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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Ventilator-associated Pneumonia
• Intervention / Treatment: Drug: 1 hour infusion; Drug: 4 hours infusion

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.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Nathalie ROQUES; Email: roques.n@chu-toulouse.fr
• Study Contact Backup: Name: Stéphanie RUIZ, MD; Phone Number: 0561777032; Email: ruiz.s@chu-toulouse.fr

Study Locations

• France
  • Toulouse, France, 31059
    • Recruiting
    • Service Réanimation Polyvalente - CHU Rangueil
    • Contact: Stéphanie RUIZ, MD; Phone Number: 33 05 61 32 44 64; Email: Ruiz.stephanie@chu-toulouse.fr
    • Contact: Stéphanie RUIZ, MD
    • Contact: Bernard GEORGES, MD
    • Contact: Jean-Marie CONIL, MD
    • Contact: David ROUSSET

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Stéphanie RUIZ, MD, University Hospital, Toulouse

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2018
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: June 26, 2018
• First Submitted That Met QC Criteria: June 26, 2018
• First Posted (Actual): July 10, 2018

Study Record Updates

• Last Update Posted (Actual): September 25, 2024
• Last Update Submitted That Met QC Criteria: September 23, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Pneumonia; pharmacokinetics; Pseudomonas aeruginosa
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Ventilator-Associated; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Anti-Infective Agents, Urinary; Ceftolozane, tazobactam drug combination; Cephalosporins; Penicillanic Acid
• Other Study ID Numbers: RC 31/17/0334; 2018-000059-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No