What is the drug of choice for treating typhoid fever?

Drug of Choice for Typhoid Fever

Azithromycin 500 mg once daily for 7 days is the drug of choice for treating typhoid fever in adults, particularly given the widespread fluoroquinolone resistance now exceeding 70% in South Asia. 1, 2

First-Line Treatment Recommendation

• Azithromycin is superior to all alternatives, demonstrating significantly lower clinical failure rates (OR 0.48) compared to fluoroquinolones and dramatically lower relapse rates (OR 0.09) compared to ceftriaxone 1, 2
• Azithromycin reduces hospital stay by approximately 1 day compared to fluoroquinolones (mean difference -1.04 days) 1
• Pediatric dosing: 20 mg/kg/day (maximum 1g/day) orally for 7 days 1, 3

Treatment Algorithm Based on Geographic Origin and Resistance

For Cases from South or Southeast Asia (High Resistance Areas):

• Start azithromycin empirically - fluoroquinolone resistance approaches 96% in some regions 1, 2
• Never use ciprofloxacin empirically for cases originating from South Asia due to widespread resistance 4, 1, 2

For Severe Cases Requiring Hospitalization:

• Ceftriaxone 1-2g IV/IM daily for 5-7 days in adults, or 50-80 mg/kg/day (maximum 2g/day) in children 1, 3
• Transition to oral azithromycin once clinically improved and afebrile for 24 hours 3

For Confirmed Susceptible Strains Only:

• Ciprofloxacin 500 mg orally twice daily for 7 days remains effective when susceptibility is documented 5, 6
• However, this scenario is increasingly rare given resistance rates exceeding 70% globally 1, 3

Alternative Agents (When Azithromycin Unavailable)

• Ceftriaxone: Effective but higher relapse rates than azithromycin 1, 7, 8
• Cefixime: Listed only as "alternative" by WHO, with documented failure rates of 4-37.6% and requires mandatory test-of-cure at 1 week 1, 3
• Chloramphenicol: Historical agent, now considered last-resort only when no other options available 3

Expected Clinical Response and Monitoring

• 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
• Obtain blood cultures before starting antibiotics whenever possible - highest yield in first week of symptoms 1, 2
• For septic patients, start broad-spectrum therapy immediately after collecting cultures 1, 3

Critical Pitfalls to Avoid

• Do not use ciprofloxacin empirically for travel-associated cases from South/Southeast Asia - resistance is the rule, not the exception 4, 1, 2
• Complete the full 7-day course even if fever resolves early - premature discontinuation leads to 10-15% relapse rates 1
• Do not rely on cefixime as first-line - failure rates are unacceptably high (4-37.6%) 1
• Avoid combination typhoid-paratyphoid vaccines; only monovalent S. typhi preparations should be used 1

Common Adverse Effects

• Azithromycin: gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea) 1, 2
• Monitor for QT-prolonging drug interactions with azithromycin 1

Management of Complications

• Intestinal perforation occurs in 10-15% of patients with illness duration exceeding 2 weeks 1
• Surgical intervention with simple excision and closure required for perforation (88.2% success rate) 1

Historical Context (Why Older Agents Are No Longer Preferred)

While ciprofloxacin was previously considered highly effective for typhoid fever 6, and ceftriaxone showed promise as an alternative 7, 8, 9, the emergence of widespread fluoroquinolone resistance has fundamentally changed treatment paradigms 4, 10. The FDA label for ciprofloxacin still lists typhoid fever as an indication 5, but this reflects historical data rather than current resistance patterns that make azithromycin the clear first choice 1, 2.