OVERVIEW: What every clinician needs to know

Pathogen name and classification

Salmonella spp., which includes the agents of typhoid fever, Salmonella typhi, paratyphi and non-typhoidal serotypes including Salmonella typhimurium and enteritidis, which cause gastroenteritis and focal infections. Prior to 1983 it was believed that these were separate species, hence they each have species names. We now know that these are all part of one species. They are classified as serologic variants based on their antigen variation in lipopolysaccharide and flagella. Though technically incorrect, clinically the species names are still widely used.

What is the best treatment?

For typhoid fever, the typical therapy for susceptible strains is an oral fluoroquinolone (ciprofloxicin 500mg or ofloxicin 400mg bid for 5-7 days). Nalidixic resistance has been used as a marker for fluoroquinolone resistance, and higher dose treatment with ciprofloxicin 750mg bid has been successful for these strains. Recently, small numbers of nalidixic acid susceptible, fluoroquinolone resistant strains have been isolated from Africa and Asia, making specific testing for fluoroquinolone resistance essential.
A reasonable alternative therapy is oral azithromycin: 1g every day for 5 days or 1g day 1 followed by 6 days of 500mg.
Ceftriaxone, cefotaxime, and oral cefixime are also alternatives.
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Despite susceptibility testing that indicates that S. typhi are susceptible to aminoglycosides and first and second generation cephalosporins, these antibiotics are clinically ineffective and should not be used.
Other alternative therapies for susceptible strains include ampicillin 1g qid, amoxicillin 1g TID, chloramphenicol 500mg qid, and trimethoprim-sulfamethoxazole 1 double strength tablet BID for 14-21 days. These agents are inexpensive, but antibiotic resistance and availability limits their use (oral chloramphenicol is not available in the United States).
Patients with persistent nausea, vomiting, diarrhea, or altered mental status should be treated with parenteral therapy with a third-generation cephalosporin or fluoroquinolone for at least 10 days or 5 days after fever is resolved.
High dose dexamethasone therapy (initial dose 3mg/kg followed by 1mg/kg every 6 hours for 48 hours) should be considered for individuals with shock, obtundation, stupor, or coma.
Chronic carriage of S. typhi can be treated with 4-6 weeks of an antibiotic. Antibiotic therapy includes treatment with oral amoxicillin, trimethoprim-sulfamethoxazole, ciprofloxacin, or norfloxacin. Removal of anatomic abnormalities, such as gallstones or kidney stones combined with antibiotic therapy may be required in the less than 20% who fail to have eradication with antibiotic therapy alone.
Non-typhoidal Salmonella gastroenteritis is usually self-limited and does not require antibiotic therapy; fluid and electrolyte replacement should be administered. Antimicrobial therapy to prevent bacteremia, which occurs in less than 5% of patients, should be considered for those younger than 3 months of age, those older than 50 years of age who have atherosclerosis because of the risk for endovascular infection, those with prosthetic devices, immunosuppression, arthritis, or other endovascular abnormalities. Such prophylaxis should be continued only during the period a patient with Salmonella gastroenteritis is febrile. Non-typhoidal Salmonella bacteremia requires parenteral therapy and a search for endovascular infection. Individuals with HIV and a first episode of bacteremia should be treated with oral therapy for 6 weeks.

How do patients contract salmonellosis, and how do I prevent spread to other patients?

Epidemiology

Salmonella typhi and paratyphi can only infect humans and, therefore, can be acquired only from ill individuals or chronic carriers who fecally contaminate food or water. In the United States, all cases are from travelers or outbreaks related to chronic carriers. The greatest risk is in travelers to South-central and Southeast Asia that have the highest incidence of typhoid fever, although Mexico and Haiti represent significant risk. The incidence in the United States is low, with less than 500 cases per year. In contrast, worldwide estimates are approximately 27 million cases of typhoid and paratyphoid fever worldwide. The incidence of typhoid fever increases with poor sanitation and lack of access to quality water supplies. The incidence is greater in endemic regions in children and young adults.
The incidence of non-typhoidal Salmonella infections continues to increase worldwide and has doubled during the last 2 decades in the United States. Non-typhoidal Salmonella, of which there are more than 2,000 serotypes, colonize many animals and can be acquired from many food sources, including meat, eggs, poultry, and a variety of fresh and processed foods. Recent outbreaks have included fresh vegetables, frozen dinners, dairy products, peanut butter, and orange juice. The second most common serotype, Salmonella enteritidis, can colonize and penetrate into the developing chicken oviduct and, hence, can be present in the egg yolk of fresh eggs, leading to recommendations to completely cook eggs.

Infection control

Hospitalized patients should be maintained on enteric precautions. Transmission to healthcare workers is unusual and low risk, although outbreaks have been reported to be related to contaminated bed linens, noncompliance with barrier precautions, and fecally incontinent institutionalized individuals.
Theoretically, with proper dietary precautions, typhoid can be prevented in most travelers. Vaccination is recommended for those traveling to endemic areas at high risk for typhoid fever, including South-central and Southeast Asia, South America, Latin America, Africa, and the Caribbean. Vaccination is not a substitute for good dietary practice, as vaccinated individuals can contract the disease. Two vaccines are commercially available, an oral and a parenteral vaccine are also available. Ty21a is an oral attenuated live vaccine given on sequential days in four doses with a booster after 5 years. It is contraindicated in pregnant women, the immunosuppressed, those on antibiotic therapy, and those younger than 6 years of age. The parenteral Vi polysaccharide vaccine is given IM with a booster every 2 years and is not administered to those younger than 2 years of age because of poor response to this type of vaccine.
Anti-infective prophylaxis is not recommended.

What host factors protect against this infection?

Both humoral- and cell-mediated immunity are required for protection against Salmonella. Humans with deficiencies in interferon-gamma and IL-12 receptor pathways are particularly susceptible to non-typhoidal Salmonellae. Those who have HIV, have received a transplant, or have a lymphoproliferative disease have increased susceptibility to Salmonellae.
HIV-infected individuals, those with low stomach acidity, including those on antacids, residents of nursing homes, neonates, those treated with TNF-alpha antagonists, persons with sickle cell disease (osteomyelitis is a one manifestation), patients who have lymphoproliferative diseases, and transplant recipients are at higher risk. Also, those with underlying TNF/IL-12 receptor defects and neutrophil defects are more susceptible.
In non-typhoidal salmonellosis, there is acute neutrophil infiltration of the bowel. This is absent in typhoid fever, and, instead, one sees enlargement of the Peyer’s Patches and recruitment of macrophages and monocytes with lymphoid enlargement and proliferation.

What are the clinical manifestations of infection with Salmonellae?

Salmonella typhi and paratyphi cause enteric fever, a syndrome associated with fever and abdominal pain. Non-typhoidal Salmonella cause gastroenteritis. Approximately 5% of patients with gastroenteritis develop bacteremia, which can lead to focal infections, particularly endovascular infections in those with atherosclerotic cardiovascular disease.

What common complications are associated with infection with Salmonellae?

Typhoidal infections can be associated with relapse. The most common complications are intestinal bleeding and perforation. Neurological complications can occur because of meningitis and other poorly understood central nervous system (CNS) phenomena.

Non-typhoidal Salmonella can cause dehydration, and toxic megacolon is a rare complication. Focal infections of the endovascular tissues can result in acute rupture and bleeding.

How should I identify Salmonella species?

Typhoid fever is diagnosed by culture of blood, bone marrow, stool, or intestinal secretions. The sensitivity of blood culture alone is low (40-80%). Culture of buffy coat or the lysis centrifugation method for culturing blood can improve sensitivity. Bone-marrow culture and examination should be performed if the diagnosis is strongly suspected. The duodenal string test is also another non-invasive culture method for isolation of S. typhi. Stool cultures in children have higher sensitivity for culture of S. typhi (60%) versus adults (27%). A number of serologic tests for S. typhi have been developed, among which the most widely used is the Widal test, but it is neither sensitive nor specific and is not recommended.
Non-typhoidal gastroenteritis is diagnosed by stool culture. Bacteremia and focal infections are diagnosed by blood cultures or direct culture of infected tissue.
Salmonellae are Gram-negative bacilli that measure 2-3 by 0.4-0.6 uM in size. They are motile and have typical Enterobacteriaceae characteristics, including fermentation of glucose, reduction of nitrates, and do not produce cytochrome oxidase.
Freshly passed stool can be cultured on low selectivity agar medium (MacConkey, deoxycholate) and intermediate selectivity medium (Salmonella-Shigella, xylose-lysine-deoxycholate, or Hektoen) used to screen for enteric pathogens. Increasingly, laboratories use selective chromogenic medium, such as CHROMagar, for primary isolation. In the case of low numbers of organisms, enrichment using tetrathionate and selenite enrichment broths can be used. The organisms can be detected on semi-selective media, such as MacConkey agar, which colorimetrically identify lactose fermentation. Less than 1% of Salmonellae ferment lactose. The differential metabolism of sugars can be used to distinguish Salmonellae serotypes. S. typhi is the only organism that does not produce gas on sugar fermentation. Commercially available polyvalent antisera can be used to identify common serotypes or groups. Because the organism is reportable to public health authorities, it can then be sent to a reference lab for further identification.
There are polymerase chain reaction (PCR)-based tests, and some are commercially available; however, none have currently replaced culture methods, and the clinical sensitivity and specificity are not known.

How do Salmonella species cause disease?

The pathogen uses intracellular entrance, survival, and replication within the phagosome as a virulence strategy. The replication of bacteria allows innate immune stimulation that leads to inflammation and disease manifestations. The bacteria sense host environments through specific environmental sensors, remodel their surface to resist innate immune killing, and modify the host through delivery of more than 50 virulence proteins using type III secretion systems, which translocate proteins across host membranes to promote bacterial entrance and phagosome remodeling.
Reorganization of the host cytoskeleton and delivery of specific effector proteins to the cytoplasm in the intestinal tract stimulates inflammatory responses that lead to neutrophil infiltration and diarrhea in the intestinal tract. In typhoidal Salmonella infection, organisms are predominately intracellular, and this allows for a chronic febrile illness that requires antibiotics with intracellular killing capacity to resolve the infection. Relapsing disease may also occur from intracellular foci.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

CDC Yellow Book Recommendations for International Travel 2012. 2012. (This is a standard reference from the US Centers for Disease Control and Prevention providing data about health risks for international travelers. It is updated every two years.)

Mandell, GL, Douglas, RG, Bennett, JE, Mandell, Gerald L., Bennett, John E., Dolin, Raphael. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 2009. (This print and online reference manual contains detailed information on the diagnosis, treatment and epidemiology of infectious diseases, and it contains more detail on treatment recommendations in the chapter Salmonella Species, Including Salmonella Typhi, 2887-2903.)

Guerrant, RL, Walker, DH, Weller, PF. “Nontyphoidal Salmonellosis”. Tropical Infectious Diseases: Principles, Pathogens and Practice (Expert Consult – Online and Print). 2011. (Contains sections related to treatment, diagnosis and epidemiology, as well as on prevention of infection by the organism.)

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Salmonella species, including S. typhi