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

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)

Overview

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.

Interventions

• Drug Cefiderocol
  Test drug regimen
• Drug Ampicillin-sulbactam
  Synergistic combination
• Drug Colistin
  Historical comparator
• Drug Meropenem
  Historical comparator synergistic combination

Primary outcome measures

• All cause mortality [Time frame: 28 days]

Secondary outcome measures (9)

• All cause mortality [Time frame: 14 days]
• Clinical failure [Time frame: Day 10-14]
• Microbiological failure [Time frame: Day 5-7]
• Resistance development to cefiderocol [Time frame: 28 days]
• Hospital stay [Time frame: 28 days]
• Decline in functional capacity [Time frame: 28 days]
• Adverse event - Clostridiodes difficile infection [Time frame: 28 days]
• Adverse event - renal failure [Time frame: 28 days]
• Adverse event - Acute liver injury [Time frame: 28 days]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Israel · 3 centers

• Rambam Health Care Campus — Haifa
• Sheba Tel HaShomer Medical Campus — Ramat Gan
• Shamir Medical Center (Assaf Harofeh) — Tel Aviv

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 Carbapene PMID 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 b PMID 29456043

Identifiers

NCT: NCT05922124 · V0.1 May 2023

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗