Multicenter Open-label Randomized Controlled Trial (RCT) to Compare Colistin Alone Versus Colistin Plus Meropenem

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the addition of meropenem to colistin is better than colistin alone in the treatment of clinically significant infections caused by multi-drug resistant bacteria

Official Title
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Multicenter Open-label RCT to Compare Colistin Alone vs. Colistin Plus Meropenem

Conditions
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Gram-Negative Bacterial Infections

Intervention / Treatment
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* Drug: Colistin
* Drug: Meropenem


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult inpatients Clinically significant, microbiological-documented infection caused by carbapenem-resistant and colistin-susceptible Gram-negative bacteria and identified according to CDC criteria- blood stream infections, hospital acquired pneumonia, ventilator associated pneumonia, and urinary tract infections Patient recruitment will occur only after microbiological documentation and susceptibility testing. Patients will be included within 96 hours of the time the index culture was taken (typically within 48 hours of isolate identification), regardless of the antibiotic treatment administered during this time period. Exclusion Criteria: Previous inclusion in the trial. Patients will be included in the RCT only once for the first identified episode of infection Pregnant women Epilepsy or prior seizures Known allergy to colistin or a carbapenem

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colistin and Meropenem<br>IV meropenem, 2 gram q8h, adjusted for renal function IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function | Drug: Colistin<br>* IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function, for 10 days.<br>* Other names: Coliracin;Drug: Meropenem<br>* IV meropenem, 2 gram q8h, adjusted for renal function, for up to 10 days.<br>* Other names: Meronem;|
| Active Comparator: Colistin<br>IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function | Drug: Colistin<br>* IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function, for 10 days.<br>* Other names: Coliracin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical success | defined as a composite of all of the following, all measured at 14 days: Patient alive Systolic blood pressure >90 mmHg without need for vasopressor support Stable or improved SOFA score, define as: for baseline SOFA ≥ 3: a decrease of at least 30%; for baseline SOFA <3: stable or decreased SOFA score For patients with HAP/ VAP, PaO2/FiO2 ratio stable or improved For patients with bacteremia, no growth of the initial isolate in blood cultures taken on day 14 if patient still febrile | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary outcomes and adverse events | 14 and 28-day all-cause mortality. If patients are discharged or death occurs before end of follow-up (day 28), we will end data collection at that date. We will attempt to determine survival status at day 28 for all patients (central registry in Israel; re-admissions, rehabilitation centers, hospital transfers in Greece and Italy). | 14 and 28 days | 
| Clinical success with modification | Clinical success, but with modification to the antibiotic treatment not permitted by protocol | 14 days | 
| Time to defervescence | defined as time to reach a temperature of <38°C with no recurrence for 3 days | 28 days | 
| Time to weaning | Time to weaning from mechanical ventilation in VAP for patients weaned alive | 28 days | 
| Time to hospital discharge | Time to hospital discharge for patient discharged alive | 28 days | 
| Microbiological failure | Microbiological failure, defined as isolation of the initial isolate (phenotypically identical) in a clinical sample (blood or other) 7 days or more after start of treatment or its identification in respiratory samples. For all patients with VAP/ HAP sputum or tracheal aspirates will be obtained on day 7, regardless of clinical response For all patients with UTI, a repeat urine culture will be obtained on day 7, regardless of clinical response For patients with bacteremia, blood cultures will be repeated on day 7 and 14, only if the patient is febrile at that time | 28 days | 
| Superinfections | Defined as a new clinically or microbiologically-documented infections by CDC criteria within 28 days | 28 days | 
| New resistant infection | Colonization or infection by newly-acquired (other species than the initial infection) carbapenem-resistant or colistin-resistant Gram-negative bacteria. Colonization will be assessed by rectal surveillance | 28 days | 
| CDAD | Clostridium-difficile-associated diarrhea, defined by diarrhea with a positive C. difficile toxin test | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gram-Negative Bacterial Infections, Resistant Bacteria, Drug Resistance, Bacterial, Colistin