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Introduction <p>Aztreonam–avibactam was approved for adults with limited treatment options for multiple infections due to aerobic Gram-negative organisms in the European Union and for complicated intra-abdominal infection in the US, following the phase 3 REVISIT and ASSEMBLE trials. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) assigned minimum inhibitory concentration (MIC) breakpoints for aztreonam–avibactam against Enterobacterales of susceptible ≤ 4&#xa0;mg/l and resistant &gt; 4&#xa0;mg/l.</p> Methods <p>A comprehensive synthesis of data supporting MIC breakpoint determination is summarized, including: joint probability of pharmacokinetic/pharmacodynamic target attainment (JPTA) analyses (based on population pharmacokinetic modeling) for aztreonam–avibactam dose selection; MIC distributions of target pathogens; clinical and microbiological efficacy outcomes; and exposure–response analyses.</p> Results <p>Among 100,228 Enterobacterales isolates, including 2449 metallo-β-lactamase-positive isolates from global surveillance studies (2017–2021), 99% had aztreonam–avibactam MICs of ≤ 8&#xa0;mg/l. At MIC = 8&#xa0;mg/l, the predicted JPTA at steady state was 89% to &gt; 99% across subgroups of varying renal function, based on approved doses for aztreonam–avibactam. Clinical trial isolates fell within the same MIC distribution as surveillance studies. There was no evidence of decreased favorable microbiological responses with increasing aztreonam–avibactam MICs in clinical trials; however, in the clinical dataset, there were few Enterobacterales isolates with aztreonam–avibactam MICs of &gt; 4&#xa0;mg/l.</p> Conclusions <p>MIC distributions and JPTA simulations supported a susceptible MIC breakpoint for aztreonam–avibactam against Enterobacterales of ≤ 8&#xa0;mg/l. However, limited clinical outcomes data for Enterobacterales with aztreonam–avibactam MIC ≥ 4&#xa0;mg/l justified the more conservative breakpoints established by EUCAST.</p> Clinical Trial Registration <p>ClinicalTrials.gov, NCT03329092 and NCT03580044. Studies/analyses sponsored by Pfizer.</p>

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Microbiological, Clinical, and Pharmacokinetic/Pharmacodynamic Data to Support EUCAST Aztreonam–Avibactam Minimum Inhibitory Concentration Susceptibility Breakpoints Against Enterobacterales

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Susan R. Raber,
  • Rujia Xie,
  • Halley Rogers,
  • Elena Soto,
  • Francis F. Arhin,
  • Gregory G. Stone,
  • Heidi Leister-Tebbe,
  • Joseph W. Chow

摘要

Introduction

Aztreonam–avibactam was approved for adults with limited treatment options for multiple infections due to aerobic Gram-negative organisms in the European Union and for complicated intra-abdominal infection in the US, following the phase 3 REVISIT and ASSEMBLE trials. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) assigned minimum inhibitory concentration (MIC) breakpoints for aztreonam–avibactam against Enterobacterales of susceptible ≤ 4 mg/l and resistant > 4 mg/l.

Methods

A comprehensive synthesis of data supporting MIC breakpoint determination is summarized, including: joint probability of pharmacokinetic/pharmacodynamic target attainment (JPTA) analyses (based on population pharmacokinetic modeling) for aztreonam–avibactam dose selection; MIC distributions of target pathogens; clinical and microbiological efficacy outcomes; and exposure–response analyses.

Results

Among 100,228 Enterobacterales isolates, including 2449 metallo-β-lactamase-positive isolates from global surveillance studies (2017–2021), 99% had aztreonam–avibactam MICs of ≤ 8 mg/l. At MIC = 8 mg/l, the predicted JPTA at steady state was 89% to > 99% across subgroups of varying renal function, based on approved doses for aztreonam–avibactam. Clinical trial isolates fell within the same MIC distribution as surveillance studies. There was no evidence of decreased favorable microbiological responses with increasing aztreonam–avibactam MICs in clinical trials; however, in the clinical dataset, there were few Enterobacterales isolates with aztreonam–avibactam MICs of > 4 mg/l.

Conclusions

MIC distributions and JPTA simulations supported a susceptible MIC breakpoint for aztreonam–avibactam against Enterobacterales of ≤ 8 mg/l. However, limited clinical outcomes data for Enterobacterales with aztreonam–avibactam MIC ≥ 4 mg/l justified the more conservative breakpoints established by EUCAST.

Clinical Trial Registration

ClinicalTrials.gov, NCT03329092 and NCT03580044. Studies/analyses sponsored by Pfizer.