What is the indicated treatment for a typical patient with typhoid fever?

Treatment of Typhoid Fever

Azithromycin 500 mg once daily for 7 days is the preferred first-line treatment for adults with typhoid fever, with 20 mg/kg/day (maximum 1g/day) for 7 days in children. 1, 2, 3

Why Azithromycin is First-Line

The shift away from fluoroquinolones is driven by overwhelming resistance patterns:

• Over 70% of S. typhi isolates from South Asia are fluoroquinolone-resistant, with some regions approaching 96% resistance 4, 1, 2
• More than 70% of isolates imported into the UK demonstrate fluoroquinolone resistance 4, 3
• Azithromycin demonstrates superior clinical outcomes with lower risk of treatment failure (OR 0.48) compared to fluoroquinolones 1, 2, 3
• Hospital stays are approximately 1 day shorter with azithromycin (mean difference -1.04 days) 1, 2, 3
• Relapse risk is dramatically lower with azithromycin (OR 0.09) compared to ceftriaxone 1, 2, 3

Treatment Algorithm

Step 1: Obtain Blood Cultures Before Starting Antibiotics

• Blood cultures have the highest yield within the first week of symptom onset (40-80% sensitivity) 4, 3
• Collect cultures whenever possible before initiating therapy 1, 2, 3

Step 2: Initiate Empiric Therapy Immediately

For uncomplicated typhoid fever:

• Adults: Azithromycin 500 mg once daily orally for 7 days 1, 2, 3
• Children: Azithromycin 20 mg/kg/day (maximum 1g/day) for 7 days 1, 2, 3

For severe cases requiring IV therapy:

• Adults: Ceftriaxone 1-2g IV/IM daily for 5-7 days 1, 3
• Children: Ceftriaxone 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days 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 antimicrobial resistance or alternative diagnosis 4

Step 4: Complete Full Course

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

Critical Pitfalls to Avoid

Never Use Ciprofloxacin Empirically for Travel-Associated Cases

• Ciprofloxacin is FDA-approved for typhoid fever 5, but resistance has rendered it ineffective for empiric use in most endemic regions
• Fluoroquinolone resistance exceeds 70% in South Asia, making empiric ciprofloxacin inappropriate 4, 1, 2
• Ciprofloxacin disc testing is unreliable; only isolates also sensitive to nalidixic acid should be considered fluoroquinolone-sensitive 4, 3

Avoid Cefixime as First-Line Therapy

• Cefixime has documented treatment failure rates of 4-37.6% 4, 1
• Cefixime performs significantly worse than fluoroquinolones in head-to-head trials 1
• If cefixime must be used, a mandatory test-of-cure at 1 week is required 1
• Fever clearance time with cefixime is significantly longer (median 8.5 days vs 4.4 days with ofloxacin) 6

Do Not Discontinue Antibiotics Prematurely

• Complete the full 7-day course to prevent relapse 1, 2, 3
• Relapse occurs in 10-15% of inadequately treated cases 1, 2

When Fluoroquinolones Can Still Be Used

Fluoroquinolones remain effective only when susceptibility is confirmed 1:

• Isolates must be sensitive to both nalidixic acid and the fluoroquinolone on disc testing 4, 3
• In sensitive isolates, fluoroquinolones achieve fever clearance in <4 days with cure rates >96% 4
• Gatifloxacin 10 mg/kg/day for 7 days showed equivalent efficacy to azithromycin in a 2008 trial (median fever clearance 106 hours for both) 7

Management of Complications

Intestinal Perforation

• Occurs in 10-15% of patients when illness duration exceeds 2 weeks 4, 1
• Requires immediate surgical intervention with simple excision and closure 1
• Successful in up to 88.2% of cases 1

Encephalopathy

• Occurs in 10-15% of patients, more likely if illness duration >2 weeks 4

Monitoring and Adverse Effects

Expected Clinical Response

• Fever should clear within 4-5 days of appropriate antibiotic therapy 1, 2, 3
• Blood cultures remain positive for approximately 1 week after symptom onset 4, 3

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

Alternative Regimens Based on Resistance Patterns

If Azithromycin Resistance is Documented (Currently Rare)

• Ceftriaxone 1-2g IV/IM daily for 5-7 days in adults 1, 3
• All isolates reported to the UK Health Protection Agency in 2006 were sensitive to ceftriaxone 4

If Fluoroquinolone Sensitivity is Confirmed

• Ciprofloxacin or ofloxacin can be used with average fever clearance time <4 days 4
• Relapse rates <8% with fluoroquinolones when used for 14 days 4

Prevention Strategies

Vaccination Recommendations

• Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa) 1, 2, 3
• Two vaccines available: Ty21a oral vaccine (four doses on alternate days) and Vi-polysaccharide parenteral vaccine (0.5 mL subcutaneously, two doses ≥4 weeks apart) 4, 1
• Vaccination provides only 50-80% protection and does not protect against Salmonella Paratyphi 1, 2, 3
• Booster doses: Ty21a every 5 years, parenteral vaccine every 3 years 4, 1

Important Limitations

• Hand hygiene and food/water safety precautions remain essential and should not be replaced by vaccination alone 1, 2, 3