What is the preferred antibiotic, azithromycin or cefixime (cephalosporin), for treating typhoid fever?

Azithromycin vs Cefixime for Typhoid Fever

Azithromycin is the preferred first-line antibiotic for treating typhoid fever over cefixime, particularly given the high rates of fluoroquinolone resistance in endemic regions and cefixime's documented treatment failures. 1, 2

Primary Recommendation

Use azithromycin 500 mg once daily for 7 days in adults or 20 mg/kg/day (maximum 1g/day) for 7 days in children as first-line therapy for uncomplicated typhoid fever. 1, 2, 3

Evidence Supporting Azithromycin Over Cefixime

Clinical Efficacy

• Azithromycin demonstrates significantly lower risk of clinical failure (OR 0.48,95% CI 0.26-0.89) compared to fluoroquinolones, and cefixime performs worse than fluoroquinolones in head-to-head trials 4, 5
• Azithromycin reduces hospital stay by approximately 1 day compared to fluoroquinolones (MD -1.04 days, 95% CI -1.73 to -0.34 days) 4
• Azithromycin shows dramatically lower relapse rates (OR 0.09,95% CI 0.01-0.70) compared to ceftriaxone, while cefixime has documented relapse rates of 4-37.6% 4, 5

Documented Problems with Cefixime

• Cefixime has reported treatment failure rates of 4-37.6% in clinical practice 4
• Clinical failure may be significantly increased with cefixime compared to fluoroquinolones (RR 13.39,95% CI 3.24-55.39) 6
• Microbiological failure is higher with cefixime (RR 4.07,95% CI 0.46-36.41) 6
• Relapse rates are elevated with cefixime (RR 4.45,95% CI 1.11-17.84) 6
• Time to defervescence is longer with cefixime by approximately 1.7 days (MD 1.74 days, 95% CI 0.50-2.98) 6

Treatment Algorithm

Step 1: Initial Empiric Therapy

• Start azithromycin immediately for suspected typhoid fever, especially for cases from South Asia where fluoroquinolone resistance exceeds 70% 1, 2
• Obtain blood cultures before starting antibiotics when possible (highest yield in first week of symptoms) 4, 1

Step 2: Dosing

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

Step 3: Monitoring Response

• Expect fever clearance within 4-5 days of appropriate therapy 1, 2
• If no clinical improvement by day 5, consider resistance or alternative diagnosis 1
• Complete the full 7-day course even if fever resolves early to prevent relapse 1, 2

Step 4: When to Consider Alternatives

• Use ceftriaxone (NOT cefixime) for severe cases requiring parenteral therapy: 1-2g IV/IM daily for adults or 50-80 mg/kg/day (maximum 2g/day) for children for 5-7 days 1, 3
• Switch to oral azithromycin once clinical improvement occurs and patient has been afebrile for 24 hours 3

Critical Pitfalls to Avoid

Never Use Cefixime as First-Line

• Cefixime should only be considered when ceftriaxone is unavailable AND azithromycin cannot be used 4
• Even WHO guidelines list cefixime only as an "alternative" option, not first-line 4
• If cefixime must be used, dose at 400 mg orally once daily in adults or 8 mg/kg/day in children, and mandatory test-of-cure at 1 week is required due to high failure rates 4, 3

Geographic Considerations

• Over 70% of S. typhi isolates from South Asia are fluoroquinolone-resistant, making azithromycin even more critical 4, 1
• Resistance patterns vary geographically but are trending toward increased resistance globally 1, 6

Treatment Duration Errors

• Do not discontinue antibiotics prematurely even if fever resolves 1, 2
• Inadequate treatment duration leads to 10-15% relapse rates 1

Comparative Study Data

A direct comparison study in children showed azithromycin achieved 87% clinical cure rate versus 93% for cefixime, with mean defervescence time of 4.05 days for azithromycin versus 3.41 days for cefixime 7. However, this single small study must be weighed against the broader evidence showing cefixime's high failure and relapse rates in other trials 4, 6, and azithromycin's superior performance against fluoroquinolones in multiple larger studies 4, 5.

Safety Profile

• Azithromycin adverse effects are typically mild: nausea, vomiting, abdominal pain, and diarrhea 1, 2
• Monitor for QT-prolonging drug interactions with azithromycin 1
• Both drugs are generally well-tolerated with minimal serious adverse events 7, 5

Complications Requiring Escalation

• Intestinal perforation occurs in 10-15% of patients with illness duration >2 weeks 1, 2
• If perforation occurs, surgical intervention with simple excision and closure is required (successful in 88.2% of cases) 1
• For patients with sepsis features, start broad-spectrum therapy immediately after blood cultures 1, 3