Aztreonam-Avibactam in Immunocompromised Hosts

Infections caused by metallo-β-lactamase-producing Enterobacterales (MBL-E) represent a growing clinical challenge, particularly among immunocompromised patients. These individuals are at increased risk of infections caused by multidrug-resistant microorganisms, inappropriate empirical antibiotic treatment, and unfavorable clinical outcomes.

The combination of ceftazidime-avibactam plus aztreonam (CZA-ATM) has demonstrated improved clinical outcomes in patients with MBL-E infections. However, the simultaneous administration of two separate antibiotics presents pharmacokinetic and pharmacodynamic limitations. Aztreonam-avibactam (ATM-AVI), a fixed-dose combination, provides synchronized exposure to both components and improved pharmacokinetic/pharmacodynamic target attainment. Nevertheless, real-world clinical evidence regarding its effectiveness and safety remains limited, particularly in immunocompromised populations.

Study Design

IMMUNO-AVI is an international, multicenter, observational, analytical cohort study involving specialized healthcare centers.

The study aims to provide real-world evidence regarding ATM-AVI use in immunocompromised adults and to inform future treatment decisions for infections caused by MBL-E.

The study uses a mixed time perspective, combining a prospective cohort of participants treated with aztreonam-avibactam and a retrospective historical comparison cohort of participants treated with ceftazidime-avibactam plus aztreonam. Both cohorts will be evaluated using standardized study definitions to allow comparative analyses.

• Prospective cohort: Immunocompromised adults with microbiologically confirmed MBL-E infections who receive definitive treatment with ATM-AVI as part of routine clinical care.
• Retrospective cohort: Immunocompromised adults with microbiologically confirmed MBL-E infections previously treated with CZA-ATM, serving as a historical comparison group.

Treatment decisions are made independently by the treating physicians. The study does not assign antimicrobial treatments or modify routine patient care.

Data Collection and Follow-up

Clinical and microbiological information will be collected using standardized electronic case report forms through Research Electronic Data Capture (REDCap).

Collected information will include demographic characteristics, underlying diseases, immunocompromising conditions, previous healthcare exposures, risk factors for multidrug-resistant infections, infection characteristics, severity of illness, microbiological findings, antimicrobial susceptibility, treatment regimens, and clinical outcomes.

Microbiological identification and antimicrobial susceptibility testing will follow validated local laboratory procedures. Carbapenemase production and resistance mechanisms will be characterized using available phenotypic and molecular methods.

Participants in the prospective cohort will be followed for up to 60 days after treatment initiation. Clinical response, treatment outcomes, mortality, infection recurrence, and potential treatment-related adverse events will be assessed at predefined time points.

Quality Assurance, Data Validation, and Study Monitoring

A centralized quality assurance plan will be implemented to ensure the accuracy, completeness, consistency, and reliability of data collected across participating centers. Standardized electronic case report forms (eCRFs) will be used through Research Electronic Data Capture (REDCap), with predefined study variables and operational definitions.

Data Quality Checks

Data validation procedures will include:

• Identification of missing, incomplete, or unavailable data.
• Detection of outliers and implausible values.
• Assessment of internal consistency between related variables.
• Verification of chronological consistency among infection onset, antimicrobial treatment initiation, treatment completion, and follow-up assessments.
• Review of compliance with predefined study definitions, including infection classification, microbiological confirmation, treatment exposure, and clinical outcomes.

Identified inconsistencies will be reviewed and addressed through communication with the corresponding participating centers.

Study Monitoring and Quality Control

Data will be entered locally by authorized study personnel and monitored centrally to promote consistency across participating institutions.

Quarterly quality assessments will review recruitment performance, completeness of key variables, and adherence to predefined follow-up assessments at day 7, end of treatment, day 30, and day 60.

A midpoint interim assessment will evaluate overall recruitment, data completeness, and potential deviations from protocol definitions. These assessments will be descriptive and will not involve formal hypothesis testing or changes to study procedures.

Before final statistical analysis, the database will undergo cleaning and validation to identify unresolved inconsistencies and assess overall data quality.

Statistical Analysis

Descriptive analyses will summarize baseline characteristics, clinical presentation, antimicrobial treatment, effectiveness, and safety outcomes.

Comparative analyses will evaluate differences between the prospective ATM-AVI cohort and the historical CZA-ATM cohort. Multivariable logistic regression and time-to-event analyses, including Kaplan-Meier estimates and Cox proportional hazards models, will be used as appropriate.

To address potential confounding, inverse probability of treatment weighting (IPTW) based on propensity scores will be applied. Covariate balance will be assessed using standardized mean differences.

Additional analyses will examine clinically relevant subgroups, including neutropenic and non-neutropenic participants, solid organ and hematopoietic stem cell transplant recipients, and participants with bacteremic and non-bacteremic infections.

Sample Size Calculation

Based on the historical case volume at participating centers, a minimum of 200 participants is expected to be enrolled in the prospective aztreonam-avibactam (ATM-AVI) cohort, allowing a descriptive assessment of clinical effectiveness and safety outcomes.

For the comparative analysis, the sample size was calculated assuming a mortality rate of 20% in the historical ceftazidime-avibactam plus aztreonam (CZA-ATM) cohort and an expected mortality rate of 12% in the ATM-AVI cohort, corresponding to a 40% relative reduction and an 8-percentage-point absolute difference.

Using a two-sided significance level of 0.05, 80% statistical power, and a 1:2 allocation ratio between the ATM-AVI and CZA-ATM cohorts, the estimated sample size was 732 evaluable participants (244 in the ATM-AVI cohort and 488 in the CZA-ATM cohort).

Allowing for up to 10% of participants with incomplete data, loss to follow-up, or non-evaluable outcomes, the anticipated total enrollment is approximately 814 participants, including 271 in the prospective ATM-AVI cohort and 543 in the retrospective CZA-ATM cohort.