Clinical trial NCT05922124: 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)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Carbapenem Resistant Bacterial Infection
Acinetobacter Bacteremia
Acinetobacter Pneumonia
Lead sponsor: Rambam Health Care Campus
Sponsor class: OTHER
Collaborators: name: Monaldi Hospital
name: Rutgers Robert Wood Johnson Medical School
name: Pisa University Hospital
name: Assaf-Harofeh Medical Center
name: Sheba Medical Center
First posted: 2023-06-28
Enrollment: 734
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Controlled clinical study with historical controls
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: All cause mortality
timeFrame: 28 days
Secondary outcomes:
measure: All cause mortality
timeFrame: 14 days
measure: Clinical failure
timeFrame: Day 10-14
measure: Microbiological failure
timeFrame: Day 5-7
measure: Resistance development to cefiderocol
timeFrame: 28 days
measure: Hospital stay
timeFrame: 28 days
measure: Decline in functional capacity
timeFrame: 28 days
measure: Adverse event - Clostridiodes difficile infection
timeFrame: 28 days
measure: Adverse event - renal failure
timeFrame: 28 days
measure: Adverse event - Acute liver injury
timeFrame: 28 days
Other outcomes:
measure: Desirability of Outcome Ranking (DOOR)
timeFrame: 28 days
Locations:
Study officials:
affiliation: Pisa University Hospital
name: Marco Falcone
role: PRINCIPAL_INVESTIGATOR
affiliation: Sheba Medical Center
name: Dafna Yahav
role: PRINCIPAL_INVESTIGATOR
affiliation: Rambam Health Care Campus
name: Mical Paul
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.