For a severe carbapenem‑resistant Gram‑negative infection, especially metallo‑β‑lactamase‑producing, should I use colistin or aztreonam plus ceftazidime‑avibactam (Zerbaxa) as the preferred therapy?

Aztreonam + Ceftazidime-Avibactam (Zerbaxa) Over Colistin for Metallo-β-Lactamase-Producing CRE

For severe carbapenem-resistant Gram-negative infections caused by metallo-β-lactamase (MBL)-producing organisms, use aztreonam plus ceftazidime-avibactam (Zerbaxa) instead of colistin. This combination demonstrates superior mortality reduction and clinical outcomes while avoiding the nephrotoxicity associated with polymyxins.

Key Recommendation

The 2023 guidelines explicitly recommend aztreonam plus ceftazidime-avibactam as the preferential choice for MBL-producing CRE infections 1. The 2022 ESCMID guidelines similarly suggest this combination for severe infections caused by CRE carrying metallo-β-lactamases and/or resistant to new antibiotic monotherapies (conditional recommendation, moderate evidence) 2.

Evidence Supporting This Approach

Mortality Benefit

The combination of aztreonam plus ceftazidime-avibactam achieved a 30-day mortality rate of 19.2% compared to 44% with other active antimicrobial agents (including colistin-based regimens) in patients with MBL-producing CRE bloodstream infections 1. This represents:

• 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)

A 2024 meta-analysis confirmed these findings, showing a pooled risk ratio for 30-day mortality of 0.51 (95% CI: 0.34-0.76) favoring aztreonam-avibactam over polymyxins 3.

Microbiological Rationale

Aztreonam is not hydrolyzed by metallo-β-lactamases (NDM, VIM, IMP), while avibactam protects it from other β-lactamases (KPC, OXA-48) that may co-exist 1. This creates excellent in vitro synergy against NDM-producing and KPC-producing isolates 1.

When to Use Each Regimen

Use Aztreonam + Ceftazidime-Avibactam When:

• MBL production is confirmed or suspected (NDM, VIM, IMP)
• Severe infections including bloodstream infections, hospital-acquired pneumonia, or intra-abdominal infections
• Patient can tolerate β-lactam therapy
• Carbapenemase type should be ascertained before treatment whenever possible 1

Colistin Should Be Avoided When Possible Because:

• Significant nephrotoxicity risk - colistin should be used judiciously in patients with renal insufficiency 1
• Inferior mortality outcomes compared to newer combinations 3, 4
• Guidelines recommend avoiding polymyxins where alternatives exist 5
• When colistin must be used (no alternatives available), combine with another active agent 2

Practical Implementation

Dosing for Aztreonam + Ceftazidime-Avibactam:

Adults (CrCl >50 mL/min):

• Ceftazidime-avibactam: 2.5g IV every 8 hours (infused over 2 hours)
• Aztreonam: 2g IV every 8 hours 6

Adjust for renal impairment - both agents require dose reduction 7

Critical Caveats:

1. Identify the carbapenemase type first - this combination is specifically for MBL producers. For KPC or OXA-48 alone, ceftazidime-avibactam monotherapy may suffice 2

2. Heteroresistance exists - particularly concerning with cefiderocol (an alternative for MBL-CRE), which shows variable susceptibility 8

3. Combination therapy is essential - do not use aztreonam alone for CRE, as it will be hydrolyzed by co-existing carbapenemases 1

4. Monitor for clinical response - if using cefiderocol as an alternative, close monitoring is required due to heterogeneous susceptibility patterns 9

Alternative Considerations

If aztreonam plus ceftazidime-avibactam is unavailable:

• Cefiderocol may be considered for MBL-producing CRE if susceptibility is confirmed, though resistance rates can be high (77.8% in some series) 9
• Meropenem-colistin combination showed synergistic activity in only 57.1% of isolates in vitro, with undefined interactions in 17.5% 9
• Polymyxin-based combinations remain an option only when no alternatives exist 2