What are the latest guidelines for treating Multidrug-Resistant (MDR) enteric fever, including causal organisms and treatment options?

Multidrug-Resistant Enteric Fever: Definition, Causative Organisms, and Treatment Guidelines

Definition and Causative Organisms

Multidrug-resistant (MDR) enteric fever is caused by Salmonella enterica serovars Typhi and Paratyphi A that are resistant to chloramphenicol, ampicillin, and cotrimoxazole. 1

• The primary causative organisms are Salmonella enterica serovar Typhi (typhoid fever) and Salmonella enterica serovar Paratyphi A (paratyphoid fever) 1, 2
• An increasingly concerning pattern is MDR+FQ (multidrug resistance plus fluoroquinolone resistance), where isolates are resistant to ciprofloxacin in addition to the three first-line agents 3
• Extensively drug-resistant (XDR) enteric fever has emerged, particularly from Pakistan, showing resistance to chloramphenicol, ampicillin, cotrimoxazole, fluoroquinolones, AND third-generation cephalosporins 4, 3

Current Resistance Patterns

Fluoroquinolone resistance is now extremely prevalent, with 90% of S. Typhi and 97% of S. Paratyphi A isolates resistant to ciprofloxacin in recent surveillance data. 3

• XDR cases have risen sharply: zero before 2017, one in 2017, six in 2018, and 32 in 2019, with all XDR cases imported from Pakistan 3
• Travel to Pakistan is strongly associated with ciprofloxacin resistance (adjusted OR 32.0) and MDR+FQ resistance (adjusted OR 3.5) 3
• Travel to India is also associated with ciprofloxacin resistance (adjusted OR 21.8) but less likely to have MDR+FQ patterns 3
• Azithromycin resistance has not yet been documented in surveillance studies 3

Latest Treatment Guidelines

First-Line Treatment for Uncomplicated MDR Enteric Fever

Azithromycin is the preferred first-line treatment for uncomplicated MDR enteric fever, given at 1 gram once daily (or 20 mg/kg/day in children) for 5 days. 1, 2

• Azithromycin significantly reduces clinical failure compared to fluoroquinolones (OR 0.48,95% CI 0.26-0.89) in populations with MDR and nalidixic acid-resistant strains 2
• Azithromycin reduces relapse compared to ceftriaxone (OR 0.09,95% CI 0.01-0.70) 2
• For nalidixic acid-resistant typhoid, azithromycin achieves faster fever clearance (135 hours vs 174 hours with ofloxacin) and better fecal clearance (0% vs 41% positive cultures) 1
• Meta-analysis confirms azithromycin can be recommended as a second-line drug in MDR typhoid fever with clinical failure risk ratio of 0.46 (95% CI 0.25-0.82) compared to older fluoroquinolones 5

Alternative Treatment Options

Ceftriaxone is an effective alternative for MDR enteric fever, particularly when azithromycin is unavailable or in severe cases requiring parenteral therapy. 4

• Ceftriaxone may result in decreased clinical failure compared to azithromycin (RR 0.42,95% CI 0.11-1.57), though evidence certainty is low 4
• Time to defervescence may be shorter with ceftriaxone compared to azithromycin (mean difference -0.52 days) 4
• Ceftriaxone performs similarly to fluoroquinolones and chloramphenicol in older trials 4

Cefixime is less effective than fluoroquinolones and should be avoided when other options are available. 4

• Clinical failure is significantly increased with cefixime compared to fluoroquinolones (RR 13.39,95% CI 3.24-55.39) 4
• Relapse is more common with cefixime (RR 4.45,95% CI 1.11-17.84) 4
• Fever clearance time is longer with cefixime (mean difference 1.74 days) 4

Treatment Algorithm Based on Geographic Origin

For travelers returning from Pakistan:

• Avoid fluoroquinolones and third-generation cephalosporins as empiric therapy due to high rates of XDR (all XDR cases originated from Pakistan) 3
• Use azithromycin as first-line empiric treatment (no documented resistance) 3
• Obtain blood cultures and antimicrobial susceptibility testing urgently 6

For travelers returning from India:

• Azithromycin remains first-line due to 98% ciprofloxacin resistance 3
• Third-generation cephalosporins are acceptable alternatives (XDR not yet documented from India) 3

For travelers returning from Bangladesh or Africa:

• Azithromycin is preferred first-line 3
• Ciprofloxacin resistance is lower from Africa (60%) but rising rapidly 3

Treatment Duration and Monitoring

Standard treatment duration is 5 days for azithromycin and 7-14 days for cephalosporins. 1, 4

• Monitor clinical response at 48-72 hours and obtain blood cultures before initiating therapy 6
• Infectious disease consultation is recommended for all suspected XDR cases 6

Critical Pitfalls to Avoid

Never use fluoroquinolones (ciprofloxacin, ofloxacin) as empiric therapy for enteric fever from South Asia due to extremely high resistance rates (90-98%) 3

Do not use cefixime when azithromycin or ceftriaxone are available due to significantly higher failure and relapse rates 4

Obtain antimicrobial susceptibility testing before initiating therapy to guide definitive treatment, especially for cases from Pakistan where XDR is emerging 6, 3

Monitor for treatment failure at 48-72 hours and escalate therapy if no clinical improvement, as this may indicate XDR strains 6