What empirical antibiotic regimen should be used for an adult with suspected typhoid fever who has no drug allergies, is not pregnant, and has no documented resistance pattern?

Empirical Antibiotic Treatment for Typhoid Fever

Azithromycin 500 mg once daily for 7 days is the preferred empirical treatment for adults with suspected typhoid fever, particularly given the widespread fluoroquinolone resistance exceeding 70% in South and Southeast Asia. 1, 2

First-Line Empirical Regimen

• Start azithromycin 500 mg orally once daily for 7 days as the initial empirical therapy for suspected typhoid fever in adults 1, 2, 3
• Azithromycin demonstrates a 52% reduction in clinical failure compared to fluoroquinolones (OR 0.48,95% CI 0.26-0.89) 2, 3
• Hospital stay is shortened by approximately 1 day versus fluoroquinolones (mean difference -1.04 days) 2, 3
• Relapse risk is dramatically lower with azithromycin than ceftriaxone (OR 0.09,95% CI 0.01-0.70) 2, 3

Critical Action Before Starting Therapy

• Obtain blood cultures immediately before initiating antibiotics—blood cultures have the highest diagnostic yield (40-80% sensitivity) within the first week of symptoms 3
• Also collect stool and urine cultures, though these become positive only after the first week 3
• In patients with sepsis features, start broad-spectrum empirical therapy immediately after collecting cultures; do not delay treatment 1

Alternative Regimens When Azithromycin Cannot Be Used

Second-Line: Ceftriaxone

• Ceftriaxone 1-2 g IV/IM once daily for 5-7 days is the recommended alternative when azithromycin is unavailable or contraindicated 2, 3
• All S. Typhi isolates from the UK in 2006 remained 100% susceptible to ceftriaxone despite >70% fluoroquinolone resistance 3
• Ceftriaxone may result in decreased clinical failure compared to azithromycin, though relapse rates may be higher 4

Avoid Cefixime as Empirical Therapy

• Do not use cefixime empirically—treatment failure rates range from 4% to 37.6% 2, 3
• Cefixime carries a 13-fold higher risk of clinical failure compared to fluoroquinolones (RR 13.39,95% CI 3.24-55.39) 3, 4
• If cefixime must be used, a mandatory test-of-cure at 1 week is required 2

Fluoroquinolones: Geographic Restrictions Apply

• Never use ciprofloxacin or ofloxacin empirically for cases from South or Southeast Asia—resistance rates exceed 70% and approach 96% in some regions 1, 2, 3
• In Thailand, 93% of S. Typhi isolates are ciprofloxacin-resistant 2, 3
• Fluoroquinolones may only be considered when culture confirms nalidixic acid susceptibility AND the case is not from South/Southeast Asia 3

Expected Clinical Response and Monitoring

• Fever should resolve within 4-5 days of appropriate therapy 2, 3, 5
• If no clinical improvement occurs by day 5, consider antimicrobial resistance or alternative diagnosis and switch therapy 2, 5
• Complete the full 7-day course even if fever resolves early—premature discontinuation increases relapse risk to 10-15% 2, 3, 5

Critical Pitfalls to Avoid

• Never use cefuroxime (a second-generation cephalosporin)—it has significantly weaker activity against Salmonella species compared to third-generation agents and is not listed in WHO, AAP, or IDSA guidelines 2
• Do not rely on Widal serologic testing—it has inadequate sensitivity and specificity and should not replace culture-based diagnosis 3
• Avoid empiric fluoroquinolones for travelers returning from endemic areas—resistance patterns make them unreliable as first-line therapy 1, 2, 3

When to Switch Therapy

• If ceftriaxone fails to achieve fever clearance within 5 days, switch immediately to azithromycin 5
• Monitor for persistent fever, worsening symptoms, or development of complications as indicators of treatment failure 5
• Obtain repeat blood cultures before switching to guide definitive therapy 5

Complications Requiring Urgent Attention

• Intestinal perforation occurs in 10-15% of patients when illness duration exceeds 2 weeks—surgical intervention is required with an 88% success rate 2, 3
• Other severe complications (gastrointestinal bleeding, typhoid encephalopathy) also affect 10-15% of patients with prolonged untreated illness 3

Common Adverse Effects of Azithromycin

• Gastrointestinal symptoms are most common: nausea, vomiting, abdominal pain, and diarrhea 3, 5
• Monitor for potential QT-prolonging drug interactions 3, 5