Azithromycin Partially Mitigates Dysregulated Repair of Lung Allograft Small Airway Epithelium.

BACKGROUND: Dysregulated airway epithelial repair following injury is a proposed mechanism driving posttransplant bronchiolitis obliterans (BO), and its clinical correlate bronchiolitis obliterans syndrome (BOS). This study compared gene and cellular characteristics of injury and repair in large (LAEC) and small (SAEC) airway epithelial cells of transplant patients. METHODS: Subjects were recruited at the time of routine bronchoscopy posttransplantation and included patients with and without BOS. Airway epithelial cells were obtained from bronchial and bronchiolar brushing performed under radiological guidance from these patients. In addition, bronchial brushings were also obtained from healthy control subjects comprising of adolescents admitted for elective surgery for nonrespiratory-related conditions. Primary cultures were established, monolayers wounded, and repair assessed (±) azithromycin (1 µg/mL). In addition, proliferative capacity as well as markers of injury and dysregulated repair were also assessed. RESULTS: SAEC had a significantly dysregulated repair process postinjury, despite having a higher proliferative capacity than large airway epithelial cells. Addition of azithromycin significantly induced repair in these cells; however, full restitution was not achieved. Expression of several genes associated with epithelial barrier repair (matrix metalloproteinase 7, matrix metalloproteinase 3, the integrins ß6 and ß8, and ß-catenin) were significantly different in epithelial cells obtained from patients with BOS compared to transplant patients without BOS and controls, suggesting an intrinsic defect. CONCLUSIONS: Chronic airway injury and dysregulated repair programs are evident in airway epithelium obtained from patients with BOS, particularly with SAEC. We also show that azithromycin partially mitigates this pathology.

Pseudomonas aeruginosa antibiotic resistance in Australian cystic fibrosis centres.

BACKGROUND AND OBJECTIVE: In cystic fibrosis (CF), chronic Pseudomonas aeruginosa infection is associated with increased morbidity, antibiotic treatments and mortality. By linking Australian CF registry data with a national microbiological data set, we examined the association between where treatment was delivered, its intensity and P. aeruginosa antibiotic resistance. METHODS: Sputa were collected from paediatric and adult CF patients attending 18 Australian CF centres. P. aeruginosa antibiotic susceptibilities determined by local laboratories were correlated with clinical characteristics, treatment intensity and infection with strains commonly shared among Australian CF patients. Between-centre differences in treatment and antibiotic resistance were also compared. RESULTS: Large variations in antibiotic usage, maintenance treatment practices and multi-antibiotic resistant P. aeruginosa (MARPA) prevalence exist between Australian CF centres, although the overall proportions of MARPA isolates were similar in paediatric and adult centres (31% vs 35%, P = 0.29). Among paediatric centres, MARPA correlated with intravenous antibiotic usage and the Australian state where treatment was delivered, while azithromycin, reduced lung function and treating state predicted intravenous antibiotic usage. In adult centres, body mass index (BMI) and treating state were associated with MARPA, while intravenous antibiotic use was predicted by gender, BMI, dornase-alpha, azithromycin, lung function and treating state. In adults, P. aeruginosa strains AUST-01 and AUST-02 independently predicted intravenous antibiotic usage. CONCLUSION: Increased treatment intensity in paediatric centres and the Australian state where treatment was received are both associated with greater risk of MARPA, but not worse clinical outcomes.