Microbiological, Clinical, and Pharmacokinetic/Pharmacodynamic Data to Support EUCAST Aztreonam–Avibactam Minimum Inhibitory Concentration Susceptibility Breakpoints Against Enterobacterales
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".