Salmonellosis: Introduction

Bacteria of the genus Salmonella are highly adapted for growth in both humans and animals
and cause a wide spectrum of disease. The growth of serotypes S. typhi and S. paratyphi is
restricted to human hosts, in whom these organisms cause enteric (typhoid) fever. The
remaining serotypes (nontyphoidal Salmonella, or NTS) can colonize the gastrointestinal
tracts of a broad range of animals, including mammals, reptiles, birds, and insects. More than
200 serotypes are pathogenic to humans, in whom they often cause gastroenteritis and can be
associated with localized infections and/or bacteremia.
Etiology
This large genus of gram-negative bacilli within the family Enterobacteriaceae consists of
two species: S. enterica, which contains six subspecies, and S. bongori. S. enterica subspecies
I includes almost all the serotypes pathogenic for humans. According to the current
Salmonella nomenclature system, the full taxonomic designation S. enterica subspecies
enterica serotype typhimurium can be shortened to Salmonella serotype typhimurium or
simply S. typhimurium.
Members of the seven Salmonella subspecies are classified into >2500 serotypes (serovars)
according to the somatic O antigen [lipopolysaccharide (LPS) cell-wall components], the
surface Vi antigen (restricted to S. typhi and S. paratyphi C), and the flagellar H antigen. For
simplicity, most Salmonella serotypes are named for the city where they were identified, and
the serotype is often used as the species designation.
Salmonellae are gram-negative, non-spore-forming, facultatively anaerobic bacilli that
measure 23 by 0.40.6
m. The initial identification of salmonellae in the clinical
microbiology laboratory is based on growth characteristics. Salmonellae, like other
Enterobacteriaceae, produce acid on glucose fermentation, reduce nitrates, and do not
produce cytochrome oxidase. In addition, all salmonellae except S. gallinarum-pullorum are
motile by means of peritrichous flagella, and all but S. typhi produce gas (H2S) on sugar
fermentation. Notably, only 1% of clinical isolates ferment lactose; a high level of suspicion
must be maintained to detect these rare clinical lactose-fermenting isolates.
Although serotyping of all surface antigens can be used for formal identification, most
laboratories perform a few simple agglutination reactions that define specific O-antigen
serogroups, designated A, B, C1, C2, D, and E. Strains in these six serogroups cause
99%
of Salmonella infections in humans and other warm-blooded animals. Molecular typing
methods, including pulsed-field gel electrophoresis and polymerase chain reaction (PCR)
fingerprinting, are used in epidemiologic investigations to differentiate Salmonella strains of
a common serotype.
Pathogenesis
All Salmonella infections begin with ingestion of organisms, most commonly in
contaminated food or water. The infectious dose is 103106 colony-forming units. Conditions
that decrease either stomach acidity (an age of <1 year, antacid ingestion, or achlorhydric

disease) or intestinal integrity (inflammatory bowel disease, prior gastrointestinal surgery, or

alteration of the intestinal flora by antibiotic administration) increase susceptibility to
Salmonella infection.
Once S. typhi and S. paratyphi reach the small intestine, they penetrate the mucus layer of the
gut and traverse the intestinal layer through phagocytic microfold (M) cells that reside within
Peyer's patches. Salmonellae can trigger the formation of membrane ruffles in normally
nonphagocytic epithelial cells. These ruffles reach out and enclose adherent bacteria within
large vesicles by a process referred to as bacteria-mediated endocytosis (BME). BME is
dependent on the direct delivery of Salmonella proteins into the cytoplasm of epithelial cells
by a specialized bacterial secretion system (type III secretion). These bacterial proteins
mediate alterations in the actin cytoskeleton that are required for Salmonella uptake.
After crossing the epithelial layer of the small intestine, S. typhi and S. paratyphi, which
cause enteric (typhoid) fever, are phagocytosed by macrophages. These salmonellae survive
the antimicrobial environment of the macrophage by sensing environmental signals that
trigger alterations in regulatory systems of the phagocytosed bacteria. For example,
PhoP/PhoQ (the best-characterized regulatory system) triggers the expression of outermembrane proteins and mediates modifications in LPS so that the altered bacterial surface
can resist microbicidal activities and potentially alter host cell signaling. In addition,
salmonellae encode a second type III secretion system that directly delivers bacterial proteins
across the phagosome membrane into the macrophage cytoplasm. This secretion system
functions to remodel the Salmonella-containing vacuole, promoting bacterial survival and
replication.
Once phagocytosed, typhoidal salmonellae disseminate throughout the body in macrophages
via the lymphatics and colonize reticuloendothelial tissues (liver, spleen, lymph nodes, and
bone marrow). Patients have relatively few or no signs and symptoms during this initial
incubation stage. Signs and symptoms, including fever and abdominal pain, probably result
from secretion of cytokines by macrophages and epithelial cells in response to bacterial
products that are recognized by innate immune receptors when a critical number of organisms
have replicated. Over time, the development of hepatosplenomegaly is likely to be related to
the recruitment of mononuclear cells and the development of a specific acquired cellmediated immune response to S. typhi colonization. The recruitment of additional
mononuclear cells and lymphocytes to Peyer's patches during the several weeks after initial
colonization/infection can result in marked enlargement and necrosis of the Peyer's patches,
which may be mediated by bacterial products that promote cell death as well as the
inflammatory response.
In contrast to enteric fever, which is characterized by an infiltration of mononuclear cells into
the small-bowel mucosa, NTS gastroenteritis is characterized by massive polymorphonuclear
leukocyte (PMN) infiltration into both the large- and small-bowel mucosa. This response
appears to depend on the induction of interleukin (IL) 8, a strong neutrophil chemotactic
factor, which is secreted by intestinal cells as a result of Salmonella colonization and
translocation of bacterial proteins into host cell cytoplasm. The degranulation and release of
toxic substances by neutrophils may result in damage to the intestinal mucosa, causing the
inflammatory diarrhea observed with nontyphoidal gastroenteritis.
Enteric (Typhoid) Fever

Enteric (typhoid) fever is a systemic disease characterized by fever and abdominal pain and
caused by dissemination of S. typhi or S. paratyphi. The disease was initially called typhoid
fever because of its clinical similarity to typhus. However, in the early 1800s, typhoid fever
was clearly defined pathologically as a unique illness on the basis of its association with
enlarged Peyer's patches and mesenteric lymph nodes. In 1869, given the anatomic site of
infection, the term enteric fever was proposed as an alternative designation to distinguish
typhoid fever from typhus. However, to this day, the two designations are used
interchangeably.
Epidemiology
In contrast to other Salmonella serotypes, the etiologic agents of enteric feverS. typhi and
S. paratyphi serotypes A, B, and Chave no known hosts other than humans. Most
commonly, food-borne or waterborne transmission results from fecal contamination by ill or
asymptomatic chronic carriers. Sexual transmission between male partners has been
described. Health care workers occasionally acquire enteric fever after exposure to infected
patients or during processing of clinical specimens and cultures.
With improvements in food handling and water/sewage treatment, enteric fever has become
rare in developed nations. Worldwide, however, there are an estimated 22 million cases of
enteric fever, with 200,000 deaths annually. The incidence is highest (>100 cases per 100,000
population per year) in south central and Southeast Asia; medium (10100 cases per 100,000)
in the rest of Asia, Africa, Latin America, and Oceania (excluding Australia and New
Zealand); and low in other parts of the world (Fig. 153-1). A high incidence of enteric fever
correlates with poor sanitation and lack of access to clean drinking water. In endemic regions,
enteric fever is more common in urban than rural areas and among young children and
adolescents. Risk factors include contaminated water or ice, flooding, food and drinks
purchased from street vendors, raw fruits and vegetables grown in fields fertilized with
sewage, ill household contacts, lack of hand washing and toilet access, and evidence of prior
Helicobacter pylori infection (an association probably related to chronically reduced gastric
acidity). It is estimated that there is one case of paratyphoid fever for every four cases of
typhoid fever, but the incidence of infection associated with S. paratyphi A appears to be
increasing, especially in India; this increase may be a result of vaccination for S. typhi
Multidrug-resistant (MDR) strains of S. typhi emerged in 1989 in China and Southeast Asia
and have since disseminated widely. These strains contain plasmids encoding resistance to
chloramphenicol, ampicillin, and trimethoprimantibiotics long used to treat enteric fever.
With the increased use of fluoroquinolones to treat MDR enteric fever in the 1990s, strains of
S. typhi and S. paratyphi with reduced susceptibility to ciprofloxacin [minimal inhibitory
concentration (MIC), 0.1251
g/mL] have emerged in the Indian subcontinent, southern
Asia, and (most recently) sub-Saharan Africa and have been associated with clinical
treatment failure. Testing of isolates for resistance to the first-generation quinolone nalidixic
acid detects most but not all strains with reduced susceptibility to ciprofloxacin.
The incidence of enteric fever among U.S. travelers is estimated at 330 cases per 100,000.
Of 1902 cases of S. typhiassociated enteric fever reported to the Centers for Disease Control

and Prevention (CDC) in 19992006, 79% were associated with recent international travel,
most commonly to India (47%), Pakistan (10%), Bangladesh (10%), Mexico (7%), and the
Philippines (4%). Only 5% of travelers diagnosed with enteric fever had received S.
typhivaccine. Overall, 13% of S. typhi isolates in the United States were resistant to
ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole (TMP-SMX), and the
proportion of isolates resistant to nalidixic acid increased from 19% in 1999 to 58% in 2006.
Infection with nalidixic acid-resistant (NAR) S. typhi was associated with travel to the Indian
subcontinent. Of the 2530% of reported cases of enteric fever in the United States that are
domestically acquired, the majority are sporadic, but outbreaks linked to contaminated food
products and previously unrecognized chronic carriers continue to occur.
Clinical Course
Enteric fever is a misnomer, in that the hallmark features of this diseasefever and
abdominal painare variable. While fever is documented at presentation in >75% of cases,
abdominal pain is reported in only 3040%. Thus, a high index of suspicion for this
potentially fatal systemic illness is necessary when a person presents with fever and a history
of recent travel to a developing country.
The incubation period for S. typhi averages 1014 days but ranges from 321 days,
depending on the inoculum size and the host's health and immune status. The most prominent
symptom is prolonged fever (38.840.5C; 101.8104.9F), which can continue for up to 4
weeks if untreated. S. paratyphi A is thought to cause milder disease than S. typhi, with
predominantly gastrointestinal symptoms. However, a prospective study of 669 consecutive
cases of enteric fever in Kathmandu, Nepal, found that the infections were clinically
indistinguishable. In this series, symptoms reported on initial medical evaluation included
headache (80%), chills (3545%), cough (30%), sweating (2025%), myalgias (20%),
malaise (10%), and arthralgia (24%). Gastrointestinal symptoms included anorexia (55%),
abdominal pain (3040%), nausea (1824%), vomiting (18%), and diarrhea (2228%) more
commonly than constipation (1316%). Physical findings included coated tongue (5156%),
splenomegaly (56%), and abdominal tenderness (45%).
Early physical findings of enteric fever include rash ("rose spots"; 30%), hepatosplenomegaly
(36%), epistaxis, and relative bradycardia at the peak of high fever (<50%). Rose spots (Fig.
153-2; see also Fig. e7-9) make up a faint, salmon-colored, blanching, maculopapular rash
located primarily on the trunk and chest. The rash is evident in
30% of patients at the
end of the first week and resolves without a trace after 25 days. Patients can have two or
three crops of lesions, and Salmonella can be cultured from punch biopsies of these lesions.
The faintness of the rash makes it difficult to detect in highly pigmented patients.
The development of severe disease (which occurs in
1015% of patients) depends on
host factors (immunosuppression, antacid therapy, previous exposure, and vaccination), strain
virulence and inoculum, and choice of antibiotic therapy. Gastrointestinal bleeding (1020%)
and intestinal perforation (13%) most commonly occur in the third and fourth weeks of
illness and result from hyperplasia, ulceration, and necrosis of the ileocecal Peyer's patches at
the initial site of Salmonella infiltration. Both complications are life-threatening and require
immediate fluid resuscitation and surgical intervention, with broadened antibiotic coverage

for polymicrobial peritonitis (Chap. 127) and treatment of gastrointestinal hemorrhages,

including bowel resection. Neurologic manifestations occur in 240% of patients and include
meningitis, Guillain-Barr syndrome, neuritis, and neuropsychiatric symptoms (described as
"muttering delirium" or "coma vigil"), with picking at bedclothes or imaginary objects.
Rare complications whose incidences are reduced by prompt antibiotic treatment include
disseminated intravascular coagulation, hematophagocytic syndrome, pancreatitis, hepatic
and splenic abscesses and granulomas, endocarditis, pericarditis, myocarditis, orchitis,
hepatitis, glomerulonephritis, pyelonephritis and hemolytic-uremic syndrome, severe
pneumonia, arthritis, osteomyelitis, and parotitis. Up to 10% of patients develop mild relapse,
usually within 23 weeks of fever resolution and in association with the same strain type and
susceptibility profile.
Up to 10% of untreated patients with typhoid fever excrete S. typhi in the feces for up to 3
months, and 14% develop chronic asymptomatic carriage, shedding S. typhi in either urine
or stool for >1 year. Chronic carriage is more common among women, infants, and persons
who have biliary abnormalities or concurrent bladder infection with
Schistosomahaematobium. The anatomic abnormalities associated with the latter conditions
presumably allow prolonged colonization.
Diagnosis
Since the clinical presentation of enteric fever is relatively nonspecific, the diagnosis needs to
be considered in any febrile traveler returning from a developing region, especially the Indian
subcontinent, the Philippines, or Latin America. Other diagnoses that should be considered in
these travelers include malaria, hepatitis, bacterial enteritis, dengue fever, rickettsial
infections, leptospirosis, amebic liver abscesses, and acute HIV infection (Chap. 123). Other
than a positive culture, no specific laboratory test is diagnostic for enteric fever. In 1525%
of cases, leukopenia and neutropenia are detectable. Leukocytosis is more common among
children, during the first 10 days of illness, and in cases complicated by intestinal perforation
or secondary infection. Other nonspecific laboratory findings include moderately elevated
liver function tests and muscle enzyme levels.
The definitive diagnosis of enteric fever requires the isolation of S. typhi or S. paratyphi from
blood, bone marrow, other sterile sites, rose spots, stool, or intestinal secretions. The
sensitivity of blood culture is only 4080%, probably because of high rates of antibiotic use
in endemic areas and the small quantities of S. typhi (i.e., <15 organisms/mL) typically
present in the blood. Since almost all S. typhi organisms in blood are associated with the
mononuclear-cell/platelet fraction, centrifugation of blood and culture of the buffy coat can
substantially reduce the time to isolation of the organism but do not increase sensitivity.
Bone marrow culture is 5590% sensitive, and, unlike that of blood culture, its yield is not
reduced by up to 5 days of prior antibiotic therapy. Culture of intestinal secretions (best
obtained by a noninvasive duodenal string test) can be positive despite a negative bone
marrow culture. If blood, bone marrow, and intestinal secretions are all cultured, the yield is
>90%. Stool cultures, while negative in 6070% of cases during the first week, can become
positive during the third week of infection in untreated patients.
Several serologic tests, including the classic Widal test for "febrile agglutinins," are available.
None of these tests is sufficiently sensitive or specific to replace culture-based methods for

the diagnosis of enteric fever in developed countries. PCR and DNA probe assays to detect S.
typhi in blood have been identified but have not yet been developed for clinical use.
Treatment: Enteric (Typhoid) Fever
Prompt administration of appropriate antibiotic therapy prevents severe complications of
enteric fever and results in a case-fatality rate of <1%. The initial choice of antibiotics
depends on the susceptibility of the S. typhi and S. paratyphi strains in the area of residence
or travel (Table 153-1). For treatment of drug-susceptible typhoid fever, fluoroquinolones are
the most effective class of agents, with cure rates of
98% and relapse and fecal carriage
rates of <2%. Experience is most extensive with ciprofloxacin. Short-course ofloxacin
therapy is similarly successful against infection caused by nalidixic acidsusceptible strains.
However, the increased incidence of NAR S. typhi in Asia, which is probably related to the
widespread availability of fluoroquinolones over the counter, is now limiting the use of this
drug class for empirical therapy. Patients infected with NAR S. typhi strains should be treated
with ceftriaxone, azithromycin, or high-dose ciprofloxacin. High-dose fluoroquinolone
therapy for 7 days for NAR enteric fever has been associated with delayed resolution of fever
and high rates of fecal carriage during convalescence. For NAR strains, 1014 days of highdose ciprofloxacin is preferred.

Ceftriaxone, cefotaxime, and (oral) cefixime are effective for treatment of MDR enteric fever,
including NAR and fluoroquinolone-resistant strains. These agents clear fever in

1 week,

with failure rates of

510%, fecal carriage rates of <3%, and relapse rates of 36%. Oral
azithromycin results in defervescence in 46 days, with rates of relapse and convalescent
stool carriage of <3%. Against NAR strains, azithromycin is associated with lower rates of
treatment failure and shorter durations of hospitalization than are fluoroquinolones. Despite
efficient in vitro killing of Salmonella, first- and second-generation cephalosporins as well as
aminoglycosides are ineffective in the treatment of clinical infections.
Most patients with uncomplicated enteric fever can be managed at home with oral antibiotics
and antipyretics. Patients with persistent vomiting, diarrhea, and/or abdominal distension
should be hospitalized and given supportive therapy as well as a parenteral third-generation
cephalosporin or fluoroquinolone, depending on the susceptibility profile. Therapy should be
administered for at least 10 days or for 5 days after fever resolution.
In a randomized, prospective, double-blind study of critically ill patients with enteric fever
(i.e., those with shock and obtundation) in Indonesia in the early 1980s, the administration of
dexamethasone (an initial dose of 3 mg/kg followed by eight doses of 1 mg/kg every 6 h)
with chloramphenicol was associated with a substantially lower mortality rate than was
treatment with chloramphenicol alone (10% vs 55%). Although this study has not been
repeated in the "post-chloramphenicol era," severe enteric fever remains one of the few
indications for glucocorticoid treatment of an acute bacterial infection.
The 15% of patients who develop chronic carriage of Salmonella can be treated for 46
weeks with an appropriate oral antibiotic. Treatment with oral amoxicillin, TMP-SMX,

ciprofloxacin, or norfloxacin is
80% effective in eradicating chronic carriage of
susceptible organisms. However, in cases of anatomic abnormality (e.g., biliary or kidney
stones), eradication often requires both antibiotic therapy and surgical correction.
Prevention and Control
Theoretically, it is possible to eliminate the salmonellae that cause enteric fever since they
survive only in human hosts and are spread by contaminated food and water. However, given
the high prevalence of the disease in developing countries that lack adequate sewage disposal
and water treatment, this goal is currently unrealistic. Thus, travelers to developing countries
should be advised to monitor their food and water intake carefully and to consider
vaccination.
Two typhoid vaccines are commercially available: (1) Ty21a, an oral live attenuated S.
typhivaccine (given on days 1, 3, 5, and 7, with a booster every 5 years); and (2) Vi CPS, a
parenteral vaccine consisting of purified Vi polysaccharide from the bacterial capsule (given
in 1 dose, with a booster every 2 years). The old parenteral whole-cell typhoid/paratyphoid A
and B vaccine is no longer licensed, largely because of significant side effects (see below).
An acetone-killed whole-cell vaccine is available only for use by the U.S. military. The
minimal age for vaccination is 6 years for Ty21a and 2 years for Vi CPS. Currently, there is
no licensed vaccine for paratyphoid fever.
A large-scale meta-analysis of vaccine trials comparing whole-cell vaccine, Ty21a, and Vi
CPS in populations in endemic areas indicates that, while all three vaccines are similarly
effective for the first year, the 3-year cumulative efficacy of the whole-cell vaccine (73%)
exceeds that of both Ty21a (51%) and Vi CPS (55%). In addition, the heat-killed whole-cell
vaccine maintains its efficacy for 5 years, whereas Ty21a and Vi CPS maintain their efficacy
for 4 and 2 years, respectively. However, the whole-cell vaccine is associated with a much
higher incidence of side effects (especially fever: 16% vs 12%) than the other two vaccines.
Vi CPS typhoid vaccine is poorly immunogenic in children <5 years of age because of T cell
independent properties. In the recently developed Vi-rEPA vaccine, Vi is bound to a nontoxic
recombinant protein that is identical to Pseudomonas aeruginosa exotoxin A. In 2- to 4-yearolds, two injections of Vi-rEPA induced higher T cell responses and higher levels of serum
IgG antibody to Vi than did Vi CPS in 5- to 14-year-olds. In a two-dose trial in 2- to 5-yearold children in Vietnam, Vi-rEPA provided 91% efficacy at 27 months and 88% efficacy at 43
months and was very well tolerated. This vaccine is not yet commercially available in the
United States. At least three new live vaccines are in clinical development and may prove
more efficacious and longer-lasting than previous live vaccines.
Typhoid vaccine is not required for international travel, but it is recommended for travelers to
areas where there is a moderate to high risk of exposure to S. typhi, especially those who are
traveling to southern Asia and other developing regions of Asia, Africa, the Caribbean, and
Central and South America and who will be exposed to potentially contaminated food and
drink. Typhoid vaccine should be considered even for persons planning <2 weeks of travel to
high-risk areas. In addition, laboratory workers who deal with S. typhi and household contacts
of known S. typhi carriers should be vaccinated. Because the protective efficacy of vaccine
can be overcome by the high inocula that are commonly encountered in food-borne
exposures, immunization is an adjunct and not a substitute for avoiding high-risk foods and

beverages. Immunization is not recommended for adults residing in typhoid-endemic areas or

for the management of persons who may have been exposed in a common-source outbreak.
Enteric fever is a notifiable disease in the United States. Individual health departments have
their own guidelines for allowing ill or colonized food handlers or health care workers to
return to their jobs. The reporting system enables public health departments to identify
potential source patients and to treat chronic carriers in order to prevent further outbreaks. In
addition, since 14% of patients with S. typhi infection become chronic carriers, it is
important to monitor patients (especially child-care providers and food handlers) for chronic
carriage and to treat this condition if indicated.