What is the treatment for typhoid fever caused by Salmonella Typhi?

Treatment of Typhoid Fever (Salmonella Typhi)

Azithromycin 500 mg once daily for 7 days is the preferred first-line treatment for typhoid fever in adults, particularly given that fluoroquinolone resistance now exceeds 70% in most endemic regions. 1, 2, 3

First-Line Treatment Regimen

Adults

• Azithromycin 500 mg orally once daily for 7 days 1, 2, 3
• This regimen demonstrates superior outcomes with lower clinical failure rates (OR 0.48) compared to fluoroquinolones 1, 3
• Hospital stays are approximately 1 day shorter with azithromycin (mean difference -1.04 days) 1, 2, 3

Children

• Azithromycin 20 mg/kg/day (maximum 1g/day) orally once daily for 7 days 1, 2, 3

Why Azithromycin Over Fluoroquinolones

The shift away from fluoroquinolones as first-line therapy is driven by overwhelming resistance data:

• Over 70% of S. typhi isolates from South Asia are fluoroquinolone-resistant, with some regions approaching 96% resistance 4, 1, 2, 3
• More than 70% of isolates imported into the UK demonstrate fluoroquinolone resistance 4, 3
• Azithromycin has dramatically lower relapse rates (OR 0.09) compared to ceftriaxone 1, 2, 3
• Relapse occurs in less than 3% of azithromycin-treated patients versus up to 8% with ceftriaxone 4

Critical Diagnostic Steps Before Treatment

1. Obtain blood cultures immediately before starting antibiotics - they have the highest yield within the first week of symptom onset (sensitivity 40-80%) 4, 1, 3
2. Stool and urine cultures become positive only after the first week and have lower sensitivity 4
3. Do not rely on the Widal test - it lacks both sensitivity and specificity and is not recommended 4

Alternative Treatment Options

For Severe Cases Requiring IV Therapy

• Ceftriaxone 1-2g IV/IM daily for 5-7 days in adults 1
• Ceftriaxone 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days in children 1
• All isolates reported to UK surveillance in 2006 were sensitive to ceftriaxone 4

When Fluoroquinolones Can Be Used

• Only use fluoroquinolones when susceptibility is confirmed AND the isolate is also sensitive to nalidixic acid 4, 3
• Ciprofloxacin disc testing alone is unreliable for determining true fluoroquinolone sensitivity 4, 3
• When appropriate, fluoroquinolones achieve fever clearance in less than 4 days with cure rates exceeding 96% 4

Critical Pitfalls to Avoid

Never Use Ciprofloxacin Empirically for Travel-Associated Cases

• Avoid empiric ciprofloxacin for any case originating from South or Southeast Asia - resistance is nearly universal 4, 1, 2
• Even when labeled as "indicated" by FDA for typhoid fever 5, local resistance patterns override this designation

Avoid Cefixime as First-Line

• Cefixime has documented treatment failure rates of 4-37.6% 4, 1
• If cefixime must be used, a mandatory test-of-cure at 1 week is required 1

Complete the Full Course

• Never discontinue antibiotics prematurely, even if fever resolves early 1, 2, 3
• Relapse occurs in 10-15% of inadequately treated cases 1, 2
• The full 7-day course is essential to prevent relapse 1, 2

Expected Clinical Response and Monitoring

• Fever should clear within 4-5 days of appropriate antibiotic therapy 4, 1, 2, 3
• If no clinical improvement by day 5, consider antibiotic resistance or alternative diagnosis 1
• Monitor for common azithromycin adverse effects: nausea, vomiting, abdominal pain, and diarrhea 1, 2, 3
• Watch 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 4, 1, 2
• Typically occurs in the third week of disease (range 24 hours to 16 days) 4
• Requires immediate surgical intervention with simple excision and closure, successful in up to 88.2% of cases 4, 1
• Other surgical options include resection with primary anastomosis or limited right hemicolectomy 4

Other Severe Complications

• Gastrointestinal bleeding and typhoid encephalopathy occur in 10-15% of patients 4
• Addition of steroids may be helpful in severe cases 4

Prevention Strategies

Vaccination

• Two typhoid vaccines are available in the United States: oral live-attenuated Ty21a vaccine (4 capsules on alternate days) and Vi-polysaccharide parenteral vaccine (single 0.5 mL IM dose) 4, 2, 3
• Both vaccines provide only 50-80% protection 4, 2, 3
• Vaccination does not protect against Salmonella Paratyphi 4, 2, 3
• Booster doses required every 5 years for oral vaccine and every 2 years for injectable vaccine 4
• Live-attenuated Ty21a vaccine should not be used in immunocompromised persons 4

Non-Vaccine Prevention

• Hand hygiene after using the toilet, before eating, and after handling animals or their environments 4
• Appropriate food safety practices to avoid cross-contamination 4
• These measures remain essential and should not be replaced by vaccination alone 2, 3

Asymptomatic Carriers

• Asymptomatic people in low-risk settings who practice hand hygiene do not need treatment 4
• Exception: Asymptomatic carriers of S. typhi may be treated empirically to reduce transmission potential 4
• Those in high-risk settings (healthcare workers, food service employees, childcare providers) should be treated according to local public health guidance 4