Typhoid fever

Guideline 2019 for the
management of Typhoid Fever
By
Dr . Magdy Shafik Ramadan
Senior Pediatric and Neonatology consultant
M.S, Diploma, Ph.D of Pediatrics

What is Typhoid Fever?
systemic infection caused by S. typhi. Clinically
characterized by typical continuous fever for
3 to 4 weeks, relatively bradycardia with
involvement of intestinal lymphoid tissues,
reticulo endothelial system & gall bladder.
• “Enteric fever” includes both typhoid and
paratyphoid fever.
• May occur sporadically, epidemically or
endemically.
Found only in human.

Related with TYPHOID
HISTORICAL
PERSONALITIES

Antonius Musa, a Roman physician who
achieved fame by treating the Emperor
Augustus 2,000 year ago, with cold baths
when he fell ill with typhoid.
Thomas Willis who is credited with the first
description of typhoid fever in 1659.

French physician Pierre Charles
Alexandre Louis first proposed
the name “typhoid fever”
William Wood Gerhard who was the first
to differentiate clearly between typhus
fever and typhoid in 1837

Carl Joseph Eberth who discovered the
typhoid bacillus in 1880.
•Georges Widal who described the
•„Widal agglutination reaction‟ of the blood in 1896.

History of Antibiotic Therapy in Enteric
Fever
Chlor ampheni col wa s t he drug of choice for
the treatment of enteric fever since 1948,
but plasmid-mediated resistance and its rare
side-effect of bone marrow aplasia put it behind
on the shelf.
use of trimethoprim-sulfamethoxazole
and ampicillin in the 1970s;
• however, their rampant use led the pathogen
to get resistant to them.

In the 1980s, ceftriaxone and ciprofloxacin proved to
be effective against multidrugresistant
and were therefore the drugs of choice..(MDR) strains
of S. typhi.
Ciprofloxacin and ofloxacin were preferred to
ceftriaxone due to their oral use and cost
effectiveness.
Since the 1990s, azithromycin has been showing
good results and is a promising alternative to
fluoroquinolones and cephalosporins.

PROBLEM
STATEMENT
Typhoid fever

Typhoid fever is prevalent in many
regions in the world
High endemicity (>100 cases per lac per year)
Medium endemicity (10 cases per lac per year)
Low endemicity (<10 cases per lac per year

•WHO estimate
Infects roughly 21.6
million people each year

•WHO estimate
Kills 216000- 600000 people
each year

• WHO estimate
62% of these occurring in Asia
and 35% in Africa

India
• World largest outbreak of typhoid in SANGLI on
December 1975 to February 1976. This disease is
endemic in India.
1992 : 352,980 cases with 735 deaths
• 1993 : 357,452 cases and 888 deaths
• 1994 : 278,451 cases and 304 deaths
• 2011 : 1.06million cases & 346 deaths
Case fatality rate due to typhoid has been
varying
between 1.1% to 2.5 % in last few years.
• In south-East Asia 50% or more of the strains of
bacteria has MDR

Typhoid fever in Egypt
In Egypt, current estimates of typhoid fever
incidence are derived from case reports received
from passive hospital-based surveillance,
without laboratory confirmation of disease.
In the year 2000, the estimated incidence of ty-
phoid fever in Egypt was 15 cases per 100,000
persons per year (Egyptian national syndrome-
based surveillance, unpub-lished data).

This estimate may not reflect the true incidence of
disease, as less than 1% of these cases we re culture-
confirmed.
Furthermore, as many patients may never be
hospitalized, hospital-based surveillance may not
accu-rately represent the population with typhoid
fever.
In 2001, the Egyptian Ministry of Health and Popula-
tion (MOHP), the U.S. Naval Medical Research Unit-
3(NAMRU-3), and the Centers for Disease Control and
Pre-vention (CDC) piloted a rapid, community-based
surveillance method to measure the incidence of
typhoid fever and other causes of acute febrile illnesses
in Bilbeis distric

• The estimated incidence of typhoid fever was
calculatedto be 13 cases per 100,000 persons
.per year.
• The estimated incidence of typhoid fever was
59/100,000 persons/year. We estimate 71% of
typhoid fever patients are managed by primary
care providers. Multidrug-resistant (MDR)
Salmonella Typhi (resistant to chloramphenicol,
ampicillin, and trimethoprim-sulfamethoxazole)
was isolated from 26 (29%) patients. Population-
based surveillance indicates moderate typhoid
fever incidence in Fayoum, and a concerning
prevalence of MDR typhoid..
• (Copyright 2006 The American Society of
Tropical Medicine

EPIDEMIOLOGICAL
DETERMINANTS
1. Agent factors
2. Host factors
3. Environmental & social factors
4. Incubation period
5. Mode of transmission

1- AGENT FACTORS
a- Host
• Typhoid Fever mainly caused by the bacterium
Salmonella typhi from the family
Enterobacteriacea.
• S. para A&b are relatively infrequent.
• S. typhi is a gram-negative, facultative
aerobic, non spore forming bacteria that is
motile due to its peritrichous flagella.
• The bacteria grows best at 37 C.

Antigenic structure of
Salmonella
Two sets of antigens
Detection by serotyping
1 Somatic or 0 Antigens contain long chain
polysaccharides ( LPS ) comprises of heat stable
polysaccharide commonly.
• 2 Flagellar or H Antigens are strongly
immunogenic and induces antibody formation
rapidly and in high titers following infection or
immunization. The flagellar antigen is of a dual
•nature, occurring in one of the two phases.

b- Reservoir of infection
human is the only reservoir
1. Cases
• A case is infectious as
long as bacilli appears
in stools or urine.
• Case may be missed,
mild or severe.
2. Carriers
• Temporary/incubatory excrete
bacilli for 6 to 8 weeks
• Chronic- excrete bacilli
for more than a year,
organism persist in gall
bladder/biliary tract.

• Mary Mallon was a cook in
Oyster Bay, New York in
early 1900s.
• Gave rise to more than
1300 cases in her life
time.
• She died of pneumonia
after 26 years in
quarantine.

c- Source of infection
•Secondary sources
• Contaminated
– Water
– Food
– Fingers
– Flies
Primary sources
• Faeces & urine of cases
and carriers.
• Faecal carriers are more
frequent than urinary
carriers

How does the bacteria cause disease ?
•1-Ingestion of contaminated food or water
•Salmonella bacteria
2- Invade small intestine and enter the bloodstream
3-Carried by white blood cells in the liver, spleen, and
bone marrow
4-Multiply and reenter the bloodstream
5- Bacteria invade the gallbladder, biliary system, and
the lymphatic tissue of the bowel and multiply in high
numbers.
6- Then pass into the intestinal tract and can be
identified for diagnosis in cultures from the stool
tested in the laboratory

2- HOST FACTORS
• (a) Age- occur at any age but highest incidence in 5-19
yrs age group.
(b) Sex- cases more in Males than Female
carrier rate is more in females.
c) Immunity- antibody may be stimulated by infection or
immunization. Antibody against (O) antigen is higher in
patient with the disease and antibody against (H)
antigen is higher in immunized person. S.Typhi is
intracellular
organism so cell mediated immunity plays a major role in
combating the infection.

3- ENVIRONMENTAL & SOCIAL FACTORS
• Typhoid fever regarded as “Index of general
sanitation” in any country.
• Increase incidence in July-September.
• Vegetables grow in sewage plant
• Pollution of drinking water supplies.
• Open area defecation & urination
• Low personal hygiene
• Health ignorance.

4- INCUBATION PERIOD
Usually 10-14 days but it may be as short as 3 days or
as long as 21 days depending upon the dose of the
bacilli ingested.

CLINICAL FEATURES
• First week: malaise, headache, cough & sore
throat in prodromal stage. The disease
classically presents with step-ladder fashion
rise in temperature (40 - 41°C) over 4 to 5 days,
accompanied by headache, vague abdominal
pain, and constipation or pea soup Diarrhoea.
• Second week: Between the 7th -10th day of
illness, mild hepatosplenomegally occurs in
majority of patients. Relative bradycardia may
occur and rose-spots may be seen.

• • Third week: The patient will appear in the
"typhoid state" which is a state of prolonged
apathy, toxemia, delirium, disorientation and/or
coma. Diarrhoea will then become apparent. If
left untreated by this time, there is a high risk (5-
10%) of intestinal hemorrhage and perforation.
complications:Rare
Hepatitis, Pneumonia, Thrombophlebitis,
Myocarditis, Cholecystitis, Nephritis, Osteomyelitis,
and Psychosis.
2-5% patients may become Gall-bladder carriers

Can Typhoid occur without fever
Up to 1 in every 20 people who survive typhoid
fever without being treated will become
carriers of the infection.
This means the Salmonella typhi bacteria
continue to live in the carrier's body and can be
spread as normal in faeces or urine, but the
carrier doesn't have any noticeable symptoms of
typhoid fever.

LABORATORY
DIAGNOSIS OF TYPHOID
1. Microbiological procedures
2. Serological procedures
3. New diagnostic tests

1- Microbiological procedure
Blood Cultures
Bacteremia occurs early in the disease
Blood Cultures are positive in
1st week in 90%
2nd week in 75%
3rd week in 60%
4th week and later in 25%

2- SEROLOGICAL PROCEDURE
FELIX-WIDAL TEST
Significant Titers helps in Diagnosis:
• Widal i s the most widely used test in many regions as it is
relatively cheaper, easy to perform, and requires minimal
training and equipment.
• Serum agglutinins raise abruptly during the 2nd or 3rd week
• • Following Titers of antibodies against the antigens are
significant when single sample
is tested
O > 1 in 160
H > 1 in 320
• • Testing a paired sample (7-10 days) for raise of antibodies
carries a greater significance

I i s d i f f i c u l t t o pinpoint a definite cut-off for
a positive result since it varies between areas and between
times in given areas.
A fourfold rise in antibody titer in a paired serum is
considered more diagnostic.
How long widal test is positive
H antibodies once positive can remain positive for a long time.

Limitations of Widal test:
• Classically, a four-fold rise of antibody in paired
sera Widal test is considered diagnostic of
typhoid fever.
• However, paired sera are often difficult to obtain
and specific chemotherapy has to be instituted on the
basis of a single Widal test.
• Furthermore, in areas where fever due to
infectious causes is a common occurrence the
possibility exists that false positive reactions may
occur as a result of non-typhoid

3- NEW DIAGNOSTIC TESTS
• IDL Tubex detects IgM09 antibodies with in
few minutes
• Typhidot test that detects presence of IgM
and IgG in one hour (sensitivity>95%,
Specificity 75%)
• Typhidot-M, that detects IgM only (sensitivity
90% and specificity 93%)
• Typhidot rapid (sensitivity 85% and Specificity
99%) is a rapid 15 minute
immunochromatographic test to detect IgM.
• IgM dipstick test

Typhoid Management Guidelines – 2019
Any patient presenting with fever with no clear focus of infection in an endemic
setting, for more than 3 days should be suspected to have typhoid fever.
in the early course of the disease, the patient is likely to experience:
Fever that starts low and increases daily, possibly reaching as high as 104.9 F
(40.5 C)
Headache
Coated tongue
Weakness and fatigue
Muscle aches
Sweating
Dry cough
Loss of appetite and weight loss
Abdominal pain
Diarrhea or constipation
Rash
Abdominal distention

Laboratory Findings
• Microbiological Diagnosis:
• Blood culture is the gold standard test for the diagnosis
of typhoid and must be sent before starting antibiotics.
• The culture of Typhi can be done from many body fluids
such as blood, bone marrow, urine, rose spot biopsy
extracts, duodenal aspirates and stool, while the blood
culture remains the mainstay of definitive diagnosis.
• Blood cultures are positive in 40-80% of cases usually
early in the course of the disease.
• Culture of bone marrow aspirate is 90% sensitive until at
least 5 days after commencement of antibiotics.

• Cultures from stool are usually not positive in early
disease.
• Blood cultures can still be sent even if the patient is
already on antibiotics.
• The volume of blood cultured is one of the most
important factors in the isolation of Typhi from
typhoid patients:
• At least 20ml of blood should be obtained from an
adult patient.
• For children:
3-5 ml- for children < 5years
5-10ml –from children 5-12 years
10-15ml –from children >12 years

• Serological Tests:
• Serological tests (Widal and Typhidot)
are not recommended in the diagnosis of
typhoid.
• Both have low sensitivity and specificity and
do not provide information on antimicrobial
sensitivity.

Case Definition of Typhoid:
• Probable/Suspected case of typhoid fever
• A patient with documented fever (38°C and
above) for at least 5 days prior to presentation,
• and having no other focus to explain the cause
of the fever (e.g. UTI, pneumonia, abscess etc.)
• OR a clinically compatible case that is
epidemiologically linked to a confirmed case of
typhoid fever

• Confirmed case of typhoid fever
• A patient with persistent fever (38 °C or above) lasting
3 or more days
• and S. Typhi isolated on blood or bone marrow
culture.
Chronic carrier
An individual excreting S. Typhi in the stool or
urine for longer than one year after a blood
culture confirmed episode of typhoid fever.
In the absence of a culture confirmation of prior
illness it is not possible to label a person as a
carrier

Note: Positive serological tests (such as Widal and
TyphiDOT) are not recommended for diagnosis of
enteric fever and are not included in case
definitions of Typhoid.
The confirmed cases of typhoid fever can be
classified as
drug-sensitive/ non-resistant,
multi-drug resistant (MDR),
extensively drug resistant (XDR)
or extended spectrum beta-lactamase positive
typhoid fever, based on drug susceptibility patterns.
•

•Classification of Typhoid Fever Cases by Drug
Resistance Status, Pakistan, 2018 A
Typhoid fever which are sensitive to first-line
drugs1 and third generation cephalosporins2,
with or without resistant to second-line
drugs3.
Non-resistant typhoid
fever
Typhoid fever which are resistant to first-line
drugs1 ,sensitive to third generation
cephalosporins2, with or without resistant to
second-line drugs
Multi-drug resistant
typhoid fever
Typhoid fever which are resistant to all the
recommended antibiotics for typhoid fever
Extensively drug
resistant typhoid fever
Typhoid fever caused by S. Typhi strains
which are resistant to third generation
cephalosporins but may be sensitive to
chloramphenicol, cotrimoxazole or
fluoroquinolones
ESBL(extended
spectrum beta-
lactamase )positive
typhoid fever

Case Definition( Egypt)
•‫المشتبهة‬ ‫الحالة‬:
•‫عن‬ ‫تزيد‬ ‫مستمرة‬ ‫حمي‬ ‫من‬ ‫يعاني‬ ‫شخص‬ ‫اي‬38‫درجة‬
‫التبلغ‬ ‫لكنها‬ ‫تتناقص‬ ‫فاكثر‬ ‫ايام‬ ‫ثالثة‬ ‫لمدة‬ ‫مئوية‬‫االساس‬ ‫خط‬
‫معوي‬ ‫ارتباك‬ ‫مع‬(‫امساك‬ ‫او‬ ‫اسهال‬ ‫او‬ ‫بالبطن‬ ‫الم‬)‫اثن‬ ‫مع‬‫ين‬
‫االتية‬ ‫االعراض‬ ‫من‬ ‫اكثر‬ ‫او‬:
•‫جاف‬ ‫سعال‬-‫القلب‬ ‫ضربات‬ ‫في‬ ‫نسبي‬ ‫بطء‬–‫فقان‬‫شهية‬-
‫شديد‬ ‫صداع‬.
•‫المحتملة‬ ‫الحالة‬:
•‫مشتبهة‬ ‫حالة‬+‫موجب‬ ‫فيدال‬160‫اكثر‬ ‫او‬

•‫المؤكدة‬ ‫الحالة‬:
‫متزايد‬ ‫ارتفاع‬(‫الضعف‬ ‫بمقدار‬)‫من‬ ‫فيدال‬ ‫اختبار‬ ‫في‬‫المرحالة‬
‫النقاهة‬ ‫مرحلة‬ ‫الي‬ ‫الحادة‬(‫تقريبا‬ ‫اسبوعين‬.)
‫الس‬ ‫ميكروب‬ ‫بعزل‬ ‫تاكيدها‬ ‫يتم‬ ‫اومحتملة‬ ‫مشتبهة‬ ‫حالة‬‫الومنيال‬
‫الدم‬ ‫من‬ ‫مزرعة‬ ‫بواسطو‬(‫اال‬ ‫ظهور‬ ‫من‬ ‫اسبوع‬ ‫اول‬ ‫في‬
‫عراض‬)‫براز‬ ‫مزرعة‬ ‫او‬(‫في‬‫وثالث‬ ‫ثاني‬‫ظهور‬ ‫من‬ ‫اسبوع‬
‫عراض‬ ‫اال‬)

Management Guidelines:
• 1-In bacteraemic patients, automated blood
cultures can turn positive as early as 4 hours, with
final identification and susceptibility results being
available in the following 48 hours.
• 2-Two sets of blood culture are optimal before
starting antibiotic therapy and in those patients
who are already on antibiotics but not responding
to therapy.
• 3-Serological tests should never be ordered or
relied upon to diagnose or rule out enteric fever.

• 4-After sending baseline investigations,
including blood cultures, commence empirical
treatment for suspected enteric fever with either
oral cefixime or IV ceftriaxone depending on the
severity of the disease.
• 5-In the absence of a positive blood culture or if
a blood culture shows no growth, re-evaluate
the diagnosis and stop or modify antibiotics if
not typhoid.

Diagnosis of Carriers
 Eradication of carriage is of prime
Importance.
Useful in screening food handlers, cooks, to
detect carrier state
Typhoid bacilli can be isolated from feces or
from bile aspirates
Detection of Vi agglutinins in the Blood
can be determinant of carrier state.

 Sa l m o n e l l a t y p h i crosses the intestinal epithelial layer
and is carried by macrophages to the liver, pancreas, and
spleen.
 From the liver, the organisms can be shed into the
gallbladder, where, they can stay for long periods and give
rise to either an active infection (cholecystitis) or a chronic
infection (carrier state).
 About 3 to 5% of infected people become carriers,
particularly those with gallbladder abnormalities, such as
gallstones.
 These people are often asymptomatic and can remain in this
state for many years

The chronic carrier state is the single most
important risk factor for development of
hepatobiliary carcinomas.

Treatment
Supportive treatment:
• Antipyretics as required
• Adequate rest, hydration, and correction of
fluid-electrolyte imbalance
• Adequate nutrition: a soft, easily digestible
diet should be continued unless the patient
has abdominal distension or ileus.
• In case of severe illness monitor blood
pressure, blood sugar, electrolytes,
hemoglobin , platelet counts and liver
functions as indicated

Diet for typhoid fever
• Avoid raw food.
• Avoid raw, unpeeled fruits and vegetables
that may have been washed with
contaminated water, especially lettuce and
fruits like berries that can't be peeled.
• Bananas, avocados, and oranges make better
choices, but be sure you peel them yourself.
• Meats , eggs, Chechen and tea can be
eaten but must be cooked well

Empiric treatment
• Start empirical treatment with cephalosporins, until blood
culture results are available.
• Oral Cefixime 400 mg q12hr or
IV Ceftriaxone 1gm q12hr or 2gm q24hr
• Once the results of blood culture are available, modify
antibiotic regimen based on the final antibiotic sensitivity
results.
• Avoid prescribing azithromycin as an empirical choice of
treatment.
• Prescribe azithromycin for extensively drug resistant (XDR)
typhoid only.
• Refer the patient to a secondary or tertiary care centre, in
cases where no clinical signs of improvement are not seen
despite switching to IV antibiotics (for at least 48 hours) and
blood cultures remains negative

Antibiotic choices for treatment of typhoid
• First-line antibiotics :
Duration
in days
Dosage:
mg/kg/day
Adult
dosage/day
Routeantibiotic
1450 mg/kg in 4
doses
500 mg q6hrOral, IVChloramphenicol
144-20 mg/kg: in
2 dose
160/800 mg
q12h
Oral, IVTrimethoprim-
Sulfamethoxazole
1475-100 mg/kg:
in 4 doses
1000-2000 mg
q6hr
Oral, IV,ImAmpicillin/Amoxi
cillin

Second-line antibiotics:
DurationDosage:
mg/kg/day
Adult
dosage/day
RouteANTIBIOTIC
10-141gm q12hr or 2
gm q24hr
IM, IVCeftriaxone
10-1420 mg/kg: in 1-
2 doses
400 mg q12hrOralCefixime
10-14500 mg to 750
mg q12hr /400
mg q12hr
Oral/IVCiprofloxacin

Third line antibiotics :
DurationDosage:
mg/kg/day
Adult dosage/dayRouteAntibiotic
7-108-10 mg/kgPatient weight <60kg:
1gm loading dose PO,
then 500mg q24hr for
7-10 days
Patient weight > 60kg: 1
gm q24hr
oralAzithromycin
10-1460mg/kg/day:
in 3 doses
1 gm q8hrI.VMeropenem
10-1420-
60mg/kg/day:
in 3/4 doses
500mg q6hr or 1g q8hI.VImipenem

Definitive treatment
• Susceptible typhoid or Non-resistant typhoid
fever:
MEDICATION TREATMENT
MDR-area
WHO RECOMMENDATIONS

•CONTROL OF
TYPHOID FEVER
•1. Control of reservoirs cases
& carriers
2. Control of sanitation
3. Immunization

CASES
I. Early diagnosis by culture of blood & stool
II. Notification done where it is mandatory
III. Isolation till 3 negative tests
IV. Treatment by appropriate antibiotics
V. Disinfection of stool & urine by 5% cresol for 2
hours and cloths by 2% chlorine
VI. Follow-up examination of stool & urine at 3-4
months & at 12 months after discharge

Treatment of Carriers
• 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.
• Ciprofloxacin750 mg BD x 4/52 Ciprofloxacin
is not recommended for pregnant women. It
can be used among children if the benefits
outweigh the potential harms

•Treatment by intensive course of
ampicillin/amoxicillin with probenecid for 6
weeks.
•ORCholecystectomy if lithiasis is present
•Treat schistosomiasis if present
• Vi (virulence) antibody test useful to screen
carriers

2- CONTROL OF SANITATION
• Protection & purification of drinking
water supplies
• Improvement of basic sanitation
• Promotion of food hygiene

Simple hand hygiene and
washing can reduce several cases
of Typhoid

3- IMMUNIZATION
Vaccination recommended to-
1- those live in endemic area
2- household contacts
3- Group at risk like school children and hospital staff etc.
4- those attending melas & yatras
Two types of vaccines-
1.Injectable Typhoid vaccine
(TYPHIM –Vi, TYPHIVAX)
2. The live oral vaccine (TYPHORAL)

Injectable Typhim –Vi Vaccine
• 1. This single-dose injectable typhoid vaccine,
from the bacterial capsule of S. typhi strain of
Ty21a.
• 2. This vaccine is recommended for use in
children over 2 years of age.
• 3. Sub-cutaneous or intramuscular injection
4. Efficacy : 64% -72%

Typhoral Vaccine
1. This is a live-attenuated-bacteria
vaccine manufactured from the
Ty21a strain of S. typhi.
2. The efficacy rate of the oral
typhoid vaccine ranges from 50-80%
3. Not recommended for use in
children younger than 6 years of age.

4. The course consists of one capsule orally,
taken an hour before food with a glass of
water or milk (1stday, 3rd day & 5th day)
5. No antibiotic should be taken during this
period
6. Immunity starts 2-3 weeks after
administration and lasts for 3 years
7. A booster dose after 3 years

Facts of Vaccines for Typhoid
Need a booster
Immunity lasts for 3 years
Vaccines are not effective in
prevention of Paratyphoid fevers

Typhoid fever

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Typhoid fever