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Typhoid Management Guidelines – 2019

Introduction

Typhoid fever is endemic in Pakistan. With the emergence of the extensively drug
resistant Salmonella Typhi, its management has become a challenge. This document is
intended to guide all physicians regarding the appropriate management of typhoid in
the setting of high antimicrobial resistance.

Presentation

Typhoid and paratyphoid fevers are commonly grouped together under the collective
term ‘enteric fever’. Typhoid fever is caused by Salmonella enterica serovar Typhi and
paratyphoid fever is caused by either Salmonella Paratyphi A, B, or C. Both S. Typhi
and S. Paratyphi cause a fecal oral transmitted systemic disease, however, S. Paratyphi
causes a less severe illness.

Typhoid fever is an acute, life-threatening, febrile illness. The clinical syndromes

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associated with S. Typhi and Paratyphi are indistinguishable. Typhoid fever begins 7-14

days after ingestion of the organism. Signs and symptoms are likely to develop
gradually — often appearing one to three weeks after exposure to the disease. 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.

The clinical presentation of typhoid fever varies from a mild illness with low grade
fever, headache, fatigue, malaise, loss of appetite, cough, constipation and skin rash or
rose spots to in some cases, a fatal complications such as intestinal perforations,
gastrointestinal hemorrhages, encephalitis and cranial neuritis.

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

In the later course of the disease, if timely management is not initiated, the patient
may become delirious and life threatening complications may develop at this time. In

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some cases, signs and symptoms may return up to two weeks after the fever has
subsided.

Laboratory Findings

• The criterion standard for diagnosis of typhoid fever has long been culture
isolation of the organism. Cultures are widely considered 100% speci�c.
• Most patients with typhoid fever are usually anemic, have normal blood counts, a
slightly raised erythrocyte sedimentation rate (ESR), occasional
thrombocytopenia, and relative leucopenia. CRP is not required.
• Liver transaminase and serum bilirubin values usually rise to twice the reference
range. LFTs should be done to di�erentiate from acute viral hepatitis, which can
begin with non-localizing fever.
• Mild hyponatremia and hypokalemia are common.
• Dengue and malaria should also be ruled out

Microbiological Diagnosis

• The culture of Typhi can be done from many body �uids such as blood, bone
marrow, urine, rose spot biopsy extracts, duodenal aspirates and stool, while the
blood culture remains the mainstay of de�nitive diagnosis
• Positive serological tests (such as Widal and TyphiDOT) are not recommended for
diagnosis of enteric fever.
• Blood culture is the gold standard test for the diagnosis of typhoid and must be
sent before starting antibiotics
• 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. However, this technique is extremely painful,
which may outweigh its bene�t.
• Cultures from stool are usually not positive in early disease.
• Empirical treatment for typhoid should not be commenced without obtaining
blood cultures. Blood cultures can be taken even if patient is currently afebrile.
• Blood cultures can still be sent even if the patient is already on antibiotics.
• A blood culture report is available in around 7 days after sample submission in

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cases where there is no growth of any microorganisms.

• In case of a positive blood culture, a report with organism identi�cation and
antibiotic sensitivity testing will be available in as early as 3 to 4 days.
• A negative culture does not exclude typhoid and may warrant a repeat blood
culture if the fever is not responding in 7-9 days of commencing treatment.
• 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 and
inoculated (10ml each) in to the aerobic and anaerobic blood culture bottles.
◦ For children the following volumes are recommended in the single pediatric
bottle:
▪ 3-5 ml- for children < 5years
▪ 5-10ml –from children 5-12 years
▪ 10-15ml –from children >12 years
◦ A preliminary report of gram negative rods, which is followed by Non-lactose
fermenters, oxidase negative, from a blood culture sent while suspecting
enteric fever, is highly suggestive of Salmonella species and should be
treated on the lines of typhoid fever

Serological Tests

• Serological tests (Widal and Typhidot) are not recommended in the diagnosis of

typhoid. Both have low sensitivity and speci�city and do not provide information
on antimicrobial sensitivity.

Case De�nition of Typhoid:

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A patient with documented fever (38°C and above) for at

least 5 days prior to presentation, with rising trend in
clinic and having no other focus to explain the cause of

Probable/Suspected the fever (e.g. UTI, pneumonia, abscess etc.) ORA clinically

case of typhoid fever compatible case that is epidemiologically linked to a

con�rmed 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
Con�rmed case of
marrow culture.
typhoid fever
 

An individual excreting S. Typhi in the stool or urine for

longer than one year after a blood culture con�rmed
Chronic carrier episode of typhoid fever. In the absence of a culture
con�rmation of prior illness it is notpossible 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
de�nitions of Typhoid

The con�rmed cases of typhoid fever can be classi�ed 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.

Classi�cation of Typhoid Fever Cases by Drug Resistance Status, Pakistan, 2018 A 

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Classi�cation Case De�nition

Typhoid fever caused by S. Typhi and or S. Paratyphi A, B or C

strains which are sensitive to �rst-line drugs 1 and third

Non-resistant generation cephalosporins2, with or without resistant to

typhoid fever second-line drugs3.

Typhoid fever caused by S. Typhi and or S. Paratyphi A, B or C

strains which are resistant to �rst-line drugs 1 ,sensitive to third
Multi-drug
generation cephalosporins2, with or without resistant to
resistant typhoid
second-line drugs3.
fever
 

Typhoid fever caused by S. Typhi strains which are resistant to

Extensively drug
all the recommended antibiotics for typhoid fever4.
resistant typhoid
fever  

Typhoid fever caused by S. Typhi strains which are resistant to

third generation cephalosporins but may be sensitive to
ESBL positive
chloramphenicol, cotrimoxazole or �uoroquinolones.
5
typhoid fever
 

 1 Chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole

2 Ce�xime is recommended by the International Academy of the Philippines (IAP) for

uncomplicated typhoid fever. Ceftriaxone is recommended for complicated typhoid
fever.

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3 Fluoroquinolones

4 First and second-line drugs, and third generation cephalosporins

5
 MMIDSP has added a further category to this classi�cation on reports of S. Typhi
strains that are resistant to third generation cephalosporins but sensitive to
chloramphenicol, cotrimoxazole or �uoroquinolones.

Management Guidelines:

• In bacteraemic patients, automated blood cultures can turn positive as early as 4

hours, with �nal identi�cation and susceptibility results being available in the
following 48 hours.
• 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.
• Serological tests should never be ordered or relied upon to diagnose or rule out
enteric fever.
• It is important to rule out malaria, dengue and other possible causes of febrile
illness in a patient who presents with acute febrile illness of more than 3 days of
duration
• After sending baseline investigations, including blood cultures, commence
empirical treatment for suspected enteric fever with either oral ce�xime or IV
ceftriaxone depending on the severity of the disease.
• 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.
• Fever defervescence is prolonged in typhoid fever and may take 5-7 days to
improve. Do not rush to change antibiotics, monitor for improvement in
frequency and intensity of fever.
• The appetite and general condition of the patient may improve before
improvement in fever is noticed.
• Monitor for complications like abdominal distension, tenderness, vomiting,
alteration of GCS and laboratory parameters like bicytopenia.

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Treatment

• Supportive treatment:
• Antipyretics as required
• Adequate rest, hydration, and correction of �uid-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
• Empiric treatment
◦ Antibiotic treatment should be started as soon as possible to prevent
complications, relapse, and the development of chronic carriage.
◦ Typhoid is usually treated with a single agent antibiotic.
◦ It is important to obtain appropriate specimens before treatment so that
antimicrobial susceptibilities can be determined to guide treatment.
◦ Start empirical treatment with cephalosporins, until blood culture results
are available.
▪ Oral Ce�xime 400 mg q12hr or
IV Ceftriaxone 1gm q12hr or 2gm q24hr
◦ If the initial therapy was PO ce�xime, switch to IV ceftriaxone, if:
▪ there are no clinical signs of improvement after 5 days of treatment or
▪ any signs of complications appear
◦ Once the results of blood culture are available, modify antibiotic regimen
based on the �nal antibiotic sensitivity results. Refer to section on De�nitive
treatment for further details.
◦ 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.
◦ Avoid prescribing azithromycin as an empirical choice of treatment.
◦ Prescribe azithromycin for extensively drug resistant (XDR) typhoid only.
◦ De�nitive treatment

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▪ Susceptible typhoid or Non-resistant typhoid fever: This includes

typhoid caused by Typhi strains that are sensitive to ampicillin,
trimethoprim-sulfamethoxazole, chloramphenicol, third-generation
cephalosporins and/or �uoroquinolones. Cephalosporins can be de-
escalated to the any of the �rst-line options. Please refer to the table
below for dosage. Complete 14 days of treatment.
▪ MDR typhoid fever: This includes typhoid caused by Typhi strains that
are resistant to ampicillin, trimethoprim-sulfamethoxazole,
chloramphenicol, and/or �uoroquinolones. These strains are sensitive
to third-generation cephalosporins. Cephalosporins can be continued
in this scenario. IV ceftriaxone can be switched to oral ce�xime. Please
ensure at least 14 days of therapy with cephalosporins is completed.
Shorter courses may lead to relapse.
▪ XDR typhoid fever: This includes typhoid caused by Typhi strains, that
are resistant to all recommended antibiotics for typhoid fever, but is
sensitive to carbapenems and azithromycin. In this scenario, proceed
as follows:
▪ If the patient is clinically stable and able to tolerate orally,
discontinue cephalosporins, start azithromycin with dose according to
body weight.
▪ For a patient weighing <60kg, give 1gm loading dose orally, followed by
500mg PO q24hr for 7-10 days.
▪ For those weighing > 60kg – give PO 1 gm q24hr for 7-10 days
▪ If the patient is unable to take orally, is hemodynamically
unstable, deteriorating rapidly or develops complications, admit or
refer to a tertiary care centre. Choice of antibiotic in this situation
would be:
▪ Imipenem: 500mg q6h for 10 or 14 days or
▪ Meropenem: 1gm q8hr for 10 – 14 days or
▪ Ertapenem: 1gm q24hr for 10 – 14 days

Note: The treatment may be de-escalated to oral Azithromycin once the patient is
clinically improving and is able to tolerate oral medication to complete a total of 14

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days of therapy 

• ESBL positive typhoid fever: If the blood culture shows growth of an ESBL
positive strain of Typhi that is resistant to third-generation cephalosporins and
sensitive to carbapenems, azithromycin, as well to chloramphenicol,
cotrimoxazole or �uoroquinolones, then chose one of the �rst line options, if the
patient is clinically stable or de-escalate to the �rst line option after initial therapy
with carbapenems or azithromycin. Complete 14 days of treatment.

• Always aim to switch from IV to PO, once the patient is clinically stable and is able
to take orally. Also in case of isolation of a susceptible strain, aim to de-escalate
from a broad spectrum to a narrow spectrum drug.
• Despite completion of treatment, patients should be monitored for relapse or
complications for 3 months after treatment has commenced.

Complicated Typhoid:

• Suspected or culture proven enteric fever with jaundice, drowsiness, severe

abdominal pain and intestinal haemorrhage, severe sepsis or septic shock.
• Patients with complicated enteric fever should be managed at tertiary care
centres.

Prevention:
Vaccines: Two vaccines against typhoid are currently available in Pakistan.

• A single dose of injectable Vi polysaccharide vaccine for children > 2 years of

age. Revaccination is needed every 3 years for continued protection.
• A single dose typhoid conjugate vaccine is approved for use in children ≥ 6
months of age. O�ers protection for at least 3 years to adults, children, and
infants over 6 months of age. Revaccination schedule is under study at the
moment.
• Neither vaccine is 100 percent e�ective and would require repeat immunizations,

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as vaccine e�ectiveness diminishes over time.

• Vaccinate everyone, including:
◦ All household members of a con�rmed case (including adults and children
over 6 months of age)
◦ All healthcare workers
◦ All food handlers

• Because vaccines do not provide complete protection, or protection against other

water/food borne infections following preventive strategies should be followed:
◦ Hand washing
◦ Boiling of water before consumption
◦ Avoid raw vegetables and fruits that cannot be peeled. When you eat raw
fruit or vegetables that can be peeled, wash them thoroughly and peel them
yourself. (Wash your hands with soap �rst.) Do not eat the peelings.
◦ Avoid foods and beverages from street vendors.
◦ Ask for drinks without ice unless the ice is made from boiled or treated
water.
◦ Avoid �avored ice and juice because they may have been made with
contaminated water
◦ Choose hot foods: Eat foods that have been thoroughly cooked.
◦ Control of �ies: Ensure that cooked food is covered to protect it from �ies.
◦ Avoid meat which is undercooked

Antibiotic choices for treatment of typhoid 2

Adult Dosage: Duration

Antibiotic Route
dosage/day mg/kg/day in days

First-line antibiotics :

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Oral, 50 mg/kg in 4
Chloramphenicol 500 mg q6hr 14
IV doses *

Trimethoprim- Oral, 160/800 mg 4-20 mg/kg: in 2

14
Sulfamethoxazole IV q12hr dose

Oral, 1000-2000 mg 75-100 mg/kg: in

Ampicillin/Amoxicillin 14
IV, IM q6hr 4 doses

Second-line antibiotics:

1gm q12hr or 2
Ceftriaxone IM, IV – 10-14
gm q24hr

400 mg 20 mg/kg: in 1-2

Ce�xime Oral 10-14
q12hr doses

500 mg to 750
Cipro�oxacin Oral/IV mg q12hr /400 – 10-14
mg q12hr

Third line antibiotics :

Patient weight
<60kg: 1gm
loading dose
PO, then
500mg q24hr
Azithromycin Oral 8-10 mg/kg 7 – 10
for 7-10 days.

Patient weight
> 60kg: 1 gm
q24hr

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60mg/kg/day: in
Meropenem IV 1 gm q8hr 10-14
3 doses

500mg q6hr or 20-60mg/kg/day:

Imipenem IV 10-14
1g q8hr in 3/4 doses

Ertapenem IV 1 gm q24hr – 10-14

* Dose of chloramphenicol may be reduced to 25 mg/kg after defervescence

References

1. https://www.who.int/csr/don/27-december-2018-typhoid-pakistan/en/
2. Current Trends in the Management of Typhoid Fever. SP Kalra et al. MJAFI 2003;
59 : 130-135
3. World Health Organization. (2003). Background document: the diagnosis,
treatment and prevention of typhoid fever. Geneva: World Health Organization.
http://www.who.int/iris/handle/10665/68122

• These guidelines have been made in reference to the currently available literature
on typhoid and in consultation with Medical Microbiology and Infectious Diseases
experts of the MMIDSP.
• For any queries in reference to these guidelines, please send an email at:
[email protected], [email protected]

MMIDSP O�cer Bearers:

President General Secretary Treasurer

Prof. Bushra Jamil Dr Summiya Nizamuddin

Dr Sunil Dodani (SIUT)
(AKUH) (SKMCH&RC)

‘Typhoid Management Guidelines’ can be downloaded by clicking the following link:

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MMIDSP Typhoid Management Guidelines

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