What is the recommended treatment and prevention for suspected or confirmed typhoid fever in adults (including in regions with multidrug‑resistant Salmonella Typhi), children, and pregnant women?

Typhoid Fever: Treatment and Prevention

First-Line Treatment for Uncomplicated Typhoid Fever

Azithromycin 500 mg once daily for 7 days (adults) or 20 mg/kg/day for 7 days (children) is the preferred first-line treatment for uncomplicated typhoid fever, particularly for cases originating from South or Southeast Asia where fluoroquinolone resistance exceeds 70%. 1, 2

Why Azithromycin is Superior

• Azithromycin reduces clinical failure risk by 52% compared to fluoroquinolones (OR 0.48) 1, 2
• Hospital stay is shortened by approximately 1 day versus fluoroquinolones 1, 2
• Relapse rates are dramatically lower with azithromycin (OR 0.09) compared to ceftriaxone, with relapse occurring in <3% of cases 1, 2
• Common adverse effects include gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea) 1, 2

Treatment for Severe or Complicated Typhoid Fever

For severe disease, sepsis, or inability to tolerate oral therapy, use ceftriaxone 1-2 g IV/IM once daily for 5-7 days (adults) or 50-80 mg/kg/day IV/IM for 5-7 days (children, maximum 2 g/day). 1, 2

• Extend treatment to 14 days to further reduce relapse risk, which is <8% with a full course 1
• Ceftriaxone is especially critical for cases from Asia where fluoroquinolone resistance approaches 96% 1

Geographic Resistance Patterns: Critical Treatment Decisions

South and Southeast Asia (India, Pakistan, Bangladesh, Thailand, Vietnam)

• Never use ciprofloxacin empirically for cases from this region—resistance exceeds 70% and approaches 96% in some areas 3, 1, 2
• Nalidixic acid resistance (a marker for decreased ciprofloxacin susceptibility) increased from 19% in 1999 to 59% in 2008 3
• Multidrug resistance (ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole) affects 58-96% of isolates 4
• Start with azithromycin or ceftriaxone immediately 1, 2

Sub-Saharan Africa

• Ciprofloxacin may be considered only if nalidixic acid susceptibility is documented 1
• Otherwise, default to azithromycin as first-line 2

Diagnostic Approach Before Treatment

Obtain blood cultures immediately before starting antibiotics—sensitivity is 40-80% when collected in the first week of illness. 1

• Collect multiple large-volume specimens (≈20 mL) to maximize yield 1
• In clinically unstable or septic patients, start empiric therapy immediately after culture collection 1, 2
• Exclude malaria in all febrile travelers from tropical regions using thick/thin smears and rapid diagnostic tests 1
• Avoid the Widal test—it has only 68% specificity and 6% positive predictive value 1

Expected Clinical Response and Monitoring

• Fever typically clears within 4-5 days of appropriate antibiotic therapy 1, 2
• If fever persists >48 hours in a stable patient, reassess for alternative diagnoses or complications rather than changing antibiotics prematurely 1
• Persistent fever >3 days despite therapy warrants investigation for breakthrough infection or complications 1

Critical Treatment Duration

Complete a full 14-day antibiotic course even after fever resolution to minimize relapse risk. 1, 2

• Inadequately treated cases experience relapse in 10-15% of patients 1, 2
• Never discontinue antibiotics prematurely 2

Life-Threatening Complications

• Complications (intestinal perforation, encephalopathy, gastrointestinal bleeding) occur in 10-15% of untreated adults, usually in the second week 1
• Intestinal perforation is most common after >2 weeks of illness 1
• Surgical repair (simple excision and closure) achieves ≈88% success 1
• Consider corticosteroids in severe cases with toxic delirium or encephalopathy 1

Special Populations

Pregnant Women

• Ceftriaxone is the safest option during pregnancy 3
• Azithromycin may be used if benefits outweigh risks (Category B) 2
• Avoid fluoroquinolones due to potential cartilage toxicity 5

Children

• Azithromycin 20 mg/kg/day (maximum 1 g/day) for 7 days is preferred 1, 2
• Ceftriaxone 50-80 mg/kg/day (maximum 2 g/day) IV/IM for 5-7 days for severe disease 1, 2
• Fluoroquinolones should be avoided in children <18 years except when no alternatives exist 3

Alternative Agents (When First-Line Options Unavailable)

• Ciprofloxacin 500 mg twice daily for 7-14 days may be used only when susceptibility is confirmed and the case is not from South/Southeast Asia 2, 5
• Cefixime is listed only as an "alternative" option with documented failure rates of 4-37.6%; if used, mandatory test-of-cure at 1 week is required 2

Prevention: Vaccination Recommendations

Who Should Be Vaccinated

Vaccinate travelers to endemic areas (Latin America, Asia, Africa) with prolonged exposure to potentially contaminated food and water. 3, 6

• Persons with intimate exposure to documented typhoid carriers 6
• Microbiology laboratory workers who frequently handle S. Typhi 3, 6

Vaccine Options and Administration

Oral Ty21a vaccine (Vivotif):

• One enteric-coated capsule on alternate days for a total of four capsules 3, 6, 2
• Take with cool liquid ≤37°C, approximately 1 hour before meals 6, 2
• Booster every 5 years 3, 6, 2
• Efficacy: 50-67% for at least 4 years 6
• Contraindicated in children <6 years and immunocompromised persons (including HIV) 3, 6

Vi polysaccharide vaccine:

• 0.5 mL subcutaneously or intramuscularly as a single dose (adults and children ≥10 years) 6
• 0.25 mL subcutaneously for children 6 months to <10 years, given on two occasions separated by ≥4 weeks 6
• Booster every 2-3 years 3, 6
• Efficacy: 55% at 3 years 6

Vi-TT conjugate vaccine (preferred when available):

• Superior efficacy: 78% at 4 years 6
• Effective in infants and young children 2
• Less frequent boosting required 2

Critical Vaccine Limitations

• Vaccines provide only 50-80% protection and do not protect against Salmonella Paratyphi 6, 2, 5
• Vaccination is not a substitute for hand hygiene and safe food/water practices 3, 6, 2
• Protection can be overwhelmed by large inocula of S. Typhi 6
• Never use combination typhoid-paratyphoid vaccines—only monovalent S. Typhi preparations are recommended 2

Infection Control and Public Health Measures

• Typhoid fever is a notifiable disease—report cases promptly to local/state health authorities 1
• Implement contact precautions (gloves, gowns) and hand hygiene with soap and water (alcohol alone is insufficient) 3, 1
• Asymptomatic carriers in high-risk settings (healthcare, food service, childcare) should receive treatment per local public health guidance 3, 1
• Hand hygiene should be performed after using the toilet, changing diapers, before and after preparing food, before eating, and after handling garbage or soiled laundry 3

Common Pitfalls to Avoid

• Do not use ciprofloxacin empirically for cases from South or Southeast Asia 1, 2
• Do not rely on the Widal test for diagnosis 1
• Do not discontinue antibiotics when fever resolves—complete the full 14-day course 1, 2
• Do not use cefixime as first-line therapy—high failure rates necessitate test-of-cure 2
• Do not use oral Ty21a vaccine in immunocompromised patients 3, 6