What is the recommended treatment for enteric fever?

Treatment of Enteric Fever

The recommended first-line treatment for enteric fever is azithromycin, particularly in areas with high fluoroquinolone resistance, with ceftriaxone as an alternative for severe cases requiring parenteral therapy. 1, 2

First-Line Treatment Options

• Azithromycin is recommended as first-line therapy with a dosage of 20 mg/kg/day (maximum 1g/day) orally for 7 days, especially in areas with known fluoroquinolone resistance 1, 2
• Azithromycin has shown lower risk of clinical failure (OR 0.48) and shorter hospital stays compared to fluoroquinolones in systematic reviews 3, 4
• For fully susceptible Salmonella typhi strains, fluoroquinolones such as ciprofloxacin (500 mg twice daily for 7-10 days) or ofloxacin (400 mg twice daily for 7-10 days) may be used, but resistance is increasingly common worldwide 1, 5
• In a human challenge model study, ciprofloxacin demonstrated faster fever clearance and blood culture clearance compared to azithromycin, though both were effective 6

Second-Line Treatment Options

• Ceftriaxone (50-80 mg/kg/day, maximum 2g/day) intravenously for 5-7 days is recommended for severe cases requiring hospitalization 1, 2
• Cefixime (8 mg/kg/day in children or 400 mg daily in adults) is an appropriate oral alternative, particularly when other options are unavailable 2
• Chloramphenicol may be considered as a last-resort option when no other antibiotics are available, according to WHO recommendations 3

Treatment Based on Resistance Patterns

• Local susceptibility patterns should guide therapy choice as resistance patterns vary geographically and change over time 1, 4
• Over 70% of S. typhi isolates in many regions, particularly South Asia, are now resistant to fluoroquinolones, making azithromycin or ceftriaxone better empiric choices 2, 7
• Fluoroquinolone resistance is essentially a class effect and is increasing globally 2, 7
• In areas with known high resistance to both fluoroquinolones and cephalosporins, combination therapy with azithromycin and cefixime is being investigated 8

Treatment Duration and Monitoring

• For most patients with uncomplicated enteric fever, 7 days of appropriate antibiotics is recommended 2
• Patients treated initially with parenteral antibiotics should be transferred to an oral regimen as soon as clinical improvement occurs and temperature has been normal for 24 hours 2
• Monitor for clinical response, with expected fever clearance within 4-5 days of appropriate therapy 2
• Reassessment of fluid and electrolyte balance, nutritional status, and optimal dose and duration of antimicrobial therapy is recommended in people with persistent symptoms 1

Special Considerations

• Always obtain blood cultures before starting antibiotics when possible 1, 2
• For patients with clinical features of sepsis, broad-spectrum antimicrobial therapy should be started immediately after collection of blood cultures 1, 4
• Treatment should be modified based on antimicrobial susceptibility testing results when available 1, 4

Common Pitfalls to Avoid

• Avoid using ciprofloxacin empirically for cases originating from South Asia due to high resistance rates 2
• Do not rely solely on clinical presentation for diagnosis; obtain cultures whenever possible 2
• Consider travel history when selecting empiric therapy, as resistance patterns vary geographically 1, 4
• In a Cochrane review, cefixime showed higher rates of clinical failure, microbiological failure, and relapse compared to fluoroquinolones, so it should not be first choice when other options are available 9

Emerging Evidence

• A recent study comparing azithromycin and ciprofloxacin in a controlled human infection model found that while both were effective, azithromycin was associated with prolonged bacteremia (median 90.8 hours vs. 20.1 hours) and longer fever clearance times compared to ciprofloxacin 6
• This may be due to azithromycin's pharmacokinetics, where systemic plasma concentrations may not exceed the minimum inhibitory concentration for extracellular S. Typhi 6
• Combination therapy with azithromycin and cefixime is being investigated as a potential strategy to improve outcomes and prevent resistance 8