Microbiological and immunologic considerations with aerosolized drug delivery

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 tobramyci n plus standard cystic fibrosis (CF) care to placebo plus standard CF care, examined the following microbiological parameters: percent-age of patients with at least one Pseudomonas aeruginosa (PA) strain with a minimal inhibi tory concentration (MIC) > 16 mug/mL (ie, the break-point for tobramycin re sistance delivered by the parenteral route); changes in the levels of the l owest concentration required to inhibit the growth of 50% of strains tested (MIC50) and 90% of strains tested (MIC50); 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 month s, which included three on-drug and off-drug cycles of 4 weeks' duration ea ch, the percentage of tobramycin-treated patients with at least one PA isol ate and with an MIC > 16 mug/mL was 13% at baseline, 26% at 20 weeks, and 2 3% at 24 weeks vs 10%, 17%, and 8%, respectively, for placebo-treated patie nts. No significant change was observed in MIC50 at 20 and 24 weeks. The in crease in MIC90 was not statistically significant. At 24 weeks, there was n o increase in the percentage of patients in either group in whom the PA str ain 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 I month off d rug therapy. A preliminary analysis of the 12-month and 18-month data showe d 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 o bserved at 24 months. The mechanism of resistance in this setting is believ ed to he increased impermeability to drug. At all time points, pulmonary fu nction improved even in patients with MICs of greater than or equal to 128 mug/mL. At 6 months, no increase was seen in the rates of superinfection wi th tobramycin-resistant, Gram-negative pathogens. Increases in Stenotrophom onas maltophilia were detected in patients after 18 and 24 months of tobram ycin therapy and were similar to those rates in patients receiving placebo. These rates may be independent of inhalation therapy.