Treatment of Typhoid Fever

First-Line Treatment Recommendation

Azithromycin 500 mg once daily for 7 days is the preferred first-line treatment for typhoid fever in adults, particularly for cases originating from South Asia where fluoroquinolone resistance exceeds 70%. 1, 2

For children, azithromycin should be dosed at 20 mg/kg/day (maximum 1g/day) for 7 days. 1, 2

Treatment Algorithm Based on Geographic Origin and Severity

For Uncomplicated Cases from South Asia or Unknown Origin

Start with oral azithromycin as empiric therapy due to fluoroquinolone resistance rates approaching 96% in some South Asian regions. 1
Azithromycin demonstrates superior outcomes with lower risk of clinical failure (OR 0.48) compared to fluoroquinolones. 1, 2
Hospital stays are approximately 1 day shorter with azithromycin compared to fluoroquinolones (MD -1.04 days). 1
Relapse risk is dramatically lower with azithromycin (OR 0.09) compared to ceftriaxone. 1, 2

For Severe Cases or Unstable Patients

Initiate IV ceftriaxone 2g daily for adults (or 50-80 mg/kg/day, maximum 2g/day for children) for patients with sepsis features or severe illness. 3, 2
Continue ceftriaxone for 14 days to reduce relapse risk. 3
Transition to oral therapy when clinically improved. 2
Alternative dosing: 1-2g IV/IM daily for 5-7 days in adults has been used successfully in some studies. 1

For Confirmed Susceptible Isolates

Fluoroquinolones (ciprofloxacin or ofloxacin) remain effective when susceptibility is confirmed by testing. 1, 2
Critical caveat: Ciprofloxacin disc testing alone is unreliable; the organism must also be sensitive to nalidixic acid on disc testing to be considered truly fluoroquinolone-sensitive. 3
The FDA approves ciprofloxacin for typhoid fever caused by Salmonella typhi. 4

Critical Diagnostic Steps Before Treatment

Obtain blood cultures before starting antibiotics whenever possible, as they have the highest yield (40-80% sensitivity) within the first week of symptom onset. 1, 3
For patients with sepsis features, start broad-spectrum antimicrobial therapy immediately after collecting blood, stool, and urine cultures. 1, 2
Bone marrow cultures have higher sensitivity than blood cultures but are rarely practical. 3
The serological Widal test lacks sensitivity and specificity and is not recommended. 3

Monitoring and Expected Clinical Response

Expect fever clearance within 4-5 days of appropriate therapy. 1, 2
If no clinical response by day 5, consider antimicrobial resistance or alternative diagnosis. 1
Mean defervescence time with ceftriaxone is approximately 4-5 days. 5, 6
Complete the full 7-day course (for azithromycin) or 14-day course (for ceftriaxone) to prevent relapse, which occurs in 10-15% of inadequately treated cases. 1, 3

Common Pitfalls to Avoid

Never use ciprofloxacin empirically for cases from South or Southeast Asia due to widespread resistance exceeding 70%. 1, 3, 2
Do not use cefixime as first-line therapy: it has documented treatment failure rates of 4-37.6% and relapse rates of 4-37.6%. 1
If cefixime must be used, a mandatory test-of-cure at 1 week is required due to high failure rates. 1
The WHO lists cefixime only as an "alternative" option, not first-line. 1
Do not discontinue antibiotics prematurely even if fever resolves early. 1
Avoid combination typhoid-paratyphoid vaccines; only monovalent S. typhi preparations should be used. 1

Management of Complications

Complications occur in 10-15% of patients with illness duration exceeding 2 weeks, including gastrointestinal bleeding, intestinal perforation, and typhoid encephalopathy. 1, 3
Intestinal perforation requires surgical intervention with simple excision and closure, reported successful in up to 88.2% of cases. 1

Adverse Effects and Drug Interactions

Common azithromycin adverse effects include gastrointestinal symptoms: nausea, vomiting, abdominal pain, and diarrhea. 1, 2
Monitor for potential drug interactions with azithromycin, particularly QT-prolonging medications. 1, 2

Specific Dosing Summary

Azithromycin (First-Line):

Adults: 500 mg once daily for 7 days 1, 2
Children: 20 mg/kg/day (maximum 1g/day) for 7 days 1, 2

Ceftriaxone (Severe Cases or Alternative):

Adults: 2g IV daily for 14 days 3 or 1-2g IV/IM daily for 5-7 days 1
Children: 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days 1

Fluoroquinolones (Only for Confirmed Susceptible Isolates):

Use only when susceptibility confirmed by both ciprofloxacin and nalidixic acid disc testing 3
Avoid empirically for South Asian cases 1, 3, 2

Prevention Considerations

Typhoid vaccination is recommended for travelers to endemic areas, particularly Latin America, Asia, and Africa. 1, 3, 2
Vaccination provides incomplete protection (does not protect against paratyphoid) and should not replace food and water safety precautions. 1, 3, 2
Hand hygiene and appropriate food safety practices remain essential. 1

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