What is the recommended treatment for typhoid fever in adults, children, and pregnant women, including first‑line antibiotics and alternatives for those with drug allergies or contraindications?

Treatment of Typhoid Fever

Azithromycin is the preferred first-line treatment for typhoid fever at 500 mg once daily for 7 days in adults or 20 mg/kg/day (maximum 1g/day) for 7 days in children, particularly given widespread fluoroquinolone resistance exceeding 70% in South Asia. 1, 2

First-Line Treatment Algorithm

Start with azithromycin empirically for all suspected typhoid fever cases, especially those with travel history to South Asia where fluoroquinolone resistance approaches 96% in some regions. 1, 3

Dosing by Population:

• Adults: Azithromycin 500 mg once daily for 7-14 days 1, 2
• Children and adolescents: Azithromycin 20 mg/kg/day (maximum 1g/day) for 7 days 1, 2, 3
• Pregnant women: Azithromycin is safe and follows the same adult dosing 1

Evidence Supporting Azithromycin:

• Lower clinical failure rate (OR 0.48) compared to fluoroquinolones 4, 1, 2
• Shorter hospital stays by approximately 1 day (mean difference -1.04 days) 4, 1, 2
• Dramatically lower relapse rates (OR 0.09) compared to ceftriaxone 4, 1, 2
• 94% cure rate in children with typhoid fever 2, 3

Second-Line Options for Severe Cases

For hospitalized patients or those unable to tolerate oral therapy, use ceftriaxone intravenously:

• Adults: Ceftriaxone 1-2g IV/IM daily for 5-7 days 1
• Children: Ceftriaxone 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days 1, 2, 3
• Transition to oral azithromycin once clinically improved and afebrile for 24 hours 3

Important Caveat About Ceftriaxone:

While ceftriaxone is effective, it may result in higher relapse rates compared to azithromycin (OR 10.05 for relapse with ceftriaxone vs azithromycin), though it achieves faster fever clearance by approximately 0.5 days. 1, 5

Critical Pitfalls to Avoid

Never use ciprofloxacin or other fluoroquinolones empirically for cases originating from South or Southeast Asia due to resistance rates of 70-96%. 1, 3 Fluoroquinolones should only be considered when susceptibility is confirmed by culture and the case is not from endemic resistance areas. 1

Avoid cefixime as first-line therapy due to documented treatment failure rates of 4-37.6% and high relapse rates. 1 If cefixime must be used (8 mg/kg/day as single daily dose for 7-14 days), a mandatory test-of-cure at 1 week is required. 1, 3

Do not use combination typhoid-paratyphoid vaccines; only monovalent S. typhi preparations should be used, as paratyphoid antigens increase reaction risk without proven efficacy. 4

Diagnostic Approach Before Treatment

Obtain blood cultures before starting antibiotics whenever possible, as they have the highest yield within the first week of symptom onset. 1, 3 For patients presenting with sepsis features, start broad-spectrum antimicrobial therapy immediately after collecting blood cultures. 1

Stool and urine cultures become positive after the first week of illness and are less useful for initial diagnosis. 3

Monitoring Treatment Response

Expect fever clearance within 4-5 days of appropriate antibiotic therapy. 1, 2, 3 If no clinical improvement occurs by day 5, consider:

• Antibiotic resistance (obtain culture and sensitivity if not already done) 1
• Alternative diagnosis 1
• Complications requiring surgical intervention 1

Complete the full 7-day course even if fever resolves early, as premature discontinuation leads to relapse in 10-15% of inadequately treated cases. 1

Management of Complications

Intestinal perforation occurs in 10-15% of patients when illness duration exceeds 2 weeks. 1, 2, 3 This requires immediate surgical intervention with simple excision and closure, which has an 88.2% success rate. 1, 2

Other serious complications include gastrointestinal bleeding and typhoid encephalopathy, occurring in 10-15% of patients overall. 3

Drug-Specific Considerations

Azithromycin Adverse Effects:

• Common gastrointestinal symptoms: nausea, vomiting, abdominal pain, and diarrhea 1, 2
• Monitor for QT prolongation, particularly with concomitant QT-prolonging medications 1, 2

Alternatives for Drug Allergies:

• Macrolide allergy: Use ceftriaxone as outlined above 1, 3
• Beta-lactam allergy: Azithromycin remains first-line; if also allergic to macrolides, consider fluoroquinolones only with confirmed susceptibility 1

Geographic Resistance Patterns

South Asia (India, Pakistan, Bangladesh, Nepal): Fluoroquinolone resistance exceeds 70%; azithromycin is mandatory first-line. 1, 3 Extensively drug-resistant strains have emerged in Pakistan. 5

Southeast Asia (Thailand, Vietnam): 93% ciprofloxacin resistance and 50% levofloxacin resistance documented. 1 Treatment failure with levofloxacin in resistant strains results in significantly prolonged illness (76.4 hours vs 41.2 hours for susceptible strains). 1

Consider travel history when selecting empiric therapy, as resistance patterns vary geographically and change over time. 1, 5

Prevention for Travelers

Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa), particularly those with prolonged exposure to potentially contaminated food and drink. 4

Vaccination Options:

• Ty21a oral vaccine (preferred): One enteric-coated capsule on alternate days for total of 4 capsules, taken with cool liquid ≤37°C, 1 hour before meals; booster every 5 years 4, 1
• Parenteral inactivated vaccine: 0.5 ml subcutaneously in 2 doses separated by ≥4 weeks; booster every 3 years 4, 1

Critical limitation: Vaccination provides only 50-80% protection and does not protect against Salmonella Paratyphi. 1, 3 Hand hygiene and food/water safety precautions remain essential and cannot be replaced by vaccination. 4, 1