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.
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 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)
- Coated tongue
- Weakness and fatigue
- Muscle aches
- Dry cough
- Loss of appetite and weight loss
- Abdominal pain
- Diarrhea or constipation
- 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 some cases, signs and symptoms may return up to two weeks after the fever has subsided.
- The criterion standard for diagnosis of typhoid fever has long been culture isolation of the organism. Cultures are widely considered 100% specific.
- 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 differentiate 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
- 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
- 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 benefit.
- 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 cases where there is no growth of any microorganisms.
- In case of a positive blood culture, a report with organism identification 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 (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, with rising trend in clinic and having no other focus to explain the cause of the fever (e.g. UTI, pneumonia, abscess etc.) ORA 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 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 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
|Non-resistant typhoid fever||Typhoid fever caused by S. Typhi and or S. Paratyphi A, B or C strains which are sensitive to first-line drugs 1 and third generation cephalosporins2, with or without resistant to second-line drugs3.
|Multi-drug resistant typhoid fever||Typhoid fever caused by S. Typhi and or S. Paratyphi A, B or C strains which are resistant to first-line drugs 1 ,sensitive to third generation cephalosporins2, with or without resistant to second-line drugs3.
|Extensively drug resistant typhoid fever||Typhoid fever caused by S. Typhi strains which are resistant to all the recommended antibiotics for typhoid fever4.
|ESBL positive typhoid fever5||Typhoid fever caused by S. Typhi strains which are resistant to third generation cephalosporins but may be sensitive to chloramphenicol, cotrimoxazole or fluoroquinolones.
1 Chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole
2 Cefixime is recommended by the International Academy of the Philippines (IAP) for uncomplicated typhoid fever. Ceftriaxone is recommended for complicated typhoid fever.
4 First and second-line drugs, and third generation cephalosporins
5 MMIDSP has added a further category to this classification on reports of S. Typhi strains that are resistant to third generation cephalosporins but sensitive to chloramphenicol, cotrimoxazole or fluoroquinolones.
- 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.
- 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 cefixime 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.
- 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
- 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 Cefixime 400 mg q12hr or
IV Ceftriaxone 1gm q12hr or 2gm q24hr
- Oral Cefixime 400 mg q12hr or
- If the initial therapy was PO cefixime, 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 final antibiotic sensitivity results. Refer to section on Definitive 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.
- Definitive treatment
- 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 fluoroquinolones. Cephalosporins can be de-escalated to the any of the first-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 fluoroquinolones. These strains are sensitive to third-generation cephalosporins. Cephalosporins can be continued in this scenario. IV ceftriaxone can be switched to oral cefixime. 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 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 fluoroquinolones, then chose one of the first line options, if the patient is clinically stable or de-escalate to the first 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.
- 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.
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. Offers 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 effective and would require repeat immunizations, as vaccine effectiveness diminishes over time.
- Vaccinate everyone, including:
- All household members of a confirmed 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 first.) 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 flavored ice and juice because they may have been made with contaminated water
- Choose hot foods: Eat foods that have been thoroughly cooked.
- Control of flies: Ensure that cooked food is covered to protect it from flies.
- Avoid meat which is undercooked
Antibiotic choices for treatment of typhoid 2
|Antibiotic||Route||Adult dosage/day||Dosage: mg/kg/day||Duration in days|
|First-line antibiotics :|
|Chloramphenicol||Oral, IV||500 mg q6hr||50 mg/kg in 4 doses *||14|
|Trimethoprim-Sulfamethoxazole||Oral, IV||160/800 mg q12hr||4-20 mg/kg: in 2 dose||14|
|Ampicillin/Amoxicillin||Oral, IV, IM||1000-2000 mg q6hr||75-100 mg/kg: in 4 doses||14|
|Ceftriaxone||IM, IV||1gm q12hr or 2 gm q24hr||–||10-14|
|20 mg/kg: in 1-2 doses||10-14|
|Ciprofloxacin||Oral/IV||500 mg to 750 mg q12hr /400 mg q12hr||–||10-14|
|Third line antibiotics :|
|Azithromycin||Oral||Patient weight <60kg: 1gm loading dose PO, then 500mg q24hr for 7-10 days.||8-10 mg/kg||7 – 10|
|Patient weight > 60kg: 1 gm q24hr|
|Meropenem||IV||1 gm q8hr||60mg/kg/day: in 3 doses||10-14|
|Imipenem||IV||500mg q6hr or 1g q8hr||20-60mg/kg/day: in 3/4 doses||10-14|
|Ertapenem||IV||1 gm q24hr||–||10-14|
* Dose of chloramphenicol may be reduced to 25 mg/kg after defervescence
- Current Trends in the Management of Typhoid Fever. SP Kalra et al. MJAFI 2003; 59 : 130-135
- World Health Organization. (2003). Background document: the diagnosis, treatment and prevention of typhoid fever. Geneva: World Health Organization.
- 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:
MMIDSP Officer Bearers:
|Prof. Bushra Jamil (AKUH)||Dr Summiya Nizamuddin (SKMCH&RC)||Dr Sunil Dodani (SIUT)|
‘Typhoid Management Guidelines’ can be downloaded by clicking the following link: