Should I consider using ceftazidime-avibactam with aztreonam synergy and carbapenem for treating resistant Gram-negative bacterial infections?

Testing for Ceftazidime-Avibactam + Aztreonam Synergy and Carbapenem Susceptibility

Yes, you should request susceptibility testing for both ceftazidime-avibactam and carbapenems, and specifically ask for aztreonam testing when metallo-β-lactamase (MBL)-producing organisms are suspected or confirmed, as this combination represents a critical treatment option for these highly resistant pathogens. 1

When to Request This Testing

For Carbapenem-Resistant Enterobacterales (CRE)

• Request ceftazidime-avibactam susceptibility testing for all CRE isolates, as it is active against Ambler class A (KPC) and certain class D (OXA-48) carbapenemases 1
• Add aztreonam susceptibility testing when MBL production is suspected or confirmed (NDM, VIM, IMP producers), as ceftazidime-avibactam alone is inactive against MBL producers 1
• Always include carbapenem susceptibility testing to determine if meropenem MIC ≤8 mg/L, which may allow carbapenem-based therapy and preserve newer agents 1

For Severe Infections

The 2022 ESCMID guidelines specifically recommend aztreonam plus ceftazidime-avibactam combination therapy for patients with severe infections caused by CRE carrying metallo-β-lactamases and/or resistant to new antibiotic monotherapies (conditional recommendation, moderate certainty evidence) 1

Clinical Algorithm for Testing Decisions

Step 1: Identify High-Risk Scenarios

Request comprehensive testing when:

• Patient has healthcare-associated infections with risk factors for multidrug-resistant organisms 1
• Previous isolation of ESBL-producing or carbapenem-resistant organisms 1
• Recent travel to areas with high MBL prevalence (South Asia, Mediterranean regions) 2
• Clinical failure on standard carbapenem therapy 1

Step 2: Determine Carbapenemase Type

• Ascertain the carbapenemase type before initiating ceftazidime-avibactam treatment whenever possible 1
• If KPC or OXA-48 producers: ceftazidime-avibactam monotherapy may suffice 1
• If MBL producers (NDM, VIM, IMP): aztreonam plus ceftazidime-avibactam combination is required 1

Step 3: Request Specific Testing

For suspected MBL producers:

• Ceftazidime-avibactam MIC determination 3
• Aztreonam MIC determination 4
• Carbapenem MIC (specifically meropenem) 1
• Molecular testing for carbapenemase genes when available 1, 5

Evidence Supporting the Combination

Synergy Data

The combination of aztreonam with ceftazidime-avibactam demonstrates good in vitro synergy against both NDM-producing and KPC-producing organisms 1. Aztreonam is not hydrolyzed by metallo-β-lactamases, while avibactam protects aztreonam from degradation by serine β-lactamases 5, 6

• In one prospective study of MBL-producing CRE bloodstream infections, 30-day mortality was 19.2% with ceftazidime-avibactam plus aztreonam versus 44% with other active agents (P=0.007) 1
• Synergistic activity was demonstrated in 16 out of 19 VIM-producing isolates tested 7
• The combination restored bactericidal activity in 80% of MBL-producing Pseudomonas aeruginosa isolates 8

Laboratory Considerations

Ceftazidime in the combination does not affect the in vitro activity of aztreonam-avibactam - all tested isolates showed MICs within one 2-fold dilution regardless of ceftazidime concentration 6. This means laboratories can reliably test aztreonam-avibactam susceptibility as a surrogate when considering the ceftazidime-avibactam plus aztreonam combination 6

Critical Pitfalls to Avoid

Resistance Development

• Resistance to ceftazidime-avibactam can emerge during treatment in 3.7-8.1% of patients through KPC protein mutations or novel β-lactamases like VEB-25 1
• This underscores the importance of combination therapy for severe infections and appropriate antimicrobial stewardship 1

Inappropriate Monotherapy

• Do not use ceftazidime-avibactam alone for confirmed or suspected MBL producers - it lacks activity against metallo-β-lactamases 1, 5
• For non-severe infections in stable patients, consider older agents (aminoglycosides, colistin) based on susceptibility to preserve newer agents 1

Testing Limitations

• Standard automated susceptibility testing may not detect all resistance mechanisms 1
• When MBL production is suspected based on resistance patterns but molecular testing is unavailable, empirically treat as MBL-positive and request aztreonam testing 2

Antibiotic Stewardship Considerations

Reserve ceftazidime-avibactam and the aztreonam combination for extensively resistant bacteria 1. The 2022 ESCMID guidelines emphasize avoiding new β-lactam/β-lactamase inhibitor combinations for infections caused by organisms susceptible to older agents due to stewardship considerations 1

For non-severe CRE infections, use older antibiotics chosen from in vitro active agents on an individual basis according to infection source (good practice statement) 1