What is the recommended management for typhoid fever?

Management of Typhoid Fever

Azithromycin 500 mg once daily for 7-14 days is the recommended first-line treatment for typhoid fever in adults, given widespread fluoroquinolone resistance exceeding 70% in endemic regions, particularly South Asia. 1, 2

First-Line Antibiotic Therapy

Adults

• Azithromycin 500 mg orally once daily for 7-14 days is the preferred empiric treatment 1, 2, 3
• This recommendation is based on superior clinical outcomes compared to fluoroquinolones, with significantly lower risk of treatment failure (OR 0.48) 1, 2
• Hospital stays are approximately 1 day shorter with azithromycin (mean difference -1.04 days) compared to fluoroquinolones 1, 2
• Relapse risk is dramatically lower with azithromycin (OR 0.09) compared to ceftriaxone 1, 2

Children

• Azithromycin 20 mg/kg/day (maximum 1g/day) orally for 7-14 days 1, 2, 3

Why Fluoroquinolones Should NOT Be Used Empirically

• Fluoroquinolone resistance exceeds 70% in South Asia and approaches 96% in some regions 1, 2
• Over 70% of S. typhi and S. paratyphi isolates imported into the UK are fluoroquinolone-resistant 2
• Critical pitfall: Never use ciprofloxacin empirically for travel-associated cases from South/Southeast Asia—resistance is nearly universal 1, 3
• Despite FDA approval for typhoid fever at 500 mg every 12 hours for 10 days, ciprofloxacin is empirically inappropriate for cases originating from endemic regions 4

Treatment Algorithm Based on Clinical Severity

Uncomplicated Typhoid Fever

• Obtain blood cultures before initiating antibiotics when possible (highest yield within first week of symptoms) 1, 2, 3
• Start azithromycin 500 mg once daily orally for 7-14 days 1, 2, 3
• Expect fever clearance within 4-5 days of appropriate therapy 1, 2, 3

Severe Cases Requiring IV Therapy

• Ceftriaxone 1-2g IV/IM daily for 5-7 days in adults 2
• For children: ceftriaxone 50-80 mg/kg/day (maximum 2g/day) 2
• Transition to oral azithromycin when clinically improved 3

Fully Susceptible Strains (Rare)

• If susceptibility testing confirms full susceptibility including nalidixic acid sensitivity, fluoroquinolones (ofloxacin or ciprofloxacin) may be used 3
• Alternative options include chloramphenicol, amoxicillin, or trimethoprim-sulfamethoxazole 3

Critical Pitfalls to Avoid

• Do not discontinue antibiotics prematurely—complete the full 7-14 day course even if fever resolves early, as relapse occurs in 10-15% of inadequately treated cases 1
• Avoid cefixime as first-line therapy—documented treatment failure rates of 4-37.6% and requires mandatory test-of-cure at 1 week if used 1
• Ciprofloxacin disc testing is unreliable for determining sensitivity; only isolates also sensitive to nalidixic acid should be considered fluoroquinolone-sensitive 2
• Blood cultures have 40-80% sensitivity, with higher yields in the first week of symptoms 2

Monitoring and Expected Response

• Fever should clear within 4-5 days of appropriate antibiotic therapy 1, 2, 3
• Monitor for common azithromycin adverse effects: nausea, vomiting, abdominal pain, and diarrhea 1, 2, 3
• Watch for potential drug interactions with azithromycin, particularly QT-prolonging medications 1, 3
• Complete the full antibiotic course to prevent relapse 1

Management of Complications

• Intestinal perforation occurs in 10-15% of patients when illness duration exceeds 2 weeks 1
• Requires immediate surgical intervention with simple excision and closure, successful in up to 88.2% of cases 1
• For patients with clinical features of sepsis, start broad-spectrum antimicrobial therapy after collection of blood, stool, and urine cultures 3

Prevention Strategies

• Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa), particularly those with moderate to high risk of exposure 5, 1, 2, 3
• Two vaccines are available in the United States: Ty21a oral vaccine and Vi-polysaccharide parenteral vaccine 5, 1, 2

Ty21a Oral Vaccine Dosing

• Adults and children ≥10 years: one enteric-coated capsule taken on alternate days to a total of four capsules 5
• Each capsule should be taken with cool liquid no warmer than 37°C, approximately 1 hour before a meal 5
• Capsules must be kept refrigerated, and all four doses must be taken to achieve maximum efficacy 5
• Revaccination with the entire four-dose series every 5 years 5

Parenteral Inactivated Vaccine Dosing

• Adults and children ≥10 years: 0.5 ml subcutaneously, given on two occasions, separated by ≥4 weeks 5
• Children <10 years: 0.25 ml subcutaneously, given on two occasions, separated by ≥4 weeks 5
• Booster doses should be given every 3 years under conditions of continued or repeated exposure 5

Important Vaccination Limitations

• Vaccination provides only 50-80% protection and does not protect against Salmonella Paratyphi 1, 2, 3
• Hand hygiene and food/water safety precautions remain essential and should not be replaced by vaccination alone 1
• Typhoid vaccination is not a substitute for careful selection of food and drink, since vaccines are not 100% effective 5

Emerging Resistance Concerns

• Always consider local resistance patterns when selecting empiric therapy, as these vary geographically and change over time 1
• Ciprofloxacin-resistant and ceftriaxone-resistant typhoid is common in Pakistan 6