What is the recommended management for typhoid fever?

Management of Typhoid Fever

First-Line Treatment

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

For children, use azithromycin 20 mg/kg/day (maximum 1g/day) for 7 days. 1, 2

Why Azithromycin Over Other Options

Superior Clinical Outcomes

• Azithromycin demonstrates significantly lower risk of clinical failure (OR 0.48) compared to fluoroquinolones 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, 3

Resistance Patterns Make Fluoroquinolones Unreliable

• Fluoroquinolone resistance exceeds 70% in isolates from South Asia, with some regions approaching 96% resistance 4, 1, 2
• Over 70% of S. typhi and S. paratyphi isolates imported into the UK are fluoroquinolone-resistant 4
• In Nepal, 97.8% of S. typhi isolates were resistant to ciprofloxacin, 91.3% to ofloxacin, and 89.1% to levofloxacin 5
• Ciprofloxacin disc testing is unreliable for determining sensitivity; only isolates also sensitive to nalidixic acid should be considered fluoroquinolone-sensitive 4

Treatment Algorithm

Step 1: Obtain Blood Cultures

• Collect blood cultures before starting antibiotics whenever possible, as they have the highest yield within the first week of symptom onset 4, 1, 2
• For patients with sepsis features, start broad-spectrum antimicrobial therapy immediately after collecting cultures 1, 3

Step 2: Initiate Empiric Therapy

• Start azithromycin 500 mg once daily for 7 days in adults 1, 2, 3
• For children: azithromycin 20 mg/kg/day (maximum 1g/day) for 7 days 1, 2
• For severe cases requiring IV therapy: ceftriaxone 1-2g IV/IM daily for 5-7 days in adults, or 50-80 mg/kg/day (maximum 2g/day) in children 1, 3

Step 3: Monitor Response

• Expect fever clearance within 4-5 days of appropriate therapy 1, 2, 3
• If no clinical improvement by day 5, consider antibiotic resistance or alternative diagnosis 1
• Watch for complications: intestinal perforation and gastrointestinal bleeding occur in 10-15% of patients when illness duration exceeds 2 weeks 4, 1, 2

Step 4: Complete Full Course

• Complete the full 7-day course to prevent relapse, which occurs in 10-15% of inadequately treated cases 1, 2
• Never discontinue antibiotics prematurely, even if fever resolves early 1, 2

Alternative Treatment Options (When Azithromycin Cannot Be Used)

For Fully Susceptible Isolates

• Fluoroquinolones (ciprofloxacin or ofloxacin) remain effective when susceptibility is confirmed 4, 3, 6
• Chloramphenicol, amoxicillin, or trimethoprim-sulfamethoxazole can be used for susceptible strains 3, 7
• In Nepal, 97.8% of S. typhi isolates remained susceptible to conventional first-line antibiotics (ampicillin, chloramphenicol, cotrimoxazole) 5

For Quinolone-Resistant Strains

• Ceftriaxone 1-2g IV/IM daily for 5-7 days (adults) or 50-80 mg/kg/day (children) 1, 3
• Cefixime is listed as an alternative but has documented treatment failure rates of 4-37.6% and requires mandatory test-of-cure at 1 week if used 4, 1

Critical Pitfalls to Avoid

Never Use Ciprofloxacin Empirically for Travel-Associated Cases

• Do not use ciprofloxacin empirically for cases originating from South or Southeast Asia—resistance is nearly universal in these regions 1, 2, 3
• The FDA label for ciprofloxacin lists typhoid fever as an indication, but this does not account for current resistance patterns 6

Avoid Cefixime as First-Line

• Cefixime has high treatment failure rates (4-37.6%) and should not be used as first-line therapy 4, 1
• If cefixime must be used, mandatory test-of-cure at 1 week is required 1

Complete the Full Antibiotic Course

• Do not discontinue antibiotics prematurely, even if fever resolves early 1, 2
• Incomplete treatment leads to relapse in 10-15% of cases 1, 2

Management of Complications

Intestinal Perforation

• Occurs in 10-15% of patients when illness duration exceeds 2 weeks 4, 1, 2
• Requires immediate surgical intervention with simple excision and closure 1, 2
• Surgical success rates reach 88.2% with appropriate management 1, 2

Other Complications

• Gastrointestinal bleeding, typhoid encephalopathy, and meningism can occur 4
• These are more likely if duration of illness exceeds 2 weeks before treatment 4

Monitoring and Adverse Effects

Expected Clinical Response

• Fever should clear within 4-5 days of appropriate antibiotic therapy 1, 2, 3
• Blood cultures have 40-80% sensitivity, with higher yields in the first week of symptoms 4
• Stool and urine cultures become positive after the first week 4

Common Azithromycin Adverse Effects

• Gastrointestinal symptoms: nausea, vomiting, abdominal pain, and diarrhea 1, 2, 3
• Monitor for potential drug interactions with QT-prolonging medications 1, 2, 3

Prevention Strategies

Vaccination

• Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa) 1, 2, 3
• Two vaccines available: Ty21a oral vaccine and Vi-polysaccharide parenteral vaccine 2
• Vaccination provides only 50-80% protection and does not protect against Salmonella Paratyphi 1, 2, 3
• Vaccination should not replace food and water safety precautions 1, 2

Hygiene Measures

• Hand hygiene and appropriate food safety practices remain essential 1
• These measures are critical even for vaccinated individuals 1, 2

Emerging Resistance Concerns

Azithromycin Resistance

• Trends of increasing azithromycin MIC values among S. typhi have been observed, with MIC ranging from 2 to 8 μg/mL in Nepal 5
• While azithromycin resistance remains rare currently, this trend requires ongoing surveillance 4, 5

Geographic Variation

• Always consider local resistance patterns when selecting empiric therapy, as these vary geographically and change over time 1, 2, 3
• In Vietnam (2004-05), gatifloxacin remained effective despite widespread resistance to older fluoroquinolones 8