Salmonellae are both commensal as well as pathogenic for humans and many animals, including mammals, reptiles, birds, and insects. Salmonellae cause clinical disease when acquired by the oral route. They are typically transmitted via contaminated water or food from animals and animal products to humans; clinically, Salmonellae are the cause of enteritis, systemic infection, and enteric fever; however, asymptomatic colonization may also occur.

Morphology and Identification

 Salmonellae are non-spore-forming, facultative anaerobic, Gram-negative bacilli that vary in length. Most isolates are motile with peritrichous flagella. Salmonellae grow readily on simple agar media; they are able to utilize citrate as a sole carbon source and lysine as a nitrogen source, but they almost never ferment lactose or sucrose. Salmonellae do not produce cytochrome oxidase, that is they are oxidase negative. They form acid and sometimes gas from fermentation of glucose and mannose. They usually produce H₂S. They are also capable of surviving freezing in water for long periods. Salmonellae are resistant to certain chemicals (eg, brilliant green, sodium tetrathionate, sodium deoxycholate) that inhibit other enteric bacteria; such compounds are therefore useful for inclusion in agar media to specifically select for isolation of Salmonella species from feces.

Classification

The taxonomic classification of salmonellae is complex because the organisms are a continuum rather than a defined species. The members of the genus Salmonella were originally classified on the basis of epidemiology; host range; biochemical reactions; and structures of the O, H, and Vi antigens according to the Kauffman-White scheme. The names (eg, Salmonella Typhi and Salmonella typhimurium) were originally written as if they were genus and species; this form of the nomenclature remains in widespread but incorrect use. DNA–DNA hybridization studies have demonstrated that there are seven evolutionary groups. Currently, the genus Salmonella is divided into two species each with multiple subspecies and serotypes. The two species are Salmonella enterica and Salmonella bongori (formerly subspecies V). Based on the phenotypic profiles, S. enterica is further subdivided into six subspecies, which are subspecies enterica (subspecies I), subspecies salamae (sub species II), subspecies arizonae (subspecies IIIa), subspecies diarizonae (subspecies IIIb), subspecies houtenae (subspecies IV), and subspecies indica (subspecies VI). Most human ill ness is caused by S. enterica subspecies I strains, which are usually found in warm-blooded animals and humans. Rarely human infections may be caused by subspecies IIIa and IIIb or the other subspecies that are frequently found in cold-blooded animals or the environment. Infections due to subspecies IIIa and IIIb are commonly associated with exotic pets such as reptiles.

Furthermore, salmonellae can be classified by their serotype; serotypes are assigned according to antigenically diverse surface structures: somatic O antigens and flagellar H anti gens. The 2 species of Salmonella and their respective subspecies consist of more than 2500 serotypes (serovars), including more than 1400 in DNA hybridization group I. Less than 100 serotypes account for the majority of all human infections, worldwide. The widely accepted nomenclature for classification at the present time is as follows: for example, S. enterica subspecies enterica serotype Typhimurium, which can be shortened to Salmonella Typhimurium with the genus name in italics and the serotype name in roman type. National and international reference laboratories may use the antigenic formulas following the subspecies name because they impart more precise information about the isolates ( Table 1).

Table1. Representative Antigenic Formulas of Salmonellae

Based on their serotype, Salmonella species (specifically S. enterica) are further classified as “typhoidal” and “non typhoidal”. Typhoidal Salmonella refers to those specific serotypes that cause typhoid (“enteric”) fever, and include the serotypes Typhi, Paratyphi A, Paratyphi B, and Paratyphi C. Non-typhoidal Salmonella refers to all other serotypes. The non-typhoidal Salmonella serotypes Enteritidis and Typhimurium are the two most common serotypes reported in the United States. The more than 1400 other salmonellae that are isolated in clinical laboratories are serogrouped by their O antigens as A, B, C1 , C2 , D, and E; however, some are nontypeable with this set of antisera. These isolates are then sent to reference laboratories for definitive serologic identification. Definitive serologic typing allows public health officials to monitor and assess the epidemiology of Salmonella infections on a statewide and nationwide basis.

Variation

 Some salmonellae may lose H antigens and become non motile. Loss of O antigen is associated with a change from smooth to rough colony form. Vi antigen may be lost partially or completely. Antigens may be acquired (or lost) in the process of transduction.

Pathogenesis and Clinical Findings

 Typhoidal Salmonella serotypes Typhi and Paratyphi are highly adapted to humans and have no other known natural host, and infection with these organisms implies acquisition from a human source. Non-typhoidal Salmonella serotypes are the leading cause of gastroenteritis, worldwide. The Non typhoidal salmonellae can be acquired from many different animals as well as from the environment. While many animals become infected with salmonellae through their environment, other, different animals may naturally harbor salmonellae in their intestine without obvious disease. Animals known to commonly carry salmonellae include food and farm animals, as well as pets; these include, for example, poultry, pigs, cattle, cats, dogs, rodents, turtles, parrots, and other (exotic) pet animals.

Humans almost always acquire the bacteria via the oral route, usually with contaminated food or drink. The mean infective dose to produce clinical or subclinical infection in humans is 10⁵–10⁸ salmonellae; however, the infectious dose for typhoid fever caused by Salmonella Typhi is significantly lower (perhaps ≤10³ organisms). Among the host factors that contribute to “resistance” to Salmonella infection are gastric acidity, normal intestinal microbiota, and local intestinal immunity.

Salmonellae produce three main types of disease in humans, but mixed forms may occur (Table 2).

Table2. Clinical Diseases Induced by Salmonellae

A. The “Enteric Fevers” (Typhoid Fever)

Enteric fever is a severe, systemic illness, caused by Salmonella Typhi (most common) or Salmonella Paratyphi. While the disease is common in many parts of the world, it occurs less frequently in developed countries (eg, United States, Canada, and Western Europe); annually, approximately 300 cases are reported in the United States, with many of these cases being related to foreign travel. After ingestion of contaminated foods or beverages, the salmonellae reach the small intestine, from which they pass through the epithelium via specialized M-cells overlying the Peyer’s patches, and then enter the intestinal lymphatics with subsequent invasion into the bloodstream. Via bloodstream the salmonellae are spread to many other organs (eg, bone marrow). The organ isms also multiply within the intestinal lymphoid tissue and are excreted in stools. The principal lesions are hyperplasia and necrosis of lymphoid tissue (eg, Peyer’s patches); hepatitis; focal necrosis of the liver; and inflammation of the gall bladder, periosteum, lungs, and other organs have been also described.

After an incubation period of 10–14 days, fever, malaise, headache, constipation, bradycardia, and myalgia occur. The fever rises to a high plateau (39°C to 40°C), and the spleen and liver become enlarged. Rose spots, 1–4 mm blanching pink macules, are the classic cutaneous manifestation of enteric fever. Rose spots are typically observed on the chest and abdomen; however, they are fairly uncommon (<5%) in patients with uncomplicated typhoid fever. Abdominal symptoms may include diarrhea, constipation, and general abdominal pain; however, invasive diarrhea is typically not observed in typhoid fever. Contrary to the elevated white blood cell counts (WBC) in patients with sepsis, the WBC in patients with typhoid fever is normal or low. In the preantibiotic era, the chief complications of enteric fever were intestinal hemorrhage and perforation, and the mortality rate was as high as 10–15%. With the advent of successful antibiotic treatment, the mortality rate has decreased to less than 1%.

B. Bacteremia and Other Invasive Salmonella Infections

 Bacteremia and vascular infection occurs in approximately 8% of patients with non-typhoidal Salmonella infections. Cases of meningitis, septic arthritis, and osteomyelitis have been reported as a complication of Salmonella bacteremia, but are exceedingly rare events. Bacteremia and vascular infections may occur more frequently with Salmonella choleraesuis and Salmonella Dublin, but can be caused by any Salmonella serotype. Bacteremia is more common among patients with comorbidities (eg, immunosuppression), as well as infants and the elderly. Furthermore, salmonellae have a tendency to cause infections of vascular sites or persistent high-level bacteremia. Endovascular infection complicating Salmonella bacteremia usually involves the aorta, often associated with atherosclerotic plaques or aneurysms; people older than 50 years have a higher risk of developing such complications. In general, mortality from Salmonella bacteremia in children is less than 10%; however, the risk of death and other complications is higher in adults and patients with underlying conditions. Mortality associated with Salmonella bacteremia increases with duration of bacteremia and potential progression to septic shock; rates range from 14% to 60% in patients with concomitant endovascular invasion.

C. Enterocolitis

This is the most common manifestation of Salmonella infection. In the United States, Salmonella typhimurium and Salmonella enteritidis may be most common causes, but enterocolitis can be caused by any of the more than 1400 group I serotypes of salmonellae. Eight to 48 hours after ingestion of contaminated food or water, there is nausea, headache, vomiting, and profuse diarrhea; however, incubation periods of up to 7 days have been reported as well. Microscopic stool examinations typically show leukocytes, and red cells are less often observed. Inflammatory lesions of the small and large intestine are present. Low-grade fever (38°C to 39°C) and abdominal cramping are very common clinical symptoms. Diarrhea is usually self-limited with a typical duration of 3 to 7 days. Bacteremia is a rare (2–4%) complication, except in immunocompromised patients. Blood culture results are usually negative; however, stool cultures are positive for salmonellae and may remain positive for several weeks after clinical recovery. The mean duration for carriage of organ isms after resolution of the infection is 4–5 weeks; antibiotic therapy may increase the duration of carriage

Diagnostic Laboratory Tests

A. Specimens

Freshly passed stool is the preferred specimen for the diagnosis of non-typhoidal Salmonella; specimens collected during the early stages of the enteric illness have the highest yield for recovery of the causative organism. Collection of multiple stool specimens may enhance the recovery rate of Salmonella, as well as other enteric pathogens (eg, Shigella).

For the definitive diagnosis of enteric fever, Salmonella Typhi or Salmonella Paratyphi must be isolated in culture; appropriate specimens are blood, bone marrow, other sterile sites, urine, or intestinal secretions. While blood cultures are the most commonly used method of diagnosis, blood must often be taken repeatedly in order to increase the yield of recovering the organism. In enteric fevers and septicemias, blood culture results are often positive in the first week of the disease. The addition of stool cultures may increase the overall yield of recovering the causative organism. While bone marrow cultures have the highest sensitivity (80% to 95%), they are clinically less practical for patients suspected to have enteric fever. Urine culture results may be positive after the second week of the illness. A positive culture of duodenal drainage establishes the presence of salmonellae in the biliary tract in patients who are carriers of the organisms.

B. Bacteriologic Methods for Isolation of Salmonellae

 1. Differential medium cultures—EMB, MacConkey, or deoxycholate medium permits rapid detection of lactose nonfermenters (not only salmonellae and shigellae but also Proteus, Pseudomonas, etc). Gram-positive organisms are somewhat inhibited. Bismuth sulfite medium permits rapid detection of salmonellae, which form black colonies because of H₂S production. Most salmonellae produce H₂S (Figure 1A).

2. Selective medium cultures—The specimen may also be plated on salmonella-shigella (SS) agar, Hektoen enteric (HE) agar (Figure 1B), xylose-lysine desoxycholate (XLD) agar, or desoxycholate-citrate agar, all of which favor growth of salmonellae and shigellae over other Enterobacteriaceae. Chromogenic agars specifically for salmonella recovery are also available.

3. Enrichment cultures—The specimen (usually stool) can also be placed into selenite F or tetrathionate broth, both of which inhibit replication of normal intestinal bacteria and permit multiplication of salmonellae. After incubation for 1–2 days, an aliquot from this broth is plated on differential and selective media.

4. Final identification—Suspect colonies from solid media are identified by biochemical reaction patterns and slide agglutination tests with specific sera.

Fig1. A: Salmonella species on TSI agar slant. B: Salmonella species on HE agar. Salmonella spp. do not ferment the carbohydrates present in the HE agar; however, the organism produces H₂S, and the ferric ammonium citrate in the HE agar result in the Salmonella colonies to appear black. On TSI agar slant, Salmonella spp. ferment glucose, but not lactose; they produce H₂S and gas [K/A,G H₂S+]. (Courtesy of S. Riedel.)

C. Serologic Methods

 Serologic techniques are used to identify unknown cultures with known sera and may also be used to determine antibody titers in patients with unknown ill ness, although the latter is not very useful in the diagnosis of Salmonella infections.

 1. Agglutination test—In this test, known sera and unknown culture are mixed on a slide. Clumping, when it occurs, can be observed within a few minutes. This test is particularly useful for rapid preliminary identification of cultures. There are commercial kits available to agglutinate and serogroup salmonellae by their O antigens: A, B, C1 , C2 , D, and E.

 2. Tube dilution agglutination test (Widal test)—Serum agglutinins rise sharply during the second and third weeks of S serotype Typhi infection. The Widal test to detect these antibodies against the O and H antigens has been in use for decades. At least two serum specimens, obtained at intervals of 7–10 days, are needed to prove a rise in antibody titer. Serial dilutions of unknown sera are tested against antigens from representative salmonellae. False positive and false-negative results occur. The interpretive criteria when single serum specimens are tested vary, but a titer against the O antigen of greater than 1:320 and against the H antigen of greater than 1:640 is considered positive. High titer of antibody to the Vi antigen occurs in some carriers. Alternatives to the Widal test include rapid colorimetric and EIA methods. There are conflicting reports in the literature regarding superiority of these methods to the Widal test. Results of serologic tests for Salmonella infection cannot be relied upon to establish a definitive diagnosis of typhoid fever and are most often used in resource poor areas of the world where blood cultures are not readily available.

D. Nucleic Acid Amplification Tests

 As mentioned above for the shigellae, several commercial NAATs are available for direct detection of salmonellae in fecal samples of patients with acute diarrhea. Since these assays are new, performance characteristics of the assays and their impact on public health surveillance are still under investigation.

Immunity

 Infections with Salmonella Typhi or Salmonella Paratyphi usually confer a certain degree of immunity. While reinfection may occur, it is often milder than the initial infection. Circulating antibodies to O and Vi are related to resistance to infection and disease. However, relapses may occur in 2–3 weeks after recovery despite antibodies. Secretory IgA antibodies may pre vent attachment of salmonellae to intestinal epithelium.

Patients, specifically children, with sickle cell disease or sickle cell trait are exceedingly more susceptible to Salmonella infections and particularly to Salmonella bacteremia and its complications (eg, osteomyelitis) when compared to people with normal hemoglobin.

Treatment

 Early diagnosis and prompt initiation of appropriate anti biotic therapy prevents complications of enteric fever and Salmonella bacteremia/sepsis. As mentioned above, prompt and appropriate antibiotic treatment results in a significant decrease of the mortality rate ( <1%) ); the mortality rate in untreated cases of enteric fever is greater than 10%. Uncomplicated enteric fever can be managed in the outpatient set ting with oral azithromycin (1 g once, followed by 500 mg daily for 7 days); patients with complications should be hospitalized, and treatment with a parenteral third-generation cephalosporin or fluoroquinolone for at least 10 days is recommended. Non-typhoidal Salmonella bacteremia should be empirically treated with a third-generation cephalosporin (eg, ceftriaxone) and a fluoroquinolone, until results from antimicrobial susceptibility testing (AST) are available. In cases of documented (or suspected) endovascular infection (eg, infected aneurysm), patients should be treated with intravenous ceftriaxone, or ampicillin, or a fluoroquinolone for 6 weeks, followed by oral therapy. Early surgical resection of the infected aneurysm is also recommended.

Since non-typhoidal Salmonella gastroenteritis is typically a self-limited illness, antimicrobial therapy is usually not necessary and not recommended. In fact, clinical symptoms and excretion of the salmonellae may be prolonged by antimicrobial therapy. In cases with severe diarrhea, replacement of fluids and electrolytes is essential. How ever, antimicrobial treatment of Salmonella gastroenteritis should be considered in neonates as well as patients with immunosuppression (eg, chemotherapy, HIV), and those older than 50 years with suspected or confirmed atherosclerosis, cardiac valvular, and endovascular disease.

For susceptible organisms, oral therapy with amoxicillin, trimethoprim–sulfamethoxazole, or a fluoroquinolone is appropriate. For immunocompromised patients, treatment may be as long as 7–14 days. Plasmid-mediated multiple drug resistance has been increasingly noted among Salmonella isolates, and specifically in Salmonella Typhi. Antimicrobial susceptibility testing is an important laboratory test, specifically for Salmonella isolates from extraintestinal specimens, in order to select the most appropriate antibiotic for therapy.

In most patients who are carriers, the organisms persist in the gallbladder (particularly if gallstones are present) and in the biliary tract. Some chronic carriers have been cured by ampicillin alone, but in most cases cholecystectomy must be combined with antibiotic treatment.

Epidemiology

 The incidence and mortality of enteric (typhoid) fever due to Salmonella Typhi and Paratyphi vary significantly by region; rates are lowest in developed countries such as the Unites States, Canada, and Western Europe. Since S. Typhi and S. Paratyphi are pathogens restricted to humans only, transmission occurs from either a carrier or an infected person to others; in addition, fecally contaminated food and water are an important source for the infection, and the organisms can persist for weeks after passage in water and on environmental surfaces and food stuff.

While the incidence of non-typhoidal Salmonella human infection has significantly increased over the past decades in many countries, worldwide, the incidence of non-typhoidal salmonellosis in the United States has not changed significantly during the past 15 years; in fact, the CDC reported a slight decrease during the years 2012 and 2013. According to the CDC, an estimated 1.2 million cases of foodborne salmonellosis occur annually in the United States. Unlike Salmonella Typhi and S Paratyphi, the many non-typhoidal Salmonella can be acquired from various reservoirs, humans, animals, or a contaminated environmental source. The feces of people who have unsuspected subclinical disease or who are carriers are a more important source of contamination than frank clinical cases that are usually isolated promptly after recognition; carriers “shedding” organisms, who are working as food handlers (eg, commercial food preparation industry), are a major source of larger outbreaks of salmonellosis. In addition, many animals, including cattle, rodents, and fowl, are naturally infected with a variety of salmonellae and have the bacteria in their tissues (meat), excreta, or eggs. The high incidence of salmonellae in commercially prepared chickens has been widely publicized. This problem is furthermore aggravated by the widespread use of animal feeds containing antimicrobial drugs that in turn favor the proliferation of drug-resistant salmonellae and their potential transmission to humans. Finally, human salmonellosis associated with exposure to pet animals is a recurring public health problem in the United States, and individual cases or even small outbreaks have been reported.

A. Carriers

 After manifest or subclinical infection, some individuals continue to harbor salmonellae in their tissues for variable lengths of time (i.e., convalescent carriers or healthy permanent carriers). Three percent of survivors of typhoid fever become permanent carriers, harboring the organisms in the gallbladder, biliary tract, or, rarely, the intestine or urinary tract.

B. Sources of Infection

The sources of infection are food and drink that have been contaminated with salmonellae. The following sources are important:

1. Water—Contamination with feces often results in explosive epidemics

 2. Milk and other dairy products (ice cream, cheese, custard)—Contamination with feces and inadequate pasteurization or improper handling; some outbreaks are traceable to the source of supply

 3. Shellfish—From contaminated water

 4. Dried or frozen eggs—From infected fowl or contaminated during processing

 5. Meats and meat products—From infected animals (poultry) or contamination with feces by rodents or humans

6. “Recreational” drugs—Marijuana and other drugs

 7. Animal dyes—Dyes (eg, carmine) used in drugs, foods, and cosmetics

 8. Household pets—Dogs, cats, hedgehogs, birds, and exotic pets such as reptiles (eg, turtles, iguanas, snakes)

Prevention and Control

 Sanitary measures must be taken to prevent contamination of food and water by rodents or other animals that excrete salmonellae. Infected poultry, meats, and eggs must be thoroughly cooked. Carriers must not be allowed to work as food handlers or in food preparation areas, and should observe strict personal hygienic precautions.

Two typhoid vaccines are currently available in the United States: an oral live, attenuated vaccine (Ty21a) and a parenteral Vi capsular polysaccharide vaccine (Vi CPS) for intramuscular use. Vaccination is recommended for travelers to endemic regions, especially if the traveler visits rural areas or small villages where food choices are limited. Both vaccines have an efficacy of 50–80%. The time required for primary vaccination and age limits for each vaccine varies, and individuals should consult the Centers for Disease Control and Prevention’s website or obtain advice from a travel clinic regarding the latest vac cine information.

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مواضيع ذات صلة

Rapidly Growing Nontuberculous mycobacteria (RGM)

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Anaerobic Gram-Positive and Gram-Negative Cocci

The shigellae

Diseases Caused by Enterobacteriaceae Other than Salmonella and Shigella

Antigenic Structure of Enterobacteriaceae

Gram-Negative Rods

Gram-Positive, non–Spore- Forming Bacilli

Gram-Positive, Spore Forming Bacilli

Morphology and Identification of Enterobacteriaceae

Clinical Findings of Enterococci