Why are ceftazidime (CAZ)-avibactam and aztreonam not effective for treating Acinetobacter infections?

Ceftazidime-Avibactam and Aztreonam Are Not Effective Against Acinetobacter Infections

Ceftazidime-avibactam and aztreonam are not recommended for treating Acinetobacter infections due to inherently high resistance rates exceeding 50% in Acinetobacter baumannii. 1

Mechanisms of Resistance in Acinetobacter

• Acinetobacter species demonstrate intrinsic resistance to ceftazidime-avibactam, with resistance rates exceeding 50%, significantly higher than observed in Enterobacterales (which maintain good susceptibility) or even Pseudomonas aeruginosa (with resistance rates of 2.9-18%) 1

• The resistance is primarily due to:

  • Intrinsic production of OXA-type carbapenemases (class D) that are not effectively inhibited by avibactam 2
  • Efflux pump mechanisms that reduce intracellular antibiotic concentrations 1
  • Membrane protein alterations that limit antibiotic penetration 1

Treatment Recommendations for Acinetobacter Infections

• For CRAB (Carbapenem-Resistant Acinetobacter baumannii) infections, guidelines recommend:

  • Tigecycline-based combination therapy or polymyxin-based combination therapy as preferred options 2
  • Selection between these regimens should be based on patient-specific factors such as renal function (avoid polymyxins in renal insufficiency) and hepatic function (use tigecycline cautiously with liver impairment) 2

• Neither ceftazidime-avibactam nor aztreonam appears in treatment recommendations for Acinetobacter infections in major guidelines, reflecting their lack of efficacy 2

Contrast with Effectiveness Against Other Pathogens

• While ineffective against Acinetobacter, ceftazidime-avibactam is highly effective against:

  • KPC-producing Carbapenem-Resistant Enterobacterales (CRE) 2
  • OXA-48-like producing CRE 2

• Ceftazidime-avibactam combined with aztreonam shows significant efficacy against:

  • Metallo-β-lactamase (MBL) producing CRE, including NDM and VIM producers 2
  • This combination has demonstrated lower 30-day mortality (HR: 0.37,95% CI 0.13-0.74) and lower clinical failure rates compared to other antimicrobial therapies 2

Clinical Implications

• Using ceftazidime-avibactam or aztreonam for Acinetobacter infections would likely result in treatment failure and potentially promote further resistance 1, 3

• The inherent resistance of Acinetobacter to these agents means they should not be considered even as part of combination therapy for these infections 1

• For severe Acinetobacter infections, clinicians should focus on agents with demonstrated activity and consider combination therapy approaches with agents like polymyxins, tigecycline, or other locally active agents based on susceptibility testing 2

Important Considerations for Antimicrobial Testing

• When testing susceptibility for MBL-producing organisms, the presence of ceftazidime does not affect the in vitro activity of aztreonam/avibactam, which is relevant for laboratory testing but not applicable to Acinetobacter infections 4

• The high level of resistance to ceftazidime-avibactam in Acinetobacter makes susceptibility testing generally unnecessary for this specific pathogen-drug combination 1