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* From the Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI.
Correspondence to: John J. LiPuma, MD, University of Michigan, 1150 W Medical Center Dr, 8323 MSRB III, Box 0646, Ann Arbor, MI 48109; e-mail: jlipuma{at}umich.edu
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.
Key Words: aerosolized • breakpoint • cystic fibrosis • Gram-negative pathogens • minimal inhibitory concentration • Pseudomonas aeruginosa • superinfection • tobramycin
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