To determine a safe, effective, and systematic approach to antibiotic treatment of Pseudomonas infection in young children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF), an autosomal recessive disorder without a cure, has a current median survival of over 33 years and affects approximately 25,000-30,000 individuals in the United States. The primary cause of morbidity and mortality in patients with CF is progressive obstructive pulmonary disease associated with chronic Pseudomonas aeruginosa endobronchial bacterial infection and an intense neutrophil-dominated host inflammatory response. Pseudomonas aeruginosa (Pa) is the most important pathogen in cystic fibrosis (CF) lung disease. Pa infection begins very early in life, and the prevalence of Pa in respiratory cultures increases with age, from 30% at ages 2-5 years, to 50% at ages 6-10 years, and to 80% at ages over 18 years (3). Chronic Pa endobronchial infection is highly resistant to antibiotics. Once established, chronic Pa endobronchial infection is virtually impossible to eradicate. Pa infection has been associated with poorer clinical outcomes, including more rapid decline in pulmonary function and higher mortality rates in patients with CF. Features of early CF lung disease suggest that there may be a "window of opportunity" during which time anti-pseudomonal therapy may be effective in eradicating Pa. Thus, there is a growing interest in aggressive, early anti-pseudomonal intervention in order to delay or prevent chronic Pa infection and its clinical consequences.

DESIGN NARRATIVE: Young children, ages 1 to 12, with cystic fibrosis (CF) will be enrolled at one of 60 clinical centers nationwide in an 18-month clinical trial that will include approximately 300 children. The clinical trial is designed to allow randomized controlled evaluation of early intervention with inhaled and oral antipseudomonal therapy in young patients with CF at first isolation of Pseudomonas aeruginosa (PA) from respiratory cultures. The clinical trial will investigate two different antimicrobial treatment regimens: (1) Culture-based antibiotic therapy, i.e., treatment based on microbiology findings of Pa positive respiratory cultures, and (2) Cycled antibiotic therapy, i.e., treatment provided systematically in quarterly cycles until the end of the 18-month study period. Inhaled tobramycin and oral ciprofloxacin have been selected as first choice antimicrobials for this trial, based on a consensus conference at which therapies were selected and ranked based on the amount of evidence and of safety data available.

The primary outcome of the clinical trial is the proportion of recurrent PA positive cultures during the 18-month study period, comparing participants assigned to the culture-based treatment group with participants assigned to the cycled treatment group. Another key clinical outcome measure will evaluate the time to occurrence of a pulmonary exacerbation. The secondary outcomes will evaluate the effect of antibiotic therapy on safety (adverse events profile with particular reference to musculo-skeletal symptoms, renal function as measured by serum creatinine, hearing acuity, liver function tests, and complete blood count); clinical variables (occurrence of hospitalization during 18 months, proportion of patients with pulmonary exacerbations, linear growth, weight gain, forced expiratory volume in one second (FEV1), and total inpatient days); microbiology findings (presence and pattern of mucoid Pa isolates identified by colony morphology, changes in antibiotic susceptibility of Pa isolates from oropharyngeal cultures, and changes in the genotype of Pa isolates from baseline to the end of the study); and Pa serology (changes in and patterns of anti-pseudomonal antibody titers against Exotoxin A and other selected pseudomonas antigens).

Ages Eligible for Study:  1 Year   -   12 Years,  Genders Eligible for Study:  Both

Criteria