## Protocol Section
### Identification Module
**NCT ID:** NCT06419296

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

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

#### Organization Study ID Info
**ID:** 6915
#### Organization
**Class:** OTHER
**Full Name:** Hospital Italiano de Buenos Aires
### Status Module
#### Completion Date
**Date:** 2024-07-01

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-17

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-14

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2024-07-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-05-15

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-17
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-14
**Study First Submit QC Date:** 2024-05-14
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Hospital Italiano de Buenos Aires

#### Responsible Party

**Investigator Affiliation:** Hospital Italiano de Buenos Aires

**Investigator Full Name:** Mariana Vaena

**Investigator Title:** MD

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** 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.

**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.

### Conditions Module

**Conditions:**

- Bacteremia

**Keywords:**

- multicenter

- target trial emulation

- bacteremia

- metallo-beta-lactamase

- carbapenemase-producing Enterobacteriaceae

- ceftazidime-avibactam aztreonam

### Design Module

#### Design Info

**Observational Model:** OTHER

**Time Perspective:** RETROSPECTIVE

#### Enrollment Info

**Count:** 300

**Type:** ESTIMATED

**Study Type:** OBSERVATIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 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.

**Label:** CAZAVI + ATM

#### Arm Group 2

**Description:** 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.

**Label:** Other Active Antibiotics treatment group

### Outcomes Module

#### Primary Outcomes

**Description:** death from any cause

**Measure:** All-cause mortality

**Time Frame:** within 30 days from the initiation of treatment (follow-up period)

#### Secondary Outcomes

**Description:** including the associated enzymatic mechanisms

**Measure:** Describe the resistance profile of the isolated microorganisms

**Time Frame:** 30-day follow-up period

**Description:** 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)

**Measure:** Compare clinical failure

**Time Frame:** 30-day follow-up period

**Description:** (leukocyte count less than 12x109/L). (leukocyte co(leukocyte count less than 12x109/L).unt less than 12x109/L)

**Measure:** Compare the number of days to normalization of the leukocyte count in the laboratory

**Time Frame:** 30-day follow-up period

**Description:** including: neutropenia, thrombocytopenia, renal failure, hepatotoxicity, skin reactions and ion-losing tubulopathy

**Measure:** Compare the proportion of adverse events

**Time Frame:** 30-day follow-up period

**Description:** Appearance of positive C. difficile toxin or positive C. difficile PCR

**Measure:** compare the occurrence of Clostridium difficile infection

**Time Frame:** 30-day follow-up period

**Description:** such as KPC, NDM, VIM, IMP, OXA or EVR-producing CLD, detected in both clinical and surveillance samples

**Measure:** compare the occurrence of new multidrug-resistant microorganisms

**Time Frame:** 30-day follow-up period

### Eligibility Module

**Eligibility Criteria:** 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 Age:** 18 Years

**Sampling Method:** NON_PROBABILITY_SAMPLE

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

**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).

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** mariana.vaena@hospitalitaliano.org.ar

**Name:** Mariana Vaena, MD

**Phone:** 5493624628553

**Role:** CONTACT

#### Overall Officials

**Official 1:**

**Affiliation:** Hospital Italiano de Buenos Aires

**Name:** Ivan Huespe, MD, MPh

**Role:** STUDY_DIRECTOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

**Citation:** van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae. Virulence. 2017 May 19;8(4):460-469. doi: 10.1080/21505594.2016.1222343. Epub 2016 Aug 11.

**PMID:** 27593176

**Citation:** Zhou R, Fang X, Zhang J, Zheng X, Shangguan S, Chen S, Shen Y, Liu Z, Li J, Zhang R, Shen J, Walsh TR, Wang Y. Impact of carbapenem resistance on mortality in patients infected with Enterobacteriaceae: a systematic review and meta-analysis. BMJ Open. 2021 Dec 14;11(12):e054971. doi: 10.1136/bmjopen-2021-054971.

**PMID:** 34907071

**Citation:** Lee YL, Ko WC, Hsueh PR. Geographic patterns of global isolates of carbapenem-resistant Klebsiella pneumoniae and the activity of ceftazidime/avibactam, meropenem/vaborbactam, and comparators against these isolates: Results from the Antimicrobial Testing Leadership and Surveillance (ATLAS) program, 2020. Int J Antimicrob Agents. 2022 Nov-Dec;60(5-6):106679. doi: 10.1016/j.ijantimicag.2022.106679. Epub 2022 Oct 12.

**PMID:** 36241011

**Citation:** Tsolaki V, Mantzarlis K, Mpakalis A, Malli E, Tsimpoukas F, Tsirogianni A, Papagiannitsis C, Zygoulis P, Papadonta ME, Petinaki E, Makris D, Zakynthinos E. Ceftazidime-Avibactam To Treat Life-Threatening Infections by Carbapenem-Resistant Pathogens in Critically Ill Mechanically Ventilated Patients. Antimicrob Agents Chemother. 2020 Feb 21;64(3):e02320-19. doi: 10.1128/AAC.02320-19. Print 2020 Feb 21.

**PMID:** 31818820

**Citation:** El Nekidy WS, Al Ali M, Abidi E, Ghazi IM, Attallah N, El Lababidi R, Mooty M, Ghosn M, Mallat J. Microbiologic outcomes of ceftazidime-avibactam dosing in patients with sepsis utilizing renal replacement therapies. Hemodial Int. 2023 Jul;27(3):289-295. doi: 10.1111/hdi.13090. Epub 2023 May 5.

**PMID:** 37144742

**Citation:** Caston JJ, Cano A, Perez-Camacho I, Aguado JM, Carratala J, Ramasco F, Soriano A, Pintado V, Castelo-Corral L, Sousa A, Farinas MC, Munoz P, Abril Lopez De Medrano V, Sanz-Pelaez O, Los-Arcos I, Gracia-Ahufinger I, Perez-Nadales E, Vidal E, Doblas A, Natera C, Martinez-Martinez L, Torre-Cisneros J. Impact of ceftazidime/avibactam versus best available therapy on mortality from infections caused by carbapenemase-producing Enterobacterales (CAVICOR study). J Antimicrob Chemother. 2022 Apr 27;77(5):1452-1460. doi: 10.1093/jac/dkac049.

**PMID:** 35187577

**Citation:** Zheng G, Cai J, Zhang L, Chen D, Wang L, Qiu Y, Deng H, Bai H, Bian X, He J. Ceftazidime/Avibactam-Based Versus Polymyxin B-Based Therapeutic Regimens for the Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infection in Critically Ill Patients: A Retrospective Cohort Study. Infect Dis Ther. 2022 Oct;11(5):1917-1934. doi: 10.1007/s40121-022-00682-0. Epub 2022 Aug 17.

**PMID:** 35976531

**Citation:** Qu J, Xu J, Liu Y, Hu C, Zhong C, Lv X. Real-world effectiveness of ceftazidime/avibactam versus polymyxin B in treating patients with carbapenem-resistant Gram-negative bacterial infections. Int J Antimicrob Agents. 2023 Aug;62(2):106872. doi: 10.1016/j.ijantimicag.2023.106872. Epub 2023 May 27.

**PMID:** 37247645

**Citation:** Yang P, Li Y, Wang X, Chen N, Lu X. Efficacy and safety of ceftazidime-avibactam versus polymyxins in the treatment of carbapenem-resistant Enterobacteriaceae infection: a systematic review and meta-analysis. BMJ Open. 2023 May 3;13(5):e070491. doi: 10.1136/bmjopen-2022-070491.

**PMID:** 37137556

**Citation:** Nagvekar V, Shah A, Unadkat VP, Chavan A, Kohli R, Hodgar S, Ashpalia A, Patil N, Kamble R. Clinical Outcome of Patients on Ceftazidime-Avibactam and Combination Therapy in Carbapenem-resistant Enterobacteriaceae. Indian J Crit Care Med. 2021 Jul;25(7):780-784. doi: 10.5005/jp-journals-10071-23863.

**PMID:** 34316172

**Citation:** Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, Humphries RM, Spellberg B, Hujer KM, Marshall EK, Rudin SD, Perez F, Wilson BM, Wasserman RB, Chikowski L, Paterson DL, Vila AJ, van Duin D, Kreiswirth BN, Chambers HF, Fowler VG Jr, Jacobs MR, Pulse ME, Weiss WJ, Bonomo RA. Can Ceftazidime-Avibactam and Aztreonam Overcome beta-Lactam Resistance Conferred by Metallo-beta-Lactamases in Enterobacteriaceae? Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02243-16. doi: 10.1128/AAC.02243-16. Print 2017 Apr.

**PMID:** 28167541

**Citation:** Falcone M, Daikos GL, Tiseo G, Bassoulis D, Giordano C, Galfo V, Leonildi A, Tagliaferri E, Barnini S, Sani S, Farcomeni A, Ghiadoni L, Menichetti F. Efficacy of Ceftazidime-avibactam Plus Aztreonam in Patients With Bloodstream Infections Caused by Metallo-beta-lactamase-Producing Enterobacterales. Clin Infect Dis. 2021 Jun 1;72(11):1871-1878. doi: 10.1093/cid/ciaa586.

**PMID:** 32427286

**Citation:** Hoffman KL, Schenck EJ, Satlin MJ, Whalen W, Pan D, Williams N, Diaz I. Comparison of a Target Trial Emulation Framework vs Cox Regression to Estimate the Association of Corticosteroids With COVID-19 Mortality. JAMA Netw Open. 2022 Oct 3;5(10):e2234425. doi: 10.1001/jamanetworkopen.2022.34425.

**PMID:** 36190729

**Citation:** Huttner A, Albrich WC, Bochud PY, Gayet-Ageron A, Rossel A, Dach EV, Harbarth S, Kaiser L. PIRATE project: point-of-care, informatics-based randomised controlled trial for decreasing overuse of antibiotic therapy in Gram-negative bacteraemia. BMJ Open. 2017 Jul 13;7(7):e017996. doi: 10.1136/bmjopen-2017-017996.

**PMID:** 28710229

**Citation:** Tingsgard S, Bastrup Israelsen S, Ostergaard C, Benfield T. Emulating a Target Trial of Shorter Compared to Longer Course of Antibiotic Therapy for Gram-Negative Bacteremia. Clin Infect Dis. 2024 Feb 17;78(2):292-300. doi: 10.1093/cid/ciad670.

**PMID:** 37949816

#### See Also Links

**Label:** Global antimicrobial resistance and use surveillance system (GLASS) report: 2022. World Health Organization; 9 Dec 2022 \[cited 3 Oct 2023\].

**URL:** https://www.who.int/publications/i/item/9789240062702

**Label:** Surveillance of antimicrobial resistance in Europe 2017. In: European Centre for Disease Prevention and Control

**URL:** https://www.ecdc.europa.eu/en/publications-data/surveillance-antimicrobial-resistance-europe-2017

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000001424

- Term: Bacterial Infections

- ID: D000001423

- Term: Bacterial Infections and Mycoses

- ID: D000007239

- Term: Infections

- ID: D000018805

- Term: Sepsis

- ID: D000018746

- Term: Systemic Inflammatory Response Syndrome

- ID: D000007249

- Term: Inflammation

- ID: D000010335

- Term: Pathologic Processes

### Condition Browse Module - Browse Branches

- Abbrev: BC01

- Name: Infections

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

### Condition Browse Module - Browse Leaves

- ID: M18877

- Name: Bacteremia

- Relevance: HIGH

- As Found: Bacteremia

- ID: M10283

- Name: Infections

- Relevance: LOW

- As Found: Unknown

- ID: M6368

- Name: Communicable Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M4722

- Name: Bacterial Infections

- Relevance: LOW

- As Found: Unknown

- ID: M12136

- Name: Mycoses

- Relevance: LOW

- As Found: Unknown

- ID: M4721

- Name: Bacterial Infections and Mycoses

- Relevance: LOW

- As Found: Unknown

- ID: M20864

- Name: Sepsis

- Relevance: LOW

- As Found: Unknown

- ID: M16869

- Name: Toxemia

- Relevance: LOW

- As Found: Unknown

- ID: M16355

- Name: Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M20818

- Name: Systemic Inflammatory Response Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M10293

- Name: Inflammation

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000016470

- Term: Bacteremia

### Intervention Browse Module - Browse Branches

- Abbrev: Infe

- Name: Anti-Infective Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M4222

- Name: Anti-Bacterial Agents

- Relevance: LOW

- As Found: Unknown

- ID: M1889

- Name: Meropenem

- Relevance: LOW

- As Found: Unknown

- ID: M3924

- Name: Amikacin

- Relevance: LOW

- As Found: Unknown

- ID: M5692

- Name: Ceftazidime

- Relevance: LOW

- As Found: Unknown

- ID: M4224

- Name: Antibiotics, Antitubercular

- Relevance: LOW

- As Found: Unknown

- ID: M8951

- Name: Gentamicins

- Relevance: LOW

- As Found: Unknown

- ID: M6319

- Name: Colistin

- Relevance: LOW

- As Found: Unknown

- ID: M99884

- Name: Avibactam, ceftazidime drug combination

- Relevance: LOW

- As Found: Unknown

- ID: M233142

- Name: Avibactam

- Relevance: LOW

- As Found: Unknown

- ID: M8700

- Name: Fosfomycin

- Relevance: LOW

- As Found: Unknown

- ID: M1948

- Name: Tigecycline

- Relevance: LOW

- As Found: Unknown

- ID: M4696

- Name: Aztreonam

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
