What is the recommended oral antibiotic regimen for treating typhoid fever?

Oral Antibiotic Treatment for Typhoid Fever

Azithromycin 500 mg once daily for 7 days is the recommended first-line oral antibiotic for typhoid fever in adults, particularly given the high rates of fluoroquinolone resistance exceeding 70% in South Asia. 1, 2

First-Line Treatment Recommendation

• Azithromycin demonstrates superior clinical outcomes compared to fluoroquinolones, with significantly lower risk of clinical failure (OR 0.48) and approximately 1-day shorter hospital stays. 1
• The standard adult dosing is 500 mg orally once daily for 7 days. 1, 2
• For children, the dose is 20 mg/kg/day (maximum 1g/day) orally for 7 days. 3
• Azithromycin shows dramatically lower relapse rates (OR 0.09) compared to ceftriaxone, making it the preferred oral option. 1

Alternative Oral Antibiotics Based on Susceptibility

When Fluoroquinolones Can Be Used

• Ciprofloxacin 500 mg orally every 12 hours for 10 days is FDA-approved for typhoid fever, but should ONLY be used when susceptibility is confirmed. 4
• Never use ciprofloxacin empirically for cases originating from South or Southeast Asia due to resistance rates approaching 96% in some regions. 1, 2
• Ofloxacin is an alternative fluoroquinolone option when susceptibility is documented. 2

Third-Generation Cephalosporins

• Cefixime 400 mg orally once daily for 7-14 days is an alternative oral option, though it has documented treatment failure rates of 4-37.6%. 1, 3
• The World Health Organization lists cefixime only as an "alternative" option, not first-line therapy. 1
• If cefixime must be used, a mandatory test-of-cure at 1 week is required due to high failure rates. 1
• For children, cefixime dosing is 8 mg/kg/day as a single daily dose. 3

Treatment Algorithm

1. Start azithromycin empirically for all suspected typhoid fever cases, especially those with travel to South Asia. 1, 2
2. Obtain blood cultures before initiating antibiotics whenever possible, as they have the highest yield within the first week of symptoms. 1, 2
3. Monitor for fever clearance within 4-5 days; if no response by day 5, consider resistance or alternative diagnosis. 1, 2
4. Complete the full 7-day course even if fever resolves early to prevent relapse, which occurs in 10-15% of inadequately treated cases. 1
5. Adjust therapy based on culture and susceptibility results when available. 4

Clinical Monitoring and Expected Response

• Expect defervescence (fever clearance) within 3-5 days of appropriate therapy. 5, 6, 7
• The mean fever clearance time with azithromycin is approximately 5.8 days for multidrug-resistant and nalidixic acid-resistant strains. 7
• Clinical cure rates with azithromycin reach 82-94% in clinical trials. 3, 7

Common Adverse Effects

• Azithromycin commonly causes gastrointestinal symptoms including nausea, vomiting, abdominal pain, and diarrhea. 1, 2
• Monitor for potential QT-prolonging drug interactions with azithromycin. 2
• Ciprofloxacin may cause joint-related adverse events, particularly in pediatric populations. 8, 4

Critical Pitfalls to Avoid

• Do not use ciprofloxacin empirically for cases from South Asia—resistance exceeds 70% in most regions. 1, 2
• Do not discontinue antibiotics prematurely even if fever resolves; complete the full 7-day course. 1
• Do not rely on older first-line agents (chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole) as multidrug resistance is common. 5, 6, 7
• Avoid cefixime as first-line therapy due to high failure rates; reserve for cases where azithromycin cannot be used. 1

Special Populations

Pediatric Patients

• Azithromycin 20 mg/kg/day (maximum 1g/day) orally for 7 days is first-line. 3
• Ciprofloxacin is not a drug of first choice in pediatric populations due to increased incidence of joint-related adverse events. 8, 4
• For severe cases requiring hospitalization, transition to oral therapy when clinically improved and temperature has been normal for 24 hours. 3

Pregnant Women

• Consider local resistance patterns and consult infectious disease specialists, as fluoroquinolone safety in pregnancy has not been fully established. 8

Resistance Patterns to Consider

• Over 70% of S. typhi isolates from South Asia demonstrate fluoroquinolone resistance. 1, 3
• Multidrug resistance (to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole) affects 58-88% of isolates in endemic regions. 5, 7
• Ciprofloxacin-resistant and ceftriaxone-resistant typhoid is increasingly common in Pakistan. 9