What is the diagnosis and treatment of typhoid fever, including the role of blood cultures, stool cultures, and the Widal test, and what are the recommended antibiotics and their dosages?

Typhoid Fever: Pathology, Diagnosis, and Treatment

What is Typhoid Fever?

Typhoid fever is a systemic infection caused by Salmonella typhi (and S. paratyphi) that presents with fever and non-specific symptoms including headache, constipation/diarrhea, and dry cough. 1 Fever is almost invariable, but other symptoms are highly variable, making clinical diagnosis unreliable without laboratory confirmation. 1

Diagnostic Approach: When Different Cultures Become Positive

Blood Culture (Gold Standard)

• Blood cultures have the highest yield within the first week of symptom onset, with sensitivity of 40-80% using modern methods 1, 2
• Draw 3-4 blood cultures within the first 24 hours of fever onset, before starting antibiotics 1
• Blood cultures should be 20-30 mL per culture, drawn from separate venipunctures using strict aseptic technique 1
• Bone marrow culture has higher sensitivity (35-65%) than blood culture but is more invasive 1, 3

Stool and Urine Cultures

• Stool and urine cultures become positive after the first week of illness 1, 3
• Stool culture sensitivity: 35-65% 1
• Urine culture sensitivity: 0-58% 1
• These are useful when blood cultures are negative or when patients present late 1

Timeline Summary

• Week 1: Blood culture most sensitive 1, 2
• After Week 1: Stool and urine cultures become positive 1, 3

What is the Widal Test?

The Widal test is a serological test that detects antibodies (O and H agglutinins) against Salmonella antigens, but it lacks sensitivity and specificity and is NOT recommended for diagnosis. 1

Why Widal Test is Unreliable

• Poor sensitivity (71.4%) and specificity (68.4%) compared to blood culture 4
• High false-positive rate: 81% of patients tested positive by Widal but only 10.1% actually had typhoid 5
• Poor agreement with blood culture (kappa = 0.014) 5
• The Widal test is positive in 25% of individuals in endemic areas without active infection 1
• Newer rapid serological tests (Typhidot, Typhidot-M, Tubex) have shown mixed results 1

When Widal May Have Limited Use

• If used despite limitations, titers of O ≥1:80 and H ≥1:160 suggest recent infection 4
• Negative predictive value is good (98.9%), meaning a negative test helps exclude disease 4
• However, guideline consensus is clear: Widal test is not recommended 1

Treatment of Typhoid Fever

First-Line Treatment: Intravenous Ceftriaxone

For patients with suspected typhoid fever, especially those returning from Asia, intravenous ceftriaxone is now the preferred first-line agent due to widespread fluoroquinolone resistance. 1, 2, 6, 3

• Ceftriaxone 50-80 mg/kg/day (maximum 2g/day) IV for 5-7 days initially 3
• Continue treatment for 14 days total to reduce relapse risk 1, 6, 3
• Over 70% of S. typhi and S. paratyphi isolates from Asia are fluoroquinolone-resistant 1, 6, 3
• All isolates reported to UK Health Protection Agency in 2006 were sensitive to ceftriaxone 1
• Relapse rate with ceftriaxone: <8% 1, 6

Oral Alternative: Azithromycin

For uncomplicated typhoid fever, azithromycin is the preferred oral alternative, especially when fluoroquinolone resistance is confirmed. 1, 6, 3

• Azithromycin 20 mg/kg/day (maximum 1g/day) for 7 days 3
• Relapse rate: <3% 1, 6
• Azithromycin resistance is currently rare 1
• Lower risk of clinical failure compared to fluoroquinolones 3

Fluoroquinolones: Use Only with Confirmed Sensitivity

Fluoroquinolones should only be used if the isolate is sensitive to BOTH ciprofloxacin AND nalidixic acid on disc testing. 1, 6

• Ciprofloxacin disc testing alone is unreliable for determining fluoroquinolone sensitivity 1, 6
• When sensitive: Ciprofloxacin 500 mg every 12 hours for 10 days (per FDA label) 7
• Average fever clearance time: <4 days 1, 6
• Cure rates: >96% 1, 6
• Relapse rate: <8% 1
• Avoid empiric fluoroquinolone use for cases from South Asia due to high resistance rates 3

Cefixime: Less Reliable Alternative

• Cefixime has reported treatment failure rates of 4-37.6% 1
• Not recommended as first-line therapy 1

Severe Cases and Complications

For patients with unstable clinical condition or features of sepsis, start empiric treatment immediately after collecting blood cultures. 1, 6

• Addition of steroids may be helpful in severe cases 1, 2, 6
• Monitor for complications: gastrointestinal bleeding, intestinal perforation, typhoid encephalopathy 1, 6, 3
• Complications occur in 10-15% of patients, more likely if illness duration >2 weeks 1, 6, 3

Treatment Algorithm

1. Collect 3-4 blood cultures before starting antibiotics 1, 2
2. If patient is unstable or has sepsis features: Start IV ceftriaxone immediately 1, 6, 3
3. If patient is stable with uncomplicated disease: Start oral azithromycin 1, 6, 3
4. Continue treatment for 14 days total 1, 6, 3
5. Add steroids if severe disease 1, 2, 6
6. Monitor for complications, especially if >2 weeks of illness 1, 6, 3

Critical Pitfalls to Avoid

• Never rely on Widal test alone for diagnosis 1, 5, 4
• Never use ciprofloxacin disc testing alone to determine fluoroquinolone sensitivity—must also check nalidixic acid sensitivity 1, 6
• Never use empiric fluoroquinolones for patients from Asia without confirmed sensitivity 1, 3
• Never treat for less than 14 days—shorter courses increase relapse risk 1, 6, 3
• Always collect blood cultures before starting antibiotics 1, 2, 3

Additional Baseline Tests

• Full blood count (look for lymphopenia and thrombocytopenia) 2
• Urea, electrolytes, and liver function tests 2
• Malaria film and rapid diagnostic test (mandatory in all febrile travelers from tropical areas) 2