Chest
Volume 120, Issue 3, Supplement, September 2001, Pages 118S-123S
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Microbiological and Immunologic Considerations With Aerosolized Drug Delivery

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The development of drug resistance is a major theoretical concern with the long-term delivery of aerosolized antibiotics via inhalation. A randomized, placebo-controlled, double-blind study, which compared inhaled tobramycin plus standard cystic fibrosis (CF) care to placebo plus standard CF care, examined the following microbiological parameters: percentage of patients with at least one Pseudomonas aeruginosa (PA) strain with a minimal inhibitory concentration (MIC) > 16 μg/mL (ie, the breakpoint for tobramycin resistance delivered by the parenteral route); changes in the levels of the lowest concentration required to inhibit the growth of 50% of strains tested (MIC50) and 90% of strains tested (MIC90); the percentage of patients with an increase, decrease, or change in the MIC of the most resistant and most prevalent PA strains; and the percentage of patients in whom the PA strain with the highest MIC also was the most prevalent. During the first 6 months, which included three on-drug and off-drug cycles of 4 weeks' duration each, the percentage of tobramycin-treated patients with at least one PA isolate and with an MIC > 16 μg/mL was 13% at baseline, 26% at 20 weeks, and 23% at 24 weeks vs 10%, 17%, and 8%, respectively, for placebo-treated patients. No significant change was observed in MIC50 at 20 and 24 weeks. The increase in MIC90 was not statistically significant. At 24 weeks, there was no increase in the percentage of patients in either group in whom the PA strain with the highest MIC became most the prevalent strain. After the third on-drug cycle, 33% of the tobramycin group showed an increase in the MIC of the strain with the highest MIC. This decreased to 26% after 1 month off drug therapy. A preliminary analysis of the 12-month and 18-month data showed a decrease in the proportion of resistant PA isolates after each off-drug cycle. This return to susceptibility following an off-drug cycle was not observed at 24 months. The mechanism of resistance in this setting is believed to be increased impermeability to drug. At all time points, pulmonary function improved even in patients with MICs of ≥ 128 μg/mL. At 6 months, no increase was seen in the rates of superinfection with tobramycin-resistant, Gram-negative pathogens. Increases in Stenotrophomonas maltophilia were detected in patients after 18 and 24 months of tobramycin therapy and were similar to those rates in patients receiving placebo. These rates may be independent of inhalation therapy.

Section snippets

Rationale for Aerosolized Antibiotic Therapy in CF

The primary rationale for the use of aerosolized antibiotics, rather than parenteral antibiotics, in the treatment of PA in CF patients is improved delivery to the site of infection. Table 1 shows the differences in mean peak sputum and serum concentrations of the drug when delivered IV and as an aerosol by means of three different nebulizers.123 While the highest serum concentration is achieved with IV dosing, sputum concentration, which reflects drug delivery to the site of bacterial

Concerns and Questions

A major concern of the long-term delivery of an antibiotic to the lung is the development of resistant forms of PA, the principal organism infecting the airway in CF patients. The following two questions arise from this concern: (1) what is the significance of this resistance for inhaled therapy?; and (2) what are the implications of this resistance for subsequent parenteral therapy using the same antimicrobial?

To address these questions, it is important to understand the concept of minimal

Mechanisms of Resistance

Microorganisms can acquire drug resistance by a number of different mechanisms (Table 3). Some have inactivating enzymes such as aminoglycoside transferases or β-lactamases. Aminoglycoside transferases are enzymes that are generally encoded by plasmids, while β-lactamases can be carried either on plasmids or on a chromosome. Microorganisms also can alter the target for a specific antibiotic. For example, organisms can become resistant to β-lactam antibiotics by altering their penicillin-binding

Chronic Intermittent Inhaled Tobramycin Trial: Microbiological Outcomes at 6 Months

A randomized, placebo-controlled, double-blind study compared 300-mg bid dosing of tobramycin solution for inhalation (TSI) (TOBI; PathoGenesis Corporation; Seattle, WA) and standard CF care to placebo and standard CF care over a 6-month period.34 The microbiological parameters studied during the first 6 months of the trial included the following:

  • 1.

    the percentage of patients with at least one PA isolate with an MIC ≥ 16 μg/mL (the resistance breakpoint for parenteral tobramycin);

  • 2.

    changes in

Unpublished Data at 18 and 24 Months

Following the 6-month randomized study, patients were allowed to enroll in three consecutive 6-month open-label extension studies, resulting in up to 24 months of total exposure to TSI, during which microbiology continued to be monitored.

Unpublished data (PathoGenesis Corporation) show an incremental increase in the percentage of patients with an isolate with the highest MIC that would be considered resistant at the parenteral breakpoint (ie, ≥ 16 μg/mL) with each successive 6 months of

Improvement in Pulmonary Function

While changes in bacterial susceptibility to tobramycin did occur over time, the clinical significance of this effect in terms of pulmonary function did not appear to be important. Figure 4 shows the percentage of patients with improvement in FEV1 as a function of MIC. At all time points, even patients with an MIC ≥ 128 μg/mL, which would be considered a resistant value using parenteral breakpoint values, continued to show a clinical response to TSI therapy. This clinical improvement, despite

Immunologic Considerations of Inhaled Therapies

In addition to the concern of altered drug susceptibility in the setting of long-term intermittent therapy with inhaled antibiotics, there is also a concern that inhaling any therapeutic agent may result in host immune reactions to that agent. The concern that such reactions may occur is based on responses to such allergens as grain dust, fungi, and molds, all of which can trigger profound allergic reactions when inhaled.7 While the studies of inhaled tobramycin did not measure these

Conclusions: Microbiology

Lung infection in patients with CF cannot be eradicated with current therapeutic modalities. Rather, repeated courses of antimicrobial therapy are aimed at slowing the lung damage that results from such infection. The experience to date with TSI indicates that long-term, intermittent treatment results in the emergence of PA with increased tobramycin MIC values. This finding is not surprising. Repeated courses of antibiotics, regardless of class or administration route, typically result in the

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