TYPHOID FEVER

INTRODUCTION
Typhoid fever, also known as enteric fever, is a potentially life-threatening multi-systemic bacterial infection
or illness caused primarily by Salmonella typhi (Brusch et al., 2016), usually through ingestion of
contaminated food or water (WHO.int, 2015). Fever is present in majority of patients (>90 %) irrespective of
their age group (Kumar and Kumar, 2016). Some people who get typhoid become carriers, who can spread
the disease to others.

CAUSES OF TYPHOID FEVER

Causative organism
Typhoid fever is caused by Salmonella enteric serotype Typhi (S.typhi ) and Salmonella enterica serotype
Paratyphi (S. paratyphi) (Kumar and Kumar, 2016). S. paratyphi can be commonly divided into S. paratyphi
A, B (tartrate negative), and C (Brusch et al., 2016; CDC, 2015), Salmonella typhi, the causative agent of
typhoid fever, is approximately 50,000 years old (Kidgell et al., 2002).

S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor sanitation,
crowding, and social chaos (Brusch et al., 2016).

The name S.typhi is derived from the ancient Greek typhos, an ethereal smoke or cloud that was believed to
cause disease and madness (Brusch et al., 2016). In the advanced stages of typhoid fever, the patient's level of
consciousness is truly clouded (Brusch et al., 2016).

Figure 1: Salmonella typhi (Encyclopedia Britannica, 2016)

PATHOPHYSIOLOGY

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. Nontyphoidal
salmonellae are phagocytized throughout the distal ileum and colon. With toll-like receptor (TLR)5 and TLR-
4/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.
In contrast to the nontyphoidal 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.

S 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.

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 bacteraemia 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.

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.

CLINICAL PRESENTATION

Patient History
A severe nonspecific febrile illness in a patient who has been exposed to typhoidal salmonella should always
raise the diagnostic possibility of typhoid fever (enteric fever).

Classic typhoid fever syndrome

The clinical syndromes associated with S typhi and paratyphi are indistinguishable. Typhoid fever begins 7-
14 days after ingestion of the organism. The fever pattern is stepwise, characterized by a rising temperature
over the course of each day that drops by the subsequent morning. The peaks and troughs rise progressively
over time.

Over the course of the first week of illness, the notorious gastrointestinal manifestations of the disease develop.
These include diffuse abdominal pain and tenderness and, in some cases, fierce colicky right upper quadrant
pain. Monocytic infiltration inflames Peyer patches and narrows the bowel lumen, causing constipation that
lasts the duration of the illness. The individual then develops a dry cough, dull frontal headache, delirium, and
an increasingly stuporous malaise. At approximately the end of the first week of illness, the fever plateaus at
103-104F (39-40C). The patient develops rose spots, which are salmon-colored, blanching, truncal,
maculopapules usually 1-4 cm wide and fewer than 5 in number; these generally resolve within 2-5 days.
These are bacterial emboli to the dermis and occasionally develop in persons with shigellosis or nontyphoidal
salmonellosis.

During the second week of illness, the signs and symptoms listed above progress. The abdomen becomes
distended, and soft splenomegaly is common. Relative bradycardia and dicrotic pulse (double beat, the second
beat weaker than the first) may develop.

In the third week, the still febrile individual grows more toxic and anorexic with significant weight loss. The
conjunctivae are infected, and the patient is tachypneic with a thready pulse and crackles over the lung bases.
Abdominal distension is severe. Some patients experience foul, green-yellow, liquid diarrhea (pea soup
diarrhea). The individual may descend into the typhoid state, which is characterized by apathy, confusion, and
even psychosis. Necrotic Peyer patches may cause bowel perforation and peritonitis. This complication is
often unheralded and may be masked by corticosteroids. At this point, overwhelming toxaemia, myocarditis,
or intestinal haemorrhage may cause death.

If the individual survives to the fourth week, the fever, mental state, and abdominal distension slowly improve
over a few days. Intestinal and neurologic complications may still occur in surviving untreated individuals.
Weight loss and debilitating weakness last months. Some survivors become asymptomatic S typhi carriers and
have the potential to transmit the bacteria indefinitely.

Various presentations of typhoid fever

The clinical course of a given individual with typhoid fever may deviate from the above description of classic
disease. The timing of the symptoms and host response may vary based on geographic region, race factors,
and the infecting bacterial strain. The stepladder fever pattern that was once the hallmark of typhoid fever now
occurs in as few as 12% of cases. In most contemporary presentations of typhoid fever, the fever has a steady
insidious onset. 1-5% of patients, depending on age, become chronic carriers harbouring S.typhi in the
gallbladder.

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.
Bronchitis cough is common in the early stage of the illness. During the period of fever, up to 25% of
patients show exanthem (rose spots), on the chest, abdomen and back.
Complicated disease: Depending on the clinical setting and the quality of available medical care, up
to 10% of typhoid patients may develop serious complications. The presence of occult blood is a
common finding in the stool of 10-20% of patients, and up to 3% may have melena. 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.

Young children, individuals with AIDS, and one third of immunocompetent adults who develop typhoid fever
develop diarrhoea rather than constipation. In addition, in some localities, typhoid fever is generally more apt
to cause diarrhoea than constipation.

Atypical manifestations of typhoid fever include isolated severe headaches that may mimic meningitis, acute
lobar pneumonia, isolated arthralgias, urinary symptoms, severe jaundice, or fever alone. Some patients,
especially in India and Africa, present primarily with neurologic manifestations such as delirium or, in
extremely rare cases, parkinsonian symptoms or Guillain-Barr syndrome. Other unusual complications
include pancreatitis, [30] meningitis, orchitis, osteomyelitis, and abscesses anywhere on the body. [2]

Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever

Incubation Week 1 Week 2 Week 3 Week 4 Post

Systemic
Stepladder fever Very Very common Recovery 10%-20%
pattern or insidious commona phase or relapse; 3%-
onset fever death (15% 4% chronic
Acute high fever Very rareb of untreated carriers;
Chills Almost allc cases)
Rigors Uncommon
Anorexia Almost all
Diaphoresis Very common long-term
Neurologic neurologic
Malaise Almost all Almost all Typhoid sequelae
Insomnia Very state (extremely
common (common) rare);
Confusion/delirium Commond Very
common
Psychosis Very rare Common
Catatonia Very rare gallbladder
cancer
Frontal headache Very
(RR=167;
(usually mild) common
carriers)
Meningeal signs Raree Rare
Parkinsonism Very rare
Ear, nose, and throat
Coated tongue Very
common
Sore throatf
Pulmonary
Mild cough Common
Bronchitic cough Common
Rales Common
Pneumonia Rare Rare Common
(lobar) (basal)

Cardiovascular
Dicrotic pulse Rare Common
Myocarditis Rare
Pericarditis Extremely
rareg
Thrombophlebitis Very rare
Gastrointestinal
Constipation Very Common
common
Diarrhea Rare Common (pea soup)
Bloating with Very
tympany common
(84%) [35]
Diffuse mild Very
abdominal pain common
 Sharp right lower Rare
quadrant pain
Gastrointestinal Very rare; Very common
haemorrhage usually
trace
intestinal perforation Rare
Hepatosplenomegaly Common
Jaundice Common
Gallbladder pain Very rare
Urogenital
Urinary retention Common
Haematuria Rare
Renal pain Rare
Musculoskeletal
Myalgia Very rare
Arthralgia Very rare
Rheumatologic
Arthritis (large joint) Extremely rare
Dermatologic
Rose spots Rare
Miscellaneous
Abscess (anywhere) Extremely Extremely Extremely
rare rare rare
a Very common: symptoms occur in well over half of cases (approximately 65-95%)
b Very rare: symptoms occur in less than 5% of cases.
c Almost all: symptoms occur in almost all cases.
d Common: symptoms occur in 35%-65% of cases.
e Rare: symptoms occur in 5% - 35% of cases.
f Blank cells: no mention of the symptoms at that phase was found in the literature
g Extremely rare: symptoms have been described in occasional case reports

Treated typhoid fever

If appropriate treatment is initiated within the first few days of full-blown illness, the disease begins to remit
after about 2 days, and the patient's condition markedly improves within 4-5 days. Any delay in treatment
increases the likelihood of complications and recovery time.

CASE PRESENTATION
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. 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.

Contamination and Transmission

Salmonella typhi infection is unique to humans, no animal or environmental reservoirs have been identified.

Typhoid and paratyphoid fever are most often acquired through consumption of water or food that has been
contaminated by faeces of an acutely infected or convalescent person or a chronic, asymptomatic carrier.
Transmission through sexual contact, especially among men who have sex with men, has been documented
rarely.

DIAGNOSIS
Infection with typhoid or paratyphoid fever results in a low-grade septicaemia. (CDC.gov, 2016). The
diagnosis of typhoid fever (enteric fever) is primarily clinical.

Laboratory Studies
Culture
The criterion standard for diagnosis of typhoid fever has long been culture isolation of the organism. Cultures
are widely considered 100% specific.

Culture of bone marrow aspirate is 90% sensitive until at least 5 days after commencement of antibiotics.
However, this technique is extremely painful, which may outweigh its benefit. Bone marrow culture increases
the diagnostic yield to approximately 80% of cases

Blood culture is the mainstay of diagnosis in typhoid fever, a single culture is positive in only approximately
50% of cases. Stool culture is not usually positive during the earliest phase of the disease. Stool culture alone
yields a sensitivity of less than 50%, and urine culture alone is even less sensitive. Blood, intestinal secretions
(vomitus or duodenal aspirate), and stool culture results are positive for S typhi in approximately 85%-90% of
patients with typhoid fever who present within the first week of onset. They decline to 20%-30% later in the
disease course. In particular, stool culture may be positive for S typhi several days after ingestion of the
bacteria secondary to inflammation of the intraluminal dendritic cells. Later in the illness, stool culture results
are positive because of bacteria shed through the gallbladder. Stool culture alone yields a sensitivity of less
than 50%

Multiple blood cultures (>3) yield a sensitivity of 73%-97%. Large-volume (10-30 mL) blood culture and clot
culture may increase the likelihood of detection. Multiple cultures increase the sensitivity and may be required
to make the diagnosis.

Cultures of punch-biopsy samples of rose spots reportedly yield a sensitivity of 63% and may show positive
results even after administration of antibiotics.
S typhi has also been isolated from the cerebrospinal fluid, peritoneal fluid, mesenteric lymph nodes, resected
intestine, pharynx, tonsils, abscess, and bone, among others.

Table 2. Sensitivities of Cultures

Incubation Week 1 Week 2 Week 3 Week 4

90% (may decrease after 5 days of

Bone marrow aspirate (0.5-1 mL)
antibiotics)

Blood (10-30 mL), stool, or duodenal aspirate

40%-80% ~20% Variable (20%-60%)
culture

Urine 25%-30%, timing unpredictable

Polymerase chain reaction

Polymerase chain reaction (PCR) has been used for the diagnosis of typhoid fever with varying success.
Nested PCR, which involves two rounds of PCR using two primers with different sequences within the H1-d
flagellin gene of S typhi, offers the best sensitivity and specificity. Combining assays of blood and urine, this
technique has achieved a sensitivity of 82.7% and reported specificity of 100%. However, no type of PCR is
widely available for the clinical diagnosis of typhoid fever.

Specific serologic tests

Assays that identify Salmonella antibodies or antigens support the diagnosis of typhoid fever, but these results
should be confirmed with cultures or DNA evidence.

The Widal test was the mainstay of typhoid fever diagnosis for decades. It is used to measure agglutinating
antibodies against H and O antigens of S typhi. Neither sensitive nor specific, the Widal test is no longer an
acceptable clinical method.

Indirect hemagglutination, indirect fluorescent Vi antibody, and indirect enzyme-linked immunosorbent assay
(ELISA) for immunoglobulin M (IgM) and IgG antibodies to S typhi polysaccharide, as well as monoclonal
antibodies against S typhi flagellin, are promising, but the success rates of these assays vary greatly in the
literature.

Other nonspecific laboratory studies

Most patients with typhoid fever are moderately anaemic, have an increased erythrocyte
sedimentation rate (ESR), thrombocytopenia, and relative lymphopenia.
Most also have a slightly elevated prothrombin time (PT) and activated partial thromboplastin time
(aPTT) and decreased fibrinogen levels.
Circulating fibrin degradation products commonly rise to levels seen in subclinical disseminated
intravascular coagulation (DIC).
Liver transaminase and serum bilirubin values usually rise to twice the reference range.
Mild hyponatremia and hypokalemia are common.
A serum alanine amino transferase (ALT)tolactate dehydrogenase (LDH) ratio of more than 9:1
appears to be helpful in distinguishing typhoid from viral hepatitis. A ratio of greater than 9:1 supports
a diagnosis of acute viral hepatitis, while ratio of less than 9:1 supports typhoid hepatitis.
Imaging Studies

Radiography: Radiography of the kidneys, ureters, and bladder (KUB) is useful if bowel perforation
(symptomatic or asymptomatic) is suspected.

CT scanning and MRI: These studies may be warranted to investigate for abscesses in the liver or bones,
among other sites.

Histologic Findings

Liver biopsy specimens from patients with typhoid fever often show cloudy swelling, balloon degeneration
with vacuolation of hepatocytes, moderate fatty change, and focal typhoid nodules. Intact typhoid bacilli can
be observed at these sites.

Staging

The proper treatment approach to typhoid fever depends on whether the illness is complicated or
uncomplicated. Complicated typhoid fever is characterized by melena (3% of all hospitalized patients with
typhoid fever), serious abdominal discomfort, intestinal perforation, marked neuropsychiatric symptoms, or
other severe manifestations. Depending on the adequacy of diagnosis and treatment, complicated disease may
develop in up to 10% of treated patients. Delirium, obtundation, stupor, coma, or shock demands a particularly
aggressive approach (see Treatment).

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.
General management for children
Fluids to prevent dehydration:

The aim is to prevent dehydration.

The fluid lost in childrens sick (vomit) and/or diarrhoea needs to be replaced.
Children should continue with their normal diet and usual drinks. In addition, they should also be
encouraged to drink extra fluids.
However, avoid fizzy drinks or large amounts of concentrated fruit juices as these can make diarrhoea
worse. Babies under 6 months old are at increased risk of dehydration.
Seek medical advice if they develop gastroenteritis.
Breast-feeds or bottle-feeds should be encouraged as normal. The baby's demand for feeds increases.
It is also being advised to give extra fluids (either water or rehydration drinks) in between feeds.
It is important that your child is rehydrated before they have any solid food.
Rehydration drinks provide a perfect balance of water, salts, and sugar. The small amount of sugar and
salt helps the water to be absorbed better from the gut (intestines) into the body.
If rehydration drinks are not available for whatever reason, make sure you keep giving the child water,
diluted fruit juice or some other suitable liquid.
Fluids to treat dehydration

It is important that the infected child is rehydrated before they have any solid food.
The amount of rehydration drink can depend on the age and the weight of your child.
If you are breast-feeding, you should continue with this during this time. Otherwise, don't give your
child any other drinks unless the doctor or nurse has said that this is OK.
It is important that your child is rehydrated before they have any solid food.
Sometimes a child may need to be admitted to hospital for treatment if they are dehydrated.
Treatment in hospital usually involves giving rehydration solution through a special tube called a
nasogastric tube. This tube passes through your child's nose, down their throat and directly into their
stomach.
An alternative treatment is with fluids given directly into a vein (intravenous fluids).
If your child is sick (vomits), wait 5-10 minutes and then start giving drinks again but more slowly
(for example, a spoonful every 2-3 minutes). Use of a syringe can help in younger children who may
not be able to take sips.

Diet

Correcting any dehydration is the first priority. However, if the child is not dehydrated (most cases) or once
any dehydration has been corrected, encourage the child to have their normal diet. Do not 'starve' a child with
salmonella. This used to be advised but is now known to be wrong. So:

Breast-fed babies should continue to be breast-fed if they will take it. This will usually be in addition
to extra rehydration drinks (described above).
Bottle-fed babies should be fed with their normal full-strength feeds if they will take them. Again, this
will usually be in addition to extra rehydration drinks (described above).
Older children - offer them some food every now and then. However, if he or she does not want to eat,
that is fine. Drinks are the most important and food can wait until their appetite returns.

General management for adults

Fluids

The aim is to prevent lack of fluid in the body (dehydration), or to treat dehydration if it has developed. (Note:
if it is suspected that an infected patient is dehydrated, you should contact a doctor.)

As a rough guide, drink at least 200 mls after each watery stool (after each bout of diarrhoea).
This extra fluid is in addition to what an adult would normally drink. For example, an adult will
normally drink about two litres a day but more in hot countries. The above '200 mls after each watery
stool' is in addition to this usual amount that an adult would drink.
If you are sick (vomit), wait 5-10 minutes and then start drinking again but more slowly. For example,
a sip every 2-3 minutes but making sure that your total intake is as described above.
You will need to drink even more if you are dehydrated. A doctor will advise on how much to drink if
you are dehydrated.

For most adults, fluids drunk to keep hydrated should include water, fruit juice and soups. It is best not to have
drinks that contain a lot of sugar, such as cola or pop, as they can sometimes make diarrhoea worse.

Rehydration drinks are recommended in people who are frail, or over the age of 60, or who have underlying
health problems. They are made from sachets that you can buy from pharmacies. (The sachets are also
available on prescription.) You add the contents of the sachet to water. Rehydration drinks provide a good
balance of water, salts, and sugar. The small amount of sugar and salt helps the water to be taken up (absorbed)
better from the gut into the body. They do not stop or reduce diarrhoea. Do not use home-made salt/sugar
drinks, as the quantity of salt and sugar must be exact.

Diet

It used to be advised to 'starve' for a while if you had food poisoning. However, now it is advised to eat small,
light meals if you can. Be guided by your appetite. You may not feel like eating food and most adults can do
without food for a few days. Eat as soon as you are able but don't stop drinking. If you do feel like eating,
avoid fatty, spicy or heavy food. Plain foods such as wholemeal bread and rice are good foods to try eating.

Antimicrobial therapy
Efficacy, availability and cost are important criteria for the selection of first-line antibiotics to be used in
developing countries. 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.

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,
viz. chloramphenicol, ampicillin, amoxicillin and trimethoprim-sulfamethoxazole (Table 3). Most 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, 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

Table 3: Recommended treatment of uncomplicated cases of typhoid fever for adults

Antibiotic Daily dose mg/kg Duration
(days)

Optimal Ciprofloxacin 15 5
treatment

Alternative Chloramphenicol 50-75 14-21

treatment
Amoxicillin 75-100 14
Cotrimoxazole 8-40 14
Based on WHO guideline for diagnosis, treatment and prevention of typhoid fever 2003.
Table 4: Simplified dosing of ciprofloxacin for children

Age group Dose * Days

Children under 2 7.5 mg/kg twice a day 5
years
Children 2 to 7 125 mg ( tablet of 250 mg or tablet 5
years of 500 mg) twice a day
Children 8 to 11 250 mg (1 tablet of 250 mg or tablet 5
years of 500 mg) twice a day
Adults and 500 mg (2 tablets of 250 mg or 1 tablet 5
children 12 years of 500 mg) twice a day
and older
* Optimal dose 15 mg/kg per day; maximum dose 30 mg/kg per day. Paediatric dosing estimates were based
on US growth charts for children

To prevent development of antibiotic resistance, ciprofloxacin should only be used for patients with confirmed
or suspected typhoid fever. It should not be used for treatment of mild diarrhoea without fever or blood.
Regardless of which antibiotic is prescribed, patients must be explained the importance of finishing the entire
course of treatment, even when they feel better. Every effort should be made to make sure that the patient
takes the entire course. Ideally, the treatment should be directly observed (DOT).

Management of complicated cases

Table 5 lists the recommended treatment of severe cases of typhoid fever. The third-generation cephalosporin
(e.g. ceftriaxone) and azithromycin are as effective as ciprofloxacin. However, these are more expensive and
should be reserved for treatment of severe patients and/or patients who don't respond to ciprofloxacin
treatment.

Patients with intestinal perforation need intensive care as well as surgical intervention. Early intervention is
crucial as morbidity/mortality rates increase with delayed surgery after perforation
Table 5: Treatment of severe and drug resistant typhoid fever cases

Antibiotic Daily dose Duration (days)

mg/kg

Treatment for Ciprofloxacin IV or 15 10-14

severe typhoid oral

Ceftriaxone IV 60 10-14
Multidrug Azithromycin 8-10 7
resistance
Quinolone Ceftriaxone or 60 10-14
resistant cefotaxime 80
Based on WHO guideline for diagnosis, treatment and prevention of typhoid fever 2003

High-dose corticosteroid treatment, in combination with antibiotic treatment and supportive care, reduces
mortality in critically ill patients
Management of carriers
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.
Carriers should be excluded from any activities involving food preparation and serving,

as should convalescent patients and any persons with possible symptoms of typhoid fever. Although it would
be difficult for typhoid carriers in developing countries to follow this recommendation, food handlers should
not resume their duties until they have had three negative stool cultures at least one month apart.

ANTIMICROBIAL RESISTANCE

Treatment of typhoid fever has been complicated by the development and rapid dissemination of typhoidal
organisms resistant to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol. Additionally,
development of increasing resistance to fluoroquinolones is a growing challenge.

Multidrug resistance Multidrug-resistant (MDR) strains (i.e., those resistant to ampicillin, trimethoprim-
sulfamethoxazole, and chloramphenicol) are prevalent worldwide.

MDR strains of S.typhi and S. paratyphi have caused numerous outbreaks in endemic regions, including South
and Southeast Asia, China, and Africa. Because of this, ampicillin, trimethoprim-sulfamethoxazole, and
chloramphenicol have no longer been used as first-line agents for treatment of typhoid fever. Subsequently,
some locations have reported a decrease in the prevalence of MDR strains. As an example, in a surveillance
study from Kolkata, India conducted from 2009 to 2013, 18 percent of S.typhi and no S. paratyphi isolates
were MDR. Nevertheless, MDR strains remain frequent worldwide. In locations such as Bangladesh, Vietnam,
and Cambodia, MDR isolates account for the vast majority of S.typhi. Prevalence of MDR strains varies
throughout Africa, the Middle East, and Central Asia, from 10 to 80 percent, depending on the country.
Genome sequencing and analysis of international isolates has identified a predominant MDR S.typhi strain,
H58, that has disseminated throughout Asia and Africa, displacing more susceptible strains and driving
ongoing MDR epidemics.

These patterns of resistance are reflected in travelers returning to nonendemic regions. In an analysis of over
1000 isolates submitted to the United States Centers for Disease Control and Prevention (CDC) between 2008
and 2012, most of which were from infections acquired in South Asia, 12 percent of S.typhi and no S.
paratyphi isolates were MDR strains. A similar prevalence of MDR strains was reported from a surveillance
study in Switzerland between 2002 and 2013.

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.
Safe water
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.

Food safety

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.

Typhoid can be transmitted by chronic carriers who do not apply satisfactory food-related hygiene practices.
These carriers should be excluded from any activities involving food preparation and serving. They should
not resume their duties until they have had three negative stool cultures at least one month apart.

Sanitation
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

Health education

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 (e.g. media, schools, womens groups, religious groups) must be applied.
Community involvement is the cornerstone of behaviour change regarding 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
Vaccine
Indications for Use

CDC recommends typhoid vaccine for travellers to areas where there is an increased risk of exposure to
Salmonella Typhi. Two typhoid vaccines are available:

Oral live attenuated vaccine (Vivotif, manufactured from the Ty21a strain of Salmonella Typhi by
PaxVax)
Vi capsular polysaccharide vaccine (ViCPS) (Typhim Vi, manufactured by Sanofi Pasteur) for
intramuscular use

Both typhoid vaccines protect 50%80% of recipients; travellers should be reminded that typhoid
immunization is not 100% effective, and typhoid fever could still occur. Available typhoid vaccines offer
limited or no protection against Salmonella paratyphi infection.

Vaccine Administration

Table 6 provides information on vaccine dosage, administration, and revaccination. The time required for
primary vaccination differs for the 2 vaccines, as do the lower age limits.

Primary vaccination with oral Ty21a vaccine consists of 4 capsules, 1 taken every other day. The capsules
should be kept refrigerated (not frozen), and all 4 doses must be taken to achieve maximum efficacy. Each
capsule should be taken with cool liquid no warmer than 98.6F (37C), approximately 1 hour before a meal.
This regimen should be completed 1 week before potential exposure. The vaccine manufacturer recommends
that Ty21a not be administered to infants or children aged <6 years. Anyone whose immune system is
weakened should not get this vaccine. They should get the typhoid shot instead. This includes anyone who:

has HIV/AIDS or another disease that affects the immune system,

is being treated with drugs that affect the immune system, such as steroids for 2 weeks or longer,
has any kind of cancer, is taking cancer treatment with radiation or drugs.
Oral typhoid vaccine should not be given until at least 3 days after taking certain antibiotics.

Primary vaccination with ViCPS consists of one 0.5-mL (25-mg) dose administered intramuscularly. One
dose of this vaccine should be given 2 weeks before expected exposure. The manufacturer does not
recommend the vaccine for infants and children aged <2 years.

Vaccine Safety and Adverse Reactions

Adverse reactions to Ty21a vaccine are rare and mainly consist of abdominal discomfort, nausea, vomiting,
and rash. ViCPS vaccine is most often associated with headache (16%20%) and injection-site reactions (7%).

Precautions and Contraindications

No information is available on the safety of these vaccines in pregnancy; it is prudent on theoretical grounds
to avoid vaccinating pregnant women. Live attenuated Ty21a vaccine should not be given to
immunocompromised travelers, including those infected with HIV. The intramuscular vaccine presents a
theoretically safer alternative for immunocompromised travelers. (The Advisory Committee on Immunization
Practices does not recommend against vaccinating household contacts of immunocompromised people with
Ty21a; although vaccine organisms can be shed transiently in the stool of vaccine recipients, secondary
transmission of vaccine organisms has not been documented.) The only contraindication to vaccination with
ViCPS vaccine is a history of severe local or systemic reactions after a previous dose. Neither vaccine should
be given to people with an acute febrile illness.

Theoretical concerns have been raised about the immunogenicity of live, attenuated Ty21a vaccine in people
concurrently receiving antimicrobial agents (including antimalarial chemoprophylaxis), viral vaccines, or
immune globulin. The growth of the live Ty21a strain is inhibited in vitro by various antibacterial agents, and
vaccination with Ty21a should be delayed for >72 hours after the administration of any antibacterial agent.
Available data do not suggest that simultaneous administration of oral polio or yellow fever vaccine decreases
the immunogenicity of Ty21a. If typhoid vaccination is warranted, it should not be delayed because of
administration of viral vaccines. Simultaneous administration of Ty21a and immune globulin does not appear
to pose a problem.

Table 6: Vaccines to prevent typhoid fever

DOSE, MODE OF
VACCINA- NUMBER DOSING BOOSTING
AGE (y) ADMINISTRA-
TION OF DOSES INTERVAL INTERVAL
TION

Oral, Live, Attenuated Ty21a Vaccine (Vivotif)1

Primary series 6 1 capsule,2 oral 4 48 hours Not applicable

Booster 6 1 capsule,2 oral 4 48 hours Every 5 years

Vi Capsular Polysaccharide Vaccine (Typhim Vi)

Primary series 2 0.50 mL, intramuscular 1 Not applicable Not applicable

Booster 2 0.50 mL, intramuscular 1 Not applicable Every 2 years

1
The vaccine must be kept refrigerated (35.6F46.4F, 2 C8C).
2
Administer with cool liquid no warmer than 98.6F (37C).

Goal of therapy

The goals of therapy by health care providers for typhoid infected patients or carriers include
To prevent dehydration of the patient
To diagnose the present of S.typhi or typhoid fever in a person
To ensure that infected patients complete their dosage regimen in order to prevent multi-drug
resistance
To reduce or complete remove the S.typhi organisms from the body of an infected person or carriers
To prevent further contamination and transmission of typhoid fever to uninfected persons
To improve the quality of life of infected persons.
REFERENCES
Brusch, J., Corales, R., Schmitt, S. and Garvey, T. (2016). Typhoid Fever: Background, Pathophysiology,
Epidemiology. [online] WHO.int. (2015). WHO | Typhoid. [online] Available at:
http://www.who.int/immunization/diseases/typhoid/en/ [Accessed 12 Dec. 2016].

Emedicine.medscape.com. Available at: http://emedicine.medscape.com/article/231135-overview [Accessed

12 Dec. 2016].
CDC.gov. (2016). Symptoms & Treatment| Typhoid Fever | CDC. [online] Available at:
https://www.cdc.gov/typhoid-fever/symptoms.html [Accessed 12 Dec. 2016].
Kumar, P. and Kumar, R. (2016). Enteric Fever. The Indian Journal of Pediatrics.
Kidgell, C., Reichard, U., Wain, J., Linz, B., Torpdahl, M., Dougan, G. and Achtman, M. (2002). Salmonella
typhi, the causative agent of typhoid fever, is approximately 50,000 years old. Infection, Genetics and
Evolution, 2(1), pp.39-45.

Prevention, C. (2015). Typhoid & Paratyphoid Fever - Chapter 3 - 2016 Yellow Book | Travelers' Health |
CDC. [online] Wwwnc.cdc.gov. Available at: https://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-
diseases-related-to-travel/typhoid-paratyphoid-fever [Accessed 15 Dec. 2016].
Encyclopedia Britannica. (2016). Salmonella typhimurium | bacteria. [online] Available at:
https://www.britannica.com/science/Salmonella-typhimurium [Accessed 15 Dec. 2016].

Anon, (2016). [online] Available at: https://www.linkedin.com/pulse/homeopathy-treatment-typhoid-fever-

cancer-homoeo-clinic [Accessed 15 Dec. 2016].