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

Overview

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.

Full Title of Study: “Comparison of Short Infusion Versus Prolonged Infusion of Ceftolozane-tazobactam Among Patients With Ventilator Associated-pneumonia to Pseudomonas Aeruginosa in Intensive Care Units”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: July 2021

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.

Interventions

  • Drug: 1 hour infusion
    • Intravenous administration of ceftolozane-tazobactam (ZERBAXA®) : 2000 mg by infusion for 60 minutes every 8 hours.
  • Drug: 4 hours infusion
    • Intravenous administration of ceftolozane-tazobactam (ZERBAXA®) : 2000 mg by infusion for 4 hours every 8 hours

Arms, Groups and Cohorts

  • 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.
  • 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. .

Clinical Trial Outcome Measures

Primary Measures

  • 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 Measures

  • 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.
  • 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
  • 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
  • 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
  • Number of days without artificial ventilation
    • Time Frame: at Day 28
    • The number of days without artificial ventilation
  • The duration of hospitalization
    • Time Frame: at Day 28
    • the duration of hospitalization in number of day
  • Survival at D28
    • Time Frame: at Day 28
    • survival in number of patient alive
  • 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
  • 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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University Hospital, Toulouse
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Stéphanie RUIZ, MD, Principal Investigator, University Hospital, Toulouse
  • Overall Contact(s)
    • Stéphanie RUIZ, MD, 33561777032, ruiz.s@chu-toulouse.fr

References

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, François 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. Review.

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.

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.

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