Cefiderocol and Ampicillin-sulbactam vs. Colistin +/- Meropenem for Carbapenem Resistant A. Baumannii
- Conditions
- Carbapenem Resistant Bacterial InfectionAcinetobacter BacteremiaAcinetobacter Pneumonia
- Interventions
- Registration Number
- NCT05922124
- Lead Sponsor
- Rambam Health Care Campus
- 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 734
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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cefiderocol + ampicillin-sulbactam Cefiderocol 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. Cefiderocol + ampicillin-sulbactam Ampicillin-sulbactam 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 Colistin 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. Colistin or colistin + meropenem Meropenem 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.
- Primary Outcome Measures
Name Time Method All cause mortality 28 days Death from any cause
- Secondary Outcome Measures
Name Time Method 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.
Adverse event - renal failure 28 days 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.)
Resistance development to cefiderocol 28 days 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
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
Clinical failure Day 10-14 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 startHospital stay 28 days Among 28-day survivors
Adverse event - Acute liver injury 28 days 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.
All cause mortality 14 days Death from any cause