How does the antibacterial spectrum of ceftazidime‑avibactam (Zavicefta) combined with aztreonam compare to that of colistin (polymyxin E)?

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Ceftazidime-Avibactam/Aztreonam Demonstrates Superior Mortality Outcomes Compared to Colistin for Carbapenem-Resistant Enterobacterales

For metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE), ceftazidime-avibactam combined with aztreonam should be strongly preferred over colistin-based regimens, as it reduces 30-day mortality from 44% to 19.2% (HR 0.37,95% CI 0.13-0.74). 1

Key Coverage Differences

Zavicefta/Aztreonam Combination Spectrum:

  • Highly effective against MBL-producing CRE (NDM, VIM producers) - aztreonam is not hydrolyzed by metallo-β-lactamases while ceftazidime-avibactam protects it from ESBLs and other cephalosporinases 2, 1
  • Excellent activity against KPC-producing CRE - nearly 100% susceptibility 2
  • Good activity against OXA-48-producing CRE 2, 1
  • Limited activity against carbapenem-resistant Pseudomonas aeruginosa - only 12.5% susceptibility in recent data 3
  • No activity against carbapenem-resistant Acinetobacter baumannii (CRAB) 4
  • No activity against MRSA or anaerobes 4

Colistin (Polymyxin) Spectrum:

  • Broad Gram-negative coverage including most CRE, CRPA, and CRAB 2
  • Variable activity against MBL-producing CRE - 54% resistance rate reported in recent studies 5
  • No activity against Gram-positive organisms (MRSA, streptococci)
  • No activity against anaerobes

Clinical Outcomes: The Critical Difference

The most compelling evidence comes from direct comparative studies showing ceftazidime-avibactam/aztreonam significantly outperforms colistin in mortality reduction:

  • 30-day mortality: 19.2% vs 44% (p=0.007) in MBL-producing CRE bloodstream infections 1
  • Clinical failure rate: 70% lower (HR 0.30,95% CI 0.14-0.65) 2
  • Hospital length of stay: Significantly shorter (HR 0.49) 2

Importantly, the highest mortality rates were observed specifically in patients receiving colistin-containing regimens 1, making this a critical safety consideration.

Toxicity Profile: A Major Distinguishing Factor

Nephrotoxicity represents a substantial clinical difference:

  • Ceftazidime-avibactam/aztreonam: 95 fewer acute renal injuries per 1000 patients (RR 0.55,95% CI 0.23-1.33) 2
  • Polymyxin-based therapy: 225 more nephrotoxicity events per 1000 patients compared to alternatives (RR 0.23,95% CI 0.11-0.46) 2
  • Colistin incidence of nephrotoxicity: significantly higher (p=0.017) 6

This toxicity difference is particularly relevant in critically ill patients with baseline renal dysfunction or those requiring prolonged therapy.

Algorithmic Approach to Selection

For CRE infections, determine carbapenemase type when possible:

  1. MBL-producing (NDM, VIM): Use ceftazidime-avibactam + aztreonam (STRONG recommendation) 2, 1

    • Alternative: Cefiderocol monotherapy (conditional, if combination unavailable)

  2. KPC-producing: Use ceftazidime-avibactam alone or with aztreonam 2

    • Colistin inferior based on mortality data

  3. OXA-48-producing: Use ceftazidime-avibactam (with or without aztreonam) 2, 1

  4. Unknown carbapenemase or mixed: Use ceftazidime-avibactam + aztreonam empirically 2

For CRAB infections: Both tigecycline-based and polymyxin-based combinations are equally preferable; colistin remains an option here 2

For carbapenem-resistant Pseudomonas: Colistin shows superior activity (80% susceptibility) compared to ceftazidime-avibactam/aztreonam (12.5% susceptibility) 3

Critical Caveats

Synergy testing is essential - the ceftazidime-avibactam/aztreonam combination is not universally synergistic. Organism-specific synergy rates vary: K. pneumoniae (91-97%), E. coli (67-93%), but P. aeruginosa only (17-37%) 7. Request synergy testing when clinically indicated.

Resistance emergence: While ceftazidime-avibactam resistance development occurs in 3.8-10.4% of cases, this is not increased with monotherapy versus combination 8. However, colistin heteroresistance is increasingly recognized and may contribute to treatment failures.

Renal function monitoring: Polymyxins should be used judiciously in patients with renal insufficiency 2. Dose adjustment is critical for both agents but particularly for colistin given its narrow therapeutic index.

Cost considerations: Despite higher acquisition costs, ceftazidime-avibactam is cost-effective for CRE bacteremia and pneumonia when mortality reduction is factored 2.

The evidence consistently demonstrates that for CRE infections, particularly MBL-producers, ceftazidime-avibactam/aztreonam provides superior clinical outcomes with better safety compared to colistin, making it the preferred first-line option when available and active in vitro. Reserve colistin for CRAB infections, carbapenem-resistant Pseudomonas when other options fail, or when newer agents are unavailable or inactive.

References

6
Research

Ceftazidime-avibactam with or without Aztreonam vs Polymyxin-based Combination Therapy for Carbapenem-resistant Enterobacteriaceae: A Retrospective Analysis.

Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine, 2023

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