Mortality of MBL-producing Enterobacteriaceae Bacteremias With the Combined Use of Ceftazidime-avibactam and Aztreonam vs. Other Active Antibiotics. A Multicenter Target Trial Emulation.

May 14, 2024 updated by: Mariana Vaena, Hospital Italiano de Buenos Aires

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.

The study expects to enroll at least 662 patients from 22 hospitals in Argentina. 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.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

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.

Study Type

Observational

Enrollment (Estimated)

300

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

The study will include a cohort of hospitalized patients from Argentine hospitals. Hospital centers will be invited to participate through the network of the Argentine Society of Medicine (SAM), the Argentine Society of Intensive Care (SATI) and the Argentine Society Of Infectious Diseases (SADI).

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
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.
Other Active Antibiotics treatment group

Patients who received a combination of at least two 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
All-cause mortality
Time Frame: within 30 days from the initiation of treatment (follow-up period)
death from any cause
within 30 days from the initiation of treatment (follow-up period)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Describe the resistance profile of the isolated microorganisms
Time Frame: 30-day follow-up period
including the associated enzymatic mechanisms
30-day follow-up period
Compare clinical failure
Time Frame: 30-day follow-up period
presence of 1) Relapse: recurrent bacteremia due to the same bacteria; 2) Restart of antibiotic therapy targeting the same germs; 3) Local suppurative complication that was not present at the beginning of the infection; 4) Distant complications of the initial infection (defined by the growth of the same bacteria causing the initial bacteremia in distant sites)
30-day follow-up period
Compare the number of days to normalization of the leukocyte count in the laboratory
Time Frame: 30-day follow-up period
(leukocyte count less than 12x109/L). (leukocyte co(leukocyte count less than 12x109/L).unt less than 12x109/L)
30-day follow-up period
Compare the proportion of adverse events
Time Frame: 30-day follow-up period
including: neutropenia, thrombocytopenia, renal failure, hepatotoxicity, skin reactions and ion-losing tubulopathy
30-day follow-up period
compare the occurrence of Clostridium difficile infection
Time Frame: 30-day follow-up period
Appearance of positive C. difficile toxin or positive C. difficile PCR
30-day follow-up period
compare the occurrence of new multidrug-resistant microorganisms
Time Frame: 30-day follow-up period
such as KPC, NDM, VIM, IMP, OXA or EVR-producing CLD, detected in both clinical and surveillance samples
30-day follow-up period

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospital Italiano de Buenos Aires

Investigators

  • Study Director: Ivan Huespe, MD, MPh, Hospital Italiano de Buenos Aires

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 15, 2024

Primary Completion (Estimated)

July 1, 2024

Study Completion (Estimated)

July 1, 2024

Study Registration Dates

First Submitted

May 14, 2024

First Submitted That Met QC Criteria

May 14, 2024

First Posted (Actual)

May 17, 2024

Study Record Updates

Last Update Posted (Actual)

May 17, 2024

Last Update Submitted That Met QC Criteria

May 14, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 6915

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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