What are the treatment guidelines for typhoid fever?

Typhoid Fever Treatment Guidelines

First-Line Treatment Recommendation

Azithromycin is the preferred first-line treatment for typhoid fever, particularly for cases originating from South Asia where fluoroquinolone resistance exceeds 70%, dosed at 500 mg once daily for 7 days in adults or 20 mg/kg/day (maximum 1g/day) for 7 days in children. 1, 2

Treatment Algorithm Based on Disease Severity and Geographic Origin

For Uncomplicated Typhoid Fever (Outpatient or Stable Patients)

• Start with oral azithromycin as empiric therapy, especially for cases from South Asia where fluoroquinolone resistance approaches 96% in some regions 1, 2
• Azithromycin demonstrates superior outcomes with significantly lower risk of clinical failure (OR 0.48) compared to fluoroquinolones and dramatically lower relapse rates (OR 0.09) compared to ceftriaxone 1
• Hospital stays are approximately 1 day shorter with azithromycin compared to fluoroquinolones (MD -1.04 days) 1

For Severe or Complicated Cases (Hospitalized Patients)

• Initiate IV ceftriaxone 50-80 mg/kg/day (maximum 2g/day) for 5-7 days in children, or 1-2g IV daily for adults 1, 3, 2
• Transition to oral therapy (azithromycin or cefixime) once the patient is clinically improved and afebrile for 24 hours 2
• Ceftriaxone is particularly appropriate for patients with unstable clinical condition or those requiring parenteral therapy 3

Specific Dosing Regimens

Azithromycin

• Adults: 500 mg once daily for 7-14 days 1
• Children: 20 mg/kg/day (maximum 1g/day) for 7 days 1, 2
• Cure rate of 94% in children with lower relapse risk compared to other agents 2

Ceftriaxone

• Adults: 1-2g IV/IM daily for 5-7 days, though 14 days may reduce relapse risk 1, 3
• Children: 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days 1, 2
• Mean defervescence time is 4-5 days with adequate therapy 1, 4

Ciprofloxacin (Only When Susceptibility Confirmed)

• Adults: 500 mg orally every 12 hours for 10 days for typhoid fever 5
• Never use empirically for cases from South or Southeast Asia due to resistance rates exceeding 70% 1, 3, 6
• Requires nalidixic acid susceptibility on disc testing in addition to ciprofloxacin disc testing to confirm true fluoroquinolone sensitivity 3

Critical Diagnostic Considerations 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, 2
• Stool and urine cultures become positive after the first week with lower sensitivities (35-65% and 0-58%, respectively) 3
• Bone marrow cultures have higher sensitivity than blood cultures but are rarely necessary 3
• Avoid the Widal serological test as it lacks adequate sensitivity and specificity 3
• For patients with sepsis features, start broad-spectrum antimicrobial therapy immediately after collecting blood cultures 1

Monitoring and Expected Clinical Response

• Expect fever clearance within 4-5 days of appropriate therapy 1, 4
• If no clinical response by day 5, consider antibiotic resistance or alternative diagnosis 1
• Complete the full 7-day course to prevent relapse, which occurs in 10-15% of inadequately treated cases 1
• Never discontinue antibiotics prematurely even if fever resolves early 1

Management of Complications

• Complications (gastrointestinal bleeding, intestinal perforation, typhoid encephalopathy) occur in 10-15% of patients, particularly when illness duration exceeds 2 weeks 1, 3, 2
• Intestinal perforation requires surgical intervention with simple excision and closure, successful in up to 88.2% of cases 1
• Monitor closely for deterioration during the second week of untreated or inadequately treated illness 6

Critical Pitfalls to Avoid

• Never use ciprofloxacin empirically for cases from South or Southeast Asia due to widespread resistance exceeding 70-96% 1, 3, 2, 6
• Do not rely solely on ciprofloxacin disc testing; the organism must also be sensitive to nalidixic acid to be considered truly fluoroquinolone-sensitive 3
• Avoid cefixime as first-line therapy due to documented treatment failure rates of 4-37.6% and high relapse rates; if used, mandatory test-of-cure at 1 week is required 1
• Do not discontinue antibiotics prematurely; complete the full course even if fever resolves early 1
• Previous vaccination provides incomplete protection (50-80%) and does not protect against paratyphoid 1, 3, 2

Adverse Effects and Drug Interactions

• Common azithromycin adverse effects include gastrointestinal symptoms: nausea, vomiting, abdominal pain, and diarrhea 1
• Monitor for potential drug interactions with azithromycin, particularly QT-prolonging medications 1
• Ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum antacids, sucralfate, or products containing calcium, iron, or zinc 5

Prevention Strategies

• Typhoid vaccination is recommended for travelers to endemic areas, particularly Latin America, Asia, and Africa 1, 3
• Three vaccine types are available, including the newer, more effective typhoid Vi-conjugate vaccines 6
• Ty21a oral vaccine: one enteric-coated capsule on alternate days for four doses total, for adults and children ≥10 years, with booster every 5 years 1
• Parenteral inactivated vaccine: 0.5 ml subcutaneously on two occasions separated by ≥4 weeks, with booster every 3 years 1
• Vaccination provides only 50-80% protection and does not protect against Salmonella Paratyphi; hand hygiene and food/water safety precautions remain essential 1, 3

Geographic Resistance Patterns

• Always consider local resistance patterns when selecting empiric therapy, as these vary geographically and change over time 1
• Over 70% of S. typhi isolates from South Asia are fluoroquinolone-resistant 1, 3, 6
• Ciprofloxacin-resistant and ceftriaxone-resistant typhoid is increasingly common in Pakistan 6
• Azithromycin resistance remains rare in most regions currently 3