What are the latest treatment guidelines for multidrug-resistant (MDR) typhoid fever?

Multidrug-Resistant Typhoid Fever: Definition and Latest Treatment Guidelines

What is Multidrug-Resistant Typhoid Fever?

Multidrug-resistant typhoid fever (MDRTF) is typhoid fever caused by Salmonella enterica serovar Typhi strains that are resistant to all three first-line antibiotics: chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole. 1 This resistance pattern emerged in the mid-1980s and has caused outbreaks globally, particularly affecting children under five years and malnourished individuals with increased morbidity and mortality. 1

Clinical Presentation

• High fever (>104°F), toxemia, abdominal distension, abdominal tenderness, hepatomegaly, and splenomegaly are commonly reported, though no pathognomonic features exist at illness onset. 1
• Blood culture remains the gold standard for diagnosis. 1

Emerging Resistance Patterns

• A critical additional resistance pattern has emerged: reduced susceptibility to fluoroquinolones (nalidixic acid resistance). 2, 3 In recent studies, 88-96% of isolates were multidrug-resistant AND 93% showed nalidixic acid resistance, rendering older fluoroquinolones like ciprofloxacin and ofloxacin suboptimal. 2, 3
• In Kenya, 69% of isolates showed reduced susceptibility to ciprofloxacin, with 70% recording intermediate MICs of 0.12-0.5 μg/mL. 4

Latest Treatment Guidelines for MDR Typhoid Fever

First-Line Recommended Treatment

For uncomplicated MDR typhoid fever, azithromycin 10-20 mg/kg/day orally once daily for 7 days is the preferred treatment based on superior efficacy, safety, and microbiological clearance. 2, 5, 3

Evidence Supporting Azithromycin:

• Clinical cure rate of 82% compared to 64% with ofloxacin alone 3
• Mean fever clearance time of 5.8 days (95% CI: 5.1-6.5 days), significantly shorter than ofloxacin (8.2 days) or combination therapy (7.1 days) 3
• Fecal carriage elimination: only 1.6% positive immediately post-treatment versus 19.4% with ofloxacin 3
• Excellent safety profile in both children and adults 2, 3
• Effective against isolates with both MDR and nalidixic acid resistance patterns 2, 3

Alternative First-Line Treatment

Gatifloxacin 10 mg/kg/day orally once daily for 7 days is an equally effective alternative, particularly in regions with high nalidixic acid resistance. 2, 5

Evidence Supporting Gatifloxacin:

• Median fever clearance time of 106 hours, identical to azithromycin (95% CI: 94-118 hours) 2
• Overall treatment failure rate of 9%, equivalent to azithromycin (9.3%) 2
• Cost advantage: approximately one-third the cost of azithromycin in developing countries 2
• More effective than ciprofloxacin and ofloxacin for bacteria showing decreased ciprofloxacin susceptibility 5

Second-Line Treatment

Ceftriaxone continues as a reliable backup option when fluoroquinolones and azithromycin fail or are contraindicated. 5

• Ceftriaxone showed 94-97% susceptibility in recent surveillance studies 4
• All isolates tested by MIC were susceptible except one 4
• However, ceftriaxone is less effective than fluoroquinolones and azithromycin for achieving rapid defervescence and preventing relapse 5

Treatment Algorithm

For uncomplicated MDR typhoid fever:

1. First choice: Azithromycin 10-20 mg/kg/day PO once daily × 7 days 2, 5, 3
2. Alternative first choice: Gatifloxacin 10 mg/kg/day PO once daily × 7 days 2, 5
3. Second-line: Ceftriaxone IV if oral therapy fails or patient cannot tolerate oral medications 5, 4

For MDR typhoid with nalidixic acid resistance (which represents >90% of current cases):

• Avoid ciprofloxacin and ofloxacin as they are suboptimal 5, 3, 4
• Use azithromycin or gatifloxacin as first-line agents 2, 5

Critical Pitfalls to Avoid

• Do not use ciprofloxacin or ofloxacin for MDR typhoid with nalidixic acid resistance, as these older fluoroquinolones have unacceptably high failure rates 5, 3
• Do not use chloramphenicol, ampicillin, or trimethoprim-sulfamethoxazole empirically in endemic areas, as 70-88% of isolates are resistant 2, 3, 4
• Do not shorten azithromycin course below 7 days, as shorter courses have not been adequately studied for MDR strains 2, 3
• Combination therapy (ofloxacin-azithromycin) offers no advantage over azithromycin monotherapy and results in longer fever clearance times 3

Important Nuances

The evidence strongly favors azithromycin over gatifloxacin when both are available and cost is not prohibitive, based on:

• Shorter fever clearance time (5.8 vs 7.1 days for combination, p<0.001) 3
• Superior fecal carriage elimination (1.6% vs 6.5-19.4%) 3
• Broader availability and established safety profile 5

However, gatifloxacin represents an excellent cost-effective alternative with equivalent clinical cure rates and overall treatment failure rates. 2

Prevention Considerations

• Mass immunization with oral live attenuated Typhi 21a or injectable unconjugated Vi typhoid vaccine in endemic areas 1
• Rational antibiotic use to prevent further resistance development 1
• Improvement in sanitation, clean water access, and safe food handling practices 1