This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The majority of individuals with cystic fibrosis (CF), the most common lethal genetic disease of childhood, suffer from chronic endobronchial infection punctuated by recurrent acute exacerbations, with progressive lung damage and premature death. psuedomonas aeruginosa is the single mostimportant pulmonary pathogen infecting patients with cystic fibrosis. Approximately 60% of CF patients overall are infected with this organism and in patients over 18 years of age, this number climbs to approximately 80%. Chronic endobronchial infection with subsequent respiratory failure is the most frequent cause of death in CF; up to 90% of deaths in CF have been attributed to P. aeruginosa infection. Surveillance cultures of CF airway secretions, now recommended quarterly by the Cystic Fibrosis Foundation, may yield as many as 4-5 morphologically distinct isolates of P. aeruginosa, with a median of about 2.5 per patient. It is generally desirable to select antibiotic combinations to which each isolate will be doubly susceptible, as single-agent treatment of P. aeruginosa infection readily selects for resistant subpopulations. Intravenous or inhaled antibiotics are a mainstay of therapy for CF endobronchial infection, but represent an ongoing clinical challenge because P. aeruginosa is notorious for its intrinsic and acquired antibiotic resistance. Antibiotic resistance is one of the most important problems faced by CF caregivers. In a recent multicenter study of isolates from more than 500 patients with CF from across the United States, 11.6% of patients had strains identified as multiply resistant. Testing for synergistic combination of agents in multiply resistant CF isolates of P. aeruginosa fails to identify potential therapy for 17%. The use of antibiotic therapy has had a dramatic affect on the health and well-being of patients with CF. The life expectancy of patients has lengthened as new agents have become available, with predicted survival increasing from age 18 years in 1972 to ages in the early 30's by 2001. Unfortunately, this progress has slowed recently and may be associated with increasing antibiotic resistance among CS isolates of P. aeruginosa in association with a decreasing rate of development of new classes of antimicrobial agents. The presence of antibiotic resistant P. aeruginosa not only limits potential antimicrobial treatment, but can also preclude patients from eligibility for lung transplantation and other potentially life-saving modalities. Thus the prospect of developing more effective strategies for antimicrobial therapy offers great hope to patients with CF for continued improvement in life-expectancy. Selection of appropriate antibiotics for CF endobronchial infection depends on susceptibility testing of bacterial isolates. At present, standard susceptibility testing is performed by culturing each bacterial isolate in liquid media as a cellular suspension (planktonic growth) and testing rapidly dividing ('log phase') cells to determine the minimum inhibitory concentration (MIC) for each antibiotic. Although this standard method of susceptibility testing is approved by the National Committee for Clinical Laboratory Standards (NCCLS), the effectiveness of the standard approach, as currently applied to the treatment of CF endobronchial infection, has not been correlated with clinical response to treatment. Among the factors that may contribute to the antibiotic resistance of P. aeruginosa is the potential for growth as a biofilm within the airways of CF patients. Biofilm growth may represent an especially important resistance mechanism. Although the exact form of CF airway biofilms is unknown, classic biofilms are organized aggregates of bacterial cells that form on surfaces, held together by a secreted matrix in which the cells are embedded. Biofilms formed by P. aeruginosa laboratory strains generally display marked resistance to the antibiotics commonly used to treat CF (i.e., thos indicated on the bsis of standard planktonic assay). Because bacterials cells within a biofilm are generally in stationary phase (i.e., not rapidly dividing), one implication of biofilm growth in the CF airway is that standard susceptibility testing may not reflect the true antibiotic susceptibility of P. aeruginosa as it exists in the airway. Antibiotics with good activity against planktonic cells in log phase growth may have little activity against biofilms. Conversely, antibiotics not traditionally thought of as anti-pseudomonal on the basis of standard susceptibility testing methods (such as the macrolides) may have promise as antibiofilm agents. Thus, re-evaluating our current arsenal of antibiotics by testing the susceptibility of P. aeruginosa CF isolates grown as biofilms may have improtant implications for the treatment of CF lung infections. Additionally, it should be noted that although standard susceptibility testing is routinely used to direct antibiotic therapy the clinical utility of this practice has never been established. The proposed randomized multi-center trial will compare the use of standard versus biofilm methods of susceptibility testing of P. aeruginosa sputum isolates to guide antibiotic selection for the treatment of airway infection in clinically stable patients with CF. Specifically, the standard method of susceptibiity testing performed on planktonic bacteria will be compared to the new method using biofilm grown organisms. The study hypothesis is that the use of biofilm susceptibility testing to guide antibiotic selection will result in a greater reduction in sputum bacterial density than the use of the standard method of susceptibility testing. The proposed trial is based on the pre-emptive strategy of treatment, therefore patients will be enrolled when clinically stable and not experiencing an acute pulmonary exacerbation. This will minimize the potential risk of non-response to antibiotic therapy. Patients will only be enrolled if they have a significant bacterial load, i.e., P. aeruginosa density must be at least 105 colony forming units per gram (CFU/gm) of sputum, and if their isolates demonstrate susceptibiity to the antibiotics tested. Thus all randomized patients could potentially benefit from treatment by having a microbiologic response to directed antibiotic therapy. The primary objective of the study is to compare the microbiological efficacy of using standard versus biofilm susceptibility testing of P. aeruginosa sputum isolates to guide antibiotic selection for treatment of airway infection in clinically stable patients with cystic fibrosis (CF).
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