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USMLE – Salmonella

Diseases
Salmonella species cause enterocolitis, enteric fevers such as typhoid fever, and septicemia with metastatic abscesses. They are one of the most common causes of bacterial enterocolitis in the United States.

Important Properties
Salmonellae are gram-negative rods that do not ferment lactose but do produce H2S-features that are used in their laboratory identification. Their antigens-cell wall O, flagellar H, and capsular Vi (virulence)-are important for taxonomic and epidemiologic purposes. The O antigens, which are the outer polysaccharides of the cell wall, are used to subdivide the salmonellae into groups A-I. There are two forms of the H antigens, phases 1 and 2. Only one of the two H proteins is synthesized at anyone time, depending on which gene sequence is in the correct alignment for transcription into mRNA. The Vi antigens are used primarily for the typing of S typhi, the agent of typhoid fever.

There are two methods for naming the salmonellae. Ewing divides the genus into three species: S typhi, Salmonella choleraesuis, and Salmonella enteritidis. In this scheme there is one serotype in each of the first two species and 1500 serotypes in the third. Kaufman and White assign different species names to each serotype; there are roughly 1500 different species, usually named for the city in which they were isolated. Salmonella dublin according to Kaufman and White would be S enteritidis serotype dublin according to Ewing. Both forms are used in the literature; the Centers for Disease Control and Prevention use the Ewing system.

Pathogenesis & Epidemiology
The three types of Salmonella infections (enterocolitis, enteric fevers, and septicemia) have different pathogenetic features.

Enterocolitis is characterized by an invasion of the epithelial and subepithelial tissue of the small and large intestines. Strains that do not invade do not cause disease. The organisms penetrate both through and between the mucosal cells into the lamina propria, with resulting inflammation and diarrhea. A polymorphonuclear leukocyte response limits the infection to the gut and the adjacent mesenteric lymph nodes; bacteremia is infrequent in enterocolitis. In contrast to Shigella enterocolitis, in which the infectious dose is very small (on the order of 100 organisms), the dose of Salmonella required is much higher, at least 100,000 organisms. Gastric acid is an important host defense; gastrectomy or use of antacids lowers the infectious dose significantly.

In typhoid and other enteric fevers, infection begins in the small intestine but few gastrointestinal symptoms occur. The organisms enter, multiply in the mononuclear phagocytes of Peyer’s patches, and then spread to the phagocytes of the liver, gallbladder, and spleen. This leads to bacteremia, which is associated with the onset of fever and other symptoms, probably caused by endotoxin. Survival and growth of the organism within phagosomes in phagocytic cells are a striking feature of this disease, as is the predilection for invasion of the gallbladder, which can result in establishment of the carrier state and excretion of the bacteria in the feces for long periods.

Septicemia accounts for only about 5-10% of Salmonella infections and occurs in one of two settings: a patient with an underlying chronic disease such as sickle cell anemia or cancer or a child with enterocolitis. The septic course is more indolent than that seen with many other gram-negative rods. Bacteremia results in the seeding of many organs, with osteomyelitis, pneumonia, and meningitis as the most common sequelae. Osteomyelitis in a child with sickle cell anemia is an important example of this type of salmonella infection. Previously damaged tissues, such as infarcts and aneurysms, especially aortic aneurysms, are the most frequent sites of metastatic abscesses.

The epidemiology of Salmonella infections is related to the ingestion of food and water contaminated by human and animal wastes. Salmonella typhi, the cause of typhoid fever, is transmitted only by humans, but all other species have a significant animal as well as human reservoir. Human sources are either persons who temporarily excrete the organism during or shortly after an attack of enterocolitis or chronic carriers who excrete the organism for years. The most frequent animal source is poultry and eggs, but meat products that are inadequately cooked have been implicated as well. Dogs and other pets, including turtles, are additional sources.

Clinical Findings
After an incubation period of 12-48 hours, enterocolitis begins with nausea and vomiting and then progresses to abdominal pain and diarrhea, which can vary from mild to severe, with or without blood. Usually the disease lasts a few days, is self-limited, causes nonbloody diarrhea and does not require medical care except in the very young and very old. The most common cause of enterocolitis is Salmonella typhimurium, but virtually every species has been implicated.

In typhoid fever, caused by Salmonella typhi, and in enteric fever, caused by organisms such as Salmonella paratyphi A, B, and C (Salmonella paratyphi B and C are also known as Salmonella schottmuelleri and Salmonella hirschfeldii, respectively), the onset of illness is slow, with fever and constipation rather than vomiting and diarrhea predominating. After the first week, as the bacteremia becomes sustained, high fever, delirium, tender abdomen, and enlarged spleen occur. “Rose spots,” ie, rose colored macules on the abdomen, are associated with typhoid fever but occur only rarely. The disease begins to resolve by the third week, but severe complications such as intestinal hemorrhage or perforation can occur. About 3% of typhoid fever patients become chronic carriers. The carrier rate is higher among women, especially those with previous gallbladder disease and gallstones.

Septicemia is most often caused by Salmonella choleraesuis. The symptoms begin with fever but little or no enterocolitis and then proceed to focal symptoms associated with the affected organ, frequently bone, lung, or meninges.

Laboratory Diagnosis
In enterocolitis, the organism is most easily isolated from a stool sample. However, in the enteric fevers, a blood culture is the procedure most likely to reveal the organism during the first 2 weeks of illness.

Salmonellae form non-lactose-fermenting (colorless) colonies on MacConkey’s or EMB agar. On TSI agar, an alkaline slant and an acid butt, frequently with both gas and H2S (black color in the butt), are produced. Salmonella typhi is the major exception; it does not form gas and produces only a small amount of H2S. If the organism is urease-negative (Proteus organisms, which can produce a similar reaction on TSI agar, are urease-positive), the Salmonella isolate can be identified and grouped by the slide agglutination test. Definitive serotyping of the O, H, and Vi antigens is performed by special public health laboratories for epidemiologic purposes. Salmonellosis is a notifiable disease and an investigation to determine its source should be undertaken. In certain cases of enteric fever and sepsis, when the organism is difficult to recover, the diagnosis can be made serologically by detecting a rise in antibody titer in the patient’s serum (Widal test).

Treatment
Enterocolitis caused by Salmonella is usually a self-limited disease that resolves without treatment. Fluid and electrolyte replacement may be required. Antibiotic treatment does not shorten the illness or reduce the symptoms; in fact, it may prolong excretion of the organisms, increase the frequency of the carrier state and select mutants resistant to the antibiotic. Antimicrobial agents are indicated only for neonates or persons with chronic diseases who are at risk of septicemia and disseminated abscesses. Plasmid-mediated antibiotic resistance is common and antibiotic sensitivity tests should be done. Drugs that retard intestinal motility (ie, that reduce diarrhea) appear to prolong the duration of symptoms and the fecal excretion of the organisms.

The treatment of choice for enteric fevers such as typhoid fever and septicemia with metastatic infection is either ceftriaxone or ciprofloxacin. Ampicillin or ciprofloxacin should be used in patients who are chronic carriers of Salmonella typhi. Cholecystectomy may be necessary to abolish the chronic carrier state. Focal abscesses should be drained surgically when feasible.

Prevention
Salmonella infections are prevented mainly by public health and personal hygiene measures. Proper sewage treatment, a chlorinated water supply that is monitored for contamination by coliform bacteria, cultures of stool samples from food handlers to detect carriers, hand washing prior to food handling, pasteurization of milk and proper cooking of poultry, eggs, and meat are all important.

Three vaccines are available, but they confer limited (50-80%) protection against Salmonella typhi. One contains the Vi capsular polysaccharide of Salmonella typhi (given intramuscularly) and the second contains a live, attenuated strain of Salmonella typhi (given orally). These two vaccines cause fewer side effects than the third vaccine, which contains killed, whole Salmonella typhi organisms. The vaccine is recommended for those who will travel or reside in high-risk areas and for those whose occupation brings them in contact with the organism.

Lillian Thompson By Lillian Thompson

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