What is the treatment for New Delhi metallo-beta-lactamase (NDM) Escherichia coli (E. coli) resistant to ceftazidime (Ceftazidime)-avibactam (Avibactam) and aztreonam (Aztreonam) combination?

Treatment for NDM E. coli Resistant to Ceftazidime-Avibactam and Aztreonam Combination

For NDM-producing E. coli resistant to ceftazidime-avibactam plus aztreonam combination, cefiderocol is the preferred treatment option, though it should be used with caution due to potential resistance development.

First-Line Treatment Option

Cefiderocol

• Cefiderocol is the most effective option for treating NDM-producing E. coli resistant to ceftazidime-avibactam plus aztreonam 1
• Clinical cure rates of 75% have been demonstrated in patients with MBL-producing CRE infections treated with cefiderocol compared to 29% with best available therapy 1
• Recent analysis of the CREDIBLE-CR and APEKS-NP trials showed higher rates of clinical cure (70.8%) and microbiological eradication (58.3%), and lower 28-day mortality (12.5%) in patients receiving cefiderocol 1

Alternative Treatment Options

Fosfomycin

• Consider fosfomycin for NDM-producing E. coli, particularly those with PBP3 insertions that further reduce susceptibility to aztreonam combinations 2
• 98% of NDM-expressing E. coli isolates with PBP3 insert were susceptible to fosfomycin at MIC ≤32 mg/L 2
• May be used alone for urinary tract infections or in combination for systemic infections

Combination Therapies

• Consider combinations based on susceptibility testing:
  • Colistin-based combinations (though associated with higher mortality compared to newer agents) 1
  • Tigecycline-containing regimens for appropriate infections 1
  • Fosfomycin combinations for synergistic effects 1

Important Clinical Considerations

Resistance Monitoring

• Monitor for development of resistance during therapy, especially with cefiderocol
• A recent case report documented sequential treatment failure with aztreonam-ceftazidime-avibactam followed by cefiderocol due to preexisting and acquired resistance mechanisms in NDM-producing E. coli 3

Infection Site Considerations

• For urinary tract infections: Consider fosfomycin if susceptible (particularly effective in this site)
• For bloodstream infections: Cefiderocol is preferred based on clinical evidence 1
• For complicated intra-abdominal infections: Consider combination therapy based on susceptibility

Dosing Considerations

• Cefiderocol: 2g IV every 8 hours (adjust for renal function)
• Fosfomycin: 6-8g IV every 8 hours for systemic infections
• Ensure appropriate dose optimization based on pharmacokinetic/pharmacodynamic principles

Treatment Algorithm

1. Confirm NDM production and resistance to ceftazidime-avibactam plus aztreonam
2. Perform comprehensive susceptibility testing including cefiderocol and fosfomycin
3. If susceptible to cefiderocol: Use as first-line therapy
4. If resistant to cefiderocol or unavailable:
   • For UTI: Consider fosfomycin if susceptible
   • For systemic infections: Use combination therapy based on susceptibility (e.g., colistin + fosfomycin, tigecycline + fosfomycin)
5. Monitor clinical response closely and repeat cultures to detect emergence of resistance
6. Consider infectious disease consultation for complex cases

Pitfalls and Caveats

• High MIC values, risk of treatment-emergent resistance, and uncertain role of combination therapy are concerns with cefiderocol use against MBL-producing organisms 1
• Monotherapy may be insufficient for severe infections; consider combination approaches based on susceptibility
• Resistance can develop rapidly during treatment, necessitating close monitoring 3
• Limited clinical data exists for treating NDM-producing E. coli resistant to both ceftazidime-avibactam and aztreonam combination

The treatment of NDM-producing E. coli resistant to ceftazidime-avibactam plus aztreonam remains challenging, with cefiderocol currently representing the most promising therapeutic option despite concerns about resistance development.