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

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ClinicalTrials.gov Identifier: NCT03581370
Recruitment Status : Recruiting
First Posted : July 10, 2018
Last Update Posted : March 3, 2021
Sponsor:
Information provided by (Responsible Party):
University Hospital, Toulouse

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Ventilator-associated Pneumonia Drug: 1 hour infusion Drug: 4 hours infusion Phase 3

Detailed Description:

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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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The patient will be randomized either in the 4-hours or in the 1-hour infusion group
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Comparison of Short Infusion Versus Prolonged Infusion of Ceftolozane-tazobactam Among Patients With Ventilator Associated-pneumonia to Pseudomonas Aeruginosa in Intensive Care Units
Actual Study Start Date : September 20, 2018
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : February 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Pneumonia
Drug Information available for: Tazobactam

Arm Intervention/treatment
Active Comparator: 1 hour infusion

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
Intravenous administration of ceftolozane-tazobactam (ZERBAXA®) : 2000 mg by infusion for 60 minutes every 8 hours.
Other Name: Zerbaxa 1 g/0.5 g powder

Experimental: 4 hours infusion

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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Drug: 4 hours infusion
Intravenous administration of ceftolozane-tazobactam (ZERBAXA®) : 2000 mg by infusion for 4 hours every 8 hours
Other Name: Zerbaxa 1 g/0.5 g powder




Primary Outcome Measures :
  1. Time that the concentration spends above 5 Minimum inhibitory Concentration (T>5*MIC) [ Time Frame: Time between two administrations (8 hours) ]
    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.


Secondary Outcome Measures :
  1. Percentage of patients with concentrations greater than 5*Minimum inhibitory Concentration [ Time Frame: Time between two administrations (8 hours) ]
    The percentage of patients with concentrations greater than 5*Minimum inhibitory Concentration over an 8-hour post administration interval.

  2. Bactericidal rate [ Time Frame: at Day 10 ]
    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

  3. Percentage of patients recovering at the end of the treatment period [ Time Frame: at Day 10 ]
    Number of patients recovering in relation to the total number of patients

  4. Percentage of patients failing at the end of the treatment period [ Time Frame: at Day 10 ]
    Number of patients failing in relation to the total number of patients

  5. Number of days without artificial ventilation [ Time Frame: at Day 28 ]
    The number of days without artificial ventilation

  6. The duration of hospitalization [ Time Frame: at Day 28 ]
    the duration of hospitalization in number of day

  7. Survival at D28 [ Time Frame: at Day 28 ]
    survival in number of patient alive

  8. The alveolar concentration of Ceftolozane-Tazobactam [ Time Frame: between 24 hour and 48 hour after time 0 ]
    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

  9. Evaluation of the serious adverse events [ Time Frame: Day 28 ]
    Evaluation of the serious adverse events at the doses and regimen recommended in the trial



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03581370


Contacts
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Contact: Stéphanie RUIZ, MD 33561777032 ruiz.s@chu-toulouse.fr
Contact: Nathalie ROQUES roques.n@chu-toulouse.fr

Locations
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France
Service Réanimation Polyvalente - CHU Rangueil Recruiting
Toulouse, France, 31059
Contact: Stéphanie RUIZ, MD    05 61 32 44 64 ext 33    Ruiz.stephanie@chu-toulouse.fr   
Sub-Investigator: Bernard GEORGES, MD         
Principal Investigator: Stéphanie RUIZ, MD         
Sub-Investigator: Jean-Marie CONIL, MD         
Sub-Investigator: David ROUSSET         
Sponsors and Collaborators
University Hospital, Toulouse
Investigators
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Principal Investigator: Stéphanie RUIZ, MD University Hospital, Toulouse
Publications:
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Responsible Party: University Hospital, Toulouse
ClinicalTrials.gov Identifier: NCT03581370    
Other Study ID Numbers: RC 31/17/0334
2018-000059-42 ( EudraCT Number )
First Posted: July 10, 2018    Key Record Dates
Last Update Posted: March 3, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital, Toulouse:
Pneumonia
Pseudomonas aeruginosa
pharmacokinetics
Additional relevant MeSH terms:
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Pneumonia
Pneumonia, Ventilator-Associated
Respiratory Tract Infections
Infections
Lung Diseases
Respiratory Tract Diseases
Healthcare-Associated Pneumonia
Cross Infection
Iatrogenic Disease
Disease Attributes
Pathologic Processes
Ceftolozane, tazobactam drug combination
Cephalosporins
Penicillanic Acid
Anti-Infective Agents, Urinary
Anti-Infective Agents
Renal Agents
Anti-Bacterial Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action