Nebulized Aztreonam for Prevention of Gram Negative Ventilator-associated Pneumonia

Ventilator Associated Pneumonia Clinical Trial

— AZLIS  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03749226
• Other study ID #: AZLI-2018-AR
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: March 19, 2019
• Est. completion date: December 31, 2019

Study information

• Verified date: June 2021
• Source: Hospital Universitari Joan XXIII de Tarragona.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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: 1. Safety and tolerability of AZLI administered during 5 days in adults patients under mechanical ventilation heavily colonized by Gram-negative bacteria 2. The pharmacokinetic profile in endotracheal aspirate (EA) or bronchoalveolar lavage (BAL). 3. The plasma levels of nebulized AZLI in patients under mechanical ventilation heavily colonized by Gram-negative bacteria.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 9
• Est. completion date: December 31, 2019
• Est. primary completion date: September 4, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age = 18 years.

2. Patients under mechanical ventilation for more than 5 day.

3. Patient with heavy colonization by Gram-negative microorganisms.

4. No clinical suspicion of infections-related ventilator-associated complications (IVAC) according CDC criteria (Figure 1).

5. 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.

6. Informed consent signed

Exclusion Criteria:

1. Suspected of IVAC.

2. Patients with known hypersensitivity to Aztreonam.

3. Patients who received more than 48 hours of broad spectrum antibiotics.

4. Evidence of active mycobacterium infections, chronic pulmonary infection or bronchial obstruction.

5. Granulomatous disease, lung cancer or lung transplant.

6. Acute respiratory distress syndrome (ARDS)

7. Woman who is pregnant or breast-feeding while enrolled in this study.

8. 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

Related Conditions & MeSH terms

• Pneumonia
• Pneumonia, Ventilator-Associated
• Prevention
• Respiratory Infection Other
• Respiratory Tract Infections
• Ventilator Associated Pneumonia

Intervention

Drug:
• Aztreonam lysine
nebulization

Device:
• Aerogen Solo
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.
• CombiHaler
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.

Locations

Country	Name	City	State
Spain	Critical Care Department - Hospital Universitario de Tarragona Joan XXIII	Tarragona

Sponsors (1)

Lead Sponsor	Collaborator
Hospital Universitari Joan XXIII de Tarragona.

Country where clinical trial is conducted

Spain, 

References & Publications (30)

American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005 Feb 15;171(4):388-416. — View Citation

Assael BM, Pressler T, Bilton D, Fayon M, Fischer R, Chiron R, LaRosa M, Knoop C, McElvaney N, Lewis SA, Bresnik M, Montgomery AB, Oermann CM; AZLI Active Comparator Study Group. Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: a comparative efficacy trial. J Cyst Fibros. 2013 Mar;12(2):130-40. doi: 10.1016/j.jcf.2012.07.006. Epub 2012 Sep 15. — View Citation

Azim A, Dwivedi M, Rao PB, Baronia AK, Singh RK, Prasad KN, Poddar B, Mishra A, Gurjar M, Dhole TN. Epidemiology of bacterial colonization at intensive care unit admission with emphasis on extended-spectrum beta-lactamase- and metallo-beta-lactamase-producing Gram-negative bacteria--an Indian experience. J Med Microbiol. 2010 Aug;59(Pt 8):955-960. doi: 10.1099/jmm.0.018085-0. Epub 2010 Apr 22. — View Citation

Boukhettala N, Porée T, Diot P, Vecellio L. In vitro performance of spacers for aerosol delivery during adult mechanical ventilation. J Aerosol Med Pulm Drug Deliv. 2015 Apr;28(2):130-6. doi: 10.1089/jamp.2013.1091. Epub 2014 Jul 22. — View Citation

Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med. 2002 Apr 1;165(7):867-903. Review. — View Citation

Coates AL, Green M, Leung K, Chan J, Ribeiro N, Louca E, Ratjen F, Charron M, Tservistas M, Keller M. Rapid pulmonary delivery of inhaled tobramycin for Pseudomonas infection in cystic fibrosis: a pilot project. Pediatr Pulmonol. 2008 Aug;43(8):753-9. doi: 10.1002/ppul.20850. — View Citation

Craven DE, Chroneou A, Zias N, Hjalmarson KI. Ventilator-associated tracheobronchitis: the impact of targeted antibiotic therapy on patient outcomes. Chest. 2009 Feb;135(2):521-528. doi: 10.1378/chest.08-1617. Epub 2008 Sep 23. Review. — View Citation

Craven DE. Ventilator-associated tracheobronchitis (VAT): questions, answers, and a new paradigm? Crit Care. 2008;12(3):157. doi: 10.1186/cc6912. Epub 2008 Jun 18. — View Citation

Drakulovic MB, Bauer TT, Torres A, Gonzalez J, Rodríguez MJ, Angrill J. Initial bacterial colonization in patients admitted to a respiratory intensive care unit: bacteriological pattern and risk factors. Respiration. 2001;68(1):58-66. — View Citation

Dugernier J, Wittebole X, Roeseler J, Michotte JB, Sottiaux T, Dugernier T, Laterre PF, Reychler G. Influence of inspiratory flow pattern and nebulizer position on aerosol delivery with a vibrating-mesh nebulizer during invasive mechanical ventilation: an in vitro analysis. J Aerosol Med Pulm Drug Deliv. 2015 Jun;28(3):229-36. doi: 10.1089/jamp.2014.1131. Epub 2014 Nov 13. — View Citation

File TM Jr. New diagnostic tests for pneumonia: what is their role in clinical practice? Clin Chest Med. 2011 Sep;32(3):417-30. doi: 10.1016/j.ccm.2011.05.011. Epub 2011 Jul 12. Review. — View Citation

Gibson RL, Retsch-Bogart GZ, Oermann C, Milla C, Pilewski J, Daines C, Ahrens R, Leon K, Cohen M, McNamara S, Callahan TL, Markus R, Burns JL. Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis. Pediatr Pulmonol. 2006 Jul;41(7):656-65. — View Citation

Horianopoulou M, Legakis NJ, Kanellopoulou M, Lambropoulos S, Tsakris A, Falagas ME. Frequency and predictors of colonization of the respiratory tract by VIM-2-producing Pseudomonas aeruginosa in patients of a newly established intensive care unit. J Med Microbiol. 2006 Oct;55(Pt 10):1435-1439. doi: 10.1099/jmm.0.46713-0. — View Citation

Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O'Grady NP, Bartlett JG, Carratalà J, El Solh AA, Ewig S, Fey PD, File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016 Sep 1;63(5):e61-e111. doi: 10.1093/cid/ciw353. Epub 2016 Jul 14. Erratum in: Clin Infect Dis. 2017 May 1;64(9):1298. Erratum in: Clin Infect Dis. 2017 Oct 15;65(8):1435. Clin Infect Dis. 2017 Nov 29;65(12):2161. — View Citation

Klompas M. Ventilator-associated events surveillance: a patient safety opportunity. Curr Opin Crit Care. 2013 Oct;19(5):424-31. doi: 10.1097/MCC.0b013e3283636bc9. Review. — View Citation

Kollef MH, Hamilton CW, Montgomery AB. Aerosolized antibiotics: do they add to the treatment of pneumonia? Curr Opin Infect Dis. 2013 Dec;26(6):538-44. doi: 10.1097/QCO.0000000000000004. Review. — View Citation

Martin-Loeches I, Povoa P, Rodríguez A, Curcio D, Suarez D, Mira JP, Cordero ML, Lepecq R, Girault C, Candeias C, Seguin P, Paulino C, Messika J, Castro AG, Valles J, Coelho L, Rabello L, Lisboa T, Collins D, Torres A, Salluh J, Nseir S; TAVeM study. Inci — View Citation

McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008 Nov 1;178(9):921-8. doi: 10.1164/rccm.200712-1804OC. Epub 2008 Jul 24. — View Citation

McKindley DS, Boucher BA, Hess MM, Croce MA, Fabian TC. Pharmacokinetics of aztreonam and imipenem in critically ill patients with pneumonia. Pharmacotherapy. 1996 Sep-Oct;16(5):924-31. — View Citation

Niederman MS. Respiratory tract infections: advances in diagnosis, management and prevention. Clin Chest Med. 2011 Sep;32(3):xiii-xiv. doi: 10.1016/j.ccm.2011.07.001. — View Citation

Nseir S, Ader F, Marquette CH. Nosocomial tracheobronchitis. Curr Opin Infect Dis. 2009 Apr;22(2):148-53. doi: 10.1097/QCO.0b013e3283229fdb. Review. — View Citation

Nseir S, Di Pompeo C, Pronnier P, Beague S, Onimus T, Saulnier F, Grandbastien B, Mathieu D, Delvallez-Roussel M, Durocher A. Nosocomial tracheobronchitis in mechanically ventilated patients: incidence, aetiology and outcome. Eur Respir J. 2002 Dec;20(6):1483-9. — View Citation

Nseir S, Povoa P, Salluh J, Rodriguez A, Martin-Loeches I. Is there a continuum between ventilator-associated tracheobronchitis and ventilator-associated pneumonia? Intensive Care Med. 2016 Jul;42(7):1190-2. doi: 10.1007/s00134-016-4283-x. Epub 2016 Apr 1 — View Citation

Oermann CM, McCoy KS, Retsch-Bogart GZ, Gibson RL, McKevitt M, Montgomery AB. Pseudomonas aeruginosa antibiotic susceptibility during long-term use of aztreonam for inhalation solution (AZLI). J Antimicrob Chemother. 2011 Oct;66(10):2398-404. doi: 10.1093/jac/dkr303. Epub 2011 Jul 22. — View Citation

Palmer LB. Ventilator-associated infection: the role for inhaled antibiotics. Curr Opin Pulm Med. 2015 May;21(3):239-49. doi: 10.1097/MCP.0000000000000160. Review. — View Citation

Poulakou G, Siakallis G, Tsiodras S, Arfaras-Melainis A, Dimopoulos G. Nebulized antibiotics in mechanically ventilated patients: roadmap and challenges. Expert Rev Anti Infect Ther. 2017 Mar;15(3):211-229. doi: 10.1080/14787210.2017.1268052. Epub 2017 Jan 2. Review. — View Citation

Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev-K M, Borowitz D, Bowman CM, Marshall BC, Marshall S, Smith AL. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999 Jan 7;340(1):23-30. — View Citation

Rodríguez A, Barcenilla F. Nebulized antibiotics. An adequate option for treating ventilator-associated respiratory infection? Med Intensiva. 2015 Mar;39(2):97-100. doi: 10.1016/j.medin.2014.10.006. Epub 2015 Feb 2. English, Spanish. — View Citation

Rodríguez A, Cabrera M, Reyes LF, Bodí M, Trefler S, Canadell L, Barahona D, Ehrmann S, Martin-Loeches I, Restrepo MI, Vecellio L. In vitro evaluation of aerosol delivery of aztreonam lysine (AZLI): an adult mechanical ventilation model. Expert Opin Drug — View Citation

Venier AG, Leroyer C, Slekovec C, Talon D, Bertrand X, Parer S, Alfandari S, Guerin JM, Megarbane B, Lawrence C, Clair B, Lepape A, Perraud M, Cassier P, Trivier D, Boyer A, Dubois V, Asselineau J, Rogues AM, Thiébaut R; DYNAPYO study group. Risk factors for Pseudomonas aeruginosa acquisition in intensive care units: a prospective multicentre study. J Hosp Infect. 2014 Oct;88(2):103-8. doi: 10.1016/j.jhin.2014.06.018. Epub 2014 Aug 1. — View Citation

* Note: There are 30 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Pharmacokinetic of aztreonam lysine in respiratory samples	Maximum bronchial concentration[Cmax]	day 0 and day 2
Secondary	Pharmacokinetic of aztreonam lysine in respiratory samples	time to maximum bronchial concentration[Tmax]	day 0 and day 2
Secondary	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
Secondary	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
Secondary	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
Secondary	Pharmacokinetic profile of aztreonam lysine in serum samples	Time to maximum serum concentration[Tmax] in serum samples	day 3
Secondary	Pharmacokinetic profile of aztreonam lysine in serum samples	Area under the serum concentration-time curve [AUC] in serum samples	day 3
Secondary	Pharmacokinetic profile of aztreonam lysine in serum samples	Terminal elimination half-time [t1/2] in serum samples	day 3
Secondary	SAEs and AEs assessments	adverse events as assessed by CTCAE v5.0	10 days