Inhaled aztreonam for chronic Burkholderia infection in cystic fibrosis: a placebo-controlled trial.

BACKGROUND: Individuals with Burkholderia spp. infection have historically been excluded from efficacy trials of inhaled antibiotics, including aztreonam for inhalation solution (AZLI). METHODS: A double-blind, placebo-controlled, 24-week trial of continuous AZLI/placebo treatment was undertaken in individuals with cystic fibrosis (CF) and chronic Burkholderia spp. infection. All subjects also received usual medical care (determined by their physicians). Additional antibiotic use was not restricted. RESULTS: Baseline FEV1% predicted values ranged from 15.8% to 114.6%. No significant treatment differences (AZLI vs. placebo) were observed at week 24 for any endpoints, including FEV1% predicted, number of respiratory exacerbations requiring systemic/inhaled antibiotics, or hospitalizations. Continuous AZLI administration was well tolerated. Burkholderia spp. susceptibility to antibiotics commonly used in CF therapy showed little change. CONCLUSIONS: 24-weeks of continuous AZLI treatment did not significantly improve lung function in CF subjects with chronic Burkholderia spp. infection. Non-study antibiotic use may have confounded any potential AZLI effects.

Eradication of Pseudomonas aeruginosa biofilms on cultured airway cells by a fosfomycin/tobramycin antibiotic combination.

Chronic biofilm formation by Pseudomonas aeruginosa in cystic fibrosis (CF) lungs is a major cause of morbidity and mortality for patients with CF. To gain insights into effectiveness of novel anti-infective therapies, the inhibitory effects of fosfomycin, tobramycin, and a 4:1 (wt/wt) fosfomycin/tobramycin combination (FTI) on Pseudomonas aeruginosa biofilms grown on cultured human CF-derived airway cells (CFBE41o-) were investigated. In preformed biofilms treated for 16 h with antibiotics, P. aeruginosa CFU per mL were reduced 4 log10 units by both FTI and tobramycin at 256 mg L(-1) , while fosfomycin alone had no effect. Importantly, the FTI treatment contained five times less tobramycin than the tobramycin-alone treatment. Inhibition of initial biofilm formation was achieved at 64 mg L(-1) FTI and 16 mg L(-1) tobramycin. Fosfomycin (1024 mg L(-1)) did not inhibit biofilm formation. Cytotoxicity was also determined by measuring lactate dehydrogenase (LDH). Intriguingly, sub-inhibitory concentrations of FTI (16 mg L(-1)) and tobramycin (4 mg L(-1)) and high concentrations of fosfomycin (1024 mg L(-1)) prevented bacterially mediated airway cell toxicity without a corresponding reduction in CFU. Overall, it was observed that FTI and tobramycin demonstrated comparable activity on biofilm formation and disruption. Decreased administration of tobramycin upon treatment with FTI might lead to a decrease in negative side effects of aminoglycosides.

Optimal airway antimicrobial therapy for cystic fibrosis: the role of inhaled aztreonam lysine.

IMPORTANCE OF THE FIELD: Chronic endobronchial infection in cystic fibrosis (CF) leads to progressive lung function loss and respiratory failure. Most adult CF patients are infected with Pseudomonas aeruginosa, an important predictor of mortality. Suppressing chronic P. aeruginosa infection with inhaled antibiotics is standard of care for CF patients. AREAS COVERED IN THIS REVIEW: This review describes the development (2003 - 2010) of aztreonam lysine 75 mg powder and solvent for nebulizer solution (AZLI; Cayston), an aerosolized formulation of the monobactam antibiotic aztreonam. WHAT THE READER WILL GAIN: AZLI was studied in patients with CF and chronic P. aeruginosa airway infection. In placebo-controlled trials, AZLI improved respiratory symptoms, increased forced expiratory volume in 1 sec (FEV(1)), decreased sputum P. aeruginosa density, and was well tolerated. An open-label follow-on trial of nine 'on/off' courses showed that AZLI was safe and the effect durable with repeated administration. AZLI was recently approved for use in CF patients in Australia and the USA, and conditionally approved in Canada and the European Union. AZLI is given three times daily for 28 days (2 - 3 min/dose), followed by 28 days off-drug. AZLI is used only with the Altera Nebulizer System, which provides appropriate particle size and small airway deposition, and has excellent portability. TAKE HOME MESSAGE: AZLI is a new therapy that is safe and effectively improves respiratory symptoms and FEV(1) in patients with CF.

Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection.

BACKGROUND: Bronchiectasis and pulmonary infection with nontuberculous mycobacteria (NTM) may be associated with disease-causing mutations in the cystic fibrosis transmembrane regulator (CFTR). METHODS: Fifty adult patients at Stanford University Medical Center with a diagnosis of bronchiectasis and/or pulmonary NTM infection were prospectively characterized by sweat chloride measurement, comprehensive mutational analysis of CFTR, and sputum culture results. RESULTS: A de novo diagnosis of cystic fibrosis (CF) was established in 10 patients (20%). Patients with CF were more likely than those without CF to have mucus plugging seen on chest high-resolution CT, and women with a CF diagnosis were thinner, with a significantly lower mean body mass index than the non-CF subjects. Thirty CFTR mutations were identified in 24 patients (50% prevalence). Sweat chloride concentration was elevated > 60 mEq/dL (diagnostic of CF) in seven patients (14%), and from 40 to 60 mEq/dL in eight patients (16%). The frequency of CFTR mutations was elevated above that expected in the general population: heterozygous DeltaF508 (12% vs 3%), R75Q (14% vs 1%), and intron 8 5T (17% vs 5 to 10%). Other known CFTR mutations identified were V456A, G542X, R668C, I1027T, D1152, R1162L, W1282X, and L183I. Three novel CFTR mutations were identified: A394V, F650L, and C1344S. CONCLUSIONS: Mutations in CFTR that alter RNA splicing and/or functional chloride conductance are common in this population, and are likely to contribute to the susceptibility and pathogenesis of adult bronchiectasis and pulmonary NTM infection. Careful clinical evaluation for disease cause should be undertaken in this clinical context.

Risk factors for death of patients with cystic fibrosis awaiting lung transplantation.

RATIONALE: The optimal timing for listing of cystic fibrosis patients for lung transplantation is controversial. OBJECTIVES: We conducted a retrospective cohort study of 343 patients listed for lung transplantation at four academic medical centers to identify risk factors for death while awaiting transplantation. METHODS: Data on possible risk factors were abstracted from medical records. MEASUREMENTS: Time to death, patient demographic characteristics, and risk factors for death while awaiting transplantation were assessed. Univariate and multivariate survival analyses were performed using Cox regression. RESULTS: By univariate analyses, FEV1 < or = 30% predicted (HR, 3.8; 95% CI, 2.0-7.5), Pa(CO2) > or = 50 mm Hg (HR, 1.85; 95% CI, 1.1-3.0), and shorter height (HR, 1.8; 95% CI, 1.1-3.0) were associated with a higher risk of death. Referral from an accredited cystic fibrosis center was associated with a lower risk (HR, 0.53; 95% CI, 0.30-0.92). The final multivariate model included referral from an accredited cystic fibrosis center (HR, 0.5; 95% CI, 0.3-1.0) and listing year after 1996 (HR, 0.4; 95% CI, 0.2-0.7); both were associated with a lower risk of death. FEV1 < or = 30% predicted (HR, 6.8; 95% CI, 2.4-19.3), Pa(CO2) > or = 50 mm Hg (HR, 6.9; 95% CI, 1.5-32.1), and use of a nutritional intervention (HR, 2.3; 95% CI, 1.3-4.1) were associated with increased risk. Patients with FEV1 > 30% predicted had a higher risk of death only when their Pa(CO2) was > or = 50 mm Hg (HR, 7.0; 95% CI, 1.5-32), while the increased risk of death with FEV1 < or = 30% was not further influenced by the presence of hypercapnia. CONCLUSIONS: We identified risk factors for waiting list mortality that could impact on transplant listing and allocation guidelines.

Inflammatory and microbiologic markers in induced sputum after intravenous antibiotics in cystic fibrosis.

Induced sputum has been used to study airway inflammation. We sought to determine whether markers of infection and inflammation in induced sputum were a useful and safe outcome measure in cystic fibrosis. We hypothesized that bacterial density and inflammatory content of induced sputum would decrease after antibiotic therapy. Induced sputum was assayed for bacterial density, cell count, and differential and inflammatory markers before and after treatment with intravenous antibiotics. Fifty-five of the 72 subjects enrolled (mean age +/- SD 18.2 +/- 7.9 years) completed the study. FEV1 increased by an average 0.3 +/- 0.3 L (10.4 +/- 8.7% predicted FEV1), p<0.0001; density of Pseudomonas aeruginosa and Staphylococcus aureus decreased by 2.4 +/- 3.1 log10 cfu/g (p<0.0005) and 4.0 +/- 2.3 log10 cfu/ml (p<0.0001), respectively; neutrophil count decreased by 0.4 +/- 0.6 log10 cells/ml (p<0.0001), interleukin-8 concentration by 0.5 +/- 1.3 log10 pg/ml (p<0.05), and neutrophil elastase by 0.4 +/- 0.7 log10 microg/ml (p<0.005). Seven of 127 (6%) sputum induction procedures showed a decrease in FEV1 of 20% or more. We conclude that markers in induced sputum may be useful, noninvasive outcome measures to assess response to therapies in cystic fibrosis studies.