What is the recommended management of uncomplicated typhoid fever?

Management of Uncomplicated Typhoid Fever

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

Initial Diagnostic Approach

• Obtain blood cultures immediately before starting antibiotics; they provide the highest diagnostic yield (40-80% sensitivity) within the first week of symptom onset 1, 2
• In patients presenting with sepsis or hemodynamic instability, initiate empiric antimicrobial therapy immediately after collecting blood cultures—do not delay treatment 1, 2
• Stool and urine cultures become positive only after the first week and should not delay treatment decisions 1

First-Line Treatment Regimen

Adults

• Azithromycin 500 mg orally once daily for 7 days 1, 2
• This regimen reduces clinical failure by 52% compared to fluoroquinolones (OR 0.48,95% CI 0.26-0.89) 1, 3
• Hospital stay is shortened by approximately 1 day versus fluoroquinolones (mean difference -1.04 days) 1, 3
• Relapse risk is 91% lower than with ceftriaxone (OR 0.09,95% CI 0.01-0.70) 1, 3

Children

• Azithromycin 20 mg/kg/day (maximum 1 g/day) orally for 7 days 1, 4, 2
• Achieves 94% cure rate in pediatric typhoid fever 4, 5

Alternative Regimens for Severe Cases

When patients require hospitalization or cannot tolerate oral therapy:

• Ceftriaxone 1-2 g IV/IM daily for 5-7 days (adults) 1
• Ceftriaxone 50-80 mg/kg/day (maximum 2 g/day) IV/IM for 5-7 days (children) 1, 4
• Ceftriaxone reduces treatment failure risk compared to gatifloxacin (hazard ratio 0.24,95% CI 0.08-0.73) 1
• Switch to oral azithromycin once fever has been normal for 24 hours and clinical improvement occurs 4

Geographic Resistance Patterns: Critical Decision Points

When to AVOID Fluoroquinolones

• Never use ciprofloxacin or other fluoroquinolones empirically for cases originating from South or Southeast Asia 1, 2
• Fluoroquinolone resistance exceeds 70% in South Asia, with some regions approaching 96% 1, 2
• Even when susceptibility testing suggests sensitivity, nalidixic acid-resistant strains show suboptimal clinical response to fluoroquinolones 1

When Fluoroquinolones May Be Considered

Fluoroquinolones should be used only when ALL of the following criteria are met:

• Culture demonstrates nalidixic acid susceptibility 1
• Infection is NOT acquired from South or Southeast Asia 1
• Ciprofloxacin disc testing confirms susceptibility 1

When these criteria are met, fluoroquinolones achieve fever clearance in fewer than 4 days with cure rates exceeding 96% 1

Why Cefixime Is NOT Recommended

Cefixime should be avoided as empiric therapy despite being an oral cephalosporin:

• Treatment failure rates range from 4% to 37.6% 1, 6
• 13-fold higher risk of clinical failure compared to fluoroquinolones (RR 13.39,95% CI 3.24-55.39) 6
• The World Health Organization lists cefixime only as an "alternative" agent, not first-line 1
• If cefixime must be used, a mandatory test-of-cure at 1 week is required 1

Expected Clinical Response & Monitoring

• Fever should clear within 4-5 days of appropriate azithromycin therapy (mean fever clearance time 5.8 days, 95% CI 5.1-6.5) 1, 2
• If no clinical improvement by day 5, consider antimicrobial resistance or alternative diagnosis 1
• Complete the full 7-day course even if fever resolves earlier; premature discontinuation increases relapse risk to 10-15% 1

Management of Complications

Intestinal Perforation

• Occurs in 10-15% of patients with illness duration exceeding 2 weeks before effective treatment 1
• Surgery is the treatment of choice: simple excision and closure achieves 88% success rate 7, 1
• Primary repair is appropriate for single perforations with minimal peritoneal contamination 7
• For multiple perforations or unhealthy tissue, resection with primary anastomosis is recommended 7

Other Severe Complications

• Gastrointestinal bleeding and typhoid encephalopathy also affect 10-15% of patients with prolonged untreated illness 1

Special Populations

Pregnancy

• Azithromycin is FDA Pregnancy Category B and may be used safely 1
• Fluoroquinolones are contraindicated in pregnancy 1

Infants Under 3 Months

• Treat with a third-generation cephalosporin (ceftriaxone) 4

Common Pitfalls to Avoid

1. Do not use empiric ciprofloxacin for cases from South/Southeast Asia—resistance is nearly universal 1, 2
2. Do not discontinue antibiotics prematurely—complete the full 7-day course to prevent relapse 1
3. Do not rely on the Widal serologic test—it has inadequate sensitivity and specificity 1
4. Do not use cefixime as first-line therapy—failure rates are unacceptably high 1, 6
5. Do not delay treatment in septic patients—start empiric therapy immediately after obtaining cultures 1, 2

Adverse Effects & Drug Interactions

• Azithromycin is generally well tolerated; most common adverse effects are mild gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea) 1
• Monitor for QT-prolonging drug interactions when prescribing azithromycin 1

Prevention Strategies

• Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa) 1, 2
• Two vaccines available: Ty21a oral vaccine (booster every 5 years) and Vi-polysaccharide parenteral vaccine (booster every 3 years) 1, 2
• Vaccination provides only 50-80% protection and does not protect against Salmonella Paratyphi 1, 2
• Hand hygiene and food/water safety precautions remain essential regardless of vaccination status 1, 2

Historical Context: Chloramphenicol

While chloramphenicol was historically used for typhoid fever and the FDA label still lists it for acute infections caused by Salmonella typhi 8, it is no longer recommended due to widespread multidrug resistance and the availability of safer, more effective alternatives 4. Chloramphenicol may be considered only as a last-resort option when no other antibiotics are available 4.