shiv.pdf

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Etiology, Epidemiology, and clinical Aspects of Typhoid Fever
A
Dissertation submitted to Dr. APJ AKTU for the partial fulfillment
Of the Degree of
BACHELOR OF PHARMACY
Submitted By
SHIV CHANDRA
(ROLL NO – 1355250020)
Supervised By
Mrs. Roohi Kesharwani
Assistant Professor
Chandra Shekhar Singh College of Pharmacy
Koilaha, Puramufti, Kaushambi
2017

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DECLARATION
I, hereby declare that the matter embodied in the dissertation entitled ’Typhoid Fever’ is a bonafied
and genuine research work carried out by me in partial fulfillment of the requirements of the degree
of Bachelor of Pharmacy under the supervision and guidance of Mrs. Roohi Keasharwani
(Assistant Professor), Chandra Shekhar Singh College of Pharmacy, Koilaha, Puramufti,
Kaushambi, U.P. The work embodied in this dissertation is original and has not been submitted as
the basis for the award of any Degree or Diploma or fellowship of any other university or Institution.

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Chandra Shekhar Singh College
of Pharmacy
Apprved by.AICTE, New Delhi. Affiliated by APJKTU, Lucknow. PCI Affiliation file No.296-32-1(103/09)
Koilaha(G.T. Road),Puramufti, Kaushambi, Allahabad (UP)
Tele.Fax: 0532-2584092, E.mail: csscp.allahabad@gmail.vom, Website: www.csscp.co.in
CERTIFICATE
This is certify that the work reported in the dissertation entitled Typhoid fever has been carried out
by Mr. Shiv Chandra under the supervision at Chandra Shekhar Singh College of pharmacy
Koilaha, Puramufti, Kaushambi, Allahabad, Uttar Pradesh, India during the eight semester of
academic session 2016-17
Mr. Dilip Kr. Patel
( Head of Department )

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ENDORSMENT BY THE PRINCIPAL/ HEAD OF THE INSTITUTION
This is to certify that the desertation work entitled ”Etiology, Epidemiology and clinical
aspect of Typhoid Fever” submitted in partial fulfillment of the requirement for the degree
of Bachelor of pharmacy in Dr. A.P.J. Abdul Kalam Technical University Lucknow is a
bonafide work carried out by Mr.Dinesh gupta under the genial guidance and supervision of
Mr. Dilip Kr. Patel (Supervisor).
Mr. Dilip Kr. Patel
( Head of Department )

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Acknowledgement
It is a good to have an end to journey towards; but it is the journey that matters in the end. Looking
back over this journey ,I have the feeling that it was a productive and intensive stage of my life.
However, to come to this end would not have been possible without the help of many people both
from the academic community and outside of the academic environment. It is a pleasant aspect that I
have now the opportunity to express my gratitude for all of them.
I would like to give my heart full thanks to Prof. S.K. Gupta (Pricipal) and Mr.Dilip Kr. Patel
(HOD) of Chandra Shekhar Singh College of Pharmacy, who gave me the opportunity to make
this project.
I express my gratitude and homage with regard to Mrs. Roohi Kesharwani for her all time
encouragement, suggestion and valuable criticism by which I was able to harbor my project work in
the best possible way.
I feel honored to express my warm and sincere thanks to entire faculity of CSSCP. Mr. Hridesh
Singh Chauhan, mrs. Roohi Kesharwani ,Ms. Mona Arora, Mrs. Usha Singh, Ms. Preeti
Yadav, Ms. Shilpi Sonkar, Mr. Manish Yadav, Mr. Praveen Dubey, Ms. Shalini Kesharwani,
Mr. Dinesh Vishwakarma.
I am highly obliged to all my technical staff, as they have extended all possible help and always made
my lab work esier.
I would like to thanks My friends for their unforgettable help rendered to me for the completion of
my project work.
I also take this opportunity to express my gratitude and appreciation to My parents whose
tremendous encouragement, support, prayer and love which has proved to be a real sources of
inspiration for me to achieve this success and to all those who were directly or indirectly related in
the completion of this project.
SHIV CHANDRA

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TABLE OF CONTENT
Topic
1. Introduction
2. The disease
3. Epdemiology
4. History
5. Symptoms
6. Complicated disease
7. Magnitude of the problem
8. Case definition
9. Transmission
10.Pathogenesis
11.Diagnosis of typhoid fever
12.Drugs for typhoid fever
13.Prevention
14.Treatment of typhoid fever
15.Patient case report
16.Recent drugs for typhoid
17.Conclusion
18.Reference

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TYPHOID FEVER
1.Introduction:
Typhoid fever is a life-threatening illness caused by the bacterium Salmonella Typhi.
Salmonella Typhi lives only in humans. Persons with typhoid fever carry the bacteria in their
bloodstream and intestinal tract.Transmitted through the ingestion of food or drink
contaminated by the feces or urine of infected people. The etiologic agent of the disease
characterized by prolonged fever, is a gram negative rod with capacity of living and growing
in mononuclear phagocytic cells of the reticuloendothelial tissue.
The spread to a healthy and susceptible person occurs usually from patients with typhoid
fever or carriers by oral-fecal route. Each year, the world over, there are at least 13-17 million
cases of typhoid fever, resulting in 600,000 deaths.The cause is the
bacterium Salmonella Typhi, also known as Salmonella enterica serotype Typhi, growing in
the intestines and blood.
2.The organism:
Typhoid fever is caused by Salmonella typhi, a Gram-negative bacterium. A very similar
but often less severe disease is caused by Salmonella serotype paratyphi A. The
nomenclature for these bacteria is confused because the criteria for designating bacteria as
individual species are not clear. Two main views on the nomenclature of the genus
Salmonella have been discussed.
Le Minor and Popoff suggested that two species should be recognized: Salmonella bongori
and Salmonella enterica. S. enterica included six subspecies, of which subspecies I (one)
contained all the pathogens of warm-blooded animals. S. typhi was a serotype within
subspecies I: Salmonella enterica subspecies I serotype typhi. This proposal was rejected by
the International Judicial Commission because the name was not well known to clinicians
and its use might cause accidents endangering health or life.
The original rules therefore remain in force. Ezaki and colleagues have noted in the
International Journal of Systematic and Evolutionary Microbiology that the correct
nomenclature for the causal agent of typhoid fever is Salmonella typhi and have requested
that the current subspecific status of serotype paratyphi should be raised to specific status, i.e.

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Salmonella paratyphi A. S. typhi has several unique features, the genetic basis of many of
which is known as a result of early genetic studies and the recent sequencing of the whole
genome.
Although many genes are shared with E. coli and at least 90% with S. typhimurium, there are
several unique clusters of genes known as pathogenicity islands and many more single genes
that seem to have been acquired by S. typhi during evolution.
S. typhi can be identified in the laboratory by several biochemical and serological tests. One
of the most specific is that of polysaccharide capsule Vi, which is present in about 90% of all
freshly isolated S. typhi and has a protective effect against the bactericidal action of the serum
of infected patients.
This capsule provides the basis for one of the commercially available vaccines . Vi antigen is
present in some other bacteria (Citrobacter freundii, Salmonella paratyphi C and Salmonella
dublin) but not in exactly the same genetic context. The ratio of disease caused by S. typhi to
that caused by S. paratyphi is about 10 to 1 in most of the countries where this matter has
been studied.
3.The disease:
During an acute infection, S. typhi multiplies in mononuclear phagocytic cells before being
released into the bloodstream. After ingestion in food or water, typhoid organisms pass
through the pylorus and reach the small intestine.
They rapidly penetrate the mucosal epithelium via either microfold cells or enterocytes and
arrive in the lamina propria, where they rapidly elicit an influx of macrophages (Mp) that
ingest the bacilli but do not generally kill them. Some bacilli remain within Mp of the small
intestinal.
The diagnosis, treatment and prevention of typhoid fever lymphoid tissue. Other typhoid
bacilli are drained into mesenteric lymph nodes where there is further multiplication and
ingestion by Mp. It is believed that typhoid bacilli reach the bloodstream principally by
lymph drainage from mesenteric nodes, after which they enter the thoracic duct and then the
general circulation.
As a result of this silent primary bacteraemia the pathogen reaches an intracellular haven
within 24 hours after ingestion throughout the organs of the reticuloendothelial system
(spleen, liver, bone marrow, etc.), where it resides during the incubation period, usually of 8
to14 days.

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The incubation period in a particular individual depends on the quantity of inoculum, i.e. it
decreases as the quantity of inoculum increases, and on host factors.Incubation periods
ranging from 3 days to more than 60 days have been reported.Clinical illness is accompanied
by a fairly sustained but low level of secondarybacteraemia (~1-10 bacteria per ml of blood).
4. Epidemiology:
In 2000, typhoid fever caused an estimated 21.7 million illnesses and 217000 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. Historically, in the pre-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 will develop a chronic infection in the
gall bladder. Since S. 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 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.

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5.History:
In 430 BC, a plague, which some believe to have been typhoid fever, killed one-third of the
population of Athens, including their leader Pericles. Following this disaster, the balance of
power shifted from Athens to Sparta, ending the Golden Age of Pericles that had marked
Athenian dominance in the Greek ancient world. The ancient historian Thucydides also
contracted the disease, but he survived to write about the plague.
His writings are the primary source on this outbreak, and modern academics and medical
scientists consider typhoid fever the most likely cause. In 2006, a study detected DNA
sequences similar to those of the bacterium responsible for typhoid fever in dental pulp
extracted from a burial pit dated to the time of the outbreak. The cause of the plague has long
been disputed and other scientists have disputed the findings, citing serious methodologic
flaws in the dental pulp-derived DNA study.
The disease is most commonly transmitted through poor hygiene habits and public sanitation
conditions; during the period in question related to Athens above, the whole population of
Attica was besieged within the Long Walls and lived in tents. Some historians believe that
English colony of Jamestown, Virginia, died out from typhoid.
Typhoid fever killed more than 6000 settlers in the New World between 1607 and 1624. A
long held belief is that 9th US President William Henry Harrison died of pneumonia but
recent studies suggest he likely died from typhoid. This disease may also have been a
contributing factor in the death of 12th US President Zachary Taylor due to the unsanitary
conditions in Washington DC in the mid 19th century.
During the American Civil War, 81,360 Union soldiers died of typhoid or dysentery, far more
than died of battle wounds. 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.
During the Spanish–American War, American troops were exposed to typhoid fever in
stateside training camps and overseas, largely due to inadequate sanitation systems. The
Surgeon General of the Army, George Miller Sternberg, suggested that the War Department
create a Typhoid Fever Board. Major Walter Reed, Edward O. Shakespeare, and Victor C.
Vaughan were appointed August 18, 1898, with Reed being designated the President of the
Board. The Typhoid Board determined that during the war, more soldiers died from this
disease than from yellow fever or from battle wounds.

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The Board promoted sanitary measures including latrine policy, disinfection, camp
relocation, and water sterilization, but by far the most successful antityphoid method was
vaccination, which became compulsory in June 1911 for all federal troops. The most
notorious carrier of typhoid fever, but by no means the most destructive, was Mary Mallon,
also known as Typhoid Mary. In 1907, she became the first carrier in the United States to be
identified and traced. She was a cook in New York who is closely associated with 53 cases
and three deaths.
Public health authorities told Mary to give up working as a cook or have her gall bladder
removed, as she had a chronic infection that kept her active as a carrier of the disease. 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.
6.Symptoms:
 Nosymptoms-ifonlyamildexposure;somepeoplebecome"carriers"oftyphoid.
 Poorappetite,
 Headaches,
 Generalizedachesandpains,
 Fever,Lethargy,Lethargy,
 Lethargy,
 Diarrhea,
 Have a sustained fever as high as103to1040
F(39to400
C),
 Chest congestion develops in many patients ,and abdominal pain and discomfort are
common,Constipation, mild vomiting, slow heartbeat.
 Symptoms usually develop 1–3 weeks after exposure, and may be mild or severe.
First week:
 High fever 103 or 104 F (39.4 or 40 C)
 Malaise
 Headache
 Constipation (adults) or diarrhea (children)
 Rose-colored spots on the chest
 Enlarged spleen and liver
 Healthy carrier state may follow acute illness.

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Second week:
 Continuing high fever
 Either diarrhea that has the color and
 consistency of pea soup, or severe constipation
 Considerable weight loss
 Extremely distended abdomen
Third week:
 Become delirious
 Lie mo;onless and exhausted with your eyes half--‐closed in what's known as the typhoid
state
 Life-threatening complictions often develop at this time.
Fourth week:
 Improvement may come slowly during the fourth week
 Fever is likely to decrease gradually until your temperature returns to normal in another week
to 10 days signs and symptoms can return up to two weeks after fever has subsided.
The clinical presentation of typhoid fever varies from a mild illness with low-grade fever,
malaise, and slight dry cough to a severe clinical picture with abdominal discomfort and
multiple complications. Many factors influence the severity and overall clinical outcome of
the infection.
They include the duration of illness before the initiation of appropriate therapy, the choice of
antimicrobial treatment, age, the previous exposure or vaccination history, the virulence of
the bacterial strain, the quantity of inoculums ingested, host factors (e.g. HLA type, AIDS or
other immunosuppression) and whether the individual was taking other medications such as
H2 blockers or antacids to diminish gastric acid. Patients who are infected with HIV are at
significantly increased risk of clinical infection with S. typhi and S. paratyphi.
Evidence of Helicobacter pylori infection also represents an increased risk of acquiring
typhoid fever. Acute non-complicated disease: Acute typhoid fever is characterized by
prolonged fever, disturbances of bowel function (constipation in adults, diarrhoea in
children), headache, malaise and anorexia. Bronchitic cough is common in the early stage of
the illness.

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During the period of fever, up to 25% of patients show exanthem (rose spots), on the chest,
abdomen and back.
7.Complicated disease:
Acute typhoid fever may be severe. Depending on the clinical setting and the quality of
available medical care, up to 10% of typhoid patients may develop serious complications.
Since the gut-associated lymphoid tissue exhibits prominent pathology, the presence of occult
blood is a common finding in the stool of 10-20% of patients, and up to 3% may have
melena.
Intestinal perforation has also been reported in up to 3% of hospitalized cases. Abdominal
discomfort develops and increases. It is often restricted to the right lower quadrant but may
be diffuse. The symptoms and signs of intestinal perforation and peritonitis sometimes
follow, accompanied by a sudden rise in pulse rate, hypotension, marked abdominal
tenderness, rebound tenderness and guarding, and subsequent abdominal rigidity.
A rising white blood cell count with a left shift and free air on abdominal radiographs are
usually seen. Altered mental status in typhoid patients has been associated with a high case-
fatality rate. Such patients generally have delirium or obtundation, rarely with coma. Typhoid
meningitis, encephalomyelitis, Guillain-Barré syndrome, cranial or peripheral neuritis, and
psychotic symptoms, although rare, have been reported.
Other serious complications documented with typhoid fever include haemorrhages (causing
rapid death in some patients), hepatitis, myocarditis, pneumonia, disseminated intravascular
WHO/V&B/03.07 3 coagulation, thrombocytopenia and haemolytic uraemic syndrome.
In the pre-antibiotic era, which had a different clinical picture, if patients did not die with
peritonitis or intestinal haemorrhage, 15% of typhoid fever cases died with prolonged
persistent fever and diseases for no clear reason. Patients may also experience genitourinary
tract manifestations or relapse, and/or a chronic carrier state may develop.
Carrier state: 1-5% of patients, depending on age, become chronic carriers harbouring
S.typhi in the gall-bladder.

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8. Magnitude of the problem:
Typhoid fever is a global health problem. Its real impact is difficult to estimate because the
clinical picture is confused with those of many other febrile infections. Additionally, the
disease is underestimated because there are no bacteriology laboratories in most areas of
developing countries.
These factors are believed to result in many cases going undiagnosed. On the basis of the
literature and the incidence of typhoid fever recorded in control groups in large vaccine field
trials with good laboratory support it has been estimated that approximately 17 million cases
of typhoid fever and 600000 associated deaths occur annually. However, the estimates have
been biased because study populations have usually been in areas of high incidence.
Furthermore, these estimates of burden relate to the clinical syndrome of typhoid fever but
not to S. typhi exposure.
Since the prevalence of bacteraemia in febrile children is quite high (2-3%) in areas of
endemicity it is suggested that exposure to the bacteria is higher than indicated by the figures
that are based solely on the clinical syndrome of typhoid fever. The incidence of the disease
in areas of endemicity may resemble the incidences observed in control groups in large
vaccine field trials, viz. between 45 per 100000 per year and over 1000 per 100000 per year.
Preliminary results from recent studies conducted in Bangladesh by ICDDR,B show an
incidence of approximately 2000 per 100 000 per year.
Typhoid fever also has a very high social and economic impact because of the
hospitalization of patients with acute disease and the complications and loss of income
attributable to the duration of the clinical illness .
It is important to note that reports from some provinces in China and Pakistan have indicated
more cases of paratyphoid fever caused by S. paratyphi than by S. typhi. In areas of
endemicity and in large outbreaks, most cases occur in persons aged between 3 and 19 years.
In 1997, for example, this age range was reported during an epidemic of the disease in
Tajikistan. Nevertheless, clinically apparent bacteraemic S. typhi infection in children aged
under three years has been described in Bangladesh, India, Jordan, Nigeria, and elsewhere .
In Indonesia there is a mean of 900 000 cases per year with over 20 000 deaths. In Indonesia,
people aged 3_19 years accounted for 91% of cases of typhoid fever and the attack rate of
blood-culture-positive typhoid fever was 1026 per 100 000 per year.

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A similar situation was reported from Papua New Guinea. When typhoid fever was highly
endemic in certain countries in South America the incidence of clinical typhoid fever in
children aged under 3 years was low. In Chile, however, single blood cultures for all children
aged under 24 months who presented at health centres with fever, regardless of other clinical
symptoms, showed that 3.5% had unrecognized bacterial infections caused by S. typhi or S.
paratyphi .
Enteric fever had not been suspected on clinical grounds in any of the children. In South
America the peak incidence occurred in school students aged 5-19 years and in adults aged
over 35 years. This kind of study has not been conducted in other areas of endemicity. 4 The
diagnosis, treatment and prevention of typhoid fever Between 1% and 5% of patients with
acute typhoid infection have been reported to become chronic carriers of the infection in the
gall bladder, depending on age, sex and treatment regimen.
The propensity to become a carrier follows the epidemiology of gall bladder disease,
increasing with age and being greater in females than in males.
The propensity to become a chronic carrier may have changed with the present availability
and selection of antibiotics as well as with the antibiotic resistance of the prevalent strains.
The role of chronic carriers as a reservoir of infection was studied in Santiago, Chile, where a
crude rate of 694 carriers per 100000 inhabitants was found.
9.Case definition:
Confirmed case of typhoid fever
A patient with fever (38°C and above) that has lasted for at least three days, with a
laboratory-confirmed positive culture (blood, bone marrow, bowel fluid) of S. typhi.
Probable case of typhoid fever .A patient with fever (38°C and above) that has lasted for at
least three days, with a positive sero-diagnosis or antigen detection test but without S. typhi
isolation Chronic carrier.
Excretion of S.typhi in stools or urine (or repeated positive bile or duodenal string cultures)
for longer than one year after the onset of acute typhoid fever. Short-term carriers also exist
but their epidemiological role is not as important as that of chronic carriers. Some patients
excreting S. typhi have no history of typhoid fever.

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10.Transmission:
The bacterium that 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. According to
statistics from the United States Centers for Disease Control and Prevention (CDC),
the chlorination of drinking water has led to dramatic decreases in the transmission of typhoid
fever. The cause is the bacterium Salmonella Typhi, also known as Salmonella
enterica serotype Typhi. How does the bacteria cause disease ?
11.Pathogenesis:
Salmonella organisms penetrate the mucosa of both small and large bowel, coming to
lie intracellularly where they proliferate. There is not the same tendency to mucosal damage
as occurs with Shigella infections but ulceration of lymphoid follicles may occur.

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12,Diagnosis of typhoid fever:
The definitive diagnosis of typhoid fever depends on the isolation of S. typhi from
blood, bone marrow or a specific anatomical lesion. The presence of clinical symptoms
characteristic of typhoid fever or the detection of a specific antibody response is suggestive of
typhoid fever but not definitive. Blood culture is the mainstay of the diagnosis of this disease.
Although ox bile medium (Oxgall) is recommended for enteric fever pathogens (S. typhi and
S. paratyphi), only these pathogens can be grown on it.
In a general diagnostic laboratory, therefore, where other pathogens are suspected, a general
blood culture medium should be used. More than 80% of patients with typhoid fever have the
causative organism in their blood. A failure to isolate the organism may be caused by several
factors:
(i)the limitations of laboratory media (ii) the presence of antibiotics (iii) the volume of the
specimen cultured or(iv) the time of collection, patients with a history of fever for 7 to 10
days being more likely than others to have a positive blood culture.
Bone marrow aspirate culture is the gold standard for the diagnosis of typhoid fever and is
particularly valuable for patients who have been previously treated, who have a long history
of illness and for whom there has been a negative blood culture with the recommended
volume of blood.
Duodenal aspirate culture has also proved highly satisfactory as a diagnostic test but has not
found widespread acceptance because of poor tolerance of duodenalaspiration, particularly in
children .
1. Specimens
If a bacteriology laboratory is not available on site, clinical specimens for culture can be
transported to a main laboratory for processing. For blood culture it is essential to inoculate
media at the time of drawing blood. For other specimens it is advisable to make the time of
transportation to the laboratory as short as possible. It is more important to process the
specimens quickly than to keep them cold. Once they have been inoculated, blood culture
bottles should not be kept cold. They should be incubated at 37°C or, in tropical countries,
left at room temperature, before being processed in the laboratory.
1.1 Blood:
The volume of blood cultured is one of the most important factors in the isolation of S. typhi
from typhoid patients: 10-15 ml should be taken from schoolchildren and adults in order to

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achieve optimal isolation rates; 2-4 ml are required from toddlers and preschool children.
This is because children have higher levels of bacteraemia than adults.
In some regions it may be impossible to collect such large volumes of 8 The diagnosis,
treatment and prevention of typhoid fever blood and so alternative diagnostic methods may
be necessary for cases in which blood cultures are negative.
Because reducing the blood volume reduces the sensitivity of the blood culture, however, an
effort should be made to draw sufficient blood if at all possible. Blood should be drawn by
means of a sterile technique of venous puncture and should be inoculated immediately into a
blood culture bottle with the syringe that has been used for collection.
Several reports of pseudobacteraemia have been associated with the reinoculation of blood
culture bottles after the collection of blood in contaminated vessels. The practice of
inoculating blood culture bottles from specimens taken for biochemical or haematological
analysis should therefore be avoided. The optimum ratio of the volume of blood to traditional
culture broth should be 1 to 10 or more. Some commercial blood culture systems have special
resins in the media which allow higher volumes of blood to be used.
The instructions with commercial blood culture systems should always be read and the
recommended amounts should not be exceeded.In general, if 5 ml of blood are drawn they
should be inoculated into 45 ml or more of broth. If 10-15 ml of blood are drawn the
specimen can be divided into equal aliquots and inoculated into two or more blood culture
bottles. This allows the use of standard blood culture bottles of 50 ml.
For small children the volume of blood drawn can be reduced but should still be inoculated
into 45 ml of culture broth. In order to assist the interpretation of negative results the volume
of blood collected should be carefully recorded. The blood culture bottle should then be
transported to the main laboratory at ambient temperature (15°C to 40°C) as indicated above.
Blood cultures should not be stored or transported at low temperatures.
If the ambient temperature is below 15°C it is advisable to transport blood cultures in an
incubator. In the laboratory, bloodn culture bottles should be incubated at 37°C and checked
for turbidity, gas formation and other evidence of growth after 1, 2, 3 and 7 days. For days 1,
2 and 3, only bottles showing signs of positive growth are cultured on agar plates. On day 7
all bottles should be subcultured before being discarded as negative.
1.2 Serum:

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For serological purposes, 1-3 ml of blood should be inoculated into a tube without
anticoagulant. A second sample, if possible, should be collected at the convalescent stage, at
least 5 days later.
After clotting has occurred the serum should be separated and stored in aliquots of 200 ml at
+4°C. Testing can take place immediately or storage can continue for a week without
affecting the antibody titre. The serum should be frozen at -20°C if longer-term storage is
required.
1.3 Stool samples:
Stools can be collected from acute patients and they are especially useful for the
diagnosis of typhoid carriers. The isolation of S. typhi from stools is suggestive of typhoid
fever. However, the clinical condition of the patient should be considered. Stool specimens
should be collected in a sterile wide-mouthed plastic container.
The likelihood of obtaining positive results increases with the quantity of stools collected.
Specimens should preferably be processed within two hours after collection. If there is a
delay the specimens should be stored in a refrigerator at 4°C or in a cool box with freezer
packs, and should be transported to the laboratory in a cool box.
Stool culture may increase the yield of culture-positive results by up to 5% in acute typhoid
fever. If a stool sample cannot be obtained, rectal swabs inoculated into Carry Blair transport
medium can been used but these are less successful.
2. Microbiological procedures:
2.1 Blood culture:
A typical blood culture bottle contains 45 ml of tryptic soy broth or brain heart infusion
broth. These are inoculated with 5 ml of fresh blood and incubated at 37°C. Negatives should
be kept for at least seven days. Because S. typhi is not the only bacterial pathogen found in
blood, subculturing is performed on days 1, 2, 3 and 7 on non-selective agar. The best agar is
blood agar (horse or sheep blood) as this allows the growth of most bacterial pathogens.
If blood agar is not available, nutrient agar can be used in combination with MacKonkey
agar. In some laboratories the use of MacConkey agar alone is preferred as this allows the
growth of only bile-tolerant bacteria such as S. typhi and does not allow the growth of many
Gram-positive contaminants.

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The contamination of blood cultures reduces isolation rates for S. typhi and should be
prevented as far as possible. It is important to identify contaminating bacteria that come from
the skin of patients or the air of the laboratory so that measures can be taken to prevent
further problems.
MacKonkey agar should therefore not be used as the only agar for the sampling of blood
cultures in a diagnostic microbiology laboratory. Furthermore, because it is selective,
MacKonkey agar does not permit the growth of Gram-positive pathogens or even all E. coli.
For suspected tyhoid fever, subculture plates should be incubated at 37°C for 18-24 hours in
an aerobic incubator.
2.2 Stool or rectal swab culture:
This involves inoculating 1 g of stool into 10 ml of selenite F broth and incubating at 37°C
for 18-48 hours. Because selenite broth is very sensitive to heat the manufacturer’s
instructions should be carefully followed during preparation and overheating of the broth
during sterilization should be avoided.
Once a batch is prepared it should be stored at 4°C. Selenite broth inhibits the motility of E.
coli found in stools but does not kill this bacterium. A subculture of selenite broth on a
selective agar is therefore made from the surface of the broth without disturbing the sediment.
The choice of agar media includes Mac Conkey agar, desoxycholate citrate agar, xylose-
lysinedesoxycholate agar, and hektoen enteric agar or SS (Salmonella_Shigella). The plate is
incubated at 37°C for 24 hours.
Different batches of agar plates can give slightly different colonies of S. typhi and it is
therefore important to keep one strain of S. typhi for use in quality control for each batch of
agar plates and selenite broth.
New batches of media are inoculated with the control strain and the amount of growth and the
appearance of the colonies are recorded. If S. typhi does not grow as well as usual in any
batch of medium, discard the medium and make a fresh one.
The identification of colonies as S. typhi is straightforward if reagents of satisfactory quality
are available. Colonies from solid media can be used for agglutination with specific antisera.
Several salmonellae may share the same antigenic structure. Consequently, confirmation by
means of biochemical tests is always necessary.
2.3 Colony characteristics:
Blood agar:

21
On blood agar, S. typhi and S. paratyphi usually produce non-haemolytic smooth white
colonies.
MacConkey agar:
On MacConkey agar, salmonellae produce lactose non-fermenting smooth colonies.
SS agar:
On SS agar, salmonellae usually produce lactose non-fermenting colonies with black centres
(except S. paratyphi A, whose colonies do not have black centres).
Desoxycholate agar:
On desoxycholate agar, salmonellae produce lactose non-fermenting colonies with black
centres (except S. paratyphi A, whose colonies do not have black centres).
Xylose-lysine-desoxycholate agar:
On xylose-desoxycholate agar, salmonellae produce transparent red colonies with black
centres (except S. paratyphi A, whose colonies do not have black centres).
Hektoen enteric agar:
On hektoen enteric agar, salmonellae produce transparent green colonies with black centres
(except S. paratyphi A, whose colonies do not have black centres).
Bismuth sulfite agar:
On this medium, salmonellae produce black colonies.
Felix-Widal test:
This test measures agglutinating antibody levels against O and H antigens. The levels are
measured by using doubling dilutions of sera in large test tubes. Usually, O antibodies appear
on days 6-8 and H antibodies on days 10-12 after the onset of the disease.The test is usually
performed on an acute serum (at first contact with the patient).A convalescent serum should
preferably also be collected so that paired titrations can be performed.
In practice, however, this is often difficult. At least 1 ml of blood should be collected each
time in order to have a sufficient amount of serum. In exceptional circumstances the test can
be performed on plasma without any adverse effect on the result.
The test has only moderate sensitivity and specificity. It can be negative in up to 30% of
culture-proven cases of typhoid fever. This may be because of prior antibiotic therapy that
has blunted the antibody response. On the other hand, S. typhi shares O and H antigens with
other Salmonella serotypes and has cross-reacting epitopes with other Enterobacteriacae, and
this can lead to false-positive results.

22
Such results may also occur in other clinical conditions, e.g. malaria, typhus, bacteraemia
caused by other organisms, and cirrhosis. In areas of endemicity there is often a low
background level of antibodies in the normal population. Determining an appropriate cut-off
for a positive result can be difficult since it varies between areas and between times in given
areas .
It is therefore important to establish the antibody level in the normal population in a
particular locality in order to determine a threshold above which the antibody titre is
considered significant. This is particularly important if, as usually happens,a single acute
sample is available for testing.
If paired sera are available a fourfold rise in the antibody titre between convalescent and
acute sera is diagnostic. Quality control of the test is achieved by running a standard serum
with a known antibody titre in parallel in each batch of assays.
The variations in the standard serum should not exceed one tube, i.e. double dilution. Despite
these limitations the test may be useful, particularly in areas that cannot afford the more
expensive diagnostic methods.
This is acceptable so long as the results are interpreted with care in accordance with
appropriate local cut-off values for the determination of positivity. This test is unnecessary if
the diagnosis has already been confirmed by the isolation of S. typhi from a sterile site. New
diagnostic tests are being developed.
New diagnostic tests: current status and usefulness:
There is a need for a quick and reliable diagnostic test for typhoid fever as an alternative
to the Widal test.
Recent advances include the IDL Tubex® test marketed by a Swedish company, which
reportedly can detect IgM O9 antibodies from patients within a few minutes. Another rapid
serological test, Typhidot®, takes three hours to perform.It was developed in Malaysia for the
detection of specific IgM and IgG antibodies against a 50 kD antigen of S. typhi.
A newer version of the test, Typhidot-M®, was recently developed to detect specific IgM
antibodies only. The dipstick test, developed in the Netherlands, is based on the binding of S.
typhi-specific IgM antibodies in samples to S. typhi lipopolysaccharide (LPS) antigen and the
staining of bound antibodies by an anti-human IgM antibody conjugated to colloidal dye
particles.

23
IDL Tubex® test
The Tubex® test is simple (essentially a one-step test) and rapid (taking approximately two
minutes). It exploits the simplicity and user-friendliness of the Widal and the slide latex
agglutination tests but uses the separation of coloured particles in solution to improve
resolution and sensitivity.
Specificity is improved by means of an inhibition assay format and by detecting antibodies
to a single antigen in S. typhi only.The O9 antigen used in the test is extremely specific
because its immunodominant epitope is a very rare dideoxyhexose sugar that occurs in
nature.
This antigen has beenfound in serogroup D salmonellae but not in other microorganisms. The
closest to it is the tyvelose antigen found in Trichinella spiralis but antibodies to these two
antigens do not cross-react with each other. A positive result given by Tubex® invariably
suggests a Salmonella infection, although the test cannot tell which group D Salmonella is
responsible.
Infections caused by other serotypes, including S. paratyphi A, give negative
results.Immunogenically, the O9 antigen is immunodominant and robust. Unlike the capsular
(Vi) and flagellar antigens that are thymus-independent type II in nature and poorly
immunogenic in infants, the O9 antigen (or LPS in general) is thymus-independent type I,
immunogenic in infants, and a potent B cell mitogen.
It can stimulate B cells without the help of T cells (unlike protein antigens) and,
consequently, anti-O9 responses are rapid. This is important teleologically, as they form the
first line of host defence. For reasons yet to be elucidated, Tubex® detects IgM antibodies but
not IgG. This makes it invaluable as an aid in the diagnosis of current infections.
The reagents are stable for over a year at 4°C, and for at least some weeks at ambient
temperature. A drop of test serum is mixed for about one minute with a drop of reagent A in
the tube. Two drops of reagent B are then added and the contents are mixed thoroughly for 1-
2 minutes.
The set of tubes is then placed on a magnet-embedded stand, across which they are slid
several times. The result, which can be read immediately or up to many hours later, is based
on the colour of the reaction mixture.
A range of colours involving varying proportions of redness and blueness can be expected,
and a colour chart is provided for the purpose of scoring. Red indicates negativity while
increasing blueness denotes increasing positivity. The rationale of the test is as follows. If the

24
serum is negative for O9 antibodies the antibody-coated indicator particles bind to the
antigen-coated magnetic beads.
When a magnet is applied, the magnetic particles settle to the bottom of the tube together
with any blue indicator particles associated with these. Consequently a background red colour
is left in the solution.
This background colour is actually exploited to camouflage the sample colour of haemolysed
sera. If, on the other hand, the patient’s serum contains O9 antibodies, these bind to the
magnetic particles and prevent the indicator particles from binding to them. The indicator
particles thus remain suspended and the resultant colour of the solution is blue.
Typhidot® test
This test makes use of the 50 kD antigen to detect specific IgM and IgG antibodies to S. typhi
. It has undergone full-scale multinational clinical evaluation of its diagnostic value . This dot
EIA test offers simplicity, speed, specificity (75%), economy, early diagnosis, sensitivity
(95%) and high negative and positive predictive values.
The detection of IgM reveals acute typhoid in the early phase of infection, while the detection
of both IgG and IgM suggests acute typhoid in the middle phase of infection. In areas of high
endemicity where the rate of typhoid transmission is high the detection of specific IgG
increases.
Since IgG can persist for more than two years after typhoid infection the detection of specific
IgG cannot differentiate between acute and convalescent cases. Furthermore, false-positive
results attributable to previous infection may occur. On the other hand, IgG positivity may
also occur in the event of current reinfection.
In cases of reinfection there is a secondary immune response with a significant boosting of
IgG over IgM, such that the latter cannot be detected and its effect is masked. A possible
strategy for solving these problems is to enable the detection of IgM by ensuring that it is
unmasked.
In order to increase diagnostic accuracy in these situations the original Typhidot® test was
modified by inactivating total IgG in the serum sample. Studies with the modified test,
Typhidot-M®, have shown that inactivation of IgG removes competitive binding and allows
access of the antigen to the specific IgM when it is present.
The detection of specific IgM within three hours suggests acute typhoid infection.
Evaluations of Typhidot® and Typhidot-M® in clinical settings showed that they performed
better than the Widal test and the culture method.

25
In laboratory diagnoses of typhoid fever the method used as the gold standard should
approach 100% in sensitivity, specificity and positive and negative predictive values.
Evaluation studies have shown that Typhidot-M® is superior to the culture method.
Although culture remains the gold standard it cannot match Typhidot-M® in sensitivity
(>93%), negative predictive value and speed. Typhidot-M® can replace the Widal test when
used in conjunction with the culture method for the rapid and accurate diagnosis of typhoid
fever. The high negative predictive value of the test suggests that Typhidot-M® would be
useful in areas of high endemicity.
IgM dipstick test:
The typhoid IgM dipstick assay is designed for the serodiagnosis of typhoid fever through the
detection of S. typhi-specific IgM antibodies in serum or whole blood samples. The assay
consists of a dipstick, a lyophilized non-enzymatic detection reagent, liquid to reconstitute the
detection reagent, liquid to wet the test strip of the dipstick before incubation with serum and
detection reagent, and test tubes.
The components are stable for two years if stored in the temperature range 4-25°C in a dry
place and protected from direct exposure to sunlight. Tubex® has not been evaluated
extensively but several trials are being planned.
In a preliminary study involving stored sera the test performed better than the Widal test in
both sensitivity and specificity The assay is based on the binding of S. typhi-specific IgM
antibodies to S. typhi LPS antigen and the staining of bound antibodies by an anti-human IgM
antibody conjugated to colloidal dye particles.
The white test strip of the dipstick contains the antigen immobilized in a distinct line. The
strip also has a control line with anti-human IgM antibodies.
The assay is performed by incubation of the wetted test strip in a mixture of serum and
detection reagent, the serum being diluted at 1:50 in the detection reagent.
Whole blood may be tested at a 1:25 dilution in detection reagent. The incubation period is
three hours at room temperature. When incubation is complete the test strip is rinsed
thoroughly with water and then allowed to dry. The result is read by visual inspection of the
test strip for staining of the antigen and control lines.
The test result is scored negative if no staining of the antigen line occurs and is graded 1+,
2+, 3+ or 4+ if there is weak, moderate strong or very strong staining as indicated by
comparison with a coloured reference strip. The control line should stain in all runs.

26
Evaluations of the dipstick test in laboratory-based studies in Indonesia , Kenya, Viet Nam
and Egypt have shown consistent results.
These studies indicated sensitivities of 65% to 77% for samples collected at the time of first
consultation from culture-confirmed patients and specificities of 95% to 100%. The results of
culture and serological investigation may be influenced by various factors, among them the
time of sample collection and the use of antibiotics before consultation and sample collection.
In a study conducted in Makassar, Indonesia, the sensitivity of the blood culture method was
estimated to be 66%, and that of the dipstick test calculated for the combined group of
culture-confirmed and culture-negative patients with a final clinical diagnosis of typhoid
fever was 48%.
The sensitivity ranged from 29% for samples collected during the first week of illness to 96%
for samples collected at a later stage. Tests on follow-up samples showed seroconversion in
the majority of the dipstick-negative typhoid patients.
The dipstick test provides a rapid and simple alternative for the diagnosis of typhoid fever,
particularly in situations where culture facilities are not available. The assay can be
performed by people without formal training and in the absence of specialized equipment.
Electricity is not required, as the components can be stored without cooling.
The results of the dipstick test can be obtained on the day when patients present. This makes
prompt treatment possible.
Specific antibodies usually only appear a week after the onset of symptoms and signs. This
should kept in mind when a negative serological test result is being interpreted.

27
Drugs for typhoid:
1. fluoroquinolones:
Ofloxacin (400 mg BD), levofloxacin (500 mg OD/BD) anDpefloxacin (400 mg BD) are
nearly equally efficacious alternatives to ciprofloxacin. Ciprofloxacin is the first choice
drug in typhoid fever since chloramphenicol, ampicillin and cotrimoxazole have become
unreliable due to development of resistance.
In India and elsewhere up to 95% S. typhi isolates are sensitive to ciprofloxacin. However,
increasing number of nonresponsive cases are being reported. A dose of 500–750 mg BD
for 10 days is recommended. Patients unable to take the drug orally may be treated with
200 mg. i.v. 12 hourly in the beginning. Being bactericidal the advantages of ciprofloxacin
are:
• Quick defervescence: On an average fever subsides in 4–5 days.
• Early abetment of symptoms; low incidence of complications and relapse.
• Prevention of carrier state due to cidal action, good penetration into infected cells, high
biliary and intestinal mucosal concentration. It can also be used to treat typhoid carriers(750
mg BD for 4–8 weeks). This has been found to achieve 92% eradication rate compared to
50% by ampicillin.
Mechanism of action:

28
The FQs inhibit the enzyme bacterial DNA gyrase, which nicks double-stranded DNA,
introduces negative supercoils and then reseals the nicked ends. This is necessary to prevent
excessive positive supercoiling of the strands when they separate to permit replication or
transcription. The DNA gyrase consists of two A and two B subunits.
The A subunit carries out nicking of DNA, B subunit introduces negative supercoils and then
A subunit reseals the strands. FQs bind to A subunit with high affinity and interfere with its
strand cutting and resealing function.
Recent evidence indicates that in gram-positive bacteria the major target of FQ action is a
similar enzyme topoisomerase IV which nicks and separates daughter DNA strands after
DNA replication. Greater affinity for topoisomerase IV may confer higher potency against
gram-positive bacteria.
Ceftriaxone :
Ceftriaxone, sold under the trade name Rocephin, is an antibiotic useful for the treatment of
a number of bacterial infections. This includes middle ear infections, endocarditis,
meningitis, pneumonia, bone and joint infections, intra-abdominal infections, skin infections,
urinary tract infections, gonorrhea, and pelvic inflammatory disease.
It is also sometimes used before surgery and following a bite wound to try to prevent
infection. Ceftriaxone can be given by injection into a vein or into a muscle. Common side
effects include pain at the site of injection and allergic reactions.
Other possible side effects include C. difficile associated diarrhea, hemolytic anemia, gall
bladder disease, and seizures.

29
It is not recommended in those who have had anaphylaxis to penicillin but may be used in
those who have had milder reactions. The intravenous form should not be given with
intravenous calcium.
There is tentative evidence that ceftriaxone is relatively safe during pregnancy and
breastfeeding. It is a third generation cephalosporin that works by preventing bacteria from
making a cell wall.
Medical use:
Ceftriaxone and other third generation antibiotics are used to treat organisms that tend to be
resistant to many other antibiotics. Due to emergent resistance, ceftriaxone should not be
used for the treatment of Enterobacter infections.
Before using ceftriaxone, it is important to determine the susceptibility of the bacteria. If
sepsis is being considered, empiric therapy
may be initiated prior to susceptibility testing. Medical uses include:
 lower respiratory tract infections
 acute bacterial otitis media
 skin and skin structure infections
 urinary tract infections
 uncomplicated gonorrhea
 pelvic inflammatory disease
 bacterial septicemia
 intra-abdominal infections
 meningitis
 surgical prophylaxis lyme disease
It is also a choice drug for treatment of bacterial meningitis caused by pneumococci,
meningococci, Haemophilus influenzae, and "susceptible enteric Gramnegative rods, but not
Listeria monocytogenes. In combination with doxycycline or azithromycin, ceftriaxone is
recommended by the United States Centers for Disease Control for the treatment of gonorrhea.
By itself, it is not recommended due to the potential for resistance development.
Like other third generation cephalosporins, ceftriaxone is active against Citrobacter spp.,
Serratia marcescens, and beta-lactam as producing strains of Haemophilus and Neisseria.
However, unlike ceftazidime and cefoperazone, ceftriaxone does not have useful activity
against Pseudomonas aeruginosa.

30
It is generally not active against Enterobacter species, and its use should be avoided in the
treatment of Enterobacter infections, even if the isolate appears susceptible, because of the
emergence.
Adverse effects
Although generally well tolerated, the most common adverse reactions associated with
ceftriaxone are changes in white blood cell counts, local reactions at site of administration,
rash, and diarrhea. Incidence of adverse effects greater than 1%.
Ceftriaxone is a third generation antibiotic from the cephalosporin family of antibiotics. It is
within lactam family of antibiotics. Ceftriaxone selectively and irreversibly inhibits bacterial
cell wall synthesis by binding to trans-peptidases, also called trans-amidase, which are
penicillin binding proteins (PBPs) that catalyze the crosslinking of the peptidoglycan
polymers forming the bacterial cell wall.
The peptidoglycan cell wall is made up of penta-peptide units attached to a polysaccharide
backbone with alternating units of N-acetyl glucosamine and N-acetyl muramic acid. PBPs
act on a terminal D-alanine moiety on a penta peptide unit and catalyze the formation of a
peptide bond between the penultimate D-alanine and a glycine unit on an adjacent
peptidoglycan strand, releasing the terminal D-alanine unit in the process.
The structure of ceftriaxone mimics the D-alanine moiety, and the PBP attacks the beta-
lactam ring in ceftriaxone as if it were its normal D-alanine substrate. The peptidoglycan

31
crosslinking activity of PBPs is a construction and repair mechanism that normally helps to
maintain bacterial cell wall integrity, so the inhibition of PBPs leads to damage and
destruction of the cell wall and eventually to cell lysis.
Pharmacokinetics:
Absorption:
Ceftriaxone can be administered intravenously and intramuscularly, and the drug is
completely absorbed. It is not available orally.
Metabolism:
3367% of ceftriaxone is renally excreted as unchanged drug, but no dose adjustments are
required in renal impairment with dosages up to 2 grams per day. The rest is excreted in the
bile as inactive compounds from hepatic and gut flora metabolism.
Distribution:
Ceftriaxone penetrates tissues and body fluids well, including cerebrospinal fluid to treat
central nervous system infections. The average volume of distribution in adults is 5.813.5
liters.
Elimination:
The average elimination half-life in healthy adults is 5.88.7 hours. In people with renal
impairment, the average elimination half-life increases to 11.415.7 hours.
Currently, it is the most reliable and fastest acting bactericidal drug for enteric fever.
Practically all S. typhi isolates, including multidrug resistant ones, are susceptible. However,
it has to be injected i.v. (4 g daily for 2 days followed by 2 g/day till 2 days after fever
subsides; children 75 mg/kg/day) and is expensive.
Generally 7–10 days treatment is required. Being bactericidal, it also prevents relapses and
carrier state. Ceftriaxone is to be preferred over FQs in children, pregnant women and in
areas with FQ resistance. Cefoperazone and cefotaxime are the other third generation
cephalosporins used in typhoid.

32
2.Chloramphenicol:
Chloramphenicol is an antibiotic useful for the treatment of a number of bacterial infections.
This includes as an eye ointment to treat conjunctivitis. By mouth or by injection into a vein it
is used to treat meningitis, plague, cholera, and typhoid fever.
Its use by mouth or by injection is only recommended when safer antibiotics cannot be used
and if used monitoring both blood levels of the medication and blood cell levels every two days
is recommended during treatment.
Common side effects include bone marrow suppression, nausea, and diarrhea. The bone
marrow suppression may result in death. To reduce the risk of side effects treatment duration
should be as short as possible. People with liver or kidney problems may need lower doses. In
young children a condition known as gray baby syndrome may occur which results in a swollen
stomach and low blood pressure.
Its use near the end of pregnancy and during breastfeeding is typically not recommended.
Chloramphenicol is a broad spectrum antibiotic that typically stops bacterial growth by
stopping the production of proteins. Chloramphenicol was discovered in 1947.
It is on the World Health Organization's List of Essential Medicines, the most effective and
safe medicines needed in a health system. It is available as a generic medication. The wholesale
cost in the developing world of an intravenous dose is about 0.40 to 1.90 USD.
In the United States a intravenous dose costs about 41.47 USD. Global issues relating to
bacterial resistance have revived interest in its use.
Since majority of S.typhi strains are now chloramphenicol resistant, it has become clinically
unreliable. It is seldom used, only in case the local strain is known to be sensitive and clinical
experience supports its use. It is administered orally (0.5 g 6 hourly till fever subsides, then
0.25 g 6 hourly for another 5–7 days), and is inexpensive.
Medical uses
The original indication of chloramphenicol was in the treatment of typhoid, but the now almost
universal presence of multiple drug resistant Salmonella typhi has meant it is seldom used for
this indication except when the organism is known to be sensitive. Chloramphenicol may be
used as a second line agent in the treatment of tetracycline resistant cholera.
Because of its excellent blood brain barrier penetration (far superior to any of the
Cephalosporins), chloramphenicol remains the first choice treatment for staphylococcal brain

33
abscesses. It is also useful in the treatment of brain abscesses due to mixed organisms or when
the causative organism is not known.
Chloramphenicol is active against the three main bacterial causes of meningitis: Neisseria
meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. In the West,
chloramphenicol remains the drug of choice in the treatment of meningitis in patients with
severe penicillin or cephalosporin allergy and general practitioners are recommended to carry
intravenous chloramphenicol in their bag.
In low income countries, the WHO no longer recommends oily chloramphenicol as first line to
treat meningitis, but recognizes it may be used with caution if there are no available
alternatives.
Chloramphenicol has been used in the U.S. in the initial empirical treatment of children with
fever and a petechial rash, when the differential diagnosis includes both Neisseria meningitidis
septicaemia and Rocky Mountain spotted fever, pending the results of diagnostic
investigations.
Spectrum
Chloramphenicol has a broad spectrum of activity and has been effective in treating ocular
infections caused by a number of bacteria including Staphylococcus aureus, Streptococcus
pneumoniae, and Escherichia coli. It is not effective against Pseudomonas aeruginosa. The
following susceptibility data represent the minimum inhibitory concentration for a few
medically significant organisms.
Escherichia coli: 0.01510,000 μg/ml
Staphylococcus aureus: 0.06 μg/ml >128 μg/ml
Streptococcus pneumoniae: 216μg/ml
Each of these concentrations is dependent upon the bacterial strain being targeted. Some strains
of E. coli, for example, show spontaneous emergence of chloramphenicol resistance.

34
Chloramphenicol is a bacteriostatic by inhibiting protein synthesis. It prevents protein chain
elongation by inhibiting the peptidyl transferase activity of the bacterial ribosome. It
specifically binds to A2451 and A2452 residues in the 23S r-RNA of the 50S ribosomal
subunit, preventing peptide bond formation.
While chloramphenicol and the macrolide class of antibiotics both interact with ribosomes,
chloramphenicol is not a macrolide. It directly interferes with substrate binding, whereas
macrolides sterically block the progression of the growing peptide.
Resistance:
Three mechanisms of resistance to chloramphenicol are known: reduced membrane
permeability, mutation of the 50S ribosomal subunit, and elaboration of chloramphenicol
acetyl-transferase. It is easy to select for reduced membrane permeability to chloramphenicol
in vitro by serial passage of bacteria, and this is the most common mechanism of low level
chloramphenicol resistance.
High level resistance is conferred by the cat gene; this gene codes for an enzyme called
chloramphenicol acetyl transferase, which inactivates chloramphenicol by covalently linking
one or two acetyl groups, derived from acetyl S coenzyme A, to the hydroxyl groups on the
chloramphenicol molecule. The acetylation prevents chloramphenicol from binding to the
ribosome.
Resistance conferring mutations of the 50S ribosomal subunit are rare. Chloramphenicol
resistance may be carried on a plasmid that also codes for resistance to other drugs.
One example is the AC Co T plasmid (A=ampicillin, C=chloramphenicol, Co=cotrimoxazole,
T=tetracycline), which mediates multiple drug resistance in typhoid (also called R factors).

35
Adverse effects:
Aplastic anemia:
The most serious side effect of chloramphenicol treatment is aplastic anaemia. This effect
is rare and sometimes fatal. The risk of AA is high enough that alternatives should be
strongly considered. Treatments are available but expensive. No way exists to predict who
may or may not get this side effect.
The effect usually occurs weeks or months after treatment has been stopped, and a genetic
predisposition may be involved.
It is not known whether monitoring the blood counts of patients can prevent the development
of aplastic anaemia, but patients are recommended to have a baseline blood count with a
repeat blood count every few days while on treatment.
Chloramphenicol should be discontinued if the complete blood count drops below 2.5 x 10
cells/l.
The highest risk is with oral chloramphenicol (affecting 1 in 24,000-40,000) and the lowest
risk occurs with eye drops (affecting less than one in 224,716 prescriptions). Thiamphenicol,
a related compound with a similar spectrum of activity, is available in Italy and China for
human use, and has never been associated with aplastic anaemia.
Thiamphenicol is available in the U.S. and Europe as a veterinary antibiotic, but is not
approved for use in humans.
Bone marrow suppression:
Chloramphenicol may cause bone marrow suppression during treatment; this is a direct
toxic effect of the drug on human mitochondria. This effect manifests first as a fall in
hemoglobin levels, which occurs quite predictably once a cumulative dose of 20 g has been
given.
The anaemia is fully reversible once the drug is stopped and does not predict future
development of aplastic anaemia. Studies in mice have suggested existing marrow damage
may compound any marrow damage resulting from the toxic effects of chloramphenicol.

36
Leukemia:
Leukemia, a cancer of the blood or bone marrow, is characterized by an abnormal increase
of immature white blood cells. The risk of childhood leukemia is increased, as demonstrated
in a Chinese case-controlled study, and the risk increases with length of treatment.
Gray baby syndrome:
Intravenous chloramphenicol use has been associated with the so called gray baby
syndrome. This phenomenon occurs in newborn infants because they do not yet have fully
functional liver enzymes (i.e. UDP gluconyl transferase), so chloramphenicol remains in the
body. This causes several adverse effects, including hypotension and cyanosis. The condition
can be prevented by using the drug at the recommended doses, and monitoring blood levels.
Hypersensitivity reactions:
Fever, macular and vesicular rashes, angioedema, urticaria, and anaphylaxis may occur.
Herxheimer’s reactions have occurred during therapy for typhoid fever.
Neurotoxic reactions:
Headache, mild depression, mental confusion, and delirium have been described in patients
receiving chloramphenicol. Optic and peripheral neuritis have been reported, usually
following long-term therapy. If this occurs, the drug should be promptly withdrawn.
Pharmacokinetics:
Chloramphenicol is extremely lipid soluble; it remains relatively unbound to protein and is a
small molecule. It has a large apparent volume of distribution and penetrates effectively into
all tissues of the body, including the brain.
Distribution is not uniform, with highest concentrations found in the liver and kidney, with
lowest in the brain and cerebrospinal fluid.
The concentration achieved in brain and cerebrospinal fluid is around 30 to 50% of the
overall average body concentration, even when the meninges are not inflamed; this increases
to as high as 89% when the meninges are inflamed. Chloramphenicol increases the absorption
of iron.

37
Use in special populations:
Chloramphenicol is metabolized by the liver to chloramphenicol glucuronate (which is
inactive). In liver impairment, the dose of chloramphenicol must therefore be reduced. No
standard dose reduction exists for chloramphenicol in liver impairment, and the dose should
be adjusted according to measured plasma concentrations.
The majority of the chloramphenicol dose is excreted by the kidneys as the inactive
metabolite, chloramphenicol glucuronate. Only a tiny fraction of the chloramphenicol is
excreted by the kidneys unchanged. Plasma levels should be monitored in patients with renal
impairment, but this is not mandatory.
Chloramphenicol succinate ester (an intravenous prodrug form) is readily excreted
unchanged by the kidneys, more so than chloramphenicol base, and this is the major reason
why levels of chloramphenicol in the blood are much lower when given intravenously than
orally .Chloramphenicol passes into breast milk, so should therefore be avoided during breast
feeding, if possible.
Dose monitoring:
Plasma levels of chloramphenicol must be monitored in neonates and patients with
abnormal liver function. Plasma levels should be monitored in all children under the age of
four, the elderly, and patients with renal failure.
Because efficacy and toxicity of chloramphenicol are associated with a maximum serum
concentration, peak levels (one hour after the intravenous dose is given) should be 1020
μg/ml with toxicity > 40 μg/ml; trough levels (taken immediately before a dose) should be
510 μg/ml.
Drug interactions:
Administration of chloramphenicol concomitantly with bone marrow depressant drugs is
contraindicated, although concerns over aplastic anaemia associated with ocular
chloramphenicol have largely been discounted.
Chloramphenicol is a potent inhibitor of the cytochrome P450 isoforms CYP2C19 and
CYP3A4 in the liver. Inhibition of CYP2C19 causes decreased metabolism and therefore
increased levels of, for example, antidepressants, anti-epileptics, proton pump inhibitors, and
anticoagulants if they are given concomitantly.
Inhibition of CYP3A4 causes increased levels of, for example, calcium channel blockers,
immune-suppressants, chemotherapeutic drugs, benzodiazepines, azole antifungals, tricyclic

38
antidepressants, macrolide antibiotics, SSRIs, statins, cardiac anti-arrhythmics, antivirals,
anticoagulants, and PDE5 inhibitors.
Drug antagonistic:
Chloramphenicol is antagonistic with most Cephalosporins and using both together should be
avoided in the treatment of infections.
Cotrimoxazole:
Costs less than 25 USD.
It was effective in typhoid till plasmid mediated multidrug resistance spread among S. typhi.
Now it is rarely used.

39
4.Ampicillin/amoxicillin:
These antibiotics are no longer dependable therapy for typhoid because of multi-drug
resistance. Response rate is low and defervescence takes longer even in patients who respond.
Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in
bacteri-cidal activity against susceptible bacteria. At least as effective as chloramphenicol in
rapidity of defer-vescence and relapse rate.
Convalescence carriage occurs less commonly than with other agents whenorganisms are
fully susceptible. Usually given PO with a daily dose of 75-100 mg/kg tid (three times a day)
for 14 d.
2. Combination therapy:
There is no evidence that combination of any two or more AMAs is better than the single
drug to which the infecting strain of S. typhi is responsive
Prevention:-
In many developing nations, the public health goals that can help prevent and control
typhoid fever - safe drinking water, improved sanitation and adequate medical care may be
difficult to achieve.
For that reason, some experts believe that vaccinating high-risk populations is the best way to
control typhoid fever.A vaccine is recommended if you're traveling to areas where the risk of
getting typhoid fever is high.
Vaccines:
Two vaccines are available.

40
One is injected in a single dose at least one week before travel. One is given orally in four
capsules, with one capsule to be taken every other day.
Neither vaccine is 100 percent effective and both require repeat immunizations, as vaccine
effectiveness diminishes over time. Because the vaccine won't provide complete protection,
follow these guidelines when traveling to high-risk areas:
Wash your hands:
Frequent hand-washing in hot, soapy water is the best way to control infection. Wash
before eating or preparing food and after using the toilet. Carry an alcohol-based hand
sanitizer for times when water isn't available.
Avoid drinking untreated water.
Contaminated drinking water is a particular problem in areas where typhoid fever is
endemic. For that reason, drink only bottled water or canned or bottled carbonated beverages,
wine and beer. Carbonated bottled water is safer than uncarbonated bottled water is ask for
drinks without ice. Use bottled water to brush your teeth, and try not to swallow water in the
shower.
Avoid raw fruits and vegetables.
Because raw produce may have been washed in unsafe water, avoid fruits and vegetables
that you can't peel, especially lettuce. To be absolutely safe, you may want to avoid raw foods
entirely.
Choose hot foods.
Avoid food that's stored or served at room temperature. Steaming hot foods are best. And
although there's no guarantee that meals served at the finest restaurants are safe, it's best to
avoid food from street vendors it's more likely to be contaminated.

41
Prevent infecting others:
If you're recovering from typhoid fever, these measures can help keep others safe.
Take your antibiotics.
Follow your doctor's instructions for taking your antibiotics, and be sure to finish the entire
prescription.
Wash your hands often.
This is the single most important thing you can do to keep from spreading the infection to
others. Use hot, soapy water and scrub thoroughly for at least 30 seconds, especially before
eating and after using the toilet.
Avoid handling food.
Avoid preparing food for others until your doctor says you're no longer contagious. If you
work in the food service industry or a health care facility, you won't be allowed to return to
work until tests show that you're no longer shedding typhoid bacteria.
Treatment of Typhoid Fever:
General management Supportive measures are important in the management of typhoid
fever, such as oral or intravenous hydration, the use of antipyretics, and appropriate nutrition
and blood transfusions if indicated.
More than 90% of patients can be managed at home with oral antibiotics, reliable care and
close medical follow-up for complications or failure to respond to therapy . However,
patients with persistent vomiting, severe diarrhoea and abdominal distension may require
hospitalization and parenteral antibiotic therapy.
Antimicrobial therapy Efficacy, availability and cost are important criteria for the selection of
first-line antibiotics to be used in developing countries. This section reviews the therapeutic
guidelines for the treatment of typhoid fever across all age groups. It should be noted,
however, that therapeutic strategies for children, e.g. the choice of antibiotics, the dosage
regimen and the duration of therapy, may differ from those for adults.

42
The fluoro-quinolones are widely regarded as optimal for the treatment of typhoid fever in
adults. They are relatively inexpensive, well tolerated and more rapidly and reliably effective
than the former first-line drugs, viz. chloramphenicol, ampicillin, amoxicillin and
trimethoprim-sulfamethoxazole.
The majority of isolates are still sensitive. The fluoro-quinolones attain excellent tissue
penetration, kill S. typhi in its intracellular stationary stage in monocytes/macrophages and
achieve higher active drug levels in the gall bladder than other drugs.
They produce a rapid therapeutic response, i.e. clearance of fever and symptoms in three to
five days, and very low rates of post-treatment carriage . Evidence from various settings in
Asia indicates that the fluoroquinolones are equally effective in the treatment of typhoid fever
in children.
How-ever, the emergence of MDR strains has reduced the choice of antibiotics in many
areas. There are two categories of drug resistance: resistance to antibiotics such as
chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole (MDR strains) and
resistance to the fluoroquinolone drugs.
Resistance to the fluoroquinolones may be total or partial. The so-called nalidixic-acid-
resistant S. typhi (NARST) is a marker of reduced susceptibility to fluoroquinolones
compared with nalidixic-acid-sensitive strains.
Nalidixic acid itself is never used for the treatment of typhoid. These isolates are susceptible
to fluoroquinolones in disc sensitivity testing according to current guidelines. However, the
clinical response to treatment with fluoroquinolones of nalidixic-acid-resistant strains is
significantly worse than with nalidixic-acid-senstive strains.
There is a significant number of MDR strains from the Indian subcontinent 20 The diagnosis,
treatment and prevention of typhoid fever and some other Asian countries (not Indonesia). S.
typhi has recently emerged as a problem in Kenya.
Nalidixic acid resistant strains are now endemic in many areas of Viet Nam and have also
been reported from the Indian subcontinent and Tajikistan. There are disturbing recent reports
of the emergence of fluorquinolone-resistant isolates in various parts of Asia and there have
been a few reports of resistance to third-generation cephalopsorins in the same region.
Reassuringly, however, many of these reports are coupled with evidence of the re-emergence
of sensitive isolates in the same regions.
The available fluoroquinolones (ofloxacin, ciprofloxacin, fleroxacin, perfloxacin) are highly
active and equivalent in efficacy (with the exception of norfloxacin which has inadequate oral

43
bioavailability and should not be used in typhoid fever). The fluoroquinolone drugs are
generally very well tolerated.
However, in some countries the use of fluoroquinolones is relatively contraindicated in
children because of concerns that they may cause articular damage. These agents are not
registered for routine use in children. The concerns have arisen because of evidence of
articular damage in growing, weight-bearing joints in beagles.
There is now extensive experience in the use of these drugs in large numbers of children with
a variety of conditions, often with long-term follow-up (cystic fibrosis, typhoid), and in the
extensive use of short courses of fluoroquinolones in children for the treatment of both
typhoid fever and bacillary dysentery.
Their considerable benefits, particularly in areas where there are no affordable oral
alternatives, outweigh the putative risk. The only known articular side-effect is Achilles
tendon rupture in patients who are also taking corticosteroids, and this has been reported only
rarely. Ciprofloxacin, ofloxacin, perfloxacin and fleroxacin have generally proved effective.
In recent years, however, there have been many reports of reduced susceptibility and
treatment failure for ciprofloxacin.
No evidence of toxicity and impact on growth has been described in children with typhoid
who have received ciprofloxacin. There is no evidence of the superiority of any particular
fluoroquinolone. Nalidixic acid and norfloxacin do not achieve adequate blood
concentrations after oral WHO/V&B/03.07 21 administration and should not be used.
For nalidixic-acid-sensitive S. typhi, seven-day regimens have proved highly effective.
Courses of treatment of three and five days have also proved highly effective against
nalidixic-acid-sensitive strains. These very short courses are best reserved for outbreaks when
antibiotics are in short supply.
For nalidixic-acid-resistant infections a minimum of seven days of treatment at the maximum
permitted dosage is necessary and 1014 days are usually required. Courses shorter than seven
days are unsatisfactory. Chloramphenicol, despite the risk of a granulocytosis in 1 per 10 000
patients, is still widely prescribed in developing countries for the treatment of typhoid fever.
S. typhi strains from many areas of the world, e.g. most countries in Africa and Asia, remain
sensitive to this drug and it is widely available in most primary care settings in developing
countries for the treatment of pneumonia.

44
The disadvantages of using chloramphenicol include a relatively high rate of relapse (7%),
long treatment courses (14 days) and the frequent development of a carrier state in adults.
The recommended dosage is 50-75 mg per kg per day for 14 days divided into four doses per
day, or for at least five to seven days after defervescence.
The usual adult dose is 500 mg given four times a day. Oral administration gives slightly
greater bioavailability than intramuscular (i.m.) or intravenous (i.v.) administration of the
succinate salt. Ampicillin and amoxicillin are used at 50 to 100 mg per kg per day orally, i.m.
or i.v., divided into three or four doses.
No benefit has been reported to result from the addition of clavulanic acid to amoxicillin.
Trimethoprim-sulfamethoxazole, (TMPSMZ) can be used orally or i.v. in adults at a dose of
160 mg TMP plus 800 mg SMZ twice daily or in children at 4 mg TMP per kg and 20 mg
SMZ per kg for 14 days. Of the third-generation cephalosporins, oral cefixime (1520 mg per
kg per day for adults, 100-200 mg twice daily) has been widely used in children in a variety
of geographical settings and found to be satisfactory.
However, a trial of cefixime in MDR typhoid in Viet Nam indicated significantly higher
treatment failure rates than with ofloxacin. Other agents, e.g. cefodoxime, have proved
successful against typhoid fever. Because of the rising rates of quinolone resistance there is a
clear need to identify improved strategies for treating MDR typhoid in childhood.
Recent data on the use of azithromycin in children indicate that it may be safely given as an
alternative agent for the treatment of uncomplicated typhoid fever. Azithromycin in a dose of
500 mg (10 mg/kg) given once daily for seven days has proved effective in the treatment of
typhoid fever in adults and children with defervescence times similar to those reported for
chloramphenicol.
A dose of 1 g per day for five days was also effective in adults . If intravenous antibiotics are
required, i.v. cephalosporins can be given in the following doses: ceftriaxone, 50-75
mg/kg/day (2-4 g/day for adults) in one or two doses; cefotaxime, 40-80 mg/kg/day (24 g/day
for adults) in two or three doses; and cefoperazone, 50-100 mg per kg per day (2-4 g/day for
adults) in two doses.
Ciprofloxacin, ofloxacin and pefloxacin are also available for i.v. use. The diagnosis,
treatment and prevention of typhoid fever There are few data on the treatment of typhoid in
pregnancy. The beta-lactams are considered safe. There have been several case reports of the
successful use of fluoroquinolones but these have generally not been recommended in
pregnancy because of safety concerns.

45
Ampicillin is safe in pregnant or nursing women, as is ceftriaxone in such women with severe
or MDR disease. Although there are no data indicating that azithromycin is unsafe for
pregnant or nursing women, alternatives should be used if available. Most of the data from
randomized controlled trials relate to patients treated in regions of endemicity.
There are few data from such trials relating to patients treated in regions where the disease is
not endemic or to returning travellers. Knowledge of the antibiotic sensitivity of the infecting
strain is crucial in determining drug choice. If no culture is available a knowledge of likely
sensitivity as indicated by the available global data may be useful.
The evidence suggests that the fluoroquinolones are the optimal choice for the treatment of
typhoid fever in adults and that they may also be used in children.
The recent emergence of resistance to fluoroquinolones, however, suggests that their
widespread and indiscriminate use in primary care settings should be restricted.
In areas of the world where the fluoroquinolones are not available or not registered for public
health use and where the bacterium is still fully sensitive to traditonal first-line drugs
(chloramphenicol, amoxicillin or Trimethoprimsulfamethoxazole), these remain appropriate
for the treatment of typhoid fever.
Antibiotic therapy is the only effective treatment for typhoid fever
– Ciprofloxacin
– Ceftriaxone
Supportive therapy:
Drinking fluids helps prevent the dehydration that results from a prolonged fever and
diarrhea. Healthy diet. Non bulky, high-calorie meals help replace the nutrients patients lose
when they’re sick.
The rediscovery of oral rehydration therapy in the 1960s provided a simple way to prevent
many of the deaths of diarrheal diseases in general. 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. Cefiximes is a
suitable oral alternative.
Antibiotics,such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, amoxicillin,
and ciprofloxacin, have been commonly used to treat typhoid fever in microbiology.

46
PATIENT REPORT:
Patient name: Dhananjay
Age: 15 year
Sex: Male

47
Patient name: Sunil kumar
Age: 19 Year
Sex: Male

48
Patient name: Raj Kumar
Age: 63 Year
Sex: male

49
Recent drugs for typhoid:
s.n. Drug Dose/mg Form %
1 Biomax-o 200 Tablet 30 %
2 Cefanz-o 200 Tablet 35 %
3 Monocef 1000 Injection 60 %
4 Ciprofloxacin 500 Tablet 54 %
5 Ibugesic plus 500 Tablet 55 %
1 Gudcef plus 200 Tablet 65 %
2 Taxime 500 Injection 60 %
3 Ciplox-500 500 Tablet 55 %
4 Ciprovit 500 Tablet 45 %
5 Cefotim 200 Tablet 55 %
1 Mahacef plus 200 Tablet 70 %
2 alltaxim 500 Injection 40 %
3 Zenflox plus 200 Tablet 60 %
4 Cefpo-of 200 Tablet 40 %
5 Cefdac plus 200 Tablet 45 %

50
1 Kemtrax 250 Injection 30 %
2 Metacef 1000 Injection 55 %
3 Alcidox 200 Tablet 45 %
4 Tambac 100/200 Tablet 50 %
5 Bioxime-ox 200 Tablet 40 %

51
Conclusion:
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 awits the provision of sanitary water supply and proper
disposal of human sewage. Its eradication would probably be accelerated by programs of
mass vaccination in endemic region. 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 patient with intestinal perforation and other complication.
Typhoid fever remains a major public health problems in India. The infection can be
prevented by good sanitation, improving good water supply the provision of proper sewage
disposal system, as well as the effective use of the available typhoid vaccines. The
government and people should rise up to the challenge of stamping out this ugly trend.

52
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