What is the first-line treatment for Typhoid (Typhi) fever?

First-Line Treatment for Typhoid Fever

Azithromycin 500 mg once daily for 7 days is the recommended first-line treatment for typhoid fever, particularly given the high rates of fluoroquinolone resistance in most endemic regions. 1

Treatment Algorithm Based on Geographic Origin and Resistance Patterns

For Patients from South/Southeast Asia (High Fluoroquinolone Resistance)

• Start with azithromycin 500 mg daily for 7 days as empiric therapy, since >70% of S. typhi isolates from these regions demonstrate fluoroquinolone resistance 2, 1
• Azithromycin demonstrates superior outcomes with lower clinical failure rates (OR 0.48) and significantly reduced relapse risk (OR 0.09 compared to ceftriaxone) 1
• Fever clearance typically occurs within 5-6 days with azithromycin 3, 4

For Severe or Complicated Cases

• Initiate IV ceftriaxone as first-line therapy for patients presenting with sepsis, severe illness, or inability to tolerate oral medications 1, 5
• Transition to oral azithromycin once clinical improvement occurs 1
• Consider adding corticosteroids in severe cases with complications 2, 5

For Fully Susceptible Strains (Rare)

• Fluoroquinolones (ciprofloxacin or ofloxacin) remain highly effective only if nalidixic acid sensitivity is confirmed, achieving fever clearance <4 days and cure rates >96% 2, 6
• However, nalidixic acid resistance increased from 19% in 1999 to 59% in 2008, making this scenario increasingly uncommon 2

Critical Treatment Duration

• Continue treatment for 14 days regardless of agent used to minimize relapse risk 2, 5, 6
• Relapse rates: azithromycin <3%, ceftriaxone <8%, fluoroquinolones <8% 2, 5, 6

Alternative Oral Agents (Second-Line)

• Cefixime can be used as an alternative oral agent, though treatment failure rates of 4-37.6% have been reported 2
• Ceftriaxone (IV/IM) remains universally sensitive, with all UK isolates in 2006 showing susceptibility 2

Critical Pitfalls to Avoid

• Never use ciprofloxacin empirically for cases from South/Southeast Asia due to widespread resistance and poor clinical outcomes despite in vitro "susceptibility" 2, 1
• Ciprofloxacin disc testing is unreliable; isolates must also be nalidixic acid-sensitive to be truly fluoroquinolone-susceptible 5
• Decreased susceptibility to ciprofloxacin (DCS) doesn't meet resistance criteria by laboratory standards but is associated with clinical failure 2
• Avoid live-attenuated Ty21a vaccine in immunocompromised patients 2

Monitoring for Treatment Response

• Expect fever clearance within 4-5 days of appropriate therapy 1
• If no clinical response within 24-48 hours, consider alternative diagnoses or resistant organisms 2
• Common azithromycin adverse effects include gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea) 1
• Obtain blood cultures before initiating therapy when possible, as sensitivity is 40-80% in the first week 5, 6

Resistance Considerations

• Multidrug resistance (to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole) remains common at 58-88.7% in endemic regions 3, 4
• Fluoroquinolone resistance now affects 89-97.8% of isolates from South Asia 7
• Emerging azithromycin MIC increases warrant monitoring, though clinical resistance remains rare 1, 7