Nebulized Aztreonam for Prevention of Gram Negative Ventilator-associated Pneumonia

Study Overview
=================
Brief Summary
-----------------
Aerosol antibiotic administration offers the theoretical advantages of achieving high drug concentration at the infection site and low systemic absorption, thereby avoiding toxicity. Antibiotic aerosolization has good results in patients with cystic fibrosis, but data are scarce for patients under mechanical ventilation. Prospective, randomized 1:1, open-label study to assess the microbiological cure and pharmacokinetics (PK), safety and efficacy of nebulized Aztreonam lysine (75 mg dose) each 8 hr during 5 days in ventilated patients heavily colonized by Gram-negative bacteria. It is planned to include a total of 20 ventilated patients heavily colonized. Only ten of them (active group) will receive 5 days of treatment with nebulized AZLI.The control group will not receive treatment.

Detailed Description
-----------------
The main objectives of this study is: To compare the microbiological cure at day 5 of treatment and the incidence of Gram-negative IVAC between 7th and 10th days after last dose in patients heavily colonized by Gram-negative bacteria treated with nebulized AZLI vs. no treatment. The secundary objective of this study are: Safety and tolerability of AZLI administered during 5 days in adults patients under mechanical ventilation heavily colonized by Gram-negative bacteria The pharmacokinetic profile in endotracheal aspirate (EA) or bronchoalveolar lavage (BAL). The plasma levels of nebulized AZLI in patients under mechanical ventilation heavily colonized by Gram-negative bacteria.

Official Title
-----------------
Efficacy, Safety and Pharmacokinetics Profile of Nebulized Aztreonam Lysine (AZLI) for Prevention of Gram Negative Pneumonia in Heavily Colonized Mechanically Ventilated Patients

Conditions
-----------------
Ventilator Associated Pneumonia, Prevention, Respiratory Infection Other

Intervention / Treatment
-----------------
* Drug: Aztreonam lysine
* Device: Aerogen Solo
* Device: CombiHaler


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years. Patients under mechanical ventilation for more than 5 day. Patient with heavy colonization by Gram-negative microorganisms. No clinical suspicion of infections-related ventilator-associated complications (IVAC) according CDC criteria (Figure 1). Patients or his/her legal representative with ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and to return for the required assessments. Informed consent signed Exclusion Criteria: Suspected of IVAC. Patients with known hypersensitivity to Aztreonam. Patients who received more than 48 hours of broad spectrum antibiotics. Evidence of active mycobacterium infections, chronic pulmonary infection or bronchial obstruction. Granulomatous disease, lung cancer or lung transplant. Acute respiratory distress syndrome (ARDS) Woman who is pregnant or breast-feeding while enrolled in this study. Any medical condition which, in the opinion of the Investigator, places the patient at an unacceptable risk for toxicities if entered into the clinical study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Twenty consecutive patients heavily colonized by Gram-negative bacteria will be eligible for this study. Patients will be randomized to receive either AZLI nebulized or nothing via 1:1 randomization at study or control group. Patients assigned to study group will receive nebulized Aztreonam lysine (AZLI 75 mg-dose) three times /day during 5 days by mean of the ultrasonic nebulizer (Aeroneb solo®) plus Combihaler® spacer adapted of the ventilator. All patients will be on conventional volume-control ventilator setting during the antibiotic therapy. Systemic antibiotics will not be used in any patient. If the attending physician saw the need to administer intravenous antibiotics after the patient has entry in the study, this patients should be removed from the study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: AZLI group<br>Patients assigned to study group will receive nebulized Aztreonam lysine (AZLI 75 mg-dose) three times /day during 5 days by mean of the ultrasonic nebulizer (Aeroneb solo®) plus Combihaler® spacer adapted of the ventilator | Drug: Aztreonam lysine<br>* nebulization<br>Device: Aerogen Solo<br>* Aerogen's vibrating mesh technology, available within the Aerogen® Solo has been adopted for use of conventional mechanical ventilation. Aerogen Solo utilizes active vibrating mesh technology, where energy applied to the vibrational element, causes vibration of each of the 1000 funnel shaped apertures within the mesh. The mesh acts as a micropump drawing liquid through the holes producing a low velocity aerosol optimized for targeted drug delivery to the lungs. According our study (Rodriguez A et al , Expert Opin Drug Deliv. 2017 Dec;14(12):1447-1453) Aeroneb Solo showed an excellent aerosol delivery profile for Aztreonam lysine (AZLI) in an in vitro model of MV with short drug delivery time.<br>Device: CombiHaler<br>* The inhalation chamber CombiHaler™ spacer for mechanical ventilation and critical care (ICU) allows using both a vibrating mesh nebulizer such as Aeroneb ™, and a pMDI. It saves 50% of the nebulized drug when used in invasive ventilation. The inhalation chamber CombiHaler® is integrated on a circuit of a breathing device in invasive ventilation in particular for connexion of an Aeroneb® Pro or an Aeroneb® Solo. According our study (Rodriguez A et al , Expert Opin Drug Deliv. 2017 Dec;14(12):1447-1453) a better aerosol delivery performance (30%) was obtained using the Conbihaler spacer.<br>|
| No Intervention: Control group<br>Patients assigned to control group will no receive any intervention for heavy Gram negative colonization | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microbiological cure | Microbiological cure was defined as endotracheal aspirate (EA) or BAL cultures with consistently negative results after five day of therapy. | 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic of aztreonam lysine in respiratory samples | Maximum bronchial concentration[Cmax] | day 0 and day 2 | 
| Pharmacokinetic of aztreonam lysine in respiratory samples | time to maximum bronchial concentration[Tmax] | day 0 and day 2 | 
| Pharmacokinetic of aztreonam lysine in respiratory samples | Maximum bronchial concentration [Cmax] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples | day 0 and day 2 | 
| Pharmacokinetic of aztreonam lysine in respiratory samples | Area under the bronchial concentration-time curve [AUC] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples | day 0 and day 2 | 
| Pharmacokinetic of aztreonam lysine in respiratory samples | Terminal elimination half-time [t1/2] in tracheal aspirate (EA) or bronchoalveolar lavage (BAL) samples | day 0 and day 2 | 
| Pharmacokinetic profile of aztreonam lysine in serum samples | Time to maximum serum concentration[Tmax] in serum samples | day 3 | 
| Pharmacokinetic profile of aztreonam lysine in serum samples | Area under the serum concentration-time curve [AUC] in serum samples | day 3 | 
| Pharmacokinetic profile of aztreonam lysine in serum samples | Terminal elimination half-time [t1/2] in serum samples | day 3 | 
| SAEs and AEs assessments | adverse events as assessed by CTCAE v5.0 | 10 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nebulized antibiotic, Ventilator associated pneumonia, Ventilated associated tracheobronchitis, Aztreonam lysine