Aerosolized Antibiotics in the Treatment of Ventilator Associated Pneumonia (AAINTVAP)

May 26, 2023 updated by: Wright State University

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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].

Study Type

Interventional

Enrollment (Actual)

16

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Ohio
      • Dayton, Ohio, United States, 45409
        • Miami Valley Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

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

Exclusion Criteria:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Aerosolized Placebo
Placebo tobramycin 0.5 mL 0.9% normal saline q.12h. Placebo vancomycin 0.5 mL 0.9% normal saline q.8h.
Drug: Aerosolized Placebo
Placebo tobramycin: 5 ml 0.9% normal saline q. 12h. Placebo vancomycin: 5m 0.9% normal saline q. 8 hr.
Other Names:
  • Normal saline solution
Experimental: Aerosolized Tobramycin or Vancomycin
Aerosolized 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.
Drug: Aerosolized Tobramycin or Vancomycin
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.
Other Names:
  • Tobi, Tobrex; Vancocin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recurrence of Pneumonia
Time Frame: 9-21 days after initiating antibiotic therapy
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.
9-21 days after initiating antibiotic therapy
Persistence of Pneumonia
Time Frame: 8 days after initiation of therapy for 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.
8 days after initiation of therapy for pneumonia

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ventilator-free Days
Time Frame: 28 days
number of days not on vent in first 28 days after randomization
28 days
Intensive Care Unit (ICU) -Free Days in 28 Days
Time Frame: 28 days
number of days not in ICU after initiation of therapy
28 days
28-day ICU Mortality
Time Frame: 28 days
number of patients treated in each arm who die in ICU within 28 days of initiation of therapy
28 days
Renal Insufficiency
Time Frame: 28 days
patients who develop acute kidney injury after randomization
28 days
Emergence of Resistant Organisms
Time Frame: 28 days
patients with failure of therapy or persistence who grow resistant organisms after being treated initially
28 days
Number of Antibiotic Days
Time Frame: 28 days
total days antibiotics administered for pneumonia after randomization
28 days
Multiple Organ Dysfunction Score Calculated at Randomization and on Day 7 of Treatment
Time Frame: 7 days
multiple organ dysfunction score at randomization and on day 7 of aerosolized antibiotics/placebo treatment
7 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Wright State University

Investigators

  • Principal Investigator: John K. Bini, MD, Wright State University
  • Study Director: Priti Parikh, PhD, Wright State University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2015

Primary Completion (Actual)

February 1, 2017

Study Completion (Actual)

July 1, 2022

Study Registration Dates

First Submitted

April 30, 2015

First Submitted That Met QC Criteria

June 17, 2015

First Posted (Estimated)

June 23, 2015

Study Record Updates

Last Update Posted (Actual)

May 31, 2023

Last Update Submitted That Met QC Criteria

May 26, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 6517

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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