Infections from Salmonella enterica serotypes Typhi and Paratyphi,

collectively known as enteric fever, present a complex clinical challenge for

clinicians worldwide. This activity offers a comprehensive overview of these
infections, covering epidemiology, pathophysiology, treatment,
complications, patient education, and preventive measures. With symptoms
often presenting subtly, clinicians must grasp the nuances of typhoid and
paratyphoid fever, recognizing signs such as fever, fatigue, anorexia,
headache, malaise, and abdominal discomfort. Moreover, the evolving
landscape of antimicrobial-resistant strains, including extensively drug-
resistant variants, underscores the need for clinicians to stay updated on the
best treatment approaches.
Through this course, clinicians learn the pivotal role of the interprofessional
healthcare team in addressing enteric fever. Collaboration among clinicians,
public health experts, and other healthcare professionals enhances patient
care by leveraging a multidisciplinary approach. By working collaboratively,
clinicians can optimize patient outcomes, especially in low- and middle-
income countries where enteric fevers pose significant public health
challenges.
Objectives:
 Identify the key clinical manifestations and diagnostic tests to promptly
diagnose typhoid and paratyphoid fever.
 Implement appropriate treatment strategies, incorporating the latest
research and guidelines, for efficient typhoid fever management.
 Apply an understanding of individual risk factors to appropriately
counsel patients about preventing typhoid and other infections
transmitted through the oral route, including vaccination strategies.
 Coordinate with other healthcare professionals to ensure a
multidisciplinary approach in the care and management of typhoid
fever, including reporting to public health officials.
Access free multiple choice questions on this topic.
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Introduction
Typhoid fever and paratyphoid fever are clinically indistinguishable febrile
multisystemic illnesses caused by Salmonella enterica serotypes Typhi (S
Typhi) and Paratyphi (S Paratyphi) A, B, and C. Collectively known as
enteric fever, more than 9 million people are sickened, and 110,000 die from
the disease every year around the globe.[WHO. Typhoid Fact Sheet. 2023]
Enteric fever is the leading cause of community-acquired bloodstream
infections in South and Southeast Asia.[1] A reportable disease in the United
States and many other developed nations, enteric fever is second only to
malaria as a cause of severe and sometimes life-threatening infection in
travelers.[2]
Following an incubation period of 6 to 30 days, enteric fever presents
insidiously with the gradual onset of fever with fatigue, anorexia, headache,
malaise, and abdominal symptoms. If treatment is delayed or inadequate,
meningitis, sepsis, or intestinal perforation can occur. With a history
of S Typhi and S Paratyphi strains rapidly developing antimicrobial resistance
with the widespread use of successive antibiotics, the recent emergence of
extensively drug-resistant strains has greatly complicated treatment and
raised alarms.
S Typhi and S Paratyphi are said to spread by the "4 Fs" (flies, fingers, feces,
and fomites). They afflict people living or traveling in low- and middle-
income countries around the globe that lack clean water, adequate sanitation,
and hygiene, known collectively as WASH. Improved WASH infrastructure
is the foundation for decreasing the incidence of enteric fever and other
diseases spread via the fecal-oral route.
Historically, enteric fever has received less investment and attention than the
"big 3" (human immunodeficiency virus/acquired immunodeficiency
syndrome, tuberculosis, and malaria). However, with the specter of
untreatable variants on the horizon, enteric fever control efforts have been
renewed. Recently developed typhoid conjugate vaccines, improved
surveillance and understanding of antimicrobial resistance patterns, and
WASH initiatives have decreased the disease burden.
This activity covers the epidemiology, pathophysiology, treatment,
management, complications, patient education, prevention measures, and the
role of the interprofessional team in improving patient care and decreasing
the burden of this disease. While several barriers to controlling this disease
exist, recent advancements provide hope that the impact of enteric fevers can
be limited or eliminated in the future.
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Etiology
Like other members of the Enterobacteriaceae family, Salmonellae are gram-
negative, acid-fast, facultative anaerobic bacillae. Salmonella comprises 2
main species, Salmonella enterica and Salmonella bongori (prev S
enterica subspecies V). S enterica, in turn, comprises 6 subspecies, of
which S enterica subsp enterica has the most serovars (or serotypes) and is
the most important to human infection.[1] This includes S Typhi
and S Paratyphi, with the complete scientific
names Salmonella enterica subspecies enterica Typhi
and Salmonella enterica subspecies enterica Paratyphi, respectively. Unlike
many other Salmonella species, S Typhi and S Paratyphi are exclusively
human pathogens.[CDC. Yellow Book. 2024] Other species within
the genus Salmonella are collectively known as nontyphoidal salmonella
(NTS), many of which are pathogenic to humans or other animals. NTS
infections are mainly limited to gastroenteritis in humans, although invasive
nontyphoidal serovars (iNTS) exist.
S Typhi and S Paratyphi serovars have been classified by phage typing since
the early 1900s within an established, continuously evolving taxonomic
structure as new variants arise.[2] With the advent of genetic techniques,
enteric fever classification is increasingly based on genotypes for research,
surveillance, and clinical purposes. Genotyping improves the ability
to identify and track outbreaks and antimicrobial resistance and monitor for
emerging antimicrobial resistance mechanisms. When combined with
emerging clinical antimicrobial susceptibility patterns, this provides
additional guidance for empiric therapy. Single nucleotide variants are used
to assign S Typhi genomes into the GenoTyphi scheme, comparable to
existing phenotypic taxonomic structures.[3]
See StatPearls' companion article "Salmonella" for more information on the
spectrum of Salmonella bacteria and illness.
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Epidemiology
Transmission
Transmission is primarily through the fecal-oral route, via consumption of
food or water contaminated with the feces of a convalescent or chronic
asymptomatic carrier. The importance of chronic carriage to ongoing
transmission is well documented in non-endemic countries; however, the role
in endemic countries is not well understood. Sexual transmission has rarely
been documented among men who have sex with men.[CDC. Yellow
Book. 2024] S Typhi and S Paratyphi can exist in the environment for a
prolonged period in a nonculturable, nonreplicative state. This creates a
persistent environmental reservoir that can lead to infection and outbreaks,
such as via contaminated crops.[2]
Risk Factors
Different factors determine the risk of enteric fever in endemic versus non-
endemic countries. In non-endemic countries, the acquisition of enteric fever
is related to travel, contact with a traveler from an endemic country, or
exposure to food prepared by a chronic carrier. In contrast, risk factors in
endemic countries include individual host factors, environmental exposures,
and climate and geographic factors.
Individual host factors
On average, the incidence of enteric fever peaks between the ages of 5 and 9.
However, this masks great variability in the age of onset in different
locations, with a younger peak age incidence correlating to a higher
prevalence of enteric fever. In very high prevalence areas, peak incidence
may occur in infants due to increased exposures and the greater accumulated
immunity acquired with repeat clinical, subclinical, or asymptomatic
infections as people age. Reinfections demonstrate that only a moderate level
of protection is conferred by clinical infection.[2]
Typhoid fever is more severe in debilitated and immunocompromised
patients such as those with human immunodeficiency virus, on glucocorticoid
therapy, or with altered phagocyte function (eg, patients with malaria and
sickle cell anemia). Salmonellae are most commonly acid-sensitive bacteria
and are destroyed in the stomach by gastric acid unless a large dose is
ingested.[4] Achlorhydria and intake of antacids and antihistamines increase
susceptibility to infection with smaller doses.
Normal flora of the gut is protective against the infection. The use of broad-
spectrum antibiotics that destroy the normal flora allows increased invasion.
Malnutrition decreases normal gut flora and also increases the susceptibility
to infection.[5] Human genetics likely plays a role in susceptibility to
typhoid, with a marker mapping to the HLA class II region strongly
associated with enteric fever resistance.[2]
Environmental exposures
A meta-analysis demonstrated that having an improved water source with a
protected well can reduce the risk of culture-confirmed typhoid infection by
half.[6] Having surface water as a water source doubles the risk of typhoid
fever compared to other unimproved water sources, such as an unprotected
well or spring. Using any household water treatment reduces the risk
compared to no treatment. Using metal lids and keeping water containers
covered is associated with an 80% lower odds of typhoid infection than
keeping water in open containers, while using dirty containers doubles the
risk.
People using unimproved pit latrines had 50 times the risk of enteric fever
than those having limited, basic, or safely managed sanitation facilities.
Those defecating in the open had 1.2 times the risk. A lack of a handwashing
facility with soap and water at home increases the odds by 2.3 compared to
those without such facilities.[6] Independent of vaccination, living in a house
with better WASH facilities significantly decreases the risk of enteric fever.
Climatic and geographic factors
A distinct seasonal pattern of enteric fever incidence exists globally, with
variability accentuated further from the equator. Similarly, a higher incidence
of enteric fever occurs with increased temperatures. Between 11° and 35° N,
previous rainfall events are positively associated with the incidence of enteric
fever. Climate change will likely increase the incidence of enteric fever and
other gastrointestinal illnesses via increased flooding, drought, and
temperatures, compromising food and water safety.[2]
Burden of Disease
Enteric fever is a prime example of the "infectious divide" between high-
income countries (gross national income per capita in 2021 of >$12,695) and
those with low and middle incomes (≤$1046 and >$1047-$12,695,
respectively).[7] In high-income countries, where improvements to sanitation
started in the early 1900s, enteric fever is now seen primarily in travelers
returning from endemic areas. Incidence remains high in many low- and
middle-income countries with poor WASH.
Due to diagnostic challenges, underdeveloped surveillance systems, and the
lack of access to universal health care in many areas, the true incidence
of S Typhi and S Paratyphi in much of the world can only be estimated. The
2019 Global Burden of Disease Study models rates using existing
epidemiological data and case counts from population-based studies.[8] The
vast majority of enteric fever cases worldwide are due to S Typhi. In 2019, an
estimated 9.2 million (95% CI 5.9-14.1) typhoid fever cases and 110,000
(95% confidence interval; 53,000-191,000) deaths occurred worldwide. This
compares to 11 to 21 million cases and 148,000 to 161,000 deaths in 2015.
[8] While S Typhi comprises the majority of enteric fever cases worldwide,
the percentage of cases due to S Paratyphi varies widely across
regions. S Paratyphi accounts for about 25% of all enteric fever cases in
South Asia.[2] Approximately 3.8 million S Paratyphi infections occurred
globally in 2019.[8]
High-Income Countries
As an example of a high-income country, about 400 cases of typhoid fever
and 50 to 100 cases of paratyphoid fever were reported each year in the
United States from 2016 to 2018. Of these, 85% and 92% are attributed to
international travel, with the remainder due to local transmission.
[CDC. Yellow Book. 2024] Fewer cases were reported in 2020, likely
reflecting decreased travel due to the coronavirus pandemic.[CDC. Typhoid
and Paratyphoid Surveillance. 2020] The median age was 26 and 24 years for
typhoid and paratyphoid cases, respectively. No deaths were reported,
although about 82% of cases for which data is available were hospitalized.
In 76% of cases, international travel was reported where a travel history was
available. More than 75% of those with a single destination identified travel
to India or Pakistan. The most common reason for international travel was to
visit friends and relatives (VFR), with 48% of S Typhi infections and 64%
of S Paratyphi infections reporting VFR. Just under 6% of people
with S Typhi reported receiving the typhoid fever vaccine in the previous 5
years.[CDC. Typhoid and Paratyphoid Surveillance. 2020] Longer travel
duration is associated with a higher incidence of infection, although infection
can occur even during short visits of less than 1 week to highly endemic
areas.[CDC. Yellow Book. 2024]
Low- and Middle-Income Countries
The 2019 Global Burden of Disease Report identifies 44 countries with a
high estimated typhoid burden (≥100 cases/100,000 persons/year).[8] The
highest estimated incidences of enteric fever occur in Southeast Asia, Eastern
Mediterranean (187 cases/100,000 persons/year), and African World Health
Organization superregions (respectively 306, 187, and 111 cases/100,000
persons/year).[8] Together, typhoid and paratyphoid were the 18th leading
causes of disability-adjusted life-years (DALYs) globally for children aged 0
to 9 years and 14th for those aged 10 to 24 years in 2019. While typhoid and
paratyphoid fever represent a greater proportion of all DALYs in 2019 than
in 1990, the age-standardized rates for DALYs declined 51% and 16%,
respectively, since 1990.[8] In South and Southeast Asia, S Typhi is the
leading cause of nonhospital acquired bloodstream infections.[2]
Outbreaks are an additional signal of disease burden. The US Centers for
Disease Control (CDC) Global Disease Detection Operation Center reported
7 confirmed outbreaks globally between 2017 and 2022, with 14,056
becoming ill in the Philipines in 2022; 1312, 3187, 7134 people affected in 3
separate outbreaks in Zimbabwe in 2017 and 2018; 14,894 sickened with
XDR Typhi in Pakistan in 2018 and 2019; and 23 infections occurring in 1
building in China in 2022.[7]
Antimicrobial Resistance
In low- to middle-income countries, antimicrobial resistance patterns often
follow the pattern of antibiotic use and the acquisition and spread of
mutations. In high-income countries where travel is the primary risk factor
for the acquisition of enteric fever, the prevalence and the pattern of drug
resistance among isolates reflect the destination countries for travel. In the
United States in 2020, 99% of isolates had a decreased susceptibility to
fluoroquinolones. None were multiple drug resistant (MDR), and none were
resistant to ceftriaxone, although extremely drug resistant (XDR) cases have
previously been reported.[CDC. Typhoid and Paratyphoid
Surveillance. 2020] Up-to-date information on typhoid and paratyphoid
resistance patterns in the United States can be found on the CDC's National
Antimicrobial Resistance Monitoring System website.
Multidrug Resistance
Worldwide, an estimated 2.5 million MDR S Typhi infections and 7.4 million
fluoroquinolone non-susceptibility (FQNS) S Typhi infections occurred in
2019.[9] MDR strains are common in sub-Saharan Africa, increasing from an
estimated 6% of all typhoid strains in 1990 to 72.7% in 2019.[9] The rate of
MDR typhoid is declining in South and Southeast Asia, comprising 55.4% of
all typhoid infections in South Asia in 1990 and 26.4% in 2019.[9] Rates of
MDR are also more variable in Asia than in Africa, ranging from an
estimated 3% in India and Nepal to 68% in Pakistan and 76% in Cambodia.
[3] The Southeast Asian, East Asian, and Oceania superregion has a lower
overall prevalence of MDR typhoid compared to South Asia, declining from
an estimated 19.0% to 4.7% between 1990 and 2019.[9] Northern Africa and
the Middle East have shown a stable rate in MDR, with little change from the
19.4% estimated in 1990.[9] MDR Typhi is virtually absent in Micronesia
and Latin America.[3] Globally, the prevalence of MDR in S Paratyphi
strains was an estimated 9.2% in 1990, while in 2019, it was 0.2%. FQNS
was present in 0.6% of S Paratyphi in 1990 and 95.0% in 2019.[9]
Fluoroquinolone Non-Susceptibility
Nonsusceptibility to fluoroquinolones is widespread among S Typhi strains.
Globally, 1.1% of strains were estimated to be FQNS in 1995.[9] Rates have
increased since then, although they vary highly across countries and regions.
The estimated prevalence of FQNS strains in South Asia overall was 95.2%
in 2019, while in the superregion comprising Southeast Asia, East Asia, and
Oceania, it was 36.4%. In 2019, Pakistan had an estimated rate of 99.1%
FQNS, while in Indonesia, it was 10.4%.[9]
The increase in FQNS started later in Africa than in Asia, and the prevalence
continues to be lower. In 2019, rates of FQNS in Africa were variable across
regions and countries, often reflecting travel interconnections with Southeast
Asia.[10] In sub-Saharan Africa, 24 of 38 countries had a prevalence of
FQNS greater than 15%. In North Africa and the Middle East, the overall rate
of FQNS was estimated to be 35.0%.[9] FQNS is emerging in some areas of
Latin America, such as Chile.[3]
Extensive Drug Resistance
In Pakistan, about 70% of all isolates were XDR in 2020, with resistance to
chloramphenicol, ampicillin, co-trimoxazole, ciprofloxacin, and 3rd
generation cephalosporins.[3] While large epidemiological studies have not
determined XDR strains to be widespread in other countries, this must be
interpreted cautiously, as modeling studies derive estimates based on a
fraction of total cases.[3]
In 2019, 16 countries were known to have imported cases of XDR typhoid.
[10] Diagnosis of XDR S Typhi cases in people without a history of travel to
Pakistan indicates a wider spread than can be detected by surveillance
systems. For example, in the UK, XDR S Typhi infection in a traveler to
India indicates XDR has been introduced at least once. Nine XDR typhoid
cases without travel outside the United States were identified between
November 2019 and October 2020; the S Typhi genotype matched those
circulating in Pakistan.[11] In 2022, 23 cases were linked to an apartment
building in Beijing.[10]
Countries that have a high incidence of typhoid and extensive travel with
Pakistan have an extremely high risk of XDR transmission. For example,
Afghanistan has one of the highest estimated typhoid fever burdens globally
and was the destination for 3.37 million trips in 2021.[10] While Saudi
Arabia and the United Arab Emirates have reported no or 1 case of XDR
typhoid, this likely reflects low detection and reporting of cases. A high rate
of travel exists between these highly populated Gulf States and Pakistan, yet
reports far fewer cases than in countries with fewer travel connections (eg,
the United States, Ireland, and the United Kingdom).[10] Note that
cephalosporin resistance also occurs in strains without other antimicrobial
resistance. Levels of cephalosporin resistance were low in all endemic
countries except for Pakistan.[3]
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Pathophysiology
The pathophysiologies of S Typhi and S Paratyphi infections have not been
fully elucidated, mainly due to the complexity of pathogenic mechanisms and
the restriction of infection to humans. S Typhimurium infection in a mouse
model and controlled human challenge studies (CHIM) have significantly
contributed to the current understanding of enteric fever pathogenesis. In the
CHIM studies, S Paratyphi requires a 10 times lower dose of bacteria
than S Typhi (1000 cf 10,000 cfu) to induce clinical infection in 60% and
67% of volunteers, respectively.[2] The median onset of symptoms is 8 days.
Bacteremia is longer in S Paratyphi than in S Typhi, and asymptomatic
infection was more common.
S Typhi and S Paratyphi have diverse mechanisms to address the critical tasks
in their pathogenesis and survival: evasion of stomach acidity, invasion of the
intestinal epithelium, dissemination and intracellular survival, excretion and
transmission, and the development of antimicrobial resistance. Virulence
genes are carried in Salmonella pathogenicity islands, chromosomal elements
acquired through horizontal transmission from other pathogenic bacteria. To
date, 15 Salmonella pathogenicity islands have been identified, carrying
genes affecting pathogen survival, virulence, adhesion, evasion of host
defenses, cellular death, proinflammatory mediators, bacterial multiplication,
and others.[4]
The Vi antigen is well known as an exopolysaccharide capsule possessed
by S Typhi, along with several other Salmonella and non-Salmonella spp.
The target of modern conjugate vaccines, Vi is considered important
to S Typhi pathogenesis; however, the precise role remains unclear, notably
as S Paratyphi lacks a Vi capsule and yet produces a clinically
indistinguishable illness. S Typhi and S Paratyphi do not share any other
unique virulence factors. Moreover, Vi antigen-negative S Typhi bacteria
have also been identified.[4]
Ingestion and Invasion
Following ingestion, food and beverages act as buffers against gastric acid,
facilitating bacteria reaching the small bowel.[5] S Typhi and S Paratyphi
then rapidly cross the gut epithelium. Invasion likely occurs via several
routes as with other Salmonellae: transcellular or by direct invasion of
enterocytes and the M cells that overlie Peyer patches. In contrast to
noninvasive salmonella, invasion causes a minimal inflammatory response.
In S Typhi, this is mediated by a protein that downregulates flagellin (also
known as flagellar H antigen), which is associated with inflammation and
upregulates Vi production.[4]
Initial Dissemination
Intracellular dissemination occurs during the asymptomatic incubation period
of enteric fever and is of primary importance in its pathogenesis. Two-thirds
of the S Typhi or S Paratyphi load during an infection is estimated to be
intracellular.[6] Intracellular dissemination occurs via CD18 cells of the
reticuloendothelial system, including macrophages, dendritic cells,
polymorphonuclear monocytes, and phagocytes.[4] Invasive Salmonellae can
live intracellularly by forming a modified phagosome that does not allow
normal fusion with the cell's phagocyte oxidase complex.[2] In S Typhi
infection, the Vi antigen capsule is thought to play a role. The intracellular
nature of the bacteria safeguards against extracellular antibiotics, limiting the
available options for treatment.[7]
A transient primary bacteremia, detectable by the presence of bacterial
deoxyribonucleic acid, occurs within the first 24 hours of ingestion, possibly
coinciding with this bacterial dissemination.[4] A systemic cytokine response
occurs, whether or not systemic illness ensues. The eosinophil count begins
to drop 5 days before symptoms develop.[2]
Clinical Illness
Increasing fever begins with the persistent secondary bacteremia of
established infection.[4] The gallbladder is colonized through hematogenous
or local spread, more commonly if gallstones or structural abnormalities are
present (see Image. Gallbladder Affected by Typhoid Fever). Lymphoid
tissue within Peyer patches is a site of primary infection, reinfection, and
chronic infection, becoming a secondary source for fecal excretion and
transmission. The proliferation of lymphoid tissue may cause constipation.
Endotoxin-mediated necrosis may occur, resulting in intestinal bleeding,
perforation, or tertiary bacteremia with enteric microorganisms.[4] The total
white count, lymphocytes, platelets, and neutrophils begin to drop with the
onset of symptoms. Immunoglobulin (Ig) IgG, IgM, and IgA antibodies
develop against flagellin and lipopolysaccharide in those who develop
clinical disease but not against Vi.[2]
Host Immunity
CHIM studies demonstrate that immunity to S Typhi and S Paratyphi is
incomplete following clinical infection. If challenged with the same organism
an average of 19 months following the initial S Typhi or S Paratyphi
infection, prior infection reduced the risk of clinical illness by 36% and 57%,
respectively.[2] No symptoms or clinical severity change was seen in those
previously challenged. Likewise, there was no reduction in risk if the second
challenge was with the alternate organism.
Antimicrobial Resistance
Antimicrobial resistance has been a significant threat to the control of enteric
fever since the advent of antibiotic treatment. Multidrug resistance to all 3
first-line drugs, ampicillin, chloramphenicol, and co-trimoxazole, was first
identified in 1972 and became common by the 1980s. The accumulated
resistance genes of MDR strains are encoded on a large conjugative (self-
transmissible) plasmid.[3]
Estimated to have originated in South Asia in the mid-1980s, H58 isolates are
thought to have spread widely due to plasmid-encoded MDR. More
susceptible than other S Typhi genotypes to acquiring mutations or mobile
genetic elements encoding resistance determinants, H58 (renamed clade
4.3.1, along with its derived genotypes) strains are now found throughout
Asia and Southern Africa.[3] With the decreased use of the original first-line
antibiotics, the reproductive fitness cost of maintaining the MDR-encoding
plasmid has led to its lower prevalence in most of Asia. However, the
plasmid has been integrated into the Typhi chromosome several times,
resulting in the fixation of the MDR phenotype in multiple lineages found
mainly in Pakistan and East Africa.
Fluoroquinolone nonsusceptibility, or FQNS, arose as the use of these
antibiotics subsequently became more common.[8] Genomic studies have
shown a variety of mechanisms that confer FQNS:
 The stepwise accumulation of 1 to 3 mutations in core chromosomal
genes that directly impact fluoroquinolone binding (QRDR mutations).
  The presence of plasma-mediated quinolone resistance (PMQR) genes
in strains already carrying a QRDR mutation.
 Or this could include a combination of the above.
A wide variety of QRDR mutations and PMQR plasmids confer
fluoroquinolone resistance. Core chromosomal mutations have arisen
independently in at least 80 different strains around the globe, more
commonly in H58 strains.[3] The number of mutations and the presence of a
PMQR plasmid correlate with the degree of resistance. For example, 1
mutation may only result in a small increase in minimal inhibitory
concentration (MIC) and minimal clinical impact. In contrast, those strains
with 3 QRDR mutations or a PMQR plasmid and 1 or more PMQR mutations
may have a MIC of 1 mg/L or more of ciprofloxacin, denoting a high degree
of resistance. Genomic studies have used the term fluoroquinolone-resistant
to describe these highly nonsusceptible strains.[3]
Most common strains carry genes that confer nonsusceptibility across a wide
range of cephalosporins. However, different mutations may confer differing
levels of non-susceptibility to other cephalosporins. As such, the utility of
nalidixic acid in determining fluoroquinolone resistance levels has been
challenged.[6] Third-generation cephalosporins (eg, ceftriaxone and
cefixime) and azithromycin increased in use following the emergence of
ciprofloxacin resistance. Azithromycin resistance has emerged primarily in
Bangladesh, with at least 13 independent events resulting in 13 different
genotypes, each having 1 to 3 mutations. The gene for extended beta-
lactamase resistance has migrated to the chromosome in some strains.[3] An
XDR strain of Typhi arose in Hyderabad, Pakistan, in 2016. This is a typical
combination of chromosomal MDR genes, IncY plasmid-mediated
ciprofloxacin, and extended beta-lactamase resistance. The XDR strain has
since spread throughout Pakistan and neighboring countries.[3]
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History and Physical

Typhoid and paratyphoid present with febrile, nonspecific illnesses
indistinguishable from each other, as well as other febrile illnesses in
travelers and endemic areas. The history and physical exam seek to confirm
or exclude risk factors, signs, and symptoms of typhoid, paratyphoid, malaria,
meningitis, dengue, or other febrile illnesses that the patient may be at risk of
depending on geographic and other exposure risks.
History
After an incubation period of 10 to 14 days (range 6-30), enteric fever has an
insidious onset, with a stepwise increase in fever and fatigue, reaching 38 to
40 °C by the third or fourth day of illness.[CDC. Yellow Book. 2024] The
fever is often lowest in the morning and peaks in the afternoon or evening.
Travelers may have a more abrupt onset of fever than people who live in
endemic areas.[6] Anorexia, headache, and malaise are nearly universal, and
abdominal symptoms such as pain, bloating, constipation, and diarrhea are
common. Diarrhea ranges from mild to severe, with or without blood. Dry
cough, myalgias, and sore throat may also be present.[2][9]
Children present with diarrhea, vomiting, febrile seizures, or other
neurological symptoms more often than adults. Immunocompromised
patients with human immunodeficiency virus, particularly those with low
CD4 counts, more commonly present with severe diarrhea and tend to have
more serious metastatic infections.[6][10]
The history must include the onset of symptoms, progression of illness, and a
full review of symptoms. Symptoms that could indicate severe illness include
an altered level of consciousness, severe abdominal pain exacerbated by
movement, or severe bloody diarrhea. Pale stool and dark urine may signal
hepatitis or biliary complications, while chest pain may be associated with
myocarditis or pericarditis. Pancreatitis may present with severe epigastric
pain radiating to the back. Osteomyelitis is associated with bone pain.
Symptoms of abscesses will depend on their location in the body.[11]
A travel history is essential to confirm risks for enteric fever, exclude other
infectious diseases in the differential diagnosis, and guide empiric treatment.
This should include the following:
 History of residence in or travel to endemic and outbreak areas in the
previous 30 days: departure date, time since departure from a risk area
 Type of travel: work-related, extreme sport, immigration, volunteer,
missionary
 Potential exposures for infectious diseases: drinking potentially
contaminated water, eating undercooked or poorly prepared food,
 animal contact, insect bites, sexual contact, medical care, drug use, or
poor accommodations [12][CDC. Yellow Book. 2024]
Past medical history may indicate risks for complications or more severe
illness. Other factors to consider are immunization history, socioeconomic
status, and any previous or ongoing treatment. This includes prior antibiotics
or malaria chemoprophylaxis, including the dose and interval of the
medication. Patients should be asked whether there are other ill individuals in
their household or with whom they traveled. For treatment purposes, the
WHO classifies mild disease as not critically ill with no signs of intestinal
perforation, peritonitis, or septic shock. Severe illness is defined as those who
have confirmed or suspected intestinal perforation, peritonitis, sepsis, or
septic shock.[WHO. Aware. 2022]
Physical Exam
Physical examination findings in enteric fever can be nonspecific. Initially,
patients may look pale, lethargic, and dehydrated. If the disease progresses
untreated, patients may appear toxic and with notable weight loss. Rose
spots, such as blanching and 2 to 4 mm erythematous maculopapular lesions,
are present in less than a quarter of enteric fever patients (see Image. Rose
Spots on Chest, Patient with Typhoid Fever), primarily over the chest and
abdomen.[13] They are very difficult to see in people with darker skin tones.
Some patients have jaundice with yellowish skin and sclera with more severe
disease. Pulmonary and cardiac exams should seek signs of pneumonitis,
pulmonary abscess, or myocarditis, such as tachypnea, crackles over the lung
base, or cardiac rubs. Relative bradycardia may accompany the fever in the
first week but is neither sensitive nor specific for typhoid. On abdominal
exam, hepatosplenomegaly may be found in 29% to 50% of cases.[2] While
diffuse abdominal distension and tenderness are common, rebound
tenderness, rigidity, and guarding of the abdomen later in the illness indicate
intestinal bleeding or perforation.
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Evaluation
A timely and accurate diagnosis of enteric fever is important to minimize
complications, hospitalizations, and death. However, laboratory confirmation
in the first week of illness is difficult due to the poor performance of
available laboratory testing methodologies. The development of rapid
multiplex diagnostic tests with improved sensitivity and specificity is
urgently needed.[9]
The initial workup must include ruling out other potentially critical causes of
undifferentiated fever as appropriate, such as malaria and meningitis. Without
another obvious diagnosis, a fever on at least 3 of 7 days is sufficient to
suspect enteric fever and initiate treatment for anyone living in an endemic
area, traveling from an endemic area within 28 days, or being a household
contact within 28 days of someone who is a confirmed case of typhoid (acute,
convalescent, or chronic).[WHO. Aware. 2022] Based on this broad
definition of a suspect case, a diversity of undifferentiated febrile illnesses
are unavoidably treated as enteric fever in endemic countries.
Confirmation of typhoid or paratyphoid fever requires S Typhi or S Paratyphi
bacteria or deoxyribonucleic acid from the organism to be isolated from a
normally sterile site by culture or molecular test, respectively. Laboratory
confirmation should be obtained wherever possible. In resource-constrained
settings, the WHO's AWaRe (Access, Watch, Reserve) antibiotic book does
not deem laboratory diagnosis necessary in uncomplicated cases of enteric
fever.[WHO. Aware. 2022]
Culture
The culture of S Typhi or S Paratyphi from a normally sterile site, usually the
blood or bone marrow, is the gold standard for diagnosing enteric fever.
Blood or bone marrow culture is 100% specific and essential to determining
antimicrobial susceptibility and the appropriateness of ongoing treatment.
However, expense and limited technical capacity worldwide limit the
widespread use of blood or bone marrow culture in endemic countries.
Low sensitivity and long lag time further limit the use of culture to diagnose
enteric fever. The preferred and most common culture method, a single blood
culture, is positive in only about 50% to 66% of cases in endemic areas.[6]
[CDC. Yellow Book. 2024] Studies have found a median of 1 to 2.5 cfu/mL
in mixed blood or bone marrow samples.[6] Multiple cultures and larger
samples (7 mL) are recommended to increase sensitivity.[2][14]
[CDC. Yellow Book. 2024] Cultures are most sensitive in the first week of
infection when the viral load in the blood is high; observation for as long as 7
days may be needed before confirming a negative result. In travelers, blood
culture is much more sensitive (>90%).[6]
Due to the larger number of microorganisms in the bone marrow, bone
marrow culture is the most sensitive culture method at 80% to 96%
[CDC. Yellow Book. 2024][6][15] Bone marrow cultures may continue to
show growth for several weeks after the onset of illness and are relatively
unaffected by prior antibiotic use. However, the test is highly invasive and
not routinely used.
Stool culture is inappropriate for diagnosing acute S Typhi and S Paratyphi as
results can also be positive in convalescent disease or chronic carriage. Stool
culture has a low sensitivity and generally does not yield positive results until
after the first week of the disease. Other culture diagnostic methods,
including duodenal content culture via string capsule and urine culture, are
not regularly used to identify S Typhi or S Paratyphi. Where characteristic
rose spots are present, a punch biopsy may yield culturable S Typhi
or S Paratyphi.
Immunological Tests
The Widal agglutination test is a classic serological test that has been
controversial since its development in the late nineteenth century due to its
low sensitivity and specificity.[13] However, it is the most commonly
available test in endemic countries. An antibody titer of greater than 1:160
and greater than 1:80 for anti-H antigen and anti-O antigen is considered the
cutoff level to predict recent infection of S Typhi or S Paratyphi A in an
endemic area—although cutoffs vary somewhat across regions.[15] An
increase in titer over 4 weeks improves test performance but is often omitted
due to cost and the need for a prompt diagnosis.
Various serological tests for diagnosing typhoid are commercially available
and increasingly used due to their low cost and rapid results. However,
sensitivity and specificity are only moderate due to cross-reactivity with
other Salmonella serovars and preexisting antibodies from prior infection.
[2] The best-performing test in a 2017 Cochrane review had a sensitivity of
73.8% and a specificity of 94.5%.[2] Recent identification of alternate
antigens for diagnosis has led to promising results. For example, a test using
lipopolysaccharide and HlyE-specific IgA, validated in Bangladesh and
Nepal, provides greater than 90% sensitivity and specificity.[2]
Some authors have advised against using currently available rapid diagnostic
tests in endemic countries to prevent their misuse. However, the World
Health Organization's Strategic Advisory Group of Experts on in vitro
diagnostics rejected this proposal due to the lack of better alternatives.
Diagnostic algorithms may improve the utility of rapid diagnostic tests.[14]
Molecular Tests
Nucleic acid detection methods such as multiplex polymerase chain reaction
(PCR) or whole genome sequencing allow the genetic signature of the
specific genotype to be determined, including the resistance pattern. Direct
testing of clinical samples results in low sensitivities due to the low
concentrations of bacteria in the blood; combined culture-PCR may improve
sensitivity.[6] Having replaced serotyping in many developed nations,
nucleic acid testing is cost-prohibitive in many settings. Stool PCR may
indicate chronic infection or recent oral typhoid vaccine.
Additional metabolite biomarkers for diagnosing enteric fever and
differentiating acute from chronic infection are under investigation.[16] For
example, the metabolites ethanolamine, phenylalanine, gluconic acid,
monosaccharide, and saccharide show differences in those with S Typhi
infection compared to healthy controls and other febrile illnesses.
[17] Upregulation of hepcidin and altered breakdown of tryptophan are also
highly correlated with S Typhi infection. Molecular studies may also be
combined with other tests. For example, various diagnostic biomarkers and
IgG, IgM, and IgA antibodies could distinguish typhoid from other febrile
illnesses in CHIM studies. Work is ongoing to optimize composite panels and
cutoff standards to maximize sensitivity and specificity.
Other Laboratory Tests
Thick and thin blood smears should be ordered if malaria is a risk. For those
with a prominent headache or neck stiffness, a lumbar puncture with fluid
should be sent for gram stain, culture, and sensitivity. Cerebrospinal fluid is
often normal in enteric fever, although mild pleocytosis (<35 cells/mL) may
be present.[18] About 15% to 25% of people with enteric fever will have
leukopenia and neutropenia. Among children younger than 5, 41% have
leukocytosis, and 71% have anemia.[2] Liver function tests may be elevated,
similar to viral hepatitis. An electrocardiogram, ultrasound, or x-ray may be
required to rule out complications such as myocarditis, abscess, or intestinal
perforation.
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Treatment / Management
Antibiotic therapy is the mainstay of treatment for enteric fever. Treatment
should be started as soon as the diagnosis is suspected, as delays prolong the
course of illness and result in a higher risk of complications and severe
disease. While most patients with enteric fever are hospitalized in the United
States and other nonendemic areas, most people with uncomplicated illness in
endemic countries receive outpatient treatment.[2]
Empiric Antibiotic Treatment
The AWaRe (access, watch, reserve) antibiotic book provides global
recommendations for empiric treatment choice based on the severity of
illness at presentation and the prevalence of ciprofloxacin resistance in the
likely place of acquisition.[3][WHO. Aware. 2022] A cutoff of 10% is
common, although this was not defined in the AWaRe document.
[6] Antibiotic dosages should be adjusted for renal function in adults and
children. Treatment should be extended if clinical improvement has not
occurred and the patient has not been afebrile for at least 48 hours.
[WHO. Aware. 2022]
Where the prevalence of ciprofloxacin resistance is high, including in most of
Asia and sub-Saharan Africa, azithromycin is the drug of choice for adults
with mild cases of enteric fever. A loading dose of 1 g azithromycin is given
on day 1, followed by 500 mg once daily for 7 days. For severe cases,
ceftriaxone 2 g intraveneously daily for 10 days is the empiric drug of choice.
In areas with a low prevalence of fluoroquinolone resistance, ciprofloxacin is
the drug of choice. In adults, ciprofloxacin 500 mg orally every 12 hours is
given for 7 days in mild cases and 10 days in severe.[WHO. Aware. 2022]
Based on several Cochrane reviews, these antibiotics have roughly
comparable effectiveness against enteric fever caused by susceptible
organisms in terms of tolerance and clinical and biological failure.
[6] [10] Azithromycin has fewer failures than fluoroquinolones (odds
ratio, .48; 95% confidence interval, .26-.89). Ceftriaxone may have a higher
relapse rate when compared to azithromycin.[6]
The WHO recommends the same empiric antibiotics for children. The
antibiotic dosage must be adjusted to the child's weight. Ciprofloxacin is
given orally at a dosage of 15 mg/kg/dose every 12 hours; 20 mg/kg/dose of
azithromycin is given orally every 24 hours; and 80 mg/kg/dose of
ceftriaxone is given intravenously every 24 hours.[WHO. Aware. 2022]
Azithromycin is recommended as empiric treatment for uncomplicated
illness, and carbapenem for more severe disease for travelers and residents in
areas with high rates of XDR, such as Pakistan or Iraq.[CDC. Yellow
Book. 2024] Azithromycin is given as a loading dose of 1g on day 1 and then
500 mg once daily for 7 days. Meropenem is the most commonly used
carbapenem, with 20 mg/kg given 3 times daily.[11]
Where available, locally determined AMR patterns or national guidelines
provide additional insight into the choice of empiric treatment. In the United
States, most S Typhi and S Paratyphi infections are not susceptible to
ciprofloxacin, with greater than 90% of resistant infections occurring among
travelers returning from South Asia.[CDC. Yellow Book. 2024]
Azithromycin and ceftriaxone are recommended for empiric treatment. If the
patient has traveled to Pakistan or Iraq or has not traveled internationally,
empiric treatment for XDR should be initiated.
(Refer to the Epidemiology section for more information on the global
distribution of AMR).
Ongoing Treatment
If the initial antibiotic is effective, fever decreases over the following 3 to 5
days, and treatment is continued for the recommended interval. If fever
persists for more than 5 days, a search for a persistent locus of infection or
treatment with alternate antibiotics should be considered, based on bacterial
susceptibility whenever possible.[CDC. Yellow Book. 2024] Defervescence
can be slow with cephalosporins.[12] Cefixime can be an alternative to
ceftriaxone, although its relative effectiveness may be lower than
fluoroquinolones.[10] This is likely due to cefixime's low intracellular
penetrance. Ofloxacin demonstrates similar performance to ciprofloxacin.[6]
Other Antibiotic Regimens
While susceptibility to chloramphenicol, ampicillin, and co-trimoxazole has
re-emerged in some areas, they are no longer recommended as first-line
agents due to the persistent threat of MDR.[2] They can be used as
alternatives only in areas or infections with known sensitivity.[13] Studies
comparing current WHO-recommended therapies to chloramphenicol have
shown these to be equally effective.[2][6]
Due to S Typhi and S Paratyphi's dual intracellular and extracellular nature,
dual antibiotic use targeting these 2 spaces is proposed to improve clinical
outcomes and decrease the probability of resistance emerging.[6] A small
randomized control trial in Nepal found that adding azithromycin (principally
intracellular activity) to oral cefixime or iv ceftriaxone (principally
extracellular activity) halved the time it took to clear the fever.[12] A large-
scale outpatient double-blinded one-to-one randomized control trial is
ongoing to compare azithromycin and cefixime versus azithromycin alone in
uncomplicated typhoid.[6] Results are expected in late 2024.
For XDR strains, a combination of azithromycin and meropenem versus
meropenem or azithromycin alone was not found to significantly change the
time to defervescence or the treatment failure rate.[11] The cost of additional
therapy must be a consideration in treatment choice in resource-constrained
settings, with meropenem costing an order of magnitude more than
azithromycin and requiring inpatient treatment.
The oral carbamazepine tebipenem is effective in vitro against S Typhi
and S Paratyphi, alone or synergistically with azithromycin.[6] Licensed in
Japan for pediatric respiratory infections, its use in enteric fever is being
explored. The risks and benefits of deploying an oral carbapenem must be
carefully considered in areas with unregulated prescribing and significant
resistance in other Enterobacteriaceae.[6]
Supportive and Other Treatment
Outpatient treatment consists of oral antibiotics, antipyretics, and
commercially available oral replacement fluids when required for vomiting
and diarrhea. For severe illness where supportive measures are needed,
treatment must be on an inpatient basis. Intravenous fluids and blood
products should aggressively replace losses due to diarrhea or bleeding.
Ventilation and oxygenation may be required for pulmonary complications.
Steroids are recommended for severe illness, particularly where central
nervous system involvement and shock are found.[12] This is given as
dexamethasone 3 mg/kg intravenously over 30 minutes, followed by 1 mg/kg
every 6 hours for a total of 8 doses. (Refer to the Complications section for
further discussion on managing complications).
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Differential Diagnosis
Enteric fever presents as an undifferentiated acute febrile illness resembling
multiple other infectious diseases (most commonly confused with malaria).
Factors such as time since returning home from travel, ill travel partners, or
unusual exposures may suggest or exclude particular diagnoses. While
symptoms vary in frequency across different conditions, most are not
sufficiently specific upon presentation to be useful to rule in or out particular
conditions. The CDC Yellow Book describes the approach to a febrile
returning traveler, with a complete list of potential illnesses and their
associated incubation periods.[CDC. Yellow Book. 2024]
The parasite Plasmodium falciparum causes the most deadly form of
malaria. This parasite has an incubation period of 8 to 11 days, while most
other Plasmodium species have an incubation period of 9 to 17 days. For P
malaria, the incubation period is usually 18 to 40 days but can rarely last
several years. Rigors are more commonly seen with malaria than with enteric
fever. The use of preventive medication does not rule out the diagnosis.
Amoebiasis is a less common parasitic infection in the differential. Like
enteric fever, amoebiasis is transmitted via the fecal-oral route and can
present with fever, bloody diarrhea, and abdominal pain.
The many bacterial illnesses on the differential include leptospirosis, scrub
and murine typhus, bacterial meningitis, brucellosis, and bacterial
gastroenteritis. Those with leptospirosis may have a history of contact with
animals or adventure sports and contact with mud. People with typhus may
be found to have a bite mark initially resembling a cigarette burn but
developing into black eschar. Those with bacterial gastroenteritis may be
more likely to have profuse diarrhea.
A wide variety of viral illnesses can also present with an undifferentiated
fever. These include influenza, COVID-19, dengue, viral hepatitis,
Chikungunya, viral meningitis, yellow fever, Ebola viruses, and many others,
depending on the location of residence or travel. Cough is usually more
prominent in influenza and COVID, with associated upper viral symptoms.
People with dengue or "breakbone" fever may have severe arthralgias.
Returning home more than 6 days before the onset of symptoms would
exclude yellow fever, dengue, and Chikungunya.
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Prognosis
Enteric fever can result in serious complications and death, particularly if
antibiotics are delayed or inadequate. The overall case-fatality rate
for S Typhi infection has fallen drastically from 10% to 30% in the pre-
antibiotic era to less than 1% in patients who receive early treatment
today. The overall pooled case fatality rate is an estimated 4.2% in non-
surgical hospital sites and varies significantly across regions: 0.9% in Asia,
5.4% in Africa, 7.2% in Oceania, 6.7% in the Americas, and 1% in Europe.
[10] Among cases in global non-hospital sites, the estimate is 0.2%.
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Complications
Complications usually occur 2 to 3 weeks after the onset of illness. In a 2020
global systematic review and meta-analysis of typhoid fever complications,
26% of lab-confirmed, predominantly hospitalized cases of typhoid
experienced a complication.[10] Reviews completed in 2018 and 2019 found
similar results.[2][6][10] The frequency of specific complications depends on
age, sex, pre-existing medical conditions, and geographic region.
Gastrointestinal Complications
Children younger than 5 present more frequently with diarrhea and
dehydration than adults and older children. Hepatitis is also reported to occur
in 36% of children in this age group.[2] Terminal ileum perforation occurs in
about 1.3% of hospitalized confirmed cases of enteric fever due to
hypertrophy and necrosis of Peyer patches.[10] Intestinal perforation occurs
approximately 2 times more frequently in men than women, mainly in people
older than 15.[10] Intestinal perforation is more common in sub-Saharan
Africa (7.6%) than in Asia (0.7%). The rate of intestinal perforation is
increasing in areas with increasing AMR typhoid. Gastrointestinal bleeding
can also occur, although it is rarely severe.
Surgical repair and peritoneal lavage is indicated for intestinal perforation.
Resultant peritonitis and septic shock require treatment with broad-spectrum
antibiotics, inotropes, and fluid replacement in an intensive care unit setting.
Blood replacement may be necessary for gastrointestinal hemorrhage.
[11] The average hospital stay for surgically treated perforation is 18 days.[2]
Even with treatment, the case fatality rate for intestinal perforation or
hemorrhage can be high. For intestinal perforation, higher rates occur in
confirmed cases in Africa, ranging from 13.7% to 28.0% across sites, than in
Asia, where the range is 0% to 8.4%.[10] The median case mortality for
intestinal perforation in Asia is 4.6% and 19.7% in Africa, likely owing to
more difficult access to quality medical care services in Africa.[10] A
hallmark of severe typhoid, intestinal perforations in endemic countries
should be considered probable enteric fever cases. While a late marker of
disease, reporting these can help identify outbreaks in countries with
underdeveloped enteric fever surveillance systems.[3]
Neuropsychiatric Complications
Delirium is a common complication of enteric fever, occurring in a quarter of
confirmed hospitalized cases. Neurological manifestations are otherwise not
common in adults, manifesting with meningitis, encephalopathy, sleep
irregularities, acute psychosis, myelitis, ataxia, muscle rigidity, and focal
neurologic deficits.[2][12] Delirium, encephalopathy, and febrile seizures
occur more often in school-aged children.[10] Clinical symptoms are thought
to be due to cortical irritation by typhoid toxin. Corticosteroids have been
suggested for severe cases of encephalopathy.[13]
Other Complications
Anemia is one of the most common complications of enteric fever, affecting
up to one-fifth of hospitalized cases. Anemia is more common in South Asia
than anywhere else in the world.[2] One study showed a miscarriage rate of 1
in 6 in pregnant women with confirmed typhoid.[10] Widespread
dissemination of bacteria can cause multiorgan failure due to disseminated
intravascular coagulation and septicemia.[14] Focal abscesses are
uncommon. Lung complications, including bronchitis and pneumonia, occur
primarily in children and patients with lung cancer, glucocorticoid use, and
other structural lung diseases.[15]
Relapse
Relapse is defined as a recurrence of symptoms with laboratory confirmation
of S Typhi from a normally sterile site within 1 month of completing an
appropriate course of antimicrobial treatment and resolution of symptoms.
Relapse occurs in less than 10% of patients, usually 1 to 3 weeks after
clinical recovery. Further antibiotic treatment is required.
Chronic Carriage
Convalescent carriage of S Typhi and S Paratyphi can continue for a few
weeks to months after treatment of enteric fever. Usually, this clears without
further treatment. However, 1% to 4% of patients with typhoid fever become
chronic carriers, demonstrating shedding for at least 12 months after finishing
an appropriate course of antibiotics.[CDC. Yellow Book. 2024] Chronic
carriage is less common with adequate antibiotic treatment and S Paratyphi
infections.
Confirmation of chronic carriage is difficult due to intermittent shedding and
low organism levels in the stool. A stool culture or polymerase chain reaction
is used to determine persistent carriage. Sufficient time must elapse between
finishing antibiotics and testing to ensure antibiotic clearance. PCR testing
can also detect bacterial DNA well after viable bacteria are cleared. An anti-
Vi antibody-based test has been developed for use in nonendemic areas but is
unreliable in medium- to high-prevalence areas where regular infection or
exposure results in higher baseline titers.[2]
Underlying biliary structural abnormalities and cholelithiasis are underlying
risk factors for chronic carriage, which are more commonly seen in women
and older individuals. Chronic carriage of S Typhi and S Paratyphi for
gallstones is associated with biofilm development.[2] Chronic carriers of
typhoid have 4.28 times the risk of developing biliary cancer compared to the
general population.[12] Kidney stones and, in Africa, S
haematobium infections increase the odds of urinary tract infection and
chronic urinary carriage.
Current evidence for treating chronic carriage is lacking. The 2003 WHO
guidelines and a 2022 systematic review are based on evidence that precedes
1990.[6][12] Cholecystectomy cures chronic carriage in 70% to 90% of
cases.[12] However, because it carries significant anesthetic and surgical risk,
cholecystectomy is only recommended if other indications for surgery exist.
[2][6] Household members of chronic typhoid carriers may be advised to be
vaccinated.
Go to:

Deterrence and Patient Education

Patients with Enteric Fever
Patients treated on an outpatient basis or who return home after
hospitalization and their caretakers need to be aware of methods to prevent
transmission within the household. Convalescent carriage of S Typhi
and S Paratyphi may last for weeks or even months after acute illness. Hand
hygiene with soap and water is of critical importance. Caretakers must be
given instructions about caring for the ill person, including the need for
gloves, strict hygiene, and safe disposal of potentially contaminated feces or
urine. Recently ill people should not prepare food or engage in other
activities that may result in transmission within the household. Patients
should be informed that previous enteric fever does not provide long-lasting
protection. Vaccination should be recommended if future or ongoing risk
exists.
Individual Prevention Measures
Washing hands frequently with soap and water and drying hands thoroughly
after washing are basic measures for avoiding enteric illnesses. This includes
before preparing food, after using the bathroom or changing diapers, and after
caring for an ill person. Alochol-based sanitizers containing at least 60%
alcohol can be used where water and soap are not available but are not as
effective as soap and water for some pathogens.[CDC. Yellow Book. 2024]
Hands should be thoroughly washed immediately after using sanitizers.
Maintaining food and water precautions is also essential for travelers and
people living in endemic areas. Raw or undercooked meat, fish, shellfish, and
produce carry the greatest risk of contamination. Unpasteurized fruit juices,
salads, unpeeled fruits, and unpasteurized milk and cheeses should be
avoided. All cooked foods should be fully cooked and served hot. Patients
should be advised to avoid foods in restaurants that may have been cooked
ahead and reheated before serving, such as lasagna, and those sold by street
vendors. Buffets should be avoided. Where drinking water safety is uncertain,
water should be adequately treated, or only bottled water should be consumed
—this includes drinking, preparing food and beverages, brushing teeth,
making ice, and cooking. Hot drinks such as tea or coffee are generally
considered safe.
For bottle-fed infants, either prepared liquid formula should be used, or
particular care should be taken when preparing formula. Water for
reconstitution should be hot (≥70 °C).[CDC. Yellow Book. 2024] The
formula should be used within 2 hours, and any remaining after feeding
should be discarded. Counsel patients about when to seek medical if febrile.
VFR travelers are most likely to become infected with enteric fever, as they
are less likely to maintain precautions regarding food and water and are less
likely than other travelers to obtain pretravel advice.[CDC. Yellow
Book. 2024]
Vaccination
Typhoid vaccination is recommended for travelers to endemic areas,
particularly those traveling to South Asia and those with health- or travel-
related risks traveling to other endemic areas. This includes children, VFR,
prolonged travel abroad, anatomic or functional asplenia, the use of acid
suppressants, or personal preference. Vaccination does not preclude the need
for hand hygiene and food and water precautions. The vaccines currently
available in nonendemic areas are not fully effective, and the risk of other
illnesses transmitted by the fecal-oral route remains. In endemic countries
where typhoid vaccination is not integrated into routine vaccination
schedules, patients at higher risk of severe disease may obtain typhoid
vaccination for private pay.
Unconjugated Vaccines
There are 2 licensed, unconjugated vaccines in the United States: an
inactivated Vi capsular polysaccharide (ViPS) vaccine and a live vaccine of
an attenuated Ty21a S Typhi strain.[CDC. Yellow Book. 2024] These are
about 50% to 60% effective in preventing typhoid fever.[16][CDC. Yellow
Book. 2024] The intramuscular Vi capsular polysaccharide vaccine is
appropriate for those 2 years and older; this should be given 2 weeks or more
before travel, and a booster should be provided every 2 to 3 years, depending
on national recommendations.[23] The CDC recommends every 2 years.[20]
[CDC. Yellow Book. 2024]
The Ty21a vaccine is indicated for people 6 years or older. One capsule
every other day for a total of 4 doses is taken with liquid no warmer than
body temperature at least 1 hour before a meal. The series should be
completed at least 1 week before exposure, and a booster is indicated every 5
to 7 years.[17][CDC. Yellow Book. 2024]
The oral vaccine is contraindicated in people who are immunocompromised,
acutely ill with a gastrointestinal condition, or breastfeeding. It should only
be used in pregnant women if the injectable attenuated vaccine is unavailable
and a careful risk assessment is done. Though not licensed for this indication,
the oral Ty21a vaccine may offer some protection
against Salmonella Paratyphi B.[CDC. Yellow Book. 2024]
Typhoid Conjugate Vaccines
The WHO has prequalified 2 typhoid conjugate vaccines (TCVs): Typbar-
TCV and TYPHIBEV. By conjugating the Vi capsule to a protein carrier (eg,
tetanus toxoid), these vaccines induce a more robust and enduring T-cell-
mediated immune response than previous vaccines; these can be used in
children under 5 and infants as young as 6 months.[2] Given as a single-dose
intramuscular dose, TCVs were found to be 79% to 95% effective in the first
2 years after vaccination in studies covering more than 100,000 children in
diverse locations. The antibody response can persist for up to 7 years.
[8] Endemic countries are implementing TCV vaccines as part of routine
immunization programs. However, they are not licensed in Europe or North
America, precluding their use for travel. (Refer to the Enhancing Healthcare
Team Outcomes section for more information on the use of typhoid vaccines
in endemic countries.)
Go to:

Enhancing Healthcare Team Outcomes

Despite public health efforts, enteric fever is still a significant cause of
morbidity and mortality worldwide. In the United States and other developed
nations, it is a source of life-threatening illness, mainly in travelers. An
interprofessional healthcare team is essential to all aspects of enteric fever
prevention and treatment.
Access to Quality Health Care
Primary care and public health providers are important resources for travelers
and people living in endemic areas to emphasize individual prevention
measures to decrease the risk of enteric fever and other food and water-borne
diseases. For example, in nonendemic countries, healthcare providers can
advise patients of their risk of typhoid before travel and advise vaccine. In
areas with poor sanitation in endemic countries, campaigns promoting the use
of soap and water have been shown to decrease the risk of gastrointestinal
illnesses.
Healthcare providers in primary care and emergency settings are usually the
first to encounter febrile travelers. A broad differential diagnosis and high
index of suspicion in these settings allow the timely diagnosis of enteric
fever. Using established regional, national, or international guidelines
developed by infectious disease and public health colleagues can improve
empiric treatment and avoid unnecessary complications. Reporting enteric
fever is usually required within 24 hours in most developed countries to
minimize community spread. For patients treated at home, community
nursing can provide follow-up and recommend hygiene measures to avoid
illness in other family members. For patients requiring hospitalization, timely
referral to surgical, infectious disease, or critical care specialists may be
required.
The provision of quality care includes the need for increased diagnostic and
surveillance capacity in low- to middle-income countries.[3] Community
health education about the mode of transmission, prevention, signs and
symptoms, and the importance of early treatment can also reduce the
incidence and burden of disease. Intersectoral coordination by public health
and nonmedical organizations and authorities in sanitation management,
awareness of individual prevention measures, and nutritional programs boost
disease control and prevention.
WASH
The importance of improved global access to and use of infrastructure
supporting safe washing, sanitation, and hygiene cannot be understated.
However, coverage for basic sanitation services was less than 50% in sub-
Saharan Africa, India, Bangladesh, and Nepal in 2015.[8] Improving clean
drinking water access is necessary but insufficient to decrease enteric fever's
burden. Human waste must also be disposed of safely away from populations,
water supplies, and crops. Legislation may be required to address agricultural
practices. Point-of-collection disinfection methods can provide lower-cost
and easier-to-use options when governmental resources are insufficient to
develop and maintain complicated water treatment infrastructure.[2] WASH
is critical to overall population health improvement, decreasing the incidence
not only of enteric fever but also other food and water-borne diseases. WASH
improvement is the 6th sustainable development goal and a building block of
the WHO Global Action Plan on antimicrobial resistance.[8]
Population Approaches to Vaccination
Vaccination is an important adjunct to WASH efforts to control typhoid
globally. The current (2018) WHO guidelines on the use of typhoid vaccines
recommend the programmatic use of TCVs in countries with endemic
typhoid in combination with health education, WASH improvements, and
HCW training on typhoid fever diagnosis and treatment.[16] Integration into
routine vaccination schedules improves coverage. Prioritization of those
countries with the highest incidences of disease or high rates of AMR is
advised. Co-administration with other vaccines has been proven to not
interfere with immune responses.[17] TCV use in outbreaks in endemic
countries is also recommended and has been effectively used in outbreaks in
Zimbabwe and Pakistan.
Integration into routine childhood immunization programs is estimated to be
cost-effective or highly cost-effective in all countries with high to very high
typhoid fever incidence.[16] In some Asian countries, the programmatic use
of TCV could be cost-saving. In all countries, programmatic decisions such
as immunization age should be based on the local epidemiology of typhoid
fever, antimicrobial resistance patterns, cost analyses, and consideration of
the routine childhood immunization program.
Catch-up vaccination campaigns targeting children aged up to 14 are also
recommended where feasible and supported by data to maximize impact.
[18] Single-age vaccine programs may be more cost-saving in some settings.
For example, providing 1 dose at 9 months of age with a parallel catch-up
program at 15 could avert up to 67 million cases in the 73 low- to middle-
income countries eligible for Gavi the Vaccine Alliance funding over 10
years.[18] Depending on the age structure and vaccination coverage, 46% to
74% of cases in individual countries could be avoided.
Six countries now have a childhood vaccination program. Starting in 2019,
Pakistan was the first country to implement a campaign through a phased
approach. Since then, Liberia (2021), Nepal (2022), Zimbabwe (2021),
Samoa (phased, starting 2021), and Malawi (2023) have implemented
programs.[18] In Nepal, Pakistan, and Zimbabwe, integrated campaigns were
conducted, including various other interventions such as identifying un- or
under-vaccinated children, administering other vaccines, supplementing
vitamin A, and promoting hygiene. Post-campaign coverage in these
countries ranged from 63% to 95%.[18] The COVID-19 pandemic and other
competing health priorities have likely delayed the introduction of
immunization programs in some countries. Insufficient disease burden data
has also limited national vaccine decisions. However, inadequate surveillance
data to monitor vaccine impact should not preclude introducing TCVs.[18]
(Refer to "Surveillance and Reporting" for more information on challenges
with enteric fever surveillance).
Public Health Measures and Outbreak Control
In countries where enteric fever is a reportable disease, once a report is
received, public health assesses whether the source of infection (ie, travel
versus locally acquired) poses an ongoing risk of transmission to the local
population and ensures that the affected individual does not transmit the
illness to others. The discovery of local transmission triggers an
investigation, which can include searching for additional cases, food testing,
interviewing coworkers, and public communications to advise others who
may be at risk, for example, if a person worked while ill or was a chronic
carrier.
Local, state, or national codes or guidelines determine specific requirements
for exclusion. Public health authorities may restrict recently recovered
individuals from daycare attendance or participating in certain high-risk
occupations for transmission until 2 to 3 stool cultures taken at least 48 hours
apart are negative for S Typhi and S Paratyphi.[17][WA Gov. Typhoid. 2018]
[FL Gov. Typhoid. 2013] High-risk occupations include food handlers,
healthcare and childcare workers, and water park employees. The collection
of stool samples must allow antibiotics to be used in treatment to clear them
first. For example, many local state codes stipulate that samples must be
taken at least 1 week after treatment [CA Gov. Typhoid. 2015][WA
Gov. Typhoid. 2018][FL Gov. Typhoid. 2013] while other jurisdictions allow
the collection to occur 2 days after ciprofloxacin and 2 weeks after
ceftriaxone or azithromycin.[BCCDC. Enteric Exclusions. 2023] People who
have ever traveled or lived in a country with schistosomiasis may be required
to have at least 1 negative urine sample. People who traveled with the ill
person may also be excluded from work in sensitive settings until stool
cultures are clear.
Public health commonly addresses outbreaks even where individual case
follow-up does not occur. Outbreaks may be identified by increased
hospitalizations or incidence of nontraumatic intestinal perforations. In these
instances, coordinated public health education campaigns, swiftly
administering vaccines, and addressing sanitation concerns can decrease the
burden of typhoid fever illness.[20]
Antimicrobial Stewardship
Increasing antimicrobial resistance is one of the most pressing global public
health issues. While new antimicrobials continue to be developed, bacteria
develop resistance far faster. Although S Typhi and S Paratyphi are
exclusively human pathogens, antimicrobial resistance factors mediated by
plasmids can transfer between Salmonella and other bacteria. Thus, the lack
of access to health care and widespread use of antibiotics for undifferentiated
fevers, particularly in typhoid-endemic areas, contributes to the global burden
of AMR. The occasional azithromycin-resistant Salmonella strain and the
discovery of plasmid-mediated carbapenem-resistant Escherichia coli co-
circulating with MDR typhoid are particularly problematic, with the concern
for strains resistant to all current antibiotics developing.
In addition to WASH measures, improved diagnostic modalities and
vaccination programs can effectively decrease AMR due to enteric disease.
Due to the high rate of treatment for enteric fever, with an estimated 3 to 25
infections treated per every culture-confirmed case, typhoid vaccinations
integrated into childhood vaccination programs would also decrease AMR
due to typhoid by 16% and reduce resistance in bystander organisms.[8]
Surveillance and Reporting
Accurate surveillance and reporting are critical to enteric fever control to
assess disease burden, rapidly detect outbreaks, determine emerging AMR
patterns, and evaluate vaccine impact. However, the capacity for surveillance
and the precision and accuracy of estimates vary significantly between
nations. For example, reporting positive S Typhi and S Paratyphi results by
laboratories to local public health authorities must occur within 24 hours in
the United States. From there, clinical data on laboratory-confirmed S Typhi
and S Paratyphi cases is reported to the National Typhoid and Paratyphoid
Surveillance System; laboratory-confirmed and clinically compatible cases
linked to a laboratory-confirmed case of enteric fever are entered into the
National Notifiable Diseases Surveillance System (NNDSS). Highly accurate
totals of clinical disease are generally obtained, notwithstanding the
likelihood that NNDSS data is incomplete due to incomplete reporting and
the inability to reconcile data sets during the COVID-19 pandemic.
[CDC. Typhoid and Paratyphoid Surveillance. 2020] However, even robust
surveillance systems cannot capture the true incidence due to subclinical
infections.
The WHO recommends facility-based surveillance in all endemic countries,
with laboratory confirmation of the infection. The recommended minimum
parameters for monitoring the disease burden are mortality, morbidity, and
economic impact. The United Nations rolled out an electronic Joint Reporting
Form in 2018, with reporting to the WHO and UNICEF.[19] The WHO
Global Antimicrobial Surveillance System (GLASS) additionally collates
AMR patterns across all Salmonella species, with suggestions from some
authors that typhoidal Salmonellae be separated from NTS in the future.
In recent years, substantial investments in surveillance systems in less
developed endemic countries have been made. However, significant regional
surveillance gaps remain. In many endemic countries, the number of lab-
confirmed cases dramatically underestimates the true incidence of enteric
fever due to the following:
 Similarity between clinical presentation and those of other acute febrile
illnesses in areas where typhoid is endemic
 Low sensitivity or specificity of available diagnostic technologies
 High use of antibiotic use before presentation to healthcare
  Low availability of blood culture
 Lack of well-developed surveillance systems in many
jurisdictions [19]
Population studies are required to estimate the true incidence of disease more
accurately.[19] These are costly, time-consuming, technically challenging,
and unavailable in most countries. Three ongoing surveillance projects
covering 10 countries are essential for population estimates (Bangladesh,
Nepal, Malawi, Pakistan, Burkina Faso, the Democratic Republic of the
Congo, Ethiopia, Ghana, Madagascar, and Nigeria). The Global Burden of
Disease Study, most recently published in 2019, estimates rates and case
counts from published studies, publically available data sets, and contributed
data across 369 diseases and injuries across 205 countries and territories.[21]
More recently, global collaborations, improved surveillance systems and
distribution, and improved methods to estimate the incidence of enteric fever
and determine the prevalence of AMR have improved the availability of more
granular AMR patterns, including in areas with little or no data.[3][8] For
example, a 2024 spatiotemporal mathematical modeling study estimated
phenotypic AMR prevalence in 75 endemic countries using 601 data sources
for S Typhi antibiotic resistance patterns from 45 countries over 30 years. A
2023 meta-analysis used all available published and unpublished Typhi
genomes from the previous 21 years (12,965 high-quality genomes from 110
countries).[3] This study analyzed AMR patterns using whole genome
sequencing to determine phenotype. The study also used specimens from
travel-related cases from national reference laboratories in high-income
countries to provide some data in countries and regions with low capacity for
performing blood cultures.
This need to maximize information recovery from other sources is well-
recognized. Countries without robust surveillance can improve disease
estimates using data from various sources, including neighboring countries or
regions, population-based studies, modeling data, lab-confirmed cases, AMR
testing studies, outbreak reports, and non-traumatic intestinal perforation case
reports. The recent use of pooled genomic surveillance may allow for early
identification of shifts in AMR patterns or evidence of clonal spread. For
example, the identification of the extensively drug-resistant strain identified
in Pakistan in 2016 was found to have emerged in 2015.[22]
Research and innovation
Improving diagnostic technologies for enteric fever is a priority for research
and innovation. Limitations contribute to under- and over-diagnosis, poorer
clinical outcomes, and increased antimicrobial resistance. Improved
diagnostic techniques will also enhance surveillance. (Refer to the Evaluation
section for further information on recent advances in diagnostic
technologies).
Another priority is the development of a paratyphoid vaccine. While the
Ty21a vaccine may provide some cross-coverage against S Paratyphi B, no
vaccine is currently sufficiently effective for controlling S Paratyphi
infection; this is particularly concerning in South and Southeast Asia,
where S Paratyphi is most prevalent. Paratyphi may also increase
proportionally as Typhoid vaccination increases.
With very few options available, new antimicrobial therapies are also needed.
[8] While resistance to former first-line antibiotics is decreasing in some
areas due to reduced use, high resistance in other regions and the constant
threat of re-emergence continue to limit widespread utility.
Expanded and improved surveillance and epidemiological methodologies are
also a priority in improving enteric fever control. For example, environmental
surveillance using a nucleic acid amplification test is hoped to enhance
understanding of the incidence of infection, prevalence of AMR, and other
critical surveillance issues.[8] By identifying countries at the highest risk of
AMR S Typhi and S Paratyphi, phylogeographic studies can help prioritize
the implementation of WASH measures, vaccination programs, and
improvements to public health capacity.[23]
The expansion of genomic surveillance is predicted to improve the
measurement of the impact of TCVs on local S Typhi populations and
decisions about future combination Typhi vaccines, using techniques already
used for pneumococcal conjugate vaccines.[3][17] Genomic surveillance will
be important in monitoring changes in clinically important resistances
in S Typhi and S Paratyphi. Combined with environmental surveillance, early
evidence of clonal spread of known resistant organisms could provide early
warning of a likely increase in prevalence. Emerging mutations in
chromosomal areas that code for resistance can likewise flag the need to
watch for emerging resistance in clinical settings.[8]
 Go to:

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Figure
Rose Spots on Chest, Patient With Typhoid Fever. This condition is due to
the bacterium Salmonella Typhi. Symptoms of typhoid fever may include a
sustained fever as high as 103 to 104 °F (39 to 40 °F), weakness, stomach
pains, (more...)

Figure
Gallbladder Affected by Typhoid Fever. The image shows a gallbladder with
cholecystitis and ulceration from typhoid fever, a digestive system disease
caused by Salmonella Tyhpi. Contributed by CN Farmer; Centers for Disease
Control and Prevention (more...)
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Disclosure: Jenish Bhandari declares no relevant financial relationships with

ineligible companies.

Disclosure: Pawan Thada declares no relevant financial relationships with

ineligible companies.

Disclosure: Muhammad Hashmi declares no relevant financial relationships with

ineligible companies.

Disclosure: Elizabeth DeVos declares no relevant financial relationships with

ineligible companies.
Copyright © 2024, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
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In this Page
 Continuing Education Activity
 Introduction
 Etiology
 Epidemiology
 Pathophysiology
 History and Physical
 Evaluation
 Treatment / Management
 Differential Diagnosis
 Prognosis
 Complications
 Deterrence and Patient Education
 Enhancing Healthcare Team Outcomes
 Review Questions
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