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| ID | Type | Description | Link |
|---|---|---|---|
| 2018-000059-42 | EudraCT Number |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 hour infusion | Active Comparator | 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. |
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| 4 hours infusion | Experimental | 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. . |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 1 hour infusion | Drug | Intravenous administration of ceftolozane-tazobactam (ZERBAXA®) : 2000 mg by infusion for 60 minutes every 8 hours. |
|
| 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) |
| 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 |
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inclusion criteria
Non inclusion criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Stéphanie RUIZ, MD | Contact | 0561777032 | ruiz.s@chu-toulouse.fr | |
| Nathalie ROQUES | Contact | roques.n@chu-toulouse.fr |
| Name | Affiliation | Role |
|---|---|---|
| Stéphanie RUIZ, MD | University Hospital, Toulouse | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Service Réanimation Polyvalente - CHU Rangueil | Recruiting | Toulouse | 31059 | France |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27999665 | Background | Colomb-Cotinat M, Lacoste J, Brun-Buisson C, Jarlier V, Coignard B, Vaux S. Estimating the morbidity and mortality associated with infections due to multidrug-resistant bacteria (MDRB), France, 2012. Antimicrob Resist Infect Control. 2016 Dec 12;5:56. doi: 10.1186/s13756-016-0154-z. eCollection 2016. | |
| 27184564 | Background |
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| ID | Term |
|---|---|
| D053717 | Pneumonia, Ventilator-Associated |
| D011014 | Pneumonia |
| D011552 | Pseudomonas Infections |
| ID | Term |
|---|---|
| D000077299 | Healthcare-Associated Pneumonia |
| D003428 | Cross Infection |
| D007239 | Infections |
| D012141 | Respiratory Tract Infections |
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| ID | Term |
|---|---|
| C000594038 | ceftolozane, tazobactam drug combination |
| D011208 | Powders |
| ID | Term |
|---|---|
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
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The patient will be randomized either in the 4-hours or in the 1-hour infusion group
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| 4 hours infusion | Drug | Intravenous administration of ceftolozane-tazobactam (ZERBAXA®) : 2000 mg by infusion for 4 hours every 8 hours |
|
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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 |
| Vincent JL, Bassetti M, Francois B, Karam G, Chastre J, Torres A, Roberts JA, Taccone FS, Rello J, Calandra T, De Backer D, Welte T, Antonelli M. Advances in antibiotic therapy in the critically ill. Crit Care. 2016 May 17;20(1):133. doi: 10.1186/s13054-016-1285-6. |
| 26021991 | Background | Gelfand MS, Cleveland KO. Ceftolozane/Tazobactam Therapy of Respiratory Infections due to Multidrug-Resistant Pseudomonas aeruginosa. Clin Infect Dis. 2015 Sep 1;61(5):853-5. doi: 10.1093/cid/civ411. Epub 2015 May 28. No abstract available. |
| 27550351 | Background | Monogue ML, Pettit RS, Muhlebach M, Cies JJ, Nicolau DP, Kuti JL. Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6578-6584. doi: 10.1128/AAC.01566-16. Print 2016 Nov. |
| 26096377 | Background | Xiao AJ, Miller BW, Huntington JA, Nicolau DP. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Pharmacol. 2016 Jan;56(1):56-66. doi: 10.1002/jcph.566. Epub 2015 Aug 25. |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D007049 | Iatrogenic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D016905 | Gram-Negative Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |