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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Carbapenem Resistant Bacterial Infection, Acinetobacter Bacteremia, Acinetobacter Pneumonia

Intervention / Treatment
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* Drug: Cefiderocol
* Drug: Ampicillin-sulbactam
* Drug: Colistin
* Drug: Meropenem


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Controlled clinical study with historical controls
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cefiderocol + ampicillin-sulbactam<br>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. | Drug: Cefiderocol<br>* Test drug regimen<br>* Other names: Fetroja;Drug: Ampicillin-sulbactam<br>* Synergistic combination<br>* Other names: Unasyn;|
| Active Comparator: Colistin or colistin + meropenem<br>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. | Drug: Colistin<br>* Historical comparator<br>Drug: Meropenem<br>* Historical comparator synergistic combination<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause mortality | Death from any cause | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All cause mortality | Death from any cause | 14 days | 
| Clinical failure | Composite of: Death Systolic blood pressure ≤90 mmHg or need for vasopressor support Worsening sequential organ failure assessment score (SOFA) score, define as: for baseline SOFA ≥ 3: stable or increased for baseline SOFA <3: any increase For patients with hospital-acquired pneumonia (HAP)/ ventilator-associated pneumonia (VAP), partial pressure of oxygen in arterial blood (PaO2)/ fraction of inspired oxygen (FiO2) ratio worsened For patients with bacteremia, growth of the initial isolate in blood cultures after ≥ 5 days since study treatment start | 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 |