Enteric (typhoid and paratyphoid) fevers


– Enteric fevers are systemic infections caused by bacteria of the genus Salmonella. The organisms enter the body via the gastrointestinal tract and gain access to the bloodstream via the lymphatic system.
– Typhoid fever is due to Salmonella enterica serotype Typhi and paratyphoid fever is due to Salmonella enterica serotype Paratyphi A, B or C.
– 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 on the Indian subcontinent, Southeast Asia, sub-saharan Africa and, to a lesser extent, in Latin America1; they mainly affect children under 15 years.

Clinical features

Typhoid fever
Clinical manifestations vary from mild to severe forms. 
– The characteristic sign is prolonged, mild (38-39 °C) or high (40-41 °C) fever. The fever gradually increases during the first week, plateaus the second week then decreases between the third and fourth week.  
– Fever is accompanied by non-specific signs and symptoms: gastrointestinal disturbances (abdominal pain, constipation or diarrhoea, vomiting), headache, malaise, chills, asthenia, non productive cough and/or splenomegaly. 
– Other more specific signs may be present: erythematous maculopapular rash on the trunk (5 to 30% of patients), stupor and extreme fatigue, relative bradycardia (heart rate-temperature dissociation).
– Serious complications, mainly gastrointestinal (gastrointestinal haemorrhage or perforation, peritonitis) occur in 10 to 15% of cases. In pregnant women, risk of foetal complications (miscarriage, preterm delivery, intrauterine death).

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

Paratyphoid fever
The symptoms of paratyphoid fever are the same as those of typhoid fever, although the illness is usually shorter and less severe. 

Laboratory

– In all cases, rule out malaria in endemic regions (rapid test).
– Diagnosis: culture of S. Typhi or Paratyphi and antibiotic susceptibility test (blood sample the first week or stool sample from second week). For blood cultures collect 10 ml of blood. 
– Other tests:
• Blood cell count: a normal or low leucocyte count can be an indication.  
• Widal-Felix agglutination reaction: this test is still used in certain endemic countries as it is cheap. Threshold titer vary according to the region. It should not be performed before the second week of illness. Two samples must be collected 10-15 days apart to detect an increase in antibodies. Its specificity and sensitivity are low. 

Treatment

– Hydrate and treat fever (Chapter 1), which will not decrease until 4 to 5 days after starting antibiotherapy.
– Uncomplicated cases (approximately 90% of patients): outpatient antibiotherapy by oral route for 7 days. 
– Severe cases (e.g. alteration of the general state, neurological disorders, oral administration not possible due to persistant vomiting, etc.) and pregnant women: inpatient antibiotherapy by parenteral route, then switch to oral route as soon as possible to complete 14 days (or 21 days) of treatment. Closely monitor patients to rapidly detect any complications (worsening abdominal pain, meteorism and abdominal guarding, dehydration, etc.). 
– Choice of antibiotherapy: the choice depends on the susceptibility of the strain to antibiotics, or if antibiotic susceptibility testing is not available, on recent regional data on susceptibility of isolated strains. The appearance of multiresistant strains (resistant to first-line antibiotics: chloramphenicol, ampicilin and cotrimoxazole) has led to the frequent use of fluoroquinolones. Fluoroquinolone resistance is currently endemic in Asia2.

Antibiotherapy (except in pregnant or breast-feeding women)

Uncomplicated cases

No resistance to ciprofloxacin

ciprofloxacin PO 
Children: 15 mg/kg 2 times daily (max. 1 g daily)
Adults: 500 mg 2 times daily

Resistance to ciprofloxacin

azithromycin PO 
Children: 10 to 20 mg/kg once daily (max. 1 g daily)
Adults: 1 g once daily
or
cefixime PO 
Children: 10 mg/kg 2 times daily (max. 400 mg daily)
Adults: 200 mg 2 times daily

Region with data on susceptibility to these antibiotics from recent drug susceptibility tests

chloramphenicol PO 
Children > 1 year and < 13 years: 25 mg/kg 3 times daily (max. 3 g daily)
Children ≥ 13 years and adults: 1 g 3 times daily

amoxicillin PO 
Children: 30 mg/kg 3 times daily (max. 3 g daily)
Adults: 1 g 3 times daily

co-trimoxazole PO 
Children: 20 mg SMX + 4 mg TMP/kg 2 times daily (max. 1600 mg SMX + 320 mg TMP daily)
Adults: 800 mg SMX + 160 mg TMP 2 times daily

Severe cases

No resistance to ciprofloxacin 
or
Resistance to ciprofloxacin

ceftriaxone IV1  
Children: 50 to 100 mg/kg once daily (max. 4 g daily)
Adults: 2 g once daily or 2 times daily

Region with data on susceptibility to these antibiotics from recent drug susceptibility tests

chloramphenicol IV 
Children > 1 year and < 13 years: 25 mg/kg every 8 hours (max. 3 g daily)
Children ≥ 13 years and adults: 1 g every 8 hours

ampicillin IV 
Children: 50 mg/kg every 6 to 8 hours (max. 3 g daily)
Adults: 1 g every 6 to 8 hours


Antibiotherapy in pregnant or breast-feeding women

Preferably use cefixime or azithromycin or ceftriaxone. If none of them are available, use ciprofloxacin, the life-threatening risk of typhoid outweighs the risk of adverse effects.

– In case of severe typhoid fever with neurological disorders (hallucinations, altered mental status):
dexamethasone IV: initial dose of 3 mg/kg then 1 mg/kg every 6 hours for 2 days (8 doses)

– Treatment in intensive care unit in case of gastrointestinal haemorrhage; surgery in case of gastrointestinal perforation.

Prevention

– Hygiene measures common to all diarrhoeas: handwashing; consumption of treated water (chlorinated, boiled, bottled, etc.); washing/cooking of food, etc.
– In hospitals: disinfection of excreta with 2% chlorinated solution.
– Vaccination: in endemic regions the WHO recommends the administration of a single dose of 0.5 ml of conjugated typhoid vaccine in children from the age of 6 months to adults aged 45 years to reduce typhoid morbidity as well as the use of antibiotics, and to slow the development of resistance of Salmonella Typhi3. This vaccine does not protect againt paratyphoid fever.



Footnotes
Ref Notes
1

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.


References

  1. Crump JA, Mintz ED. Global trends in typhoid and paratyphoid Fever. Clin Infect Dis. 2010;50(2):241-6.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798017/pdf/nihms154999.pdf [Accessed 15 november 2018]

  2. John Wain, Rene S Hendriksen, Matthew L Mikoleit, Karen H Keddy, R Leon Ochiai. Typhoid fever. Seminar. Lancet. 2015 Mar 21;385(9973):1136-45.

  3. World Health Organization. Weekly epidemiological record Relevé épidémiologique hebdomadaire 30 MARCH 2018, 93th YEAR / 30 MARS 2018, 93e ANNÉE No 13, 2018, 93, 153–172
    http://apps.who.int/iris/bitstream/handle/10665/272272/WER9313.pdf?ua=1 [Accessed 12 november 2018]