Salmonella Infection (Salmonellosis)

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Background

Salmonellae are gram-negative motile, nonsporulating, straight-rod bacteria. The genus Salmonella is named after Daniel E. Salmon, an American veterinarian who first isolated Salmonella choleraesuis from pigs with hog cholera in 1884.[1] .

Salmonellae are intracellular facultative pathogens that may survive in variable conditions. They pose a great threat to the food industry because they are able to adapt to environmental conditions that differ significantly from those in which they normally grow. Pathogenic Salmonella species can move using peritrichal flagellum.

Salmonellae can be isolated in the microbiology laboratory using numerous low-selective media (MacConkey agar, deoxycholate agar), intermediate-selective media (Salmonella-Shigella [SS] agar, Hektoen [HE] agar), and highly selective media (selenite agar with brilliant green). Salmonellae are oxidase-negative and predominantly lactose-negative. Fewer than 1% of nontyphoidal Salmonella (NTS) isolates are lactose-positive (pink on MacConkey agar), but most produce hydrogen sulfide, which is detectable on HE or SS agar. As facultative anaerobes, they grow well both in bottles of standard automated systems for blood cultures and on culture media routinely used for urine, tissue, and respiratory cultures.[2] Individual isolates can then be distinguished with serogrouping, pulsed-field gel electrophoresis, and bacteriophage serotyping techniques.

Nomenclature and classification

The nomenclature and classification of Salmonella species have been changed and restructured multiple times. Traditionally, Salmonella species were named in accordance with the Kaufmann-White typing system, defined by different combinations of somatic O, surface Vi, and flagellar H antigens. In 2005, Salmonella enterica finally gained official approval as the type species of the genus Salmonella. The genus Salmonella also contains the species Salmonella bongori and Salmonella subterranean, which was recognized in 2005.[3]

Currently, Salmonella species have the serologically defined names appended as serovars or serotypes. For instance, the current nomenclature of Salmonella typhi is S enterica serovar Typhi. S enterica is preferred over confusing name S choleraesuis, which is also the name of a commonly isolated serotype.[4] To date, more than 2500 serovars of S enterica have been described. Certain serovars are host-restricted, while others have a broad host range.[5]

Pathophysiology

Salmonellosis is caused by all nontyphoid serotypes of the Salmonella genus except for S typhi and Salmonella paratyphi A, B, and C. Salmonellosis-causing serotypes are isolated from humans and animals, including livestock. Serotypes Salmonella Typhimurium, Salmonella enteritidis, Salmonella newport, and Salmonella heidelberg are most often responsible for food poisoning; Salmonella Cholerasuis and Salmonella Dublin also cause diarrheic diseases.[66] Although the infectious dose varies among Salmonella strains, a large inoculum is thought to be necessary to overcome stomach acidity and to compete with normal intestinal flora. Large inocula are also associated with higher rates of illness and shorter incubation periods. In general, about 106 bacterial cells are needed to cause infection. Low gastric acidity, which is common in elderly persons and among individuals who use antacids, can decrease the infective dose to 103 cells, while prior vaccination can increase the number to 109 cells.[16]

The Salmonella infection cycle starts after the ingestion of microbes. Through the stomach, the bacteria reach the small intestine. Infection with salmonellae is characterized by attachment of the bacteria by fimbriae or pili to cells lining the intestinal lumen. Salmonellae selectively attach to specialized epithelial cells (M cells) of the Peyer patches. The bacteria are then internalized by receptor-mediated endocytosis and transported within phagosomes to the lamina propria, where they are released. Once there, salmonellae induce an influx of macrophages (typhoidal strains) or neutrophils (nontyphoidal strains).

The Vi antigen of S typhi is important in preventing antibody-mediated opsonization and complement-mediated lysis. Through the induction of cytokine release and via mononuclear cell migration, S typhi organisms spread through the reticuloendothelial system, mainly to the liver, spleen, and bone marrow. Within 14 days, the bacteria appear in the bloodstream, facilitating secondary metastatic foci (eg, splenic abscess, endocarditis). In some patients, gallbladder infection leads to long-term carriage of S typhi or S paratyphi in bile and secretion to the stool.[17] As a rule, infection with nontyphoidal salmonellae generally precipitates a localized response, while S typhi and other especially virulent strains invade deeper tissues via lymphatics and capillaries and elicit a major immune response.

Virulence factors of salmonellae are complex and encoded both on the organism's chromosome and on large (34-120 kd) plasmids. Some areas of active investigation include the means by which salmonellae attach to and invade the intestine, survive within phagosomes, effect a massive efflux of electrolytes and water into the intestinal lumen, and develop drug resistance. Several Salmonella pathogenicity islands have been identified that mediate uptake of the bacteria into epithelial cells (type III secretion system [TTSS]), nonphagocytic cell invasion (Salmonella pathogenicity-island 1 [SPI-1]), and survival and replication within macrophages (Salmonella pathogenicity-island 2 [SPI-2], phoP/phoQ).

Specific anatomical sites, such as an altered urinary or biliary tract, atherosclerotic aorta, or endovascular devices may facilitate persistent focal Salmonella infection.

Epidemiology

Salmonella infection may result from direct contact with infected animals or indirect contact via their environment.

From February 1 to May 31, 2012, 22 cases of S infantis infection were reported, 20 cases in 13 US states and 2 in Canada. Epidemiologic investigations found that 83% reported dog contacts, and, of the 11 patients who recalled types of dog food, 8 reported brands produced by Diamond Pet Foods.[20]

Transmission of salmonellae to a susceptible host usually occurs via consumption of contaminated foods. The most common sources of salmonellae include beef, poultry, and eggs. By one estimate, consumption of eggshell fragments contaminated with S enteritidis was responsible for approximately 182,060 cases of enteritis in the United States in 2000. Improperly prepared fruits, vegetables, dairy products, and shellfish have also been implicated as sources of Salmonella.

Most often, meat becomes infected with Salmonella species during the production process, when bacteria that are abundant in animal intestines may transfer onto meat because of careless processing or improper hygiene.[63] Meat is a suitable environment for the growth of pathogenic Salmonella species owing to a high content of nutrients, pH of 5.5-6.5, and high water activity.

In addition, vegetables contaminated with animal fecal microbiota may constitute a reservoir for Salmonella species.[65]

In spring 2008, 1442 persons across 43 US states developed infection with S enterica serotype Saintpaul, with the same genetic fingerprint linking contaminated jalapeno and serrano peppers as a source of infection.[6] Almost any type food product could serve as a source for infection, including peanut butter, as seen during a 2008 outbreak of more than 600 cases.[7] Powdered infant formula has been implicated in two consecutive large outbreaks of S enterica serotype Agona among infants in France.[8]

Human-to-human and animal-to-human transmissions can also occur. For example, amphibian and reptile exposures are associated with approximately 74,000 Salmonella infections annually in the United States. Salmonellosis outbreaks have also been associated with handling chicks, ducklings, kittens, and hedgehogs.[9, 10, 11, 12, 13, 14] In 2007, a study of 28 Styphimurium infections identified pet rodents as a previously unrecognized source of human Salmonella infection.[15]

Frequency

United States

The incidence of Salmonella infections in the United States has been stable since 2004 but has decreased approximately 8% from 1996-1998 levels.[18] In 2007, the reported annual incidence of salmonellosis was 14.9 cases per 100,000 population.[18] The true annual burden of NTS infection in the United States is calculated to be 520 cases per 100,000 population, compared with 13.4 laboratory-confirmed cases per 100,000 population per year. This reflects an estimate of approximately 38.6 cases of NTS infection for each culture-confirmed case.[19]

In 2007, 364 Salmonella infections (5.4% of the overall reported cases) were associated with salmonellosis outbreaks, similar to the proportion in previous years. Four large multistate outbreaks of Salmonella infections that included FoodNet sites were investigated in 2007: an outbreak of S enterica serotype Tennessee infections caused by contaminated peanut butter, an outbreak of S enterica serotype I 4,5,12:i:- caused by contaminated frozen pot pies, an outbreak of S enterica serotype Wandsworth and Styphimurium infections attributed to a puffed vegetable snack, and an outbreak of S paratyphi B variant Java associated with exposure to turtles.[18]

In 2008-2009, a nationwide outbreak of S typhimurium was traced to peanut products and frozen chicken products. Because the contaminated peanuts were used to make a variety of products that were distributed across the country, this outbreak highlighted how difficult it can be to trace the source of an outbreak.[21]

Although the prevalence of Salmonella infections is highest in children, salmonellosis outbreaks are common among individuals who are institutionalized and residents of nursing homes. Approximately one case of paratyphoid fever is reported per every four of typhoid fever. Typhoid fever is increasingly associated with travel to developing countries (currently 72% of approximately 400 cases per year). Common sources of infection include India (30%), Pakistan (13%), Mexico (12%), Bangladesh (8%), Philippines (8%), and Haiti (5%).[22]

International

The incidence of salmonellosis has markedly increased in many countries; however, a paucity of good surveillance data exists. In 2000, approximately 21.6 million worldwide cases of typhoid fever caused 216,500 deaths.[23] By other estimates, a total of 26.9 million typhoid fever episodes occurred in 2010. The geographical distribution of the disease differs widely. Incidence of typhoid fever in south-central Asia, Southeast Asia, and, possibly, southern Africa was high (>100 cases per 100,000 population per year). The rest of Asia, Africa, Latin America, and Oceania (except for Australia and New Zealand) typically see intermediate rates of typhoid fever (10-100 cases per 100,000 population), while the incidence is low in the other parts of the world (< 10 cases per 100,000 population). In countries where typhoid fever is endemic, most cases of the disease occur in children aged 5-19 years and young adults.[24]

In developed countries, the disease mainly affects people who travel to endemic areas located in low- and middle-income destinations. Low- and middle-income countries are mainly affected owing to a lack of clean water and proper sanitation.

Mortality/Morbidity

Infection with nontyphoidal salmonellae typically produces a self-limiting gastroenteritis, and dehydrated patients occasionally require hospitalization. Death is rare. The mortality rate associated with S enteritidis infection outbreaks in the United States from 1985-1991 was 0.4%. Case-fatality rates were 70 times higher in nursing homes and hospitals. Mortality rates associated with typhoid fever are similarly low in the United States (< 1%), but mortality rates of 10-30% have been reported in some Asian and African countries. Between 1996 and 1999, an estimated 1.4 million NTS infections occurred in the United States, with an estimated 15,000 hospitalizations and 400 deaths annually. A related study during the same period found that 22% of people infected with NTS required hospitalization, with an annual incidence of 0.08 deaths per 100,000 population.

Development of bacteremia worsens the prognosis. In the 1990s, at Massachusetts General Hospital, 18% of 45 patients with Salmonella bacteremia died.[2]

Although uncommon, extraintestinal complications of salmonellosis caused by seeding of other organs are associated with increased mortality rates. Such complications include endocarditis, vascular infections, cholecystitis, hepatic and splenic abscesses, urinary tract infections, pneumonia or empyema, meningitis, septic arthritis, and osteomyelitis. Half of all Salmonella CNS infections are fatal.[2]

Multidrug-resistant typhoid fever in childhood is associated with increased risk of mortality, especially in infancy,[24] possibly because of the increased virulence of multidrug-resistant S typhi, as well as a higher number of circulating bacteria.[25]

Race

Salmonellosis has no racial predilection.

Sex

Salmonellosis has no sexual predilection.

Age

The pathogenicity of Salmonella species depends on the serotype and the host’s immunity.

NTS infection usually manifests as self-limited acute gastroenteritis but may also cause severe invasive infections (almost exclusively among children or immunosuppressed individuals). The incidence of salmonellosis in the United States is greatest among children younger than 5 years (61.8 per 100,000 people), with a peak among those younger than 1 year.

Infants and people older than 60 years are most susceptible and tend to have more severe infections. Infants are at a high risk of developing CNS infection due to Salmonella bacteremia. In one 4-year surveillance study, 47% of people hospitalized with NTS infections were older than 60 years.

Role of Comorbidities

In a 2001 study of 129 nonfecal Salmonella isolates at Massachusetts General Hospital, the most common risk factors were found to be corticosteroid use, malignancy, diabetes, HIV infection, prior antimicrobial therapy, and immunosuppressive therapy.[2]

Sickle cell disease, malaria, schistosomiasis, bartonellosis, and pernicious anemia have been mentioned in the literature as other comorbidities that predispose to salmonellosis.

History

Salmonella infections typically produce 1 of 3 distinct syndromes: nontyphoidal enterocolitis, nontyphoidal focal disease, or typhoid (enteric) fever.

Nontyphoidal enterocolitis

Infection with nontyphoidal salmonellae usually causes enterocolitis similar to that caused by other bacterial enteric pathogens.

The incubation period depends on the host and the inoculum is generally 6-72 hours. In most cases, stools are loose and bloodless.

In rare cases, Salmonella infections cause large-volume choleralike diarrhea or may be associated with tenesmus. The diarrhea is typically self-limiting and resolves within 3-7 days.

Fever, abdominal cramping, chills, headache, and myalgia are common. Fever usually resolves within 48 hours.

Nontyphoidal focal disease

Focal disease is due to transient or persistent bacteremia. Almost any organ can be affected, with sites of preexisting structural abnormalities being the most vulnerable.

Although postoperative NTS infections are rare, patients with malignant brain tumors who require tumor resections and receive corticosteroids are at great risk.[59]

The diagnosis of brain abscess should be considered in all cases of NTS meningitis after surgery for brain tumor.[58] Adequate drainage (if possible), early isolation of the pathogens, and control of the infection via antibiotic therapy guided by antimicrobial susceptibility testing are vital components in preventing this potentially fatal condition.[59]

Bacteremia

Approximately 5% of patients with NTS gastroenteritis develop bacteremia, and the incidence of extra-intestinal focal infection in patients with NTS bacteremia is about 40%. The organism can reach an extra-intestinal focus via blood dissemination, direct extension from the surrounding organs, and direct bacterial inoculation (eg, invasive medical procedures).[55]

Invasive Salmonella infection can develop even in previously healthy adults. Chronic Salmonella carriage is a predisposing factor for invasive infection, and influenza infection may contribute to such "breakthrough infections."[57] The diagnosis may be challenging since there may be no clear exposure or focal physical signs.[56]

Typhoid fever

The clinical course of typhoid fever varies greatly, ranging from fever with little other morbidity to marked multisystem toxemia.

About 10-15% of patients develop severe disease.[24]

In endemic regions, the diagnosis can be missed because of nonspecific features such as diarrhea, vomiting, or predominantly respiratory symptoms.

Typhoid fever typically has incubation period of 10-14 days and is usually associated with prolonged low-grade fever, dull frontal headache, malaise, myalgia, dry cough, anorexia, and nausea.

The fever may progress in a stepwise manner to become persistent and high grade by the end of second week. It can last up to 4 weeks if left untreated, followed by return to a normal temperature.

Relative bradycardia at the peak of the fever is an indicator of typhoid fever, although this finding is not universal.

Rose spots develop on the back, arms, and legs in up to 25% of cases late in the first week of fever.[24]



View Image

Rose spots on abdomen of a patient with typhoid fever due to the bacterium Salmonella typhi. Courtesy of CDC/Armed Forces Institute of Pathology, Char....

Coated tongue, alteration of bowel habits (varying from constipation in adults to diarrhea in children), tender abdomen, and hepatosplenomegaly are common symptoms of typhoid fever.

Malaise and lethargy can continue for a couple of months.

In areas where malaria or schistosomiasis is endemic, typhoid fever may have an atypical presentation.[25, 26]

Other presentations of Salmonella infection

Urolithiasis or structural abnormalities and immunosuppressive therapy predispose to Salmonella urinary tract infections.

Relapses can occur, even with appropriate therapy. In an Israeli series, 2.2% of patients experienced a bacteriologically proven relapse.[17] The relapse rate is significantly higher in immunosuppressed patients with Salmonella bacteremia.

Physical

Nontyphoidal gastroenteritis

The physical findings of nontyphoidal gastroenteritis are generally limited to nonbloody loose stool or watery diarrhea. Bloody diarrhea suggests infection with Shigella or enterohemorrhagic E coli.

Typhoid fever

Patients with typhoid fever may develop pink, blanchable, slightly raised macules (rose spots) on the chest and abdomen. However, rose spots are not diagnostic and are occasionally caused by other enteric infections.[17]

In many patients, fever is accompanied by prostration and an apathetic-lethargic state (the so-called tuphos of the ancient Greeks). In some patients, CNS symptoms, including delirium, psychosis, and focal neurological deficit, occur, without any evidence of direct CNS involvement of the infection.[27]

Headache is common and may be severe.

Abdominal tenderness (approximately 50%), mild hepatosplenomegaly (approximately 50%), and coated tongue are common in individuals with typhoid fever.

A sudden worsening of abdominal pain suggests bowel perforation.

Relative bradycardia is associated with typhoid fever but lacks specificity (also found in patients with borreliosis, malaria, or dengue fever, among others). Electrocardiographic changes, usually QT prolongation, are not uncommon but rarely evolve into a myocarditislike syndrome.[28]

While secondary pneumonia is rare, cough is common.[17]

Causes

The following were the 7 most commonly isolated Salmonella strains causing human disease reported to the US Centers for Disease Control and Prevention in 2007:[18]

Enteric fever is caused by S typhi and S paratyphi.

Complications

Nontyphoidal Salmonella species causes about 40% of cases of infective aortitis, which is characterized by high morbidity and mortality.[55]

Persistent Salmonella infection can lead to the development of other severe diseases such as inflammatory bowel disease (IBD) and cancer. The mechanisms by which Salmonella infection leads to colitis-associated colon cancer include (1) impaired intestinal mucosal barrier function via acute infection, (2) the effectors of the T3SS activating essential host cell pathways causing immune regulation disorders, and (3) Salmonella-associated dysbiosis.[54]

Laboratory Studies

Microbiology

Modern blood culture systems are 80-100% accurate in detecting bacteremia. As the disease duration increases, the sensitivity of blood cultures decreases, while the sensitivity of stool isolation increases.

Freshly passed stool is the preferred specimen for isolation of nontyphoidal Salmonella species. Since stool carriage of S typhi may be prolonged, the interpretation of positive results merits caution, and the diagnosis should be established only when accompanied by clinical findings that are typical of infection.[17]

Bone marrow aspirate and culture is superior to blood culture, since the bacterial concentration in bone marrow is 10 times that of peripheral blood. In patients who received antibiotic therapy prior to hospitalization, bone marrow aspirate may still be positive for Salmonella even if blood culture results are negative.[29]

In cases of typhoid fever, S typhi or S paratyphi may also be isolated from urine, rose spot biopsy, or gastric or intestinal secretions.

Grouping of Salmonella isolates is usually performed with polyvalent antisera specific for O and Vi antigen. S typhimurium belongs to group B; S enteritidis and S typhi belong to group D.

Numerous polymerase chain reaction (PCR)–based multiplex GI pathogen identification panels have been marketed for use with primary stool specimens. These panels allow rapid identification of Salmonella, Shigella, and Yersinia from primary stool specimens and offer substantially improved turnaround time for primary laboratory diagnosis compared with culture-based methods. Recovery of isolates from culture is still required for taxonomic classification and susceptibility testing.[62]

Salmonellosis is a reportable disease in the United States.

Hematology and chemistry

Although the WBC count is usually within the reference range in patients with salmonellosis, approximately one fourth of patients with typhoid fever are leukopenic, neutropenic, or anemic. Thrombocytopenia is neither universal nor diagnostic.

The eosinophil count and sedimentation rate are typically low. A high sedimentation rate suggests abscess formation or osteomyelitis. Eosinophilia should prompt a search for concomitant parasitic infection.[17]

Mild hepatocellular liver function abnormality is common.

Imaging Studies

Radiologic findings in salmonellosis are nonspecific, and literature reports are scarce. The explanation lies in the fact that most individuals who develop acute Salmonella infection do not seek specialized medical assistance, do not undergo radiographic or endoscopic workup, and, when necessary, are treated empirically but successfully with supportive therapy and broad-spectrum antibiotic therapy.[30]

In a group of 3 patients with Salmonella infection, CT examination by Balthazar et al (1996) showed slight (5-8 mm) symmetrical and homogenous thickening of the wall of the terminal ileum and slight (3-5 mm) circumferential thickening of the cecum and descending colon. In addition, thickening of the sigmoid colon and the wall of the rectum was seen in one case, and small regional mesenteric nodes (< 1 cm) were visualized in another case.[31]

Puylaert et al (1997) reported that ultrasonography might be helpful in differentiating infectious ileocecitis (caused by Salmonella, Yersinia, or Campylobacter) from ileocecal Crohn disease and appendicitis. Among the fairly specific findings that favor an infectious etiology include prominent haustration of cecum and right colon and symmetrical mural thickening of terminal ileum and cecum.[32]

It has been suggested that patients older than 50 years with nontyphoid Salmonella bacteremia should undergo clinical assessments such as computed tomography or magnetic resonance imaging to rule out concurrent vascular infections.[33]

Other Tests

Serological tests used in the diagnosis of enteric fever yield limited sensitivity and specificity. The Widal test is used to measure antibodies against O and H antigens of S typhi. Newer diagnostic tests (Typhidot, Tubex) allow direct detection of immunoglobulin M (IgM) antibodies against specific S typhi antigens. These tests are promising but need further evaluation in large community settings.[34]

Nested PCR using H1-d primers has been used to amplify specific genes of S typhi, with high sensitivity and specificity. This may eventually replace blood culture as the criterion standard.[35]

Medical Care

Salmonella gastroenteritis is usually a self-limiting disease. Fluid and electrolyte replacement may be indicated in severe cases. Because antibiotics do not appear to shorten the duration of symptoms and may actually prolong the duration of convalescent carriage, they are not routinely used to treat uncomplicated nontyphoidal Salmonella gastroenteritis. Current recommendations are that antibiotics be reserved for patients with severe disease or patients who are at a high risk for invasive disease .

Historically, recommended regimens for the treatment of typhoid fever included ampicillin, trimethoprim-sulfamethoxazole, or chloramphenicol. Emerging drug resistance over the past 20 years has limited the usefulness of these antibiotics. Presently, quinolone, macrolide, and third-generation cephalosporin antibiotics are preferred for empiric therapy pending sensitivities. Unfortunately, sensitivity to quinolones has been steadily declining, and these are no longer fool-proof agents for typhoid fever. A growing rate of resistance of nontyphoidal salmonella to nalidixic acid and ceftriaxone has been reported.[36]

Clinical data suggested reduced effectiveness of quinolone therapy in patients with nalidixic acid-resistant Salmonella strains.[37] A study of more than 1000 stored Salmonella isolates from Finland has confirmed earlier data that showed that resistance to nalidixic acid by means of disk diffusion is a sensitive and specific method of screening Salmonella isolates for reduced susceptibility to fluoroquinolones.[38]

Although uncommon in the United States, resistance to quinolone antibiotics among typhoidal and nontyphoidal salmonellae is increasingly common elsewhere. In one 22-year surveillance study in Spain, the prevalence of nalidixic acid resistance increased almost 80-fold to 38.5%.

In a review of US data from the National Antimicrobial Resistance Monitoring System, 58% of S typhimurium isolates isolated between 1997 and 1998 were resistant to at least one antibiotic, and 3 multidrug-resistant strains (resistant to ≥5 antibiotics) accounted for 74% of isolates.

The decline in prevalence of chloramphenicol resistance in many endemic areas has led to reconsideration of its use as an alternative to newer-generation fluoroquinolones or azithromycin.

There are widespread concerns about aplastic anemia with chloramphenicol and dysglycemia with gatifloxacin. In most developed settings, there are also cautions or specific constraints about the use of fluoroquinolones in children and pregnant or nursing mothers, because of potential cartilage toxicities; other adverse effects such as photosensitivity, electrocardiographic abnormalities, and tendinopathies largely affect elderly patients with concomitant problems such as renal impairment.[39]

Azithromycin is likely to be the preferred empirical treatment, often given together with ceftriaxone, in developed countries where chloramphenicol is usually reserved for life-threatening situations, for which no alternatives are available, and physicians are reluctant to use fluoroquinolones in children and lack easy access to gatifloxacin.[39]

In an endemic area such as Nepal, gatifloxacin is as effective as chloramphenicol in ambulatory young patients, and adherence to treatment is improved by the shorter duration and smaller number of tablets in the gatifloxacin regimen.[39]

Salmonella bacteremia is generally treated with a single bactericidal drug for 10-14 days. Given the resistance trends, life-threatening infections should be treated with both a third-generation cephalosporin and a fluoroquinolone until the susceptibilities of antimicrobial agents are known.[2]

If endocarditis or infectious arteritis is documented, urgent surgical treatment is usually necessary. Antimicrobial therapy for endovascular infections should be continued for a minimum of 6 weeks after successful surgery.

Years of therapy might be needed when surgery is not possible (eg, retained prosthetic devices, chronic bone and joint infections).[2]

For proven or possible CNS involvement, high-dose ceftriaxone would be the best choice for optimal penetration of the blood-brain barrier.[2]

Treatment of salmonella infection in pregnancy is controversial, and antibiotic therapy should be reserved for cases of invasive disease, using amoxicillin or cephalosporin.[40] Case reports describe of fetal loss in the setting of disseminated Salmonella infection.[41, 40]

Surgical Care

Typhoid fever is occasionally complicated by intestinal perforation or hemorrhage, cholecystitis, endocarditis, arteritis, osteomyelitis, or soft-tissue abscess formation, necessitating surgical intervention.

Long-term S typhi carriage (usually with the gallbladder as the reservoir) may necessitate cholecystectomy.

Splenectomy may be required for splenic abscesses.[2]

Surgical care dramatically improves the likelihood of survival in patients with endarteritis, especially that which involves abdominal aorta. A review of 148 cases from 1948-1999 found a 62% survival rate in all patients treated with combined surgical and medical therapy and a 77% survival rate in 30 patients who were able to undergo extra-abdominal bypass with construction of an axillobifemoral graft.[42, 43]

Consultations

Consultation with an infectious disease specialist should sought in cases of bacteremia, endovascular infections, CNS infections, and whenever typhoid fever is a strong possibility, as well as when antimicrobial resistance is suspected or documented.

Prevention

Currently, two typhoid vaccines are internationally and commercially available, and both have been shown to be safe and efficacious.[60]

The first is an oral vaccine based on a live attenuated S typhi Ty21a strain (Vivotif), which has been developed in two formulations: enteric coated capsules and a liquid formulation. Revaccination with Vivotif is recommended every 5 years. The second is a Vi capsular polysaccharide (Typhium Vi) vaccine, which is injectable. Revaccination with Typhium Vi is advised every 2 years.[44] Both vaccines are moderately effective, with a cumulative efficacy of approximately 70%. Protection may be much poorer in individuals who are frequently exposed to high inocula of S typhi. Neither of the above vaccines are available for children younger than 2 years.

The new and unlicensed modified conjugated Vi vaccine (Vi-rEPA) is based on Vi conjugated to rEPA, a recombinant exoprotein A from Pseudomonas aeruginosa. Vi-rEPA is equally efficacious and may confer longer immunity.[61] In 2013, two Vi-tetanus toxoid conjugates were licensed in India for persons aged 3 months or older. This new generation of typhoid vaccine opens up a new era of typhoid prevention and elimination.[61]

Medication Summary

The goals or pharmacotherapy are to eradicate infection, to reduce morbidity, and to prevent complications.

Ciprofloxacin (Cipro)

Clinical Context:  Fluoroquinolone with good activity against Salmonella and most aerobic gram-negative organisms, although resistance is gradually increasing. Poor activity against anaerobes and most gram-positive organisms. Inhibits bacterial DNA topoisomerases.

Azithromycin (Zithromax)

Clinical Context:  A macrolide antibiotic with enhanced gram-negative activity and a long half-life

Ceftriaxone (Rocephin)

Clinical Context:  Arrests bacterial growth by binding to one or more penicillin-binding proteins. A third-generation cephalosporin with broad-spectrum activity, although not a preferred anti-staphylococcal agent. Its gram-negative activity is limited against many multiresistant nosocomial organisms.

Trimethoprim and sulfamethoxazole (Bactrim DS, Septra)

Clinical Context:  Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. Antimicrobial activity of TMP-SMZ is broad and includes MRSA, most common UTI and diarrheal pathogens, toxoplasmosis, Isospora species, and Nocardia species, among many others.

Chloramphenicol (Chloromycetin)

Clinical Context:  Binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria. PO formulation unavailable in the United States.

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Further Outpatient Care

Attention to manifestation of metastatic extra-intestinal foci even after resolution of sepsis is necessary.

Deterrence/Prevention

Salmonella bacteria are primarily transmitted orally. Disease prevention consequently includes proper sanitation and hygiene, as well as the avoidance of insufficiently cooked or mishandled food.

To reduce the incidence of Salmonella infections, concerted efforts are needed throughout the food supply chain, from farm to processing plant to kitchen. Recognizing the need to prevent Salmonella contamination of poultry products and other meats, the US Department of Agriculture's Food Safety and Inspection Service (USDA FSIS) launched a Salmonella initiative in 2006, with enhancements in 2008.[18]

Salmonella outbreaks associated with exposure to small turtles highlight the importance of enforcing a 1975 prohibition on their sale and distribution in the United States.[18]

Persons should be aware that dry dog and cat food can be contaminated with Salmonella and should not be handled or stored in areas where human food is prepared or consumed.[20]

Washing hands is the most important step to prevent illness, especially after handling pet food or cleaning up after pets.[20]

Globally, the most effective way to prevent typhoid fever and its severe complications is to improve sanitation, ensure safe supplies of food and water, identify and treat chronic carriers, and implement vaccination.

Complications

Bacteremia

Approximately 5-8% of individuals with nontyphoidal Salmonella gastrointestinal illness develop bacteremia, which is more likely to occur in immunodeficient patients. Most healthy hosts clear the bacteremia without complication, but some patients develop a septic or typhoidal picture. Metastatic infection may follow bacteremia.[2]

Cardiovascular

Endocarditis, pericarditis, valve perforation, and arteritis may occur. Prosthetic valves and grafts may become infected. A feared complication of Salmonella bacteremia is endarteritis, especially with involvement of abdominal aorta. Although data are limited, the prognosis with medical therapy alone is typically grim.[2] .

A simple scoring algorithm can be used to identify adults older than 50 years with nontyphoid Salmonella bacteremia with a high risk of vascular infections. The 4 risk factors significantly associated with vascular infections (ie, male sex, hypertension, coronary arterial disease, and serogroup C1 infection) are each assigned +1 point. In contrast, malignancy and immunosuppressive therapy were each assigned -1 point. Based on proposed nontyphoid Salmonella vascular infection scoring, the prevalence of vascular infections in patients with fewer than 0, 1, 2, 3, or 4 points was 2.2%, 10.6%, 39.4%, 55.2%, and 100%, respectively (P< .0001).[45]

CNS infection

Meningitis, ventriculitis, and abscess may develop. CNS complications are more common in infants and young children.

Pulmonary

Pneumonia, abscess, empyema, and bronchopleural fistula are possible pulmonary complications of Salmonella infection.

Bone/joints

Septic arthritis and osteomyelitis are possible. Salmonella osteomyelitis affects the long bones and typically occurs in patients with sickle cell disease. Severe prolonged polyarticular reactive joint disease can occur after intestinal salmonellosis and is not altered by long-term antibiotic therapy.[46]

Gastrointestinal

Bowel perforation and gastrointestinal bleeding are potential gastrointestinal complications of Salmonella infection. However, bowel perforation is now rare (< 1%).[17]

Hepatobiliary

Hepatic abscess, cholecystitis, and peritonitis may occur.

Splenic

Abscess may occur.

Urinary

Cystitis, pyelonephritis, and renal abscess may occur.

Genital

Ovarian abscess, testicular abscess, prostatitis, and epididymitis may occur.

Soft tissue

Abscess may occur.

Prognosis

Nontyphoidal salmonellosis is generally self-limiting, with symptoms typically lasting 3-7 days.

Patients occasionally require hospitalization, but death is rare (< 1%).

After resolution of symptoms, the mean duration of fecal shedding of Salmonella organisms is 4-5 weeks, depending on the strain.

In the absence of risk factors for severe disease, limit treatment for enterocolitis to symptomatic care and fluid and electrolyte repletion. Indeed, some studies suggest that antibiotics actually prolong the carrier state.

In the preantibiotic era, approximately 15% of patients with typhoid fever died. More recently, mortality rates as high as 30% have been reported in certain developing countries. The mortality rate in patients with typhoid fever who are appropriately treated is less than 1%.

Patient Education

Because salmonellae are ubiquitous, their eradication is unlikely. Consequently, a mainstay of disease prevention and control is public education.

Because transmission primarily occurs through ingestion of contaminated foods, information about the importance of sanitary food handling, proper food preparation, and personal hygiene is pivotal.

Notably, the emergence of drug-resistant salmonellae illustrates the importance of responsible antibiotic use in medicine and animal husbandry.

What are salmonellae?How are Salmonella species classified?How is salmonella typically transmitted?What are less common ways salmonella is transmitted?What is the infectious dose of salmonella?What is the pathophysiology of salmonellosis?What are the virulence factors for salmonellae?What is the determining factors for the severity of salmonellosis?What are comorbidities that predispose to salmonellosis?What is the incidence of Salmonella infections in the US?What caused the 2012 salmonellosis outbreak due to S infantis?What caused the 2007 outbreak of salmonellosis?What caused the 2008-2009 outbreak of salmonellosis?Which patient groups are at highest risk for salmonellosis?What is the global incidence of salmonellosis?What is the mortality rate for salmonellosis?How does bacteremia affect the mortality rate of salmonellosis?What are the extraintestinal complications of salmonellosis?How does multidrug-resistant typhoid fever affect the prognosis of salmonellosis in children?What are the racial predilections for salmonellosis?How does the incidence of salmonellosis vary by sex?Which age groups are at highest risk for salmonellosis?Which syndromes are caused by Salmonella infections?What is the clinical presentation of nontyphoidal enterocolitis in salmonellosis?What is the incubation period for nontyphoidal enterocolitis in salmonellosis?What are rare symptoms of nontyphoidal enterocolitis in salmonellosis?What are the common symptoms of nontyphoidal enterocolitis in salmonellosis?What is the presentation of nontyphoidal focal disease in salmonellosis?What is the clinical course of typhoid fever in salmonellosis?How frequently does typhoid fever in salmonellosis result in severe disease?Why is a diagnosis of typhoid fever in salmonellosis missed in endemic regions?What is the incubation period for typhoid fever in salmonellosis?How does fever progress in salmonellosis?What is the significance of bradycardia in salmonellosis?What is the prevalence of rash in salmonellosis?What are the common symptoms of typhoid fever in salmonellosis?Which factors may affect the presentation of typhoid fever in salmonellosis?Which factors increase the risk for urinary tract infections in salmonellosis?What is the incidence of relapses of salmonellosis?Which physical findings are characteristic of nontyphoidal gastroenteritis in salmonellosis?Which physical findings suggest typhoid fever in salmonellosis?Which conditions are accompany typhoid fever in salmonellosis?What is a common and often severe symptom of salmonellosis?Which GI findings suggest salmonellosis?Which cardiac findings suggest typhoid fever in salmonellosis?Which respiratory findings suggest typhoid fever in salmonellosis?What are the most commonly isolated Salmonella strains causing salmonellosis?What are the differential diagnoses for Salmonella Infection (Salmonellosis)?What is the accuracy of blood cultures in detecting salmonellosis?What is the role of stool specimens in the diagnosis of salmonellosis?What are the advantages of bone marrow aspirate and culture for the diagnosis of salmonellosis?Which lab studies are used to diagnose salmonellosis?How is the grouping of Salmonella isolates performed in the evaluation of salmonellosis?What is the role of WBC count in the diagnosis of salmonellosis?What is the role of eosinophil count and sedimentation rate in the diagnosis of salmonellosis?What is the role of liver function testing in the evaluation of salmonellosis?What is the role of radiography in the diagnosis of salmonellosis?What is the role of CT scanning in the diagnosis of salmonellosis?What is the role of ultrasonography in the diagnosis of salmonellosis?What is the role of imaging studies in the evaluation of salmonellosis in patients older than 50 years?What is the role of serological tests in the diagnosis of salmonellosis?What is the role of nested polymerase chain reaction (PCR) in the diagnosis of salmonellosis?What are the treatment options for salmonellosis?What is the role of quinolone therapy in the treatment of salmonellosis?What is the role of chloramphenicol in the treatment of salmonellosis?What are the concerns associated with the medical care of salmonellosis?What is the role of azithromycin in the treatment of salmonellosis?What is the role of gatifloxacin in the treatment of salmonellosis?How is bacteremia managed in salmonellosis?When is urgent surgical intervention indicated for the treatment of salmonellosis?What is the role of ceftriaxone in the treatment of salmonellosis?How is salmonellosis treated during pregnancy?What is the role of surgery in the treatment of salmonellosis?When is cholecystectomy indicated in the treatment of salmonellosis?When is splenectomy indicated in the treatment of salmonellosis?What is the efficacy of surgery to treat endarteritis in patients with salmonellosis?Which specialist consultations are needed during the treatment of salmonellosis?What is the goal of drug treatment for salmonellosis?Which medications in the drug class Antibiotics are used in the treatment of Salmonella Infection (Salmonellosis)?How is salmonellosis prevented?How is salmonella reduced in the food supply chain?How can salmonella transmission from small turtles be prevented?How can salmonella transmission from dry pet food be prevented?What is the efficacy of hand washing for the prevention of salmonellosis?What is the role of vaccines in the prevention of salmonellosis?What is the prevalence of bacteremia in salmonellosis?What are the cardiovascular complications of salmonellosis?How are patients with salmonellosis and high risk of vascular infections identified?What are the CNS complications of salmonellosis?What are the pulmonary complications of salmonellosis?What are the bone/joint complications of salmonellosis?What are the GI complications of salmonellosis?What are the hepatobiliary complications of salmonellosis?What are the splenic complications of salmonellosis?What are the soft tissue complications of salmonellosis?What are the urinary complications of salmonellosis?What are the genital complications of salmonellosis?What is the duration of nontyphoidal salmonellosis last?How often do patients with salmonellosis require hospitalization?What is the duration of fecal shedding of Salmonella organisms after symptom resolution in salmonellosis?How is salmonellosis treated in the absence of risk factors for severe disease?What is the prognosis of salmonellosis?What is included in patient education about salmonellosis?

Author

Alena Klochko, MD, Infectious Disease Physician, Orlando Health, Florida

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Additional Contributors

Mark R Wallace, MD, FACP, FIDSA, Infectious Disease Physician, Skagit Valley Hospital, Skagit Regional Health

Disclosure: Nothing to disclose.

Mary D Nettleman, MD, MS, MACP, Professor and Chair, Department of Medicine, Michigan State University College of Human Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Michael Zapor, MD, PhD, and previous coauthor David P Dooley, MD, to the development and writing of this article.

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Rose spots on abdomen of a patient with typhoid fever due to the bacterium Salmonella typhi. Courtesy of CDC/Armed Forces Institute of Pathology, Charles N. Farmer.

Rose spots on abdomen of a patient with typhoid fever due to the bacterium Salmonella typhi. Courtesy of CDC/Armed Forces Institute of Pathology, Charles N. Farmer.