Drug of Choice for Enteric Fever
Azithromycin 20 mg/kg/day (maximum 1g/day) orally for 7 days is the preferred first-line treatment for uncomplicated enteric fever in adults, particularly in regions with high fluoroquinolone resistance. 1, 2
Treatment Selection Algorithm
For Mild to Moderate Uncomplicated Cases (Outpatient or Non-Severe)
Azithromycin is the drug of choice with demonstrated 94% cure rate, lower risk of clinical failure (OR 0.48,95% CI 0.26-0.89) compared to fluoroquinolones, and shorter hospital stays (-1.04 days) 3, 1, 2, 4
Azithromycin shows significantly lower relapse rates (OR 0.09,95% CI 0.01-0.70) compared to ceftriaxone 3, 2, 4
Dosing: 20 mg/kg/day (maximum 1g/day) orally for 7 days 1, 2
For Severe Cases Requiring Hospitalization
Ceftriaxone 50-80 mg/kg/day (maximum 2g/day) intravenously for 5-7 days is first-line for hospitalized patients with severe disease 1, 2
Ceftriaxone may result in faster fever clearance (0.52 days shorter time to defervescence) compared to azithromycin 2, 5
In culture-confirmed cases, ceftriaxone showed lower risk of treatment failure (HR 0.24,95% CI 0.08-0.73) compared to gatifloxacin 3, 2
Alternative Options Based on Resistance Patterns
Fluoroquinolones (ciprofloxacin, ofloxacin):
- Should be reserved for fully susceptible S. typhi strains only 1, 6
- Avoid empiric use in cases from South Asia due to >70% resistance rates 1
- Ciprofloxacin is FDA-approved for typhoid fever but resistance is essentially a class effect and increasing globally 1, 7
Cefixime:
- Oral option at 8 mg/kg/day as single daily dose for 7-14 days 1
- May have higher clinical failure rates compared to fluoroquinolones (RR 13.39,95% CI 3.24-55.39) and longer time to defervescence (MD 1.74 days) 5
- Not preferred over azithromycin or ceftriaxone 5, 8
Critical Management Steps
Initial Diagnostic Approach
Always obtain blood cultures before initiating antibiotics whenever possible 1, 2, 6
For patients with sepsis features, initiate broad-spectrum therapy immediately after culture collection, then narrow based on susceptibility results 1, 2
Monitoring and Expected Response
Expected fever clearance within 4-5 days of appropriate therapy 1
Switch from parenteral to oral therapy once temperature normal for 24 hours and clinical improvement occurs 1
Total treatment duration: 7 days for most uncomplicated cases 1, 2
Common Pitfalls to Avoid
Do not use ciprofloxacin empirically without susceptibility data, especially for infections acquired in South Asia where resistance exceeds 70% 1
Do not rely on older first-line agents (chloramphenicol, ampicillin, co-trimoxazole) as empiric therapy due to widespread multidrug resistance 3, 9
Always modify therapy when susceptibility results become available rather than continuing empiric coverage 2, 6
Chloramphenicol should only be considered as last-resort when no other options available 1
Resistance Context
The recommendation for azithromycin as first-line reflects the current global resistance landscape where fluoroquinolone resistance is widespread, particularly in South Asia 1, 8. While older WHO guidelines from 2003-2012 recommended fluoroquinolones as first-line 3, more recent evidence demonstrates azithromycin's superiority in populations with drug-resistant strains 3, 4. The 2024 WHO Essential Medicines guidelines now reflect this shift based on systematic review evidence 3.