What is the drug of choice for uncomplicated typhoid fever in adults?

Drug of Choice for Uncomplicated Typhoid Fever in Adults

Azithromycin 500 mg once daily for 7-14 days is the preferred first-line treatment for uncomplicated typhoid fever in adults, particularly given that fluoroquinolone resistance now exceeds 70% in most endemic regions. 1, 2, 3

Why Azithromycin is First-Line

Azithromycin demonstrates superior clinical outcomes compared to all other treatment options:

• Reduces clinical failure risk by 52% compared to fluoroquinolones (OR 0.48,95% CI 0.26-0.89) 4
• Shortens hospital stay by approximately 1 day compared to fluoroquinolones (mean difference -1.04 days) 1, 2
• Dramatically lowers relapse risk compared to ceftriaxone (OR 0.09,95% CI 0.01-0.70) 1, 2
• Fever clearance occurs within 4-5 days of appropriate therapy 1, 2, 3

Critical Geographic Resistance Patterns

Never use ciprofloxacin empirically for cases from South or Southeast Asia:

• Fluoroquinolone resistance exceeds 70% in South Asia, with some regions approaching 96% 5, 1, 2, 3
• Over 70% of S. typhi and S. paratyphi isolates imported into the UK from Asia are fluoroquinolone-resistant 5, 3
• Ciprofloxacin disc testing is unreliable—only if the organism is also sensitive to nalidixic acid should fluoroquinolone sensitivity be considered 5

Treatment Algorithm

Step 1: Obtain blood cultures before starting antibiotics

• Blood cultures have the highest yield (40-80% sensitivity) within the first week of symptom onset 5, 3
• Do not delay treatment in severely ill patients—collect cultures then start empiric therapy immediately 3

Step 2: Start azithromycin empirically

• Adults: 500 mg once daily orally for 7-14 days 1, 2, 3
• Children: 20 mg/kg/day (maximum 1g/day) for 7-14 days 1, 2, 3

Step 3: Monitor clinical response

• Expect fever clearance within 4-5 days 1, 2, 3
• If no improvement by day 5, consider resistance or alternative diagnosis 2

Step 4: Complete the full course

• Never discontinue antibiotics prematurely, even if fever resolves early 1, 2
• Relapse occurs in 10-15% of inadequately treated cases 1, 2

Alternative Treatment Options (When Azithromycin Cannot Be Used)

Ceftriaxone is the preferred alternative:

• Adults: 1-2g IV/IM daily for 5-7 days 2
• Children: 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days 2, 6
• Ceftriaxone may result in decreased clinical failure compared to azithromycin (RR 0.42) 7
• All isolates reported to the UK Health Protection Agency in 2006 were sensitive to ceftriaxone 5

Fluoroquinolones only if susceptibility is confirmed:

• Ciprofloxacin: 500 mg every 12 hours orally for 10 days 8
• Use only when culture confirms nalidixic acid sensitivity AND case is not from South/Southeast Asia 5, 2
• In sensitive isolates, fluoroquinolones achieve fever clearance in <4 days with cure rates >96% 5

Critical Pitfalls to Avoid

Do not use cefixime as first-line therapy:

• Cefixime has documented treatment failure rates of 4-37.6% 5, 1
• If cefixime must be used, mandatory test-of-cure at 1 week is required 1
• Clinical failure may be increased 13-fold compared to fluoroquinolones (RR 13.39) 7

Do not rely on Widal test for diagnosis:

• The Widal test lacks sensitivity and specificity and is not recommended 5
• Newer rapid serological tests (Typhidot, Tubex) have shown mixed results 5

Do not stop antibiotics when fever resolves:

• Treatment should continue for the full 7-14 days to reduce relapse risk 5, 1, 2
• Relapse rates: fluoroquinolones <5%, ceftriaxone <8%, azithromycin <3% 5

Monitoring for Complications

Watch for intestinal perforation:

• Occurs in 10-15% of patients when illness duration exceeds 2 weeks 5, 1
• Requires immediate surgical intervention with simple excision and closure (successful in 88.2% of cases) 1, 2

Common azithromycin adverse effects:

• Nausea, vomiting, abdominal pain, and diarrhea 1, 2
• Monitor for QT-prolonging drug interactions 1, 2

Prevention Considerations

Typhoid vaccination provides incomplete protection:

• Vaccination offers only 50-80% protection and does not protect against Salmonella Paratyphi 1, 2, 3
• Two vaccines available: Ty21a oral vaccine (booster every 5 years) and Vi-polysaccharide parenteral vaccine (booster every 3 years) 1, 3
• Hand hygiene and food/water safety precautions remain essential and cannot be replaced by vaccination alone 1, 2, 3