What is the drug of choice for treating typhoid?

Drug of Choice for Typhoid Fever

Azithromycin is the preferred first-line treatment for typhoid fever, particularly in areas with high fluoroquinolone resistance, at a dose of 500 mg once daily for 7 days in adults or 20 mg/kg/day (maximum 1g/day) for 7 days in children. 1

Treatment Algorithm Based on Geographic Origin and Resistance Patterns

First-Line Empiric Therapy

• Start with azithromycin as empiric therapy, especially for cases originating from South Asia where fluoroquinolone resistance exceeds 70% and reaches up to 96% in some regions 1, 2
• Azithromycin demonstrates superior outcomes with lower risk of clinical failure (OR 0.48) compared to fluoroquinolones 1
• Risk of relapse is dramatically lower with azithromycin (OR 0.09) compared to ceftriaxone, with zero relapses documented in pediatric studies 1, 2
• Hospital stays are approximately 1 day shorter with azithromycin compared to fluoroquinolones (MD -1.04 days) 1

Alternative Options When Azithromycin Is Not Available

For severe cases requiring hospitalization:

• Ceftriaxone 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days in children 3, 4, 2
• Ceftriaxone 1-2g IV/IM daily for 5-7 days in adults 1

For fully susceptible strains (when confirmed by culture):

• Ciprofloxacin 15 mg/kg twice daily for 7-10 days orally 3, 5
• However, avoid empiric ciprofloxacin use for cases from South Asia due to widespread resistance 1, 2

Critical Diagnostic Approach Before Treatment

• Obtain 2-3 blood cultures before initiating antibiotics to maximize detection given low-magnitude bacteremia 2
• Blood cultures have the highest yield within the first week of symptom onset 1, 2
• For patients with sepsis features, start broad-spectrum antimicrobial therapy immediately after collecting blood cultures 1, 4

Specific Dosing Guidelines

Azithromycin (Preferred)

• Adults: 500 mg once daily for 7-14 days 1
• Children: 20 mg/kg/day (maximum 1g/day) for 7 days 1, 4, 2

Ceftriaxone (Second-Line)

• Adults: 1-2g IV/IM daily for 5-7 days 1
• Children: 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days 3, 1, 4

Ciprofloxacin (Only for Susceptible Strains)

• 15 mg/kg twice daily for 7-10 days orally 3
• Adults: 500 mg twice daily for 7 days 5, 6

Cefixime (Alternative Oral Option)

• Children: 8 mg/kg/day as a single daily dose for 7-14 days 4
• Adults: 400 mg orally in a single dose 4
• Important caveat: Cefixime has documented treatment failure rates of 4-37.6% and requires mandatory test-of-cure at 1 week 1

Monitoring Treatment Response

• Expect fever clearance within 4-5 days of appropriate therapy 1, 2
• If no clinical response by day 5, consider antibiotic resistance or alternative diagnosis 1, 2
• Complete the full 7-day course to prevent relapse, which occurs in 10-15% of inadequately treated cases 1
• Transfer from parenteral to oral antibiotics once clinical improvement occurs and temperature has been normal for 24 hours 4

Common Pitfalls to Avoid

• Never use ciprofloxacin empirically for cases originating from South or Southeast Asia due to resistance rates approaching 96% in some regions 1, 2
• Do not discontinue antibiotics prematurely; complete the full course even if fever resolves early 1
• Do not rely solely on clinical presentation for diagnosis; obtain cultures whenever possible 4
• Avoid cefixime as first-line therapy given high failure rates (4-37.6%) compared to azithromycin 1

Evidence Supporting Azithromycin as First-Line

The superiority of azithromycin is based on multiple factors:

• Clinical failure rate significantly lower than fluoroquinolones (OR 0.48,95% CI 0.26-0.89) 1
• Dramatically reduced relapse rates compared to ceftriaxone (OR 0.09,95% CI 0.01-0.70) 1
• Achieves 94% cure rate in children 2
• Remains effective in regions where fluoroquinolone resistance has developed 1

Comparative Effectiveness of Alternatives

Ceftriaxone vs Azithromycin:

• Ceftriaxone may result in decreased clinical failure compared to azithromycin (RR 0.42,95% CI 0.11 to 1.57), though evidence is low-certainty 7
• Time to defervescence may be 0.52 days shorter with ceftriaxone compared to azithromycin 7
• However, relapse rates may be higher with ceftriaxone (RR 10.05,95% CI 1.93 to 52.38) 7

Cefixime vs Fluoroquinolones:

• Clinical failure may be increased with cefixime compared to fluoroquinolones (RR 13.39,95% CI 3.24 to 55.39) 7
• Time to defervescence may be 1.74 days longer with cefixime 7

Adverse Effects

• Common azithromycin adverse effects include gastrointestinal symptoms: nausea, vomiting, abdominal pain, and diarrhea 1
• Monitor for potential drug interactions with azithromycin, particularly QT-prolonging medications 1
• Ciprofloxacin is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals, making it not a drug of first choice in pediatric populations 5

Special Populations

Infants under 3 months:

• Use third-generation cephalosporin (ceftriaxone) due to age-specific considerations 4, 2

Pregnant women:

• Avoid fluoroquinolones; consider azithromycin or ceftriaxone based on susceptibility patterns 1