CASCADE: Cefiderocol and Ampicillin-sulbactam vs. Colistin +/- Meropenem for Carbapenem Resistant A. Baumannii
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 4 |
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 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cefiderocol + ampicillin-sulbactam Cefiderocol 2 g IV q8h and ampicillin-sulbactam 3gr IV q6hr 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. |
Drug: Cefiderocol
Test drug regimen
Drug: Ampicillin-sulbactam
Synergistic combination
|
| Active Comparator: Colistin or colistin + meropenem Colistin 9 MIU IV loading dose followed by 4.5 MIU for patients with normal creatinine clearance +/- meropenem 2 g IV administered as extended infusion of 3 hours. Dosing adjusted according to reduced and augmented renal clearance and to renal replacement therapies. |
Drug: Colistin
Historical comparator
Drug: Meropenem
Historical comparator synergistic combination
|
Outcome Measures
Primary Outcome Measures
- All cause mortality [28 days]
Death from any cause
Secondary Outcome Measures
- All cause mortality [14 days]
Death from any cause
- Clinical failure [Day 10-14]
Composite of: Death Systolic blood pressure ≤90 mmHg or need for vasopressor support Worsening SOFA score, define as: for baseline SOFA ≥ 3: stable or increased for baseline SOFA <3: any increase For patients with HAP/VAP, PaO2/FiO2 ratio worsened For patients with bacteremia, growth of the initial isolate in blood cultures after ≥ 5 days since study treatment start
- Microbiological failure [Day 5-7]
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.
- Resistance development to cefiderocol [28 days]
Development of CPE, non-CPE CRE, CRAB and CRPA resistance to cefiderocol in clinical and surveillance cultures collected as defined in the study's protocol
- Hospital stay [28 days]
Among 28-day survivors
- Decline in functional capacity [28 days]
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.
- Adverse event - Clostridiodes difficile infection [28 days]
Diarrhea with a positive C. difficile toxin test
- Adverse event - renal failure [28 days]
Renal failure due to any reason using the RIFLE 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.)
- Adverse event - Acute liver injury [28 days]
Increase in AST or ALT > 3-fold or increased bilirubin >2 above upper limits of normal (ULN) or baseline value if higher than ULN.
Other Outcome Measures
- DOOR [28 days]
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, CDI or acute liver injury
Eligibility Criteria
Criteria
Inclusion Criteria:
Adults >18 years with bacteremia or HAP/VAP (Table 3) caused by CRAB (meropenem and/ or imipenem 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
-
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
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Rambam Health Care Campus
- Monaldi Hospital
- Rutgers Robert Wood Johnson Medical School
- Pisa University Hospital
- Assaf-Harofeh Medical Center
- Sheba Medical Center
Investigators
- Principal Investigator: Marco Falcone, Pisa University Hospital
- Principal Investigator: Dafna Yahav, Sheba Medical Center
- Principal Investigator: Mical Paul, Rambam Health Care Campus
Study Documents (Full-Text)
None provided.More Information
Publications
- V0.1 May 2023