Treatment of Typhoid Fever
First-Line Treatment Recommendation
Azithromycin 500 mg once daily for 7-14 days is the preferred first-line treatment for adults with typhoid fever, particularly given widespread fluoroquinolone resistance exceeding 70% in endemic regions. 1, 2
For children, use azithromycin 20 mg/kg/day (maximum 1g/day) for 7-14 days. 1, 2
Treatment Algorithm Based on Clinical Presentation and Geographic Origin
For Uncomplicated Typhoid Fever
Start azithromycin empirically as first-line therapy, especially for cases originating from South Asia where fluoroquinolone resistance approaches 96% in some regions. 1, 2
Obtain blood cultures before initiating antibiotics when possible, as they have the highest yield (40-80% sensitivity) within the first week of symptoms. 3, 4
Expect fever clearance within 4-5 days of appropriate therapy. 1, 2
For Severe or Unstable Patients
Initiate intravenous ceftriaxone 2g daily for adults when the patient's clinical condition is unstable or if empiric treatment is needed before culture results. 3, 4
For children, use ceftriaxone 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days. 2
Continue treatment for 14 days total to reduce relapse risk. 3, 4
Why Azithromycin Over Other Options
Superior Clinical Outcomes
Azithromycin demonstrates significantly lower risk of clinical failure (OR 0.48,95% CI 0.26-0.89) compared to fluoroquinolones. 1, 2
Hospital stays are approximately 1 day shorter with azithromycin (mean difference -1.04 days, 95% CI -1.73 to -0.34 days). 1, 2
Relapse risk is dramatically lower with azithromycin (OR 0.09,95% CI 0.01-0.70) compared to ceftriaxone. 1, 2
Resistance Patterns Make Fluoroquinolones Unreliable
More than 70% of S. typhi and S. paratyphi isolates imported into the UK are fluoroquinolone-resistant. 3, 4
Ciprofloxacin disc testing alone is unreliable for determining Salmonella sensitivity—the organism must also be sensitive to nalidixic acid on disc testing to be considered truly fluoroquinolone-sensitive. 3, 4
While ciprofloxacin is FDA-approved for typhoid fever 5, resistance patterns in South Asia make it empirically inappropriate for cases from these regions. 1, 2
Critical Pitfalls to Avoid
Do Not Discontinue Antibiotics Prematurely
- Complete the full 7-14 day course even if fever resolves early, as relapse occurs in 10-15% of inadequately treated cases. 1, 2
Never Use Ciprofloxacin Empirically for South/Southeast Asian Cases
Fluoroquinolone resistance exceeds 70% in South Asia and approaches 96% in some regions, making empiric ciprofloxacin use inappropriate. 1, 2
Fluoroquinolones remain effective only when susceptibility is confirmed by culture. 2, 6
Avoid Cefixime as First-Line Therapy
Cefixime has documented treatment failure rates of 4-37.6% in clinical practice. 3, 1
If cefixime must be used, a mandatory test-of-cure at 1 week is required due to high failure rates. 1
Clinical failure, microbiological failure, and relapse may all be increased with cefixime compared to fluoroquinolones (when susceptible). 7
Alternative Treatment Options
When Azithromycin Cannot Be Used
Ceftriaxone is an effective alternative with few adverse effects, showing no significant difference in performance compared to azithromycin in head-to-head trials. 7
Ceftriaxone achieves rapid clinical response with mean defervescence time of 4 days when medical complications are excluded. 8
All isolates of S. typhi reported to the UK Health Protection Agency in 2006 were sensitive to ceftriaxone. 3
When Fluoroquinolone Susceptibility Is Confirmed
Fluoroquinolones (ciprofloxacin or ofloxacin) remain the most effective treatment option for susceptible isolates, with average fever clearance time <4 days, cure rates >96%, and low rates of fecal carriage. 3
Relapse rates for fluoroquinolones are <8%. 3
However, this applies only to confirmed susceptible isolates—never use empirically for cases from South Asia. 1, 2
Management of Complications
Intestinal Perforation
Occurs in 10-15% of patients when illness duration exceeds 2 weeks. 2, 4
Requires immediate surgical intervention with simple excision and closure, successful in up to 88.2% of cases. 1, 2
Severe Cases
The addition of steroids may be helpful in severe cases. 3
For patients with sepsis features, start broad-spectrum antimicrobial therapy immediately after collecting blood cultures. 2
Monitoring and Expected Response
Clinical Response Timeline
Fever should clear within 4-5 days of appropriate antibiotic therapy. 1, 2
If no response by day 5, consider resistance or alternative diagnosis. 2
Adverse Effects to Monitor
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
Prevention Strategies
Vaccination Recommendations
Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa), particularly those with moderate to high risk of exposure. 1, 2, 4
Two vaccines are available in the United States: Ty21a oral vaccine and Vi-polysaccharide parenteral vaccine. 1
Important Vaccination Limitations
Vaccination provides only 50-80% protection and does not protect against Salmonella Paratyphi. 1, 2, 4
Hand hygiene and food/water safety precautions remain essential and should not be replaced by vaccination alone. 1, 2
Careful selection of food and drink remains important even after vaccination, as vaccines are not 100% effective. 4
Emerging Resistance Concerns
Always consider local resistance patterns when selecting empiric therapy, as these vary geographically and change over time. 1, 2
Extensively drug-resistant strains of enteric fever have emerged in Pakistan, with both ciprofloxacin-resistant and ceftriaxone-resistant typhoid becoming common. 6, 7
In some areas, susceptibility to old first-line antimicrobials like chloramphenicol has re-appeared, though this should not change first-line recommendations. 7