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.

• Aztreonam-Avibactam (Drug): Aztreonam-avibactam (ATM-AVI) administered as definitive antimicrobial treatment for infections caused by metallo-β-lactamase-producing Enterobacterales. Treatment is prescribed as part of routine clinical care, independently of study participation. Dose, administration interval, infusion duration, and treatment duration are determined by the treating physician.
• Ceftazidime-Avibactam Plus Aztreonam (Drug): Ceftazidime-avibactam administered in combination with aztreonam as definitive antimicrobial treatment for infections caused by metallo-β-lactamase-producing Enterobacterales. Treatment was prescribed as part of routine clinical care, independently of study participation. Treatment information will be obtained retrospectively from existing medical records.

Primary outcomes

• All-Cause Mortality at Day 30 [Within 30 days after treatment initiation]: Proportion of participants who die from any cause within 30 days after initiation of aztreonam-avibactam (ATM-AVI) or ceftazidime-avibactam plus aztreonam (CZA-ATM), regardless of the cause of death.

Secondary outcomes

• Favorable Clinical Response at Day 7 [Day 7 after treatment initiation]: Proportion of participants with a favorable clinical response, defined as the absence of fever and hypotension, together with improvement in the signs and symptoms of the index infection.
• Clinical Cure at the End of Treatment [At completion of antimicrobial treatment for the index infection]: Proportion of participants achieving clinical cure, defined as resolution of fever and hypotension for at least 72 hours, together with resolution of the signs and symptoms of the index infection. The end of treatment corresponds to completion of all antimicrobial treatment directed at the infectious episode.
• Microbiological Cure [From treatment initiation through the end of treatment]: Proportion of evaluable participants with documented conversion of cultures from the index infection site to negative. Assessment will be based on follow-up cultures obtained as part of routine clinical care.
• All-Cause Mortality at Day 7 [Within 7 days after treatment initiation]: Proportion of participants who die from any cause within 7 days after initiation of ATM-AVI or CZA-ATM treatment.
• Infection-Related Mortality at Day 7 [Within 7 days after treatment initiation]: Proportion of participants who die within 7 days after treatment initiation in the presence of microbiological, histological, or clinical evidence of active infection, after excluding alternative causes of death.
• Infection-Related Mortality at Day 30 [Within 30 days after treatment initiation]: Proportion of participants who die within 30 days after treatment initiation in the presence of microbiological, histological, or clinical evidence of active infection, after excluding alternative causes of death.
• Infection Relapse Within 60 Days [Within 60 days after treatment initiation]: Proportion of participants experiencing recurrence of infection caused by the same microorganism responsible for the index infection within 60 days after initiation of ATM-AVI or CZA-ATM treatment.
• Incidence of Hematological Abnormalities [During treatment and up to 30 days after treatment completion]: Proportion of participants developing hematological abnormalities, including leukopenia (leukocyte count below 4,000/mm³), neutropenia (neutrophil count below 1,000/mm³), eosinophilia (eosinophil count above 500/mm³), thrombocytopenia (platelet count below 150,000/mm³), or anemia according to institutional reference ranges.
• Incidence of Hepatic Toxicity [During treatment and up to 30 days after treatment completion]: Proportion of participants developing hepatic toxicity, defined as ALT or AST above the upper limit of normal (ULN). Hepatitis is defined as transaminase elevation at least 5 times the ULN, or at least 3 times the ULN accompanied by symptoms such as abdominal pain, nausea, or vomiting.
• Incidence of Acute Kidney Injury [During treatment and up to 30 days after treatment completion]: Proportion of participants developing acute kidney injury, defined as an increase in serum creatinine of at least 0.3 mg/dL or at least 1.5 times baseline, or urine output below 0.5 mL/kg/hour for at least 6 hours.
• Incidence of Allergic Reactions [During treatment and up to 30 days after treatment completion]: Proportion of participants experiencing allergic reactions, including rash, angioedema, anaphylaxis, or severe cutaneous reactions such as erythema multiforme or toxic epidermal necrolysis.
• Incidence of Gastrointestinal Symptoms [During treatment and up to 30 days after treatment completion]: Proportion of participants experiencing diarrhea and/or vomiting during the safety assessment period.
• Incidence of Neuropsychiatric Symptoms [During treatment and up to 30 days after treatment completion]: Proportion of participants experiencing delirium, encephalopathy, or dysgeusia during the safety assessment period.
• Incidence of Clostridioides difficile Infection [During treatment and up to 30 days after treatment completion]: Proportion of participants developing Clostridioides difficile infection, defined as at least 3 unformed stools within 24 hours without an alternative explanation, together with microbiological evidence of toxigenic C. difficile by toxin detection or molecular testing.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Adult participants aged 18 years or older with microbiologically confirmed infections caused by metallo-β-lactamase-producing Enterobacterales (MBL-E).
2. Participants must meet at least one of the following immunocompromising conditions:

   * Solid organ transplant recipients receiving immunosuppressive treatment.
   * Participants with hematological malignancies or solid tumors who received chemotherapy within the previous 30 days.
   * Treatment with antilymphocyte or B-cell-depleting agents (e.g., rituximab or alemtuzumab) within the previous 6 months.
   * Use of biological or targeted therapies associated with immunosuppression (e.g., BTK inhibitors, CAR-T cells, immune checkpoint inhibitors with immunosuppressive management, or bispecific antibodies) within the previous 3 months.
   * Exposure to high-dose corticosteroids, defined as at least 20 mg/day of prednisone or equivalent for at least 14 days within the previous 30 days.
   * Allogeneic hematopoietic stem cell transplantation (HSCT), with graft-versus-host disease at any time or without graft-versus-host disease during the first year after transplantation.
   * Autologous HSCT within 6 months after transplantation.
   * Autoimmune diseases receiving immunosuppressive treatment.
3. Monomicrobial infection caused by MBL-E.
4. Definitive antimicrobial treatment with aztreonam-avibactam (prospective cohort) or ceftazidime-avibactam plus aztreonam (retrospective cohort) for at least 72 hours.

Exclusion Criteria:

1. Recurrent infections.
2. Infections requiring prolonged antibiotic treatment exceeding 28 days (e.g., osteoarticular infections).
3. Positive microbiological specimens that do not represent a true infection, including:

   * Asymptomatic bacteriuria.
   * Respiratory specimens without clinical criteria for pneumonia.
   * Superficial skin and soft tissue cultures.
   * Blood cultures obtained through a catheter without confirmation in peripheral blood cultures.
4. Participants receiving palliative care.

• Fabián Herrera, MD, Study chair, CEMIC - Centro de Educación Médica e Investigaciones Clínicas "Dr. Norberto Quirno"
• Diego Torres, MD, Study director, CEMIC - Centro de Educación Médica e Investigaciones Clínicas "Dr. Norberto Quirno"
• Maximiliano Gabriel Castro, MD, Principal investigator, CEMIC - Centro de Educación Médica e Investigaciones Clínicas "Dr. Norberto Quirno"