This document provides an overview of typhoid fever and salmonella species across 13 chapters. It discusses the history, symptoms, transmission, diagnosis and treatment of typhoid fever. It also covers salmonella nomenclature, structure, habitats and identification. Typhoid fever remains an important cause of illness in developing countries, where it is transmitted through ingestion of food or water contaminated by infected feces. Common symptoms include sustained high fever, abdominal pain, and possible complications like intestinal bleeding or perforation. Proper sanitation and antibiotic treatment have reduced typhoid prevalence in developed nations.

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SECTION I • Typhoid Disease
CHAPTER 1
Introduction ................................................................................................................................. 2
CHAPTER 2
History and Distribution ............................................................................................................... 4
CHAPTER 3
Symptoms and Transmission and Pathogenesis ........................................................................ 8
CHAPTER 4
Diagnosis and Treatment .......................................................................................................... 14
CHAPTER 5
Resistance and Prevention ......................................................................................................... 16
CHAPTER 6
Genetic and Complication ........................................................................................................ 19
__________________________________________________________
SECTION I I • Salmonella species
CHAPTER 7
Salmonella and Nomenclature .................................................................................................. 22
CHAPTER 8
Antigenic Structure ....................................................................................................................24
CHAPTER 9
Habitats ......................................................................................................................................26
CHAPTER 10
Isolation and Identification ........................................................................................................27
CHAPTER 11
Salmonella infection .................................................................................................................. 30
CHAPTER 12
Conclusion and recommendation ...............................................................................................33
CHAPTER 13
Typhoid Fever Questions and Answers .....................................................................................35
Contend

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Introduction
Typhoid, also known as Typhoid fever or Typhoid Disease , is a common worldwide
bacterial disease, transmitted by the ingestion of food or water contaminated with the
feces of an infected person, which contain the bacterium Salmonella enterica, serovar
Typhi(fig.1)
. The bacteria then perforate through the
intestinal wall and are phagocytosed by macrophages.
The organism is a Gram-negative short bacillus that is
motile due to its peritrichous flagella(fig.1)
. The
bacterium grows best at 37°C / 98.6°F – human body
temperature.
as well as by certain non-typhoid salmonella (NTS),
particularly Paratyphoid strains A, B, C. These
waterborne gram negative aerobes are associated
with poor sanitation and fecal contamination of water
and food supplies. The syndrome needs to be distinguished from that caused by many
other organisms. Today there are as many as 16-30 million cases per year, almost
exclusively in the developing world, with a mortality rate of 10%. Recent developments
in the mapping of the Salmonella genome have
provided insights into its pathogenicity and how
antibiotic resistance and human immunity
develop. Typhoid fever is important surgically
because abdominal complications such as
intestinal perforation(fig.2)
, bleeding, cholecystitis
and pancreatitis represent the most serious
complications of the illness. Typhoid perforation
of the ileum is one of the most common causes
of bowel perforation in the developing world.
This fever received various names, such as gastric fever, abdominal typhus(fig.2)
, infantile
remittant fever, slow fever, nervous fever, pythogenic fever, etc. The name of "typhoid"
comes from the neuropsychiatric symptoms common to typhoid and typhus (from
Greek τῦϕος, "stupor").
(Fig 1. Salmonella spp.)
(Fig 2. Human abdomin.)

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Typhoid fever is very contagious. An infected person can pass the bacteria out of their
body in their faeces when they have a bowel movement or, less commonly, when they
urinate. If someone else eats food or drinks water that has been contaminated with a
small amount of infected faeces or urine, they can contract typhoid fever.
Typhoid fever is an infection caused by bacteria that can spread throughout the body.
Without prompt treatment, it can cause serious complications and can be fatal. This
disease is characterised by high fever, abdominal pain with or without diarrhoea,
enlarged spleen and rose coloured spots confined to chest & abdomen. It can infect the
blood (septicaemia) which has a fatality rate of 10 - 20 % if untreated & 1% in treated
persons. The risk of infection is generally
low, approximately 1 in 30,000 for
travellers to developing countries
spending 4 weeks. Risk is 10 times
higher in parts of India, Africa, Asia and
South America(fig.3)
. Typhoid is generally
a milder illness in children under 5. Risk
is increased by failing to observe
hygiene cook it, peel it or forget it.
The fever also known as enteric fever, is a potentially fatal multisystemic illness. The
protean manifestations of typhoid fever make this disease a true diagnostic challenge.
The classic presentation includes fever, malaise, diffuse abdominal pain,
and constipation. Untreated, typhoid fever is a grueling illness that may progress
to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within
one month of onset. Survivors may be left with long-term or permanent
neuropsychiatric complications.
Salmonella typhi has been a major human pathogen for thousands of years, thriving in
conditions of poor sanitation, crowding, and social chaos. The name S typhi is derived
from the ancient Greek typhos, an ethereal smoke or cloud that was believed to cause
disease and madness. In the advanced stages of typhoid fever, the patient's level of
consciousness is truly clouded. Although antibiotics have markedly reduced the
frequency of typhoid fever in the developed world, it remains endemic in developing
countries.
(Fig 3. Distribution of thyphoid disease.)

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History
Typhoid fever was not well understood in the ancient world, probably because its
symptoms are not primarily diarrheal, but rather systemic and non-specific. It was only
in the mid-19th century that physicians began to distinguish it from typhus and malaria.
Sir William Osler’s clinical description remains unsurpassed. Typhoid fever was
frequently associated with military campaigns and was a significant cause of death in
the American Civil War and Boer War where deaths from typhoid exceeded those from
combat. With recognition that fecal contamination of food and water supplies was the
main mode of transmission of the illness and measures taken to prevent these , typhoid
fever has been restricted, in industrialized countries, to localized epidemics and
infections in travelers returning from endemic areas.
Mary Mallon ("Typhoid Mary") in a
hospital bed (foreground)(fig.4)
. She
was forcibly quarantined as a
carrier of typhoid fever in 1907 for
three years and then again from
1915 until her death in 1938.
Some historians believe that the
English colony of Jamestown,
Virginia, died out from typhoid.
Typhoid fever killed more than
6000 settlers between 1607 and
1624. During the American Civil War,
81,360 Union soldiers died of typhoid or dysentery. In the late 19th century, the typhoid
fever mortality rate in Chicago averaged 65 per 100,000 people a year. The worst year
was 1891, when the typhoid death rate was 174 per 100,000 people. The most
notorious carrier of typhoid fever was Mary Mallon, also known as Typhoid Mary. In
1907, she became the first American carrier to be identified and traced.
(Fig 4. Typhoid Mary in a hospital bed.)

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She was a cook in New York. She is closely associated with fifty-three cases and three
deaths. Public health authorities told Mary to give up working as a cook or have her gall
bladder removed. Mary quit her job but returned later under a false name. She was
detained and quarantined after another typhoid outbreak. She died of pneumonia after
26 years in quarantine.
In 1880 Karl Joseph Eberth(fig.5)
described a
bacillus that he suspected was the cause of
typhoid. In 1884 pathologist Georg
Theodor August Gaffky (1850–1918)
confirmed Eberth's findings, and the
organism was given names such as Eberth's
bacillus, Eberthella typhi and Gaffky-Eberth
bacillus. Today the bacillus that causes
typhoid fever goes by the scientific name
of Salmonella enterica , serovar Typhi.
Almroth Edward Wright developed an
effective inactivated whole-cell typhoid
vaccine that was introduced in 1896. In
1909, Frederick F. Russell, a U.S.
Army physician, developed an American
typhoid vaccine and two years later his
vaccination program became the first in
which an entire army was immunized. It
eliminated typhoid as a significant cause of
morbidity and mortality in the U.S. military.
Most developed countries saw declining rates of typhoid fever throughout the first half
of the 20th century due to vaccinations and advances in public sanitation and hygiene.
Antibiotics were introduced in clinical practice in 1942, greatly reducing mortality.
Today, the incidence of typhoid fever in developed countries is around 5 cases per
1,000,000 people per year. An outbreak in the Democratic Republic of Congo in 2004–05
recorded more than 42,000 cases and 214 deaths. Typhoid fever was also known
as suette milliaire in nineteenth-century France.
(Fig 5. Carl Joseph Eberth.)

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Distribution
In contrast to that seen in the rich countries, typhoid fever remains an important cause
of illness in the developing world where annual incidences in Papua New Guinea and
Indonesia may reach 1200/100,000 population. A recent epidemiologic study showed
that south-east and south-central Asia are the regions of highest endemicity with rates
greater than 100/100,000 cases per year; the rest of Asia, Africa, Latin America(fig.6)
, the
Caribbean and Oceania (except Australia and New Zealand) are the next highest with
incidence rates of 10-100/100,000 and Europe, North America and the rest of the
developed world have low rates of disease. Typhoid fever represents the 4th most
common cause of death in Pakistan(fig.6)
.
The majority of patients, 60-90%, are treated as outpatients and, therefore, hospital
based studies will underestimate true incidence. Two hospital based case-control
studies from Vietnam found that risk of infection was related to recent contact with an
infected person, lack of education and drinking untreated water. S. paratyphi A, which
normally causes about 15-20% of cases of typhoid fever in Asia, increasingly is becoming
a pathogen in India and China, possibly due to vaccination against S. typhi.
(Fig 6. Geografical distribution of Typhoid fever.)

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Recent epidemiologic studies also show the rise of multi-drug resistant (MDR)
organisms. In a study of 1100 hospitalized children in Pakistan, the mortality rate of
1.6% was found to be related to younger age and MDR infection. Traditionally the age
range considered to be at greatest risk was 5-25 years(fig.7)
. However this has been
questioned in a study from a private laboratory in Bangladesh, which found that the
57% of S. typhi isolates were in
children less than 5 years of age
and 27% less than 2 years. This
has significant implications for
vaccination policies.
High-risk countries
The countries with the highest
rates of typhoid fever are:
 Bangladesh
 China
 India
 Indonesia
 Laos
 Nepal
 Pakistan
 Vietnam
Worldwide, typhoid fever affects about six million people with more than 6,00,000
deaths a year. Almost 80% of cases and deaths occur in Asia, and most others in Africa
and Latin America. Among Asian countries, India probably has a large number of these
cases. In Indian statistics typhoid fever is endemic in India. Health surveys conducted by
the Central Ministry of Health in the community development areas indicated a
morbidity rate varying from 102 to 2219 per 1,00,000 population in different parts of
the country. A limited study in an urban slum showed 1% of children up to 17 years of
age suffer from typhoid fever every year.
(Fig 7. Distribution of Typhoid and paratyphoid fever.)

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Symptoms
Classically, the course of untreated typhoid fever is divided into four individual stages,
each lasting approximately one week.
In the first week, there is a slowly rising temperature with relativebradycardia, malaise,
headache, and cough (fig.8)
. A bloody nose (epistaxis) . There is leukopenia, a decrease in
the number of circulating white blood cells with eosinopenia and relative lymphocytosis,
a positive reaction and blood cultures are positive for Salmonella typhi or paratyphi. The
classic Widal test is negative in the first week.
In the second week of the infection, the patient lies prostrate with high fever in plateau
around 40 °C (104 °F) and bradycardia (sphygmothermic dissociation), classically with
a dicrotic pulse wave. Delirium is frequent, frequently calm, but sometimes agitated.
This delirium gives to typhoid the nickname of
"nervous fever". Rose spots appear on the
lower chest and abdomen in around a third of
patients. There are rhonchi in lung bases. The
abdomen is distended and painful in the right
lower quadrant where borborygmi can be
heard. Diarrhea can occur in this stage: six to
eight stools in a day, green with a characteristic
smell, comparable to pea soup. However,
constipation is also frequent. The spleen and
liver are enlarged (hepatosplenomegaly) and
tender, and there is elevation of liver
transaminases. The Widal reaction is strongly
positive with (antiO) and (antiH) antibodies.
Blood cultures are sometimes still positive at
this stage. (The major symptom of this fever is
that the fever usually rises in the afternoon up
to the first and second week.)
(Fig 8. Typhoid fever sickness )

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In the third week of typhoid fever, a number of complications can occur:
 Intestinal hemorrhage due to bleeding in congested Peyer's patches; this can be very
serious but is usually not fatal.
 Intestinal perforation in the distal ileum: this is a very serious complication and is
frequently fatal. It may occur without alarming symptoms until septicaemia or
diffuse peritonitis sets in.
 Encephalitis
 Neuropsychiatric symptoms (described as "muttering delirium" or "coma vigil"), with
picking at bedclothes or imaginary objects.
 Metastatic abscesses, cholecystitis, endocarditis and osteitis
The fever is still very high and oscillates very little over 24 hours. Dehydration ensues
and the patient is delirious (typhoid state). By the end of third week the fever has
started reducing this (defervescence). This carries on into the fourth and final week.
In the fourth week the fever reduces and comes down gradually by the end of fourth
week. And the symptoms decrease. But the Typhoid fever's danger doesn't end when
symptoms disappear, even if your symptoms seem to go away, you may still be carrying
Salmonella Typhi. If so, the illness could return, or you could pass the disease to other
people. In fact, if you work at a job where you handle food or care for small children,
you may be barred legally from going back to work until a doctor has determined that
you no longer carry any typhoid bacteria. If you are being treated for typhoid fever, it is
important to do the following:
 Keep taking the prescribed antibiotics for as long as the doctor has asked you to take
them.
 Wash your hands carefully with soap and water after using the bathroom, and do not
prepare or serve food for other people. This will lower the chance that you will pass
the infection on to someone else.
 Have your doctor perform a series of stool cultures to ensure that no Salmonella
Typhi bacteria remain in your body.

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General symptoms of Typhoid fever :
 The patient feels weak, cold and tired.
 Headache, backache, diarrhea, constipation, loss of appetite are other symptoms(fig9)
.
 Temperature rises and remains high for about 10-14 days. Body temperature
typically rises in the evening and drops in the morning(fig.9)
.
 Skin eruptions appear, tongue becomes dry and gets white patches in the center,
which causes oily taste in mouth and inflamed bones(fig.9)
.
(Fig 9. Symptoms of Typhoid fever.)

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Transmission
The bacteria which causes typhoid fever may be spread through poor hygiene habits
and public sanitation conditions, and sometimes also by flying insects feeding on feces.
Public education campaigns encouraging people to wash their hands after defecating
and before handling food are an important component in controlling spread of the
disease. Causes of Typhoid Fever are:
 Poor sanitation, contaminated water and infected milk are some of the main factors
responsible for typhoid.
 Flies contaminate the food with germs. People carrying the germs can also spread
the disease if they prepare or serve food.
 Wrong dietary habits and faulty lifestyle lead to accumulation of toxic waste in the
body and promotes typhoid fever.
 Typhoid is common in people who eat more meat and meat products.
Spread of Typhoid fever:
Salmonella Typhi lives only in humans.
Persons with typhoid fever carry the bacteria
in their bloodstream and intestinal tract. In
addition, a small number of persons, called
carriers, recover from typhoid fever but
continue to carry the bacteria. Both ill
persons and carriers shed SalmonellaTyphi in
their feces (stool). You can get typhoid fever
if you eat food or drink beverages that have
been handled by a person who is shedding
Salmonella Typhi or if sewage contaminated
with Salmonella Typhi bacteria gets into the
water you use for drinking or washing food.
Once Salmonella Typhi bacteria are eaten or
drunk, they multiply and spread into the
bloodstream. The body reacts with fever and
other signs and symptoms(fig.10)
. (Fig 10. transmission of Typhoid fever.)

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Salmonella typhi has no nonhuman vectors. The following are modes of transmission:
 Oral transmission via food or beverages handled by an individual who chronically
sheds the bacteria through stool or, less commonly, urine
 Hand-to-mouth transmission after using a contaminated toilet and neglecting
hand hygiene
 Oral transmission via sewage-contaminated water or shellfish (especially in the
developing world)
A person may become an asymptomatic carrier of typhoid fever, suffering no symptoms,
but capable of infecting others. According to the CDC approximately 5% of people who
contract typhoid continue to carry the disease after they recover. The most famous
asymptomatic carrier was Mary Mallon (commonly known as "Typhoid Mary"), a young
cook who was responsible for infecting at least 53 people with typhoid, three of whom
died from the disease. Mallon was the first apparently perfectly healthy person known
to be responsible for an "epidemic".
Many carriers of typhoid were locked into an isolation ward never to be released to
prevent further typhoid cases. These people often deteriorated mentally, driven mad by
the conditions they lived in. Typhoid fever is more common in areas of the world where
handwashing is less frequent and water is likely to be contaminated with sewage.

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Pathogenesis
Much of the genetic and cellular studies on the pathophysiology of invasive Salmonella
infection have been carried out in the murine model using S. typhimurium, which causes
invasive disease in mice but not in humans. As opposed to the Salmonella spp.
associated with human diarrheal illness, S. typhi and those strains that cause typhoid
fever are able to achieve cellular invasion.
The pathophysiology of typhoid fever is a complex process which proceeds through
several stages. during which bacteria invade macrophages and spread throughout the
reticuloendothelial system. The first week of symptomatic disease is characterized by
progressive elevation of the temperature followed by bacteremia. First ingested
bacteria must survive the acidic environment of the stomach. ncomitant Helicobacter
pylori infection may express itself via the hypochlorhydria associated with chronic
H.pylori infection. Invading organisms pass through the intestinal epithelial cells and
come into contact with phagocytic cells in the Peyer’s patches of the intestinal wall.
However the macrophages do not kill the bacteria. Thence, bacterial replication is
primarily intracellular. Salmonella avoids encapsulation in lysosomes by diverting
normal cellular mechanisms. Bacteria inject effector proteins into the cells of the innate
immune system though a type III protein secretion system (TTSS) which stimulate both
pro and anti-inflammatory responses. Over the asymptomatic incubation period of 7-14
days the bacteria proliferate and spread through the blood stream to other cells in the
reticuloendothelial system in the liver, spleen, bone marrow and gall bladder. As
replication inside phagocytic cells continues, bacteria are shed into the blood stream in
sustained but low concentrations and the clinical syndrome of fever, headache and
abdominal pain begins. The gallbladder is felt to be a significant site for ongoing
exposure of intestinal epithelial cells to the pathogen. The inflammatory response to
this process of repeated exposure is felt to give rise to the necrosis which is a prominent
feature of the disease. This occurs in areas of greatest macrophage concentration such
as the Peyer’s patches and explains why intestinal bleeding and perforation are the
most frequent complications. Elsewhere typhoid nodules, foci of macrophages and
lymphocytes proliferate. As the infection progresses the typical changes of sepsis
accumulate in the heart, brain and kidneys. If not interrupted this process may lead to
circulatory failure and death from overwhelming sepsis.

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Diagnosis
Diagnosis is made by any blood, bone marrow or stool cultures and with the Widal
test (demonstration of salmonella antibodies against antigens O-somatic and H-
flagellar). In epidemics and less wealthy countries, after excluding malaria,
dysentery or pneumonia, a therapeutic trial time with chloramphenicol is generally
undertaken while awaiting the results of Widal test and cultures of the blood and stool.
The Widal test is time consuming and often, when a diagnosis is reached, it is too late to
start an antibiotic regimen. The term "enteric fever" is a collective term that refers to
typhoid and paratyphoid.
Exams and Tests
 A complete blood count (CBC) will show a high number of white blood cells.
 A blood culture during the first week of the fever can show S. typhi bacteria.
 Other tests that can help diagnose this condition include:
 ELISA urine test to look for the bacteria that cause Typhoid fever
 Fluorescent antibody study to look for substances that are specific to Typhoid
bacteria
 Platelet count (platelet count will be low)
 Stool culture

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Treatment
You will probably be given an antibiotic to treat the disease. Three commonly prescribed
antibiotics are ampicillin, trimethoprim-sulfamethoxazole, and ciprofloxacin (Cipro).
Persons given antibiotics usually begin to feel better within 2 to 3 days, and deaths
rarely occur. However, persons who do not get treatment may continue to have fever
for weeks or months, and as many as 20% may die from complications of the infection.
Medical Treatment
Where resistance is uncommon, the treatment of choice is a fluoroquinolone such
as ciprofloxacin otherwise; a third-generation cephalosporin such asceftriaxone
or cefotaxime is the first choice. Cefixime is a suitable oral alternative.
Typhoid fever in most cases is not fatal. Antibiotics, such as ampicillin,
chloramphenicol, trimethoprim-sulfamethoxazole, amoxicillin (Amoxil) and ciprofloxacin
(Cipro), have been commonly used to treat typhoid fever in developed countries.
Prompt treatment of the disease with antibiotics reduces the case-fatality rate to
approximately 1%.
When untreated, typhoid fever persists for three weeks to a month. Death occurs in
between 10% and 30% of untreated casesIn some communities, however, case-fatality
rates may reach as high as 47%.
The rediscovery of oral rehydration therapy in the 1960s provided a simple way to
prevent many of the deaths of diarrheal diseases in general.
Surgical Treatment
Surgery is usually indicated in cases of intestinal perforation. Most surgeons prefer
simple closure of the perforation with drainage of the peritoneum. Small-bowel
resection is indicated for patients with multiple perforations.
If antibiotic treatment fails to eradicate the hepatobiliary carriage, the gallbladder
should be resected. Cholecystectomy is not always successful in eradicating the carrier
state because of persisting hepatic infection.

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Resistance
Resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole and
streptomycin is now common, and these agents have not been used as first line
treatment now for almost 20 years. Typhoid that is resistant to these agents is known
as multidrug-resistant typhoid (MDR typhoid). Ciprofloxacin resistance is an increasing
problem, especially in the Indian subcontinent and Southeast Asia. Many centres are
therefore moving away from using ciprofloxacin as the first line for treating suspected
typhoid originating in South America, India, Pakistan, Bangladesh, Thailand or Vietnam.
For these patients, the recommended first line treatment is ceftriaxone. It has also
been suggested that azithromycin is better at treating typhoid in resistant populations
than both fluoroquinolone drugs and ceftriaxone. Azithromycin significantly reduces
relapse rates compared with ceftriaxone. There is a separate problem with laboratory
testing for reduced susceptibility to ciprofloxacin: current recommendations are that
isolates should be tested simultaneously against ciprofloxacin (CIP) and against
nalidixic acid (NAL), and that isolates that are sensitive to both CIP and NAL should be
reported as "sensitive to ciprofloxacin", but that isolates testing sensitive to CIP but
not to NAL should be reported as "reduced sensitivity to ciprofloxacin". However, an
analysis of 271 isolates showed that around 18% of isolates with a reduced
susceptibility to ciprofloxacin (MIC 0.125–1.0 mg/l) would not be picked up by this
method. It is not certain how this problem can be solved, because most laboratories
around the world (including the West) are dependent on disk testing and cannot test
for MICs. Two basic actions can protect you from typhoid fever:
1. Avoid risky foods and drinks.
2. Get vaccinated against typhoid fever.
It may surprise you, but watching what you eat and drink when you travel is as
important as being vaccinated. This is because the vaccines are not completely effective.
Avoiding risky foods will also help protect you from other illnesses, including travelers'
diarrhea, cholera, dysentery, and hepatitis A.

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Prevention
Infected or asymptomatic carrier humans represent the reservoir for S. typhi. Therefore
identification and treatment of these individuals represents one strategy for
interruption of transmission.
Food and water sanitation
There is no doubt that lack of clean drinking water and unsanitary conditions for the
production and preparation of food represent the main reasons for the ongoing
endemicity of typhoid fever in the developing world. Poor water quality, sanitation and
hygiene account for some 1.7 million deaths a year world-wide mainly through
infectious diarrhea. Nine out of 10 such deaths are in children. Poverty, uncontrolled
urbanization and inadequate infrastructure all contribute to the contamination of water
supplies. Filtration and chlorination together are effective methods of interrupting the
transmission of water-borne diseases.
Vaccine
The other approach to the control and eradication of typhoid fever has been through
vaccination. Acquired immunity to S. typhi infection is both humoral and cellular but is
incomplete, allowing for subsequent infections and restricting the efficacy of vaccines.
Older, parenteral whole-cell vaccines resulted in significant local and systemic reactions.
Two new vaccines are in current use: a parenteral capsule polysaccharide vaccine based
on the Vi antigen and an oral live attenuated vaccine containing strain Ty21a. The first,
while resulting in local pain in 86% of children, requires 1 injection with a booster in 3
years and confers protection within 7-10 days of inoculation. On the other hand the
Ty21a vaccine requires several doses, is only moderately immunogenic and its efficacy is
reduced by simultaneous anti-malarial therapy, (although a report from Gabon showed
that simultaneous anti-malarial prophylaxis with atovaquone/proguanil does not have
this effect. A systematic review for the Cochrane Database showed these two vaccines
had significantly reduced efficacy (efficacy rates approx.50%) in comparison to the older
whole-cell vaccines, but fewer side effects. Current vaccines do not afford protection
against Paratyphoid strains. The search for better vaccines continues.

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The use of vaccines for travelers to endemic areas has been recommended for some
time; even if the travel is for short periods. Malaria remains the most common febrile
disease of returning travelers to Italy requiring hospital admission.
Mass vaccination campaigns have been used to lower the risk of disease in India and
Thailand, but their use in the rest of the developing world is otherwise limited. A report
from the ongoing epidemic in Tajikistan advocated mass vaccination. A recent report
from an urban slum community in Delhi, India showed the high costs of typhoid fever
and recommended more widespread vaccination. The current Vi and Ty21a vaccines are
not licensed for use in children less than 2 years, in whom its efficacy is unproven, and
therefore are deemed unsuitable for expanded immunization programs which target
infants in their first year of life. They are also costly. All these factors have restricted
mass vaccination for typhoid in endemic countries.
The World Health Organization appears to advocate mass vaccination in endemic areas.
(50;51) However this is seldom implemented. The Diseases of the Most Impoverished
(DOMI) project is undertaking a randomized cluster vaccination program in Asia which
should help to clarify the effects of mass typhoid vaccination.

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Genetics
In 2001 the entire genome of a MDR isolate of S. typhi was sequenced. This showed that
Salmonella share more than 70-80% of genes with other enteric bacteria, like E. coli.
Another feature of S. typhi genome is the presence of over 200 inactivated genes which
are felt to be related to the adaptation of the bacteria to the human host and possibly
its ability to invade human tissue. Drug resistance is encoded in a transmissible plasmid.
The development of additional horizontal genes in the salmonella pathogenicity islands
(SPI) represented the separation of the E. Coli and Salmonella lineages and allows for
the targeting of intestinal epithelial cells by Salmonella.

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Complications
Complications occur in 10-15% of patients, particularly those who have been ill for more
than 2 weeks. Gastrointestinal hemorrhage, perforation and encephalopathy are the
most important. GI hemorrhage is most common but usually resolves without
surgery. Severe typhoid may be defined as occurring in those patients with hypotension
despite rehydration and mental confusion or altered state of consciousness. These
patients may benefit from high dose dexamethasone therapy (3mg/kg followed by 8
doses of 1mg/kg q6h) with a marked reduction in mortality. This is one of the few
instances where high dose steroids are of value in sepsis.
Perforation
The surgeon is typically consulted in typhoid fever when perforation is suspected. It may
present suddenly as an acute abdomen or more commonly as worsening in an already
sick patient with increasing abdominal signs, rising pulse and falling blood pressure. The
presence of free air on abdominal xrays is pathognomonic.
These are very sick patients who require vigorous resuscitation and the addition of
metronidazole to combat gram-negative anaerobes and gentamycin for aerobes.
Conservative therapy has been abandoned with improved mortality rates. Mortality
increased when time to presentation is delayed and also with delayed time to surgery
after perforation. Mortality rates vary from 14% in Nigeria to 34% in Cote d’Ivoire. Single
perforations are most common (70%) and in the terminal ileum, but multiple
perforations may occur.
At operation the entire small bowel and proximal colon should be carefully examined for
perforation. Debate exists as to the various methods of closure from simple suture, to
wedge resection and closure to segmental resection and primary anastomosis. It is not
clear to me that any conclusion can be drawn from the evidence. Obviously multiple
perforations lend themselves to segmental resection.
Other complications
Numerous other complications are seen with typhoid fever. see Table 163-1 The most
important surgical ones being: hepatic or splenic abscess, splenic rupture and
pancreatitis. Encephalomyelitis, osteomyelitis, glomerulonephritis and renal failure may
all occur. Myocarditis is a common cause of circulatory collapse.

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Salmonella
Is a Gram-negative facultative rod-shaped bacterium in the same proteobacterial family
as Escherichia coli, the family Enterobacteriaceae, trivially known as "enteric"
bacteria. Salmonella is nearly as well-studied as E. coli from a structural, biochemical
and molecular point of view, and as poorly understood as E. coli from an ecological point
of view. Salmonellae live in the intestinal tracts of warm and cold blooded animals.
Some species are ubiquitous. Other species are specifically adapted to a particular host.
In humans, Salmonella are the cause of two diseases called salmonellosis: enteric
fever (typhoid), resulting from bacterial invasion of the bloodstream, and acute
gastroenteritis, resulting from a foodborne infection/intoxication.
(Fig 11. bacillus shape salmonella)

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enterica I
salamae II
arizonae IIIa
diarizonae IIIb
houtenae IV
bongori V
indica VI
Salmonella Nomenclature
The genus Salmonella is a member of the family Enterobacteriaceae, It is composed of
bacteria related to each other both phenotypically and genotypically. Salmonella DNA
base composition is 50-52 mol% G+C, similar to that of Escherichia,
Shigella, and Citrobacter. The bacteria of the genus Salmonella are also related to each
other by DNA sequence. The genera with DNA most closely related
to Salmonella are Escherichia, Shigella, and Citrobacter. Similar relationships were found
by numerical taxonomy and 16S ssRNA analysis. And has been controversial since the
original taxonomy of the genus was not based on DNA relatedness, rather names were
given according to clinical considerations, e.g., Salmonella typhi, Salmonella cholerae-
suis, Salmonella abortus-ovis, and so on. When serological analysis was adopted into the
Kauffmann-White scheme in 1946, a Salmonella species was defined as "a group of
related fermentation phage-type" with the result that each Salmonella serovar was
considered as a species. Since the host-specificity suggested by some of these earlier
names does not exist (e.g., S. typhi-murium, S. cholerae-suis are in fact ubiquitous),
names derived from the geographical origin of the first isolated strain of the newly
discovered serovars were next chosen, e.g., S. london, S. panama, S. stanleyville.
Susequently it was found that all Salmonella serovars
form a single DNA hybridization group, i.e., a single
species composed of seven subspecies, and
thenomenclature had to be adapted. To avoid
confusion with the familiar names of serovars, the
species name Salmonella enterica was proposed with
the following names for the subspecies:
Since this formal Latin nomenclature may not be clearly understood by physicians and
epidemiologists, who are the most familiar with the names given to the most common
serovars, the common serovars names are kept for subspecies I strains, which represent
more than 99.5% of the Salmonella strains isolated from humans and other warm-
blooded animals. The vernacular terminology seems preferred in medical practice,
e.g., Salmonella ser. Typhimurium (not italicized) or shorter Salmonella (or S.)
Typhimurium.

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Antigenic Structure
As with all Enterobacteriaceae, the genus Salmonella has three kinds of major antigens
with diagnostic or identifying applications: somatic, surface, and flagellar.
Somatic (O) or Cell Wall Antigens
Somatic antigens are heat stable and alcohol resistant. Cross-absorption studies
individualize a large number of antigenic factors, 67 of which are used for serological
identification. O factors labeled with the same number are closely related, although not
always antigenically identical.
Surface (Envelope) Antigens
Surface antigens, commonly observed in other genera of enteric bacteria
(e.g., Escherichia coli and Klebsiella), may be found in some Salmonella serovars. Surface
antigens in Salmonella may mask O antigens, and the bacteria will not be agglutinated
with O antisera. One specific surface antigen is well known: the Vi antigen. The Vi
antigen occurs in only three Salmonella serovars (out of about 2,200): Typhi, Paratyphi
C, and Dublin. Strains of these three serovars may or may not have the Vi antigen.
Flagellar (H) Antigens
Flagellar antigens are heat-labile proteins. Mixing salmonella cells with flagella-specific
antisera gives a characteristic pattern of agglutination (bacteria are loosely attached to
each other by their flagella and can be dissociated by shaking). Also, antiflagellar
antibodies can immobilize bacteria with corresponding H antigens.

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A few Salmonella entericaserovars (e.g., Enteritidis, Typhi) produce flagella which always
have the same antigenic specificity. Such an H antigen is then called monophasic.
Most Salmonella serovars, however, can alternatively produce flagella with two
different H antigenic specificities. The H antigen is then called diphasic. For example,
Typhimurium cells can produce flagella with either antigen i or antigen 1,2. If a clone is
derived from a bacterial cell with H antigen i, it will consist of bacteria with i flagellar
antigen. However, at a frequency of 10-3
- 10-5
, bacterial cells with 1,2 flagellar antigen
pattern will appear in this clone.
(Fig 12. Flagellar stain of a Salmonella Typhi)

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Habitats
The principal habitat of the salmonellae is the intestinal tract of humans and
animals. Salmonella serovars can be found predominantly in one particular host, can be
ubiquitous, or can have an unknown habitat. Typhi and Paratyphi A are strictly human
serovars that may cause grave diseases often associated with invasion of the
bloodstream. Salmonellosis in these cases is transmitted through fecal contamination of
water or food. Gallinarum, Abortusovis, and Typhisuis are, respectively, avian, ovine,
and porcine Salmonella serovars. Such host-adapted serovars cannot grow on minimal
medium without growth factors (contrary to the ubiquitousSalmonella serovars).
Ubiquitous (non-host-adapted) Salmonella serovars (e.g., Typhimurium) cause very
diverse clinical symptoms, from asymptomatic infection to serious typhoid-like
syndromes in infants or certain highly susceptible animals (mice). In human adults,
ubiquitous Salmonella organisms are mostly responsible for foodborne toxic infections.
The pathogenic role of a number of Salmonella serovars is unknown. This is especially
the case with serovars from subspecies II to VI. A number of these serovars have been
isolated rarely (some only once) during a systematic search in cold-blooded animals.
Salmonella in the Natural Environment
Salmonellae are disseminated in the natural environment (water, soil, sometimes plants
used as food) through human or animal excretion. Humans and animals (either wild or
domesticated) can excrete Salmonella either when clinically diseased or after having
had salmonellosis, if they remain carriers. Salmonella organisms do not seem to multiply
significantly in the natural environment (out of digestive tracts), but they can survive
several weeks in water and several years in soil if conditions of temperature, humidity,
and pH are favorable.

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Isolation and Identification of Salmonella
A number of plating media have been devised for the isolation of Salmonella. Some
media are differential and nonselective, i.e., they contain lactose with a pH indicator,
but do not contain any inhibitor for non salmonellae (e.g., bromocresol purple lactose
agar). Other media are differential and slightly selective, i.e., in addition to lactose and a
pH indicator, they contain an inhibitor for nonenterics (e.g., MacConkey agar and eosin-
methylene blue agar).
The most commonly used media selective for Salmonella are SS agar, bismuth sulfite
agar, Hektoen enteric (HE) medium, brilliant green agar and xylose-lisine-deoxycholate
(XLD) agar. All these media contain both selective and differential ingredients and they
are commercially available.
(Fig 13. Salmonella sp. after 24 hours growth on XLD agar)

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Media used for Salmonella identification are those used for identification of
all Enterobacteriaceae. Most Salmonella strains are motile with peritrichous flagella,
however, nonmotile variants may occur occasionally. Most strains grow on nutrient agar
as smooth colonies, 2-4 mm in diameter(fig.14)
. Most strains are prototrophs, not
requiring any growth factors. However, auxotrophic strains do occur, especially in host-
adapted serovars such as Typhi and Paratyphi A.
(Fig 14. Colonial growth Salmonella ,bacteria grown on a blood agar culture plate)

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Table 1. Characteristics shared by most Salmonella strains belonging to subspecies I
Motile, Gram-negative bacteria
Lactose negative; acid and gas from glucose, mannitol, maltose, and sorbitol; no Acid from
adonitol, sucrose, salicin, lactose
ONPG test negative (lactose negative)
Indole test negative
Methyl red test positive
Voges-Proskauer test negative
Citrate positive (growth on Simmon's citrate agar)
Lysine decarboxylase positive
Urease negative
Ornithine decarboxylase positive
H2S produced from thiosulfate
Do not grow with KCN
Phenylalanine and tryptophan deaminase negative
Gelatin hydrolysis negative
(Fig 15. Colonial growth pattern displayed by Salmonella Typhimurium cultured on a Hektoen enteric agar)

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Salmonella infections
Foodborne Salmonella toxic infections
are caused by ubiquitous Salmonella serovars (e.g., Typhimurium). About 12-24 hours
following ingestion of contaminated food (containing a sufficient number
of Salmonella), symptoms appear (diarrhea, vomiting, fever) and last 2-5 days.
Spontaneous cure usually occurs.
Salmonella may be associated with all kinds of food. Contamination of meat (cattle, pigs,
goats, chicken, etc.) may originate from animal salmonellosis, but most often it results
from contamination of muscles with the intestinal contents during evisceration of
animals, washing, and transportation of carcasses. Surface contamination of meat is
usually of little consequence, as proper cooking will sterilize it (although handling of
contaminated meat may result in contamination of hands, tables, kitchenware, towels,
other foods, etc.). However, when contaminated meat is ground, multiplication
of Salmonella may occur within the ground meat and if cooking is superficial, ingestion
of this highly contaminated food may produce a Salmonellainfection. Infection may
follow ingestion of any food that supports multiplication of Salmonella such as eggs,
cream, mayonnaise, creamed foods, etc.), as a large number of ingested salmonellae are
needed to give symptoms. Prevention of Salmonella toxic infection relies on avoiding
contamination (improvement of hygiene), preventing multiplication ofSalmonella in
food (constant storage of food at 4°C), and use of pasteurized and sterilized milk and
milk products. Vegetables and fruits may carry Salmonella when contaminated with
fertilizers of fecal origin, or when washed with polluted water.
The incidence of foodborne Salmonella infection/toxication remains reletavely high in
developed countries because of commercially prepared food or ingredients for food.
Any contamination of commercially prepared food will result in a large-scale infection.
In underdeveloped countries, foodborne Salmonella intoxications are less spectacular
because of the smaller number of individuals simultaneously infected, but also because
the bacteriological diagnosis of Salmonella toxic infection may not be available.

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Salmonella Enteritidis Infection
Egg-associated salmonellosis is an important public health problem in the United States
and several European countries. Salmonella Enteritidis, can be inside perfectly normal-
appearing eggs, and if the eggs are eaten raw or undercooked, the bacterium can cause
illness. During the 1980s, illness related to contaminated eggs occurred mosy frequently
in the northeastern United States, but now illness caused by S. Enteritidis is increasing in
other parts of the country as well.
Unlike eggborne salmonellosis of past decades, the current epidemic is due to intact and
disinfected grade A eggs. Salmonella Enteritidis silently infects the ovaries of healthy
appearing hens and contaminates the eggs before the shells are formed. Most types
of Salmonella live in the intestinal tracts of animals and birds and are transmitted to
humans by contaminated foods of animal origin. Stringent procedures for cleaning and
inspecting eggs were implemented in the 1970s and have made salmonellosis caused by
external fecal contamination of egg shells extremely rare. However, unlike eggborne
salmonellosis of past decades, the current epidemic is due to intact and disinfected
grade A eggs. The reason for this is that Salmonella Enteritidis silently infects the ovaries
of hens and contaminates the eggs before the shells are formed.
Although most infected hens have been found in the northeastern United States, the
infection also occurs in hens in other areas of the country. In the Northeast,
approximately one in 10,000 eggs may be internally contaminated. In other parts of the
United States, contaminated eggs appear less common. Only a small number of hens
seem to be infected at any given time, and an infected hen can lay many normal eggs
while only occasionally laying an egg contaminated with Salmonella Enteritidis.
A person infected with the Salmonella Enteritidis usually has fever, abdominal cramps,
and diarrhea beginning 12 to 72 hours after consuming a contaminated food or
beverage. The illness usually lasts 4 to 7 days, and most persons recover without
antibiotic treatment. However, the diarrhea can be severe, and the person may be ill
enough to require hospitalization. The elderly, infants, and those with impaired immune
systems (including HIV) may have a more severe illness. In these patients, the infection
may spread from the intestines to the bloodstream, and then to other body sites and
can cause death unless the person is treated promptly with antibiotics.

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Exotoxins
Salmonella strains may produce a thermolabile enterotoxin that bears a limited
relatedness to cholera toxin both structurally and antigenically. This enterotoxin causes
water secretion in rat ileal loop and is recognized by antibodies against both cholera
toxin and the thermolabile enterotoxin (LT) of enterotoxinogenic E. coli, but it does not
bind in vitro to ganglioside GM1 (the receptor for E. coli LT and cholera ctx).
Additionally, a cytotoxin that inhibits protein synthesis and is immunologically distinct
from Shiga toxin has been demonstrated. Both of these toxins are presumed to play a
role in the diarrheal symptoms of salmonellosis.
Antibiotic Susceptibility
During the last decade, antibiotic resistance and multiresistance of Salmonella spp. have
increased a great deal. The cause appears to be the increased and indiscriminate use of
antibiotics in the treatment of humans and animals and the addition of growth-
promoting antibiotics to the food of breeding animals. Plasmid-borne antibiotic
resistance is very frequent among Salmonella strains involved in pediatric epidemics
(e.g., Typhimurium, Panama, Wien, Infantis). Resistance to ampicillin, streptomycin,
kanamycin, chloramphenicol, tetracycline, and sulfonamides is commonly observed.
Colistin resistance has not yet been observed.
Until 1972, Typhi strains had remained susceptible to antibiotics, including
chloramphenicol (the antibiotic most commonly used against typhoid) but in 1972, a
widespread epidemic in Mexico was caused by a chloramphenicol-resistant strain
of S. Typhi. Other chloramphenicol-resistant strains have since been isolated in India,
Thailand, and Vietnam. Possible importation or appearance of chloramphenicol-
resistance strains in the United States is a real threat. Salmonella strains should be
systematically checked for antibiotic resistance to aid in the choice of an efficient drug
when needed and to detect any change in antibiotic susceptibility of strains (either from
animal or human source). Indiscriminate distribution and use of antibiotics should be
discouraged.

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Conclusions
Despite intensive scrutiny and major advances in genetic research and understanding
the details of cellular inflammation, typhoid fever remains a major cause of death and
disease in the developing world. Its eradication awaits the provision of sanitary water
supplies and proper disposal of human sewage. Its eradication would probably be
accelerated by programs of mass vaccination in endemic regions. Appropriate antibiotic
therapy may postpone the further development of MDR strains. In the meantime,
surgeons will continue to be asked to care for desperately sick typhoid patients with
intestinal perforations and other complications.

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Recommendations
1. Typhoid fever should be suspected in young children and infants with fevers of
unknown origins in endemic regions.
2. Filtration and chlorination are the two important steps in ensuring a safe water
supply. In urban areas safe drinking water should be made available though piped
systems or trucked tankers.
3. Appropriate food handling is essential: washing hands with soap before preparing
and handling food; eating only cooked or still hot food; avoiding raw food, ice.
4. Appropriate systems for human waste disposal must be available for the entire
community.
5. Countries with high rates of typhoid fever should consider mass immunization
programs using new Vi and Ty21a vaccines for those more than 2 years of age.
6. In hospitals where microbiological facilities are available for the culture of salmonella
spp., bone marrow samples, as well as blood and stool should be obtained in patients
when typhoid fever is suspected.
7. Testing should include stools of recovering patients at 3 months or urine in regions
where schistosomiasis is common, to detect the carrier state.
8. The Widal test cannot be used in the diagnosis without assessing background
antibody levels in the population. Better serologic tests should be available soon.
9. Antibiotic therapy should be based on the sensitivity spectrum of local S. typhi
strains. Chloramphenicol, ampicillin or co-trimazole may be adequate agents if strains
are susceptible.
10. In regions where MDR strains are known to exist, fluroquinolones are the agents of
choice.
11. In regions where MDR strains exist and where quinolone use has been extensive,
testing for relative flouroquinolone resistance with nalidixic acid discs should be
undertaken.
12.Patients, with “severe typhoid” manifested by hypotension and/or altered state of
consciousness, should receive short term high dose steroid therapy.
13.The treatment of typhoid perforation is aggressive resuscitation using broad
spectrum antibiotics against enteric organisms, prompt surgery with examination of
the entire small bowel and right colon with resection (local or segmental) of all full
thickness ulcers and perforations.

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Typhoid Fever Questions and Answers
I was diagnosed with viral fever by my local doctor. After 4 days when the fever did
not subside, my doctor asked me to get a blood test done as he is suspecting typhoid.
[A] What symptoms are you facing for typhoid fever?
[Q] I have Headache and fever, but commonly occurs at night, temperature not more
than 101 degree and irritation in eyes plus tiredness and fatigue.
[A] And how many days do you have the fever for?
[Q] About 4 days with sputum in chest.
[A] How is your appetite? Do you have any appetite?
[Q] My appetite seems to be ok; I don’t have a problem there.
[A] Do you have constipation?
[Q] No constipation.
[A] It’s tough to diagnose this remotely. What exactly are you looking for? Do you want
to know some home remedies for typhoid? Do you want to know about typhoid
symptoms?
[A] You must most certainly follow your doctor’s advice and get your blood check up
done to detect what the problem is – whether its typhoid fever or something else
[A] Here are some home remedies I can suggest – but use them only after you have
consulted your doctor:
 Take a lot of rest
 Cold compress if your fever goes over 40C
 Drink more water; even orange juice will be good as that will give you more energy
 Stick to easily digestible foods – liquid diet is good if you can tolerate it.
 Warm eater enema may also be administered for some people during typhoid fever.

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References
1- http://en.wikipedia.org/wiki/Typhoid_fever
2- http://www.nhs.uk/Conditions/Typhoid-fever/Pages/Introduction.aspx
3- http://www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/#top
4- http://www.tandurust.com/natural-home-remedies/typhoid-fever.html
5- http://www.ptolemy.ca/members/archives/2006/typhoid_fever.htm
6- http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002308/
7- http://www.medicinenet.com/typhoid_fever/article.htm
8- http://www.nlm.nih.gov/medlineplus/ency/article/001332.htm
9- http://www.who.int/topics/typhoid_fever/en/
10- http://www.mayoclinic.com/health/typhoid-fever/DS00538
11- http://emedicine.medscape.com/article/231135-overview
12- http://www.webmd.com/a-to-z-guides/typhoid-fever?page=2
13- http://news.softpedia.com/news/Typhoid-Bacterium-Accompanied-Us-Along-Our-
Evolution-41046.shtml
14- http://textbookofbacteriology.net/themicrobialworld/Salmonella.html
15- http://www.onlinemedicinetips.com/disease/t/typhoid/Typhoid-Causes.html
16- http://nutrivize.com/blog/general-health/mystery-rash/
17- http://www.turbosquid.com/3d-models/max-microbes-micro-organisms/644735
18- http://www.rightdiagnosis.com/phil/html/typhoid-fever/2114.html
19- http://www.humanillnesses.com/original/T-Ty/Typhoid-Fever.html#b