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Pneumonia, Ventilator-AssociatedPhase 4AAINTVAPNCT02478710

Aerosolized Antibiotics in the Treatment of Ventilator Associated Pneumonia

A Phase 4 study testing Aerosolized Tobramycin or Vancomycin in people with Pneumonia, Ventilator-Associated, run by Wright State University at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The purpose of this study is to determine if administering inhaled antibiotics directly into the lungs in conjunction with intravenous (IV) antibiotics leads to better outcomes and decreased recurrence of ventilator associated pneumonia (VAP) when compared to IV antibiotics alone. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Pneumonia, Ventilator-Associated
What is being tested?
Aerosolized Tobramycin or Vancomycin
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
16 participants
Where
1 siteUnited States
Study dates
Jun 2015to Jul 2022
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Clinical Pulmonary Infection Score (CPIS) greater than or equal to 6
  • Intubated greater than or equal to 48 hours
  • Screened for possible eligibility
  • Bronchoscopy and bronchoalveolar lavage (BAL) or combicath performed
  • Started on empiric intravenous (IV) and inhaled antibiotics after BAL for suspected ventilator associated pneumonia (VAP)
  • > 104 Colony Forming Units (CFU) on BAL

Who cannot join

  • <18 years of age
  • Pregnant
  • Human Immunodeficiency Virus (HIV) or on chronic immunosuppressants
  • Absolute Neutrophil Count <1,000
  • Allergy to vancomycin or tobramycin
  • Anaphylaxis to penicillin
Show all 9Show fewer
  • Cystic Fibrosis
  • Previous enrollment
  • Creatinine >2 mg/dl or doubled within the previous 72 hours

Trial locations and contacts

1 site in 1 country.

United States1 site
  • Miami Valley Hospital

    Dayton, Ohio, 45409

Other trials in United States

About this study

Official title: Aerosolized Antibiotics in the Treatment of Ventilator Associated Pneumonia: A Pilot Study

The purpose of this study is to determine if administering inhaled antibiotics directly into the lungs in conjunction with intravenous (IV) antibiotics leads to better outcomes and decreased recurrence of ventilator associated pneumonia (VAP) when compared to IV antibiotics alone.

Read the detailed description

Ventilator associated pneumonia (VAP) remains a serious problem in critically ill patients with an incidence of 8-28% and mortality ranging from 24-57%. A landmark study comparing eight days versus fifteen days of antibiotic therapy reported a pulmonary infection recurrence rate of 26-29%. Costs associated with VAP can reach up to $40,000 per occurrence.

Aerosolized antibiotics have been used to treat ailments such as cystic fibrosis and bronchiectasis. Previous research indicates that aerosolized antibiotics attain a 200 fold greater concentration in the lung than in the blood, and that sputum trough levels remain 20 fold greater than that of acceptable serum antibiotic troughs. Additionally, aerosolized antibiotics are considered safe (without increased risk of bacterial resistance) with better treatment success when compared to controls (OR 2.75, 95% CI 1.06-7.17), although no mortality benefit has been identified. Some studies have shown reduced systemic toxicity when using aerosolized antibiotics while others have shown no difference. Aerosolized tobramycin prevents pseudomonas infections in patients with Cystic Fibrosis. Furthermore aerosolized antibiotics improve pulmonary function in these patients, including Forced Expiratory Volume in 1 second (FEV1), and decrease the need for hospitalization. Lung transplant patients and patients with Human Immunodeficiency Virus (HIV) also benefit from aerosolized fungal prophylaxis and treatment. The benefit has been less clear in patients with non-Cystic Fibrosis bronchiectasis, and although some studies show benefits to aerosolized antibiotics in preventing and treating nosocomial pneumonias, no large prospective randomized trials have been performed to confirm the benefit or to change practice recommendations.

Antimicrobials must reach the site of infection, bind the target site, and remain bound for a sufficient time period to disrupt the life cycle of the cells. Only 21% of an administered antibiotic dose actually ends up in the lung parenchyma. Multiple studies have shown that the ideal particle size for inhalation is between 1 and 5 microns. Particles that are too small get exhaled, and particles that are too large do not reach the alveoli. Non-humidified nebulization is better for drug administration than humidified air. Isotonicity of the drug, pH, and the presence of preservatives in the solution also need to be evaluated for optimal drug delivery and function. The ideal method of administration of aerosolized antibiotics also remains to be determined.

Inhaled tobramycin has been used in several studies over the past thirty years, mostly in patients with Cystic Fibrosis. It has been shown to be effective in decreasing sputum colony counts of Pseudomonas Aeruginosa. Inhaled gentamycin has also been shown to delay acquisition of Pseudomonas in children with Cystic Fibrosis, as well as decreasing disease progression. Chest tightness and persistent cough are the side effects mentioned within these studies. This suggests that inhalation is a safe method for the administration of tobramycin.

It has been shown that in Community-Acquired Pneumonia (CAP) the alveolar macrophages initiate a pro-inflammatory cascade. Failure to control excessive inflammation, leads to an exaggerated systemic response resulting in organ damage. Local and systemic levels of these pro-inflammatory mediators have been shown to correlate with the severity of disease. The investigators speculate that a similar response exists in patients with VAP.

The investigators propose a prospective, randomized trial designed to assess the value of aerosolized antibiotics in the treatment of ventilator associated pneumonia and to evaluate the impact of co-existing, non-bacterial pathogens and cytokines on the ability to clear pneumonia in culture-proven cases of VAP. Eligible patients will be randomized at the time of bronchoalveolar lavage or combicath to receive either adjuvant aerosolized antibiotics plus routine IV antibiotics or aerosolized placebo plus routine IV antibiotics. Individual clinical indicators will be recorded and used to monitor the effect of aerosolized antibiotics [temperature, leukocyte count, chest radiograph appearance, ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2 ratio), mechanical ventilation status, and vital signs].

Being tested
Aerosolized Tobramycin or Vancomycin, Aerosolized Placebo
Medical subject headings
Pneumonia, Ventilator-Associated

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Aerosolized Tobramycin or VancomycinDrug

    Also called Tobi, Tobrex; Vancocin

    Tobramycin: 300 mg diluted in 5 mL of 0.9% normal saline q.12h. Vancomycin: 125 mg diluted in 5 mL 0.9% normal saline q.8h.

  • Aerosolized PlaceboDrug

    Also called Normal saline solution

    Placebo tobramycin: 5 ml 0.9% normal saline q. 12h. Placebo vancomycin: 5m 0.9% normal saline q. 8 hr.

Study groups in NCT02478710
Study groupRoleWhat they receive
Aerosolized PlaceboPlacebo comparatorPlacebo tobramycin 0.5 mL 0.9% normal saline q.12h. Placebo vancomycin 0.5 mL 0.9% normal saline q.8h.
Receives: Drug: Aerosolized Placebo
Aerosolized Tobramycin or VancomycinExperimentalAerosolized tobramycin 300 mg diluted in 5 mL 0.9% normal saline q.12h. Aerosolized vancomycin 125 mg diluted in 5 mL 0.9% normal saline q.8h.
Receives: Drug: Aerosolized Tobramycin or Vancomycin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Recurrence of Pneumonia

    Recurrence after a second bronchoalveolar lavage (BAL) reveals at least one bacterial species growing at concentrations of greater than 10 to the fourth power organisms during the time period of 9-21 days after initiating therapy.

    Measured: 9-21 days after initiating antibiotic therapy

  2. Persistence of Pneumonia

    Persistence will be defined as the need to continue antibiotic therapy for greater than 7 days. This is reported as the number of participants with persistence of pneumonia.

    Measured: 8 days after initiation of therapy for pneumonia

Secondary outcomes (7)
  1. Ventilator-free Days

    number of days not on vent in first 28 days after randomization

    Measured: 28 days

  2. Intensive Care Unit (ICU) -Free Days in 28 Days

    number of days not in ICU after initiation of therapy

    Measured: 28 days

  3. 28-day ICU Mortality

    number of patients treated in each arm who die in ICU within 28 days of initiation of therapy

    Measured: 28 days

  4. Renal Insufficiency

    patients who develop acute kidney injury after randomization

    Measured: 28 days

  5. Multiple Organ Dysfunction Score Calculated at Randomization and on Day 7 of Treatment

    multiple organ dysfunction score at randomization and on day 7 of aerosolized antibiotics/placebo treatment

    Measured: 7 days

  6. Emergence of Resistant Organisms

    patients with failure of therapy or persistence who grow resistant organisms after being treated initially

    Measured: 28 days

  7. Number of Antibiotic Days

    total days antibiotics administered for pneumonia after randomization

    Measured: 28 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Jun 2015 (estimated)
  2. Study startJun 2015
  3. Primary completionFeb 2017
  4. Study completionJul 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02478710
Sponsor's protocol ID
6517
Acronym
AAINTVAP
Status last verified
May 2023
First submitted
30 Apr 2015
Last updated
31 May 2023
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Klastersky J, Huysmans E, Weerts D, Hensgens C, Daneau D. Endotracheally administered gentamicin for the prevention of infections of the respiratory tract in patients with tracheostomy: a double-blind study. Chest. 1974 Jun;65(6):650-4. doi: 10.1378/chest.65.6.650. No abstract available.

    PubMed 4208908
  • Hallal A, Cohn SM, Namias N, Habib F, Baracco G, Manning RJ, Crookes B, Schulman CI. Aerosolized tobramycin in the treatment of ventilator-associated pneumonia: a pilot study. Surg Infect (Larchmt). 2007 Feb;8(1):73-82. doi: 10.1089/sur.2006.051.

    PubMed 17381399
  • Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, Clementi E, Gonzalez J, Jusserand D, Asfar P, Perrin D, Fieux F, Aubas S; PneumA Trial Group. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003 Nov 19;290(19):2588-98. doi: 10.1001/jama.290.19.2588.

    PubMed 14625336
  • MacIntyre NR, Rubin BK. Respiratory therapies in the critical care setting. Should aerosolized antibiotics be administered to prevent or treat ventilator-associated pneumonia in patients who do not have cystic fibrosis? Respir Care. 2007 Apr;52(4):416-21; discussion 421-2.

    PubMed 17417976
  • Drew RH, Dodds Ashley E, Benjamin DK Jr, Duane Davis R, Palmer SM, Perfect JR. Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients. Transplantation. 2004 Jan 27;77(2):232-7. doi: 10.1097/01.TP.0000101516.08327.A9.

    PubMed 14742987
  • Wood GC, Boucher BA. Aerosolized antimicrobial therapy in acutely ill patients. Pharmacotherapy. 2000 Feb;20(2):166-81. doi: 10.1592/phco.20.3.166.34783.

    PubMed 10678295
  • Drobnic ME, Sune P, Montoro JB, Ferrer A, Orriols R. Inhaled tobramycin in non-cystic fibrosis patients with bronchiectasis and chronic bronchial infection with Pseudomonas aeruginosa. Ann Pharmacother. 2005 Jan;39(1):39-44. doi: 10.1345/aph.1E099. Epub 2004 Nov 23.

    PubMed 15562142
  • Palmer LB, Smaldone GC, Chen JJ, Baram D, Duan T, Monteforte M, Varela M, Tempone AK, O'Riordan T, Daroowalla F, Richman P. Aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit. Crit Care Med. 2008 Jul;36(7):2008-13. doi: 10.1097/CCM.0b013e31817c0f9e.

    PubMed 18552684
  • Ioannidou E, Siempos II, Falagas ME. Administration of antimicrobials via the respiratory tract for the treatment of patients with nosocomial pneumonia: a meta-analysis. J Antimicrob Chemother. 2007 Dec;60(6):1216-26. doi: 10.1093/jac/dkm385. Epub 2007 Oct 13.

    PubMed 17934205
  • Claridge JA, Edwards NM, Swanson J, Fabian TC, Weinberg JA, Wood C, Croce MA. Aerosolized ceftazidime prophylaxis against ventilator-associated pneumonia in high-risk trauma patients: results of a double-blind randomized study. Surg Infect (Larchmt). 2007 Feb;8(1):83-90. doi: 10.1089/sur.2006.042.

    PubMed 17381400
  • Klepser ME. Role of nebulized antibiotics for the treatment of respiratory infections. Curr Opin Infect Dis. 2004 Apr;17(2):109-12. doi: 10.1097/00001432-200404000-00007.

    PubMed 15021049
  • Palmer LB, Smaldone GC, Simon SR, O'Riordan TG, Cuccia A. Aerosolized antibiotics in mechanically ventilated patients: delivery and response. Crit Care Med. 1998 Jan;26(1):31-9. doi: 10.1097/00003246-199801000-00013.

    PubMed 9428540
  • Smaldone GC. Advances in aerosols: adult respiratory disease. J Aerosol Med. 2006 Spring;19(1):36-46. doi: 10.1089/jam.2006.19.36.

    PubMed 16551213
  • Crowther Labiris NR, Holbrook AM, Chrystyn H, Macleod SM, Newhouse MT. Dry powder versus intravenous and nebulized gentamicin in cystic fibrosis and bronchiectasis. A pilot study. Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 1):1711-6. doi: 10.1164/ajrccm.160.5.9810080.

    PubMed 10556145
  • Heinzl B, Eber E, Oberwaldner B, Haas G, Zach MS. Effects of inhaled gentamicin prophylaxis on acquisition of Pseudomonas aeruginosa in children with cystic fibrosis: a pilot study. Pediatr Pulmonol. 2002 Jan;33(1):32-7. doi: 10.1002/ppul.10019.

    PubMed 11747258

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Aerosolized Tobramycin or Vancomycin in people with Pneumonia, Ventilator-Associated, run by Wright State University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 31 May 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 May 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Recurrence of Pneumonia (time frame: 9-21 days after initiating antibiotic therapy). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02478710, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 May 2023.

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