In many human infections, hosts and pathogens coexist for years or decades. Important examples include HIV, herpes viruses, tuberculosis, leprosy, and malaria. With the exception of intensively studied viral infections such as HIV͞AIDs, little is known about the extent to which the clonal expansion that occurs during long-term infection by pathogens involves important genetic adaptations. We report here a detailed, whole-genome analysis of one such infection, that of a cystic fibrosis (CF) patient by the opportunistic bacterial pathogen Pseudomonas aeruginosa. The bacteria underwent numerous genetic adaptations during 8 years of infection, as evidenced by a positive-selection signal across the genome and an overwhelming signal in specific genes, several of which are mutated during the course of most CF infections. Of particular interest is our finding that virulence factors that are required for the initiation of acute infections are often selected against during chronic infections. It is apparent that the genotypes of the P. aeruginosa strains present in advanced CF infections differ systematically from those of ''wild-type'' P. aeruginosa and that these differences may offer new opportunities for treatment of this chronic disease.chronic infection ͉ positive selection ͉ virulence ͉ antibiotic resistance M ost cystic fibrosis (CF) patients acquire chronic Pseudomonas aeruginosa infections by their teenage years, if not earlier, and these respiratory infections are responsible for much of the morbidity and mortality caused by CF (1, 2). It has been established that most of these infections are clonal (3), and even among groups of CF patients treated in specific clinics the infections are acquired independently, presumably from diverse environmental reservoirs (4). Previous studies, particularly of the O-antigen biosynthetic locus and the transcriptional regulator mucA, indicate that some P. aeruginosa genes commonly incur loss-of-function mutations as the infections progress (5-7). Mutator phenotypes also arise frequently (8).The overall picture is reminiscent of typical cancers: a clone of cells, albeit in this instance one of exogenous origin, experiences selection for an accumulation of genetic variants that promote long-term survival and clonal expansion. Our data validate this model for P. aeruginosa infections in CF and provide strong evidence for the role of selection in shaping the genotypes of the bacteria that are present during the late, life-threatening phase of the infections. Our data also focus attention on particular aspects of P. aeruginosa metabolism that are premier targets of selection, both in the patient we studied in most detail and in other, independently evolving, P. aeruginosa infections in additional CF patients.

This comprehensive State of the Art review summarizes the current published knowledge base regarding the pathophysiology and microbiology of pulmonary disease in cystic fibrosis (CF). The molecular basis of CF lung disease including the impact of defective cystic fibrosis transmembrane regulator (CFTR) protein function on airway physiology, mucociliary clearance, and establishment of Pseudomonas aeruginosa infection is described. An extensive review of the microbiology of CF lung disease with particular reference to infection with P. aeruginosa is provided. Other pathogens commonly associated with CF lung disease including Staphylococcal aureus, Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans and atypical mycobacteria are also described. Clinical presentation and assessment of CF lung disease including diagnostic microbiology and other measures of pulmonary health are reviewed. Current recommendations for management of CF lung disease are provided. An extensive review of antipseudomonal therapies in the settings of treatment for early P. aeruginosa infection, maintenance for patients with chronic P. aeruginosa infection, and treatment of exacerbation in pulmonary symptoms, as well as antibiotic therapies for other CF respiratory pathogens, are included. In addition, the article discusses infection control policies, therapies to optimize airway clearance and reduce inflammation, and potential future therapies.

for the Macrolide Study Group C YSTIC FIBROSIS (CF) IS CHARacterized by a recurrent cycle of pulmonary infection and inflammation. Pseudomonas aeruginosa is the most common pathogen in patients with CF and by age 18 years, 80% of patients are chronically infected. Neutrophils are the dominant inflammatory cells and much of the airway destruction characteristic of CF is secondary to neutrophil-derived proteases and oxidants. 1 Treatment strategies for CF lung disease have included antibiotics, mucolytics, and antiinflammatory therapies. 2 There is evidence suggesting that macrolide antibiotics may be beneficial for patients with CF. Macrolide antibiotics substantially reduced morbidity and mortality in patients in Japan with diffuse panbronchiolitis. 3,4 Diffuse panbronchiolitis shares many clinical features with CF; patients are often infected with mucoid strains of P aeruginosa and mortality is secondary to chronic pro

Pseudomonas aeruginosa lung infection is an important cause of morbidity and mortality in cystic fibrosis (CF). Longitudinal assessment of the phenotypic changes in P. aeruginosa isolated from young children with CF is lacking. This study investigated genotypic and phenotypic changes in P. aeruginosa from oropharynx (OP) and bronchoalveolar lavage fluid (BALF) in a cohort of 40 CF patients during the first 3 years of life; antibody response was also examined. A high degree of genotypic variability was identified, and each patient had unique genotypes. Early isolates had a phenotype distinct from those of usual CF isolates: generally nonmucoid and antibiotic susceptible. Genotype and phenotype correlated between OP and BALF isolates. As determined by culture, 72.5% of patients demonstrated P. aeruginosa during their first 3 years. On the basis of combined culture and serologic results, 97.5% of patients had evidence of infection by age 3 years, which suggests that P. aeruginosa infection occurs early in CF and may be intermittent or undetectable by culture.