What are the first-line antibiotic treatment options for a patient diagnosed with typhoid fever?

Antibiotic Treatment for Typhoid Fever

Azithromycin is the preferred first-line treatment for typhoid fever, given at 500 mg once daily for 7-14 days in adults (or 20 mg/kg/day for 7 days in children), particularly in regions with high fluoroquinolone resistance. 1, 2

First-Line Treatment: Azithromycin

Azithromycin demonstrates superior clinical outcomes compared to alternatives, with the following evidence-based advantages:

• Lower clinical failure rates (OR 0.48,95% CI 0.26-0.89) compared to fluoroquinolones 1, 2
• Dramatically reduced relapse rates (OR 0.09,95% CI 0.01-0.70) compared to ceftriaxone 1, 2
• Shorter hospital stays by approximately 1 day compared to fluoroquinolones (MD -1.04 days, 95% CI -1.73 to -0.34) 1
• Maintains efficacy in regions where fluoroquinolone resistance exceeds 70% in South Asia and approaches 96% in some areas 1, 2

Dosing Regimen for Azithromycin

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

Second-Line Treatment: Ceftriaxone

Ceftriaxone is the preferred second-line option, particularly for:

• Quinolone-resistant strains confirmed by susceptibility testing 1
• Severe cases requiring parenteral therapy 2
• Multidrug-resistant strains resistant to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole 1

Dosing Regimen for Ceftriaxone

• Adults: 2-4 g IV once daily for 5-7 days 1
• Children: 50-75 mg/kg IV once daily (maximum 2 g) for 5-7 days 1

Clinical Performance of Ceftriaxone

• Clinical cure rates of 79-83% in randomized trials 1
• Fever clearance occurs within 4-5 days of appropriate therapy 1, 2
• Important caveat: Ceftriaxone has significantly higher relapse rates compared to azithromycin (OR 11.1, inverse of 0.09), making azithromycin superior when both are available 1, 2

Treatment Algorithm Based on Clinical Scenario

For Uncomplicated Typhoid Fever

1. Start azithromycin empirically, especially for cases from South Asia where fluoroquinolone resistance is endemic 2
2. Obtain blood cultures before starting antibiotics when possible, as they have highest yield within the first week 2
3. Complete the full 7-14 day course even if fever resolves early, as premature discontinuation increases relapse risk to 10-15% 1, 2

For Severe Cases or When Oral Therapy Not Tolerated

1. Initiate ceftriaxone IV 2-4 g once daily 1
2. Transition to oral azithromycin when patient can tolerate oral medications 2
3. Monitor for clinical improvement by day 5; if no response, consider resistance or alternative diagnosis 1, 2

Geographic and Resistance Considerations

• Avoid empiric ciprofloxacin for cases from South or Southeast Asia due to resistance rates approaching 96% 2
• Fluoroquinolones may be considered only when susceptibility is confirmed by culture and the case is not from high-resistance regions 2
• In Thailand, 93% of isolates were ciprofloxacin-resistant and 50% levofloxacin-resistant 2

Antibiotics to Avoid or Use with Caution

Cefixime: Not Recommended as First-Line

• Treatment failure rates of 4-37.6% documented in clinical practice 2
• Significantly inferior to fluoroquinolones in head-to-head trials 2
• WHO lists cefixime only as "alternative" option, not first-line 2
• If cefixime must be used, mandatory test-of-cure at 1 week is required due to high failure rates 2

Fluoroquinolones: Geographic Restrictions Apply

• Clinical failure occurs when fluoroquinolone-resistant strains are treated with fluoroquinolones, resulting in prolonged illness (76.4 hours vs 41.2 hours for susceptible strains) 2
• Over 70% of S. typhi isolates from South Asia are fluoroquinolone-resistant 2
• May be considered only when susceptibility is confirmed and case is not from South/Southeast Asia 2

Chloramphenicol: Historical Option with Re-emerging Utility

• FDA-approved for acute infections caused by Salmonella typhi 3
• 97.8% of S. Typhi isolates in recent Nepal study were susceptible to conventional first-line antibiotics including chloramphenicol 4
• Recommended treatment duration: 8-10 days after patient becomes afebrile to lessen relapse possibility 3
• Not recommended for routine treatment of typhoid carrier state 3

Critical Pitfalls to Avoid

• Never discontinue antibiotics prematurely: Complete the full course even if fever resolves early, as relapse occurs in 10-15% of inadequately treated cases 1, 2
• Never use ciprofloxacin empirically for cases from South or Southeast Asia due to widespread resistance 2
• Do not rely on disc diffusion alone: Nalidixic acid-resistant S. typhi (NARST) may appear ciprofloxacin-susceptible by disc diffusion but have elevated MICs and poor clinical outcomes 5
• Recognize treatment failure early: If no fever clearance by day 5, consider resistance or alternative diagnosis rather than continuing ineffective therapy 1, 2

Expected Clinical Response and Monitoring

• Fever clearance should occur within 4-5 days of appropriate therapy 1, 2
• Complications (gastrointestinal bleeding, intestinal perforation, encephalopathy) occur in 10-15% of patients, more likely if illness duration exceeds 2 weeks 2, 6
• Intestinal perforation requires surgical intervention with simple excision and closure, successful in up to 88.2% of cases 2

Comparative Evidence Summary

When comparing azithromycin to ceftriaxone in three trials involving 196 participants under 18 years of age:

• Ceftriaxone may result in decreased clinical failure (RR 0.42,95% CI 0.11 to 1.57) 7
• However, ceftriaxone shows significantly increased relapse rates (RR 10.05,95% CI 1.93 to 52.38) 7
• Time to defervescence is shorter with ceftriaxone (MD -0.52 days, 95% CI -0.91 to -0.12) 7

The evidence quality for cephalosporin comparisons ranges from very low to low certainty, with most trials being small and conducted over 20 years ago 7. However, the most recent and highest quality guideline evidence from WHO (2024) clearly prioritizes azithromycin as first-line based on superior outcomes in morbidity (lower failure rates, shorter hospital stays) and quality of life (lower relapse rates) 1, 2.