What is the recommended antimicrobial regimen and supportive care for treating typhoid fever, including first‑line and second‑line options based on resistance patterns?

Typhoid Fever Management

First-Line Antimicrobial Treatment

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

Treatment Selection Algorithm

For uncomplicated typhoid fever:

• Adults: Azithromycin 500 mg PO daily for 7 days 1, 2
• Children: Azithromycin 20 mg/kg/day (maximum 1g/day) PO for 7 days 2
• Azithromycin demonstrates superior outcomes with significantly lower clinical failure rates (OR 0.48) compared to fluoroquinolones and dramatically reduced relapse risk (OR 0.09) compared to ceftriaxone 1, 2

For severe/complicated cases requiring IV therapy:

• Adults: Ceftriaxone 1-2g IV/IM daily for 5-7 days 2, 3
• Children: Ceftriaxone 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days 2
• Consider adding corticosteroids in severe cases with altered mental status or shock 3

Geographic Resistance Patterns (Critical)

Never use ciprofloxacin empirically for cases from South or Southeast Asia where fluoroquinolone resistance approaches 96% in some regions and exceeds 70% overall 1, 2, 3. The Centers for Disease Control and Prevention specifically advises against empiric fluoroquinolone use for these geographic origins due to widespread resistance and poor clinical outcomes despite in vitro "susceptibility" 1.

• Ciprofloxacin remains an alternative only if the patient traveled from sub-Saharan Africa where resistance rates remain lower 4, 2
• When testing isolates, ciprofloxacin disc testing is unreliable; organisms must also be nalidixic acid-sensitive to be considered truly fluoroquinolone-susceptible 1, 3

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 1
• Gatifloxacin appears more effective than ciprofloxacin for bacteria showing decreased ciprofloxacin susceptibility 5

Treatment Duration

Complete a full 14-day antibiotic course regardless of agent used to minimize relapse risk, even if fever resolves earlier. 1, 2, 3 The Infectious Diseases Society of America specifically recommends 14 days of treatment 1.

• Relapse rates with adequate therapy: azithromycin <3%, ceftriaxone <8%, fluoroquinolones <8% 1, 2, 3
• Relapse occurs in 10-15% of inadequately treated cases 2

Diagnostic Approach Before Treatment

Obtain blood cultures before initiating therapy whenever possible, as they have the highest diagnostic yield (40-80% sensitivity) within the first week of symptom onset. 1, 2, 3

• If the patient is clinically unstable or has sepsis features, start empiric treatment immediately after collecting cultures 2, 3
• Stool and urine cultures become reliably positive only after the first week of illness 2
• Never rely on the Widal test for diagnosis—it has poor specificity (68.44%) and very poor positive predictive value (5.7%) 2

Expected Clinical Response and Monitoring

Expect fever clearance within 4-5 days of appropriate antibiotic therapy. 1, 2, 3

• When the organism is susceptible, fluoroquinolones achieve the fastest fever clearance (often <4 days) 2, 3
• Hospital stays are approximately 1 day shorter with azithromycin compared to fluoroquinolones 2
• If fever persists beyond 48 hours in a clinically stable patient, reassess for alternative diagnoses or complications rather than empirically changing antibiotics 2

Supportive Care

Monitor for life-threatening complications that typically arise in the second week of untreated illness and occur in 10-15% of patients:

• Gastrointestinal bleeding 2, 3
• Intestinal perforation (typically occurs when illness duration exceeds 2 weeks) 2
• Typhoid encephalopathy 2, 3
• Surgical intervention with simple excision and closure is required for perforation, with success rates up to 88.2% 2

Provide oral rehydration and supportive care as needed, though dehydration is less common in typhoid than in other diarrheal illnesses. 6

Common Pitfalls to Avoid

• Never discontinue antibiotics prematurely, even if fever resolves early—complete the full course to prevent relapse 2
• Never use empiric ciprofloxacin for cases from Asia due to widespread resistance 1, 2
• Never rely solely on the Widal test—supplement with blood cultures 2
• Never assume ciprofloxacin disc susceptibility is reliable—also check nalidixic acid sensitivity 1, 3

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 2.

Prevention Considerations

Two typhoid vaccines (oral Ty21a and injectable Vi-polysaccharide) are available and offer 50-80% protection, recommended for travelers to endemic areas with booster doses every 5 years (oral) or 2 years (injectable) 4. However, vaccination provides incomplete protection and does not protect against paratyphoid 3.