NEW YORK (Reuters Health) – Fosfomycin/tobramycin for inhalation (FTI) is effective in cystic fibrosis patients with chronic Pseudomonas aeruginosa (PA) airway infection and reduced lung function, a double-blind, placebo-controlled study found.
FTI maintained the substantial improvements in lung function achieved during a run-in course of aztreonam for inhalation solution and was well-tolerated, the investigators report in the American Journal of Respiratory and Critical Care Medicine, online November 17.
“It was also effective against methicillin-resistant Staph aureus, for which there are relative fewer drugs,” first author Dr. Bruce Trapnell, of University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center, Ohio told Reuters Health.
“However, the study was not set up or powered to evaluate this outcome and the data should be considered supportive but further studies are needed,” he emphasized.
Most patients wish CF develop PA infection and chronic infection PA is linked with the decline in lung function and health status. While PA is the predominant pathogen found in the airways of adults with CF, methicillin-resistant Staphylococcus aureus (MRSA) is also increasing found.
The need for additional broad spectrum antibiotics to treat PA and other pathogens prompted the development of fosfomycin/tobramycin for inhalation (FTI).
Fosfomycin is a phosphoric acid antibiotic active against gram-positive, gram-negative, and anaerobic bacteria and tobramycin is an aminoglycoside with gram-negative activity. FTI has not yet been approved by the US Food and Drug Administration.
The current study involved 119 patients with a mean age of 32 years and mean forced expiratory volume in one second (FEV1) of 49% predicted at screening. After a 28-day open-label, run-in course of aztreonam for inhalation solution administered three times daily, patients were randomly allocated to placebo or FTI (160/40 mg or 80/20 mg administered twice daily for 28 days).
A 28-days “on” and 28-days “off” dosing schedule is used for inhaled antibiotics that are currently approved in the US for treating CF patients with airway PA, the authors note. However, the rationale for the “off” period is now being questioned.
In the current study, after the 28-day aztreonam run-in course, mean improvement in FEV1 percent predicted was 7.0%. The subsequent 28-day course of FTI maintained this improvement in lung function, whereas lung function in placebo-treated patients declined toward pre-aztreonam levels. At 28 days, the treatment effect favoring FTI 160/40 mg (over placebo) was 6.2% (P = 0.002) and 7.5% favoring FTI 80/20 mg (over placebo) (P < 0.001).
Statistically significant reductions in mean PA sputum density was also noted in the FTI 80/20 group versus placebo (P = 0.01)
“Adverse events, primarily cough, were consistent with CF disease,” the authors say. Respiratory events including dyspnea and wheeze, were less common with FTI 80/20 than FTI 160/40. All respiratory events were mild or moderate in severity. No clinically significant changes in laboratory values were noted.
Data from 63 patients co-infected with Staph aureus and PA “provided several interesting observations, including the inability to culture S. aureus from the end of the FTI treatment period to study end in 13 patients receiving FTI,” the authors note.
They emphasize, however, that the impact of FTI on S. aureus airway infection requires further investigation, using a study specifically designed to assess these infections.
The study was sponsored by Gilead Sciences, Inc., with funding from an FDA grant and NIH General Clinical Research Center grant.
Circulation 7 November 2011.