What is the preferred treatment between azithromycin and cefixime (Cefixime is a third-generation cephalosporin) for typhoid fever in India?

Azithromycin vs Cefixime for Typhoid Fever in India

Direct Recommendation

Azithromycin is the preferred treatment over cefixime for typhoid fever in India, given at 500 mg once daily for 7-14 days in adults or 20 mg/kg/day (maximum 1g/day) for 7-14 days in children. 1, 2, 3

Evidence-Based Rationale

Superior Clinical Outcomes with Azithromycin

The evidence strongly favors azithromycin over cefixime based on multiple parameters:

• Lower clinical failure rates: Azithromycin demonstrates significantly lower risk of clinical failure (OR 0.48,95% CI 0.26-0.89) compared to fluoroquinolones, while cefixime performs worse than fluoroquinolones in head-to-head trials 1

• Shorter hospital stays: Azithromycin reduces hospitalization by approximately 1 day (mean difference -1.04 days, 95% CI -1.73 to -0.34 days) compared to fluoroquinolones 4, 1

• Dramatically lower relapse rates: Azithromycin shows relapse rates of OR 0.09 (95% CI 0.01-0.70) compared to ceftriaxone, whereas cefixime has documented relapse rates of 4-37.6% 1

• Faster fever clearance: In a Bangladesh study comparing all three agents directly, azithromycin achieved mean fever clearance of 5.8 days versus 7.1 days with cefixime (p<0.001) 5

Guideline Positioning

• WHO classification: The World Health Organization lists cefixime only as an "alternative" option, not first-line therapy, while recommending azithromycin as a preferred treatment for quinolone-resistant strains 4, 1

• Current resistance patterns: Over 70% of S. typhi isolates from South Asia (including India) are fluoroquinolone-resistant, making azithromycin critical as it remains effective against these strains 1

Cefixime's Documented Limitations

• High failure rates: Cefixime has reported treatment failure rates of 4-37.6% in clinical practice 1

• Requires test-of-cure: If cefixime must be used, a mandatory test-of-cure at 1 week is required due to high failure rates 1

• Lack of strong evidence: The WHO Working Group acknowledged the lack of evidence from systematic reviews to recommend cefixime for enteric fever treatment 4

Direct Comparison Study from Bangladesh

A 2021 randomized controlled trial directly comparing these agents in South Asia showed 5:

• Clinical cure rates: Azithromycin 85% vs Cefixime 71% (p=0.053)
• Fever clearance time: Azithromycin 5.8 days vs Cefixime 7.1 days (p<0.001)
• Context: 88.7% of isolates were multidrug-resistant and 93.5% were nalidixic acid-resistant

Specific Dosing Protocol

For adults: Azithromycin 500 mg once daily for 7-14 days 1, 2, 3

For children: Azithromycin 20 mg/kg/day (maximum 1g/day) for 7-14 days 1, 2, 3

Treatment Algorithm for India

1. Obtain blood cultures before starting antibiotics when possible (highest yield in first week of symptoms) 1, 2

2. Start azithromycin empirically for uncomplicated typhoid fever given high fluoroquinolone resistance in India 1, 3

3. Monitor for fever clearance within 4-5 days; if no response by day 5, consider resistance or alternative diagnosis 1

4. Complete full 7-14 day course even if fever resolves early to prevent relapse (occurs in 10-15% of inadequately treated cases) 1, 3

5. For severe cases requiring parenteral therapy: Use ceftriaxone 1-2g IV/IM daily initially, then transition to oral azithromycin when tolerated 2, 3

Critical Caveats

• Emerging azithromycin resistance: While still rare, trends show increasing azithromycin MIC values among S. typhi in Nepal (MIC range 2-8 μg/mL), which may limit future use 6

• Common adverse effects: Gastrointestinal symptoms including nausea, vomiting, abdominal pain, and diarrhea occur with azithromycin 1, 3

• Drug interactions: Monitor for QT-prolonging medications when using azithromycin 1, 3

• Complications: Watch for intestinal perforation or GI bleeding, which occur in 10-15% of patients with illness duration exceeding 2 weeks 2, 3

When Cefixime Might Be Considered

Cefixime should only be considered as a second-line alternative when 4:

• Azithromycin is contraindicated or unavailable
• Documented azithromycin resistance is confirmed
• Patient has failed azithromycin therapy

If cefixime is used: Dose at 20 mg/kg/day in two divided doses (maximum 400mg twice daily) for 14 days, and ensure test-of-cure at 1 week 1, 7