What is the synergistic effect of combining ceftazidime (CAZ) - avibactam (AVI) with aztreonam (AZT) against Gram-negative bacteria?

Synergistic Effect of Ceftazidime-Avibactam with Aztreonam Against Gram-Negative Bacteria

Ceftazidime-avibactam combined with aztreonam is strongly recommended for treating infections caused by metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) due to significant reduction in mortality and treatment failure rates compared to other antimicrobial therapies. 1

Mechanism of Synergy

The synergistic effect of this combination is based on complementary mechanisms:

• Aztreonam: A monobactam antibiotic that is stable against hydrolysis by MBLs (like NDM, VIM, IMP) but vulnerable to other β-lactamases 2
• Ceftazidime-avibactam:
  • Avibactam: Inhibits serine β-lactamases (ESBLs, KPC, AmpC, OXA-48)
  • Ceftazidime: Provides additional antimicrobial activity against gram-negative pathogens

When combined, avibactam protects both ceftazidime and aztreonam from hydrolysis by serine β-lactamases, while aztreonam remains effective against MBL-producing organisms 3

Clinical Evidence

A prospective study demonstrated significant clinical benefits of this combination:

• 30-day mortality rate: 19.2% with ceftazidime-avibactam plus aztreonam vs. 44% with other antimicrobial agents (p=0.007) 1
• Lower clinical treatment failure rate (HR: 0.30,95% CI 0.14-0.65) 1
• Shorter length of hospital stay (HR: 0.49,95% CI 0.25-0.82) 1

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

• 77.5% curative rate in patients with NDM or NDM+OXA-48-positive CRE infections treated with ceftazidime-avibactam combined with aztreonam 1

In Vitro Evidence

Laboratory studies confirm the synergistic mechanism:

• Aztreonam shows good in-vitro synergy with ceftazidime-avibactam against NDM-producing and KPC-producing CRKP isolates 1
• Time-kill assays demonstrated a ≥4-log10-CFU decrease at 2 hours for combinations of ceftazidime-avibactam with aztreonam compared to ceftazidime-avibactam alone 3
• In murine models, nearly 4-log10-CFU reduction was observed at 24 hours for the combination versus ceftazidime-avibactam alone 3

Clinical Application Algorithm

1. Identify the carbapenemase type produced by the CRE strain before initiating treatment 1

   • Molecular testing for MBL genes (NDM, VIM, IMP)
   • Phenotypic testing (e.g., CIM test, mCIM)

2. For confirmed MBL-producing CRE infections:

   • Initiate ceftazidime-avibactam plus aztreonam
   • Consider adding polymyxin or fosfomycin based on susceptibility testing and infection site 1

3. For OXA-48-producing CRE without MBL:

   • Ceftazidime-avibactam alone may be sufficient (82.3% curative rate) 1

4. For KPC-producing CRE without MBL:

   • Ceftazidime-avibactam alone is typically effective 1

Important Considerations

• The presence of ceftazidime in the combination does not negatively affect the activity of aztreonam/avibactam against MBL-producing isolates 4
• This combination is particularly valuable for treating previously untreatable gram-negative infections that produce multiple β-lactamases 2
• The combination offers a treatment option for patients with penicillin allergies due to aztreonam's safety profile in this population 2

Pitfalls and Caveats

• Quality of evidence supporting this combination is currently rated as very low 1
• Susceptibility testing should be performed whenever possible to confirm activity
• Carbapenemase type identification is crucial for optimal therapy selection 1
• Cost considerations may impact availability in some healthcare settings
• Ongoing research is evaluating optimal dosing regimens for this combination 5

This combination represents a critical advancement in treating highly resistant gram-negative infections, particularly those producing MBLs that were previously difficult to treat with available antibiotics.