Clinical Trials And Experience

Initial trials of aerosolized antimicrobial therapy with penicillin were published six decades ago [14]. Sporadic reports about the benefit of these therapies continued to appear for the next 30 years as case reports or uncontrolled observations.

These trials evaluated different therapies and utilized several differences in study design, making comparisons difficult. Additionally, the goals of therapy and the endpoints that were measured differed significantly. Controlled studies evaluating the use of inhaled antibiotics began to appear in the 1980s. These studies addressed primarily their use as suppressive therapy, and many were performed in patients with cystic fibrosis.

There are a few reports in the literature about the use of aerosolized antibiotics in patients without cystic fibrosis; however, not many data are available about efficacy, and these observations are not randomized, controlled clinical trials. The review of the literature that follows focuses on patients with cystic fibrosis. In September 1999, a consensus document was published that summarized recommendations for the use of aerosolized antibiotics in patients with cystic fibrosis based on the current evidence [14].

Use During Acute Exacerbations

A few studies have investigated the role of inhaled aminoglycosides used with systemic antimicrobials for treatment of an acute pulmonary exacerbation [15,16] and studied patients with cystic fibrosis who were experiencing an acute pulmonary exacerbation. In the first study [15], aerosolized tobramycin (80 mg three times daily) was added to two weeks of intravenous tobramycin and ticarcillin for 12 subjects. The control group (n = 16) received the intravenous therapy alone. After two weeks of therapy, there were no differences between the groups in lung function, severity scores, various vital sign measures, or time to discharge from the hospital. Although a bacterial response (eradication of Pseudomonas) favored the inhaled group at 2 weeks (p = .03), recolonization occurred in all cases within 1-2 months after treatment of the exacerbation.

In the second study [16], 62 subjects were treated with intravenous ceftazidime and amikacin. The treatment group also received aerosolized amikacin 100 mg twice daily. Treatments were given for an average of 15 days, and subjects were reevaluated four to six weeks after hospital discharge. During treatment, transient improvements in several outcome measures were noted (e.g., x-ray score, inflammation indices, and percentage underweight); however, there were no differences in any measure at the final evaluation point. As in the earlier study, eradication of bacteria from sputum was also transient.

Although there has been interest in the role of aerosolized aminoglycosides in the management of acute exacerbations of lung disease in patients with cystic fibrosis, there are no quality data to support this practice. Results from these studies suggest minimal benefit from the addition of aerosolized antibiotic therapy added to traditional combination intravenous therapy during treatment of acute pulmonary exacerbations of cystic fibrosis. Any improvements that occurred were temporary, with no apparent long-term benefit. Currently, there is no established role for aerosolized antimicrobial therapy, either alone or in combination with systemic therapy, when treating an acute exacerbation [14].

Use in Delaying or Preventing Acquisition of Pseudomonas

Colonization with P. aeruginosa is a sentinel event in the course of cystic fibrosis. Chronic infection with this organism is associated with progressive loss of lung function attributed to chronic inflammation and recurrent pulmonary exacerbations. Thus, there is interest in strategies that may delay the acquisition of this organism.

Oral ciprofloxacin has been used in combination with aerosolized colistin as well as a combination of aerosolized colistin and tobramycin to delay the onset of P. aeruginosa colonization. Although favorable results were reported, these studies used historical controls, and the concomitant use of oral antibiotics limits interpretation of the role of the aerosolized therapy. Not many data exist on the pharmacokinetic or pharmacodynamic behavior of colistin aerosolized [17-19].

Another recent report suggested promise about the role of aerosolized antibiotics in delaying acquisition of P. aeruginosa [20]. In this report, children with cystic fibrosis, who were determined to be at risk for bacterial colonization with P. aeruginosa, inhaled 80-120mg of gentamicin twice daily. A total of 28 children were identified and evaluated in a retrospective manner. Twelve of these patients were followed for at least two years on therapy and were compared to 16 subjects who stopped therapy prematurely due to poor adherence or side effects. None of the patients who continued aerosolized gentamicin acquired P. aeruginosa during the observation period, while 7 of 16 patients in the control group exhibited positive cultures (p = .01) The authors concluded that aerosolized gentamicin therapy may be beneficial in delaying acquisition of P. aeruginosa, although a prospective controlled clinical trial is warranted.

To date, the data are sparse, and the use of aerosolized antibiotics to prevent or delay the acquisition of P. aeruginosa cannot be recommended [14].

Role as Suppressive Therapy in Reducing Exacerbation Frequency and Improving Pulmonary Function

The majority of clinical trials with inhaled antibiotics have evaluated the role of suppressive therapy between acute exacerbations in patients with cystic fibrosis. The first report evaluating the role of an aminoglycoside as suppressive therapy appeared over 20 years ago. Aerosolized carbenicillin and gentamicin was reported to result in modest improvement in lung function in 20 adult patients with cystic fibrosis [21]. Subsequently, other investigators concluded that minor benefit was achieved with this route of administration [22]. Generally, improvements in lung function or a reduced rate of decline in lung function were reported.

A meta-analysis published in 1996 [23] combined the preceding results with other research and concluded that the use of nebulized antibiotic therapy against Pseudomonas was beneficial in reducing the number of exacerbations requiring systemic antibiotics, reducing the bacterial load in the sputum, and improving lung function. The only concern identified was the potential for an increase in resistance of P. aeurginosa. This analysis comprised five trials that met the criteria for quality, and it included beta lactams, aminoglycosides, and polymyxin agents.

Colistin has been evaluated as suppressive therapy in patients with cystic fibrosis. In an uncontrolled case series, the use of colistin inhaled twice daily reduced the frequency of isolation of Pseudomonas in the sputum [24]. In another controlled trial, 40 subjects inhaled either colistin 1 million units twice daily or a saline control. After 90 days, the rate of decline in forced vital capacity was lower in subjects using colistin and the drug was tolerated [25]. In the most recent published paper, 20 patients with cystic fibrosis awaiting lung transplantation were treated with aerosolized colistin 75 mg twice daily based on the presence of multiresistant Pseudomonas in their sputum [26]. Although the study was not randomized, they were compared to 10 patients who did not receive colistin treatment. There was no difference in lung function detected between groups; however, the colistin-treated patients had sensitive organisms detected more rapidly (p = .007) than control patients.

Since the early 1990s, most of the research interest has focused on the role of aerosolized aminoglycosides as suppressive therapy for cystic fibrosis patients colonized with P. aeruginosa. In addition to the carbenicillin and gentamicin study mentioned previously [21], earlier studies reported mild to moderate benefit in reducing the frequency of exacerbations and improving lung function with inhaled aminoglycosides. However, as noted, these studies often had poor controls and small numbers of patients.

The major study that stimulated interest in the development of a commercially available inhaled tobramycin product was published in 1993 [27]. In this trial, 71 cystic fibrosis patients with stable pulmonary disease were enrolled in a double-blind, placebo-controlled crossover study in which tobramycin 600 mg was nebulized (ultrasonic nebulizer) three times daily. This dose was based on a preliminary study, which showed that sputum concentrations would exceed 10 times the MIC of P. aeruginosa isolates. This concentration has been shown to overcome the competitive binding of tobramycin reported in the sputum of patients with cystic fibrosis.

Pulmonary function improved significantly in patients receiving the tobramycin compared to placebo (3.72% increase compared to 5.97% decrease; p > .001) within the first 28 days, and the difference persisted for the duration of the study. In addition, a 100-fold reduction in the sputum density of P. aeruginosa was observed.

These findings prompted the development and evaluation of the currently available form of inhaled tobramycin, which is sterile and free of preservatives. The benefit of maintenance therapy with this inhaled tobramycin is supported by the results from two 24-week, multicenter, randomized, double blind, placebo-controlled clinical trials [6]. In these studies, patients with cystic fibrosis were at least six years of age, with an FEV1 between 25% and 75% predicted. All subjects had evidence of colonization with Pseudomonas aeruginosa. Exclusion criteria included an elevated serum creatinine or colonization with Burkholderia cepacia, which is typically resistant to tobramycin. Subjects in the active treatment arm received inhaled tobramycin 300 mg twice daily through nebulization, while control subjects inhaled a saline placebo. In each group, the nebulized treatment was administered in 28-day cycles (28 on, 28 off).

Patients receiving inhaled tobramycin (n = 258) showed significant improvement in lung function compared to the placebo group (n = 262). Reported average improvement in FEV1 from baseline after 24 weeks was 7% to 11% for tobramycin treated subjects versus 0% to 1% for placebo (p < .001). Inhaled tobramycin also significantly reduced the presence of P. aeruginosa in sputum during treatment cycles. The average number of hospital days was reduced from 8.1 days for control subjects to 5.1 days in the active treatment group (p = .001), and the average number of days of parenteral therapy was lower (9.6 days vs. 14.1 days; p = .003) during the 24-week study.

A follow-up to these pivotal studies was published in 2002 [28]. One hundred twenty-eight subjects continued in open-label trials for up to 2 years at the conclusion of the controlled studies. Evidence suggests that the clinical benefit of therapy continued to be exhibited. Patients receiving inhaled tobramycin had improvements in FEVj of 14.3% compared to 1.8% in placebo patients, and active treatment significantly reduced sputum density of P. aeruginosa (p = .0001).

Based on the clinical evidence of benefit from inhaled antibiotic suppressive therapy, the consensus conference recommendation [14] supports the use of the commercially available inhaled tobramycin on a cyclic schedule in cystic fibrosis patients colonized with P. aeruginosa. Other inhaled antibiotics may provide benefit as suppressive therapy as well, although the most compelling data support inhaled tobramycin.

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