Mortality of MBL-producing Enterobacteriaceae Bacteremias with the Combined Use of Ceftazidime-avibactam and Aztreonam Vs. Other Active Antibiotics. a Multicenter Target Trial Emulation.

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

265 participants

Study Classification

OBSERVATIONAL

Study Start Date

2024-06-01

Study Completion Date

2024-11-19

Brief Summary

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Ceftazidime-avibactam and aztreonam combination (CAZAVI + ATM) presents a potential alternative for the treatment of metallo-beta-lactamase (MBL)-type carbapenemase-producing Enterobacteriaceae (CPE) bacteremia, particularly where Cefiderocol is not readily available.

This study proposes a Target Trial Emulation (TTE) to assess the efficacy and safety of CAZAVI + ATM compared to other active antibiotics (OAAs) in patients with MBL-type CPE bacteremia, and also to evaluate all-cause 30-day mortality, resistance profiles of isolated microorganisms, clinical failure rates, leukocyte count normalization, adverse events, occurrence of Clostridium difficile infection, and emergence of new multidrug-resistant microorganisms.

Data will be collected through the REDCap database, with rigorous verification for completeness and accuracy.

The outcomes of this project will contribute vital insights into the efficacy and safety of CAZAVI + ATM, informing clinical practice guidelines for the management of MBL-type bacteremia across diverse settings.

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Detailed Description

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Patients will be categorized into two treatment groups for analysis:

CAZAVI + ATM treatment group and Other Active Antibiotics treatment group. As this study is retrospective, treatment group assignment will not be a randomized procedure. Allocation data will be collected from medical records as a dichotomous variable.

In the present study, allocation to CAZAVI + ATM or OAAs will depend on various factors such as drug availability, hospital costs, and medical criteria. Therefore, to ensure comparability among participant characteristics, baseline factors will be adjusted to mitigate indication bias.

To simulate randomization at baseline (identification of MBL-type CPE in blood samples), ensuring comparability between treatment groups, several covariates will be balanced: age, sex, comorbidities (Charlson score), Pitt score, immunosuppression with neutropenia, immunosuppression without neutropenia, days of hospitalization prior to culture, Sequential Organ Failure Assessment (SOFA) score, days of effective antibiotic treatment between blood culture and positivization \[25\]. Also, as this is a multicenter study, it will be adjusted for the characteristics of the center (public-private), including a total of 10 variables to be adjusted for.

The start of the follow-up period (Time Zero or T0) will be defined by the identification of MBL-type CPE in at least one clinical blood sample (blood culture or PCR). From this point on, all patients will be followed up. A 24-hour grace period will be considered from the identification of MBL-type CPE until the patient initiates either of the two treatment groups.

To mitigate immortality bias, the initiation of both treatment strategies will synchronize with the eligibility criteria at Time Zero of follow-up. Thus, every patient must remain alive from blood culture collection until MBL detection to be eligible for inclusion in the study, and antibiotic treatment must be initiated within 24 hours of detection. All enrolled patients will be followed until 30 days after inclusion in the study, death, or hospital discharge, whichever occurs first.

A sample calculation was performed to test the null hypothesis of equality in the proportion of deaths among patients who received CAZAVI + ATM vs. OAAs. Falcone et al. reported a 19% mortality rate 30 days after inclusion in the CAZAVI + ATM arm and a 44% mortality rate in patients with OAAs. However, for the present study we consider an 80% power is necessary to detect a clinically relevant difference of 15%, therefore we expect a mortality of 34% in the OAAs arm and 19% in the CAZAVI + ATM arm. With an alpha of 5%, two-tailed test, expected ratio CAZAVI + ATM/OAAs of 1:1, a sample size of 270 patients (135 for each branch) is calculated.

Finally, to address indication bias, an adjustment will be made with Propensity Score (PS) matching. Considering 10 confounders entered into the model, at least 10 to 20 events will be required for each variable. Therefore, as the outcome of the PS will be the CAZAVI + ATM exposure variable, at least 150 patients in the CAZAVI + ATM branch will be required. Thus,we consider the calculation of 300 patients, 150 per branch.

A meticulous data collection plan will be carried out to ensure accuracy and confidentiality of the information collected. The following procedures will be implemented:

Data source: Data will be obtained from paper or electronic medical records from each participating center. Patient tracking will be done through the bacteriology records of each hospital center.

Data recording: Variables for each patient will be uploaded to a centralized REDCap database. The principal investigator and associated investigators of each participating center will be responsible for data upload. To maintain privacy and confidentiality, each patient will receive a randomly generated registration number to anonymize their identity in the database.

Data access: Access to center-specific data will be restricted to the principal investigators. Researchers will access REDCap using personal credentials, limiting data access to authorized personnel only.

Confidentiality and anonymization: Adherence to legal provisions, such as the Argentinian National Personal Data Protection (number 25.326) and the Habeas Data, will be strictly complied with in order to protect the confidentiality and privacy of the patients involved in the study. All collected data will be anonymized, devoid of patient identifiers.

Data storage: Once the data upload is completed, the entire database will be stored under password and will only be available to the principal investigators of the study. All necessary precautions will be taken to ensure that the data are maintained in a secure and reliable environment.

The research team is dedicated to upholding data privacy, complying with legal regulations, and conducting the study ethically and responsibly.

Conditions

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Bacteremia

Study Design

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Observational Model Type

OTHER

Study Time Perspective

RETROSPECTIVE

Study Groups

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CAZAVI + ATM

patients who received antibiotic therapy with a standard bacteremia treatment dose of Ceftazidima-Avibactam + Aztreonam (2.5 grams every 8 hours of ceftazidime-avibactam + 2 grams every 8 hours of aztreonam). Dosage adjustments for prolonged infusion or according to renal function will be considered.

No interventions assigned to this group

Other Active Antibiotics treatment group

Patients who received a combination or at least one of the following antibiotics, with doses adjusted according to renal function:

Colistin: 300 mg loading and 150 mg maintenance every 12 hours. Meropenem: 1000 or 2000 mg every 8 hours via infusion in 30 minutes or 3 hours. Fosfomycin: 12 to 24 grams per day, divided every 6 to 8 hours. Aminoglycoside (amikacin: 15 mg/kg/24 hours or gentamicin: 7 mg/kg/24 hours). Tigecycline: 100 or 200 mg loading and 50 or 100 mg maintenance every 12 hours.

No interventions assigned to this group

Eligibility Criteria

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Inclusion Criteria

* Patients aged 18 years or older
* Confirmed bacteremia by MBL-type Carbapenemase-Producing Enterobacteriaceae (CPE)
* Initiation of effective antibiotic therapy within 24 hours of identification of MBL-type CPE and within 96 hours of blood sample.

Exclusion Criteria

* Bacteremia due to the following complicated infections:

* Endocarditis or other endovascular infection without extractable focus.
* Necrotizing fasciitis
* Osteomyelitis or septic arthritis
* Confirmed prostatitis
* Non-drainable abscess or other unresolved infection requiring surgical intervention (e.g., cholecystitis)
* Central nervous system infections
* Empyema
* Successive episodes of bacteremia by the same pathogen (with the same resistance profile) within the previous 60 days.
* Polymicrobial bacteremias, not classified as contaminants.
* Patients with documented allergy to beta-lactams.

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Mariana Vaena

MD

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Ivan Huespe, MD, MPh

Role: STUDY_DIRECTOR

Hospital Italiano de Buenos Aires

Locations

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Hospital Municipal de Agudos Dr. Leónidas Lucero

Bahía Blanca, Buenos Aires, Argentina

Site Status

Hospital Interzonal General de Agudos ''Profesor Dr. Luis Güemes''

Haedo, Buenos Aires, Argentina

Site Status

Hospital de Alta Complejidad del Bicentenario Esteban Echeverria

Monte Grande, Buenos Aires, Argentina

Site Status

Hospital Universitario Austral

Pilar, Buenos Aires, Argentina

Site Status

Hospital Municipal Central de San Isidro "Dr. Melchor Ángel Posse"

San Isidro, Buenos Aires, Argentina

Site Status