Though the use of aerosolized antibiotics has been part of the regular thera-peutic regimen for many CF-affected individuals for quite some time, the recent FDA approval of TOBI(tm) (Tobramycin Solution for Inhalation) marks the opening of a new chapter in the struggle against bacterial infections and the lung damage they cause. While the new development is not without its unanswered questions and areas of concern, the availability of a standardized dosage and treatment regimen for this promising drug offers some relief and assurance to patients and prescribing physicians alike.
TOBI is not a new drug per se. The antibiotic Tobramycin was discovered in 1975, and studies showing its effectiveness against P. aeruginosa were published in the late 1980's. Its use via inhalation was reported as an established therapy for CF in 1994, and by 1997 the practice of administering Tobramycin with a nebulizer had become widespread. However, the dosage levels, antibiotic/saline mixture concentration and specific nebulizing machines used for administration varied. There also was some controversy over the safety and effectiveness of the treatment because all the variables had not been sufficiently scrutinized in controlled studies. TOBI is a breakthrough because it is a precisely tailored antibiotic therapy program, with not only a specified dosage whose effectiveness and safety has been established through a series of studies, but also a carefully chosen delivery system that maximizes the delivery of the drug to its target.
TOBI was developed by doctors at Children's Hospital and Medical Center in Seattle, in conjunction with PathoGenesis Corporation, which in 1994 licensed the rights to market the new treatment. In 1989, Bonnie Ramsey, M.D., the Principal Investigator of the TOBI clinical trials, had conducted studies that evaluated the consequences of long-term, high- dosage aerosolized Tobramycin treatment. Concerns over possible toxic side effects were dispelled by the absence of kidney damage or hearing loss, two side effects sometimes seen with intravenous use of Tobramycin.
In May 1994, Dr. Ramsey and Dr. Arnold Smith published a study that examined the Tobramycin generating capacity of five different nebulizers. Over the next couple of years, studies at several other hospitals confirmed the safety of aerosolized Tobramycin and established the ability of high- dosage aerosolized Tobramycin to overwhelm otherwise resistant P. aeruginosa strains. These studies also underscored what Ramsey and Smith had been looking into: that the choice of nebulizer, nebulizing solution, and techniques of nebulization had a great impact on the amount of antibiotic that actually reached the bacteria in the lungs.
In April 1997, Ramsey and Smith published the results of a larger study of nebulizers, this one involving twelve different nebulizers as well as four different compressors. They were searching for the combination of nebulizer mechanisms and solution formulation that would yield optimum performance. They determined, among other things, that jet- type nebulizers (as distinguished from ultrasonic-type) were able to deliver higher concentrations of antibiotic and used less time to do so.
The final clinical trials for TOBI used a specially adjusted 300 mg dose of Tobramycin in combination with a PARI LC PLUS(tm) reusable nebulizer and a De Vilbiss Pumo-Aide(tm) compressor. It is this particular combination that produced the excellent results in the trials and that will be available for doctors to prescribe.
The patients participating in the two double blind trials ranged in age from 6 to 63 years. TOBI is administered twice a day (10 to 15 minutes per treatment) in a 28 day on drug/28 day off drug cycle. Those patients who received TOBI in the trial experienced a significant improvement in lung function and maintained that improvement throughout the six- month study. They spent fewer days in the hospital and required less intravenous anti-pseudomonal treatment. The only side effects were some vocal hoarseness in 13% of patients and temporary ringing of the ears in 3% of patients.
Still to be established, however, is whether TOBI will retain its effectiveness over the long term. In the trials, the therapy resulted in a significant reduction in P. aeruginosa density in sputum during the on-drug periods, but this bacterial density returned to baseline levels during the off-drug periods and successive reductions were of decreasing magnitude. It is unclear what the implications of this decrease are for the individual CF patient.
Also unsettling is the impact of the cost of TOBI upon the average cost of CF treatment. TOBI is extremely expensive, exceeding even Genentech's Pulmozyme(tm) in annual cost for use. Insurance companies and managed care organizations may balk at the financial expense that TOBI represents. Thus, while TOBI offers hope and holds promise for the CF community, the full effect of its arrival remains to be seen.
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