Background

Typhoid fever is a systemic infection with the bacterium Salmonella enterica serotype
typhi. This highly adapted, human-specific pathogen has evolved remarkable
mechanisms for persistence in its host that help to ensure its survival and
transmission. Typhoid fever was an important cause of illness and death in the
overcrowded and unsanitary urban conditions of the United States and Europe in the
19th century.1
The provision of clean water and good sewage systems led to a dramatic
decrease in the incidence of typhoid in these regions. Today most of the burden of the
disease occurs in the developing world, where sanitary conditions remain poor.
Reliable data from which to estimate the burden of disease in these areas are difficult
to obtain, since many hospitals lack facilities for blood culture and up to 90 percent of
patients with typhoid are treated as outpatients. Community based studies have
consistently shown higher levels of typhoid than public health figures suggest.
Annual incidence rates of 198 per 100,000 in the Mekong Delta region of Vietnam
and 980 per 100,000 in Delhi, India,2 have recently been reported. Annual incidence
rates of 900,000 cases/year with > 20,000 deaths are found in Indonesia. 91% of
cases are found in the age range of 3-19 years old.3
According to the best global estimates, there are at least 16 million new cases
of typhoid fever each year, with 600,000 deaths. The introduction of chloramphenicol
for the treatment of typhoid fever in 1948 transformed a severe, debilitating, and
often fatal disease into a readily treatable condition. 4 The emergence of resistance to
chloramphenicol and other antimicrobial agents has been a major setback. 5 We now
face the very real prospect that untreatable typhoid fever will reemerge.
Typhoid is usually contracted by ingestion of food or water contaminated by
fecal or urinary carriers excreting S. enterica serotype typhi. It is a sporadic disease in
developed countries that occurs mainly in returning travelers, with occasional point-

source epidemics.6 In endemic areas, identified risk factors for disease include eating
food prepared outside the home, such as ice cream or flavored iced drinks from street
vendors, drinking contaminated water, having a close contact or relative with recent
typhoid fever, poor housing with inadequate facilities for personal hygiene, and
recent use of antimicrobial drugs.7
Objective
This paper is completed in order to fulfill one of the requirements in the
Senior Clinical Assistance program in Department of Child Health of Haji Adam
Malik General Hospital, University of North Sumatera. In addition, the aim this
paper is to explore more about the theoretical aspects on typhoid fever in 6 years old
child , and to integrate the theory and application of typhoid fever in daily life.
LITERATURE REVIEW
Typhoid Fever
Definition
Typhoid fever is an acute illness associated with fever caused by the
Salmonella typhi bacteria. It can also be caused by Salmonella paratyphi, a related
bacterium that usually causes a less severe illness. The bacteria are deposited in water
or food by a human carrier and are then spread to other people in the area.7
Epidemiology
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 600 000 associated deaths occur annually. However, the estimates
have been biased because study populations have usually been in areas of high
incidence.4
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, between 45 per 100 000 per year and over 1000 per 100 000 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.5 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 A than by S. typhi.2
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.7
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.8 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 bacteraemic 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.3
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 100 000 inhabitants was
found.9
Etiology
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,B,C. Salmonella 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.10
Typhoidal salmonella have no non-human vectors. An inoculum as small as
100,000 organisms of typhi causes infection in more than 50% of healthy volunteers.
Paratyphi requires a much higher inoculum to infect, and it is less endemic in rural
areas. Hence, the patterns of transmission are slightly different.
The following are modes of transmission of typhoidal salmonella:

Oral transmission via food or beverages handled by an often asymptomatic

individuala carrierwho chronically sheds the bacteria through stool or,
less commonly, urine

Hand-to-mouth transmission after using a contaminated toilet and neglecting

hand hygiene

Oral transmission via sewage-contaminated water or shellfish (especially in

the developing world). 11
Paratyphi is more commonly transmitted in food from street vendors. It is

believed that some such foods provide a friendly environment for the microbe.
Paratyphi is more common among newcomers to urban areas, probably because they
tend to be immunologically nave to it. Also, travellers get little or no protection
against paratyphi from the current typhoid vaccines, all of which targettyphi.12
Typhoidal salmonella are able to survive a stomach pH as low as 1.5. Antacids,
histamine-2 receptor antagonists (H2 blockers), proton pump inhibitors, gastrectomy,
and achlorhydria decrease stomach acidity and facilitate S. typhi infection.4

HIV/AIDS is

clearly

associated

with

an

increased

risk

of

non

typhoidal Salmonella infection; however, the data and opinions in the literature as to
whether this is true for S typhi or paratyphi infection are conflicting. If an association
exists, it is probably minor.13
Other risk factors for typhoid fever include various genetic polymorphisms.
These risk factors often also predispose to other intracellular pathogens. For instance,
PARK2 and PACGR code for a protein aggregate that is essential for breaking down
the bacterial signaling molecules that dampen the macrophage response.
Polymorphisms in their shared regulatory region are found disproportionately in
persons infected with Mycobacterium leprae and S typhi.11
On the other hand, protective host mutations also exist. The fimbriae of S
typhi bind in vitro to cystic fibrosis transmembrane conductance receptor (CFTR),
which is expressed on the gut membrane. Two to 5% of white persons are
heterozygous for the CFTR mutation F508del, which is associated with a decreased
susceptibility to typhoid fever, as well as to cholera and tuberculosis. The
homozygous F508del mutation in CFTR is associated with cystic fibrosis. Thus,
typhoid fever may contribute to evolutionary pressure that maintains a steady
occurrence of cystic fibrosis, just as malaria maintains sickle cell disease in Africa.14
As the middle class in south Asia grows, some hospitals there are seeing a
large number of typhoid fever cases among relatively well-off university students
who live in group households with poor hygiene.14
Pathophysiology
The infectious dose of S. enterica serotype typhi in volunteers varies between 1000
and 1 million organisms. Vi-negative strains of S. enterica serotype typhi are less
infectious and less virulent than Vi-positive strains. S. enterica serotype typhi must
survive the gastric acid barrier to reach the small intestine, and a low gastric pH is an
important defense mechanism. Achlorhydria as a result of aging, previous

gastrectomy, or treatment with histamine H2-receptor antagonists, proton-pump

inhibitors, or large amounts of antacids lowers the infective dose. 4 In the small
intestine, the bacteria adhere to mucosal cells and then invade the mucosa. The M
cells, specialized epithelial cells overlying Peyers patches, are probably the site of
the internalization of S. enterica serotype typhi and its transport to the underlying
lymphoid tissue. After penetration, the invading microorganisms translocate to the
intestinal lymphoid follicles and the draining mesenteric lymph nodes, and some pass
on to the reticuloendothelial cells of the liver and spleen.15
Salmonella organisms are able to survive and multiply within the
mononuclear phagocytic cells of the lymphoid follicles, liver, and spleen. At a critical
point that is probably determined by the number of bacteria, their virulence, and the
host response, bacteria are released from this sequestered intracellular habitat into the
bloodstream. The incubation period is usually 7 to 14 days. 11 In the bacteremic phase,
the organism is widely disseminated. The most common sites of secondary infection
are the liver, spleen, bone marrow, gallbladder, and Peyers patches of the terminal
ileum. Gallbladder invasion occurs either directly from the blood or by retrograde
spread from the bile. Organisms excreted in the bile either reinvade the intestinal wall
or are excreted in the feces.4
Counts of bacteria in patients with acute typhoid fever indicate a median
concentration of 1 bacterium per milliliter of blood (about 66 percent of which are
inside phagocytic cells) and about 10 bacteria per milliliter of bone marrow. Even
though S. enterica serotype typhi produces a potent endotoxin, mortality from treated
typhoid fever for patients at this stage is less than 1 percent. Studies have shown
increased levels of circulating proinflammatory and antiinflammatory cytokines in
patients with typhoid and a reduced capacity of whole blood to produce inflammatory
cytokines in patients with severe disease. Typhoid induces systemic and local
humoral and cellular immune responses, but these confer incomplete protection
against relapse and reinfection. The interaction of host immunologic mediators and

bacterial factors in infected tissue may contribute to the necrosis of Peyers patches in
severe disease.11
The evidence for an association between typhoid and infection with the
human immunodeficiency virus (HIV) is conflicting, whereas there is a large increase
in the incidence of non-typhi salmonella bacteremia in HIV infection.16
All pathogenic Salmonella species, when present in the gut are engulfed by
phagocytic cells, which then pass them through the mucosa and present them to the
macrophages in the lamina propria. Non-typhoidal salmonellae are phagocytized
throughout the distal ileum and colon. With toll-like receptor (TLR)5 and TLR4/MD2/CD-14 complex, macrophages recognize pathogen-associated molecular
patterns (PAMPs) such as flagella and lipopolysaccharides. Macrophages and
intestinal epithelial cells then attract T cells and neutrophils with interleukin 8 (IL-8),
causing inflammation and suppressing the infection.4
In contrast to the non typhoidal salmonellae, S typhi and paratyphi enter the host's
system primarily through the distal ileum. They have specialized fimbriae that adhere
to the epithelium over clusters of lymphoid tissue in the ileum (Peyer patches), the
main relay point for macrophages traveling from the gut into the lymphatic system.
The bacteria then induce their host macrophages to attract more macrophages. 3S
typhi has a Vi capsular antigen that masks PAMPs, avoiding neutrophil-based
inflammation, while the most common paratyphi serovar, paratyphi A, does not. This
may explain the greater infectivity of typhi compared with most of its cousins.5
Typhoidal salmonella co-opt the macrophages' cellular machinery for their
own reproduction as they are carried through the mesenteric lymph nodes to the
thoracic duct and the lymphatics and then through to the reticuloendothelial tissues of
the liver, spleen, bone marrow, and lymph nodes. Once there, they pause and continue
to multiply until some critical density is reached. Afterward, the bacteria induce
macrophage apoptosis, breaking out into the bloodstream to invade the rest of the
body. The bacteria then infect the gallbladder via either bacteremia or direct extension

of infected bile. The result is that the organism re-enters the gastrointestinal tract in
the bile and reinfects Peyer patches. Bacteria that do not reinfect the host are typically
shed in the stool and are then available to infect other hosts. 4
Chronic carriers are responsible for much of the transmission of the organism.
While asymptomatic, they may continue to shed bacteria in their stool for decades.
The organisms sequester themselves either as a biofilm on gallstones or gallbladder
epithelium or, perhaps, intracellularly, within the epithelium itself. The bacteria
excreted by a single carrier may have multiple genotypes, making it difficult to trace
an outbreak to its origin.10
Clinical Manifestations
The clinical manifestations and severity of typhoid fever vary with the patient
population studied. Most patients who present to hospitals with typhoid fever are
children or young adults from 5 to 25 years of age. 1 However, community-based
studies in areas of endemic disease indicate that many patients with typhoid,
particularly children under five years of age, may have a nonspecific illness that is
not recognized clinically as typhoid.9
Between 60 and 90 percent of people with typhoid do not receive medical
attention or are treated as outpatients. After a person ingests S. enterica serotype
typhi, an asymptomatic period follows that usually lasts 7 to 14 days (range, 3 to 60).
The onset of bacteremia is marked by fever and malaise. Patients typically present to
the hospital toward the end of the first week after the onset of symptoms with fever,
influenza-like symptoms with chills (although rigors are rare), a dull frontal
headache, malaise, anorexia, nausea, poorly localized abdominal discomfort, a dry
cough, and myalgia, but with few physical signs.11
A coated tongue, tender abdomen, hepatomegaly, and splenomegaly are
common. A relative bradycardia is considered common in typhoid, although in many
geographic areas this has not been a consistent feature. Adults often have
constipation, but in young children and in adults with HIV infection, diarrhea is more

common. It is unusual for a patient hospitalized with typhoid to have no abdominal

symptoms and normal bowel movements. Initially the fever is low grade, but it rises
progressively, and by the second week it is often high and sustained (39 to 40C). 4 A
few rose spots, blanching erythematous maculopapular lesions approximately 2 to 4
mm in diameter, are reported in 5 to 30 percent of cases. They usually occur on the
abdomen and chest and more rarely on the back, arms, and legs. These lesions are
easily missed in dark-skinned patients.
There may be a history of intermittent confusion, and many patients have a
characteristic apathetic affect. Convulsions may occur in children under five years of
age. The hemoglobin level, white-cell count, and platelet count are usually normal or
reduced. Disseminated intravascular coagulation may be revealed by laboratory tests,
but it is very rarely of clinical significance. The levels of liver enzymes are usually
two to three times the upper limit of normal.1
Relapse occurs in 5 to 10 percent of patients, usually two to three weeks after the
resolution of fever. The relapse is usually milder than the original attack, and the S.
enterica serotype typhi isolate from a patient in relapse usually has the same
antibiotic-susceptibility pattern as the isolate obtained from the patient during the
original episode.
Reinfection may also occur and can be distinguished from relapse by
molecular typing. Up to 10 percent of convalescing patients with untreated typhoid
excrete S. enterica serotype typhi in the feces for up to three months; 75 percent
become long-term carriers, excreting the organism for more than one year. Up to 25
percent of longterm carriers have no history of typhoid. Chronic carriage is more
common among women and the elderly and in patients with cholelithiasis.12

Diagnosis

10

The absence of specific symptoms or signs makes the clinical diagnosis of typhoid
difficult. In areas of endemic disease, a fever without evident cause that lasts more
than one week should be considered typhoid until proved otherwise. Blood cultures
are the standard diagnostic method; provided a large volume of blood is cultured (15
ml in adults), they are positive in 60 to 80 percent of patients with typhoid. Culture of
bone marrow is more sensitive. The result is positive in 80 to 95 percent of patients
with typhoid, even patients who have been taking antibiotics for several days,
regardless of the duration of illness.11
Blood cultures are less sensitive than bone marrow cultures because of the
lower numbers of microorganisms in blood as compared with bone marrow.The
sensitivity of blood culture is higher in the first week of the illness, is reduced by
prior use of antibiotics, and increases with the volume of blood cultured and the ratio
of blood to broth. Cultures have also been made from the buffy coat of blood,
streptokinase-treated blood clots, iintestinal secretions (with the use of a duodenal
string capsule), and skin snips of rose spots. The sensitivity of stool culture depends
on the amount of feces cultured, and the positivity rate increases with the duration of
the illness.12
Stool cultures are positive in 30 percent of patients with acute typhoid fever.
For the detection of carriers, several samples should be examined because of the
irregular nature of shedding. The role of Widals test is controversial, because the
sensitivity, specificity, and predictive values of this widely used test vary
considerably among geographic areas. The test detects agglutinating antibodies to the
O and H antigens of S. enterica serotype typhi.11
Unfortunately, S. enterica serotype typhi shares these antigens with other salmonella
serotypes and shares cross-reacting epitopes with other Enterobacteriaceae.
Furthermore, patients with typhoid may mount no detectable antibody
response or have no demonstrable rise in antibody titer. Despite this, some centers
have found Widals test helpful when it is used with locally determined cutoff points.

11

A Vi agglutination reaction has been used to screen for S. enterica serotype typhi
carriers. Its reported sensitivity is 70 to 80 percent, with a specificity of 80 to 95
percent. Newer serologic tests are being developed but do not yet perform well
enough to ensure their widespread adoption.11
DNA probes and polymerase-chain-reaction protocols have been developed to detect
S. enterica serotype typhi directly in the blood. The methods are not yet widely used
and are impractical in many areas where typhoid is common.15

Confirmed case of typhoid fever = A patient with fever (38C 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 (38C and above) that
has lasted for at least three days, with a positive serodiagnosis 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.

Differential diagnosis
Typhoid must be distinguished from other endemic acute and subacute febrile
illnesses. Malaria, deep abscesses, tuberculosis, amebic liver abscess, encephalitis,
influenza, dengue, leptospirosis, infectious mononucleosis, endocarditis, brucellosis,
typhus, visceral leishmaniasis, toxoplasmosis, lymphoproliferative disease, and
connective-tissue diseases should be considered.4 For patients in countries where
typhoid is not endemic, a travel history is crucial.1

Treatment
General management

12

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.17
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, for example, the
choice of antibiotics, the dosage regimen and the duration of therapy, may differ from
those for adults.
The fluoroquinolones 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,

chloramphenicol,

ampicillin, amoxicillin and trimethoprim-sulfamethoxazole. The majority of isolates

are still sensitive.
The fluoroquinolones 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, for example clearance of fever and symptoms in three to five days, and very
low rates of post-treatment carriage.5
Evidence from various settings in Asia indicates that the fluoroquinolones are
equally effective in the treatment of typhoid fever in children. However, 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

13

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
guidelines6.
Chloramphenicol, despite the risk of agranulocytosis in 1 per 10 000 patients,
is still widely prescribed in developing countries for the treatment of typhoid fever.
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. The disadvantages of using chloramphenicol include a relatively high
rate of relapse (5-7%), 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. Trimethoprim-sulfamethoxazole, (TMP-SMZ) 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.18
Of the third-generation cephalosporins, oral cefixime (15-20 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.18 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

14

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 per kg per day (2-4 g per day for adults)
in one or two doses; cefotaxime, 40-80 mg per kg per day (2-4 g per day for adults) in
two or three doses; and cefoperazone, 50-100 mg per kg per day (2-4 g per day for
adults) in two doses. Ciprofloxacin, ofloxacin and pefloxacin are also available for
i.v. use.19
Treatment of typhoid in pregnancy
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. 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.20 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

trimethoprim-

sulfamethoxazole), these remain appropriate for the treatment of typhoid fever. They
are inexpensive, widely available and rarely associated with side-effects.18
Management of carriers.

15

An individual is considered to be a chronic carrier if he or she is asymptomatic and

continues to have positive stool or rectal swab cultures for S. typhi a year following
recovery from acute illness. Overall, some 1-5% of typhoid fever patients become
chronic carriers. The rate of carriage is slightly higher among female patients,
patients older than 50 years, and patients with cholelithiasis or schistosomiasis. If
cholelithiasis or schistosomiasis is present the patient probably requires
cholecystectomy or antiparasitic medication in addition to antibiotics in order to
achieve bacteriological cure. In order to eradicate S. typhi carriage, amoxicillin or
ampicillin (100 mg per kg per day) plus probenecid (Benemid) (1 g orally or 23 mg
per kg for children)or TMP-SMZ (160 to 800 mg twice daily) is administered for six
weeks; about 60% of persons treated with either regimen can be expected to have
negative cultures on follow-up.
Clearance of up to 80% of chronic carriers can be achieved with the
administration of 750 mg of ciprofloxacin twice daily for 28 days or 400 mg of
norfloxacin. Other quinolone drugs may yield similar results. Vi antibody
determination has been used as a screening technique to identify carriers among food
handlers and in outbreak investigations. Vi antibodies are very high in chronic S.
typhi carriers.10
Management of complications
Management of complications are both outpatients and inpatients with typhoid fever
should be closely monitored for the development of complications. Timely
intervention can prevent or reduce morbidity and mortality. The parenteral
fluoroquinolones are probably the antibiotics of choice for severe infections but there
have been no randomized antibiotic trials. In severe typhoid the fluoroquinolones are
given for a minimum of 10 days.
Typhoid fever patients with changes in mental status, characterized by
delirium, obtundation and stupor, should be immediately evaluated for meningitis by
examination of the cerebrospinal fluid. If the findings are normal and typhoid

16

meningitis is suspected, adults and children should immediately be treated with highdose intravenous dexamethasone in addition to antimicrobials. If dexamethasone is
given in an initial dose of 3 mg/kg by slow i.v. infusion over 30 minutes and if, after
six hours, 1 mg/kg is administered and subsequently repeated at six-hourly intervals
on seven further occasions, mortality can be reduced by some 80-90% in these highrisk patients.
Hydrocortisone in a lower dose is not effective. High-dose steroid treatment
can be given before the results of typhoid blood cultures are available if other causes
of severe disease are unlikely.12
Patients with intestinal haemorrhage need intensive care, monitoring and
blood transfusion. Intervention is not needed unless there is significant blood loss.
Surgical consultation for suspected intestinal perforation is indicated. If perforation is
confirmed, surgical repair should not be delayed longer than six hours. Metronidazole
and gentamicin or ceftriazone should be administered before and after surgery if a
fluoroquinolone is not being used to treat leakage of intestinal bacteria into the
abdominal cavity. Early intervention is crucial, and mortality rates increase as the
delay between perforation and surgery lengthens. Mortality rates vary between 10%
and 32%.
Relapses involving acute illness occur in 5-20% of typhoid fever cases that
have apparently been treated successfully. A relapse is heralded by the return of fever
soon after the completion of antibiotic treatment. The clinical manifestation is
frequently milder than the initial illness. Cultures should be obtained and standard
treatment should be administered. In the event of a relapse the absence of
schistosomiasis should be confirmed.11

Complication

17

Complications occur in 10 to 15 percent of patients and are particularly likely in

patients who have been ill for more than two weeks. Many complications have been
described (Table 1),of which gastrointestinal bleeding, intestinal perforation, and
typhoid encephalopathy are the most important. Gastrointestinal bleeding is the most
common, occurring in up to 10 percent of patients. It results from erosion of a
necrotic Peyers patch through the wall of an enteric vessel. In the majority of cases,
the bleeding is slight and resolves without the need for blood transfusion, but in 2
percent of cases, bleeding is clinically significant and can be rapidly fatal if a large
vessel is involved. Intestinal (usually ileal) perforation is the most serious
complication, occurring in 1 to 3 percent of hospitalized patients. Perforation may be
manifested by an acute abdomen or, more covertly, by simple worsening of
abdominal pain, rising pulse, and falling blood pressure in an already sick patient.1
A reduced level of consciousness or encephalopathy, often accompanied by
shock, is associated with high mortality.The patient is commonly apathetic although
rousable. Patients can be severely agitated, delirious, or obtunded, but complete
stupor or coma is infrequent. The incidence of these neuropsychiatric presentations
varies among countries. It ranges from 10 to 40 percent among hospitalized patients
with typhoid in Indonesia13 and Papua New Guinea but is less than 2 percent in
Pakistan and Vietnam.2 This geographic variation is unexplained. Typhoid fever
during pregnancy may be complicated by miscarriage, although antimicrobial
treatment has made this outcome less common. Vertical intrauterine transmission
from an infected mother may lead to neonatal typhoid, a rare but severe and lifethreatening illness.20

Table 1. Important Complications Of Typhoid Fever.

Abdominal

1.Gastrointestinal

perforation

2.Gastrointestinal hemorrhage
3.Hepatitis

Cholecystitis

(usually

18

Cardiovascular

subclinical)
1.Asymptomatic

electrocardiographic

changes
2.Myocarditis
Neuropsychiatric

3.Shock
1.Encephalopathy
2.Delirium
3.Psychotic states
4.Meningitis

Respiratory

5.Impairment of coordination
1.Bronchitis
2.Pneumonia

Hematologic

(Salmonella

Streptococcus pneumoniae)
1.Anemia
2.Disseminated

Other

typhi,

intravascular

coagulation (usually subclinical)

1.Focal abscess
2.Pharyngitis
3.Miscarriage
4.Relapse
5.Chronic carriage

Prevention
The major routes of transmission of typhoid fever are through drinking water or
eating food contaminated with Salmonella typhi. Prevention is based on ensuring
access to safe water and by promoting safe food handling practices. Health education
is paramount to raise public awareness and induce behaviour change.9

19

Typhoid fever is a waterborne disease and the main preventive measure is to

ensure access to safe water. The water needs to be of good quality and must be
sufficient to supply all the community with enough drinking water as well as for all
other domestic purposes such as cooking and washing. During outbreaks the
following control measures are of particular interest: In urban areas, control and
treatment of the water supply systems must be strengthened from catchment to
consumer. Safe drinking water should be made available to the population trough a
piped system or from tanker trucks.
In rural areas, wells must be checked for pathogens and treated if necessary.
At home, a particular attention must be paid to the disinfection and the storage of the
water however safe its source. Drinking-water can be made safe by boiling it for one
minute or by adding a chlorine-releasing chemical. Narrow-mouthed pots with covers
for storing water are helpful in reducing secondary transmission of typhoid fever.
Chlorine is ineffective when water is stored in metallic containers. In some situations,
such as poor rural areas in developing countries or refugee camps, fuel for boiling
water and storage containers may have to be supplied.7
Contaminated food is another important vehicle for typhoid fever
transmission. Appropriate food handling and processing is paramount and the
following basic hygiene measures must be implemented or reinforced during
epidemics: washing hands with soap before preparing or eating food; avoiding raw
food, shellfish, ice; eating only cooked and still hot food or re-heating it.7
Proper sanitation contributes to reducing the risk of transmission of all
diarrhoeal pathogens including Salmonella typhi. Appropriate facilities for human
waste disposal must be available for all the community. In an emergency, pit latrines
can be quickly built. Collection and treatment of sewage, especially during the rainy
season, must be implemented In areas where typhoid fever is known to be present, the
use of human excreta as fertilisers must be discouraged.7

20

Health education is paramount to raise public awareness on all the above

mentioned prevention measures. Health education messages for the vulnerable
communities need to be adapted to local conditions and translated into local
languages. In order to reach communities, all possible means of communication (for
example, media, schools, womens groups, religious groups) must be applied.
Community involvement is the cornerstone of behaviour change with regard to
hygiene and for setting up and maintenance of the needed infrastructures. In health
facilities, all staff must be repeatedly educated about the need for : excellent personal
hygiene at work; isolation measures for the patient; disinfection measure.9
The occurrence of S. typhi strains that are resistant to fluoroquinolones
emphasizes the need to use safe and effective vaccines to prevent typhoid fever.
WHO recommends vaccination for people travelling in high-risk areas where the
disease is endemic. People living in such areas, people in refugee camps,
microbiologists, sewage workers and children should be the target groups for
vaccination.4 The old parenteral killed whole-cell vaccine was effective but produced
strong side-effects because of LPS. Two safe and effective vaccines are now licensed
and available. One is based on defined subunit antigens, the other on whole-cell live
attenuated bacteria.
The first of these vaccines, containing Vi polysaccharide, is given in a single
dose subcutaneous (s.c.) or i.m. Protection begins seven days after injection,
maximum protection being reached 28 days after injection when the highest antibody
concentration is obtained. The vaccine is approved for persons aged over two years. A
protective efficacy of 70% was reported in a population vaccinated before or during
an outbreak situation. The Vi vaccine is licensed in Australia and in more than 92
countries in Africa, the Americas, Asia, and Europe. It is mainly used by travellers
visiting areas at high risk of typhoid fever because of the presence of multidrugresistant strains. There have been a few reports of Vi-negative S. typhi strains.
However, S. typhi strains freshly isolated from the blood of patients have always been

21

Vi-positive. Vaccinated people with Vi can be differentiated from S. typhi carriers

because of the higher level of Vi antibodies in the latter.21
The live oral vaccine Ty2la is available in enteric-coated capsule or liquid
formulation. It should be taken in three doses two days apart on an empty stomach. It
elicits protection as from 10-14 days after the third dose. It is approved for use in
children aged at least 5 years. Travellers should be revaccinated annually. The
protective efficacy of the enteric-coated capsule formulation seven years after the last
dose is still 62% in areas where the disease is endemic; the corresponding figure for
the liquid formulation is 70%.
Antibiotics should be avoided for seven days before or after the immunization
series. This vaccine is licensed in 56 countries in Africa, Asia, Europe, South
America, and the USA. Although the package insert allows simultaneous
administration of mefloquine (Lariam) or chloroquine (Nivaquine or Aralen) for
malaria prophylaxis, it is recommended that an interval of three days be maintained
between the completion of the immunization series and the first dose of mefloquine
or proguanil.21
Prognosis
The prognosis of typhoid fever in children depends among the other factors on the
period elapsing between the onset of symptoms and time of specific therapy.
Generally, untreated typhoid fever carries a mortality rate of 10%-20%. In properly
treated disease, the mortality rate is less than 1%. Treatment started after diagnosis,
mortality was 11%, whereas in another series under similar conditions where the
therapy was given immediately on admission (diagnosis being confirmed by the
laboratory in due course) the mortality was 4%.4
Other factors of important determining the prognosis are the age of the child
and nutritional status. The younger the child and the poorer the nutrition, the higher
the mortality.1

22

CASE REPORT
Objective
The objective of this paper is to report a case of 6 years 2 months old girl with a
diagnosis of Typhoid Fever.
Case

23

RMT, a 6 years 2 months old girl, with 14 kg of BW and 106 cm of BH, came to
pediatric department of infection unit in Haji Adam Malik General Hospital Medan
on April 24th 2015 at 11.45 AM.
Her chief complaint was having fever. Fever was experience since 10 days
ago, fever was not constant, increases during the evening and decreases in the
morning. Fever decreased never reached normal range. No seizures was found as well
as no shivering was found.
Vomiting and nausea was present at the day of admission. The history of
vomiting and nausea was present since 7 days ago. The frequency of vomiting is 3
times a day, with volume half of an aqua glass, with content of food which was eaten,
drink which was taken. Blood was also present.
The history of defecation was 3 days ago, with hard consistency than usual.
No black stool was found. No history of diarrhea was found. The history of urination
was 2 days ago. The colour was more yellowish than usual. The volume of urine was
little. There was no pain found during urination. Stomach pain is present since 10
days ago. The loss of appetite was found and the patient has lost weight than before.
The body weight before this was 15kg.No spontaneous bleeding was found. No
cough and flu was present.
The history of disease was RMT was brought by her mother to Haji Adam
Malik General Hospital Medan complaining having high fever. The mother explained
that the third day of fever, before coming to Haji Adam Malik General Hospital, she
took her child to a midwife. The child was given unknown medication from the
midwife. And yet the fever has not resolved. The history of medication was unclear.
The history of family was RMT is the 3rd child of 3 siblings. History of
parents medication was unclear. History of pregnancy was that the age of the mother
was 30 years old during pregnancy. The gestation age was 9 month. History of
hypertension, fever, diabetes during pregnancy was not found.

24

The history of birth of this child was assisted by a midwife, born

spontaneously, through the vagina and cried immediately. Bluish was not found.
Body weight, body length, and head circumference were not measured.
The history of feeding was 6 months of breast feeding and then the child was
given normal adult food. History of immunization was that this child had
uncompleted immunization, she only had polio vaccine 1, BCG 1 and measles
vaccination during the 9th month.
The history of growth and development from her parent was that she grew
normally. She was also on time to develop talking, crawling, and walking skill.
The physical examination on this child of the present status showed that the
level of consciousness was alert, body temperature: 38.5C, body weight 14 kg, body
length was 106 cm, body weight/age percentage was 63.63%, body length/age
percentage was 92.17%, percentage of body weight/body length was 77%, fever was
present, no anemic cyanosis and dyspnea was found.
The localized status of the child was light reflexes was positive in both eyes,
isochoric pupil, conjunctiva palpebra inferior was not pale. The ears were within the
normal range. The nose was also in the normal range. Mouth was within the normal
range but the mucosa of the mouth was dry. There was no lymph node enlargement
found in the neck. The thorax was symmetrical fusiform, with no retraction found.
The heart rate was 110 bpm regular, no murmur. The respiratory rate was 22 bpm,
regular and no ronchi was found in both lungs during auscultation. The abdomen was
soft, non tender, normal peristaltic, liver and spleen was not palpable The extremities
pulse was 110 bpm regular, adequate pressure, warm acral, CRT < 3 and no clubbing
finger. The anogenitalia examination showed that was within the normal range,
female.
The working diagnosis for this patient was typhoid fever. The differential
diagnosis was urinary tract infection, gastroenteritis and bronchopneumonia.

25

The therapy given was IVFD D 5%, NaCl 0.45%, 47gtt/i (micro), paracetamol
syrup 3 times a day, one and in the half teaspoon, ceftriaxzone injection,
700mg/12hours/iv, ordansetron injection 2mg/8hours, and the diet was 1200kkal with
28g protein.
The further investigation plan was to do a complete blood count test, CRP
test, Tubex test, blood culture and also to check the feces and routine urine.
Follow Up
The follow up on April 25th2015, the patient complaints fever and abdominal pain. No
cough or dyspneu was present. The consciousness of the patient was alert. The body
temperature of the patient was 37.6oC. The body weight of the patient was 14kg and
the body length was 106cm. Eye, ear and nose was within the normal range. The
mucosa of the lips was dry. The heart rate was 95 bpm, reguler and no murmur. The
respiratory rate was 24 times in a minute, regular and no ronchi. The examination on
the abdomen showed that soft, non tender, peristaltic was present and normal. The
liver and spleen was not palpable. The extremities has warm acral, pulse 90 bpm,
regular, adequate pressure, with capillary refill time < 3.
The working diagnosis was typhoid fever. The therapy given was IVFD D 5%, NaCl
0.45%, 47gtt/i (micro), paracetamol syrup (3 times a day, one in a half teaspoon),
ordansetron injection (2mg/8hours) and diet MB 1200kkal with 28g protein.

The laboratory findings on April 25th, 2015.

Laboratory findings:

Diftel:

Immunoserology Find

Hematology

Neutrophil 6334% (37-80)

Immunoserology Typh

HGB 12.9g% (11.3-14.1)

Lymphocyte 22.0% (20-40)

(Tubex TF) = 6

RBC 4.96 106/mm3 (4.40-4.48)

Monocyte 11.5% (2-8)

26

<2: Negative
3: Borderlin

WBC 8.14 103/mm3 (4.5-13.5)

Eosinophil 0.1% (1-6)

Ht 36.80 % (37-41)

Basophil 0.1% (0-1)

PLT 272 103/mm3 (150-450)

Absolute neutrophil 5.39 103 /L (2.4-7.3)

MCV 74.20 fl (81-95)

Absolute lymphocyte 1.79 103/ L (1.7-5.1)

MCH 26.00 pg (25-29)

Absolute monocyte 0.94 103/ L (0.2-0.6)

MCHC 35.10 g% (29-31)

Absolute eosinophil 0.01 103/ L (0.1-0,3)

RDW 12.70% (11.6-14.8)

Absolute basophil 0.01 103/ L (0-0.1)

4-5: Weak pos

>6: Strong po

Autoimmune

The follow up on April 26th, 2015, shows that the patient complaints of fever,
nausea and abdominal pain. No cough, flu, and vomiting was found. The
consciousness of the patient was alert. The temperature was 38.6 oC. The examination
of the head, neck and thorax was normal. The heart rate was 90 bpm, regular, no
murmur. The respiratory rate was 22 times per minute, regular, no ronchi. The
examination on the abdomen showed that soft, non tender, peristaltic was present and
normal. The liver and spleen was not palpable. The extremities has warm acral, pulse
90 bpm, regular, adequate pressure, with capillary refill time < 3. The working
diagnosis was typhoid fever. The therapy given was IVFD D 5%, NaCl 0.45%, 47gtt/i
(micro), cefriaxone injection (700mg/12hours/IV), paracetamol syrup (3 times a day,
one in a half teaspoon), ordansetron injection (2mg/8hours) and diet MB 1200kkal
with 28g protein.
The follow up on April 27th, 2015 was that the patient complaint of
having fever and has not defecate for the past 6 days. No vomiting or nausea was
present. The consciousness of the patient was alert. The temperature was 37.7oC. The
examination of the head, neck and thorax was normal. The heart rate was 104 bpm,
regular, no murmur. The respiratory rate was 28 times per minute, regular, no ronchi.
The examination on the abdomen showed that soft, non tender, peristaltic was present
and normal. The liver and spleen was not palpable. The extremities has warm acral,
pulse 104 bpm, regular, adequate pressure, with capillary refill time < 3. The
working diagnosis was typhoid fever. The therapy given was IVFD D 5%, NaCl

27

CRP qualitativ

0.45%, 47gtt/i (micro), cefriaxone injection (700mg/12hours/IV), paracetamol syrup

(3 times a day, one in a half teaspoon), ordansetron injection (2mg/8hours), diet MB
1200kkal with 28g protein and dulcolax supp 1 prn.

28

DISCUSSION
In this case, the patient has a history of poor hygiene. The patient rarely washes her
hand before eating and after using the toilet. Theory shows that Oral transmission via
food or beverages handled by an often asymptomatic individual a carrier who
chronically sheds the bacteria through stool or, less commonly, urine. Hand-to-mouth
transmission after using a contaminated toilet and neglecting hand hygiene.
The patient in the case is 6 years and 2 months old. The theory states that
Most patients who present to hospitals with typhoid fever are children or young
adults from 5 to 25 years of age.
The patient in the case came to the hospital after 10 days of fever, nausea,
abdominal pain, tender abdomen and with a dry mouth mucosa. No enlargement of
liver and spleen was found. The theory states that The onset of bacteremia is marked
by fever and malaise. Patients typically present to the hospital toward the end of the
first week after the onset of symptoms with fever, influenza-like symptoms with
chills (although rigors are rare), a dull frontal headache, malaise, anorexia, nausea,
poorly localized abdominal discomfort, a dry cough, and myalgia, but with few
physical signs.1 A coated tongue, tender abdomen, hepatomegaly, and splenomegaly
are common.
In this case, the patients hemoglobin level, white-cell count and platelet count
was in the normal range. The theory shows that the hemoglobin level, white-cell
count, and platelet count are usually normal or reduced. Disseminated intravascular
coagulation may be revealed by laboratory tests, but it is very rarely of clinical
significance

The

patient had fever for 10 days, temperature in the day of admission 38.5C and have a
positive Tubex test. The theory showed that confirmed case of typhoid fever are
patients with fever (38C and above) that has lasted for at least three days, with a
laboratory-confirmed positive culture (blood, bone marrow, bowel fluid) of S. typhi.
In this case, the patient was given IVFD D 5%, NaCl 0.45%, 47gtt/i (micro),

29

Paracetamol syrup 3times a day with one in a half teaspoon volume, ordansetron
injection 2mg/8hours, and the diet MB 1200kkal with 28g protein. The theory states
that 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.

SUMMARY

30

RMT, a 6 years 2 months old girl, with 14 kg of BW and 106 cm of BH, came to
pediatric department of infection unit in Haji Adam Malik General Hospital Medan
on April 24th 2015 at 11.45 AM. Her chief complaint was having fever.
Fever was experience since 10 days ago, fever was not constant, increases
during the evening and decreases in the morning. Fever decreased never reached
normal range. No seizures was found as well as no shivering was found.Vomiting and
nausea was present at the day of admission. The history of vomiting and nausea was
present since 7 days ago. The frequency of vomiting is 3 times a day, with volume
half of an aqua glass, with content of food which was eaten, drink which was taken.
Blood was also present.
The history of defecation was 3 days ago, with hard consistency than usual.
No black stool was found. No history of diarrhea was found. The history of urination
was 2 days ago. The colour was more yellowish than usual. The volume of urine was
little. There was no pain found during urination.
Abdominal pain is present since 10 days ago. The loss of appetite was found
and the patient has lose weight than before. The body weight before this was 15kg.
No spontaneous bleeding was found. No cough and flu was present.
On physical examination, all examination was in the normal range except the
patient was having pain in the abdomen and could not defecate for 6 days. In the
laboratory findings, it was concluded that the patient was having typhoid fever
because the immunoserology test show a strong positive result for typhoid. Therefore
the working diagnosis for this patient is typhoid fever.

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31

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34