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| Name | Class |
|---|---|
| Monaldi Hospital | OTHER |
| Rutgers Robert Wood Johnson Medical School | OTHER |
| Pisa University Hospital | UNKNOWN |
| Assaf-Harofeh Medical Center |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cefiderocol + ampicillin-sulbactam | Experimental | 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. |
|
| Colistin or colistin + meropenem | Active Comparator | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cefiderocol | Drug | Test drug regimen |
|
| Measure | Description | Time Frame |
|---|---|---|
| All cause mortality | Death from any cause | 28 days |
| Measure | Description | Time Frame |
|---|---|---|
| All cause mortality | Death from any cause | 14 days |
| Clinical failure | Composite of:
|
| 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 |
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:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Mical Paul | Contact | 0502062140 | paulm@technion.ac.il | |
| Marco Falcone | Contact | marco.falcone@unipi.it |
| Name | Affiliation | Role |
|---|---|---|
| Marco Falcone | Pisa University Hospital | Principal Investigator |
| Dafna Yahav | Sheba Medical Center | Principal Investigator |
| Mical Paul |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Rambam Health Care Campus | Recruiting | Haifa | Israel |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37538951 | Background | 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. | |
| 29456043 |
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Protocol will be published. At the end of the study the database will be made available from the lead author.
As soon as published
Justification to lead author
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| OTHER_GOV |
| Sheba Medical Center | OTHER_GOV |
Controlled clinical study with historical controls
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| Ampicillin-sulbactam | Drug | Synergistic combination |
|
|
| Colistin | Drug | Historical comparator |
|
| Meropenem | Drug | Historical comparator synergistic combination |
|
| Day 10-14 |
| 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 |
| 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 |
| 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 |
| 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 |
| Rambam Health Care Campus |
| Principal Investigator |
| Sheba Tel HaShomer Medical Campus | Recruiting | Ramat Gan | Israel |
|
| Shamir Medical Center (Assaf Harofeh) | Recruiting | Tel Aviv | Israel |
|
| Result |
| 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. |
| ID | Term |
|---|---|
| D000097602 | Cefiderocol |
| C035444 | sultamicillin |
| D003091 | Colistin |
| D000077731 | Meropenem |
| ID | Term |
|---|---|
| D002511 | Cephalosporins |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013843 | Thiazines |
| D013457 | Sulfur Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D011113 | Polymyxins |
| D010456 | Peptides, Cyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D055666 | Lipopeptides |
| D008055 | Lipids |
| D023181 | Antimicrobial Cationic Peptides |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000089882 | Antimicrobial Peptides |
| D052899 | Pore Forming Cytotoxic Proteins |
| D008565 | Membrane Proteins |
| D011506 | Proteins |
| D013845 | Thienamycins |
| D015780 | Carbapenems |
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