What is the recommended diagnostic work‑up and first‑line therapy for an adult with fever ≥5 days, headache, abdominal discomfort, rose‑spot rash, and recent travel to an endemic area suggesting enteric fever?

Enteric Fever: Diagnostic Work-up and First-Line Therapy

Immediate Diagnostic Priority

Obtain blood cultures immediately before initiating any antibiotics—this is the single most critical diagnostic step, with up to 80% sensitivity in the first week of illness. 1, 2 Malaria must be excluded first in all febrile returned travelers from the tropics, as it is the most important potentially fatal cause. 1

Diagnostic Work-up Algorithm

Step 1: Exclude Malaria

• Perform malaria testing (thick and thin blood films or rapid diagnostic test) in all patients with fever and tropical travel history, regardless of other symptoms 1
• Minimum incubation period of 6 days means most travelers develop symptoms after return 1

Step 2: Obtain Blood Cultures

• Blood cultures have up to 80% sensitivity in the first week of illness 1
• Collect blood cultures before any antibiotic administration 2
• In patients with sepsis features, collect cultures immediately then start empiric antibiotics without delay 2
• Consider stool and urine cultures in addition to blood cultures for comprehensive evaluation 2

Step 3: Clinical Assessment

• Enteric fever incubation period: 7-18 days (range 3-60 days) 1
• Most common in travelers returning from South Central Asia and Southeast Asia (>100 cases per 100,000 person-years) 1
• Rose spots, headache, abdominal discomfort, and sustained fever are classic but not always present 3

First-Line Empiric Therapy

For Clinically Unstable or Severe Disease (Sepsis, High Fever ≥38.5°C, Severe Illness)

Start ceftriaxone 2g IV daily (or 50-80 mg/kg/day, maximum 2g) immediately after blood cultures are obtained. 1, 2 This is the recommended first-line therapy for hospitalized patients with severe enteric fever. 2

• Duration: 5-7 days for ceftriaxone 2
• Expected fever clearance within 4-5 days of appropriate therapy 2
• Ceftriaxone shows only 0.6% resistance rates, making it highly reliable 4

For Clinically Stable Outpatients with Mild-Moderate Disease

Azithromycin 1g orally daily (or 20 mg/kg/day, maximum 1g) for 7 days is the preferred first-line oral therapy, particularly given high fluoroquinolone resistance rates. 2

• Azithromycin demonstrates 94% cure rate and significantly lower relapse risk (OR 0.09) compared to ceftriaxone 2
• Shows lower clinical failure rates (OR 0.48) and shorter hospital stays compared to fluoroquinolones 2

Geographic Considerations for Empiric Choice

If travel was from sub-Saharan Africa (SSA), ciprofloxacin remains an alternative option due to lower resistance rates in that region. 1 However, travelers from South Asia show 46% ciprofloxacin resistance, making it unsuitable for empiric use from that region. 4

Treatment Duration and Modification

• Total treatment duration: 7 days for most uncomplicated cases 2
• Switch from IV to oral therapy once clinically stable and susceptibilities are known 1
• If confirmed ciprofloxacin-sensitive, switch to ciprofloxacin for completion of therapy 1
• If resistant, use azithromycin as oral follow-on agent 1

Critical Pitfalls to Avoid

Antibiotic Resistance Patterns

• Do not use ciprofloxacin empirically for travelers from South Asia—resistance rates reach 46% 4
• Multidrug resistance (to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole) occurs in 20.2% of typhoid isolates 5, 6
• Extensively drug-resistant (XDR) typhoid from Pakistan requires azithromycin and/or meropenem 6, 7

Diagnostic Errors

• Never delay blood cultures to start antibiotics in stable patients—cultures first, then antibiotics 2
• Do not rely on Widal test alone for diagnosis—it is insufficient 3
• Absence of fever at presentation does not exclude enteric fever if there is a history of fever 3

Monitoring for Complications

• Watch for intestinal perforation (typically third week if untreated), gastrointestinal bleeding, encephalopathy, or septic shock 3
• Perforation occurs most commonly in ileum or jejunum 3
• Complications occur in 10-15% of untreated patients 5

Supportive Care

Evaluate all patients for dehydration, which increases risk of life-threatening illness, especially in young children and older adults. 2 Administer isotonic IV fluids for severe dehydration. 2

Special Populations

• Infants <3 months: Use ceftriaxone 50-80 mg/kg/day IV as mandatory first-line therapy 2
• Neurologic involvement (any age): Use third-generation cephalosporin regardless of clinical stability 2
• Immunocompromised, chronic liver disease, and malnourished children are at higher risk for severe disease 3