Salmonellosis

Last updated January 28, 2009

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. 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: FDA 2007: Salmonella).
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). NARMS 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: FDA 2007: Salmonella).

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 48.4% in 2005 (see References: FDA 2007: Salmonella); also 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 resulted from:

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).

In 2009, a large outbreak related to contaminated peanut products continued from late in the previous year and is ongoing:

The outbreak began in October 2008 and has caused more than 500 cases and a suspected 8 deaths in 43 states through January 2009; a single case has been reported in Canada (see References: CDC 2009: Investigation update: outbreak of Salmonella Typhimurium infections, 2008-2009). The outbreak strain of Salmonella Typhimurium was traced to a peanut butter processing plant in Georgia that supplied peanut butter and peanut paste to institutions, food service providers, food manufacturers, and distributors. More than 390 products made by scores of companies have been recalled because they may have been made with recalled peanut butter or paste (see References: FDA 2009: Recall of products containing peanut butter).

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)	—Side effects are uncommon. —Booster is recommended every 5 yr (US) or 7 yr (Canada). In Australia and Europe, repeat 3-dose series every 3 yr for those in endemic areas and every year for those traveling from nonendemic to endemic countries (see References: WHO 2008). —Vaccine manufacturer recommends that Ty21a not be administered to children less than 6 years of age. —The vaccine also conferred significant protection against paratyphoid B fever in two recent trials in children aged 5 to 19 yr (see References: Levine 2007).
ViCPS (capsular polysaccharide vaccine; Typhim Vi, Pasteur-Merieux)	77% at 21 mo;55% after 3 yr	One 0.5-mL IM dose	—Side effects include fever (0%-1%), headache (1.5%-3%), local erythema or induration at injection site (7%). —Booster can be given every 2 yr. WHO recommends revaccination every 3 yr to maintain protection (see References: WHO 2008). —Not for use in children <2 yr.
Vi-rEPA (polysaccharide fusion with nontoxic recombinant toxin)	89% after 46 months	Two 0.5-mL IM doses administered 6 weeks apart	—Not yet in commercial production (see References: Lin 2001). —One trial showed that the cumulative efficacy of this vaccine was greater than that of either Ty21a or ViCPS (see References: Fraser 2007).
M01ZH09 (live oral-vaccine)		Single oral dose	—Experimental vaccine, not yet in commercial production. —Side effects include headache, mild gastrointestinal symptoms (see References: Kirkpatrick 2005).
Abbreviations: IM, intramuscular.

Travel Implications

Travelers should take two basic precautions when traveling to high-risk areas, such as southeast Asia and the Indian subcontinent:

Avoid risky foods and drinks.
Get vaccinated against typhoid fever.

Travelers should be aware that foodborne inoculums can overcome vaccine efficacy, so they should be careful when eating or drinking in endemic areas (see References: AAP 2006; Freedman 2006).
Because of the presence of quinolone-resistant strains of Salmonella Typhi in developing countries, mass immunization may be useful for control of prolonged multidrug-resistant outbreaks.

Disease Prevention and Control

Infection Control Recommendations

Patients with Salmonella infection should be managed with Standard Precautions (see References: CDC/HICPAC 1996).
Contact Precautions should be added when caring for diapered or incontinent children younger than 6 years of age for the duration of illness (see References: CDC/HICPAC 1996). Contact Precautions include the following:
Place the patient in a private room, or if a private room is not available, place the patient in a room with a patient who has an active infection with the same pathogen (ie, cohort). When a private room is not available and cohorting is not possible, a spatial separation of at least 3 ft should be maintained between the infected patient and other patients and visitors.

Gloves should be worn when entering the room and removed before leaving the room; hands should be washed with an antimicrobial agent or a waterless handwashing agent immediately after removing gloves, and clean hands should not touch potentially contaminated items or environmental surfaces.
Gowns should be worn when entering the room if it is anticipated that clothing will have substantial contact with the patient, environmental surfaces, or items in the room; the gown should be removed before leaving the patient's environment.
Patient transport should be limited to essential purposes only; if the patient is transported out of the room, precautions should be maintained.
Noncritical patient-care equipment should be dedicated whenever possible. If equipment cannot be dedicated, then it should be adequately cleaned and disinfected between patients.

Public Health Prevention Measures

Control of foodborne Salmonella in the United States requires implementation of barriers to introduction and multiplication of salmonellae from farm to table.

Measures to reduce Salmonella on farms or during processing include:

Consider vaccination of feed animals. Some investigators have suggested that vaccines against Salmonella in food animals may prevent foodborne infections in people (see References: Andriaensen 2007, Selke 2007); however, implementation will require more research into better animal vaccines (see References: Boyle 2007). Vaccines for chickens (see References: Okamura 2007) and pigs (see References: Selke 2007) have shown promise in eliminating Salmonella in vivo and may eventually be used in other food animals, although the major drawback is the inability of serologic testing to distinguish vaccinated and ill animals.
Limit use of antimicrobials as growth promoters (to limit the selective pressure toward resistant organisms).
Reduce Salmonella contamination in raw meat and poultry through monitoring programs and improved processing practices. (USDA has launched an initiative to reduce Salmonella in raw meat and poultry products [see References: USDA/FSIS 2006: Salmonella verification sample result reporting: agency policy and use in public health protection]). Compounds added to sprayers and chillers can reduce bacterial contamination. Peracetic acid mixture (a combination of peracetic acid and hydrogen peroxide) has been approved as an antimicrobial for use in poultry chillers. At 85 parts per million, peracetic acid mixture reduced Salmonella-positive carcasses exiting the chiller by 92% (see References: Bauermeister 2008). Thermal inactivation (see References: Juneja 2007), bacteria (probiotics) (see References: Wassenaar 2008), and bacteriophage treatment (see References: Borie 2008) may represent other control strategies.
The FDA has introduced measures to reduce contamination in lettuce (FDA 2006: Lettuce safety initiative) and tomatoes (see References: FDA 2007: Tomato safety initiative). Hot water treatments have been shown to inactivate Salmonella in mung bean seeds, possibly providing an effective decontamination method for seeds intended for sprout production (see References: Bari 2008).
Consider the use of irradiation to eradicate organisms from foods of animal origin or contaminated fresh produce.

Measures to reduce risk in commercial food establishments (or in the home or in home food preparation) include:

Maintain good personal hygiene by food handlers.
Implement time-temperature standards for food handling.
Prohibit serving of raw or uncooked eggs.
Use pasteurized eggs for recipes requiring bulk-pooled eggs in food for nursing homes and hospitals.
Avoid cross-contamination of food items.
Assure that food handlers do not work when they have gastrointestinal symptoms.
Wash hands after handling baby poultry, reptiles, or pets (see References: CDC 2007: Peep, chirp, quack).
Physicians should maintain a high index of suspicion as well as taking the following measures:

Order the appropriate laboratory tests. This is especially critical with the increasing levels of Salmonella Paratyphi infections and antimicrobial-resistant infections among travelers (see References: Gupta 2008).
Report positive culture results to appropriate public health officials.

For prevention of Salmonella Typhi in developing countries, safe drinking water and effective sewage treatment can reduce the burden of typhoid fever; however, resources to accomplish this are lacking in many areas of the world.

References

AAP. Salmonella infections. In: Pickering LK, Baker CJ, Long SS, et al, eds: Redbook: 2006 Report of the committee on infectious diseases. Ed 27. Elk Grove Village, IL: American Academy of Pediatrics, 2006:579-84

Aarestrup FM, Hendriksen RS, Lockett J, et al. International spread of multidrug-resistant Salmonella Schwarzengrund in food products. Emerg Infect Dis 2007 May;13(5):726-31 [Full text]

Abd El Ghany M, Jansen A, Clare S, et al. Candidate live, attenuated Salmonella enterica serotype Typhimurium vaccines with reduced fecal shedding are immunogenic and effective oral vaccines. Infect Immun 2007 Apr;75(4):1835-42 [Abstract]

Ackers ML, Puhr ND, Tauxe, et al. Laboratory-based surveillance of Salmonella serotype Typhi infections in the United States: antimicrobial resistance on the rise. JAMA 2000 May 24;283(20):2668-73 [Full text]

Aguado JM, Ramos JM, Carcia-Corbeira P, et al.The clinical spectrum of focal infection due to nontyphoidal Salmonella: 32 years' experience [in Spanish]. Med Clin (Barc) 1994 Sep 17;103(8):293-8 [Abstract]

Ali A, Haque A, Haque A, et al. Multiplex PCR for differential diagnosis of emerging typhoidal pathogens directly from blood samples. Epidemiol Infect 2008 (published online Apr 16) [Abstract]

Altekruse SF, Bauer N, Chanlongbutra A, et al. Salmonella Enteritidis in broiler chickens, United States, 2000-2005. Emerg Infect Dis 2006 Dec;12(12):1848-52 [Full text]

AMA, ANA, CDC, CFSAN, FSIS. Diagnosis and management of foodborne illnesses: a primer for physicians and other health care professionals. MMWR 2004 Apr 16;53(RR4):1-35 [Full text]

Andriaensen C, De Greve H, Tian JQ, et al.A live Salmonella enterica serovar Enteritidis vaccine allowing serological differentiation between vaccinated and infected animals. Infect Immun 2007 May;75(5):2461-8 [Abstract]

Bansal NS, Gray V, McDonell F. Validated PCR assay for the routine detection of Salmonella in food. J Food Prot 2006 Feb;69(2):282-7 [Abstract]

Bari ML, Inatsu Y, Isobe S, et al. Hot water treatments to inactivate Escherichia coli O157:H7 and Salmonella in mung bean seeds. J Food Prot 2008 Apr;71(4):830-4 [Abstract]

Bauermeister LJ, Bowers JWJ, Townsend JC, et al. Validating the efficacy of peracetic acid mixture as an antimicrobial in poultry chillers. J Food Prot 2008 Jun;71(6):1119-22 [Abstract]

Beers MH, Berkow R, Bogin RM, et al. Inflammatory bowel diseases. In: Beers MH, Berkow R, Bogin, et al: The Merck Manual of Diagnosis and Therapy, Ed 18. Whitehouse Station, NJ: Merck Research Laboratories, 2006, pp 149-59

Bender JB, Hedberg CW, Boxrud DJ, et al. Use of molecular subtyping in surveillance for Salmonella enterica serotype Typhimurium. N Engl J Med 2001 Jan 18;344(3):189-95 [Abstract]

Bernstein N, Sela S, Neder-Levon S. Assessment of contamination potential of lettuce by Salmonella enterica serovar Newport added to the plant growing medium. J Food Prot 2007 Jul;70(7):1717-22 [Abstract]

Bialka KL, Demirci A. Efficacy of aqueous ozone for the decontamination of Escherichia coli O157:H7 and Salmonella on raspberries and strawberries. J Food Prot 2007 May;70(5):1088-92 [Abstract]

Bialka KL, Demirci A. Utilization of gaseous ozone for the decontamination of Escherichia coli O157:H7 and Salmonella on raspberries and strawberries. J Food Prot 2007 May;70(5):1093-8 [Abstract]

Bopp CA, Brenner FW, Fields PI, et al. Escherichia, Shigella, and Salmonella. In: Murray PR, et al; Manual of Clinical Microbiology. Ed 8. Washington, DC: ASM Press 2003:654-671

Borie C, Albala I, Sanchez P, et al. Bacteriophage treatment reduces Salmonella colonization of infected chicken. Avian Dis 2008 Mar;52(1):64-7 [Abstract]

Boyle EC, Bishop JL, Grassl GA, et al. Salmonella: from pathogenesis to therapeutics. J Bacteriol 2007 Mar;189(5):1489-95 [Full text]

Brandl MT, Amundson R. Leaf age as a risk factor in contamination of lettuce with Escherichia coli O157:H7 and Salmonella enterica. Appl Environ Microbiol 2008 Apr;74(8):2298-306 [Abstract]

Brenner FW, Villar RG, Angulo FJ, et al. Salmonella nomenclature. J Clin Microbiol 2000 Jul;38(7):2465-7 [Full text]

Cahill SM, Wachsmuth IK, Costarrica Mde L, et al. Powdered infant formula as a source of Salmonella infection in infants. Clin Infect Dis 2008 Jan 15;46(2):268-73 [Abstract]

CDC. Guidelines for specimen collection. Foodborne Outbreak Response and Surveillance Unit 2003. [Full text]

CDC. Human salmonellosis associated with animal-derived pet treats—United States and Canada, 2005. MMWR 2006 Jun 30;55(25):702-5 [Full text]

CDC. Investigation of outbreak of human infections caused by Salmonella I 4,[5], 12:i:- 2007 Oct 29 [Full text]

CDC. Investigation of outbreak of infections caused by Salmonella Agona. 2008 May 13 [Full text]

CDC. Investigation of outbreak of infections caused by Salmonella Saintpaul. 2008 Aug 28 [Full text]

CDC. Investigation update: outbreak of infections caused by Salmonella Litchfield. 2008 Apr 2 [Full text]

CDC. Investigation update: outbreak of Salmonella Typhimurium infections, 2008-2009. 2009 Jan 26 [Full text]

CDC. Multistate outbreak of human Salmonella infections associated with exposure to turtles—United States, 2007-2008. MMWR 2008 Jan 25;57(03):69-72 [Full text]

CDC. Multistate outbreak of human Salmonella infections caused by contaminated dry dog food—United States, 2006-2007. MMWR 2008 May 16;57(19):521-4 [Full text]

CDC. Multistate outbreak of Salmonella serotype Tennessee infections associated with peanut butter—United States, 2006-2007. MMWR 2007 Jun 1;56(21):521-4 [Full text]

CDC. Multistate outbreak of Salmonella serotype Typhimurium infections associated with drinking unpasteurized milk—Illinois, Indiana, Ohio, and Tennessee, 2002-2003. MMWR 2003 Jul 4;52(26):613-5 [Full text]

CDC. Multistate outbreaks of Salmonella infections associated with raw tomatoes eaten in restaurants—United States, 2005-2006. MMWR 2007 Sep 7;56(35):909-11 [Full text]

CDC. Multistate outbreaks of Salmonella serotype Poona infections associated with cantaloupe from Mexico—United States and Canada, 2000-2002. MMWR 2002 Nov 22;51(46):1044-7 [Full text]

CDC. Outbreak of multidrug-resistant Salmonella enterica serotype Newport infections associated with consumption of unpasteurized Mexican-style aged cheese—Illinois, March 2006–April 2007. MMWR 2008 Apr 25;57(16):432-5 [Full text]

CDC. Outbreak of multidrug-resistant Salmonella Newport—United States, January-April 2002. MMWR 2002 Jun 28;51(25):545-8 [Full text]

CDC. Outbreak of Salmonella serotype Kottbus infections associated with eating alfalfa sprouts—Arizona, California, Colorado, and New Mexico, February-April 2001 MMWR 2002 Jan 11;51(01):7-9 [Full text]

CDC. Outbreak of Salmonella serotype Saintpaul infections associated with multiple raw produce items—United States, 2008. MMWR 2008 Aug 29;57(34):929-34 [Full text]

CDC. Outbreaks of Salmonella infections associated with eating Roma tomatoes—United States and Canada. MMWR 2005 Apr 8;54(13):325-8 [Full text]

CDC. Outbreaks of Salmonella serotype Enteritidis infection associated with eating shell eggs—United States, 1999-2001 MMWR 2003 Jan 3;51(51-52):1149-52 [Full text]

CDC. Peep, chirp, quack! Why parents should think twice before giving baby birds for Easter. 2007 Apr 5 [Full text]

CDC. Preliminary FoodNet data on the incidence of infection with pathogens transmitted commonly through food—selected sites, United States, 2003. MMWR 2004 Apr 30;53(16):338-43 [Full text]

CDC. Preliminary FoodNet data on the incidence of infection with pathogens transmitted commonly through food—10 sites, United States, 2004. MMWR 2005 Apr 15;54(14):352-6 [Full text]

CDC. Preliminary FoodNet data on the incidence of infection with pathogens transmitted commonly through food—10 states, United States, 2005. MMWR 2006 Apr 14;55(14):392-5 [Full text]

CDC. Preliminary FoodNet data on the incidence of infection with pathogens transmitted commonly through food—10 states, 2006. MMWR 2007 Apr 13;56(14):336-9 [Full text]

CDC. Preliminary FoodNet data on the incidence of infection with pathogens transmitted commonly through food—10 states, 2007. MMWR 2008 Apr 11;57(14):366-70 [Full text]

CDC. Salmonella Oranienburg infections associated with fruit salad served in health-care facilities—northeastern United States and Canada, 2006. MMWR 2007 Oct 5;56(39):1025-8 [Full text]

CDC. Salmonella serotype Enteritidis infections among workers producing poultry vaccine—Maine, November–December 2006. MMWR 2007 Aug 31;56(34):877-9 [Full text]

CDC. Salmonella surveillance: annual summary, 2003. Atlanta, GA: US Department of Health and Human Services, CDC, 2004. [Full text]

CDC. Salmonella surveillance: annual summary, 2005. Atlanta, GA: US Department of Health and Human Services, CDC, 2007 [Full text]

CDC. Salmonella Typhimurium infection associated with raw milk and cheese consumption—Pennsylvania, 2007. MMWR 2007 Nov;56(44):1161-4 [Full text]

CDC. Salmonella Wandsworth outbreak investigation, June-July 2007. 2007 Jul 11 [Full text]

CDC. Salmonellosis. Division of Bacterial and Mycotic Diseases2005. [Full text]

CDC. Salmonellosis—outbreak investigation, February 2007. Mar 7 [Full text]

CDC. Summary of notifiable diseases—United States, 2005. MMWR 2007 Mar 30;54(53):2-92 [Full text]

CDC. Summary of notifiable diseases—United States, 2006. MMWR 2008 Mar 21;54(53):1-94 [Full text]

CDC. Three outbreaks of Salmonellosis associated with baby poultry from three hatcheries—United States, 2006. MMWR 2007 Mar 30;56(12):273-6 [Full text]

CDC. Turtle-associated salmonellosis in humans—United States, 2006-2007. MMWR 2007 Jul 6;56(26):649-52 [Full text]

CDC. Typhoid fever. 2005 [Full text]

CDC/HICPAC. Recommendations for isolation precautions in hospitals. Am J Infect Control 1996;24(1):24-52 [Full text]

CDPHE (Colorado Department of Public Health and Environment). Alamosa water tests positive for Salmonella. 2008 Mar 24 [Full text]

Celum CL, Chaisson RE, Rutherford GW, et al. Incidence of salmonellosis in patients with AIDS. J Infect Dis 1987 Dec;156(6):998-1002 [Listing]

Chicago Department of Public Health. City health dept continues investigation of food borne illnesses: reports of illness slowing down considerably. 2007 Aug 8 [Full text]

Chitnis S, Chitnis V, Hemvani N, et al. Ciprofloxacin therapy for typhoid fever needs reconsideration. J Infect Chemother 2006 Dec;12(6):402-4 [Abstract]

Chiu CH, Chen HL, Kao LS, et al. Variant Salmonella genomic island 1 antibiotic resistance gene clusters in Salmonella enterica serovar Derby isolates from humans in Taiwan. J Antimcrob Chemother 2007 Feb;59(2):325-6 [Abstract]

Chiu CH, Su LH, Chu C. Salmonella enterica serotype choleraesuis: epidemiology, pathogenesis, clinical disease, and treatment. Clin Microbiol Rev 2004 Apr;17(2):311-22 [Full text]

Chiu CH, Tang P, Chu C, et al.The genome sequence of Salmonella enterica serovar Choleraesuis, a highly invasive and resistant zoonotic pathogen. Nucleic Acids Res 2005;33(5):1690-8 [Full text]

Chiu CH, Wu TL, Su LH, et al. The emergence in Taiwan of fluoroquinolone resistance in Salmonella enterica serotype choleraesuis. N Engl J Med 2002 Feb 7;346(6):413-9 [Full text]

Choi SH, Woo JH, Lee JE, et al. Increasing incidence of quinolone resistance in human non-typhoid Salmonella enterica isolates in Korea and mechanisms involved in quinolone resistance. J Antimicrob Chemother 2005;56(6):1111-4 [Full text]

Cloeckaert A, Praud K, Doublet B, et al. Variant Salmonella genomic island 1-L antibiotic resistance gene cluster in Salmonella enterica serovar Newport. Antimicrob Agents Chemother 2006 Nov;50(11):3944-6 [Abstract]

Collier-Hyams LS, Zeng H, Sun J, et al. Cutting edge: Salmonella AvrA effector inhibits the key proinflammatory, anti-apoptotic NF-kappa beta pathway. J Immunol 2002 Sep 15;169(6):2846-50 [Full text]

Delarocque-Astagneau E, Bouillant C, Vaillant V, et al. Risk factors for the occurrence of sporadic Salmonella enterica serotype Typhimurium infections in children in France: a national case-control study. Clin Infect Dis 2000 Aug;31(2):488-92 [Abstract]

Dunn EF, Fey PD, Kludt P, et al. Emergence of domestically acquired ceftriaxone-resistant Salmonella infections associated with AmpC beta-lactamase. JAMA 2000 Dec 27;284(24):3151-6 [Full text]

DuPont HL. The growing threat of foodborne bacterial enteropathogens of animal origins. Clin Infect Dis 2007 Nov 15;45(10):1353-61 [Abstract]

FDA. Human health hazards associated with turtles: information for regulators and public health educators. 2005 Jul 5 [Full text]

FDA. Lettuce safety initiative. 2006 Aug 23 [Full text]

FDA. Recall of products containing peanut butter: Salmonella Typhimurium. 2009 Jan 26 [Full text]

FDA. Salmonella. In: NARMS retail meat annual report, 2005. Sep 2007 [Full text]

FDA. Tomato safety initiative. 2007 Jun 12 [Full text]

Fierer J, Krause M, Tauxe R, et al. Salmonella Typhimurium bacteremia: Association with the virulence plasmid. J Infect Dis 1992;166(3):639-42 [Abstract]

Fraser A, Paul M, Goldberg E, et al. Typhoid fever vaccines: systematic review and meta-analysis of randomized controlled trials. Vaccine 2007 Nov 7;25(45):7848-57 [Abstract]

Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med 2006 Jan 12;354(2):119-30 [Full text]

Garaizar J, Porwollik S, Escheita A, et al. DNA microarray-based typing of an typical monophasic Salmonella enterica serovar. J Clin Microbiol 2002 Jun;40(6):2074-8 [Full text]

Glynn MK, Reddy V, Hutwagner L, et al. Prior antimicrobial agent use increases the risk of sporadic infections with multidrug-resistant Salmonella enterica serotype Typhimurium: a FoodNet case-control study, 1996-1997. Clin Infect Dis 2004 Apr 15;38(suppl 3):S227-36 [Full text]

Gourabathini P, Brandl MT, Redding KS, et al. Interactions between food-borne pathogens and protozoa isolated from lettuce and spinach. Appl Environ Microbiol 2008 Apr;74(8):2518-25 [Abstract]

Gupta SK, Medalla F, Omondi MW, et al. Laboratory-based surveillance of paratyphoid fever in the United States: travel and antimicrobial resistance. Clin Infect Dis 2008 Jun 1;46(11):1656-63 [Abstract]

Hakanen AJ, Lindgren M, Huovinen P, et al. New quinolone resistance phenomenon in Salmonella enterica: nalidixic acid-susceptible isolates with reduced fluoroquinolone susceptibility. J Clin Microbiol 2005 Nov;43(11):5775-8 [Full text]

Hedberg CW, White KE, Johnson JA, et al. An outbreak of Salmonella Enteritidis infection at a fast-food restaurant: implications for foodhandler-associated transmission. J Infect Dis 1991 Dec;164(6):1135-40 [Abstract]

Hennessy TW, Hedberg CW, Slutsker L, et al. A national outbreak of Salmonella enteritidis infections from ice cream. N Engl J Med 1996 May 16;334(20):1281-6 [Abstract]

Hennessy TW, Cheng LH, Kassenborg H, et al. Egg consumption is the principal risk factor for sporadic Salmonella serotype Heidelberg infections: a case-control study in FoodNet sites. Clin Infect Dis 2004 Apr 15;38(suppl 3):S237-43 [Abstract]

Herikstad H, Hayes P, Mokhtar M, et al. Emerging quinolone-resistant Salmonella in the United States. Emerg Infect Dis 1997 Jul-Sep;3(3):371-2 [Full text]

Herrero A, Rodicio MR, Gonzalez-Hevia MA, et al. Molecular epidemiology of emergent multidrug-resistant Salmonella enterica serotype Typhimurium strains carrying the virulence resistance plasmid pUO-StVR2. J Antimicrob Chemother 2006 Jan;57(1):39-45 [Full text]

HHS. Healthy People 2010: Objectives for improving health: Focus area 10: Food Safety [Full text]

Hong SF, Chiu CH, Chu C, et al. Complete nucleotide sequence of a virulence plasmid of Salmonella enterica serovar Dublin and its phylogenetic relationship to the virulence plasmids of serovars Choleraesuis, Enteritidis, and Typhimurium. FEMS Microbiol Lett 2008 Mar 10;282(1):39-43 [Abstract]

Hudson DL, Layton AN, Field TR, et al. Inhibition of type III secretion in Salmonella enterica serovar Typhimurium by small-molecule inhibitors. Antimicrob Agents Chemother 2007 Jul;51(7):2631-5 [Abstract]

Hung CC, Hung MN, Hsueh PR, et al. Risk of recurrent nontyphoid Salmonella bacteremia in HIV-infected patients in the era of highly active antiretroviral therapy and an increasing trend of fluoroquinolone resistance. Clin Infect Dis 2007 Sep 1;45(suppl 2):e60-7 [Full text]

Husseiny MI, Wartha F, Hensel M. Recombinant vaccine based on translocated effector proteins of Salmonella pathogenicity island 2. Vaccine 2007 Jan 2;25(1):185-93 [Abstract]

Isenberg HD, D'Amato RF. Enterobacteriaceae. In: Gorbach SL, Barlett JG, Blacklow NR, eds. Infectious diseases. Ed 3. Philadelphia: Lippincott Williams & Wilkins 2004:1662-72

Ivanoff B. Typhoid fever: global situation and WHO recommendations. In: Proceedings of the 2nd Asia-Pacific Symposium on Typhoid Fever and other Salmonellosis. Bangkok, Thailand: Infectious Disease Association of Thailand, 1994

Izumuiya H, Mori K, Kurazono T. Characterization of isolates of Salmonella enterica serovar Typhimurium displaying high-level fluoroquinolone resistance in Japan. J Clin Microbiol 2005 Oct;43(10):5074-9 [Full text]

Jones TF, Ingram LA, Cieslak PR, et al. Salmonellosis outcomes differ substantially by serotype. J Infect Dis 2008 Jul 1;198(1):109-14 [Abstract]

Josefsen MH, Krause M, Hansen F, et al. Optimization of a 12-hour TaqMan PCR-based method for detection of Salmonella bacteria in meat. Appl Environ Microbiol 2007 May;73(9):3040-8 [Abstract]

Juneja VK. Thermal inactivation of Salmonella spp in ground chicken breast or thigh meat. Int J Food Sci Technol 2007 Dec;42(12):1443-8 [Abstract]

Karon AE, Archer JR, Sotir MJ, et al. Human multidrug-resistant Salmonella Newport infections, Wisconsin, 2003-2005. Emerg Infect Dis 2007 Nov;13(11):1777-80 [Full text]

Kim AY, Rubin RH, Goldberg MB. Salmonella: pathogenesis and vaccines. In: Gorbach SL, Barlett JG, Blacklow NR, eds. Infectious diseases. Ed 3. Philadelphia: Lippincott Williams & Wilkins 2004:1673-80

Kim JS, Lee GG, Park JS, et al. A novel multiplex PCR assay for rapid and simultaneous detection of five pathogenic bacteria: Escherichia coli O157:H7, Salmonella, Staphylococcus aureus, Listeria monocytogenes, and Vibrio parahaemolyticus. J Food Prot 2007 Jul;70(7):1656-62 [Abstract]

Kimura AC, Reddy V, Marcus R, et al. Chicken consumption is a newly identified risk factor for sporadic Salmonella enterica serotype Enteritidis infections in the United States: a case-control study in FoodNet sites. Clin Infect Dis. 2004 Apr 15;38(suppl 3):S244-52 [Abstract]

Kirkpatrick BD, Tenney KM Larsson CJ, et al. The novel oral typhoid vaccine M01ZH09 is well tolerated and highly immunogenic in 2 vaccine presentations. J Infect Dis 2005Aug 1;192(3):360-6 [Abstract]

Levine MM, Ferreccio C, Black RE, et al. Ty21 a live oral typhoid vaccine and prevention of paratyphoid fever caused by Salmonella enterica serovar Paratyphi B. Clin Infect Dis 2007 Jul 15;45(suppl 1):S24-8 [Abstract]

Levings RS, Partridge SR, Djordjevic SP, et al. SGI1-K, a variant of the SGI1 genomic island carrying a mercury resistance region, in Salmonella enterica serovar Kentucky. Antimicrob Agents Chemother 2007 Jan;51(1):317-23 [Abstract]

Levy H, Diallo S, Tennant SM, et al. PCR method to identify Salmonella enterica serovars Typhi, Paratyphi A, and Paratyphi B among Salmonella isolates from the blood of patients with clinical enteric fever. J Clin Microbiol 2008 May;46(5):1861-6 [Abstract]

Lin F, Ho V, Kheim H, et al: The efficacy of a Salmonella Typhi Vi conjugate vaccine in two-to-five-year-old children. N Engl J Med 2001 Apr 26;344(17):1263-9 [Full text]

McClelland M, Sanderson KE, Speith J, et al. Complete genome sequence of Salmonella enterica serotype Typhimurium LT2. Nature 2001 Oct 25;413(8658):852-6 [Full text]

McLaughlin JB, Castrodale LJ, Gardner MJ, et al. Outbreak of multidrug-resistant Salmonella Typhimurium associated with ground beef served at a school potluck. J Food Prot 2006 Mar;69(3):666-70 [Abstract]

Meakins S, Fisher IS, Berghold C, et al. Antimicrobial drug resistance in human nontyphoidal Salmonella isolates in Europe 2000-2004: a report from the Enter-net International surveillance network. Microb Drug Resist 2008 Spring;14(1):31-5 [Abstract]

Mearin F, Perez-Oliveras M, Perello A, et al. Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology 2005 Jul;129(1):98-104 [Abstract]

Medus C, Smith KE, Bender JB, et al. Salmonella outbreaks in restaurants in Minnesota, 1995 through 2003: evaluation of the role of infected foodworkers. J Food Prot 2006 Aug;69(8):1870-8 [Abstract]

Mermin JH, Townes JM, Gerber M, et al. Typhoid fever in the United States, 1985-1994: changing risks of international travel and increasing antimicrobial resistance. Arch Intern Med 1998 Mar 23;158(6):633-8 [Full text]

Mermin J, Hutwagner L, Vugia D, et al. Reptiles, amphibians, and human Salmonella infection: a population-based, case-control study. Clin Infect Dis 2004 Apr 15;38(suppl 3):S253-61 [Abstract]

Minnesota Department of Health. 2005 gastroenteritis outbreak summary. 2007 [Full text]

Mody R. Salmonella I 4,5,12:i- associated with pot pies. FoodNet News 2008 Summer;2(3):3 [Full text]

Molbak K. Human health consequences of antimicrobial drug-resistant Salmonella and other foodborne pathogens. Clin Infect Dis 2005 Dec 1;41(11):1613-20 [Abstract]

Nagy G, Danino V, Dobrindt U, et al. Down-regulation of key virulence factors makes the Salmonella enterica serovar Typhimurium rfaH mutant a promising live-attenuated vaccine candidate. Infect Immun 2006 Oct;74(10):5914-25 [Full text]

Negi VD, Singhamahapatra S, Chakravortty D. Salmonella enterica serovar Typhimurium strain lacking pmrG-HM-D provides excellent protection against salmonellosis in murine typhoid model. Vaccine 2007 Jul 20;25(29):5315-23 [Abstract]

Ochiai RL, Acosta CJ, Agtini M, et al. The use of typhoid vaccines in Asia: the DOMI experience. Clin Infect Dis 2007 Jul 15;45(suppl 1):S34-8 [Abstract]

Ohl ME, Miller SI. Salmonella: a model for bacterial pathogenesis. Ann Rev Med 2001;52:259-74 [Full text]

Okamura M, Tachizaki H, Kubo T, et al. Comparative evaluation of a bivalent killed Salmonella vaccine to prevent egg contamination with Salmonella enterica serovars Enteritidis, Typhimurium, and Gallinarum biovar Pullorum, using 4 different challenge models. Vaccine 2007 Jun 15;25(25):4837-44 [Abstract]

Olsen SJ, Bleasdale SC, Magnano AR, et al. Outbreaks of typhoid fever in the United States 1960-1999. Epidemiol Infect 2003 Feb;130(1):13-21 [Abstract]

Oracz G, Feleszko W, Golicka D, et al. Rapid diagnosis of acute Salmonella gastrointestinal infection. Clin Infect Dis 2003 Jan 1;36(1):112-5 [Abstract]

O'Reilly CE, Bowen AB, Perez NE, et al. A waterborne outbreak of gastroenteritis with multiple etiologies among resort island visitors and residents. Clin Infect Dis 2007 Feb 15;44(4);506-12 [Full text]

Palmera-Suarez R, Garcia P, Garcia A, et al. Salmonella Kottbus outbreak in infants in Gran Canaria (Spain), caused by bottled water, August-November 2006. Eurosurveillance Weekly 2007 Jul 12;12(7):E070712.2 [Full text]

Pandit A, Arjyal A, Day JN, et al. An open randomized comparison of gatifloxacin versus cefixime for the treatment of uncomplicated enteric fever. PLoS ONE 2007 Jun 27;2(6):e542 [Full text]

Parkhill J, Dougan G, James KD, et al. Complete genome sequence of a multiple drug resistant Salmonella enterica serovar Typhi CT18. Nature 2001 Oct 25;413(6858):848-52 [Full text]

Pegues DA, Ohl ME, Miller SI. Salmonella species, including Salmonella Typhi. In: Mandell GL, Bennett JE, Dolin R: Mandell, Douglas, and Bennett's Principles and practice of infectious diseases. Ed 6. Philadelphia: Elsevier Churchill Livingstone, 2005;2:2636-54

Perez JM, Cavalli P, Roure C, et al. Comparison of four chromogenic media and Hektoen agar for detection and presumptive identification of Salmonella strains in human stools. J Clin Microbiol 2003 Mar;41(3):1130-4 [Full text]

Pokharel BM, Koirala J, Dahal RK, et al. Multidrug-resistant and extended-spectrum beta-lactamase (ESBL)–producing Salmonella enterica (serotypes Typhi and Paratyphi A) from blood isolates in Nepal: surveillance of resistance and a search for newer alternatives. Int J Infect Dis 2006 Nov;10(6);434-8 [Abstract]

Rahman M, Ahmad A, Shoma S. Decline in epidemic of multidrug resistant Salmonella Typhi is not associated with increased incidence of antibiotic-susceptible strain in Bangladesh. Epidemiol Infect 2002 Aug;129(1):29-34 [Abstract]

Ribot EM, Wierzba RK, Angula FJ, et al. Salmonella enterica serotype Typhimurium DT104 isolated from humans, United States, 1985, 1990, and 1995. Emerg Infect Dis 2002 Apr;8(4)387-91 [Full text]

Rowe B, Ward LR, Threlfall EJ. Multidrug-resistant Salmonella Typhi: a worldwide epidemic. Clin Infect Dis 1997(Jan);24(suppl 1):S106-9 [Abstract]

Scheil W, Cameron S, Dalton C, et al. A South Australian Salmonella Mbandaka outbreak investigation using a database to select controls. Aust N Z Public Health 1998 Aug;22(5):536-9 [Abstract]

Schwartz MN. Human disease caused by foodborne pathogens of animal origin. Clin Infect Dis 2002 Jun 1;34(suppl 3):S111-22 [Abstract]

Selke M, Meens J, Springer S, et al. Immunization of pigs to prevent disease in humans: construction and protective efficacy of a Salmonella Typhimurium live negative-marker vaccine. Infect Immun 2007 May;75(5):2476-83 [Abstract]

Seo KH, Valentin-Bon IE, Brackett RE. Detection and enumeration of Salmonella Enteritidis in homemade ice cream associated with an outbreak: comparison of conventional and real-time PCR methods. J Food Prot 2006 Mar;69(3):639-43 [Abstract]

Sheth A. Snack attack: multistate outbreak of Salmonella serotypes Wandsworth and Typhimurium infections associated with consumption of a puffed vegetable snack food—United Sttates, 2007. FoodNet News 2008 Summer;2(3):3 [Full text]

Shi X, Namvar A, Kostrzynska M, et al. Persistence and growth of different Salmonella serovars on pre- and postharvest tomatoes. J Food Prot 2007 Dec;70(12):2725-31 [Abstract]

Shimoni Z, Pitlik S, Leibovici L, et al. Nontyphoid Salmonella bacteremia: age-related differences in clinical presentation, bacteriology, and outcome. Clin Infect Dis 1999 Apr;28(4):822-7 [Abstract]

Sirinavin S, Garner P. Antibiotics for treating Salmonella gut infections. Cochrane Database Syst Rev 2000;93:CD001167

Skov MN, Andersen JS, Aabo S, et al. Antimicrobial drug resistance of Salmonella isolates from meat and humans, Denmark. Emerg Infect Dis 2007 Apr;13(4):638-41 [Full text]

Srikantiah P, Bodage D, Toth B, et al. Web-based investigation of multistate salmonellosis outbreak. Emerg Infect Dis 2005 Apr;11(4):610-2 [Full text]

Srikantiah P, Vafokulov S, Luby SP, et al. Epidemiology and risk factors for endemic typhoid fever in Uzbekistan. Trop Med Intern Health 2007 Jul;12(7):838-47 [Abstract]

Stephens JC, Darsley MJ, Turner AK. Stabilization of a plasmid coding for a heterologous antigen in Salmonella enterica serotype Typhi vaccine strain CVD908-htrA by using site-specific recombination. Infect Immun 2006 Jul;74(7):4383-6 [Full text]

Stevenson JE, Gay K, Barrett TJ, et al. Increase in nalidixic acid resistance among non-Typhi Salmonella enterica isolates in the United States from 1996 to 2003. Antimicrob Agents Chemother 2007 Jan;51(1):195-7 [Abstract]

Su LH, Chiu CH, Ou JT. Antimicrobial resistance in nontyphoid Salmonella serotypes: a global challenge. Clin Infect Dis 2004 Aug 15;39(4):546-51 [Abstract]

Swanson SJ, Snider C, Braden CR, et al. Multidrug-resistant Salmonella enterica serotype Typhimurium associated with pet rodents. New Engl J Med 2007 Jan 4;356(1):21-8 [Full text]

Sztein MB. Cell-mediated immunity and antibody responses elicited by attenuated Salmonella enterica serovar Typhi strains used as live oral vaccines in humans. Clin Infect Dis 2007 Jul 15;45(suppl 1):S15-9 [Abstract]

Tacket CO, Levine MM. CVD 908, CVD 908-htrA, and CVD 909 live oral typhoid vaccines: a logical progression. Clin Infect Dis 2007 Jul 15;45(suppl 1):S20-3 [Abstract]

Thomson RB, Miller JM. Specimen collection, transport, and processing: bacteriology. In: Murray PR, et al. Manual of clinical microbiology. Ed 8. Washington, DC: ASM Press, 2003:286-325

Thompson NR, Clayton DJ, Windhorst D, et al. Comparative genome analysis of Salmonella Enteritidis PT4 and Salmonella Gallinarum 287/91 provides insights into evolutionary and host adaptation pathways. Genome Res 2008 (published online Jun 26) [Abstract]

Threlfall EJ, Ward LR, Skinner JA, et al. Ciprofloxacin-resistant Salmonella Typhi and treatment failure. Lancet 1999 May 8;353(9164):1590-1 [Full text]

Todd EC. Epidemiology of foodborne diseases: a worldwide review. World Health Stat Q 1997;50(1-2):30-50 [Abstract]

Torpdahl M, Sorensen G, Lindstedt BA, et al. Tandem repeat analysis for surveillance of human Salmonella Typhimurium infections. Emerg Infect Dis 2007 Mar;13(3):388-95 [Full text]

USDA/FSIS. Progress report on Salmonella testing of raw meat and poultry products, 1998-2007. Washington, DC: US Department of Agriculture, 2008 [Full text]

USDA/FSIS. Salmonella verification sample result reporting: agency policy and use in public health protection. Fed Reg 2006;71:9772-7 [Full text]

Varma JK, Molbek K, Barrett TJ, et al. Antimicrobial-resistant nontyphoidal Salmonella is associated with excess bloodstream infections and hospitalizations. J Infect Dis 2005 Feb 15;191(4):554-61 [Abstract]

Vij V, Ailes E, Wolyniak C, et al. Recalls of spices due to bacterial contamination monitored by the US Food and Drug Administration: the predominance of salmonellae. J Food Prot 2006 Jan;69(1);233-7 [Abstract]

Voetsch AC, Angulo FJ, Rabatsky-Ehr T, et al. Laboratory practices for stool specimen culture for bacterial pathogens, including Escherichia coli O157:H7, in the FoodNet sites, 1995-2000. Clin Infect Dis 2004 Apr 15;38(suppl 3):S190-7 [Abstract]

Wahid R, Salerno-Goncalves R, Tacket CO, et al. Cell-mediated immune responses in humans after immunization with one or two doses of oral live attenuated typhoid vaccine CVD 909. Vaccine 2007 Feb 9;25(8):1416-25 [Abstract]

Wassenaar TM, Klein G. Safety aspects and implications of regulation of probiotic bacteria in food and food supplements. J Food Prot 2008 Aug;71(8):1734-41 [Abstract]

Weinberger M, Keller N. Recent trends in the epidemiology of non-typhoid Salmonella and antimicrobial resistance: the Israeli experience and worldwide review. Curr Opin Infect Dis 2005 Dec;18(6):513-21 [Abstract]

White DG, Zhao S, Simjee S, et al. Antimicrobial resistance of foodborne pathogens. Microbes Infect 2002;4(4):405-12 [Full text]

WHO. Typhoid vaccines: WHO position paper. WHO Weekly Epidemiol Rec 2008 Feb 8;83(6):49-60 [Full text]

Witonski D, Stefanova R, Ranganathan A, et al. Variable-number tandem repeats that are useful in genotyping isolates of Salmonella enterica subsp enterica serovars Typhimurium and Newport. J Clin Microbiol 2006 Nov;44(11);3849-54 [Abstract]

Woodard DL, Khakhria R, Johnson WM. Human salmonellosis associated with exotic pets. J Clin Microbiol 1997 Nov;35(11):2786-90 [Full text]

Wright JG, Tengelsen LA, Smith KE, et al. Multidrug-resistant Salmonella Typhimurium in four animal facilities. Emerg Infect Dis 2005 Aug;11(8):1235-41 [Full text]

Yokoyama E, Maruyama S, Kabeya H, et al. Prevalence and genetic properties of Salmonella enterica serovar Typhimurium definitive phage type 104 isolated from Rattus norvegicus and Rattus rattus house rats in Yokohama City, Japan. Appl Environ Microbiol 2007 Apr;73(8):2624-30 [Abstract]

Zaidi MB, McDermott PF, Fedorka-Cray P, et al. Nontyphoidal Salmonella from human clinical cases, asymptomatic children, and raw retail meats in Yucatan, Mexico. Clin Infect Dis 2006 Jan 1;42(1):21-8 [Abstract]


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