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

NCT ID: NCT05922124

Last Updated: 2025-08-01

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 734 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-09-01
• Study Completion Date: 2026-09-30

Brief 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 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.

Conditions

Carbapenem Resistant Bacterial Infection; Acinetobacter Bacteremia; Acinetobacter Pneumonia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Cefiderocol

Intervention Type: DRUG

Test drug regimen

Ampicillin-sulbactam

Intervention Type: DRUG

Synergistic combination

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.

Group Type: ACTIVE_COMPARATOR

Colistin

Intervention Type: DRUG

Historical comparator

Meropenem

Intervention Type: DRUG

Historical comparator synergistic combination

Interventions

Cefiderocol

Test drug regimen

Intervention Type: DRUG

Ampicillin-sulbactam

Synergistic combination

Intervention Type: DRUG

Colistin

Historical comparator

Intervention Type: DRUG

Meropenem

Historical comparator synergistic combination

Intervention Type: DRUG

Other Intervention Names

Fetroja; Unasyn

Eligibility Criteria

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

• Minimum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Monaldi Hospital

OTHER

Sponsor Role: collaborator

Rutgers Robert Wood Johnson Medical School

OTHER

Sponsor Role: collaborator

Pisa University Hospital

UNKNOWN

Sponsor Role: collaborator

Assaf-Harofeh Medical Center

OTHER_GOV

Sponsor Role: collaborator

Sheba Medical Center

OTHER_GOV

Sponsor Role: collaborator

Rambam Health Care Campus

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marco Falcone

Role: PRINCIPAL_INVESTIGATOR

Pisa University Hospital

Dafna Yahav

Role: PRINCIPAL_INVESTIGATOR

Sheba Medical Center

Mical Paul

Role: PRINCIPAL_INVESTIGATOR

Rambam Health Care Campus

Locations

Rambam Health Care Campus

Haifa, , Israel

Site Status: RECRUITING

Sheba Tel HaShomer Medical Campus

Ramat Gan, , Israel

Site Status: RECRUITING

Shamir Medical Center (Assaf Harofeh)

Tel Aviv, , Israel

Site Status: RECRUITING

Countries

Israel

Central Contacts

Mical Paul

Role: CONTACT

paulm@technion.ac.il

0502062140

Marco Falcone

Role: CONTACT

marco.falcone@unipi.it

Facility Contacts

Mical Paul, MD

Role: primary

m_paul@rambam.health.gov.il

Dafna Dahav, MD

Role: primary

Dror Marchaim

Role: primary

References

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.

Reference Type: BACKGROUND

PMID: 29456043 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 37538951 (View on PubMed)

Other Identifiers

V0.1 May 2023

Identifier Type: -

Identifier Source: org_study_id