Typhoid fever CHEMOTHERAPY PHARMACOLOGY, PHARMACOTHERAPEUTICS,ETIOLOGY,EPIDEMIOLOGY......

1. TYPHOID FEVER
Introduction:
Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused
primarily by Salmonella enterica serotype typhi and, to a lesser extent, S
enterica serotypes paratyphi A, B, and C. The terms typhoid and enteric fever are commonly
used to describe both major serotypes.
Etiology:
The bacterium Salmonella typhi (S. typhi) causes typhoid fever. The bacteria spreads through
contaminated food, drink, or water. People infected with Salmonella typhi carry the bacteria in
their intestinal tract and blood.
Salmonella typhi is shed (discarded from the body) in feces (stool). You may get typhoid fever if
you ingest food or beverages prepared by someone who is shedding the bacteria and who does
not wash their hands properly. In less developed countries, sewage containing Salmonella
typhi may contaminate local water supplies.
In some cases, people who have previously had typhoid fever still carry Salmonella
typhi bacteria. These people are carriers of the disease. They may spread the infection even when
they have no symptoms (the famous case of “Typhoid Mary” in the U.S.).
SIGNS & SYMPTOMS:
In early stages of the disease, symptoms include: abdominal pain, fever, and a general feeling of
being unwell. These initial symptoms are similar to other illnesses.
As typhoid fever gets worse, symptoms often include:

2.  High fever of up to 104 degrees Fahrenheit
 Headaches
 Abdominal pain, constipation then perhaps diarrhea later
 Small, red spots on your abdomen or chest (rose-colored spots)
 Loss of appetite and weakness
Other symptoms of typhoid fever include:
 Body aches
 Bloody stools
 Chills
 Severe fatigue
 Difficulty paying attention
 Agitation, confusion, and hallucinations (seeing or hearing things that are not real)
Epedimiology:
In 2000, typhoid fever caused an estimated 21.7 million illnesses and 217,000 deaths It occurs
most often in children and young adults between 5 and 19 years old. In 2013, it resulted in about
161,000 deaths – down from 181,000 in 1990.Infants, children, and adolescents in south-central
and Southeast Asia experience the greatest burden of illness.Outbreaks of typhoid fever are also
frequently reported from sub-Saharan Africa and countries in Southeast Asia In 2000, more than
90% of morbidity and mortality due to typhoid fever occurred in Asia. In the United States,
about 400 cases occur each year, and 75% of these are acquired while traveling internationally.
Historically, before the antibiotic era, the case fatality rate of typhoid fever was 10–20%. Today,
with prompt treatment, it is less than 1%.However, about 3–5% of individuals who are infected
develop a chronic infection in the gall bladder.Since S. enterica subsp. enterica serovar Typhi is
human-restricted, these chronic carriers become the crucial reservoir, which can persist for
decades for further spread of the disease, further complicating the identification and treatment of
the disease.Lately, the study of S. enterica subsp. enterica serovar Typhi associated with a large
outbreak and a carrier at the genome level provides new insights into the pathogenesis of the
pathogen.
In industrialized nations, water sanitation and food handling improvements have reduced the
number of cases.Developing nations, such as those found in parts of Asia and Africa, have the
highest rates of typhoid fever. These areas have a lack of access to clean water, proper sanitation
systems, and proper health-care facilities. For these areas, such access to basic public-health
needs is not in the near future.
In 2004–2005 an outbreak in the Democratic Republic of Congo resulted in more than 42,000
cases and 214 deaths. Since November 2016, Pakistan has had an outbreak of extensively drug-
resistant (XDR) typhoid fever.
In Europe, a report based on data for 2017 retrieved from The European Surveillance System
(TESSy) on the distribution of confirmed typhoid and paratyphoid fever cases found that 22
EU/EEA countries reported a total of 1.098 cases, 90.9% of which were travel-related, mainly
acquired during travel to countries particularly in South Asia.

3. Pathogenesis:

4. Diagnosis:
Diagnosis is made by any blood, bone marrow, or stool cultures and with the Widal test
(demonstration of antibodies against Salmonella 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
the Widal test and cultures of the blood and stool.
Widal test:
Widal test is used to identify specific antibodies in serum of people with typhoid by using
antigen-antibody interactions.
In this test, the serum is mixed with a dead bacterial suspension of salmonella having specific
antigens on it. If the patient's serum is carrying antibodies against those antigens then they get
attached to them forming clumping which indicated the positivity of the test. If clumping does
not occur then the test is negative. The Widal test is time-consuming and prone to significant
false positive results. The test may also be falsely negative in the early course of illness.
However, unlike the Typhidot test, the Widal test quantifies the specimen with titres.
Rapid diagnostic tests:
Rapid diagnostic tests such as Tubex, Typhidot, and Test-It have shown moderate diagnostic
accuracy.
Typhidot:
The test is based on the presence of specific IgM and IgG antibodies to a specific 50Kd OMP
antigen. This test is carried out on a cellulose nitrate membrane where a specific S. typhi outer
membrane protein is attached as fixed test lines. It separately identifies IgM and IgG antibodies.
IgM shows recent infection whereas IgG signifies remote infection.
The sample pad of this kit contains colloidal gold-anti-human IgG or gold-anti-human IgM. If
the sample contains IgG and IgM antibodies against those antigens then they will react and get
turned into red color. This complex will continue to move forward and the IgG and IgM
antibodies will get attached to the first test line where IgG and IgM antigens are present giving a
pink-purplish colored band. This complex will continue to move further and reach the control
line which consists of rabbit anti-mouse antibody which bends the mouse anti-human IgG or IgM
antibodies. The main purpose of the control line is to indicate a proper migration and reagent
color. The typhidot test becomes positive within 2–3 days of infection.
Two colored bands indicate a positive test. Single-band of control line indicates a negative test.
Single-band of first fixed line or no bands at all indicates invalid tests. The most important
limitation of this test is that it is not quantitative and the result is only positive or negative.

5. Tubex test:
Tubex test contains two types of particles brown magnetic particles coated with antigen and blue
indicator particles coated with O9 antibody. During the test, if antibodies are present in the
serum then they will get attached to the brown magnetic particles and settle down at the base and
the blue indicator particles remain up in the solution giving a blue color that indicates positivity
of the test.
If the serum does not have an antibody in it then the blue particle gets attached to the brown
particles and settled down at the bottom giving no color to the solution which means the test is
negative and they do not have typhoid.
Prevention:
Sanitation and hygiene are important to prevent typhoid.
It can only spread in environments where human feces are able to come into contact with food or
drinking water.
Careful food preparation and washing of hands are crucial to prevent typhoid.
Industrialization, and in particular, the invention of the automobile, contributed greatly to the
elimination of typhoid fever, as it eliminated the public-health hazards associated with having
horse manure in public streets, which led to large number of flies, which are known as vectors of
many pathogens, including Salmonella spp.
According to statistics from the United States Centers for Disease Control and Prevention,
the chlorination of drinking water has led to dramatic decreases in the transmission of typhoid
fever in the United States.
TREATMENT:
Oral rehydration therapy
The rediscovery of Oral Rehydration Therapy in the 1960s provided a simple way to prevent
many of the deaths of diarrhoeal diseases in general.
Antibiotics:
Where resistance is uncommon, the treatment of choice is a fluoroquinolone such
as ciprofloxacin. Otherwise, a third-generation cephalosporin such as ceftriaxone or cefotaxime
is the first choice.
Cefixime is a suitable oral alternative.
Typhoid fever, when properly treated, is not fatal in most cases. Antibiotics, such as Ampicillin,
chloramphenicol, Trimethoprm-sulfamethexazole, Amoxacillin, and ciprofloxacin, have been
commonly used to treat typhoid fever. Treatment of the disease with antibiotics reduces the case-
fatality rate to about 1%.

6. Without treatment, some patients develop sustained fever, bradycardia, hepatosplenomegaly,
abdominal symptoms, and occasionally, pneumonia. In white-skinned patients, pink spots, which
fade on pressure, appear on the skin of the trunk in up to 20% of cases. In the third week,
untreated cases may develop gastrointestinal and cerebral complications, which may prove fatal
in up to 10–20% of cases.
The highest case fatality rates are reported in children under 4 years.
Around 2–5% of those who contract typhoid fever become chronic carriers, as bacteria persist in
the biliary tract after symptoms have resolved.
Surgery
Surgery is usually indicated if intestinal perforation occurs. One study found a 30-day mortality
rate of 9% (8/88), and surgical site infections at 67% (59/88), with the disease burden borne
predominantly by low-resource countries.
For surgical treatment, 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 sometimes successful, especially in patients with gallstones, but is
not always successful in eradicating the carrier state because of persisting hepatic infection.