What is the recommended treatment regimen for an adult with typhoid fever, including first‑line oral therapy, intravenous options for severe illness, and management of drug‑resistant strains?

Typhoid Fever Treatment

First-Line Oral Therapy

Azithromycin 500 mg once daily for 7 days is the preferred first-line treatment for adults with typhoid fever, particularly given fluoroquinolone resistance exceeding 70% in endemic regions. 1, 2

• For children, use azithromycin 20 mg/kg/day (maximum 1g/day) for 7 days 1, 3
• Azithromycin reduces clinical failure risk by 52% compared to fluoroquinolones (OR 0.48) 1
• Hospital stays are shortened by approximately 1 day versus fluoroquinolones 1
• Relapse risk is 91% lower than with ceftriaxone (OR 0.09) 1, 4
• Azithromycin remains effective against multidrug-resistant strains (resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole) 1, 5

Intravenous Options for Severe Illness

For severely ill or hospitalized patients, use ceftriaxone 1-2g IV/IM daily for 5-7 days in adults. 1

• For children with severe disease, administer ceftriaxone 50-80 mg/kg/day (maximum 2g/day) IV/IM for 5-7 days 1, 3
• Transition to oral azithromycin once the patient is clinically improved and afebrile for 24 hours 3
• In patients with sepsis features, start broad-spectrum antimicrobial therapy immediately after collecting blood cultures 6, 1
• Ceftriaxone reduces treatment failure risk compared to gatifloxacin in culture-confirmed cases (hazard ratio 0.24) 1

Management of Drug-Resistant Strains

Never use ciprofloxacin empirically for cases from South or Southeast Asia due to resistance rates approaching 96%. 1, 2

Geographic Resistance Patterns:

• Over 70% of S. typhi isolates from South Asia are fluoroquinolone-resistant 1, 2
• In Thailand, 93% of isolates are ciprofloxacin-resistant 1
• All S. typhi isolates imported to the UK in 2006 were ceftriaxone-susceptible, but >70% were fluoroquinolone-resistant 1

When Fluoroquinolones May Be Considered:

• Only use fluoroquinolones when culture demonstrates nalidixic acid susceptibility 1
• The infection must not be acquired from South or Southeast Asia 1
• Ciprofloxacin disc testing must be confirmed by nalidixic acid sensitivity 1
• When susceptibility is confirmed, fluoroquinolones achieve fever clearance in <4 days with cure rates >96% 1

Alternative Oral Agent (Cefixime):

• Cefixime is listed only as an "alternative" option by WHO, not first-line 1
• Treatment failure rates range from 4-37.6% 1
• Cefixime carries a 13-fold higher risk of clinical failure compared to fluoroquinolones (RR 13.39) 1
• If cefixime must be used, a mandatory test-of-cure at 1 week is required 1

Diagnostic Approach

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

• Stool and urine cultures become reliably positive only after the first week 1
• Do not use the Widal serologic test due to inadequate sensitivity and specificity 1
• Newer rapid serologic assays (Typhidot, Tubex) have mixed performance and cannot replace culture-based diagnosis 1
• In hemodynamically unstable patients, initiate empirical antimicrobial therapy promptly after obtaining blood cultures 1

Monitoring and Expected Clinical Response

Expect fever clearance within 4-5 days of appropriate azithromycin therapy; mean fever-clearance time is 5.8 days. 1, 2, 3

• If no clinical response occurs by day 5, consider resistance or alternative diagnosis 1
• Complete the full 7-day course to prevent relapse, which occurs in 10-15% of inadequately treated cases 1
• Blood cultures should be repeated on days 4 and 10 after starting therapy 5
• Stool cultures should be done on days 4,10, and 28 after starting therapy 5

Complications Requiring Surgical Intervention

Intestinal perforation occurs in 10-15% of patients with illness duration exceeding 2 weeks. 1

• Surgical intervention with simple excision and closure is required for perforation, with success rates of approximately 88% 1
• Other severe complications (gastrointestinal bleeding, typhoid encephalopathy) also affect 10-15% of patients with prolonged untreated illness 1

Common Pitfalls to Avoid

• Never discontinue antibiotics prematurely; complete the full 7-day course even if fever resolves early 1
• Do not use ciprofloxacin empirically for cases from South or Southeast Asia 1, 2
• Avoid combination typhoid-paratyphoid vaccines; only monovalent S. typhi preparations should be used 1
• Do not rely solely on clinical presentation for diagnosis; obtain cultures whenever possible 3

Adverse Effects and Drug Interactions

• Common azithromycin adverse effects include mild gastrointestinal symptoms: nausea, vomiting, abdominal pain, and diarrhea 1
• Monitor for potential QT-prolonging drug interactions when prescribing azithromycin 1

Special Populations

Azithromycin is FDA Pregnancy Category B and may be used safely in pregnant patients with typhoid fever. 1

• Fluoroquinolones are contraindicated in pregnancy 1
• Dosages must be modified for children, pregnant and nursing women, and the elderly 6

Prevention Strategies

Typhoid vaccination is recommended for travelers to endemic areas (Latin America, Asia, Africa), but provides only 50-80% protection and does not protect against paratyphoid. 1, 2, 3

Ty21a Oral Vaccine:

• One enteric-coated capsule on alternate days for a total of four capsules 1, 2
• Take with cool liquid ≤37°C, approximately 1 hour before meals 1
• Capsules must be kept refrigerated 1
• Booster dose every 5 years 1

Parenteral Inactivated Vaccine:

• 0.5 mL subcutaneously in two doses spaced ≥4 weeks apart 1, 2
• Booster dose every 3 years under conditions of continued exposure 1

Essential Non-Vaccine Measures:

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