Real-world Multicentre Study of AZtreonam-AVIbactam Treatment With Infections or Suspected Infections Caused by Multidrug-resistant Gram-negative Bacteria

1. Background and Rationale The emergence of carbapenemase-producing bacteria, particularly metallo-β-lactamase (MBL) producers such as NDM, poses a major therapeutic challenge in intensive care settings. Current guidelines recommend combining ceftazidime-avibactam (CAZ-AVI) with aztreonam for these infections, but these were developed before the availability of the fixed combination aztreonam-avibactam (ATM-AVI). ATM-AVI offers a more targeted option by pairing a β-lactam stable to MBL hydrolysis with a non-metallo β-lactamase inhibitor. While in vitro and limited in vivo data are promising, real-world evidence remains scarce.
2. Objectives -Primary Objective: To describe the frequency of clinical success of ATM-AVI in patients treated for suspected or documented MBL-producing bacterial infections. -Secondary Objectives: To assess microbiological and clinical effectiveness. To describe the emergence of resistance during treatment. To identify predictors of clinical and microbiological response. To evaluate ICU and hospital length of stay, mechanical ventilation duration, and all-cause mortality at day 28 and day 90. To assess safety and adverse events. To compare prescribing practices between infectious diseases and intensive care units.
3. Study Design Multicenter, observational study with both retrospective and prospective cohorts:

• Retrospective arm: Patients treated with ATM-AVI in the 12 months preceding study initiation.
• Prospective arm: Patients treated with ATM-AVI over a 24-month period following study initiation. Participating centers include ICUs and infectious diseases departments recruited via national professional networks.

1. Population

• Inclusion criteria: Hospitalized patients with suspected or documented infection due to MBL-producing bacteria, treated with ATM-AVI.
• Exclusion criteria: Explicit refusal by patient or legal representative.

1. Endpoints -Primary endpoint: Clinical success at the test-of-cure visit, day 7 after completion of the initial ATM-AVI regimen, defined as resolution of infection signs and symptoms without need for further active antibiotics. Death (any cause) and microbiologically confirmed relapse are considered treatment failures. -Secondary endpoints: Microbiological eradication/persistence. Mortality at day 28 and day 90. Duration of hospitalization, ICU stay, and mechanical ventilation. Adverse events attributable to ATM-AVI. Patterns of monotherapy vs. combination therapy.
2. Data Collection

• Retrospective arm: Identification of cases via ICD-10 coding (infections due to multidrug-resistant organisms), microbiology laboratory records (MBL-positive isolates), pharmacy dispensing data, and early access registries.
• Prospective arm: Data collected at the time of ATM-AVI prescription and during follow-up. All data are pseudonymized and entered into a secure electronic case report form.

1. Statistical Analysis Descriptive statistics for baseline characteristics and outcomes. Univariate and multivariate analyses to identify predictors of clinical success at day 7 post-treatment.

Propensity score analysis to compare monotherapy vs. combination therapy. All tests two-sided, p < 0.05 considered significant. Expected Results and Impact

In total, This study will provide real-world data on the effectiveness, safety, and resistance dynamics of ATM-AVI in severe infections due to MBL-producing bacteria. Results will support clinical decision-making and help refine treatment strategies in critical care and infectious diseases settings.