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Carbapenem Resistant Bacterial InfectionPhase 4CASCADENCT05922124

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

A Phase 4 study testing Cefiderocol, Ampicillin-sulbactam and Colistin in people with Carbapenem Resistant Bacterial Infection and Acinetobacter Bacteremia, run by Rambam Health Care Campus at 3 sites in Israel.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 16 years and older
What is being tested?
Cefiderocol, Ampicillin-sulbactam and Colistin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
734 participants
Where
3 sitesIsrael
Study dates
1 Sep 2024to Sep 2026
Phase
Phase 4
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 10Show fewer
  • 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

Trial locations and contacts

3 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Mical Paul contact

0502062140

paulm@technion.ac.il

Marco Falcone contact

marco.falcone@unipi.it

Israel3 sites, 3 recruiting

  • Rambam Health Care Campus

    Haifa

    Mical Paul, MD, m_paul@rambam.health.gov.il

    Mical Paul, MD

    Recruiting

  • Sheba Tel HaShomer Medical Campus

    Ramat Gan

    Dafna Dahav, MD

    Dafna Yahav, MD

    Recruiting

  • Shamir Medical Center (Assaf Harofeh)

    Tel Aviv

    Dror Marchaim

    Recruiting

Other trials in Israel

About this study

Official title: 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.

Read the 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.

Being tested
Cefiderocol, Ampicillin-sulbactam, Colistin, Meropenem

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CefiderocolDrug

    Also called Fetroja

    Test drug regimen

  • Ampicillin-sulbactamDrug

    Also called Unasyn

    Synergistic combination

  • ColistinDrug

    Historical comparator

  • MeropenemDrug

    Historical comparator synergistic combination

Study groups in NCT05922124
Study groupRoleWhat they receive
Cefiderocol + ampicillin-sulbactamExperimentalCefiderocol 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.
Receives: Drug: Cefiderocol; Drug: Ampicillin-sulbactam
Colistin or colistin + meropenemActive comparatorColistin 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.
Receives: Drug: Colistin; Drug: Meropenem

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. All cause mortality

    Death from any cause

    Measured: 28 days

Secondary outcomes (9)

  1. All cause mortality

    Death from any cause

    Measured: 14 days

  2. 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 increased
    • for 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

    Measured: Day 10-14

  3. 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.

    Measured: Day 5-7

  4. 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

    Measured: 28 days

  5. Hospital stay

    Among 28-day survivors

    Measured: 28 days

  6. 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.

    Measured: 28 days

  7. Adverse event - Clostridiodes difficile infection

    Diarrhea with a positive C. difficile toxin test

    Measured: 28 days

  8. 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.)

    Measured: 28 days

  9. 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.

    Measured: 28 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Jun 2023
  2. Study start1 Sep 2024
  3. Primary completionJul 2026 (estimated)
  4. Study completionSep 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
Controlled clinical study with historical controls
Masking
None (open label)
Enrolment
734 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05922124
Sponsor's protocol ID
V0.1 May 2023
Acronym
CASCADE
Status last verified
Jul 2025
First submitted
31 May 2023
Last updated
1 Aug 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: Protocol will be published. At the end of the study the database will be made available from the lead author.

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.

    PubMed 37538951

  • 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.

    PubMed 29456043

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Cefiderocol, Ampicillin-sulbactam and Colistin in people with Carbapenem Resistant Bacterial Infection and Acinetobacter Bacteremia, run by Rambam Health Care Campus at 3 sites in Israel.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 1 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Mical Paul (0502062140, paulm@technion.ac.il), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

All cause mortality (time frame: 28 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05922124, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Aug 2025.

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