What is the recommended management for typhoid fever?

Management of Typhoid Fever

First-Line Treatment Recommendation

Azithromycin 500 mg once daily for 7-14 days is the preferred first-line treatment for typhoid fever in adults, particularly given widespread fluoroquinolone resistance in endemic regions. 1, 2, 3

For children, use azithromycin 20 mg/kg/day (maximum 1g/day) for 7-14 days. 1, 2

Why Azithromycin Over Fluoroquinolones

The shift away from fluoroquinolones as empiric therapy is critical:

• Fluoroquinolone resistance exceeds 70% in South Asia and approaches 96% in some regions, making ciprofloxacin empirically inappropriate for cases originating from these areas 2, 3
• Azithromycin demonstrates superior clinical outcomes with lower risk of treatment failure (OR 0.48) compared to fluoroquinolones 1, 2
• Hospital stays are approximately 1 day shorter with azithromycin (mean difference -1.04 days) 2
• Relapse risk is dramatically lower with azithromycin (OR 0.09) compared to ceftriaxone 1, 3
• Research from Nepal confirms 97.8% of S. typhi isolates show resistance or intermediate susceptibility to ciprofloxacin 4

Treatment Algorithm Based on Clinical Severity

Uncomplicated Typhoid Fever

• Start azithromycin 500 mg once daily orally for 7-14 days 1, 2, 3
• Obtain blood cultures before initiating antibiotics when possible, as they have highest yield within the first week of symptoms 1, 2
• Expect fever clearance within 4-5 days of appropriate therapy 1, 3

Severe Cases or Sepsis Features

• Initiate ceftriaxone 1-2g IV/IM daily for adults (or 50-80 mg/kg/day for children, maximum 2g/day) for 5-7 days 1, 2
• Start broad-spectrum antimicrobial therapy immediately after collecting blood cultures in patients with sepsis features 2
• Transition to oral azithromycin once clinical improvement occurs 1

When Susceptibility is Confirmed

• If S. typhi is fully susceptible (rare), fluoroquinolones remain effective 1, 3
• However, never use ciprofloxacin empirically for cases from South or Southeast Asia due to resistance rates 2, 3
• The FDA-approved ciprofloxacin dose for typhoid is 500 mg every 12 hours for 10 days 5

Critical Pitfalls to Avoid

Do not discontinue antibiotics prematurely - complete the full 7-14 day course even if fever resolves early, as relapse occurs in 10-15% of inadequately treated cases 1, 2

Never use ciprofloxacin empirically for travel-associated cases from South/Southeast Asia - resistance is nearly universal in these regions 2, 3

Avoid cefixime as first-line therapy - it has documented treatment failure rates of 4-37.6% and requires mandatory test-of-cure at 1 week if used 2

Do not delay surgical consultation if intestinal perforation is suspected, as this complication occurs in 10-15% of patients with illness duration exceeding 2 weeks 1, 2

Management of Complications

Intestinal Perforation

• Occurs in 10-15% of patients when illness duration exceeds 2 weeks 1, 2
• Requires immediate surgical intervention with simple excision and closure, successful in up to 88.2% of cases 1, 2

Treatment Failure

• If no clinical response by day 5, consider antimicrobial resistance or alternative diagnosis 2
• Reassess antibiotic choice based on culture and susceptibility results 2

Monitoring and Expected Response

• Fever should clear within 4-5 days of appropriate antibiotic therapy 1, 3
• Monitor for common azithromycin adverse effects: nausea, vomiting, abdominal pain, and diarrhea 1, 3
• Watch for potential drug interactions with azithromycin, particularly QT-prolonging medications 1, 3
• Complete the full antibiotic course to prevent relapse 1, 2

Prevention Strategies

Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa), particularly those with moderate to high risk of exposure 6, 3

Two vaccines are available in the United States:

• Ty21a oral vaccine: for immunocompetent individuals ≥6 years, boosting every 5 years 6
• Vi-polysaccharide parenteral vaccine: for individuals ≥2 years, boosting every 2 years 6

Important limitations: Vaccination provides only 50-80% protection and does not protect against Salmonella Paratyphi 6, 1, 3

Hand hygiene and food/water safety precautions remain essential and should not be replaced by vaccination alone 6, 2

Emerging Resistance Concerns

• Increasing azithromycin MIC values among S. typhi may limit future effectiveness 4, 7
• Multidrug-resistant strains (resistant to ampicillin, chloramphenicol, cotrimoxazole) have declined with fluoroquinolone use, but fluoroquinolone resistance has now become the dominant pattern 4, 7
• Always consider local resistance patterns when selecting empiric therapy, as these vary geographically and change over time 2