Short Infusion Versus Prolonged Infusion of Ceftolozane-tazobactam Among Patients With Ventilator Associated-pneumonia

Study Overview
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Brief Summary
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The main objective of this study is to compare the median exposures at pharmacokinetic equilibrium of the two modalities of administration: 4-hours infusion of ceftolozane-tazobactam at a dosage of 2 gram three times a day vs 1-hour infusion of 2 gram three times a day.

Detailed Description
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Intensive care unit patients with ventilator associated-pneumonia often develop severe and rapidly life threatening Gram-negative Bacillus infections. Moreover, they present pathophysiological disturbances responsible for major pharmacokinetic changes (volume of distribution and glomerular filtration) which may lead to drugs under-exposure. Any delay in management or inadequate antibiotic therapy can have serious consequences in terms of prognosis. The association ceftolozane-tazobactam is an alternative to carbapenems in documented infections. Ceftolozane is a new cephalosporin, marketed, in combination with tazobactam (beta-lactamase inhibitor) under the name ZERBAXA®. ZERBAXA® is active on Gram-negative Bacillus, including Pseudomonas aeruginosa. This is a prospective, randomized, open pharmacokinetic/pharmacodynamic study that compares two modalities of administration of a novel antibiotic, ZERBAXA® ceftolozane-tazobactam, by 4-hours infusion at the dosage of 2 gram three times a day vs. 1-hour infusion at the dosage of 2 g three times a day, among patients with ventilator associated-pneumonia to Pseudomonas aeruginosa. The patient will be randomized either in the 4-hours or in the 1-hour infusion group. Follow up visits are daily for any intensive care patient. Those provided for biomedical research are carried out during the treatment period, at Day 15 and Day 28. For the pharmacokinetic study, 7 blood samples will be collected from 24 hours to 48 hours after the first ZERBAXA® administration.

Official Title
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Comparison of Short Infusion Versus Prolonged Infusion of Ceftolozane-tazobactam Among Patients With Ventilator Associated-pneumonia to Pseudomonas Aeruginosa in Intensive Care Units

Conditions
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Ventilator-associated Pneumonia

Intervention / Treatment
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* Drug: 1 hour infusion
* Drug: 4 hours infusion


Participation Criteria
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Eligibility Criteria
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inclusion criteria patients with ventilator associated-pneumonia to Pseudomonas aeruginosa patients hospitalized in intensive care units Pseudomonas aeruginosa susceptible to ceftolozane-tazobactam Simplified Acute Physiological Score II (SAPS II () > 20 Expected duration of survival > 7 days Informed consent of the patient or, failing that, the patient's close or trustworthy person Affiliated to a social security scheme or equivalent Non inclusion criteria: history of allergy to one of the two molecules history of allergy to betalactamines Strain Isolated resistant to Ceftolozane-Tazobactam combination Renal insufficiency with a glomerular filtration rate evaluated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) < 50 ml/min Patient on dialysis or under continuous hemodiafiltration pregnant or nursing women patient benefiting from a system of legal protection for adults patient with active immunodepression.

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
Interventional Model Description: The patient will be randomized either in the 4-hours or in the 1-hour infusion group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 hour infusion<br>The first group corresponds to 1-hour infusion : First administration of ceftolozane-tazobactam with 2000 mg by infusion for 60 minutes every 8 hours. 24h after this first administration, 7 blood samples will be collected at Hour 24, Hour 25, Hour 26, Hour 28, Hour 30, Hour 32 and Hour 48. | Drug: 1 hour infusion<br>* Intravenous administration of ceftolozane-tazobactam (ZERBAXA®) : 2000 mg by infusion for 60 minutes every 8 hours.<br>* Other names: Zerbaxa 1 g/0.5 g powder;|
| Experimental: 4 hours infusion<br>The second group corresponds to 4-hours infusion: First administration of ceftolozane-tazobactam with 2000 mg by infusion for 4 hours every 8 hours. 24h after this first administration, 7 blood samples will be collected at Hour 24, Hour 25, Hour 26, Hour 28, Hour 30, Hour 32 and Hour 48. . | Drug: 4 hours infusion<br>* Intravenous administration of ceftolozane-tazobactam (ZERBAXA®) : 2000 mg by infusion for 4 hours every 8 hours<br>* Other names: Zerbaxa 1 g/0.5 g powder;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time that the concentration spends above 5 Minimum inhibitory Concentration (T>5*MIC) | The primary endpoint is the time that the concentration spends above 5* Minimum inhibitory Concentration, expressed as a percentage of the time interval between two administrations. The T>5* Minimum inhibitory Concentration will be determined for each patient from the concentration profile measured over an 8-hour post-administration interval. Since protein binding is low (<20%), the total concentration (sum of free form and plasma protein bound) will be used as a marker for free concentration. Therefore, the T>5* Minimum inhibitory Concentration will be calculated from the total concentrations. Our study will focus on only Pseudomonas aeruginosa Pneumonia acquired under mechanical ventilation with a critical Minimum inhibitory Concentration of 4 mg/l, T>5* Minimum inhibitory Concentration will then correspond to a residual serum concentration of 20 mg/l. | Time between two administrations (8 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with concentrations greater than 5*Minimum inhibitory Concentration | The percentage of patients with concentrations greater than 5*Minimum inhibitory Concentration over an 8-hour post administration interval. | Time between two administrations (8 hours) | 
| Bactericidal rate | Bactericidal rate obtained in vitro using the Hollow Fiber device. This rate is determined for broncho-alveolar concentrations estimated in patients with pneumonia acquired during ventilation | at Day 10 | 
| Percentage of patients recovering at the end of the treatment period | Number of patients recovering in relation to the total number of patients | at Day 10 | 
| Percentage of patients failing at the end of the treatment period | Number of patients failing in relation to the total number of patients | at Day 10 | 
| Number of days without artificial ventilation | The number of days without artificial ventilation | at Day 28 | 
| The duration of hospitalization | the duration of hospitalization in number of day | at Day 28 | 
| Survival at D28 | survival in number of patient alive | at Day 28 | 
| The alveolar concentration of Ceftolozane-Tazobactam | The alveolar concentration of Ceftolozane-Tazobactam from a sample of the alveolar fluid produced by bronchial fibroscopy between the 24th hour and the 48th hour | between 24 hour and 48 hour after time 0 | 
| Evaluation of the serious adverse events | Evaluation of the serious adverse events at the doses and regimen recommended in the trial | Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pneumonia, Pseudomonas aeruginosa, pharmacokinetics