What is the recommended antibiotic regimen for treating typhoid fever?

Recommended Antibiotic for Typhoid Fever

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

First-Line Treatment Regimens

Adults

• Azithromycin: 500 mg once daily orally for 7-14 days 1, 2
• This is the preferred empiric choice, especially for cases originating from South Asia where fluoroquinolone resistance approaches 96% in some regions 1, 2

Children

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

Severe or Unstable Patients

• Ceftriaxone: 2g IV daily for adults 3
• Ceftriaxone: 50-80 mg/kg/day (maximum 2g/day) IV/IM for children for 5-7 days 1
• Use ceftriaxone for patients with unstable clinical condition or when oral therapy is not feasible 3

Why Azithromycin Over Other Options

Superior to Fluoroquinolones

• Azithromycin demonstrates significantly lower risk of clinical failure (OR 0.48,95% CI 0.26-0.89) compared to fluoroquinolones 1
• Hospital stays are approximately 1 day shorter with azithromycin (mean difference -1.04 days, 95% CI -1.73 to -0.34) 1
• Fluoroquinolone resistance exceeds 70% in South Asia, making ciprofloxacin empirically inappropriate for travel-associated cases 1, 2, 4

Superior to Ceftriaxone

• Relapse risk is dramatically lower with azithromycin (OR 0.09,95% CI 0.01-0.70) compared to ceftriaxone 1
• Azithromycin allows for shorter treatment duration (7 days vs 14 days) 1, 3

Avoid Cefixime

• Cefixime has documented treatment failure rates of 4-37.6% 1
• Clinical failure may be increased with cefixime compared to fluoroquinolones (RR 13.39,95% CI 3.24 to 55.39) 5
• If cefixime must be used, mandatory test-of-cure at 1 week is required 1

Treatment Algorithm Based on Clinical Presentation

Step 1: Obtain Blood Cultures

• Collect blood cultures before initiating antibiotics when possible, as they have the highest yield (40-80% sensitivity) within the first week of symptoms 1, 3

Step 2: Initiate Empiric Therapy

• For uncomplicated typhoid fever: Start azithromycin 500 mg once daily orally 1, 2
• For severe disease or inability to take oral medications: Start ceftriaxone 2g IV daily 3
• For patients with sepsis features: Start broad-spectrum antimicrobial therapy immediately after collecting blood cultures 1

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 antimicrobial resistance or alternative diagnosis 1

Step 4: Complete Full Course

• Complete the full 7-14 day course even if fever resolves early 1, 2
• Premature discontinuation leads to relapse in 10-15% of cases 1, 2

When to Use Alternative Antibiotics

Ciprofloxacin (FDA-Approved)

• Dosing: 500 mg every 12 hours orally for 10 days 6
• Only use when susceptibility is confirmed AND the organism is sensitive to nalidixic acid on disc testing 3
• Never use empirically for cases from South or Southeast Asia due to resistance rates approaching 96% 1, 2
• Ciprofloxacin disc testing alone is unreliable; the organism must also be sensitive to nalidixic acid 3

Ceftriaxone

• Use when oral therapy is not feasible or for severe/complicated disease 3
• Treatment duration should be 14 days to reduce relapse risk 3
• Ceftriaxone achieves rapid microbiological clearance, with blood cultures becoming negative earlier than chloramphenicol (0% positive on day 3 vs 60%) 7

Critical Pitfalls to Avoid

Geographic Resistance Patterns

• Do not use ciprofloxacin empirically for travel-associated cases from South/Southeast Asia 1, 2, 4
• Extensively drug-resistant strains have emerged in Pakistan, with resistance to both fluoroquinolones and ceftriaxone 4, 5
• Always consider local resistance patterns when selecting empiric therapy 1, 2

Treatment Duration

• Never discontinue antibiotics prematurely, even if fever resolves early 1, 2
• Incomplete treatment leads to relapse in 10-15% of cases 1, 2
• Complete the full 7-14 day course for azithromycin or 14 days for ceftriaxone 1, 3

Diagnostic Errors

• Do not rely on the Widal serological test, as it lacks sensitivity and specificity 3
• Blood cultures have highest yield in the first week; stool and urine cultures become positive after the first week 3

Monitoring and Expected Response

Clinical Improvement Timeline

• Fever should clear within 4-5 days of appropriate antibiotic therapy 1, 2, 3
• Defervescence occurred in half of patients within the first 7 days in clinical trials 7

Common Adverse Effects of Azithromycin

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

Management of Complications

Intestinal Perforation

• Occurs in 10-15% of patients when illness duration exceeds 2 weeks 1, 2, 3
• Requires immediate surgical intervention with simple excision and closure 1, 2
• Surgical success rate is up to 88.2% 1

Other Severe Complications

• Gastrointestinal bleeding, typhoid encephalopathy occur in 10-15% of patients with prolonged illness (>2 weeks) 3

Special Populations

Pediatric Considerations

• Ciprofloxacin is FDA-approved for typhoid fever in children but is not first-choice due to increased incidence of joint-related adverse events 6
• Azithromycin 20 mg/kg/day (maximum 1g/day) for 7-14 days is preferred 1, 2
• Ceftriaxone 50-80 mg/kg/day (maximum 2g/day) for severe disease 1

Pregnancy and Vaccination Status

• Previous typhoid vaccination provides incomplete protection (50-80%) and does not protect against paratyphoid 3, 4
• Vaccination status should not alter treatment approach 1