AUTHOR INFORMATION

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Authored by Robert A Barrali, Jr, MD, Director of Human Resources, Chandler Emergency Medical Group, Consulting Staff, Department of Emergency Medicine, Chandler Regional Hospital

Edited by Mark Louden, MD, FACEP, Consulting Staff, Emergency Department, Duke Health Raleigh Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Jeter (Jay) Pritchard Taylor III, MD, Compliance Officer, Attending Physician Emergency Medicine Residency, Department of Emergency Medicine, Palmetto Richland Memorial Hospital, University of South Carolina; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Jonathan Adler, MD, Attending Physician, Department of Emergency Medicine, Massachusetts General Hospital; Division of Emergency Medicine, Harvard Medical School

Author's Email:	Robert A Barrali, Jr, MD
Editor's Email:	Mark Louden, MD, FACEP

eMedicine Journal, April 5 2006, VOLUME 7, Number 4

INTRODUCTION

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Background: Salmonellosis is one of the most common bacterial infections in the United States. More than 95% of cases of Salmonella infection are food-borne. Thirty percent of deaths are believed to result from Salmonella in food-borne illness. After Campylobacter, Salmonella is the most common bacterial pathogen found in stool cultures recovered from patients presenting with gastroenteritis or severe diarrhea. It is responsible for a variety of clinical syndromes, including enteric fever (usually caused by typhoid or paratyphoid species), enterocolitis, bacteremia, and severe local infections.

Certain host factors make humans particularly susceptible to infection. However, while the pathogenesis remains uncertain and disease management is controversial, the prognosis is generally good.

Pathophysiology: The first step in the development of salmonellosis is the dose and vehicle of infection. In healthy human volunteers, a median dose of 1 million to 1 billion organisms is necessary to produce symptoms.

The mode of transmission for the development of enterocolitis (nontyphoidal Salmonella infection) is by ingestion of the organisms in food derived from infected animals or contaminated with feces of an infected individual. Pets, such as turtles, tortoises, iguanas, chicks, dogs, and cats as well as poultry, swine, cattle, rodents, and infected humans all are potential reservoirs. Raw milk and raw milk products, undercooked or raw eggs and egg products, meat and meat products, and contaminated water are potential sources. Recent outbreaks have been linked to undercooked ground beef, cheese, dry cereal, ice cream premix, sprouts, juice, cantaloupes, and other fresh vegetables. Fecal-oral transmission from person to person usually in areas with poor sanitation and contaminated water is the route for enteric or typhoid fever.

After ingestion, the bacteria must survive the acidic pH in the stomach and colonize in the small intestine. Salmonella species then can attach to and penetrate the intestinal mucosa resulting in diarrhea from direct mucosal damage or by the action of bacterial toxins. Another portal of entry is invasion of lymphoid tissues within the gastrointestinal (GI) tract and multiplication within macrophages, which results in bacteremia.

Factors that predispose an individual to infection include defects in cell-mediated immunity (eg, AIDS, transplant patients, lymphoproliferative disease), defects in phagocytic function (eg, malaria, histoplasmosis), reductions in stomach acidity observed in persons taking H2 antagonists or antacids, use of antibiotics that alter the normal gut flora, injured GI barrier as observed with recent bowel surgery, inflammatory bowel disease, and malignancy.

Frequency:

• In the US: Each year 1.4 million people develop nontyphoidal salmonellosis. It occurs more commonly in the summer and fall. While the incidence of typhoid or enteric fever has decreased in the United States, an increase has occurred in cases in those citizens who have traveled abroad. Among people from the United States, travel to India, Mexico, Philippines, El Salvador, and Haiti accounted for 80% of cases.

• Internationally: Fully industrialized nations report frequencies of gastroenteritis similar to the United States. Typhoid fever (and presumably gastroenteritis) is far more common in areas where sanitation is inadequate, as in underdeveloped countries. The overall risk of typhoid fever from travel to India is estimated to be 18 times higher than from any other geographic area.

Mortality/Morbidity: Salmonella infection occurs in 8.7% of nursing home residents and 7% of neonates. Bacteremia occurs in 2-14% of people, usually infants and elderly persons. Salmonella infection is responsible for 600 deaths in the United States each year.

Age: Attack rates are highest in persons younger than 20 years or older than 70 years. The highest rate is found in infants (130 isolates/100,000).

CLINICAL

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History:

• Query patients about recent travel to Mexico or Asia. (More than 80% of US cases are imported from these locations.)

• Determine if other patient contacts have similar illnesses, food ingestions, or animal contacts.

• The presentations can be divided into gastroenteritis (the most frequent manifestation), enteric fever, bacteremia (with or without extraintestinal infection), and the asymptomatic carrier state.

• Gastroenteritis

• The incubation period is from 8-48 hours.

• It begins with nausea and vomiting and progresses to abdominal cramping and diarrhea, which may be bloody.

• The diarrhea is usually self-limiting, typically lasting 3-7 days.

• Salmonella infection can mimic inflammatory bowel disease or pseudoappendicitis rarely.

• Enteric (typhoid) fever

• The incubation period of enteric (ie, typhoid) fever is 5-21 days.

• The patient may have symptoms of enterocolitis that resolve before the onset of fever.

• Constipation is found in 10-38% of patients.

• Abdominal pain presents in 20-40% of patients.

• Fever usually begins 1 week postexposure. It may elevate in a characteristic stepwise manner for 4-5 days before leveling off.

• Malaise, anorexia, myalgia, arthralgia, cough, sore throat, and headache may follow.

• After 1 week, untreated patients have worsening of the above symptoms and mental confusion.

• Extraintestinal manifestations

• Osteomyelitis

• Meningitis (almost exclusively in infants)

• Endocarditis

• Possible involvement from many other sites

Physical: Different signs may accompany different manifestations of the disease. The presenting signs of gastroenteritis, typhoid fever, and extraintestinal manifestations may overlap significantly.

• Gastroenteritis

• One half of patients have a temperature higher than 38.9°C.

• Other patients have mild abdominal tenderness or signs consistent with peritonitis.

• Gross or occult blood may be found on rectal examination.

• Enteric or typhoid fever

• A bradycardia out of proportion to the fever may be noted.

• Hepatosplenomegaly is found in 50% of patients.

• Rose spots may appear typically on the anterior chest wall. They are slightly raised, discrete, and irregular pink macules 2-4 mm in diameter that blanch with pressure. They arise in clusters of 5-15, last for several days, and fade away without scarring. They are noted in 30% of patients.

Causes: The list of serotypes is extensive (in the thousands). Each serotype can cause any of the clinical manifestations. Salmonella typhi and Salmonella paratyphi are commonly associated with enteric fever, while many others can result in gastroenteritis.

DIFFERENTIALS

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Abdominal Trauma, Blunt
CBRNE - Botulism
Diverticular Disease
Gastritis and Peptic Ulcer Disease
Gastroenteritis
Pediatrics, Gastroenteritis
Toxicity, Shellfish

Other Problems to be Considered:

Food poisoning
Shigellosis

WORKUP

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Lab Studies:

• None of the serologic tests developed to date have proven to be sensitive or specific for the disease.

• Complete blood count

• Anemia is common and is usually a result of blood loss and inflammation.

• The white blood cell (WBC) count is normal or low.

• Leucocytosis may result from bacteremia, peritonitis from bowel perforation, or other extraintestinal complications.

• Thrombocytopenia may occur.

• Cultures

• The diagnosis of Salmonella infection is based on isolation of the infecting organism.

• Often, the infection is transient and cultures are negative. This is particularly true with salmonella gastroenteritis.

• The results of bone marrow and rose spot cultures may be positive even when the results of blood, urine, and stool cultures are negative.

• It has been noted that, if cultures are taken from bone marrow, blood, and intestinal secretions of persons with enteric fever, more than 90% have positive results. This is rarely undertaken.

• Blood culture results in enteric fever are positive in 50-70% of cases.

Imaging Studies:

• Always consider a perforated viscous if the physical examination shows peritoneal findings. A three-way view of the abdomen may show free air under the diaphragm. This is a highly unlikely complication of Salmonella infection.

Procedures:

• A rectal examination for occult or overt bleeding is an important part of the evaluation. The hemorrhage is rarely severe enough for transfusion to be considered.

TREATMENT

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Prehospital Care: Pay particular attention to the ABCs if the patient is profoundly dehydrated or has a reduced level of consciousness.

Emergency Department Care:

• Establish oxygen, monitors, IV lines, blood for labs, and stool for culture.

• Appropriate intervention is based on the vital signs.

• Transfusions should be based on hemoglobin and hematocrit levels.

• Correction of electrolyte disturbances and control of pain, nausea, vomiting, and diarrhea is mandatory.

Consultations: It may be necessary to contact the patient’s primary care doctor or the admitting physician on call to arrange admission or outpatient follow-up care based on the patient’s general condition and response to therapy (eg, degree of dehydration, anemia, social situation). Also discuss whether or not to start the patient on antibiotics.

MEDICATION

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Antibiotics, antidiarrheals, and glucocorticoids are used to treat symptoms and/or documented Salmonella infection.

Drug Category: Antibiotics -- Salmonella gastroenteritis is generally self-limited. Controversy exists over whether or not antibiotic therapy is of any value. While it is thought that some groups at high risk for bacteremia may benefit from antibiotic prophylaxis, less than 5% of patients develop bacteremia. Nevertheless, prophylaxis should be considered in newborns, patients older than 50 years who have severe atherosclerosis, immunosuppressed patients, and those with cardiovascular abnormalities and prostheses.

Treatment duration is 48-72 hours. Enteric (ie, typhoid) fever is best treated with antibiotics for 10-14 days. Prolonged bacteremia and focal infection are treated with maximal doses of antibiotics for 4-6 weeks and a meticulous search for the source, which may require surgical intervention. Recently, some cases of salmonellosis are becoming resistant to many of the antibiotics considered to be the standard of care in the past. Stool and blood culture and sensitivities are very important.

Drug Name	Ciprofloxacin (Cipro) -- Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms, but has no activity against anaerobes. Inhibits bacterial DNA synthesis and, consequently, growth. Is effective in treatment of long-term carriers of S Typhi.
Adult Dose	500 mg PO bid
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Trimethoprim and sulfamethoxazole (Bactrim) -- Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.
Adult Dose	2 g (based on SMZ) PO bid
Pediatric Dose	<2 months: Do not administer >2 months: 8 mg/kg/d (based on TMP) PO tid/qid for 14 d
Contraindications	Documented hypersensitivity; megaloblastic anemia caused by folate deficiency
Interactions	May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly persons; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Discontinue at first appearance of rash or sign of adverse reaction; obtain CBCs frequently; discontinue therapy if significant hematologic changes occur; goiter, diuresis, and hypoglycemia may occur with sulfonamides; prolonged IV infusions or high doses may cause bone marrow depression (if signs occur, administer 5-15 mg/d leucovorin); caution in folate deficiency (eg, persons with chronic alcoholism, elderly patients, those receiving anticonvulsant therapy, or persons with malabsorption syndrome); hemolysis may occur in G-6-PD deficiency; patients with AIDS may not tolerate or respond to TMP-SMZ; caution in renal or hepatic impairment (perform urinalyses and renal function tests during therapy); give fluids to prevent crystalluria and stone formation

Drug Name	Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin binding proteins.
Adult Dose	1-2 g IV bid
Pediatric Dose	50-75 mg/kg/d IV
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment; caution in breastfeeding women and persons allergic to penicillin

Drug Name	Amoxicillin (Amoxil, Biomox, Polymox, and Wymox) -- Interferes with synthesis of cell wall mucopeptides during active multiplication resulting in bactericidal activity against susceptible bacteria.
Adult Dose	4-6 g PO qd
Pediatric Dose	100 mg/kg/d PO divided q8h
Contraindications	Documented hypersensitivity
Interactions	Reduces the efficacy of oral contraceptives
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment

Drug Category: Antidiarrheals -- May prolong the course of the disease. If used, they should be used sparingly.

Drug Name	Loperamide (Imodium) -- Acts on intestinal muscles to inhibit peristalsis and slow intestinal motility. Prolongs movement of electrolytes and fluid through bowel and increases viscosity and loss of fluids and electrolytes. Available as 2-mg tablets and 1-mg/5-mL liquid.
Adult Dose	4 mg PO initial; then 2 mg after each loose stool; not to exceed 16 mg/d
Pediatric Dose	13-20 kg: 1 mg PO bid 20-30 kg: 2 mg PO bid >30 kg: 2 mg PO tid
Contraindications	Documented hypersensitivity; diarrhea resulting from infections; pseudomembranous colitis
Interactions	Phenothiazines, tricyclic antidepressants, and CNS depressants may increase toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Discontinue use if no clinical improvement in 48 h; because primarily metabolized in liver, monitor for CNS toxicity in patients with hepatic insufficiency; do not use if high fever or blood in stool coincides with diarrhea

Drug Name	Diphenoxylate and Atropine (Lomotil) -- Drug combination that consists of diphenoxylate, which is a constipating meperidine congener, and atropine to discourage abuse. Inhibits excessive GI propulsion and motility. Supplied as diphenoxylate 2.5 mg and atropine 0.025 mg per tablet or per 5 mL of liquid.
Adult Dose	2 tabs or 10 mL PO qid
Pediatric Dose	<2 years: Not recommended > 2 years: 0.3-0.4 mg/kg/d PO divided qid
Contraindications	Documented hypersensitivity; narrow-angle glaucoma or hepatic insufficiency
Interactions	May delay metabolism of drugs in liver; CNS depressants, MAOIs, and antimuscarinic agents may increase the toxicity of drug combination
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In young children, dehydration may influence variability of response and predispose patient to delayed diphenoxylate intoxication; exercise caution in patients with ulcerative colitis; decrease in intestinal motility may be detrimental to patients with diarrhea resulting from Shigella species, Salmonella species, and toxigenic strains of Escherichia coli

Drug Category: Glucocorticoids -- May improve outcome in patients with serious complications, such as coagulopathy or CNS involvement.

Drug Name	Dexamethasone (Decadron) -- Is used in the treatment of various inflammatory diseases. Decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Adult Dose	1 mg/kg IV; followed by 1 mg/kg IV q6h for 24-48 h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; active bacterial or fungal infection
Interactions	Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

FOLLOW-UP

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Further Outpatient Care:

• Follow-up treatment with the patient's primary care physician is highly recommended.

• Worsening symptoms warrant a return visit to the ED.

Deterrence/Prevention:

• Proper hygiene and food storage

• Control of animal reservoir

Complications:

• Toxic megacolon

• Hypovolemic shock

• Metastatic abscess formation

• Acute or chronic hydrocephalus

Prognosis:

• This is generally a self-limiting illness.

• Most people are treated on an outpatient basis.

• Those with immunocompromise or who are aged at the extremes of life may have significant morbidity and mortality.

Patient Education:

• Emphasize good hand-washing, thorough cleaning of cooking utensils, and adequate cooking temperature for killing the bacteria.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Treating persons who are aged at the extremes of life and those prone to immunocompromise with supportive measures alone (They ultimately may need antibiotics.) Have a low threshold for admitting this special patient population. At minimum, arrange for his or her primary care doctor to follow up the culture results to determine if the patient needs to take antibiotics.

• Failure to query about recent travel to Asia or Mexico

• Failure to ask about previous gastric surgery, use of antacids and H2 antagonists, or any predisposition towards reduced stomach acid production

• Failure to look for extraintestinal manifestations

• Failure to consider alternative diagnoses. Perforated viscous and atypical presentation of appendicitis need to be considered.

TEST QUESTIONS

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CME Question 1: Which of the following persons is associated with an increased morbidity and mortality rate from salmonellosis?

A: Neonates
B: Elderly persons
C: Individuals with HIV
D: All of the above
E: None of the above

The correct answer is D: Persons aged at the extremes of life or those who are immunocompromised have an increased risk of severe illness, which, in some cases, may result in death.

CME Question 2: Which of the following is not a factor predisposing patients to salmonellosis?

A: Defects in cell-mediated immunity
B: Recent bowel surgery
C: Current use of H2-antagonists or antacids
D: A history of recent travel outside the US
E: None of the above

The correct answer is D: While recent travel outside of the US is an important historical factor to consider, this does not predispose patients to salmonellosis.

Pearl Question 1 (T/F): The incubation period for gastroenteritis from Salmonella infection is from 8-48 hours.

The correct answer is True: It starts with nausea and vomiting and progresses to abdominal cramping and diarrhea, which may be bloody.

Pearl Question 2 (T/F): Contaminated drinking water is the main source of salmonellosis.

The correct answer is False: Milk, meat, and poultry products are possible sources of salmonellosis, as is fecal-oral transmission.

Pearl Question 3 (T/F): Approximately 30% of Salmonella infection is associated with travel to Mexico and Asia.

The correct answer is False: As much as 70% of infection is associated with travel to Mexico and Asia.

Pearl Question 4 (T/F): Patients aged at the extremes of life, immunocompromised patients, patients older than 50 years with severe cardiovascular disease, and patients with prosthetic implants may benefit from early antibiotic therapy to treat Salmonella infection.

The correct answer is True: Controversy exists over whether or not antibiotic therapy is of any value. While it is thought that some groups at high risk for bacteremia may benefit from antibiotic prophylaxis, less than 5% of patients develop bacteremia. Nevertheless, prophylaxis should be considered in newborns, persons older than 50 years with severe atherosclerosis, immunosuppressed patients, and individuals with cardiovascular abnormalities and prostheses.

BIBLIOGRAPHY

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