
Testing by the US Department of Agriculture (USDA) Food Safety and Inspection Service (FSIS) has shown that Salmonella contamination of ground beef has declined from 3.4% in 1998 to a low of 1.1% in 2005 before climbing to 2.0% in 2006 and 2.7% in 2007 (see References: USDA/FSIS 2008: Progress report on Salmonella testing of raw meat and poultry products, 1998-2007). 2005 statistics from the National Antimicrobial Resistance Monitoring System (NARMS) revealed that 2.3% of ground beef samples (8 of 353) contained Salmonella (see References: NARMS 2005:).
Salmonella contamination of chicken-broiler carcasses increased each year between 2002 and 2005 (from 11.5% in 2002 to 16.3% in 2005) before dropping to 11.4% in 2006 and 8.5% in 2007 (see References: USDA/FSIS 2008: Progress report on Salmonella testing of raw meat and poultry products, 1998-2007). Statistics from recent testing of ground meat samples revealed that 43.3% (153 of 353) of ground chicken and 51.8% (183 of 353)of ground turkey samples contained Salmonella (see References: NARMS 2005).

Typhoid—United States

Typhoid fever in the United States has an annual incidence of less than 0.2 cases per 100,000 persons. Since 1994, the incidence of typhoid fever has shown a modest decline, with about 400 cases occurring each year. Most of the cases are acquired during international travel to developing countries (see References: CDC 2005: Typhoid fever).
Outbreaks within the United States are rare and small (median, 10 cases); most are associated with food contamination by a chronic carrier. From 1960 through 1999, 16 of 26 outbreaks (62%) were associated with an asymptomatic food handler (see References: Olsen 2003).
Since 1985, the proportion of Salmonella Typhi isolates resistant to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole had been increasing, but by 2000 it had declined to about 9% (see References: Ackers 2000). The number of isolates resistant to nalidixic acid rose to 41.8% in 2004 (see References: CDC 2007: National Antimicrobial Resistance Monitoring System), and in 2005, investigators identified the first truly ciprofloxacin-resistant Salmonella Typhi infection in the United States. Salmonella Typhi strains with decreased susceptibility to ciprofloxacin are increasingly common in south Asia, and individuals infected there might require alternative therapeutic agents (see References: CDC 2007: Summary of notifiable diseases [2005]).
Cases of Salmonella Paratyphi A made up an increasing proportion of all cases of enteric fever diagnosed in the United States (see References: CDC 2007: Summary of notifiable diseases [2005]). A cross-sectional laboratory-based surveillance study found that 80% of US patients with paratyphoid fever had acquired the disease in south Asia, and 75% were infected with nalidixic acid–resistant strains (see References: CDC 2008: Summary of notifiable diseases [2006]).

Nontyphoidal salmonellosis—global

Nontyphoidal salmonellosis remains an important public health problem worldwide. Although developing countries carry most of the global burden of diarrheal disease, very few have established disease surveillance programs.
The predominant serotypes are Salmonella Enteritidis and S Typhimurium, although the rank of serotypes varies from country to country.
Resistance rates vary with different regions of the world, serotypes, and different antibiotics.
Identification of a Salmonella serovar that contains a mercury resistance module within genomic island–1 demonstrates that multidrug-resistance regions can incorporate new DNA segments in the same way that plasmids acquire such gene cluster–containing segments (see References: Levings 2007).
Multidrug resistance has been detected in some serovars in Asian countries, in Denmark and other European countries, and in the United States (see References: Aarestrup 2007,Meakins 2008, Skov 2007).
A 3-year surveillance study from Yucatan, Mexico (see References: Zaidi 2006) noted that a high percentage of retail pork and poultry contained salmonellae. The most common serotype in ill humans was Salmonella Typhimurium, followed by S Enteritidis. Asymptomatic children carried S Agona. Retail pork and poultry were found to contain salmonellae. Resistance to antibiotics was also observed, and 27% of isolates were resistant to nalidixic acid, but none were resistant to ciprofloxacin. Multidrug resistance was most common among isolates of S Typhimurium and S Anatu.
Antimicrobial resistance has increased in many areas of the world (see References: Su 2004), and resistance to multiple antibiotics has become a significant trend with Salmonella Typhimurium (eg, S. Typhimurium DT104) and several other nontyphoidal serotypes (see References: Weinberger 2005). Animal vectors such as livestock and other farm animals carry antibiotic-resistant Salmonella, but recently other animals, such as house rats, may play a role in the epidemiology of DT104 (see References: Yokoyama 2007).
In Taiwan, the rate of resistance in Salmonella Choleraesuis isolates has increased dramatically; most isolates are resistant to ampicillin, chloramphenicol, or sulfamethoxazole-trimethoprim; and about two-thirds are resistant to ciprofloxacin (see References: Su 2004, Chiu 2005). Among isolates of Salmonella Derby from individuals in Taiwan, 13 samples manifested three different multidrug-resistance phenotypes (see References: Chiu 2007).
Resistance to other antibiotics, such as quinolones (eg, nalidixic acid) and their derivative fluoroquinolones (eg, ciprofloxacin) has also begun to emerge in several Asian countries, including Taiwan (see References: Chiu 2002, Choi 2005, Hakanen 2005, Izumiya 2005).
Mutations in pseudogenes identified in a recently sequenced strain may be a mechanism by which Salmonella strains complement gene acquisition and become more virulent (see References: Chiu 2005).

Typhoid—global

Typhoid fever remains a global problem. The WHO estimates that about 21 million cases occur worldwide annually, resulting in about 650,000 deaths (see References: WHO 2008: Typhoid vaccines). Salmonella Typhi is endemic in developing regions, especially the Indian subcontinent, Southeast Asia, South and Central America, and Africa. In India, the estimated incidence is 900 cases per 100,000 persons (see References: Ivanoff 1994).
Multidrug-resistant strains contain plasmids encoding resistance to chloramphenicol, ampicillin, and trimethoprim (see References: Rowe 1997). Unnecessary use of antimicrobials has increased development of resistant strains (see References: Srikantiah 2007).
Chromosomal- and plasmid-encoded resistance to ciprofloxacin appeared in the Indian subcontinent, Vietnam, and Tajikistan in the late 1990s (see References: Wain 1997), and high-level resistance to third-generation cephalosporins has been reported but still remains rare (see References: Rahman 2002). Some investigators have suggested that older drugs could now be used again because of declining levels of resistance and that ciprofloxacin be withdrawn as a therapeutic agent (see References: Chitnis 2006).
In a study conducted at a teaching hospital in Nepal, investigators found that among 541 isolates of Salmonella Typhi and S Paratyphi A grown from blood cultures obtained from 4,105 patients with febrile illness, 5% of S Typhi isolates and 7% of Paratyphi A isolates were resistant to two or more antibiotics. Most multidrug-resistant isolates showed reduced susceptibility to ofloxacin and ciprofloxacin and had good susceptibility to extended-spectrum cephalosporins and carbapenems (see References: Pokharel 2006).

Risk Factors for Infection

The following risk factors have been found to be associated with development of salmonellosis:

Consumption of raw or undercooked foods of animal origin (meat, poultry, eggs) (see References: Delarocque-Astagneau 2000, Hennessy 2004, Kimura 2004) or consumption of selected raw vegetables, including sprouts and tomatoes (see References: DuPont 2007)
Recent antibiotic exposure (see References: Varma 2005)
Handling reptiles (see References: CDC 2007: Turtle-associated salmonellosis; Mermin 2004)
Handling baby poultry (see References: CDC 2007: Three outbreaks of salmonellosis)
Handling infected pets or contaminated pet treats (see References: CDC 2006: Human salmonellosis associated with animal-derived pet treats; Wright 2005)
Travel to a developing region (see References: AAP 2006, Freedman 2006)
HIV infection (see References: Celum 1987) or other immunocompromised state (see References: AAP 2006)

Examples of Key Outbreaks

Multidrug resistance is an emerging problem among Salmonella serotypes, especially S Newport. Recent large multistate outbreaks associated with ground beef present a particularly troubling development (see References: CDC 2002: Outbreak of multidrug-resistant Salmonella Newport; Cloeckaert 2006).
Exposure to pet birds, pet rodents, dogs, and cats is a potential source of salmonellosis, and outbreaks of multidrug-resistant Salmonella Typhimurium infection associated with small animal veterinary facilities have been reported (see References: Wright 2005)
In 2002, a large outbreak of S Javiana occurred among attendees of the 2002 US Transplant Games. Approximately 6,000 people attended the games, including 1,500 transplant-recipient athletes. A total of 23 laboratory-confirmed Salmonella Javiana infections with indistinguishable pulsed-field gel electrophoresis (PFGE) patterns were identified among attendees. A Web-based survey identified pre-diced tomatoes as the source of the outbreak (see References: Srikantiah 2005).
In the United States, multistate outbreaks have been caused by:

Shell eggs (Salmonella Enteritidis): Among 309 outbreaks with a confirmed vehicle between 1990 and 2001, 241 were associated with shell eggs, and these accounted for 14,319 illnesses (see References: CDC 2003: Outbreaks of Salmonella serotype Enteritidis infection associated with eating shell eggs).
Produce (Salmonella Kottbus, S Poona, S Litchfeld; 2002-2008), including alfalfa sprouts (see References: CDC: 2002: Outbreak of Salmonella serotype Kottbus infections) and whole and cut cantaloupe (see References: CDC 2002: Multistate outbreaks of Salmonella serotype Poona infections associated with cantaloupe; CDC 2008: Investigation update).
Unpasteurized milk (Salmonella Typhimurium; 2002-2003) (see References: CDC 2003: Multistate outbreak of Salmonella serotype Typhimurium infections associated with drinking unpasteurized milk). Although sale of unpasteurized milk for human consumption is illegal in most states, individuals who buy milk designated as pet food or from a cow-share program have been affected.
Manufactured food products or foods that contain added ingredients, such as ice cream (Salmonella Enteriditis): The potential impact of contamination of widely distributed food products was illustrated in a 1994 multistate outbreak that involved an estimated 224,000 cases of salmonellosis caused by consumption of contaminated ice cream (see References: Hennessy 1996). More recently, a multistate outbreak in 2005 arose from ice cream containing a contaminated cake mix ingredient (see References: Minnesota Department of Health 2007). Additional outbreaks arising from several types of food have occurred from 2005 through 2008 (see sections below).

During 2004-05, the CDC reported that contact with Salmonella-contaminated pet treats of beef and seafood resulted in nine culture-confirmed human infections with Salmonella Thompson in Washington state and western Canada. Patients had handled pet treats manufactured in plants in Washington or British Columbia. This was the first such outbreak reported in the United States (see References: CDC 2006: Human salmonellosis associated with animal-derived pet treats), although outbreaks related to pet food have occurred again, in 2006-07.

Analysis of pet treats in the 2004-05 outbreak revealed multiple Salmonella strains; in addition to the Salmonella Thompson initially found, S Montevideo, S Newport, S Give, S Meleagridis, S Cerro, S Muenster, S Agona, and S Anatum were also detected. Both implicated manufacturing plants issued voluntary recalls in June 2005 (see References: CDC 2006: Human salmonellosis associated with animal-derived pet treats).
In 2006-07, an outbreak arose from contact with contaminated dry dog food (70 cases in 19 states, mostly in the northeastern United States). Salmonella Schwarzengrund was detected in dog food samples, pets, and people (see References: CDC 2008: Multistate outbreak of human Salmonella infections caused by contaminated dry dog food).

Significant outbreaks in 2005-06 resulted from:

Tomatoes: Multiple outbreaks occurred in late 2005 (Salmonella Newport, 72 cases in 16 states; S Braenderup; 82 cases in 8 states) and in 2006 (S Newport, 115 cases in 19 states; S Typhimurium, more than 180 cases in 21 states) from tomatoes consumed in restaurants (see References: CDC 2007: Multistate outbreaks of Salmonella infection associated with raw tomatoes).
Additives to ice cream: Multistate outbreak arose from ice cream that contained a cake batter additive. Investigators identified 26 cases in 9 states (Salmonella Typhimurium) (see References: MDH 2007).
Fruit salad: Salad served at healthcare facilities caused an outbreak in 2006 that was traced to a single processing plant (41 culture-confirmed cases in 10 states and Canada ) (see References: CDC 2007: Salmonella Oranienburg infections).

Significant outbreaks in 2007 arose from:

A processed vegetable product containing contaminated spices from China (69 cases in 23 states) (see References: CDC 2007: Salmonella Wandsworth outbreak investigation; Sheth 2008).
Unpasteurized Mexican-style cheese (March 2006 to April 2007; more than 85 cases in Illinois) (see References: CDC 2008: Outbreak of multidrug-resistant Salmonella enterica serotype Newport infections).
Raw milk and cheese consumption (29 cases in Pennsylvania) (see References: CDC 2007: Salmonella Typhimurium infection associated with raw milk and cheese consumption).
Hummus shirazi (a dish of herbs, tomato, and cucumber served over a chickpea paste): At a large summer food fair in Chicago, more than 790 people became ill after eating the dish, and 38 people were hospitalized. More than 190 cases were laboratory confirmed as Salmonella Heidelberg. Investigators identified the outbreak strain in patient specimens, hummus samples, and food worker specimens. Several affected patients filed lawsuits against the restaurant that served the dish (see References: Chicago Department of Public Health 2007).
Peanut butter: Salmonella Tennessee in two brands of peanut butter affected 628 persons from 47 states. The outbreak was the first time peanut butter had been implicated in an outbreak in the United States (see References: CDC 2007: Multistate outbreak of Salmonella serotype Tennessee; CDC 2007: Salmonellosis—outbreak investigation).
Pot pies: Between January and Oct 29, 2007, investigators detected a total of 401 Salmonella I 4,[5],12:i:- infections in individuals from 35 states (see References: CDC 2007: Investigation of outbreak of human infections caused by Salmonella I 4,[5],12:i:-; Mody 2008). Because of known underreporting, this number translates to an estimated 15,000 people infected. A case-control study revealed a strong statistical association between illness and consumption of pot pies (see References: Mody 2008).

In 2008, outbreaks thus far include:

Contamination of puffed rice and wheat cereals (see References: CDC 2008: Investigation of outbreak of infections caused by Salmonella Agona).
Contamination of cantaloupe (see References: CDC 2008: Investigation update).
Raw jalapeno and serrano peppers (and perhaps other fresh food items): An outbreak resulting from consumption of fresh jalapeno and serrano peppers occurred in the spring and summer of 2008. The outbreak began in April and produced more than 1,430 cases of infection with Salmonella Saintpaul in 43 states, the District of Columbia, and Canada. Investigators identified peppers from Mexico as two fresh foods responsible for some clusters of illness, but other items that are often consumed together (eg, cilantro or tomatoes) may have also played a role in the outbreak. The outbreak strain was identified in samples of raw jalapeno and serrano peppers and agricultural water from a farm in Mexico. The evidence, however, does not account for all observed cases (see References: CDC 2008: Investigation of outbreak of infections caused by Salmonella Saintpaul; CDC 2008: Outbreak of Salmonella serotype Saintpaul infections associated with multiple raw produce items).

Clinical Features

The following table outlines the features of the clinical syndromes associated with salmonellosis.

Clinical Features of Salmonellosis by Syndrome
Feature	Gastroenteritis	Enteric (Typhoid) Fever
Incubation period	1-3 days after ingestion of contaminated food or water; up to several days following consumption of foods that have low levels of contamination	5-21 days
Presentation	—Diarrhea, fever, abdominal cramps, and vomiting —Stools are loose, moderate volume and usually without blood —Rarely, stools can be watery, large volume ("cholera-like") or small volume with blood ("dysentery-like") —Fever and chills occur in about 50% —Headache, myalgias, and other systemic symptoms also can occur	—Symptoms have an insidious onset —Initial symptoms often nonspecific (chills, diaphoresis, dull frontal headache, anorexia, cough, weakness, sore throat, dizziness, and myalgias) and often are present before fever —Diarrhea is uncommon and vomiting is usually not severe —Enterocolitis with diarrhea lasting several days, but generally resolves before fever occurs —Abdominal pain and tenderness (20%-40%) —Maculopapular rash on trunk (30%) (referred to as “rose spots”)—
Laboratory findings	Microscopy reveals neutrophils in the stool, and less frequently, red blood cells	—Leukocytes present in stool —Stool protein levels are increased —Mononuclear cell infiltration —Hypertrophy of reticuloendothelial system, including Peyer's patches, lymph nodes, spleen, and bone marrow —Leukocytosis (most often in children) —Thrombocytopenia, clotting abnormalities —Moderately elevated liver function tests (AST, ALT 300-500 U/dL) and muscle enzymes
Duration of illness	—4-7 days —After gastroenteritis resolves, the pathogen may be carried in the GI tract for a mean duration of 4-5 wk, depending on the serotype —45% of children younger than age 5 excrete Salmonella 12 wk after infection, compared with 5% of older children and adults —Neonates may carry the pathogen for up to 6 mo	—About 4 wk without treatment, but about 10% relapse after fever resolution —Weakness may persist for weeks —Serotyping can distinguish relapse from reinfection —Up to 10% of untreated patients excrete S Typhi in the feces for up to 3 months, and about 1% to 4% become chronic carriers
Complications	—Cholecystitis, bacteremia, meningitis, focal infections, and endocarditis —Risk of bacteremia is greatest in infants, the elderly, and immunocompromised patients (see References: Shimoni 1999); localized infections occur in 5% to 10% of those with bacteremia (see References: Aguado 1994) —Antimicrobial-resistant nontyphoidal Salmonella has been associated with excess bloodstream infections compared with infections arising from susceptible isolates (see References: Varma 2005) —Reiter's syndrome can occur after 3 wk —Reactive arthritis may occur in about 2% of culture-proven cases —Septic arthritis and septicemia —Chronic dyspepsia or irritable bowel syndrome (see References: Mearin 2005) —Pseudoappendicitis is infrequent, and toxic megacolon is rare, but is potentially life-threatening	Intestinal perforation, endocarditis, and localized infections, such as pericarditis, pneumonitis, orchitis, and focal abscesses
Case-fatality rate (CFR)	—In the US, estimated rate of hospitalization is about 2.2 per 1 million population and about 580 deaths per year —Likelihood of hospitalization depends on Salmonella serotype; S Typhimurium and S Cholaraesuis are significantly more likely to cause hospitalization than 12 other serotypes, including S Enteritidis and S Javiana; some strains, eg, S Derby, are more commonly associated with death (see References: Jones 2008) —A disproportionate number of deaths occur among elderly and immunocompromised patients	—CFR <1% with treatment; mortality without treatment is 15%-20% but in developing countries can be as great as 30%-50%
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase. *S Typhi causes typhoid, and S Paratyphi A, S Paratyphi B, and S Typhi C cause a similar but less severe illness, paratyphoid fever.

Differential Diagnosis

Conditions that should be considered as causes of symptoms in patients with suspected salmonellosis are listed below.

Differential Diagnosis of Salmonellosis

Alternatives to nontyphoidal Salmonella infection (main symptom: watery diarrhea)
Bacillus cereus
Campylobacter species
Clostridium perfringens
Cryptosporidium parvum
Cyclospora cayetanensis
Enterotoxigenic Escherichia coli (ETEC)
Giardia lamblia
Isospora belli
Plesiomonas shigelloides
Shigella species
Vibrio cholerae
Vibrio parahemolyticus
Yersinia enterocolitica

Non-infectious causes of watery diarrhea, eg, Crohn's disease, irritable bowel syndrome

Alternatives to nontyphoidal Salmonella infection (main symptom: bloody diarrhea)
Campylobacter species
Entamoeba histolytica
Shiga toxin–producing E coli (STEC; O157:H7 and other serotypes)
Shigella species
Yersinia enterocolitica

Non-infectious casues of bloody diarrhea, eg, ulcerative colitis

Alternatives to typhoid Salmonella infection (main symptoms fever, abdominal pain, hepatosplenomegaly)
Amoebic liver abscess
Brucellosis (Brucella abortus and other Brucella species)
Leptospirosis (Leptospira interrogans)
Malaria (Plasmodium species)
Q fever (Coxiella burnetii)
Salmonella infections other than S Typhi or S Paratyphi
Septicemia caused by other bacteria
Tularemia (Francisella tularensis)
Visceral leishmaniasis (Leishmania species)
Viral syndromes (eg, dengue fever)

Adapted from Table 1 in AMA et al 2004, Beers 2006 (see References).

Laboratory Diagnosis

Salmonellosis is diagnosed by isolating the causative organism from cultures of stool, blood, urine, or focal lesions. Salmonella also can be typed from food samples (see References: AAP 2006).
Salmonella species can be identified by culture methods and biochemical testing but are usually identified from stool samples.
Definitive diagnosis of S Typhi or S Paratyphi requires isolation from blood, bone marrow, other sterile sites, rose spots, or intestinal secretions.
Typhoid fever is the only bacterial infection of humans for which bone marrow examination (sensitivity of up to 90%) is recommended routinely.

Specimen Collection and Transport for Foodborne Outbreaks

The following points are from CDC 2003: Guidelines for specimen collection and Thomson 2003 (see References).

Collection

Stool is the preferred sample and should be collected during active diarrhea, preferably as soon as possible after onset of illness.
Stool samples are collected (1 mL of liquid or 1 marble-sized piece of whole fresh stool) in sterile leak-proof wide-mouth containers (eg, urine cup).
Rectal swabs are used only for patients for whom stool sample collection is difficult (eg, infants, patients who cannot defecate, during outbreaks when specimens are collected from many people). Swabs are placed in an appropriate transport media (eg, Cary-Blair, Stuart, buffered glycerol-saline) and placed into tubes containing medium so the cotton tips are covered.
Routine stool cultures are not recommended for patients who have been in the hospital for more than 3 days and the admitting diagnosis was not gastroenteritis.

Transport

Samples should be refrigerated in at 4°C before testing. When possible, samples should be tested within 48 hours after collection; otherwise freeze samples at –70°C.
Whole stool should be refrigerated and processed within 2 hours after collection. Store a portion of each stool sample frozen at below –15°C for antigen or polymerase chain reaction (PCR) testing.

Standard Diagnostic Tests

Freshly passed stool should be plated directly onto agar plates and serotypes identified by a cascade of tests.
O and H antigens are detected in independent agglutination assays using antisera that react with groups of related antigen.
Low-selective media such as MacConkey agar and deoxycholate agar and intermediate-selective media such as Salmonella-Shigella, xylose-lysine-deoxycholate, or Hektoen agars are widely used to screen for both Salmonella and Shigella species.
Salmonella grow well on rich media, such as blood agar and nutrient broth, and such media are appropriate for culture of normally sterile body fluids.
Salmonella and Shigella organisms are less inhibited by citrate than are normal fecal coliform species, and Salmonella-Shigella agar selects for growth of either organism from stool samples.
Under the microscope, salmonellae are gram-negative, short rods.
Colonies on nutrient agar are grayish, moist, translucent to opaque, and smooth.
Broth cultures are turbid and may contain a pedicle or sediment.
Selective media are available for detecting carriers and during outbreaks.
If S Typhi is suspected, the specimen should also be plated on bismuth sulfite agar, the most efficient medium for isolation. S Typhi forms black colonies on this agar (see References: Kim 2003).

The source for much of the material above on standard testing is Bopp 2003 (see References).

Useful Biochemical Tests

Biochemical reactions for distinguishing salmonellae from other Enterobacteriaceae organisms include:

Hydrogen sulfide (+): Form green color to colonies grown on blood agar; except for Salmonella Typhi, which produces little or no hydrogen sulfide
Urease (–): Unable to metabolize urea
Motility (+)
Lysine decarboxylase (+)
Ornithine decarboxylase (+):Salmonella Typhi does not decarboxylate ornithine
Gas production from glucose (+):Salmonella Typhi does not produce gas
Lactose (–): Unable to ferment lactose and produce white colonies on solid media containing lactose and neutral red (eg, MacConkey or Salmonella-Shigella agar)
Sucrose (–): Unable to ferment sucrose

Antimicrobial Susceptibility

Subtyping methods often are used for differentiating strains of common Salmonella serotypes. In the United States, all Salmonella isolates confirmed by appropriate biochemical tests should be forwarded to reference laboratories in state health departments for more exhaustive serotyping (see References: Ohl 2001, Pegues 2005, Thompson 2003).
Phenotyping methods for characterizing outbreak-associated strains and sporadic multidrug-resistant isolates include bacteriophage typing, plasmid profile analysis, antimicrobial susceptibility, and biotyping.

Additional or Specialized Diagnostic Tests

New selective chromogenic media such as CHROMagar and COMPASS agar are more specific than other selective media and lower the need for confirmatory testing and time to identification. These are increasingly being used for primary isolation and identification of clinical stool specimens.
Tetrathioneate- and selenite-base enrichment broths often are used to aid recovery of low numbers of organisms (see References: Perez 2003).
Selenite with brilliant green medium is highly Salmonella-selective and should be reserved for suspected carriers and for use in special circumstances such as outbreaks.
Rapid tests for direct detection of Salmonella using enzyme linked immunoassay, latex agglutination, PCR assays, and monoclonal antibodies have been developed and are in use in some laboratories (see References: AAP 2006).
PCR assays may become more common for identifying Salmonella once methods are standardized:

Genus-specific primers have been developed for detection of Salmonella in food samples and compared with culture methods. PCR produced results in 4 hours that perfectly matched results from cultures; investigators had no false-positive or false-negative results in this study (see References: Bansal 2006), although false-positives have been noted with PCR techniques.
A 12-hour TaqMan PCR method has been tested for detecting Salmonella in meat and may prove useful for the food industry (see References: Josefsen 2007).
Multiplex PCR methods have been developed for typing typhoidal pathogens directly from blood samples. Blinded testing of 664 Malian and Chilean Salmonella blood isolates demonstrated 100% sensitivity and specificity (see References: Levy 2008). Another multiplex assay addresses the problem of typing Salmonella Paratyphi and V_i-negative variants of S Typhi that have so rapidly emerged in Asia (see References: Ali 2008), and an additional multiplex assay has been used for simultaneously detecting five pathogenic bacteria, including Salmonella (see References: Kim 2007).

Other molecular techniques, such as detection of variable-number tandem repeats (VNTR) and multilocus VNTR analysis (MLVA), may prove useful for differentiating selected serovars. VNTR patterns distinguished isolates of Salmonella Typhimurium and S Newport that had different PFGE patterns and also identified outbreak-associated cases that shared a common PFGE pattern (see References: Witonski 2006). MLVA has been used to discriminate S Typhimurium isolates into PFGE and MLVA types in routine surveillance in Denmark (see References: Torpdahl 2007).
Genotyping techniques such as ribotyping, pulsed-field gel electrophoresis (PFGE), insertion sequence analysis, PCR fingerprinting, and multilocus sequence typing have been used in epidemiologic studies to differentiate strains within a given serotype (see References: Bender 2001, Garaizar 2002). PFGE has been standardized for public health laboratories in the United States, but the time required for these tests limits their utility.

Serologic Testing

Most clinical laboratories group Salmonella isolates by both agglutination reactions using group-specific antisera (O antigens) and biochemical tests.
Rapid immunoglobulin M antibody–based serologic tests may supplement stool culture for diagnosis of acute Salmonella infection (see References: Oracz 2003). Rapid tests in conjunction with culture are preferred because public health laboratories require cultures to do additional typing and for outbreak detection.
The Widal agglutination test for detecting Salmonella antibodies against O and H antigens is not recommended because the test lacks adequate sensitivity and specificity in most clinical settings (see References: AAP 2006).

Treatment

Nontyphoidal Salmonella

Replacement of fluid and electrolytes is the usual therapy.
Antimicrobial treatment for gastroenteritis is not recommended for uncomplicated nontyphoidal gastroenteritis or to reduce convalescent stool excretion. A recent meta-analysis showed that antimicrobial treatment did not decrease the length of illness and was associated with an increased risk of positive stool culture after 3 weeks, increased risk of relapse, and adverse drug reactions (see References: Sirinavin 2000).
Patients less than 6 months or more than 50 years of age, immunocompromised patients, and those with certain underlying conditions (eg, valvular heart disease, prosthetic vascular grafts, malignancy, uremia) are at increased risk of bacteremia and should be treated with antibiotics.

Oral or intravenous antimicrobial therapy should be administered for 48 to 72 hours or until the patient is afebrile. Treatment with an oral fluoroquinolone, trimethoprim-sulfamethoxazole, or amoxicillin is usually adequate (see References: Pegues 2005).
Treatment for immunocompromised patients employs longer regimens.
According to the American Academy of Pediatrics, duration of therapy for children varies with site of infection, host, and clinical response (see References: AAP 2006).
HIV patients receiving highly active antiretroviral therapy (HAART) have a significantly lower incidence of recurrent nontyphoidal Salmonella bacteremia than patients from the pre-HAART era. Recurrent infections among HAART patients are increasingly resistant to fluoroquinolones (see References: Hung 2007).

Bacteremia not involving endocarditis should be treated with intravenous antibiotics for 7 to 14 days; endocarditis should be treated intravenously for 6 weeks with a beta-lactam antibiotic (such as ampicillin or ceftriaxone, depending on the sensitivities of the particular strain) (see References: Pegues 2005). Localized infections may require drainage and treatment for 2 to 4 weeks with intravenous antibiotics (see References: Pegues 2005).
Multidrug-resistant Salmonella strains (eg, DT104) and strains resistant to ceftriaxone have been increasingly recognized in the United States and elsewhere (see References: CDC 2002:Outbreak of multidrug-resistant Salmonella Newport—United States, January-April 2002; Dunne 2000; Izumiya 2005; Karon 2007; Meakins 2008; Ribot 2002; White 2002). The rise of multidrug-resistant S Newport strains is worrisome because of their decreased susceptibility to ceftriaxone, a third-generation cephalosporin that is the treatment of choice for invasive salmonellosis in children (see References: Karon 2007).
A new resistance pattern in strains from southeast Asia demonstrates a reduced susceptibility to ciprofloxacin (see References: Chiu 2005; Hakanen 2005).
Prior antibiotic use increases the risk of sporadic Salmonella infections (see References: Schwartz 2002) and infections with multidrug-resistant serotypes (see References: Glynn 2004).
Analyses of 12,252 non-Typhi S enterica isolates sent to the CDC revealed a significant increase in organisms resistant to nalidixic acid in the United States from 1996 to 2003 (0.4% to 2.3%). Fluoroquinolones are commonly used to treat infections in adults, but these agents can fail in persons infected with nalixidic acid–resistant Salmonella (see References: Stevenson 2007).

Typhoid Fever (Uncomplicated Disease)

Several options are available to treat uncomplicated typhoid fever (see References: Pegues 2005).

The first line choice is oral ciprofloxacin or ofloxacin 7.5 mg/kg twice daily for 5 to 7 days.
Second line choices include chloramphenicol for 14 to 21 days, amoxicillin for 10 to 14 days, or trimethoprim-sulfamethoxazole for 10 to 14 days.

Considerations for treating fluoroquinolone-resistant Salmonella Typhi infections include the following.

For S Typhi strains that are nalidixic acid–resistant, higher doses of ciprofloxacin or ofloxacin (10 mg/kg twice daily) for 10 to 14 days should be used.
For S Typhi strains with minimum inhibitory concentrations of ciprofloxacin of 2 mcg/mL, treatment with a third-generation cephalosporin or azithromycin should be considered (see References: Threlfall 1999).
A trial comparing gatifloxacin (a relatively inexpensive new broad-spectrum methoxyfluoroquinolone) and cefixime (a drug commonly used in south Asia) revealed that gatifloxacin was more effective than cefixime for fever (faster clearance) and also had a lower overall rate of treatment failure. For Asian nations, gatifloxacin may provide therapeutic advantages that include ease of oral administration (single dose for 7 days), speed of clinical response, reduction of secondary transmission, and lower cost (see References: Pandit 2007).

Vaccines

No vaccines are available for nontyphoidal Salmonella infections. Recent research with recombinant vaccines and live attenuated vaccine vectors may provide better vaccine candidates for testing in humans (see References: Abd El Ghany 2007, Husseiny 2007, Nagy 2006, Negi 2007, Stephens 2006). Immunity and antibody responses are only partially understood, and lack of a suitable animal model has hindered vaccine development (see References: Sztein 2007).
Additional investigation of Salmonella genes may clarify which genes are likely to be better suited for vaccine development (see References: Boyle 2007). Potential new therapies have employed small molecules that can inhibit type III secretion systems in Salmonella, preventing protein secretion, invasion of epithelial cells, and enteritis (see References: Hudson 2007).
Two vaccines are available for Salmonella Typhi infections (see table below). Heat-phenol–inactivated S Typhi vaccine (Wyeth) is no longer available.
Three other typhoid vaccines have been tested but are not yet in commercial production:

A conjugate Vi vaccine has been tested in Vietnam (Vi-rEPA; fusion of Vi polysaccharide to a nontoxic recombinant Pseudomonas aeruginosa exotoxin A). A 2-dose regimen in children ages 2 to 5 was highly immunogenic and was 91% effective in preventing disease (see References: Lin 2001). The WHO has recommended its use in school-based programs in high-risk areas, and the Diseases of the Most Impoverished (DOMI) program has focused on providing updated evidence for decision making in developing countries (see References: Ochiai 2007).
M01ZH09 (S Typhi [Ty2 aroC-ssaV-] ZH9) is a live oral typhoid vaccine candidate. A single dose is well tolerated and highly immunogenic (see References: Kirkpatrick 2005).
Genetic modification of a novel live attenuated Salmonella Typhi oral vaccine candidate (CVD 909) that constitutively expresses V_idid not alter its ability to induce T-cell responses and may provide methodology for improving vaccine potency (see References: Wahid 2007). Serologic responses to S Typhi LPS and H antigen were vigorous, and additional studies are underway (see References: Tacket 2007).
A systematic review and meta-analysis of randomized controlled trials of typhoid fever vaccines has recently been published (see References: Fraser 2007).

Commercial and Candidate Vaccines for Typhoid Fever
Typhoid Vaccine	Efficacy	Administration	Adverse Reactions/Comments
Ty21a (live attenuated; Vivotif Berna Vaccine, Swiss Serum and Vaccine Institute)	43%-96%	3 or 4 oral doses taken on alternate days (4 doses in US and Canada, 3 doses elsewhere) (see References: WHO 2008)


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