What is the recommended treatment regimen for typhoid fever?

Treatment of Typhoid Fever

Azithromycin 500 mg once daily for 7 days is the first-line treatment for typhoid fever, particularly in areas with high fluoroquinolone resistance such as South Asia, where resistance rates exceed 70%. 1, 2, 3

First-Line Treatment Selection

For Uncomplicated Typhoid Fever

• Azithromycin is the preferred oral agent with a dosage of 500 mg once daily for 7 days in adults (or 20 mg/kg/day, maximum 1g/day in children), demonstrating superior efficacy with lower risk of clinical failure (OR 0.48) and shorter hospital stays compared to fluoroquinolones 1, 3
• Azithromycin has a significantly lower risk of relapse (OR 0.09) compared to ceftriaxone and maintains effectiveness against quinolone-resistant strains 1, 3
• Expected fever clearance occurs within 4-5 days of appropriate therapy 1, 3

For Severe or Complicated Cases

• Intravenous ceftriaxone 2g daily for adults (50-80 mg/kg/day, maximum 2g/day in children) is recommended for patients with unstable clinical condition or severe disease 2, 3
• Treatment duration is 14 days to reduce relapse risk, though transition to oral therapy (azithromycin or cefixime) can occur once clinically improved and afebrile for 24 hours 2, 3
• Severe cases include those with complications such as gastrointestinal bleeding, intestinal perforation, or typhoid encephalopathy, which occur in 10-15% of patients, particularly when illness duration exceeds 2 weeks 2, 3

Treatment Algorithm Based on Geographic Origin and Resistance Patterns

Cases from South Asia (India, Pakistan, Bangladesh)

• Avoid fluoroquinolones empirically due to resistance rates exceeding 70% 1, 2, 3, 4
• Use azithromycin as first-line for uncomplicated cases 1, 3
• Use ceftriaxone for severe cases or hospitalized patients 2, 3
• Note that extensively drug-resistant strains have emerged in Pakistan, including ceftriaxone resistance 4, 5

Cases from Areas with Fully Susceptible Strains

• Fluoroquinolones (ciprofloxacin 500 mg twice daily or ofloxacin) remain effective options for 7 days 1, 6
• Alternative older agents (chloramphenicol, amoxicillin, trimethoprim-sulfamethoxazole) can be considered if susceptibility is confirmed 1

When Quinolone Resistance is Confirmed

• Azithromycin is the preferred treatment 1, 3
• Alternatives include ceftriaxone or cefixime (8 mg/kg/day as single daily dose for 7-14 days) 1, 3

Diagnostic Considerations Before Treatment

• Obtain blood cultures before starting antibiotics when possible, as they have the highest yield (40-80% sensitivity) within the first week of symptom onset 2, 3
• Stool and urine cultures become positive after the first week with lower sensitivities (35-65% and 0-58%, respectively) 2
• Bone marrow cultures have higher sensitivity than blood cultures but are rarely practical 2
• The serological Widal test lacks sensitivity and specificity and is not recommended 2

Critical Pitfalls to Avoid

Fluoroquinolone Use

• Do not use ciprofloxacin empirically for cases originating from South Asia due to high resistance rates 1, 3, 4
• When testing isolates for fluoroquinolone sensitivity, ciprofloxacin disc testing alone is unreliable; the organism must also be sensitive to nalidixic acid on disc testing to be considered truly fluoroquinolone-sensitive 2
• The FDA-approved indication for ciprofloxacin in typhoid fever notes that efficacy in eradicating the chronic typhoid carrier state has not been demonstrated 6

Monitoring and Adverse Effects

• Monitor for common adverse effects of azithromycin including gastrointestinal symptoms: nausea, vomiting, abdominal pain, and diarrhea 1
• Watch for potential drug interactions with azithromycin 1
• If fever persists beyond 4-5 days of appropriate therapy, consider treatment failure and reassess antibiotic choice based on culture sensitivities 1, 3

Vaccination Limitations

• Previous typhoid vaccination provides incomplete protection and does not protect against paratyphoid fever 1, 2, 3
• Vaccination should not alter clinical suspicion or treatment decisions 2, 3

Comparative Effectiveness Evidence

• In regions with high fluoroquinolone resistance, azithromycin demonstrates superior outcomes compared to older fluoroquinolones, with a 94% cure rate in children 3
• Ceftriaxone may result in decreased clinical failure compared to azithromycin, though time to defervescence may be 0.52 days shorter with ceftriaxone 5
• Historical data from areas with susceptible strains showed ciprofloxacin had zero clinical failures compared to 27% failure rate with ceftriaxone, with mean fever duration of 4 days versus 5 days respectively 7
• However, these older comparisons are no longer applicable in high-resistance areas where azithromycin and ceftriaxone are now preferred 1, 2, 3