375.full

Article

infectious diseases

Sa S almonella Infections John C. Christenson, MD*

Author Disclosure Dr Christenson has disclosed no financial relationships relevant to this article. This commentary does not

Practice Gaps 1. Becaus Becausee Salmonella disease causes 93.8 million illnesses and 155,000 deaths worldwide and 1 million foodborne illnesses and 350 deaths in the United States, clinicians must learn to recognize, treat, and prevent these infections. 2. Young infants, infants, persons with hemoglobin disorders, disorders, and individuals who are immune compromised, such as those with human immunodeficiency virus and cancer, are at risk for severe Salmonella disease, including bacteremia, meningitis, and osteomyelitis.

contain discussion of unapproved/ investigative use of a commercial product/ device.

Objectives 1. 2. 3. 4. 5.

After completing completing this article, article, readers readers should be able to:

Describe the epidemi Describe epidemiology ology of nontypho nontyphoidal idal salmonellosis. salmonellosis. Recognize Recogni ze the clinical features of enteric fevers. Appropriately Appropr iately treat the young child with Salmonella infection. Understand Underst and ways to prevent prevent Salmonella infections. Use typhoid vaccines vaccines when indicated.

Introduction Salmonella infection infection is a common cause of gastroenteritis and bacteremia worldwide. The consumption of contaminated water and food and the close contact with colonized animals are frequent risk factors for acquisition. Young infants, persons with hemoglobin disorders, and individuals who have immunocompromising conditions, such as human immunode �ciency virus (HIV) and cancer, are at risk for severe disease, such as bacteremia, meningitis, and osteomyelitis. Salmonella Typhi Typhi and Salmonella Paratyphi Paratyphi are responsible for signi �cant morbidity and mortality in developing countries. Clinicians must learn to recognize these infections and know how to effectively treat and prevent them. This review article provides the reader with enhanced knowledge knowledge of this diverse group of pathogens.

Microbiology The genus Salmonella is is composed of motile gram-negative bacteria within the family Enterobacteriaceae. They are oxidase-negative, indole-negative, and nonlactose fermenters. The nomenclature of the genus Salmonella can be challenging. The Centers for Disease Control and Prevention and the World Health Organization have been responsible for maintainin maintaining g the format format for formula formula designatio designation. n. There There are 2 Salmonella species, species, Salmonella enterica and and Salmonella bongori , which are classi �ed further into subspecies according to their their bioche biochemic mical al and genomi genomicc relate relatedne dness. ss. Most Most human human infect infection ionss are caused caused by a serot serotype ype Salmonella enterica subsp of Salmonella subsp enterica (subspecies (subspecies I), which infect warm-blooded animals. Five other subspecies (plus S bongori [subspecies [subspecies V]) are known to colonize cold-blooded animals and the environment: enterica subsp subsp salamae (subspecies (subspecies II), arizonae (subspecies (subspecies IIIa), diarizonae (subspecies (subspecies IIIb), houtenae (subspecies (subspecies IV), and indica (subspecies (subspecies VI). Although more than 2,600 serotypes of Salmonella have been identi �ed, most disease is caused by subspecies/serotypes Typhimurium and Enteritidis. Historically, serotypes are frequently reported as species. For simplicity, in this review we use genus and

*Ryan White Center for Pediatric Infectious Disease, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN. Pediatrics in Review Vol.34 No.9 September 2013 375

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infectious diseases salmonella

subspecies/serotype (eg, Salmonella Typhi or Salmonella Typhimurium). Non–subspecies I are rarely reported as human pathogens. Certain serotypes frequently correlate with a disease syndrome or food source. As examples, Salmonella choleraesuis and Salmonella dublin are both frequently associated with bacteremia and extraintestinal infections. (1)(2)

Epidemiology Nontyphoidal Salmonella Infections Salmonella gastroenteritis is a serious public health problem in the United States. An estimated 1 million foodborne illnesses occur each year, resulting in 350 deaths. (3) The world burden is estimated at 93.8 million illnesses, with 155,000 deaths each year. Salmonella Enteritidis is the most common isolated subspecies because it is responsible for 65% of these infections, followed by S Typhimurium at 12%. In the United States, exposures to chicken and eggs are most likely sources for infection. Many risk factors are associated with infection and dissemination. Achlorhydria, the use of antacids or proton pump inhibitors, and rapid gastric emptying favor bacterial survival. Conditions that impair cell-mediated lymphocyte function, such as HIV/AIDS, malnutrition, corticosteroid therapy, and posttransplantation immunosuppressive therapy, are major risk factors. An overloaded reticuloendothelial system with iron or hemoglobin, such as in patients with sickle cell anemia, hemolytic anemia, thalassemia, and malaria, may increase the likelihood of severe disease. Infarcts in the gastrointestinal tract and bone and defective phagocytic and opsonic function also appear to contribute to the severity of disease observed in patients who have sickle cell anemia. Diseases such as leukemia and lymphoma also impair the reticuloendothelial system function. The morbidity and mortality associated with Salmonella infections are also in �uenced by the serotype that causes the infection. Salmonella choleraesuis is more likely to cause invasive disease. In one study, 85% of isolates were recovered from extraintestinal sites, especially blood. (1) Seventy-two percent of patients were younger than 3 years. Pediatric patients were more likely to have diarrhea than adults. Most of the children with diarrhea were also bacteremic. Mycotic aneurysms, a complication observed in adults, was not detected in any of the pediatric cases. Of importance, only 21% of children had leukocytosis. Occult bacteremia, where the child presents only with fever, was a common presentation. In a population-based, case-control study of salmonellosis in infants younger than 1 year, infected infants were

more likely to be bottle fed, have exposure to reptiles, have ridden in a shopping cart next to meat or poultry, traveled abroad, or attended a day care center with an infected infant. (4) Most Salmonella infections are foodborne. In Mexico, pork, meat, and poultry were frequently found to be contaminated with Salmonella . Consumption of contaminated orange juice led to an outbreak in a theme park. An intentional contamination of restaurant salad bars was responsible for a large outbreak of Salmonella gastroenteritis in Oregon in 1984. Contaminated peanut butter, ice cream, salami products, and mozzarella cheese has been responsible for multistate outbreaks in the United States. Outbreaks have also been associated with exposure to contaminated dry dog food and pet treats. Animals such as chickens, pigs, turtles, lizards, iguanas, hedgehogs, and amphibians have been identi �ed as reservoirs of Salmonella . Many of these colonizations have resulted in human outbreaks. An outbreak of S Typhimurium was associated with exposures to pet rodents. Feeder rodents used for the feeding of reptiles and amphibians were found to be colonized with Salmonella , resulting in human infections. Patients with Salmonella arizonae acquired from iguanas and snakes have a predisposition for musculoskeletal infections. In a rare event, 2 patients developed S Enteritidis sepsis (in one case fatal) after a platelet transfusion. The donor most likely had asymptomatic bacteremia from handling his pet boa constrictor. Nosocomial outbreaks are uncommon. However, inadequate infection control practices, understaf �ng, and overcrowding may lead to environmental contamination. In some developing countries, asymptomatic carriage of Salmonella can be high among children attending day care centers. Outbreaks of salmonellosis in day care centers have been reported, but these are considered rare events. Although the incidence of salmonellosis related to international travel appears to be decreasing in the United States, many travel-acquired cases are still reported. Salmonella stanley , a common serotype in Southeast Asia (second most common in Thailand), has been frequently isolated in Europe. (5) In Southeast Asia, the serotype is frequently associated with the pork industry. Nontyphoidal Salmonella infections remain a frequent cause of invasive disease in many regions of the world, especially in sub-Saharan Africa. Children younger than 3 years and those infected with HIV have the greatest burden. Mortality remains high, especially in children with

376 Pediatrics in Review Vol.34 No.9 September 2013



bacteremia and meningitis. Seasonal peaks of disease coincide with the rainy season, which leads to fecal contamination of drinking water. In many countries, an association between malaria and Salmonella is well known. This situation often delays treatment, causing greater morbidity and mortality. Frequently, febrile persons are treated only for malaria without considering the likelihood of a coinfection. Clinical features, such as fevers, anemia, and splenomegaly, are frequent � ndings in both conditions.

Enteric Fever (Typhoid and Paratyphoid Fever) Enteric fever, an infection caused by S Typhi (typhoid fever) or S Paratyphi A, B, or C (paratyphoid fever), is a common cause of death and disease in many parts of the world. Approximately 22 million cases are thought to occur worldwide each year, with 200,000 deaths as a result. (6) Most infections occur in Southern and Southeast Asia. Parts of Africa and Latin America are also affected but at a lower frequency. In Asia, it is estimated that the incidence approximates 100 cases per 100,000 population. Travelers to endemic regions are at risk. Most cases in the United States have been associated with international travel. Travelers visiting friends and relatives are at the highest risk of infection. In countries such as India, children and adolescents in the 5- to 19-year age group are affected most. On rare occasions, neonatal infections have been reported. These infections are frequently acquired from the mother. In South and Southeast Asia, S Typhi is the most common cause of community-acquired bacteremia. Between 1960 and 1999, 60 outbreaks of typhoid fever had been reported in the United States. (7) Ninety percent were domestically acquired. Recently, cases were found to be related to the consumption of a fruit shake made from frozen mamey fruit from Guatemala. (7) In recent years, an outbreak of S Paratyphi B was found to be related to exposure to pet turtles. The major factor responsible for the magnitude of this problem is poor sanitary infrastructure, resulting in substandard drinking water and contaminated food. Person-toperson transmission from chronic asymptomatic carriage also contributes to the infection of susceptible individuals (eg, typhoid Mary).

Pathogenesis The pathogenesis of salmonellosis is complex. Several virulence genes are responsible for the severity of disease observed with certain species.

Nontyphoidal isolates are rarely invasive because most do not extend past the lamina propria or the intestinal lymphatic system. However, interactions with host cells in the intestines may lead to a release of proin �ammatory cytokines that result in the recruitment of neutrophils to the area, resulting in gastroenteritis. Some genes appear to play a role in the survival of bacteria within the liver and spleen and promote the replication within macrophages. (8) Salmonella Typhi is known to adhere to epithelial cells over the lymphatic Peyer patches, allowing for penetration through the intestinal mucosa. Engulfment by macrophages and translocation into draining lymph nodes results in bacteremia and subsequent dissemination. The organism survives within the host cells in a Salmo- nella -containing vacuole, assuring its ability to replicate, survive, and invade and resulting in the multiplication and survival of bacteria within the liver, spleen, and bone marrow. After an incubation period of 7 to 14 days, bacteremia occurs and symptoms emerge. Salmonella Typhi can be found in the gallstones of individuals who live in endemic regions. Its presence correlates with fecal shedding, and these people are known to infect others.

Clinical Aspects Nontyphoidal Salmonella Infections Gastroenteritis is the most frequent presentation. Most affected children are younger than 1 year. The usual incubation period for Salmonella gastroenteritis is 6 to 12 hours. Nausea, vomiting, and diarrhea are common symptoms. Diarrhea is usually nonbloody. Myalgias, arthralgias, and headaches are also reported. Although observed in children with Salmonella gastroenteritis, fever, chills, and abdominal pain are more commonly observed with shigellosis. The presence of rectal tenesmus accompanied by stools with mucus and/or blood is more distinctive of Shigella infections. Symptoms are generally self-limited. Hepatomegaly and splenomegaly are infrequently noted. Bacteremia is commonly observed in infants with gastroenteritis. Most children require hospitalization. Persistent bacteremia can be detected in approximately 40% of patients. Salmonella Enteritidis was a frequently isolated pathogen in bacteremic patients. In children, bacteremia is rarely fatal. In contrast, one-third of adults presenting with primary bacteremia have extraintestinal organ in volvement and will die. Clinical features or laboratory parameters were unable to detect children more likely to have persistent bacteremia. Pediatrics in Review Vol.34 No.9 September 2013 377



Although focal infections were observed in 2.5% of pre viously healthy children, one-third of children with underlying medical conditions had focal disease, consisting of meningitis, osteomyelitis, septic arthritis, pneumonia, or cholangitis. In parts of Africa, the fatality rate for bacteremia is close to 25%. Lower respiratory tract coinfections with tuberculosis and Streptococcus pneumoniae were common. Meningitis and musculoskeletal infections are common complications in infants younger than 3 months. It is estimated that 50% to 75% of Salmonella meningitis occurs in the �rst year of life. Asymptomatic disease is also common in young infants. A well-appearing infant with Salmonella gastroenteritis may be bacteremic. Malaria has been found to be a risk factor for invasive nontyphoidal Salmonella infections in children. A reduction in cases of salmonellosis was associated with a decrease in the number of malaria cases. Compared with children with gastroenteritis alone, bacteremic children appear to have a longer duration of symptoms, a less severe clinical appearance, and fewer signs of dehydration. This gradual presentation with less dehydration and fewer toxic effects may lead to premature discharges from emergency departments.

Typhoid and Paratyphoid Fever Fever, gastrointestinal symptoms (eg, vomiting, severe diarrhea, abdominal distension, and pain), cough, relative bradycardia, rose spots (pink macules frequently observed on the abdomen and chest), and splenomegaly are frequently regarded as features of typhoid and paratyphoid fever. However, many patients lack these �ndings, making diagnosis dif �cult if solely based on clinical features. In a reported foodborne epidemic, most patients had nonspeci �c symptoms, consisting of fever, headache, diarrhea, and anorexia. Hepatomegaly was seen in 7% of patients, splenomegaly in 13% of patients, and rose spots in 5% of patients. Relative bradycardia and rose spots are seldom observed in children. Jaundice is frequently observed among children. Febrile convulsions have been reported in children with enteric fever and may be the presenting symptom in some children. The incubation period for enteric fevers is generally 7 to 14 days, with a range of 3 to 60 days. In Pakistan, children younger than 5 years were found to have more severe disease. More than 95% of children had fever, 20% to 41% had hepatomegaly, 5% to 20% had splenomegaly, 19% to 28% had abdominal pain, and 8% to 35% had diarrhea. (9) Cough was

observed in approximately 15% of patients. Severe disease resulted in more hospitalizations. Intestinal perforation was a rare complication observed in less than 1% of children. Thrombocytopenia and disseminated intravascular coagulation are markers of severe disease. Splenic abscess, brain abscess, and subdural empyema are rare complications of typhoid fever. An analysis of travel-related cases in the United Kingdom found that S Typhi and S Paratyphi infections were indistinguishable clinically. (10) Infections caused by S Paratyphi can be just as severe as those caused by S Typhi. Most patients had normal white blood cell counts (91%), and 82% of patients had an elevated alanine aminotransferase level. Among travelers, more cases of enteric fever were caused by S Paratyphi A than by S Typhi. GuillainBarré syndrome has been described in association with S Paratyphi A infection. Mixed infections with multiple pathogens occur in endemic tropical countries. Treatment against enteric fever should be considered for children with unremitting fevers after completing adequate antimalarial therapy.

Diagnosis There are no features of Salmonella gastroenteritis that would allow its diagnosis based on clinical � ndings alone. The routine microscopic stool examination for polymorphonuclear cells is of limited clinical utility because a large number of children with gastroenteritis will have a negative test result ( <5 polymorphonuclear cells per highpower �eld). All young infants with diarrhea, especially those younger than 3 months with a positive stool culture result, should have a blood culture performed, even i f the infant is well-appearing. Infants younger than 3 months with a positive blood culture result should undergo a lumbar puncture and careful examination assessing for the presence of musculoskeletal involvement (Table 1). (11) Any ill-appearing infant with a positive stool culture result should undergo a blood culture and lumbar puncture, be hospitalized, and be treated with parenteral antibiotics. The Widal test, a classic test that measures antibodies against O and H antigens of S Typhi, was used for the diagnosis of typhoid fever. However, its lack of sensitivity and speci�city has limited its utility. A false-positive test result may lead to overtreatment and a delay in considering other conditions. This outcome is especially likely in parts of the world where typhoid fever is rare among children and signi �cantly less frequent than other bacterial pathogens.




Table 1.

Management of Pediatric Salmonella Gastroenteritis

Signs and Symptoms

Diagnosis

Age <3 months Diarrhea (dysentery-like, bloody): Diarrhea

5 days, not dysentery-like or bloody

<

Febrile

Management

Obtain stool culture Obtain blood culture No stool culture Stool culture positive Blood culture negative Stool culture positive Blood culture positive

History of exposure to Salmonella

Hydration No antibiotics Treat with parenteral antibiotics, 5-7 days Lumbar puncture Treat with parenteral antibiotics: Bacteremia only: 14 days Meningitis: 4-6 weeks Osteomyelitis: 4-6 weeks

Obtain stool culture Obtain blood culture

Age >3 months Diarrhea ‡5 days: Afebrile

Obtain stool culture Stool culture positive

Febrile, but non–toxic-appearing

Stool culture positive

Toxic, ill-appearing, or immunocompromised host

Stool culture positive Stool culture positive Blood culture positive

Observation No antibiotics Blood culture Observe off antibiotics Blood culture Lumbar puncture Treat with parenteral antibiotics Lumbar puncture Treat with parenteral antibiotics: Bacteremia only: 14 days Meningitis: 4-6 weeks Osteomyelitis: 4-6 weeks

Adapted from: St. Geme J, Hodes H, Marcy SM, et al. Consensus: Management of Salmonella infection in the � rst year of life. Pediatric Infectious Disease Journal . 1988; 7(9):615–621. Copyright 1988 (c) by Wolters Kluwer Health/Williams & Wilkens.

In patients with typhoid fever, blood culture results are frequently positive, but stool cultures are less so. Although liver enzyme levels are frequently elevated, leukocytosis is not always observed. Leukopenia and anemia are frequently associated with enteric fevers. A normal white blood cell count does not rule out invasive disease. Many suggest that bone marrow cultures have a higher sensitivity. Obtaining this type of specimen is much more invasive and impractical in many circumstances. Approximately 20% of patients may have pneumonia as documented by abnormal radiography results. Although pathogen-speci�c serologic and polymerase chain reaction assays are the preferred methods for diagnosing enteric fever, diagnosis is still made using clinical criteria in most lower-income countries. Unfortunately, early features of enteric fever mimic other conditions, such as pneumonia, malaria, sepsis, dengue, acute hepatitis, and rickettsial infections.

Treatment Previously healthy children and adults with uncomplicated gastroenteritis do not require antimicrobial therapy because the disease is self-limited. Infants younger than 3 months with Salmonella gastroenteritis should be treated because they have a high incidence of extraintestinal complications, such as bacteremia, meningitis, and osteomyelitis (Table 1). Antimicrobial therapy may prolong the carrier state. Therapy should be considered for those individuals with high-risk medical conditions, such as HIV, sickle cell anemia, and cancer. Antimicrobial treatment must take into account the local epidemiology and therapeutic practice in the country where the infection was acquired. Chloramphenicol, amoxicillin, and the combination of trimethoprim and sulfamethoxazole are no longer recommended as � rst-line agents for the treatment of enteric fevers. The high frequency of treatment failures, Pediatrics in Review Vol.34 No.9 September 2013 379



resistance, and relapse rates has diminished their usefulness. Antimicrobial resistance observed in many countries has in �uenced the choice of agent for treating typhoid and paratyphoid fever. Ceftriaxone remains the recommended agent in the most severe cases in which parenteral therapy is indicated. Cefotaxime is an acceptable alternative. Although � uoroquinolones, such as cipro �oxacin, are generally associated with high cure rates, defervescence within a week, and lower relapse and fecal carriage rates, isolates from many Asian countries demonstrate resistance, rendering them ineffective. Azithromycin appears fa vorable in the treatment of these infections. (12) Until recently, � uoroquinolone resistance was uncommon in most regions of Africa. In a recent study from the Democratic Republic of the Congo, decreased cipro� oxacin susceptibility was detected in 15.4% of tested isolates. (13) Proper hydration, perfusion, and fever control still remain integral components of treating enteric fever. More than 10 years ago, multidrug resistance was uncommon in Latin America. Susceptibility to ampicillin was common, and susceptibility to ceftriaxone was almost universal. At the same time, in some Mediterranean countries, close to one-third of isolates were resistant to ampicillin. In infections by S choleraesuis , resistance to cipro� oxacin was observed in 28% of pediatric cases in Taiwan, whereas more than 60% of cases in adults had a resistant strain. (1) Irrespective of age, resistance to trimethoprim-sulfamethoxazole remained high. Eighty-four percent of samples of ground meats (beef, turkey, and pork) purchased at several supermarkets in the Washington, DC, area were found to be contaminated with Salmonella isolates that were resistant to at least one antibiotic; 53% were resistant to 3 antibiotics. (14) Of greater concern, 16% of the isolates were resistant to ceftriaxone, the drug of choice for the treatment of serious infections in children. In a recent study of invasive salmonellosis among Thai children, ceftriaxone resistance was detected in 17.4% of isolates. (15) Patients with typhoid fever complicated by delirium, obtundation, shock, and coma may bene �t from dexamethasone therapy. This adjunctive therapy appears to lower mortality. (16) Relapse rates in children are only 2% to 4% after therapy but have been reported after most regimens. Prolonged carrier rates occur in less than 2% of infected children.

Prevention Improving the quality of drinking water and food will lead to a decrease in Salmonella cases, as will decreasing exposure to high-risk animals (Table 2). Routine vaccination of school-age children can be an important component of a typhoid fever control program in an endemic region. (17) Vaccinating children younger than 2 years living in slums in India with the Vi capsular polysaccharide typhoid vaccine demonstrated a 61% protective effectiveness compared with a placebo. In children age 2 to 5 years, the protective effect was 80%. Of interest, the level of protection was 44% among unvaccinated members of Vi vaccinee clusters. (18) Similar favorable results have been observed in other countries.

Preventing Salmonella Infections Table 2.

High-risk animals 1. Parents and children should be counseled about the potential risk of acquiring Salmonella when owning an iguana, lizard, snake, or turtle. 2. Owners need to wash their hands after handling animals, their cages, or their tanks. 3. Individuals at high risk of severe disease, such as children age <5 years and those who are immunocompromised, should avoid contact with high-risk animals. 4. High-risk animals should be kept out of child-care centers. 5. High-risk animals should not be allowed to roam free within the home. They should not be kept in kitchens or where food is prepared. Cages and tanks should not be washed in kitchen sinks. Food handling 6. Hand hygiene should be practiced when handling raw meat. Cutting boards must be cleaned thoroughly after preparing raw meat and food items that contain raw egg. 7. People should not consume raw eggs and undercooked meats. 8. Mothers are encouraged to breastfeed young infants. This practice has shown to reduce infections. Infection control 9. Young children with enteric fever ( Salmonella Typhi and Salmonella Paratyphi) should be kept out of child daycare centers until they have at least 3 consecutive negative stool culture results. 10. Infants and children with nontyphoidal Salmonella gastroenteritis can return to child daycare center once diarrhea has subsided.




Vaccination against typhoid fever is recommended for all travelers to developing countries in Asia, Latin America, and Africa, especially for those planning to visit friends and relatives with 2 vaccines available (Table 3). Travel to India, Pakistan, Mexico, and Bangladesh account for most travelrelated cases in the United States. Generally, typhoid vaccines are 50% to 80% effective in preventing disease. In many highly endemic countries, S Paratyphi causes close to 50% of all cases of enteric fever. In the United States, most cases of paratyphoid fever are related to international travel. No effective licensed vaccine against S Paratyphi is available. However, crossprotective ef �cacy of Ty21a oral typhoid vaccine

against paratyphoid fever B has been demonstrated. (19)(20) Parents and their children need to be counseled about the potential risk of acquiring Salmonella if they own a high-risk pet, such as an iguana, lizard, snake, or turtle (Table 2). Owners need to wash their hands after handling the animals. The Centers for Disease Control and Prevention has advised that reptiles and amphibians should be kept out of households with children younger than 5 years. Individuals at high risk of severe disease should have no contact with these animals. Reptiles and amphibians should be kept out of child care centers and households with children younger than 1 year. All documented cases of Salmonella infection must be reported to county and state health departments.

Vaccines Licensed for the Prevention of Typhoid Fever Table 3.

Oral typhoid vaccine Ty21a Live-attenuated

For persons age ‡6 years Series: 4 doses; 1 capsule every other day (days 0, 2, 4, and 6) Take with cool water, 1 hour before meal Must complete series at least 1 week before exposure Capsules must be refrigerated Capsules should not be broken and contents mixed with food/water because this inactivates the vaccine; should not be taken with antibiotics Repeat 4-dose series every 5 years if exposure continues Contraindicated in individuals with immunocompromising conditions Potential adverse effects: Nausea, abdominal pain, cramps, vomiting, fever, headaches, and rash

Injectable Vi typhoid vaccine Capsular polysaccharide

For persons ‡2 years Single injection, 0.5 mL, intramuscular, deltoid Vaccine must be administered at least 2 weeks before exposure. Thimerosal-free Booster: Every 2 years if exposure continues Potential adverse effects: Injection site pain, erythema, and induration; occasional fever and flulike symptoms.

Complications and Prognosis Ileal perforations in the tropics are frequently considered to be associated with enteric fever. Between 4% and 6% of ileal perforations were associated with S Typhi and S Paratyphi A. In parts of Africa, 50% of all admissions for typhoid-related ileal perforation were in children, with close to two-thirds occurring between ages 5 and 6 years. Underdiagnosing milder cases of enteric fever that resulted in delayed or inadequate antimicrobial treatment may have resulted in a higher rate of perforations. Fever, vomiting, and abdominal tenderness and distension are suggestive of ileal perforation. Postoperative complications are common, such as surgical wound infection, intra-abdominal abscesses, ileus, and reperforation. Mortality is high in children: close to 40% in children younger than 5 years and 20% in children older than 5 years. (21) Rhabdomyolysis with acute renal failure has been reported as a complication of typhoid fever. Pediatrics in Review Vol.34 No.9 September 2013 381



10. Patel TA, Armstrong M, Morris-Jones SD, Wright SG,

Summary • On the basis of strong research evidence, exposures to contaminated food, water, and colonized animals are major risk factors for Salmonella infections. (3)(4)(7)(14) • On the basis of research evidence and consensus, infants younger than 3 months with Salmonella gastroenteritis are at an increased risk of extraintestinal complications, such as bacteremia, meningitis, and osteomyelitis, and must be treated regardless of severity of illness. (4)(11) • On the basis of strong research and epidemiologic evidence, antimicrobial resistance is a serious problem in the treatment of typhoid fever. (12)(13)(14) • On the basis of strong research evidence, vaccines can effectively prevent typhoid fever. (17)(18)(19)(20) • On the basis of published guidelines and current standards of care, children younger than 5 years and those with immunocompromising conditions, such as human immunodeficiency virus and cancer, should avoid contact with turtles, iguanas, and snakes. (3)

References 1. Chiu CH, Chuang CH, Chiu S, Su LH, Lin TY. Salmonella enterica serotype Choleraesuis infections in pediatric patients. Pediatrics . 2006;117(6):e1193 –e1196 2. Cohen JI, Bartlett JA, Corey GR. Extra-intestinal manifestations of salmonella infections. Medicine (Baltimore). 1987;66(5):349–388 3. Chai SJ, White PL, Lathrop SL, et al. Salmonella enterica serotype Enteritidis: increasing incidence of domestically acquired infections. Clin Infect Dis . 2012;54(suppl 5):S488–S497 4. Jones TF, Ingram LA, Fullerton KE, et al. A case-control study of the epidemiology of sporadic Salmonella infection in infants. Pediatrics . 2006;118(6):2380 –2387 5. Hendriksen RS, Le Hello S, Bortolaia V, et al. Characterization of isolates of Salmonella enterica serovar Stanley, a serovar endemic to Asia and associated with travel. J Clin Microbiol . 2012;50(3): 709–720 6. Bhutta ZA. Current concepts in the diagnosis and treatment of typhoid fever. BMJ . 2006;333(7558):78–82 7. Loharikar A, Newton A, Rowley P, et al. Typhoid fever outbreak associated with frozen mamey pulp imported from Guatemala to the western United States, 2010. Clin Infect Dis . 2012;55(1):61–66 8. Lahiri A, Lahiri A, Iyer N, Das P, Chakravortty D Visiting the cell biology of Salmonella infection. Microbes Infect . 2010;12(11): 809-818. 9. Siddiqui FJ, Rabbani F, Hasan R, Nizami SQ, Bhutta ZA. Typhoid fever in children: some epidemiological considerations from Karachi, Pakistan. Int J Infect Dis . 2006;10(3):215 –222

Doherty T. Imported enteric fever: case series from the hospital for tropical diseases, London, United Kingdom. Am J Trop Med Hyg . 2010;82(6):1121 –1126 11. Geme JW III, Hodes HL, Marcy SM, et al. Consensus: management of Salmonella infection in the � rst year of life. Pediatr Infect Dis J . 1988;7(9):615 –621 12. Chinh NT, Parry CM, Ly NT, et al. A randomized controlled comparison of azithromycin and o�oxacin for treatment of multidrugresistant or nalidixic acid-resistant enteric fever. Antimicrob Agents Chemother . 2000;44(7):1855–1859 13. Lunguya O, Lejon V, Phoba MF, et al. Salmonella Typhi in the Democratic Republic of the Congo: �uoroquinolone decreased susceptibility on the rise. PLoS Negl Trop Dis . 2012;6(11): e1921 14. White DG, Zhao S, Sudler R, et al. The isolation of antibioticresistant salmonella from retail ground meats. N Engl J Med . 2001; 345(16):1147–1154 15. Punpanich W, Netsawang S, Thippated C. Invasive salmonellosis in urban Thai children: a ten-year review. Pediatr Infect Dis J . 2012;31(8):e105–e110 16. Chisti MJ, Bardhan PK, Huq S, et al. High-dose intravenous dexamethasone in the management of diarrheal patients with enteric fever and encephalopathy. Southeast Asian J Trop Med Public Health . 2009;40(5):1065 –1073 17. Bhan MK, Bahl R, Bhatnagar S. Typhoid and paratyphoid fever. Lancet . 2005;366(9487):749–762 18. Sur D, Ochiai RL, Bhattacharya SK, et al. A cluster-randomized effectiveness trial of Vi typhoid vaccine in India. N Engl J Med . 2009; 361(4):335 –344 19. Pakkanen SH, Kantele JM, Kantele A. Cross-reactive gutdirected immune response against Salmonella enterica serovar Paratyphi A and B in typhoid fever and after oral Ty21a typhoid vaccination. Vaccine . 2012;30(42):6047 –6053 20. Wahid R, Simon R, Zafar SJ, Levine MM, Sztein MB. Live oral typhoid vaccine Ty21a induces cross-reactive humoral immune responses against Salmonella enterica serovar Paratyphi A and S. Paratyphi B in humans. Clin Vaccine Immunol . 2012;19(6): 825–834 21. Ekenze SO, Ikefuna AN. Typhoid intestinal perforation under 5 years of age. Ann Trop Paediatr . 2008;28(1):53 –58

Suggested Reading Gordon MA. Invasive nontyphoidal Salmonella disease: epidemiology, pathogenesis and diagnosis. Curr Opin Infect Dis . 2011;24 (5):484–489 Tsai MH, Huang YC, Chiu CH, et al. Nontyphoidal Salmonella bacteremia in previously healthy children: analysis of 199 episodes. Pediatr Infect Dis J . 2007;26(10):909 –913 Whitaker JA, Franco-Paredes C, del Rio C, Edupuganti S. Rethinking typhoid fever vaccines: implications for travelers and people living in highly endemic areas. J Travel Med . 2009;16 (1):46–52

Parent Resources From the AAP at HealthyChildren.org The reader is likely to find material relevant to this article to share with parents by visiting these links: • English: http://www.healthychildren.org/English/health-issues/conditions/infections/Pages/Salmonella-Infections.aspx • Spanish: http://www.healthychildren.org/spanish/health-issues/conditions/infections/paginas/salmonella-infections.aspx




PIR Quiz This quiz is available online at http://www.pedsinreview.aappublications.org. NOTE: Learners can take Pediatrics in Review quizzes and claim credit online only . No paper answer form will be printed in the journal.

New Minimum Performance Level Requirements Per the 2010 revision of the American Medical Association (AMA) Physician’s Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 Credit TM. In order to successfully complete 2013 Pediatrics in Review articles for AMA PRA Category 1 Credit TM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. In Pediatrics in Review , AMA PRA Category 1 Credit TM may be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. A 6–year–old girl who presents with fever and diarrhea after a trip to India is suspected of having typhoid fever. Which of the following findings is most frequently noted with this diagnosis? A. B. C. D. E.

Normal hemoglobin level. Normal liver enzyme level. Normal white blood cell count. Positive blood culture result. Positive stool culture result.

2. A previously healthy 9–month–old with vomiting and nonbloody diarrhea has a stool culture result positive for Salmonella. Which of the following is appropriate treatment of this infant? A. B. C. D. E.

Azithromycin. Ceftriaxone. Chloramphenicol. No antibiotics. Trimethoprim-sulfamethoxazole.

3. A 7–month–old girl is traveling with her parents to Pakistan. Which of the following preventive measures is most appropriate for this child? A. B. C. D. E.

Avoid fresh fruits and vegetables. Bathe only in fresh water ponds. Injectable Vi typhoid vaccine. Oral typhoid vaccine Ty21a. Prophylaxis with azithromycin.

4. A 6–month–old female has a stool culture result positive for Salmonella. Her parents inquire as to what they could do to prevent this from happening again. Which of the following features is an established risk factor for this infection? A. B. C. D. E.

Breastfeeding. Nanny at home. Oatmeal cereal. Pet turtle at home. Travel to New Mexico.

5. Mixed infections with multiple pathogens occur in endemic tropical countries. Which of the following disorders in children treated for enteric fever who present with unremitting fevers is therapy most appropriate? A. B. C. D. E.

Dengue. Malaria. Rickettsia. Shigella. Tuberculosis.

Pediatrics in Review Vol.34 No.9 September 2013 383


Salmonella Infections

John C. Christenson 2013;34;375 DOI: 10.1542/pir.34-9-375

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Salmonella Infections

John C. Christenson Pediatrics in Review 2013;34;375 DOI: 10.1542/pir.34-9-375

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/34/9/375

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.


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