Aztreonam Combined with Ceftazidime-Avibactam for Metallo-β-Lactamase-Producing Carbapenem-Resistant Enterobacterales
Use aztreonam combined with ceftazidime-avibactam specifically for severe infections caused by metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE), where this combination demonstrates a dramatic mortality reduction (19.2% vs 44%) compared to alternative therapies. 1, 2
Primary Indication
The ESCMID guidelines conditionally recommend this combination for patients with severe CRE infections carrying metallo-β-lactamases and/or resistant to newer antibiotic monotherapies (conditional recommendation, moderate evidence). 3
- This combination is reserved for extensively resistant bacteria where other options have failed or are unavailable 3
- The combination should NOT be used for CRE infections susceptible to ceftazidime-avibactam or meropenem-vaborbactam monotherapy (strong recommendation against combination therapy in susceptible cases) 3
Mechanistic Rationale
The synergy of this combination addresses the complex resistance mechanisms in MBL-producing organisms:
- Aztreonam is uniquely stable against metallo-β-lactamases (NDM, VIM, IMP) and is not hydrolyzed by these enzymes 3, 2
- However, aztreonam monotherapy fails because MBL-producing strains co-produce ESBLs and AmpC β-lactamases that destroy aztreonam 3, 1
- Avibactam protects aztreonam by inhibiting the co-produced ESBLs and AmpC enzymes, restoring aztreonam activity 4, 5
- Ceftazidime in the combination does not interfere with aztreonam/avibactam activity—MICs remain within one 2-fold dilution regardless of ceftazidime concentration 6
Clinical Efficacy Data
In vitro testing demonstrates robust activity:
- Aztreonam susceptibility is restored in 86% of MBL-producing Enterobacterales when combined with ceftazidime-avibactam 5
- All CRE producing NDM tested in clinical studies were susceptible to the combination 7
- The combination has been used successfully in clinical cases, including NDM-5-producing E. coli urinary tract infections 5
Critical Limitations and Pitfalls
Identify the carbapenemase type before initiating treatment whenever possible, as this combination has important limitations: 1
- Ineffective against non-MBL carbapenemases: This combination does not work for KPC or OXA-48-producing organisms that are already susceptible to ceftazidime-avibactam alone 3
- Variable activity in Pseudomonas aeruginosa: MBL-producing P. aeruginosa (NDM, VIM) often remain resistant to aztreonam-ceftazidime-avibactam due to non-β-lactamase resistance mechanisms like efflux pumps and porin mutations 7, 5
- Resistance can develop: Ceftazidime-avibactam resistance emerges in 3.8-10.4% of cases during treatment 8
Dosing Strategy
Administer 6 g/1.5 g of ceftazidime/avibactam and 8 g of aztreonam per day simultaneously to optimize pharmacokinetic/pharmacodynamic parameters while minimizing aztreonam's dose-limiting hepatotoxicity 9
Antibiotic Stewardship Considerations
This combination represents a last-resort option:
- Reserve exclusively for MBL-producing CRE with severe infections where newer monotherapies (ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol) are ineffective 3, 1
- For non-severe CRE infections, use older antibiotics active in vitro on an individual basis according to infection source 3
- Avoid using new β-lactam/β-lactamase inhibitor combinations for 3rd-generation cephalosporin-resistant Enterobacterales that remain carbapenem-susceptible 3