Aerosolized Antibiotics in the Treatment of Ventilator Associated Pneumonia

Study Overview
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Brief Summary
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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.

Detailed Description
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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].

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

Conditions
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Pneumonia, Ventilator-Associated

Intervention / Treatment
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* Drug: Aerosolized Tobramycin or Vancomycin
* Drug: Aerosolized Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: <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 Cystic Fibrosis Previous enrollment Creatinine >2 mg/dl or doubled within the previous 72 hours

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Aerosolized Placebo<br>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<br>* Placebo tobramycin: 5 ml 0.9% normal saline q. 12h. Placebo vancomycin: 5m 0.9% normal saline q. 8 hr.<br>* Other names: Normal saline solution;|
| Experimental: Aerosolized Tobramycin or Vancomycin<br>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<br>* 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.<br>* Other names: Tobi, Tobrex; Vancocin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 9-21 days after initiating antibiotic therapy | 
| 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. | 8 days after initiation of therapy for pneumonia | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-free Days | number of days not on vent in first 28 days after randomization | 28 days | 
| Intensive Care Unit (ICU) -Free Days in 28 Days | number of days not in ICU after initiation of therapy | 28 days | 
| 28-day ICU Mortality | number of patients treated in each arm who die in ICU within 28 days of initiation of therapy | 28 days | 
| Renal Insufficiency | patients who develop acute kidney injury after randomization | 28 days | 
| 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 | 7 days | 
| Emergence of Resistant Organisms | patients with failure of therapy or persistence who grow resistant organisms after being treated initially | 28 days | 
| Number of Antibiotic Days | total days antibiotics administered for pneumonia after randomization | 28 days |