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infectious diseases
Salmonella 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. Because 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, persons with hemoglobin 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.
Introduction
Salmonella 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
immunodeciency virus (HIV) and cancer, are at risk for severe disease, such as bacteremia, meningitis, and osteomyelitis. Salmonella Typhi and Salmonella Paratyphi are responsible for signicant 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 of this diverse group of
pathogens.
Microbiology
The genus Salmonella 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
maintaining the format for formula designation. There are 2 Salmonella species, Salmonella
enterica and Salmonella bongori, which are classied further into subspecies according to
their biochemical and genomic relatedness. Most human infections are caused by a serotype
of Salmonella enterica subsp enterica (subspecies I), which infect warm-blooded animals.
Five other subspecies (plus S bongori [subspecies V]) are known to colonize cold-blooded
animals and the environment: enterica subsp salamae (subspecies II), arizonae (subspecies
IIIa), diarizonae (subspecies IIIb), houtenae (subspecies IV), and indica (subspecies VI).
Although more than 2,600 serotypes of Salmonella have been identied, 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.
infectious diseases
salmonella
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 inuenced 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
infectious diseases
Pathogenesis
The pathogenesis of salmonellosis is complex. Several virulence genes are responsible for the severity of disease observed with certain species.
salmonella
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 involvement 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
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Although focal infections were observed in 2.5% of previously 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.
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. GuillainBarr 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 if 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 specicity 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 signicantly less frequent than other bacterial
pathogens.
infectious diseases
Table 1.
salmonella
Diagnosis
Management
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
Toxic, ill-appearing, or
immunocompromised host
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):615621. Copyright 1988 (c) by Wolters Kluwer Health/Williams & Wilkens.
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
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resistance, and relapse rates has diminished their usefulness. Antimicrobial resistance observed in many
countries has inuenced 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 ciprooxacin, 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 favorable 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 ciprooxacin 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 ciprooxacin 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 benet 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.
infectious diseases
Table 3.
Oral typhoid
vaccine Ty21a
Live-attenuated
salmonella
infectious diseases
salmonella
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):e1193e1196
2. Cohen JI, Bartlett JA, Corey GR. Extra-intestinal manifestations
of salmonella infections. Medicine (Baltimore). 1987;66(5):349388
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):S488S497
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):23802387
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):
709720
6. Bhutta ZA. Current concepts in the diagnosis and treatment of
typhoid fever. BMJ. 2006;333(7558):7882
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):6166
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):215222
Suggested Reading
Gordon MA. Invasive nontyphoidal Salmonella disease: epidemiology, pathogenesis and diagnosis. Curr Opin Infect Dis. 2011;24
(5):484489
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):909913
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):4652
infectious diseases
salmonella
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.
1. A 6yearold 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. Normal hemoglobin level.
B. Normal liver enzyme level.
C. Normal white blood cell count.
D. Positive blood culture result.
E. Positive stool culture result.
2. A previously healthy 9monthold with vomiting and nonbloody diarrhea has a stool culture result positive for
Salmonella. Which of the following is appropriate treatment of this infant?
A. Azithromycin.
B. Ceftriaxone.
C. Chloramphenicol.
D. No antibiotics.
E. Trimethoprim-sulfamethoxazole.
3. A 7monthold 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.
4. A 6monthold 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.
Salmonella Infections
John C. Christenson
Pediatrics in Review 2013;34;375
DOI: 10.1542/pir.34-9-375
References
This article cites 24 articles, 9 of which you can access for free at:
http://pedsinreview.aappublications.org/content/34/9/375#BIBL
Subspecialty Collections
Reprints
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
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