Clinical trial NCT03581370: Short Infusion Versus Prolonged Infusion of Ceftolozane-tazobactam Among Patients with Ventilator Associated-pneumonia
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Ventilator-associated Pneumonia
Keywords: Pneumonia
Pseudomonas aeruginosa
pharmacokinetics
Lead sponsor: University Hospital, Toulouse
Sponsor class: OTHER
First posted: 2018-07-10
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The patient will be randomized either in the 4-hours or in the 1-hour infusion group
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Time that the concentration spends above 5 Minimum inhibitory Concentration (T>5*MIC)
timeFrame: Time between two administrations (8 hours)
Secondary outcomes:
measure: Percentage of patients with concentrations greater than 5*Minimum inhibitory Concentration
timeFrame: Time between two administrations (8 hours)
measure: Bactericidal rate
timeFrame: at Day 10
measure: Percentage of patients recovering at the end of the treatment period
timeFrame: at Day 10
measure: Percentage of patients failing at the end of the treatment period
timeFrame: at Day 10
measure: Number of days without artificial ventilation
timeFrame: at Day 28
measure: The duration of hospitalization
timeFrame: at Day 28
measure: Survival at D28
timeFrame: at Day 28
measure: The alveolar concentration of Ceftolozane-Tazobactam
timeFrame: between 24 hour and 48 hour after time 0
measure: Evaluation of the serious adverse events
timeFrame: Day 28
Other outcomes:
Locations:
city: Toulouse
country: France
facility: Service Réanimation Polyvalente - CHU Rangueil
Study officials:
affiliation: University Hospital, Toulouse
name: Stéphanie RUIZ, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.