Ventilator-associated Pneumonia
Conditions
Keywords
Pneumonia, Pseudomonas aeruginosa, pharmacokinetics
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.
Interventions
DRUG1 hour infusion
Intravenous administration of ceftolozane-tazobactam (ZERBAXA®) : 2000 mg by infusion for 60 minutes every 8 hours.
DRUG4 hours infusion
Intravenous administration of ceftolozane-tazobactam (ZERBAXA®) : 2000 mg by infusion for 4 hours every 8 hours
Sponsors
University Hospital, Toulouse
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The patient will be randomized either in the 4-hours or in the 1-hour infusion group
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time that the concentration spends above 5 Minimum inhibitory Concentration (T>5*MIC) | 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
| Measure | Time frame | Description |
|---|---|---|
| Bactericidal rate | 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 | 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 | at Day 10 | Number of patients failing in relation to the total number of patients |
| Number of days without artificial ventilation | at Day 28 | The number of days without artificial ventilation |
| Percentage of patients with concentrations greater than 5*Minimum inhibitory Concentration | 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. |
| Survival at D28 | at Day 28 | survival in number of patient alive |
| The alveolar concentration of Ceftolozane-Tazobactam | 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 | Day 28 | Evaluation of the serious adverse events at the doses and regimen recommended in the trial |
| The duration of hospitalization | at Day 28 | the duration of hospitalization in number of day |
Countries
France
Contacts
Primary ContactStéphanie RUIZ, MD
Backup ContactNathalie ROQUES
Outcome results
None listed