What is the recommended treatment for a patient suspected of having typhoid fever, considering factors such as travel history, vaccination status, and underlying health conditions?

Treatment of Typhoid Fever

Immediate First-Line Recommendation

Azithromycin 500 mg once daily for 7 days is the preferred first-line treatment for adults with suspected or confirmed typhoid fever, particularly given that over 70% of isolates from endemic regions (especially South Asia) are fluoroquinolone-resistant. 1, 2

Diagnostic Approach Before Treatment

• Obtain blood cultures immediately before starting antibiotics whenever the patient's clinical condition permits, as blood cultures have the highest diagnostic yield (40-80% sensitivity) within the first week of symptom onset 3, 2
• Do not rely on the Widal test for diagnosis—it has poor specificity (68.44%) and very poor positive predictive value (5.7%), making it unreliable for clinical decision-making 2
• If the patient is clinically unstable, has sepsis features, or shows signs of complications (high fever with altered mental status, abdominal distension suggesting perforation), start empiric treatment immediately after collecting blood cultures 3, 2

Treatment Algorithm Based on Clinical Severity and Geography

For Uncomplicated Typhoid Fever (Outpatient or Stable Inpatient)

Adults:

• Azithromycin 500 mg orally once daily for 7 days 1, 2
• This regimen demonstrates significantly lower clinical failure rates (OR 0.48) compared to fluoroquinolones and dramatically lower relapse rates (OR 0.09) compared to ceftriaxone 1
• Hospital stays are approximately 1 day shorter with azithromycin compared to fluoroquinolones 1

Children:

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

For Severe or Complicated Typhoid Fever (Requiring IV Therapy)

Adults:

• Ceftriaxone 1-2g IV/IM once daily for 5-7 days 1, 2
• Continue until defervescence, then for an additional 5 days 4

Children:

• Ceftriaxone 50-80 mg/kg/day IV/IM once daily (maximum 2g/day) for 5-7 days 1, 2
• A flexible duration approach (until defervescence plus 5 additional days) is reasonable and effective 4

Geographic Considerations for Antibiotic Selection

• Never use ciprofloxacin empirically for cases from South or Southeast Asia, where fluoroquinolone resistance approaches 96% in some regions 1, 2
• Fluoroquinolone resistance exceeds 70% in isolates from South Asia, making empiric use inappropriate 3, 1
• Ciprofloxacin (500 mg twice daily for 7-14 days) remains an option only if the patient traveled from sub-Saharan Africa AND susceptibility is confirmed with nalidixic acid disc testing 3, 2
• Critical testing note: Ciprofloxacin disc testing alone is unreliable for Salmonella typhi—the organism must also be sensitive to nalidixic acid on disc testing to be considered truly fluoroquinolone-sensitive 3

Expected Clinical Response and Monitoring

• Expect fever clearance within 4-5 days of appropriate antibiotic therapy 3, 1, 2
• If no clinical improvement occurs by day 5, consider antibiotic resistance or an alternative diagnosis 3
• Complete the full 7-day course (or 14 days per some guidelines) even if fever resolves early, as premature discontinuation increases relapse risk to 10-15% 1, 2
• Relapse rates with appropriate therapy: <3% for azithromycin, <8% for ceftriaxone, but 4-37.6% for cefixime 3, 1

Alternative Oral Agents (When Azithromycin Unavailable)

• Cefixime is NOT recommended as first-line due to treatment failure rates of 4-37.6% and high relapse rates 3, 1
• If cefixime must be used, a mandatory test-of-cure at 1 week is required due to high failure rates 1
• Fluoroquinolones (ciprofloxacin or ofloxacin) remain effective only when susceptibility is confirmed, but avoid empiric use for cases from Asia 1

Management of Complications

• Intestinal perforation occurs in 10-15% of patients, particularly when illness duration exceeds 2 weeks 3, 2
• Other complications include gastrointestinal bleeding and typhoid encephalopathy, occurring in 10-15% of cases 3, 2
• Surgical intervention with simple excision and closure is required for perforation, with success rates up to 88.2% 1, 2
• Consider adding corticosteroids in severe cases with complications 3

Critical Pitfalls to Avoid

• Never discontinue antibiotics prematurely, even if fever resolves early—this dramatically increases relapse risk 1, 2
• Never use empiric ciprofloxacin for cases from Asia due to widespread resistance 1, 2
• Never rely solely on the Widal test for diagnosis—supplement with blood cultures 2
• Do not use antiperistaltic agents (loperamide, diphenoxylate) if the patient has high fever or blood in stool, and discontinue if symptoms persist beyond 48 hours 3
• Avoid live oral typhoid vaccine (Ty21a) in HIV-infected or immunocompromised patients—use inactivated parenteral vaccine instead 3, 5

Adverse Effects to Monitor

• Common azithromycin adverse effects include gastrointestinal symptoms: nausea, vomiting, abdominal pain, and diarrhea 1, 2
• Monitor for potential drug interactions with azithromycin, particularly QT-prolonging medications 1
• Ceftriaxone causes fewer bone marrow suppression effects compared to chloramphenicol 6

Special Populations

HIV-Infected Patients

• Use inactivated parenteral typhoid vaccine instead of live oral preparation for prevention 3
• For treatment of active infection, use the same antibiotic regimens as immunocompetent patients (azithromycin or ceftriaxone) 1, 2
• TMP-SMZ can be considered as alternative empirical therapy for travelers with diarrhea, but use cautiously due to high adverse reaction rates 3

Pregnant Women and Children <10 Years

• Azithromycin is preferred over fluoroquinolones 1, 2
• Ceftriaxone is safe and effective in all age groups 1, 2, 7
• TMP-SMZ can be considered as alternative empirical therapy 3

Prevention Strategies

• Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa), particularly those with prolonged exposure to potentially contaminated food and drink 1, 5
• Vaccination provides only 50-80% protection and does not protect against Salmonella Paratyphi 1, 5
• Two vaccine options exist: oral Ty21a (67% efficacy for ≥4 years, booster every 5 years) and parenteral Vi polysaccharide (51-76% efficacy, booster every 2-3 years) 5
• Vaccination is NOT a substitute for food and water safety precautions—hand hygiene and avoiding high-risk foods/beverages remain essential 1, 5