CHAPTER 62: SALMONELLOSIS

Bacteria of the genus Salmonella are highly adapted for growth in both humans and animals and cause a wide spectrum of disease. The growth of serotypes Salmonella typhi and Salmonella paratyphi is restricted to human hosts, in whom these organisms cause enteric (typhoid) fever. The remaining serotypes (nontyphoidal Salmonella, or NTS) can colonize the gastrointestinal tracts of a broad range of animals, including mammals, reptiles, birds, and insects. More than 200 serotypes of Salmonella are pathogenic to humans, in whom they often cause gastroenteritis and can be associated with localized infections and/or bacteremia.

ETIOLOGY

This large genus of gram-negative bacilli within the family Enterobacteriaceae consists of two species: Salmonella enterica, which contains six subspecies, and Salmonella bongori. S. enterica subspecies I includes almost all the serotypes pathogenic for humans. Members of the seven Salmonella subspecies are classified into >2500 serotypes (serovars); for simplicity, Salmonella serotypes (most of which are named for the city where they were identified) are often used as the species designation. For example, the full taxonomic designation S. enterica subspecies enterica serotype Typhimurium can be shortened to Salmonella serotype Typhimurium or simply S. typhimurium. Serotyping is based on the somatic O antigen (lipopolysaccharide cell-wall components), the surface Vi antigen (restricted to S. typhi and S. paratyphi C), and the flagellar H antigen.

Salmonellae are gram-negative, non-spore-forming, facultatively anaerobic bacilli that measure 2–3 μm by 0.4–0.6 μm. The initial identification of salmonellae in the clinical microbiology laboratory is based on growth characteristics. Salmonellae, like other Enterobacteriaceae, produce acid on glucose fermentation, reduce nitrates, and do not produce cytochrome oxidase. In addition, all salmonellae except Salmonella gallinarum-pullorum are motile by means of peritrichous flagella, and all but S. typhi produce gas (H₂S) on sugar fermentation. Notably, only 1% of clinical isolates ferment lactose; a high level of suspicion must be maintained to detect these rare clinical lactose-fermenting isolates.

Although serotyping of all surface antigens can be used for formal identification, most laboratories perform a few simple agglutination reactions that define specific O-antigen serogroups, designated A, B, C₁, C₂, D, and E. Strains in these six serogroups cause ~99% of Salmonella infections in humans and other warm-blooded animals. Molecular typing methods, including pulsed-field gel electrophoresis, polymerase chain reaction fingerprinting, and genomic DNA microarray analysis, are used in epidemiologic investigations to differentiate Salmonella strains of a common serotype.

PATHOGENESIS

All Salmonella infections begin with ingestion of organisms, most commonly in contaminated food or water. The infectious dose ranges from 200 colony-forming units (CFU) to 10⁶ CFU, and the ingested dose is an important determinant of incubation period and disease severity. Conditions that decrease either stomach acidity (an age of <1 year, antacid ingestion, or achlorhydric disease) or intestinal integrity (inflammatory bowel disease, prior gastrointestinal surgery, or alteration of the intestinal flora by antibiotic administration) increase susceptibility to Salmonella infection.

Once S. typhi and S. paratyphi reach the small intestine, they penetrate the mucus layer of the gut and traverse the intestinal layer through phagocytic microfold (M) cells that reside within Peyer’s patches. Salmonellae can trigger the formation of membrane ruffles in normally nonphagocytic epithelial cells. These ruffles reach out and enclose adherent bacteria within large vesicles by bacterial-mediated endocytosis. This process is dependent on the direct delivery of Salmonella proteins into the cytoplasm of epithelial cells by the specialized bacterial type III secretion system. These bacterial proteins mediate alterations in the actin cytoskeleton that are required for Salmonella uptake.

After crossing the epithelial layer of the small intestine, S. typhi and S. paratyphi, which cause enteric (typhoid) fever, are phagocytosed by macrophages. These salmonellae survive the antimicrobial environment of the macrophage by sensing environmental signals that trigger alterations in regulatory systems of the phagocytosed bacteria. For example, PhoP/PhoQ (the best-characterized regulatory system) triggers the expression of outer-membrane proteins and mediates modifications in lipopolysaccharide so that the altered bacterial surface can resist microbicidal activities and potentially alter host cell signaling. In addition, salmonellae encode a second type III secretion system that directly delivers bacterial proteins across the phagosome membrane into the macrophage cytoplasm. This secretion system functions to remodel the Salmonella-containing vacuole, promoting bacterial survival and replication.

Once phagocytosed, typhoidal salmonellae disseminate throughout the body in macrophages via the lymphatics and colonize reticuloendothelial tissues (liver, spleen, lymph nodes, and bone marrow). Patients have relatively few or no signs and symptoms during this initial incubation stage. Signs and symptoms, including fever and abdominal pain, probably result from secretion of cytokines by macrophages and epithelial cells in response to bacterial products that are recognized by innate immune receptors when a critical number of organisms have replicated. Over time, the development of hepatosplenomegaly is likely to be related to the recruitment of mononuclear cells and the development of a specific acquired cell-mediated immune response to S. typhi colonization. The recruitment of additional mononuclear cells and lymphocytes to Peyer’s patches during the several weeks after initial colonization/infection can result in marked enlargement and necrosis of the Peyer’s patches, which may be mediated by bacterial products that promote cell death as well as the inflammatory response.

In contrast to enteric fever, which is characterized by an infiltration of mononuclear cells into the small-bowel mucosa, NTS gastroenteritis is characterized by massive polymorphonuclear leukocyte infiltration into both the large- and small-bowel mucosa. This response appears to depend on the induction of interleukin 8, a strong neutrophil chemotactic factor, which is secreted by intestinal cells as a result of Salmonella colonization and translocation of bacterial proteins into host cell cytoplasm. The degranulation and release of toxic substances by neutrophils may result in damage to the intestinal mucosa, causing the inflammatory diarrhea observed with nontyphoidal gastroenteritis. An additional important factor in the persistence of nontyphoidal salmonellae in the intestinal tract and the organisms’ capacity to compete with endogenous flora is the ability to utilize the sulfur-containing compound tetrathionate for metabolism in a microaerophilic environment. In the presence of intestinal inflammation, tetrathionate is generated from thiosulfate produced by epithelial cells through inflammatory cell production of reactive oxygen species.

Enteric (typhoid) fever is a systemic disease characterized by fever and abdominal pain and caused by dissemination of S. typhi or S. paratyphi. The disease was initially called typhoid fever because of its clinical similarity to typhus. In the early 1800s, typhoid fever was clearly defined pathologically as a unique illness on the basis of its association with enlarged Peyer’s patches and mesenteric lymph nodes. In 1869, given the anatomic site of infection, the term enteric fever was proposed as an alternative designation to distinguish typhoid fever from typhus. However, to this day, the two designations are used interchangeably.

EPIDEMIOLOGY

In contrast to other Salmonella serotypes, the etiologic agents of enteric fever—S. typhi and S. paratyphi serotypes A, B, and C—have no known hosts other than humans. Most commonly, food-borne or waterborne transmission results from fecal contamination by ill or asymptomatic chronic carriers. Sexual transmission between male partners has been described. Health care workers occasionally acquire enteric fever after exposure to infected patients or during processing of clinical specimens and cultures.

With improvements in food handling and water/sewage treatment, enteric fever has become rare in developed nations. Worldwide, however, there are an estimated 27 million cases of enteric fever, with 200,000–600,000 deaths annually. The annual incidence is highest (>100 cases/100,000 population) in south-central and Southeast Asia; medium (10–100 cases/100,000) in the rest of Asia, Africa, Latin America, and Oceania (excluding Australia and New Zealand); and low in other parts of the world (Fig. 62-1). A high incidence of enteric fever correlates with poor sanitation and lack of access to clean drinking water. In endemic regions, enteric fever is more common in urban than rural areas and among young children and adolescents than among other age groups. Risk factors include contaminated water or ice, flooding, food and drinks purchased from street vendors, raw fruits and vegetables grown in fields fertilized with sewage, ill household contacts, lack of hand washing and toilet access, and evidence of prior Helicobacter pylori infection (an association probably related to chronically reduced gastric acidity). It is estimated that there is one case of paratyphoid fever for every four cases of typhoid fever, but the incidence of infection associated with S. paratyphi A appears to be increasing, especially in India; this increase may be a result of vaccination for S. typhi.

Multidrug-resistant (MDR) strains of S. typhi emerged in the 1980s in China and Southeast Asia and have since disseminated widely. These strains contain plasmids encoding resistance to chloramphenicol, ampicillin, and trimethoprim—antibiotics long used to treat enteric fever. With the increased use of fluoroquinolones to treat MDR enteric fever in the 1990s, strains of S. typhi and S. paratyphi with decreased ciprofloxacin susceptibility (DCS; minimal inhibitory concentration [MIC], 0.125–0.5 μg/mL) or ciprofloxacin resistance (MIC, ≥1 μg/mL) have emerged on the Indian subcontinent, in southern Asia, and (most recently) in sub-Saharan Africa and have been associated with clinical treatment failure. Testing of isolates for resistance to the first-generation quinolone nalidixic acid detects many but not all strains with reduced susceptibility to ciprofloxacin and is no longer recommended. Strains of S. typhi and S. paratyphi producing extended-spectrum β-lactamases have emerged recently, primarily in India and Nepal.

Approximately 300 cases of typhoid and 150 cases of paratyphoid fever are reported annually in the United States. Of 1902 cases of S. typhi–associated enteric fever reported to the Centers for Disease Control and Prevention in 1999–2006, 79% were associated with recent international travel, most commonly to India (47%), Pakistan (10%), Bangladesh (10%), Mexico (7%), and the Philippines (4%). Only 5% of travelers diagnosed with enteric fever had received S. typhi vaccine. Overall, 13% of S. typhi isolates in the United States were resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole (TMP-SMX), and the proportion of DCS isolates increased from 19% in 1999 to 58% in 2006. Infection with DCS S. typhi was associated with travel to the Indian subcontinent. Of the 25–30% of reported cases of enteric fever in the United States that are domestically acquired, the majority are sporadic, but outbreaks linked to contaminated food products and previously unrecognized chronic carriers continue to occur.

CLINICAL COURSE

Enteric fever is a misnomer, in that the hallmark features of this disease—fever and abdominal pain—are variable. While fever is documented at presentation in >75% of cases, abdominal pain is reported in only 30–40%. Thus, a high index of suspicion for this potentially fatal systemic illness is necessary when a person presents with fever and a history of recent travel to a developing country.

The incubation period for S. typhi averages 10–14 days but ranges from 5 to 21 days, depending on the inoculum size and the host’s health and immune status. The most prominent symptom is prolonged fever (38.8^°–40.5^°C; 101.8^°–104.9^°F), which can continue for up to 4 weeks if untreated. S. paratyphi A is thought to cause milder disease than S. typhi, with predominantly gastrointestinal symptoms. However, a prospective study of 669 consecutive cases of enteric fever in Kathmandu, Nepal, found that the infections caused by these organisms were clinically indistinguishable. In this series, symptoms reported on initial medical evaluation included headache (80%), chills (35–45%), cough (30%), sweating (20–25%), myalgias (20%), malaise (10%), and arthralgia (2–4%). Gastrointestinal manifestations included anorexia (55%), abdominal pain (30–40%), nausea (18–24%), vomiting (18%), and diarrhea (22–28%) more commonly than constipation (13–16%). Physical findings included coated tongue (51–56%), splenomegaly (5–6%), and abdominal tenderness (4–5%).

Early physical findings of enteric fever include rash (“rose spots”; 30%), hepatosplenomegaly (3–6%), epistaxis, and relative bradycardia at the peak of high fever (<50%). Rose spots (Fig. 62-2; see also Fig. 14-9) make up a faint, salmon-colored, blanching, maculopapular rash located primarily on the trunk and chest. The rash is evident in ~30% of patients at the end of the first week and resolves without a trace after 2–5 days. Patients can have two or three crops of lesions, and Salmonella can be cultured from punch biopsies of these lesions. The faintness of the rash makes it difficult to detect in highly pigmented patients.

The development of severe disease (which occurs in ~10–15% of patients) depends on host factors (immunosuppression, antacid therapy, previous exposure, and vaccination), strain virulence and inoculum, and choice of antibiotic therapy. Gastrointestinal bleeding (10–20%) and intestinal perforation (1–3%) most commonly occur in the third and fourth weeks of illness and result from hyperplasia, ulceration, and necrosis of the ileocecal Peyer’s patches at the initial site of Salmonella infiltration (Fig. 62-3). Both complications are life-threatening and require immediate fluid resuscitation and surgical intervention, with broadened antibiotic coverage for polymicrobial peritonitis (Chap. 29) and treatment of gastrointestinal hemorrhages, including bowel resection. Neurologic manifestations occur in 2–40% of patients and include meningitis, Guillain-Barré syndrome, neuritis, and neuropsychiatric symptoms (described as “muttering delirium” or “coma vigil”), with picking at bedclothes or imaginary objects.

Rare complications whose incidences are reduced by prompt antibiotic treatment include disseminated intravascular coagulation, hematophagocytic syndrome, pancreatitis, hepatic and splenic abscesses and granulomas, endocarditis, pericarditis, myocarditis, orchitis, hepatitis, glomerulonephritis, pyelonephritis and hemolytic-uremic syndrome, severe pneumonia, arthritis, osteomyelitis, endophthalmitis, and parotitis. Up to 10% of patients develop mild relapse, usually within 2–3 weeks of fever resolution and in association with the same strain type and susceptibility profile.

Up to 10% of untreated patients with typhoid fever excrete S. typhi in the feces for up to 3 months, and 1–4% develop chronic asymptomatic carriage, shedding S. typhi in either urine or stool for >1 year. Chronic carriage is more common among women, infants, and persons who have biliary abnormalities or concurrent bladder infection with Schistosoma haematobium. The anatomic abnormalities associated with the latter conditions presumably allow prolonged colonization.

DIAGNOSIS

Because the clinical presentation of enteric fever is relatively nonspecific, the diagnosis needs to be considered in any febrile traveler returning from a developing region, especially the Indian subcontinent, the Philippines, or Latin America. Other diagnoses that should be considered in these travelers include malaria, hepatitis, bacterial enteritis, dengue fever, rickettsial infections, leptospirosis, amebic liver abscesses, and acute HIV infection (Chap. 6). Other than a positive culture, no specific laboratory test is diagnostic for enteric fever. In 15–25% of cases, leukopenia and neutropenia are detectable. Leukocytosis is more common among children, during the first 10 days of illness, and in cases complicated by intestinal perforation or secondary infection. Other nonspecific laboratory findings include moderately elevated values in liver function tests and muscle enzyme levels.

The definitive diagnosis of enteric fever requires the isolation of S. typhi or S. paratyphi from blood, bone marrow, other sterile sites, rose spots, stool, or intestinal secretions. The sensitivity of blood culture is only 40–80%, probably because of high rates of antibiotic use in endemic areas and the small number of S. typhi organisms (i.e., <15/mL) typically present in the blood. Because almost all S. typhi organisms in blood are associated with the mononuclear cell/platelet fraction, centrifugation of blood and culture of the buffy coat can substantially reduce the time to isolation of the organism but do not increase sensitivity.

Bone marrow culture is 55–90% sensitive, and, unlike that of blood culture, its yield is not reduced by up to 5 days of prior antibiotic therapy. Culture of intestinal secretions (best obtained by a noninvasive duodenal string test) can be positive despite a negative bone marrow culture. If blood, bone marrow, and intestinal secretions are all cultured, the yield is >90%. Stool cultures, although negative in 60–70% of cases during the first week, can become positive during the third week of infection in untreated patients.

Serologic tests, including the classic Widal test for “febrile agglutinins,” and rapid tests to detect antibodies to outer-membrane proteins or O:9 antigen are available for detection of S. typhi in developing countries but have lower positive predictive values than blood culture. More sensitive antigen and nucleic acid amplification tests have been developed to detect S. typhi and S. paratyphi in blood but are not yet commercially available and remain impractical in many areas where enteric fever is endemic.

TREATMENT

PREVENTION AND CONTROL

Theoretically, it is possible to eliminate the salmonellae that cause enteric fever because they survive only in human hosts and are spread by contaminated food and water. However, given the high prevalence of the disease in developing countries that lack adequate sewage disposal and water treatment, this goal is currently unrealistic. Thus, travelers to developing countries should be advised to monitor their food and water intake carefully and to strongly consider immunization against S. typhi.

Two typhoid vaccines are commercially available: (1) Ty21a, an oral live attenuated S. typhi vaccine (given on days 1, 3, 5, and 7, with a booster every 5 years); and (2) Vi CPS, a parenteral vaccine consisting of purified Vi polysaccharide from the bacterial capsule (given in a single dose, with a booster every 2 years). The old parenteral whole-cell typhoid/paratyphoid A and B vaccine is no longer licensed, largely because of significant side effects, especially fever. An acetone-killed whole-cell vaccine is available only for use by the U.S. military. The minimal age for vaccination is 6 years for Ty21a and 2 years for Vi CPS. In a recent meta-analysis of vaccines for preventing typhoid fever in populations in endemic areas, the cumulative efficacy was 48% for Ty21a at 2.5–3.5 years and 55% for Vi CPS at 3 years. Although data on typhoid vaccines in travelers are limited, some evidence suggests that efficacy rates may be substantially lower than those for local populations in endemic areas. Currently, there is no licensed vaccine for paratyphoid fever.

Vi CPS typhoid vaccine is poorly immunogenic in children <5 years of age because of T cell–independent properties. In the more recently developed Vi-rEPA vaccine, Vi is bound to a nontoxic recombinant protein that is identical to Pseudomonas aeruginosa exotoxin A. In 2- to 4-year-olds, two injections of Vi-rEPA induced higher T cell responses and higher levels of serum IgG antibody to Vi than did Vi CPS in 5- to 14-year-olds. In a two-dose trial in 2- to 5-year-old children in Vietnam, Vi-rEPA provided 91% efficacy at 27 months and 89% efficacy at 46 months and was very well tolerated. This vaccine is not yet commercially available in the United States. Efforts to improve the immunogenicity and reduce the number of doses of live attenuated oral vaccines are ongoing.

Typhoid vaccine is not required for international travel, but it is recommended for travelers to areas where there is a moderate to high risk of exposure to S. typhi, especially those who are traveling to southern Asia and other developing regions of Asia, Africa, the Caribbean, and Central and South America and who will be exposed to potentially contaminated food and drink. Typhoid vaccine should be considered even for persons planning <2 weeks of travel to high-risk areas. In addition, laboratory workers who deal with S. typhi and household contacts of known S. typhi carriers should be vaccinated. Because the protective efficacy of vaccine can be overcome by the high inocula that are commonly encountered in food-borne exposures, immunization is an adjunct and not a substitute for the avoidance of high-risk foods and beverages. Immunization is not recommended for adults residing in typhoid-endemic areas or for the management of persons who may have been exposed in a common-source outbreak.

Enteric fever is a notifiable disease in the United States. Individual health departments have their own guidelines for allowing ill or colonized food handlers or health care workers to return to their jobs. The reporting system enables public health departments to identify potential source patients and to treat chronic carriers in order to prevent further outbreaks. In addition, because 1–4% of patients with S. typhi infection become chronic carriers, it is important to monitor patients (especially child-care providers and food handlers) for chronic carriage and to treat this condition if indicated.

EPIDEMIOLOGY

In the United States, NTS causes ~12 million illnesses annually, and the incidence has remained relatively unchanged during the past two decades. In 2011, the incidence of NTS infection in this country was 16.5/100,000 persons—the highest rate among the 10 food-borne enteric pathogens under active surveillance. Five serotypes accounted for more than half of U.S. infections during the period 1996–2006: typhimurium (23%), enteritidis (16%), newport (10%), heidelberg (6%), and javiana (5%).

The incidence of nontyphoidal salmonellosis is highest during the rainy season in tropical climates and during the warmer months in temperate climates—a pattern coinciding with the peak in food-borne outbreaks. Rates of morbidity and mortality associated with NTS are highest among the elderly, infants, and immunocompromised individuals, including those with hemoglobinopathies, HIV infection, or infections that cause blockade of the reticuloendothelial system (e.g., bartonellosis, malaria, schistosomiasis, histoplasmosis).

Unlike S. typhi and S. paratyphi, whose only reservoir is humans, NTS can be acquired from multiple animal reservoirs. Transmission is most commonly associated with food products of animal origin (especially eggs, poultry, undercooked ground meat, and dairy products), fresh produce contaminated with animal waste, and contact with animals or their environments.

S. enteritidis infection associated with chicken eggs emerged as a major cause of food-borne disease during the 1980s and 1990s. S. enteritidis infection of the ovaries and upper oviduct tissue of hens results in contamination of egg contents before shell deposition. Infection is spread to egg-laying hens from breeding flocks and through contact with rodents and manure. The percentage of Salmonella outbreaks attributed to eggs has declined significantly in the United States, from 33% during 1998–1999 to 15% during 2006–2008. This decrease probably reflects the impact of the coordinated public health response to S. enteritidis infection attributed to eggs, including improved on-farm control measures, refrigeration, and education of consumers and food-service workers. Transmission via contaminated eggs can be prevented by cooking eggs until the yolk is solidified and pasteurizing egg products. Despite these control efforts, outbreaks of S. enteritidis infection associated with shell eggs continue to occur. In 2010, a national outbreak of S. enteritidis infection resulted in more than 1900 reported illnesses and the recall of 500 million eggs.

Centralization of food processing and widespread food distribution have contributed to the increased incidence of NTS in developed countries. Manufactured foods to which recent Salmonella outbreaks have been traced include peanut butter; milk products, including infant formula; and various processed foods, including packaged breakfast cereal, salsa, frozen prepared meals, and snack foods. Large outbreaks have also been linked to fresh produce, including alfalfa sprouts, cantaloupe, mangoes, papayas, and tomatoes; these items become contaminated by manure or water at a single site and then are widely distributed.

An estimated 6% of sporadic Salmonella infections in the United States are attributed to contact with reptiles or amphibians, especially iguanas, snakes, turtles, and lizards. Reptile-associated Salmonella infection more commonly leads to hospitalization and more frequently involves children, including infants, than do other Salmonella infections. Other pets, including African hedgehogs, birds, rodents, baby chicks, ducklings, dogs, and cats, are also potential sources of NTS.

Increasing antibiotic resistance in NTS species is a global problem and has been linked to the widespread use of antimicrobial agents in food animals and especially in animal feed. In the early 1990s, S. typhimurium definitive phage type 104 (DT104), characterized by resistance to at least five antibiotics (ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracyclines; R-type ACSSuT), emerged worldwide. In 2010, resistance to at least ACSSuT was reported in 4.3% of NTS isolates, including 18.6% of S. typhimurium isolates. Acquisition is associated with exposure to ill farm animals and to various meat products, including uncooked or undercooked ground beef. Although probably no more virulent than susceptible S. typhimurium strains, DT104 strains are associated with an increased risk of bloodstream infection and hospitalization. DCS and trimethoprim-resistant DT104 strains are emerging, especially in the United Kingdom.

Because of increased resistance to conventional antibiotics such as ampicillin and TMP-SMX, extended-spectrum cephalosporins and fluoroquinolones have emerged as the agents of choice for the treatment of MDR NTS infections. In 2010, 2.8% of all NTS strains were resistant to ceftriaxone. Most ceftriaxone-resistant isolates were from children <18 years of age, in whom ceftriaxone is the antibiotic of choice for treatment of invasive NTS infection. These strains contained plasmid-encoded AmpC β-lactamases that were probably acquired by horizontal genetic transfer from Escherichia coli strains in food-producing animals—an event linked to the widespread use of the veterinary cephalosporin ceftiofur.

Over the last decade, strains of DCS NTS (MIC, 0.125–1 μg/mL) have emerged and have been associated with delayed response and treatment failure. In 2009, 2.4% of NTS isolates in the United States were DCS or resistant to ciprofloxacin. These strains have diverse resistance mechanisms, including single and multiple mutations in the DNA gyrase genes gyrA and gyrB and plasmid-encoded quinolone resistance determinants that may not be reliably detected by nalidixic acid susceptibility testing. In 2012, the U.S. Clinical Laboratory Standards Institute proposed a lower ciprofloxacin susceptibility breakpoint (≥0.06 μg/mL) for all Salmonella species to address this issue. Currently, because commercial test systems do not contain ciprofloxacin concentrations low enough to allow use of these breakpoints, laboratories need to determine the ciprofloxacin MIC by Etest or another alternative method.

CLINICAL MANIFESTATIONS

Gastroenteritis

Infection with NTS most often results in gastroenteritis indistinguishable from that caused by other enteric pathogens. Nausea, vomiting, and diarrhea occur 6–48 h after the ingestion of contaminated food or water. Patients often experience abdominal cramping and fever (38–39^°C; 100.5–102.2^°F). Diarrheal stools are usually loose, nonbloody, and of moderate volume. However, large-volume watery stools, bloody stools, or symptoms of dysentery may occur. Rarely, NTS causes pseudoappendicitis or an illness that mimics inflammatory bowel disease.

Gastroenteritis caused by NTS is usually self-limited. Diarrhea resolves within 3–7 days and fever within 72 h. Stool cultures remain positive for 4–5 weeks after infection and—in rare cases of chronic carriage (<1%)—for >1 year. Antibiotic treatment usually is not recommended and may prolong fecal carriage. Neonates, the elderly, and immunosuppressed patients (e.g., transplant recipients, HIV-infected persons) with NTS gastroenteritis are especially susceptible to dehydration and dissemination and may require hospitalization and antibiotic therapy. Acute NTS gastroenteritis was associated with a threefold increased risk of dyspepsia and irritable bowel syndrome at 1 year in a study from Spain.

Bacteremia and endovascular infections

Up to 8% of patients with NTS gastroenteritis develop bacteremia; of these, 5–10% develop localized infections. Bacteremia and metastatic infection are most common with Salmonella choleraesuis and Salmonella dublin and among infants, the elderly, and immunocompromised patients, especially those with HIV infection. NTS endovascular infection should be suspected in high-grade or persistent bacteremia, especially with preexisting valvular heart disease, atherosclerotic vascular disease, prosthetic vascular graft, or aortic aneurysm. Arteritis should be suspected in elderly patients with prolonged fever and back, chest, or abdominal pain developing after an episode of gastroenteritis. Endocarditis and arteritis are rare (<1% of cases) but are associated with potentially fatal complications, including valve perforation, endomyocardial abscess, infected mural thrombus, pericarditis, mycotic aneurysms, aneurysm rupture, aortoenteric fistula, and vertebral osteomyelitis.

In some areas of sub-Saharan Africa, NTS may be among the most common causes—or even the most common cause—of bacteremia in children. NTS bacteremia among these children is not associated with diarrhea and has been associated with nutritional status and HIV infection.

Localized infections

Intraabdominal infections

Intraabdominal infections due to NTS are rare and usually manifest as hepatic or splenic abscesses or as cholecystitis. Risk factors include hepatobiliary anatomic abnormalities (e.g., gallstones), abdominal malignancy, and sickle cell disease (especially with splenic abscesses). Eradication of the infection often requires surgical correction of abnormalities and percutaneous drainage of abscesses.

Central nervous system infections

NTS meningitis most commonly develops in infants 1–4 months of age. It often results in severe sequelae (including seizures, hydrocephalus, brain infarction, and mental retardation), with death in up to 60% of cases. Other rare central nervous system infections include ventriculitis, subdural empyema, and brain abscesses.

Pulmonary infections

NTS pulmonary infections usually present as lobar pneumonia, and complications include lung abscess, empyema, and bronchopleural fistula formation. The majority of cases occur in patients with lung cancer, structural lung disease, sickle cell disease, or glucocorticoid use.

Urinary and genital tract infections

Urinary tract infections caused by NTS present as either cystitis or pyelonephritis. Risk factors include malignancy, urolithiasis, structural abnormalities, HIV infection, and renal transplantation. NTS genital infections are rare and include ovarian and testicular abscesses, prostatitis, and epididymitis. Like other focal infections, both genital and urinary tract infections can be complicated by abscess formation.

Bone, joint, and soft tissue infections

Salmonella osteomyelitis most commonly affects the femur, tibia, humerus, or lumbar vertebrae and is most often seen in association with sickle cell disease, hemoglobinopathies, or preexisting bone disease (e.g., fractures). Prolonged antibiotic treatment is recommended to decrease the risk of relapse and chronic osteomyelitis. Septic arthritis occurs in the same patient population as osteomyelitis and usually involves the knee, hip, or shoulder joints. Reactive arthritis can follow NTS gastroenteritis and is seen most frequently in persons with the HLA-B27 histocompatibility antigen. NTS rarely can cause soft tissue infections, usually at sites of local trauma in immunosuppressed patients.

DIAGNOSIS

The diagnosis of NTS infection is based on isolation of the organism from freshly passed stool or from blood or another ordinarily sterile body fluid. All salmonellae isolated in clinical laboratories should be sent to local public health departments for serotyping. Blood cultures should be done whenever a patient has prolonged or recurrent fever. Endovascular infection should be suspected if there is high-grade bacteremia (>50% of three or more positive blood cultures). Echocardiography, computed tomography (CT), and indium-labeled white cell scanning are used to identify localized infection. When another localized infection is suspected, joint fluid, abscess drainage, or cerebrospinal fluid should be cultured, as clinically indicated.

TREATMENT

PREVENTION AND CONTROL

Despite widespread efforts to prevent or reduce bacterial contamination of animal-derived food products and to improve food-safety education and training, recent declines in the incidence of NTS in the United States have been modest compared with those of other food-borne pathogens. This observation probably reflects the complex epidemiology of NTS. Identifying effective risk-reduction strategies requires monitoring of every step of food production, from handling of raw animal or plant products to preparation of finished foods. Contaminated food can be made safe for consumption by pasteurization, irradiation, or proper cooking. All cases of NTS infection should be reported to local public health departments because tracking and monitoring of these cases can identify the source(s) of infection and help authorities anticipate large outbreaks. Lastly, the prudent use of antimicrobial agents in both humans and animals is needed to limit the emergence of MDR Salmonella.