How should I treat an adult patient with enteric fever (typhoid/paratyphoid) who has no known drug allergies?

Treatment of Enteric Fever in Adults

For adults with enteric fever and no drug allergies, start azithromycin 1g orally daily for 7 days as first-line therapy, particularly if the infection originated from South Asia or other regions with high fluoroquinolone resistance. 1, 2, 3

Initial Management and Diagnostic Approach

• Obtain blood cultures immediately before starting antibiotics, as they have the highest diagnostic yield within the first week of symptoms. 1, 4
• Collect stool and urine cultures in patients with suspected sepsis or severe illness. 1, 3
• For patients presenting with sepsis, initiate broad-spectrum antimicrobial therapy immediately after culture collection, then narrow therapy based on susceptibility results. 1, 3, 4

First-Line Treatment: Azithromycin

Azithromycin is now the preferred first-line agent based on WHO 2024 guidelines, reflecting systematic review evidence showing superiority over fluoroquinolones in regions with high resistance. 1, 2

• Dosing: 1g orally daily for 7 days (or 20 mg/kg/day, maximum 1g). 2, 3
• Advantages over fluoroquinolones: Lower risk of clinical failure (OR 0.48,95% CI 0.26-0.89), shorter hospital stays by approximately 1 day, and significantly reduced relapse risk compared to ceftriaxone (OR 0.09,95% CI 0.01-0.70). 2, 5, 6
• Cure rate: Approximately 94% in clinical trials. 2
• Azithromycin achieved 82% clinical cure versus 64% with ofloxacin in multidrug-resistant and nalidixic acid-resistant typhoid. 7

Second-Line Treatment: Ceftriaxone

For severe cases requiring hospitalization or when oral therapy is not feasible, use ceftriaxone 2g IV daily for 5-7 days. 2, 4, 5

• Ceftriaxone reduces treatment failure risk compared to gatifloxacin (HR 0.24,95% CI 0.08-0.73). 2
• Continue treatment for 14 days total to reduce relapse risk (<8% with ceftriaxone versus higher rates with fluoroquinolones). 4
• Switch to oral therapy once clinically improved and afebrile for 24 hours. 2

Alternative Oral Option: Cefixime

• Dosing: 400 mg orally once daily for 7-14 days. 2
• Cefixime may have higher failure rates than fluoroquinolones (RR 13.39,95% CI 3.24-55.39) and longer time to defervescence (mean difference 1.74 days). 5
• Consider when azithromycin is unavailable and local susceptibility supports its use. 2

Fluoroquinolones: Use Only With Confirmed Susceptibility

Avoid empiric fluoroquinolone use for infections originating from South Asia due to >70% resistance rates. 1, 2, 4, 8

• Ciprofloxacin 500 mg twice daily for 7-10 days or ofloxacin 400 mg twice daily for 7-10 days may be used only when susceptibility is confirmed. 3, 9
• Fluoroquinolone resistance is now widespread globally, particularly in Pakistan where extensively drug-resistant strains have emerged. 5, 8

Treatment Based on Geographic Origin and Resistance Patterns

• South Asia (especially Pakistan): Use azithromycin or ceftriaxone; avoid fluoroquinolones and consider ceftriaxone resistance. 8
• Areas with documented fluoroquinolone susceptibility: Fluoroquinolones remain an option after susceptibility testing. 1, 3
• Multidrug-resistant strains (resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole): Azithromycin shows superior outcomes. 7, 6

Monitoring and Expected Response

• Expected fever clearance: 4-5 days with appropriate therapy. 2
• Azithromycin achieves mean fever clearance of 5.8 days versus 8.2 days with ofloxacin in resistant strains. 7
• Reassess if no clinical improvement within 48-72 hours: Consider treatment failure and adjust based on susceptibility results. 3, 4

Critical Pitfalls to Avoid

• Do not use chloramphenicol empirically due to widespread multidrug resistance, though it may be considered as last resort when no other options exist. 1, 9
• Do not rely on clinical presentation alone; always obtain cultures when possible as symptoms can be altered by previous antimicrobial use. 2, 8
• Do not use short-course therapy; inadequate duration increases relapse risk. 2, 4
• Avoid empiric ceftriaxone in Pakistan where ceftriaxone-resistant typhoid is increasingly common. 8

Special Populations

• Infants <3 months: Use third-generation cephalosporin (ceftriaxone 50-80 mg/kg/day IV). 1, 2
• Patients with neurologic involvement: Use third-generation cephalosporin. 1

Supportive Care

• Administer reduced osmolarity oral rehydration solution for mild to moderate dehydration. 3
• Use isotonic IV fluids for severe dehydration, shock, or altered mental status. 3
• Monitor for complications including gastrointestinal bleeding, intestinal perforation, and typhoid encephalopathy, which occur in 10-15% of patients, especially if illness duration exceeds 2 weeks. 4