What is the recommended treatment for typhoid fever?

Typhoid Fever Treatment

Azithromycin 500 mg once daily for 7 days is the preferred first-line treatment for typhoid fever in adults, particularly for cases originating from South Asia where fluoroquinolone resistance exceeds 70%. 1, 2

Treatment Algorithm Based on Geographic Origin and Resistance

For Cases from South or Southeast Asia (First-Line)

• Start azithromycin immediately as empiric therapy without waiting for susceptibility results, given fluoroquinolone resistance rates approaching 96% in some regions 1
• Adult dosing: 500 mg once daily for 7 days 1, 2
• Pediatric dosing: 20 mg/kg/day (maximum 1g/day) for 7 days 1
• Azithromycin demonstrates superior outcomes with lower clinical failure rates (OR 0.48) compared to fluoroquinolones 1
• Hospital stays are approximately 1 day shorter with azithromycin compared to fluoroquinolones (MD -1.04 days) 1

For Severe or Complicated Cases

• Initiate IV ceftriaxone for patients with sepsis features, unstable clinical condition, or inability to tolerate oral therapy 2, 3
• Adult dosing: 2g IV daily for 14 days 3
• Pediatric dosing: 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days 1
• Transition to oral therapy when clinically improved 2

For Confirmed Susceptible Strains Only

• Fluoroquinolones (ciprofloxacin 500 mg twice daily for 7 days) may be used only when susceptibility is confirmed and the organism is sensitive to both ciprofloxacin and nalidixic acid on disc testing 2, 3, 4
• Ciprofloxacin showed rapid defervescence (median 4 days) in older studies with susceptible strains 5, 6

Critical Diagnostic Steps Before Treatment

• Obtain blood cultures immediately before starting antibiotics, as they have highest yield (40-80% sensitivity) within the first week of symptoms 3
• For patients with sepsis features, start broad-spectrum therapy immediately after collecting cultures—do not delay 2
• Bone marrow cultures have higher sensitivity than blood cultures if diagnosis remains uncertain 3

Monitoring and Expected Response

• Expect fever clearance within 4-5 days of appropriate therapy 1, 2
• If no clinical improvement by day 5, consider antimicrobial resistance or alternative diagnosis 1
• Common azithromycin adverse effects include gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea) 1, 2
• Monitor for QT-prolonging drug interactions with azithromycin 2

Why Azithromycin Over Alternatives

Azithromycin has dramatically lower relapse rates (OR 0.09) compared to ceftriaxone, while cefixime has documented treatment failure rates of 4-37.6% 1. The World Health Organization lists cefixime only as an "alternative" option, not first-line 1. If cefixime must be used, a mandatory test-of-cure at 1 week is required due to high failure rates 1.

Ceftriaxone may result in decreased clinical failure compared to azithromycin in pediatric populations, but relapse rates appear higher 7. However, the evidence comparing ceftriaxone to azithromycin is of very low to low certainty 7.

Critical Pitfalls to Avoid

• Never use ciprofloxacin empirically for cases from South or Southeast Asia—resistance rates exceed 70% and approach 96% in some regions 1, 2
• Do not discontinue antibiotics prematurely—complete the full 7-day course even if fever resolves early, as relapse occurs in 10-15% of inadequately treated cases 1
• Do not rely on ciprofloxacin disc testing alone—the organism must also be sensitive to nalidixic acid to be considered truly fluoroquinolone-sensitive 3
• Recognize that previous typhoid vaccination provides incomplete protection and does not protect against paratyphoid 2, 3

Management of Complications

• Intestinal perforation occurs in 10-15% of patients with illness duration exceeding 2 weeks 1, 3
• Surgical intervention with simple excision and closure is required for perforation, with success rates up to 88.2% 1
• Other complications include gastrointestinal bleeding and typhoid encephalopathy, more likely after 2 weeks of untreated illness 3

Resistance Context

Over 70% of S. typhi isolates from South Asia are fluoroquinolone-resistant, and 58-96% are multidrug-resistant to older agents like chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole 1, 8. Extensively drug-resistant strains have emerged in Pakistan with resistance to both fluoroquinolones and ceftriaxone 7, 9. This makes azithromycin the most reliable empiric choice, as resistance to azithromycin remains rare in most regions 3.