Is there a sufficient antibiotic replacement for Ceftazidime (Ceftazidime)-avibactam 2g-0.5g?

Alternatives to Ceftazidime-avibactam 2g-0.5g for Multidrug-Resistant Infections

For infections caused by metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE), cefiderocol is the most appropriate replacement for ceftazidime-avibactam, while meropenem-vaborbactam or imipenem-cilastatin-relebactam are the best alternatives for KPC or OXA-48 producing CRE infections. 1

Replacement Options Based on Resistance Mechanism

For MBL-producing CRE infections:

• First choice: Cefiderocol
  • Clinical cure rates of 75% in MBL-producing CRE infections 1
  • Lower 28-day mortality (12.5%) compared to other therapies 1
  • Strength of recommendation: Conditional (Low certainty of evidence) 1

For KPC or OXA-48 producing CRE infections:

• First choice: Meropenem-vaborbactam 4g IV q8h

  • Demonstrated non-inferiority to best available treatment in CRE infections 1
  • Reduced nephrotoxicity compared to polymyxin-based regimens 1
  • Weak recommendation, low quality of evidence 1

• Alternative: Imipenem-cilastatin-relebactam 1.25g IV q6h

  • Active against most KPC-producing CRE strains 1
  • Well-tolerated compared to colistin-imipenem combination 1
  • Weak recommendation, low quality of evidence 1

Selection Algorithm Based on Infection Site

For bloodstream infections (BSI):

1. Determine carbapenemase type through molecular testing
2. For KPC/OXA-48 producers: Meropenem-vaborbactam or imipenem-cilastatin-relebactam
3. For MBL producers: Cefiderocol

For complicated urinary tract infections (cUTI):

1. Meropenem-vaborbactam 4g IV q8h or imipenem-cilastatin-relebactam 1.25g IV q6h 1
2. Plazomicin 15 mg/kg IV q12h as an alternative 1
3. For simple cystitis: Consider single-dose aminoglycoside if susceptible 1

For complicated intra-abdominal infections (cIAI):

1. Tigecycline 100mg IV loading dose then 50mg IV q12h or eravacycline 1mg/kg IV q12h 1
2. Polymyxin-based combination therapy based on susceptibility testing 1

Important Considerations and Pitfalls

• Resistance development: Emergence of resistance to ceftazidime-avibactam has been reported, particularly with KPC-3 mutations 2, 3. Similar vigilance is needed with alternative agents.

• Susceptibility testing: Always confirm in vitro activity before initiating therapy with any alternative agent 1.

• Combination therapy: For severe infections, particularly with MBL-producing strains, combination therapy may be warranted, though evidence is limited 1.

• Dosing optimization: Extended infusions (e.g., 3 hours for ceftazidime-avibactam) and appropriate renal dose adjustments are critical for optimal outcomes 1.

• Pitfall to avoid: Do not use meropenem-vaborbactam or imipenem-cilastatin-relebactam for MBL-producing CRE as they lack activity against these enzymes 1.

• Pitfall to avoid: Tigecycline monotherapy is not recommended for treatment of carbapenem-resistant Acinetobacter baumannii pneumonia (strong recommendation) 1.

The choice of alternative therapy should be guided by molecular characterization of resistance mechanisms, site of infection, and local susceptibility patterns to ensure optimal patient outcomes in terms of mortality and morbidity.