What is the recommended treatment for typhoid fever?

Treatment of Typhoid Fever

Azithromycin 500 mg once daily for 7 days is the preferred first-line treatment for adults with typhoid fever, particularly given fluoroquinolone resistance now exceeds 70% in South Asia and approaches 96% in some regions. 1, 2, 3

First-Line Treatment Recommendations

Adults

• Azithromycin 500 mg orally once daily for 7 days 1, 2, 3
• This regimen demonstrates superior outcomes with 52% lower risk of clinical failure compared to fluoroquinolones (OR 0.48) 1, 2
• Hospital stays are approximately 1 day shorter with azithromycin (mean difference -1.04 days) 1, 2, 3

Children

• Azithromycin 20 mg/kg/day (maximum 1g/day) orally for 7 days 1, 2, 3

Severe Cases Requiring Parenteral Therapy

• Ceftriaxone 1-2g IV/IM daily for 5-7 days in adults 1
• Ceftriaxone 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days in children 1

Why Azithromycin Over Fluoroquinolones

The evidence strongly favors azithromycin as empiric therapy:

• Fluoroquinolone resistance is now endemic: Over 70% of S. typhi isolates from South and Southeast Asia are fluoroquinolone-resistant, with some regions reporting 96% resistance 1, 2, 3
• Dramatically lower relapse rates: Azithromycin reduces relapse risk by 91% compared to ceftriaxone (OR 0.09) 1, 2, 3
• Faster clinical response: Fever clearance occurs within 4-5 days of appropriate azithromycin therapy 1, 2, 3
• Better tolerability: Azithromycin is well-tolerated with primarily gastrointestinal side effects (nausea, vomiting, abdominal pain, diarrhea) 1, 3

Treatment Algorithm

Step 1: Obtain Blood Cultures

• Collect blood cultures before initiating antibiotics whenever possible 1, 2, 3
• Blood cultures have 40-80% sensitivity, with highest yield within the first week of symptom onset 1, 2, 3
• Stool and urine cultures become positive only after the first week 2

Step 2: Initiate Empiric Therapy

• Start azithromycin 500 mg once daily immediately after obtaining cultures 1, 2, 3
• For hemodynamically unstable patients, initiate broad-spectrum antimicrobials promptly after blood culture collection 1, 2

Step 3: Monitor Clinical Response

• Expect fever clearance within 4-5 days 1, 2, 3
• If no clinical improvement by day 5, consider antimicrobial resistance or alternative diagnosis 1

Step 4: Complete Full Course

• Complete the entire 7-day course even if fever resolves early 1, 2
• Premature discontinuation leads to relapse in 10-15% of cases 1, 2

When Fluoroquinolones May Still Be Used

Fluoroquinolones should be reserved for highly selective circumstances only:

• Confirmed nalidixic acid susceptibility on culture 2, 3
• Case NOT acquired from South or Southeast Asia 1, 2
• Ciprofloxacin disc testing confirmed by nalidixic acid sensitivity 2, 3

When these criteria are met, fluoroquinolones achieve fever clearance in <4 days with cure rates >96% 2. However, the FDA label for ciprofloxacin indicates it is approved for typhoid fever but does not recommend it as first-choice therapy 4.

Alternative Treatment Options

Ceftriaxone

• Remains fully active: All S. typhi isolates reported in recent surveillance were susceptible to ceftriaxone 1, 2
• May reduce clinical failure compared to azithromycin in children (RR 0.42), though evidence is limited 5
• Time to defervescence may be 0.52 days shorter with ceftriaxone compared to azithromycin 5
• Use when azithromycin is contraindicated or unavailable 1, 2

Chloramphenicol

• The FDA label indicates chloramphenicol is approved for acute Salmonella typhi infections, with recommendation to continue therapeutic levels for 8-10 days after defervescence to reduce relapse 6
• Not recommended as first-line due to toxicity concerns and availability of safer alternatives 6
• Susceptibility has re-emerged in some regions where it may be considered 5

Critical Pitfalls to Avoid

Never Use Ciprofloxacin Empirically for Travel-Associated Cases

• Resistance approaches 96% in South Asia 1, 2, 3
• In Thailand, 93% of isolates are ciprofloxacin-resistant 1, 2
• Empiric fluoroquinolone use in resistant strains prolongs illness by 35 hours (76.4 vs 41.2 hours) 1

Never Use Cefixime as First-Line Therapy

• Treatment failure rates of 4-37.6% have been documented 1, 2
• 13-fold higher risk of clinical failure compared to fluoroquinolones (RR 13.39) 1, 5
• If cefixime must be used, mandatory test-of-cure at 1 week is required 1

Never Discontinue Antibiotics Prematurely

• Complete the full 7-day course even if fever resolves early 1, 2
• Relapse occurs in 10-15% of inadequately treated cases 1, 2

Never Rely on Widal Test for Diagnosis

• Inadequate sensitivity and specificity 2
• Newer rapid serologic assays (Typhidot, Tubex) have mixed performance and cannot replace culture-based diagnosis 2

Management of Complications

Intestinal Perforation

• Occurs in 10-15% of patients when illness duration exceeds 2 weeks before effective treatment 1, 2
• Requires immediate surgical intervention with simple excision and closure 1, 2
• Surgical success rate is approximately 88% 1, 2

Other Severe Complications

• Gastrointestinal bleeding and typhoid encephalopathy also affect 10-15% of patients with prolonged untreated illness 2

Monitoring and Adverse Effects

Expected Clinical Response

• Fever should clear within 4-5 days of appropriate antibiotic therapy 1, 2, 3
• Monitor for clinical improvement; lack of response by day 5 suggests resistance or alternative diagnosis 1

Common Azithromycin Adverse Effects

• Gastrointestinal symptoms: nausea, vomiting, abdominal pain, and diarrhea 1, 3
• Monitor for QT prolongation, especially with concomitant QT-prolonging medications 1

Prevention Strategies

Vaccination Recommendations

• Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa) 1, 2, 3
• Two vaccines available in the United States: 1, 2
  • Ty21a oral vaccine: One enteric-coated capsule on alternate days for total of four capsules, taken with cool liquid ≤37°C, one hour before meals; booster every 5 years 1
  • Vi-polysaccharide parenteral vaccine: 0.5 mL subcutaneously in two doses spaced ≥4 weeks apart; booster every 3 years 1

Important Vaccination Limitations

• Provides only 50-80% protection 1, 2, 3
• Does NOT protect against Salmonella Paratyphi 1, 2, 3
• Never use combination typhoid-paratyphoid vaccines - only monovalent S. typhi preparations are recommended due to increased adverse reactions without proven benefit 1

Essential Non-Vaccine Prevention

• Hand hygiene and food/water safety precautions remain essential and cannot be replaced by vaccination alone 1, 2, 3

Emerging Resistance Concerns

Extensively Drug-Resistant (XDR) Typhoid

• XDR strains have emerged in Pakistan resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporins 5, 7
• Requires treatment with azithromycin and/or meropenem 7

Geographic Resistance Patterns

• Always consider local resistance patterns when selecting empiric therapy, as these vary geographically and change over time 1, 2, 3
• Over 70% of S. typhi and S. paratyphi isolates imported into the UK from Asian countries are fluoroquinolone-resistant 2, 3