Cefiderocol and Ampicillin-sulbactam vs. Colistin +/- Meropenem for Carbapenem Resistant A. Baumannii (CASCADE)

Cefiderocol and Ampicillin-sulbactam vs. Colistin or Colistin-meropenem for Carbapenem Resistant Acinetobacter Baumannii Bacteremia or Hospital-acquired Pneumonia: Controlled Clinical Study With Historical Controls (CASCADE)

Patients with bloodstream infections, hospital acquired pneumonia or ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB) treated with cefiderocol combined with ampicillin sulbactam will be compared to patients treated treated with colistin alone or colistin combined with meropenem.

Study Overview

• Status: Recruiting
• Conditions: Carbapenem Resistant Bacterial Infection; Acinetobacter Bacteremia; Acinetobacter Pneumonia
• Intervention / Treatment: Drug: Cefiderocol; Drug: Ampicillin-sulbactam; Drug: Colistin; Drug: Meropenem

Detailed Description

This will be a prospective controlled clinical study with historical controls.

In the prospective CASCADE study consecutive consenting patients with bloodstream infections, hospital acquired pneumonia or ventilator-associated pneumonia will be treated with cefiderocol combined with ampicillin sulbactam in 3 hospitals in Israel and 2 hospitals in Italy, all endemic for CRAB. We plan to recruit 150 patients into this prospective studies.

The CASCADE cohort will be compared to patients treated for the same types of infection in two recently completed randomized controlled trials (AIDA and OVERCOME). These trials compared between treatment with colistin vs. treatment with colistin-meropenem combination therapy, both finding no difference between treatment groups among patients with carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia. Thus, patients in CASCADE will be compared to all patients with CRAB bloodstream infections, hospital acquired pneumonia or ventilator-associated pneumonia in these randomized controlled trials.

• Study Type: Interventional
• Enrollment (Estimated): 734
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Marco Falcone; Email: marco.falcone@unipi.it
• Study Contact Backup: Name: Mical Paul; Phone Number: 0502062140; Email: paulm@technion.ac.il

Study Locations

• Israel
  • Haifa, Israel
    • Recruiting
    • Rambam Health Care Campus
    • Contact: Mical Paul, MD; Email: m_paul@rambam.health.gov.il
    • Principal Investigator: Mical Paul, MD
  • Ramat Gan, Israel
    • Recruiting
    • Sheba Tel HaShomer Medical Campus
    • Contact: Dafna Dahav, MD
    • Principal Investigator: Dafna Yahav, MD
  • Tel Aviv, Israel
    • Recruiting
    • Shamir Medical Center (Assaf Harofeh)
    • Contact: Dror Marchaim

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Adults >18 years with bacteremia or hospital-acquired pneumonia (HAP)/ ventilator-associated pneumonia (VAP) (Table 3) caused by carbapenem-resistant A. baumannii (CRAB) (meropenem and/ or imipenem minimal inhibitory concentration (MIC) >8 μg/mL) susceptible to cefiderocol (disc zone diameter >=17 mm, corresponding to an MIC <2 μg/mL). We will include CRAB regardless of colistin, ampicillin-sulbactam, minocycline, tigecycline, trimethoprim/sulfamethoxazole and/or aminoglycoside susceptibility of the isolate. Attribution of the HAP/ VAP to CRAB will be allowed with isolation of CRAB from any respiratory sample within 7 days prior to the clinical diagnosis of pneumonia.

Exclusion Criteria:

• More than 72 hours of therapy with in-vitro coverage against the CRAB within 96 hours of enrolment
• Polymicrobial carbapenem-susceptible infections: growth of other pathogens susceptible to carbapenems, or another beta-lactam, deemed clinically-significant by the treating physicians in blood or sputum (with HAP/ VAP). We will allow recruitment of patients with other carbapenem-resistant Gram-negative bacteria
• CRAB susceptible any beta-lactam other than cefiderocol
• Coronavirus 2019 (COVID-19) co-infection
• Immediate-type hypersensitivity to penicillin
• Pregnant women
• Previous participation in the trial
• Lack of informed consent, considering the procedures acceptable to ethics committees per locale, including deferred consent
• Infection requiring treatment for over 14 days, at the discretion of the investigators
• Life expectancy less than 24 hours or expected futility of antibiotic treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cefiderocol + ampicillin-sulbactam; Cefiderocol 2 gram intravenous (IV) q8 hours and ampicillin-sulbactam 3 gram IV q6 hours for patients with normal creatinine clearance, both administered as extended infusion of 3 hours. Dosing adjusted according to reduced and augmented renal clearance and to renal replacement therapies.	Drug: Cefiderocol; Test drug regimen; Other Names: Fetroja; Drug: Ampicillin-sulbactam; Synergistic combination; Other Names: Unasyn
Active Comparator: Colistin or colistin + meropenem; Colistin 9 million units (MIU) intravenous (IV) loading dose followed by 4.5 MIU for patients with normal creatinine clearance +/- meropenem 2 gram IV administered as extended infusion of 3 hours. Dosing adjusted according to reduced and augmented renal clearance and to renal replacement therapies.	Drug: Colistin; Historical comparator; Drug: Meropenem; Historical comparator synergistic combination

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All cause mortality	Death from any cause	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All cause mortality	Death from any cause	14 days
Microbiological failure	Isolation of the initial isolate (phenotypically identical) in blood cultures 5 days or more after start of treatment or in respiratory samples 7 days or more.	Day 5-7
Hospital stay	Among 28-day survivors	28 days
Decline in functional capacity	Functional capacity will be assessed in four categories: independent; requires some assistance; requires assistance for activities of daily living (ADL); and bedridden. Decline in functional capacity will be defined as any 1-category worsening.	28 days
Adverse event - Clostridiodes difficile infection	Diarrhea with a positive C. difficile toxin test	28 days
Clinical failure	Composite of: Death; Systolic blood pressure ≤90 mmHg or need for vasopressor support; Worsening sequential organ failure assessment score (SOFA) score, define as:for baseline SOFA ≥ 3: stable or increasedfor baseline SOFA <3: any increase; For patients with hospital-acquired pneumonia (HAP)/ ventilator-associated pneumonia (VAP), partial pressure of oxygen in arterial blood (PaO2)/ fraction of inspired oxygen (FiO2) ratio worsened; For patients with bacteremia, growth of the initial isolate in blood cultures after ≥ 5 days since study treatment start	Day 10-14
Resistance development to cefiderocol	Development of carbapenemase-producing Enterobacterales (CPE), non-CPE carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant A. baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) resistance to cefiderocol in clinical and surveillance cultures collected as defined in the study's protocol	28 days
Adverse event - renal failure	Renal failure due to any reason using the RIFLE ( risk, injury, failure, loss, End stage kidney disease) criteria (classifying patients to None, Risk, Injury, Failure, Loss and ESRD) at day 14 and day 28 and defined as worsening by two RIFLE categories (e.g. from Risk to Failure, etc.)	28 days
Adverse event - Acute liver injury	Increase in aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3-fold or increased bilirubin >2 above upper limits of normal (ULN) or baseline value if higher than ULN.	28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Desirability of Outcome Ranking (DOOR)	Defined DOOR outcome analysis: Alive no event; Alive 1 event; Alive 2 events; Alive 3 events; Dead. The DOOR events will be: (1) Clinical failure as defined above (2) Hospital stay >14 days from enrolment (3) Adverse events: renal failure, Clostridiodes difficile infection or acute liver injury	28 days

Collaborators and Investigators

• Sponsor: Rambam Health Care Campus
• Collaborators: Assaf-Harofeh Medical Center; Sheba Medical Center; Monaldi Hospital; Rutgers Robert Wood Johnson Medical School; Pisa University Hospital
• Investigators: Principal Investigator: Marco Falcone, Pisa University Hospital; Principal Investigator: Dafna Yahav, Sheba Medical Center; Principal Investigator: Mical Paul, Rambam Health Care Campus

Publications and helpful links

General Publications

• Kaye KS, Marchaim D, Thamlikitkul V, Carmeli Y, Chiu CH, Daikos G, Dhar S, Durante-Mangoni E, Gikas A, Kotanidou A, Paul M, Roilides E, Rybak M, Samarkos M, Sims M, Tancheva D, Tsiodras S, Kett D, Patel G, Calfee D, Leibovici L, Power L, Munoz-Price S, Stevenson K, Susick L, Latack K, Daniel J, Chiou C, Divine GW, Ghazyaran V, Pogue JM. Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms. NEJM Evid. 2023 Jan;2(1):10.1056/evidoa2200131. doi: 10.1056/evidoa2200131. Epub 2022 Dec 6.
• Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, Skiada A, Andini R, Eliakim-Raz N, Nutman A, Zusman O, Antoniadou A, Pafundi PC, Adler A, Dickstein Y, Pavleas I, Zampino R, Daitch V, Bitterman R, Zayyad H, Koppel F, Levi I, Babich T, Friberg LE, Mouton JW, Theuretzbacher U, Leibovici L. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 2018 Apr;18(4):391-400. doi: 10.1016/S1473-3099(18)30099-9. Epub 2018 Feb 16.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: May 31, 2023
• First Submitted That Met QC Criteria: June 18, 2023
• First Posted (Actual): June 28, 2023

Study Record Updates

• Last Update Posted (Actual): August 1, 2025
• Last Update Submitted That Met QC Criteria: July 29, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Infections; Infections; Respiratory Tract Diseases; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Lung Diseases; Bacterial Infections and Mycoses; Pneumonia; Bacteremia; Bacterial Infections; Beta Lactam Antibiotics; Anti-Bacterial Agents; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Chelating Agents; Sequestering Agents; beta-Lactamase Inhibitors; Siderophores; Iron Chelating Agents; Meropenem; Cefiderocol; Colistin; Ampicillin; Sulbactam; Sultamicillin
• Other Study ID Numbers: V0.1 May 2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Protocol will be published. At the end of the study the database will be made available from the lead author.
• IPD Sharing Time Frame: As soon as published
• IPD Sharing Access Criteria: Justification to lead author
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes