What is the recommended treatment for uncomplicated typhoid fever?

Treatment of Uncomplicated Typhoid Fever

Azithromycin 500 mg once daily for 7 days is the preferred first-line treatment for adults with uncomplicated typhoid fever, particularly given that over 70% of Salmonella Typhi isolates from South Asia are now fluoroquinolone-resistant. 1, 2

First-Line Treatment Regimen

Adults

• Azithromycin 500 mg orally once daily for 7 days 1, 2
• This regimen achieves a 94% cure rate and demonstrates superior outcomes compared to fluoroquinolones 1, 3

Children

• Azithromycin 20 mg/kg/day (maximum 1 g/day) orally for 7 days 1, 3

Why Azithromycin Over Other Options

Superiority Over Fluoroquinolones

• Azithromycin reduces clinical failure by 52% compared to fluoroquinolones (OR 0.48,95% CI 0.26-0.89) 1, 4
• Hospital stays are approximately 1 day shorter with azithromycin (mean difference -1.04 days) 1, 4
• Fluoroquinolone resistance now exceeds 70% in South Asia, with some regions approaching 96% resistance 5, 1, 2
• All isolates imported to the UK from Asia in 2006 were ceftriaxone-sensitive but over 70% were fluoroquinolone-resistant 5, 2

Superiority Over Ceftriaxone

• Azithromycin dramatically reduces relapse risk compared to ceftriaxone (OR 0.09,95% CI 0.01-0.70) 1, 4
• Relapse occurs in 10-15% of inadequately treated cases 1, 2

Problems with Cefixime

• Cefixime has unacceptably high treatment failure rates of 4-37.6% 5, 1
• Clinical failure risk is 13-fold higher with cefixime compared to fluoroquinolones (RR 13.39,95% CI 3.24-55.39) 6
• If cefixime must be used, mandatory test-of-cure at 1 week is required 1

Alternative Treatment Options

When Azithromycin Cannot Be Used

• Ceftriaxone 1-2 g IV/IM daily for 5-7 days (adults) 1
• Ceftriaxone 50-80 mg/kg/day (maximum 2 g/day) IV/IM for 5-7 days (children) 1, 3
• All S. Typhi isolates reported to UK Health Protection Agency in 2006 remained ceftriaxone-sensitive 5, 2

When Susceptibility Is Confirmed

• Fluoroquinolones may be used ONLY when:
  • Susceptibility is confirmed by culture showing nalidixic acid sensitivity 5
  • The case is NOT from South or Southeast Asia 1, 2
  • Ciprofloxacin disc testing alone is unreliable; the isolate must also be nalidixic acid-sensitive 5, 2
• When susceptible, fluoroquinolones achieve fever clearance in <4 days with cure rates >96% 5, 2

Critical Diagnostic Steps

Before Starting Treatment

• Obtain blood cultures immediately - they have the highest yield within the first week of symptom onset (sensitivity 40-80%) 5, 2
• Stool and urine cultures become positive after the first week 5
• Do NOT use the Widal serological test - it lacks adequate sensitivity and specificity 5, 2
• Newer rapid tests (Typhidot, Tubex) have shown mixed results and cannot replace culture-based diagnosis 5, 2

For Unstable Patients

• Start empirical treatment immediately after obtaining blood cultures if clinical condition is unstable 5
• For patients with sepsis features, initiate broad-spectrum therapy immediately after culture collection 1, 3

Expected Clinical Response and Monitoring

Timeline

• Fever should clear within 4-5 days of appropriate therapy 1, 2
• If no clinical improvement by day 5, consider resistance or alternative diagnosis 1

Duration of Treatment

• Complete the full 7-day course even if fever resolves early 1, 2
• Premature discontinuation increases relapse risk to 10-15% 1, 2

Common Adverse Effects

Azithromycin

• Gastrointestinal symptoms: nausea, vomiting, abdominal pain, diarrhea 1, 2
• Monitor for QT-prolonging drug interactions 1, 2
• Generally well tolerated with few serious adverse events 7, 8

Critical Pitfalls to Avoid

Geographic Resistance Patterns

• NEVER use ciprofloxacin empirically for cases from South or Southeast Asia - resistance is nearly universal 1, 2
• Over 70% of S. Typhi and S. Paratyphi isolates from Asia are fluoroquinolone-resistant 5, 2
• In Thailand, 93% of isolates are ciprofloxacin-resistant 1

Treatment Duration

• Do NOT stop antibiotics when fever resolves - complete the full 7-day course 1, 2
• Inadequate treatment duration leads to 10-15% relapse rates 1, 2

Diagnostic Errors

• Do NOT rely on Widal test for diagnosis 5, 2
• Do NOT interpret ciprofloxacin disc sensitivity without confirming nalidixic acid sensitivity 5, 2

Management of Complications

Intestinal Perforation

• Occurs in 10-15% of patients when illness duration exceeds 2 weeks 5, 1, 2
• Requires immediate surgical intervention with simple excision and closure 1, 2
• Surgical success rate is approximately 88% 1, 2

Other Severe Complications

• Gastrointestinal bleeding, typhoid encephalopathy occur in 10-15% of patients with prolonged illness 5
• More likely when duration of illness exceeds 2 weeks before treatment 5

Prevention Considerations

Vaccination

• Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa) 1, 2
• Two vaccines available: Ty21a oral vaccine (booster every 5 years) and Vi-polysaccharide parenteral vaccine (booster every 3 years) 1
• Important limitation: Vaccination provides only 50-80% protection and does NOT protect against Salmonella Paratyphi 1, 2
• Hand hygiene and food/water safety precautions remain essential and cannot be replaced by vaccination alone 1, 2

Vaccine Administration

• Ty21a oral: One capsule on alternate days for total of 4 capsules, taken with cool liquid ≤37°C, 1 hour before meals 1
• Parenteral: 0.5 mL subcutaneously in 2 doses spaced ≥4 weeks apart 1
• Do NOT use combination typhoid-paratyphoid vaccines - only monovalent S. Typhi preparations are recommended 1