What is the role of ceftazidime (CAZ)-avibactam (AVI) in combination with aztreonam (AZT) in treating complicated infections caused by multi-drug resistant Gram-negative bacteria?

Ceftazidime-Avibactam and Aztreonam Synergistic Action in Multi-Drug Resistant Gram-Negative Infections

Ceftazidime-avibactam combined with aztreonam is strongly recommended as the preferred treatment for infections caused by metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacteriaceae (CRE), showing significantly reduced mortality and clinical failure rates compared to other antimicrobial regimens. 1

Mechanism of Synergistic Action

The synergistic action between ceftazidime-avibactam (CAZ-AVI) and aztreonam (AZT) works through complementary mechanisms:

• Aztreonam is stable against metallo-β-lactamases (MBLs) but can be hydrolyzed by serine β-lactamases
• Avibactam inhibits serine β-lactamases (including ESBLs, AmpC, and KPC enzymes)
• When combined, aztreonam is protected from hydrolysis by serine β-lactamases due to avibactam, while maintaining its activity against MBL-producing organisms 1, 2

Clinical Evidence for Efficacy

The strongest evidence comes from a prospective study of patients with bloodstream infections caused by MBL-producing CRE:

• 30-day mortality: 19.2% with CAZ-AVI+AZT vs. 44% with other active antimicrobial agents (p=0.007)
• CAZ-AVI+AZT was associated with:
  • Lower 30-day mortality (HR: 0.37,95% CI 0.13-0.74)
  • Lower clinical treatment failure (HR: 0.30,95% CI 0.14-0.65)
  • Shorter hospital stay (HR: 0.49,95% CI -0.82) 1

Another study of 57 CRE infections (71.9% critical cases) showed:

• 77.5% cure rate in patients with NDM or NDM+OXA-48-positive CRE treated with CAZ-AVI+AZT 1

Treatment Algorithm for MDR Gram-Negative Infections

1. Identify the carbapenemase type before initiating treatment whenever possible 1

   • This is crucial for selecting the appropriate therapy

2. For MBL-producing organisms (NDM, VIM, IMP):

   • First-line: CAZ-AVI+AZT combination 1
   • This combination has shown synergistic activity against both NDM-producing and VIM-producing strains 3

3. For serine carbapenemase producers only (KPC, OXA-48):

   • CAZ-AVI alone may be sufficient (82.3% cure rate) 1

4. For organisms with multiple β-lactamase types:

   • CAZ-AVI+AZT is effective against strains producing both MBLs and serine β-lactamases 4, 5

Microbiological Considerations

• In vitro studies demonstrate excellent synergy between CAZ-AVI and AZT against:

  • NDM-producing Enterobacteriaceae (86% susceptibility restoration) 4
  • VIM-producing organisms (synergy in 16/19 isolates) 3
  • Organisms co-producing multiple β-lactamases 6

• The combination is effective against both:

  • MBL-producing Enterobacteriaceae (primary target)
  • Some MBL-producing Pseudomonas aeruginosa, though with less consistent results 5

Important Clinical Considerations and Pitfalls

1. Susceptibility testing challenges:

   • No standardized antimicrobial susceptibility testing methods or clinical interpretative breakpoints are currently approved for the CAZ-AVI+AZT combination 1
   • Consider using specialized testing methods to confirm synergy

2. Resistance development:

   • Monitor for potential resistance development during therapy
   • Studies with CAZ-AVI alone have shown resistance rates of 3.8-10.4% 1

3. Dosing considerations:

   • Prolonged infusion (3 hours) of CAZ-AVI and appropriate renal adjustment are associated with improved 30-day survival 1
   • Ensure proper dosing of both agents

4. Patient selection:

   • The combination is particularly valuable for critically ill patients with limited treatment options
   • Most evidence is from patients with bloodstream infections and complicated intra-abdominal infections

This combination represents one of the few effective options for treating infections caused by MBL-producing organisms, which are often extremely drug-resistant and associated with high mortality rates.