Enteric (typhoid and paratyphoid) fevers

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    Last updated: September 2022

     

     

    Enteric fevers include typhoid fever, due to Salmonella enterica serotype Typhi (S. Typhi) and paratyphoid fever, due to Salmonella enterica serotype Paratyphi A, B or C (S. Paratyphi).

    Enteric fevers are acquired by the ingestion of water or food contaminated with excreta of symptomatic or asymptomatic carriers or by direct contact (dirty hands).

    Enteric fevers are endemic in South, Central and Southeast Asia, sub-saharan Africa, Oceania and, to a lesser extent, in Latin America.

    Effective treatment significantly reduces the risk of complications and death.

    Clinical features

    Clinical manifestations of typhoid and paratyphoid fevers are the same. Enteric fevers have insidious onset and vary from mild to severe. 

    • The characteristic sign is prolonged fever, which gradually increases during the first week, plateaus the second week then decreases between the third and fourth week.  
    • Non-specific signs and symptoms are frequently associated: gastrointestinal disturbances (abdominal pain, constipation or diarrhoea, vomiting), headache, malaise, chills, fatigue, non productive cough and/or hepatosplenomegaly. 
    • Erythematous maculopapular rash on the trunk extreme fatigue and/or relative bradycardia (heart rate-temperature dissociation) may be present.
    • Serious complications affect about 27% of hospitalised patients [1] Citation 1. Cruz Espinoza LM, McCreedy E, Holm M, et al. Occurrence of typhoid fever complications and their relation to duration of illness preceding hospitalization: a systematic literature review and meta-analysis. Clin Infect Dis 2019;69(Suppl 6):S435-48.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821330/ [Accessed 28 June 2022]
      and usually occur during the second or third week of illness. These may incude decreased level of consciousness, intestinal haemorrhage or perforation or peritonitis, shock, or nephritis. In pregnant women, severe infection may lead to foetal complications (miscarriage, preterm delivery, intrauterine death).
    • Relapse may occur 2 to 3 weeks after recovery. It is usually not due to antibiotic resistance, and re-treatment is required.

     

    Clinical diagnosis is difficult as enteric fevers resembles other infections present in regions where they are endemic. The main differential diagnoses are: malaria, brucellosis, leptospirosis, typhus, rickettsiosis, sepsis and dengue.

    Laboratory

    • Culture of S. Typhi or Paratyphi and drug susceptibility test (blood and stool specimens).
    • In all cases, rapid test for malaria in endemic regions (and antimalarial treatment if needed, see Malaria, Chapter 6). 
    • Widal agglutination test, other serologic tests, and rapid diagnostic tests are not recommended (low sensitivity and specificity). 

    Treatment

    In all cases

    • Hydrate and treat fever (Chapter 1). Fever usually resolves 4 to 5 days after starting effective antibiotic treatment.
    • Choice of antibiotic treatment depends on the susceptibility of the strain, or when susceptibility is unknown, on recent data on susceptibility of strains in the region. Check national recommendations. For information:
      • Strains resistant to chloramphenicol, ampicillin/amoxicillin and co-trimoxazole (multidrug-resistant, MDR strains) are present in most parts of the world. 
      • Ciprofloxacin is used as first-line treatment in some countries, however fluoroquinolone resistance is endemic in Asia and is increasing in several parts of the world [2] Citation 2. Browne AJ, Hamadani BHK, Kumaran EAP, Rao P, et al. Drug-resistant enteric fever worldwide, 1990 to 2018: a systematic review and meta-analysis. BMC Medicine 2020;18:1+22.
        https://doi.org/10.1186/s12916-019-1443-1 [Accessed 23 February 2022]
        .
      • Ceftriaxone resistance has been identified in several regions [2] Citation 2. Browne AJ, Hamadani BHK, Kumaran EAP, Rao P, et al. Drug-resistant enteric fever worldwide, 1990 to 2018: a systematic review and meta-analysis. BMC Medicine 2020;18:1+22.
        https://doi.org/10.1186/s12916-019-1443-1 [Accessed 23 February 2022]
        .
      • MDR strains also resistant to fluoroquinolones and third-generation cephalosporins (extensively drug-resistant, XDR strains) have developed [3] Citation 3. Klemm EJ, Shakoor S, Page AJ, Qamar FN, et al. Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins. mBio. 2018 Jan-Feb; 9(1): e00105-18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821095/ [Accessed 26 June 2022] .​​​

    Uncomplicated cases (outpatients)

    Uncomplicated cases (the vast majority of cases) can be treated with an oral antibiotic treatment.

    • First-line antibiotics:
      azithromycin PO for 7 days (including for MDR and XDR cases, and pregnant women)
      Children: 10 to 20 mg/kg (max. 1 g) once daily 
      Adults: 500 mg to 1 g once daily or 1 g on D1 then 500 mg once daily
      or
      cefixime PO for 10 to 14 days (except for third-generation cephalosporin resistance and XDR cases)
      Children: 10 mg/kg (max. 200 mg) 2 times daily
      Adults: 200 mg 2 times daily
    • Alternatives include, only if recent data show susceptibility of strains to these antibiotics in the region:
      amoxicillin PO for 14 days
      Children: 30 mg/kg (max. 1 g) 3 times daily 
      Adults: 1 g 3 times daily
      or
      co-trimoxazole PO for 14 days
      Children: 20 mg SMX + 4 mg TMP/kg (max. 800 mg SMX + 160 mg TMP) 2 times daily 
      Adults: 800 mg SMX + 160 mg TMP 2 times daily

    Severe cases (inpatients)

    • Severe cases include:
      • toxic appearance or decreased level of consciousness or medical or surgical complication;
      • oral administration not possible due to persistent vomiting.

    These cases should be treated under close monitoring. Antibiotic treatment is initially parenteral, then oral when there is decreasing fever, clinical improvement and the patient can tolerate oral treatment.

    • Start with ceftriaxone IV a Citation a. The solvent of ceftriaxone for IM injection contains lidocaine. Ceftriaxone reconstituted using this solvent must NEVER be administered by IV route. For IV administration, water for injection must always be used. (including for pregnant women)
      Children: 50 to 100 mg/kg (max. 4 g) once daily
      Adults: 2 g once daily or 2 times daily
      Then change to azithromycin PO (as above) to complete at least 7 days of treatment.
    • For suspected or confirmed ceftriaxone resistance or XDR stains, use meropenem IV, including for pregnant women, then change to azithromycin PO to complete at least 7 days of treatment.

    Additional measures

    • In case of decreased level of consciousness or shock, dexamethasone IV: 3 mg/kg then 1 mg/kg every 6 hours for 2 days (total of 8 doses)   
    • Treat in intensive care unit patients with shock, significant intestinal haemorrhage or suspected perforation/peritonitis. If suspected perforation/peritonitis, get urgent surgical review and add metronidazole to ceftriaxone for anaerobic bacterial coverage b Citation b. Do not add metronidazole if the patient receives meropenem (meropenem already covers anaerobic bacteria). .

    Prevention

    • Hygiene measures common to all diarrhoeas: handwashing; consumption of treated water (chlorinated, boiled, bottled, etc.); washing/cooking of food, etc.
    • In hospitals: for patients with watery diarrhoea, consider disinfection of excreta with chlorinated solution, if stools are collected in buckets.
    • Vaccination with the typhoid conjugate vaccine in endemic regions c Citation c. For more information, see Typhoid vaccines: WHO position paper:
      http://apps.who.int/iris/bitstream/handle/10665/272272/WER9313.pdf?ua=1
      . This vaccine can be used to control typhoid outbreaks. It does not protect against paratyphoid fever.

     

    Footnotes
    • (a)The solvent of ceftriaxone for IM injection contains lidocaine. Ceftriaxone reconstituted using this solvent must NEVER be administered by IV route. For IV administration, water for injection must always be used.
    • (b)Do not add metronidazole if the patient receives meropenem (meropenem already covers anaerobic bacteria).
    • (c)For more information, see Typhoid vaccines: WHO position paper:
      http://apps.who.int/iris/bitstream/handle/10665/272272/WER9313.pdf?ua=1
    References
    • 1.Cruz Espinoza LM, McCreedy E, Holm M, et al. Occurrence of typhoid fever complications and their relation to duration of illness preceding hospitalization: a systematic literature review and meta-analysis. Clin Infect Dis 2019;69(Suppl 6):S435-48.
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821330/ [Accessed 28 June 2022]
    • 2. Browne AJ, Hamadani BHK, Kumaran EAP, Rao P, et al. Drug-resistant enteric fever worldwide, 1990 to 2018: a systematic review and meta-analysis. BMC Medicine 2020;18:1+22.
      https://doi.org/10.1186/s12916-019-1443-1 [Accessed 23 February 2022]
    • 3.Klemm EJ, Shakoor S, Page AJ, Qamar FN, et al. Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins. mBio. 2018 Jan-Feb; 9(1): e00105-18. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821095/ [Accessed 26 June 2022]