Inhaled Tobramycin Associated With Extended Survival in Cystic Fibrosis

Kate Johnson

October 27, 2010

October 27, 2010 — Inhaled tobramycin is associated with significantly extended survival rates in patients with cystic fibrosis (CF), according to results of a study reported at the Annual North American Cystic Fibrosis Conference.

Use of the medication was associated with a 21% reduction in the odds of subsequent-year mortality, reported lead investigator Gregory S. Sawicki, MD, MPH, associate director of the Cystic Fibrosis Center at Children's Hospital Boston, and assistant professor of pediatrics at Harvard Medical School, Boston, Massachusetts.

In addition, compared with patients who never used the medication, those who used it "always" had a 36% reduction in the odds of subsequent-year mortality, he said.

Pseudomonas aeruginosa (PA) is the most common pathogen contributing to CF mortality, and its treatment is recognized as an important factor in improved outcomes in patients with CF, said Dr. Sawicki in an interview with Medscape Medical News.

However, to date, studies have focused on short-term outcomes of therapy such as lung function and hospitalization rates, rather than mortality rates.

The current study, funded by Novartis, analyzed data from the Cystic Fibrosis Foundation Patient Registry between the years of 1996 and 2008.

Data from 12,740 patients who met criteria for tobramycin therapy were analyzed during a mean follow-up period of 6 years to assess the effect of tobramycin on mortality rates.

Patients were a mean age of 22 years when they met criteria for treatment, and 49.2% were women.

Criteria for tobramycin therapy included:

  • chronic PA infection, defined as a history of 4 or more positive cultures;

  • age 6 years or older; and

  • moderate to severe lung function, defined as a forced expiratory volume in 1 second between 25% and 75% of predicted in the current or prior year.

The analysis controlled for multiple confounding factors that are associated with CF mortality, including socioeconomic factors, comorbidities, underweight, disease severity, other infections (Burkholderia cepacia, methicillin-resistant Staphylococcus aureus), and other treatments (dornase alfa, pancreatic supplements, high-dose ibuprofen, and transplantation), Dr. Sawicki said.

There were a total of 2538 deaths reported during the study period.

The data showed that among patients who had used tobramycin therapy in the previous year there was a 21% boost in subsequent-year survival (odds ratio [OR], 0.79) compared with in patients who had not used tobramycin in the previous year.

In addition, when patients who had never used tobramycin were compared with patients who "always" used it there was a 36% boost in overall survival (OR, 0.64) among users.

Although the study shows no more than an association between tobramycin treatment and survival, "these data suggest is that tobramycin should be a lifelong therapy," Dr. Sawicki said. "It is a burden — but if it adds years to patients' lives, then it is a risk that most families and clinicians would be willing to undertake."

Although the treatment is normally prescribed twice daily every other month, the duration of therapy depends on clinical judgment, he explained.

"Up to 80% of adolescents and adults with particularly moderate to severe lung disease have Pseudomonas infection, and once it's detected, it's very rare that we completely eradicate it," he said.

In such patients, despite initiation of treatment and even negative cultures, maintenance therapy may often be warranted. "Even though we've reduced the organism or even perhaps eradicated it, we might want to maintain them on therapy to suppress the development of future infection."

Studies show that only about two thirds of eligible patients are optimally treated with inhaled tobramycin, said Dr. Sawicki. He suggested that although costs and adverse effects may present minor barriers, the inconvenience of treatment is significant.

"The nebulization time is about 10 to 15 minutes per dose. Particularly for people who have very active lives, who are either trying to go to school or to work, and to fit in another therapy such as airway clearance, the daily burden for CF treatments can be upwards of 2 hours a day."

Because it is an inhaled medication, with little systemic absorption, adverse effects from tobramycin are considered to be minimal — although regular screening for tinnitus and kidney function is recommended, he said. "In my clinical experience, patients tolerate the therapy very well, even for multiple years at a time."

And in terms of cost, he said he has never encountered refusal of payment by an insurance company. The wholesale cost of a single 28-day course of inhaled tobramycin is $4103.39, according to a company spokesman, and patients may be eligible for assistance through a company support program.

The findings "support our current philosophy of lifelong suppressive antibiotic therapy," said Stanley B. Fiel, MD, professor of medicine at Mount Sinai School of Medicine, in New York City. Dr. Fiel is a recognized authority on CF and was not involved with the study.

"Although it is a retrospective study, it also reinforces what appears to be a well-tolerated long-term treatment, and this is encouraging, since other aerosol or dry powder antibiotics are in development or, in the case of Cayston [aztreonam; Gilead], are just recently approved," he said.

The study also underscores the importance of registries such as the Cystic Fibrosis Foundation patient registry in enabling research on large patient populations over a span of many years, he added.

Dr. Fiel serves is on speakers bureaus and advisory boards for Gilead, Pfizer, GlaxoSmithKline, and Novartis and has received grants from Vertex Pharmaceuticals and Mpex Pharmaceuticals. Dr. Sawicki serves on advisory boards for Novartis and Genentech.

Annual North American Cystic Fibrosis Conference: Abstract 402. Presented October 21, 2010.


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