Comparison of short infusion versus prolonged infusion of ceftolozane-tazobactam among patients with ventilator associated-pneumonia to Pseudomonas aeruginosa in intensive care units

INTERVENTION: Trade Name: ZERBAXA Pharmaceutical Form: Concentrate for solution for infusion CONDITION: Therapeutic area: Diseases [C] ‐ Bacterial Infections and Mycoses [C01] Ventilator associated‐pneumonia to Pseudomonas aeruginosa in intensive care units ; MedDRA version: 20.1 Level: LLT Classification code 10052596 Term: Nosocomial pneumonia System Organ Class: 100000004862 PRIMARY OUTCOME: Main Objective: 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 g three times a day (tid) vs 1‐hour infusion of 2 g tid. Primary end point(s): The primary endpoint is the time that the concentration spends above 5*MIC, expressed as a percentage of the time interval between two administrations. The T>5*MIC 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*MIC will be calculated from the total concentrations. Our study will focus on only Pseudomonas aeruginosa PAVM with a critical MIC of 4 mg/l, T>5*MIC will then correspond to a residual serum concentration of 20 mg/l. Secondary Objective: Compare the average exposition obtained with the current recommendations for the 2 products: ceftolozane and tazobactam; Estimate the percentage of patients correctly exposed to the 2 products: ceftolozane and tazobactam; Determine if Ceftolozane‐Tazobactam 4‐hours infusion is linked to an improved bacteriological progression in broncho‐alveolar liquid; Determine if Ceftolozane‐Tazobactam 4‐hours infusion is linked to an improved clinical progression; Determine alveolar concentration of Ceftolozane‐Tazobactam from a sample of the alveolar fluid produced by bronchial fibroscopy between the 24th hour and the 48th hour Timepoint(s) of evaluation of this end point: For the pharmacokinetic study, 7 blood samples will be collected from 24 hours to 48 hours after the first ZERBAXA® administration. SECONDARY OUTCOME: Secondary end point(s): The percentage of patients with concentrations greater than 5*MIC over an 8‐hour post administration interval ; 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, ; Bacteriological evaluation at the end of treatment and on day 15, based on actual bacteriological cure, presumed bacteriological cure, failure or bacterial superinfection to another germ. ; Percentage of patients recovering or failing at the end of the treatment period ; The number of days without artificial ventilation at D28, ; The duration of hospitalization, ; Survival at D28 ; 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. Timepoint(s) of evaluation of this end point: Depending on the secondary end points, the timepoints will occur: ; ‐ Beetween the 24th hour and the 48th hour (after the beginning of the first infusion) ; ‐ En fin de traitement (J7 à J10) ; ‐ A J15 ; ‐ A J28 INCLUSION CRITERIA: Age = 18 years patients with ventilator associated‐pneumonia to Pseudomonas aeruginosa patients hospitalized in intensive care units Pseudomonas aeruginosa susceptible to ceftolozane‐tazobactam SAPS II (Simplified Acute. Physiological Score 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 40 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20