Now Take a Deep Breath! Inhalational Tobramycin

abstract & commentary

Synopsis: Inhaled tobramycin is effective in the management of Pseudomonas aeruginosa infection in cystic fibrosis.

Source: Ramsey BW, et al. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med 1999;340:23-30.

A preparation of tobramycin (tobi) for inhalational administration received FDA approval as an orphan drug at the end of 1997 for the treatment of Pseudomonas aeruginosa infections in cystic fibrosis on the basis of two randomized clinical trials involving more than 500 patients. In these studies, cyclical administration to patients older than 6 years of age (mean age of the participants was 21 years) with serum creatinine less than 2 mg/dL who were not infected with Burkholderia cepacia was associated with a significant improvement of FEV1 over baseline. The density of P. aeruginosa decreased during treatment periods, but returned to baseline during periods when the drug was not administered. Of note, however, is that the diminution in density of P. aeruginosa in sputum during periods when tobramycin as administered was progressively attenuated during the 24 weeks of cyclical therapy. Drug recipients experienced a mean of three fewer days of hospitalization and a mean of 4.4 days fewer of parenteral antibiotic therapy treatment when compared to placebo recipients. The only toxicities noted more frequently in the antibiotic recipients than the placebo recipients were transient tinnitus and voice alteration.

Comment by Stan Deresinski, MD, FACP

The high and variable concentrations of tobramycin in sputum, as well as the adverse effects of sputum and its components on the antibacterial activity of aminoglycosides, makes interpretation of the predictive value of in vitro susceptibility tests problematic. Thus, the definition of resistance for parenteral administration does not apply to inhaled tobramycin. There is a hint, however, that high levels of in vitro resistance (MIC > 128 mcg/mL) of P. aeruginosa may be predictive of failure. As expected, the administration of tobramycin over this prolonged period was associated with "MIC creep;" the proportion of P. aeruginosa MICs greater than 16 mcg/mL increased from 13% at baseline to 23% at the end of therapy. Tobramycin inhalation was not associated with increased risk of infection with B. cepacia, Stenotrophomonas maltophilia, or Alcaligenes xylosidans; however, Candida albicans and Aspergillus species were isolated with increased frequency.1

Antibiotics, including tobramycin, have frequently been administered by inhalation in the past, in the absence of products such as TOBI that were designed specifically for this use. Whether TOBI is more effective or safer than tobramycin compounded for parenteral administration is, to my knowledge, unknown. This is an important issue given the high cost of TOBI.

The inhalational route has a number of theoretical benefits, including the potential for achievement of extremely high antibiotic concentrations in respiratory secretions and the limitation of systemic toxicity. The tobramycin concentration in sputum approximately 10 minutes after inhalation of a 300-mg dose is, however, highly variable, ranging from 35 to 7414 mcg/g (mean, 1237 mcg/g) and exhibits a rapid decline to approximately one-seventh of these early levels after two hours. Absorption is minimal, with a mean serum concentration one hour after a single 300 mg administration to children with cystic fibrosis of approximately 1 mcg/mL. It is of interest that administration by inhalation of antibiotics in liposomes is associated with greater persistence in respiratory secretions.

Administration by this route is safer than systemic administration. The PARC LC nebulizer generates particles with a mean mass diameter of 4 mm and delivers drug primarily to the airways; avoidance of delivery of drug to the alveoli presumably limits systemic absorption. Neither nephrotoxicity nor hearing loss has been described in clinical studies with this agent, although transient tinnitus has been reported. Bronchospasm may, on occasion, follow tobramycin inhalation.

TOBI is provided in single-dose ampules, each containing 300 mg of tobramycin. It is supplied in boxes of 56, providing enough drug for a q 12h 28-day supply. It is approved for use in patients with cystic fibrosis in whom it is recommended that it be administered for 28- day cycles with intervening 28 days of treatment-free cycles for a total of 24 weeks. It is administered via a PARI LC PLUS reusable jet nebulizer powered by a DeVilbiss Pulmo-Aide compressor.2

Unpublished evidence suggests that TOBI may also be effective in the treatment of P. aeruginosa infection in adults with bronchiectasis.

References

1. Burns JL, et al. Effect of chronic intermittent administration of inhaled tobramycin on respiratory microbial flora in patients with cystic fibrosis. J Infect Dis 1999; 179:1190-1196.

2. http://www.pathogenesis.com/tobi

Which of the following is correct with regard to inhalational tobramycin (TOBI)?

a. Peak serum concentration after a 300 mg dose is approximately 10 mcg/ML.

b. Peak sputum concentration after a 300 mg dose is approximately 10 mcg/mL.

c. Neither nephrotoxicity nor hearing loss was reported in clinical trials of this drug in cystic fibrosis.

d. It should be administered to patients with P. aeruginosa infections and cystic fibrosis in a dose of 300 mg every other day.