Aerosolized Antibiotics in the Treatment of Ventilator Associated Pneumonia

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 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].

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) 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