Impact of azithromycin on serum inflammatory markers in children with cystic fibrosis and new Pseudomonas.

Chronic azithromycin improves outcomes in cystic fibrosis (CF), but its mechanism of action is unclear. The OPTIMIZE trial demonstrated improvement in time to first pulmonary exacerbation in children with new Pseudomonas treated with azithromycin. Azithromycin effect on systemic markers of inflammation over 18 months was assessed by change from baseline for high-sensitivity C-reactive protein, myeloperoxidase, calprotectin and absolute neutrophil count in the OPTIMIZE population. Subjects treated with chronic azithromycin or placebo had samples collected at baseline, 39 and 78 weeks of treatment. In 129 subjects, a significant decrease in high-sensitivity C-reactive protein was present at 39 weeks in the azithromycin group compared to placebo, but no significant difference between the groups at 78 weeks. No differences in change from baseline in myeloperoxidase, calprotectin or absolute neutrophil count were present at either time point. This supports the concept of a transient immunomodulatory effect for chronic azithromycin therapy in children with CF.

A new path for CF clinical trials through the use of historical controls.

BACKGROUND: Given future challenges in conducting large randomized, placebo controlled trials for future CF therapeutics development, we evaluated the potential for using external historical controls to either enrich or replace traditional concurrent placebo groups in CF trials. METHODS: The study included data from sequentially completed, randomized, controlled clinical trials, EPIC and OPTIMIZE respectively, evaluating optimal antibiotic therapy to reduce the risk of pulmonary exacerbation in children with early Pseudomonas aeruginosa infection. The primary treatment effect in OPTIMIZE, the risk of pulmonary exacerbation associated with azithromycin, was re-estimated in alternative designs incorporating varying numbers of participants from the earlier trial (EPIC) as historical controls. Bias and precision of these estimates were characterized. Propensity scores were derived to adjust for baseline differences across study populations, and both Poisson and Cox regression were used to estimate treatment efficacy. RESULTS: Replacing 86 OPTIMIZE placebo participants with 304 controls from EPIC to mimic a fully historically controlled trial resulted an 8% reduction in risk of pulmonary exacerbations (Hazard ratio (HR):0.92 95% CI 0.61, 1.34) when not adjusting for key baseline differences between study populations. After adjustment, a 37% decrease in risk of exacerbation (HR:0.63, 95% CI 0.50, 0.80) was estimated, comparable to the estimate from the original trial comparing the 86 placebo participants to 77 azithromycin participants on azithromycin (45%, HR:0.55, 95% CI: 0.34, 0.86). Other adjusted approaches provided similar estimates for the efficacy of azithromycin in reducing exacerbation risk: pooling all controls from both studies provided a HR of 0.60 (95% x`CI 0.46, 0.77) and augmenting half the OPTIMIZE placebo participants with EPIC controls gave a HR 0.63 (95% CI 0.48, 0.82). CONCLUSIONS: The potential exists for future CF trials to utilize historical control data. Careful consideration of both the comparability of controls and of optimal methods can reduce the potential for biased estimation of treatment effects.

The impact of SARS-CoV-2 on the cystic fibrosis foundation therapeutics development network.

The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) global pandemic significantly impacted CF clinical research within the Cystic Fibrosis Foundation Therapeutics Development Network (CFF TDN). A Research Electronic Data Capture (REDCap) survey was developed and sent to network sites to monitor and understand the impact on research teams, ongoing and anticipated clinical research, and specific clinical and research procedures. Key findings indicated an early impact on participant enrollment, research team stability, and procedures such as spirometry and sputum induction. These trends steadily improved over the months as research activities began to recover across the TDN. While SARS-CoV-2 created a significant challenge it also highlights new opportunities to expand CF research with greater focus on data collection outside of research centers and increased access for remote participation.

Worsening anxiety and depression after initiation of lumacaftor/ivacaftor combination therapy in adolescent females with cystic fibrosis.

In both phase III studies of LUM/IVA, as well as an extension study, worsening of mental health was not reported as a common side effect. Here we describe five cases in adolescent female patients that suggest a worsening of anxiety or depression associated with its use. In these five patients, two experienced suicidal ideation and three made suicide attempts that resulted in psychiatric hospitalizations.

Continuous alternating inhaled antibiotics for chronic pseudomonal infection in cystic fibrosis.

BACKGROUND: Inhaled antibiotics are standard of care for treating chronic pseudomonal respiratory infections in cystic fibrosis patients, initially approved for intermittent administration. However, use of continuous inhaled antibiotic regimens of differing combinations is growing. METHODS: This double-blind trial compared continuous alternating therapy (CAT) to an intermittent treatment regimen. Subjects were treated with 3cycles of 28-days inhaled aztreonam (AZLI) or placebo 3-times daily alternating with 28-days open-label tobramycin inhalation solution (TIS). RESULTS: 90 subjects were randomized over 18months. Study enrollment was limited, in part because of evolving practices by clinicians of adopting a CAT regimen in clinical practice; consequently the study was underpowered. AZLI/TIS treatment reduced exacerbation rates by 25.7% (p=0.25; primary endpoint) and rates of respiratory hospitalizations by 35.8% compared with placebo/TIS (p=0.14). AZLI/TIS CAT therapy was well tolerated. CONCLUSIONS: This trial illustrates challenges with studying treatment regimens in a constantly evolving CF care environment. Nonetheless, the results of this trial indicate that AZLI/TIS CAT is well tolerated and may provide additional clinical benefit in CF patients compared with intermittent use of TIS alone. Clinicaltrials.gov: NCT01641822.

A Multidisciplinary Children's Airway Center: Impact on the Care of Patients With Tracheostomy.

BACKGROUND: Children with complex airway problems see multiple specialists. To improve outcomes and coordinate care, we developed a multidisciplinary Children's Airway Center. For children with tracheostomies, aspects of care targeted for improvement included optimizing initial hospital discharge, promoting effective communication between providers and caregivers, and avoiding tracheostomy complications. METHODS: The population includes children up to 21 years old with tracheostomies. The airway center team includes providers from pediatric pulmonology, pediatric otolaryngology/head and neck surgery, and pediatric gastroenterology. Improvement initiatives included enhanced educational strategies, weekly care conferences, institutional consensus guidelines and care plans, personalized clinic schedules, and standardized intervals between airway examinations. A patient database allowed for tracking outcomes over time. RESULTS: We initially identified 173 airway center patients including 123 with tracheostomies. The median number of new patients evaluated by the center team each year was 172. Median hospitalization after tracheostomy decreased from 37 days to 26 days for new tracheostomy patients <1 year old discharged from the hospital. A median of 24 care plans was evaluated at weekly conferences. Consensus protocol adherence increased likelihood of successful decannulation from 68% to 86% of attempts. The median interval of 8 months between airway examinations aligned with published recommendations. CONCLUSIONS: For children with tracheostomies, our Children's Airway Center met and sustained goals of optimizing hospitalization, promoting communication, and avoiding tracheostomy complications by initiating targeted improvements in a multidisciplinary team setting. A multidisciplinary approach to management of these patients can yield measurable improvements in important outcomes.

Impact of Sustained Eradication of New Pseudomonas aeruginosa Infection on Long-term Outcomes in Cystic Fibrosis.

BACKGROUND: Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the airways in individuals with cystic fibrosis. A key question is whether children with newly acquired Pa infection who are able to achieve sustained eradication after early antipseudomonal therapy demonstrate improved long-term health outcomes compared with those who are unable to achieve a sustained microbiologic response. METHODS: This cohort study utilized observational follow-up data on children participating in the Early Pseudomonas Infection Control trial who received standardized therapy for newly acquired Pa. Sustained eradicators were defined as those who maintained Pa-negative cultures for 12 months after initial antipseudomonal therapy. Associations between eradication status and outcomes were assessed. RESULTS: Of the 249 trial participants included in the study, 172 (69%) achieved sustained eradication of Pa during the trial (sustained eradicators). Over the median 5-year follow-up, sustained eradicators had a 74% reduced risk of developing chronic Pa (hazard ratio [HR], 0.26; 95% confidence interval [CI], .17-.40) and a 57% reduced risk of mucoidy (HR, 0.43; 95% CI, .25-.73) compared with nonsustained eradicators. Sustained eradicators had significantly less anti-Pa antibiotic usage during follow-up compared with nonsustained eradicators. There was no association between eradication status and clinical outcomes including rate of exacerbation and lung function decline. CONCLUSIONS: This is the first study to quantify the long-term durability of microbiological response associated with early antipseudomonal therapy, demonstrating the critical importance of optimizing antipseudomonal therapies during early Pa infection. The clinical impact of failure to achieve sustained Pa eradication remains unclear, however, and may be confounded by anti-Pa antibiotic usage. CLINICAL TRIALS REGISTRATION: NCT00097773.

Highly effective cystic fibrosis clinical research teams: critical success factors.

BACKGROUND: Bringing new therapies to patients with rare diseases depends in part on optimizing clinical trial conduct through efficient study start-up processes and rapid enrollment. Suboptimal execution of clinical trials in academic medical centers not only results in high cost to institutions and sponsors, but also delays the availability of new therapies. Addressing the factors that contribute to poor outcomes requires novel, systematic approaches tailored to the institution and disease under study. OBJECTIVE: To use clinical trial performance metrics data analysis to select high-performing cystic fibrosis (CF) clinical research teams and then identify factors contributing to their success. DESIGN: Mixed-methods research, including semi-structured qualitative interviews of high-performing research teams. PARTICIPANTS: CF research teams at nine clinical centers from the CF Foundation Therapeutics Development Network. APPROACH: Survey of site characteristics, direct observation of team meetings and facilities, and semi-structured interviews with clinical research team members and institutional program managers and leaders in clinical research. KEY RESULTS: Critical success factors noted at all nine high-performing centers were: 1) strong leadership, 2) established and effective communication within the research team and with the clinical care team, and 3) adequate staff. Other frequent characteristics included a mature culture of research, customer service orientation in interactions with study participants, shared efficient processes, continuous process improvement activities, and a businesslike approach to clinical research. CONCLUSIONS: Clinical research metrics allowed identification of high-performing clinical research teams. Site visits identified several critical factors leading to highly successful teams that may help other clinical research teams improve clinical trial performance.

Pseudomonas aeruginosa in vitro phenotypes distinguish cystic fibrosis infection stages and outcomes.

RATIONALE: Pseudomonas aeruginosa undergoes phenotypic changes during cystic fibrosis (CF) lung infection. Although mucoidy is traditionally associated with transition to chronic infection, we hypothesized that additional in vitro phenotypes correlate with this transition and contribute to disease. OBJECTIVES: To characterize the relationships between in vitro P. aeruginosa phenotypes, infection stage, and clinical outcomes. METHODS: A total of 649 children with CF and newly identified P. aeruginosa were followed for a median 5.4 years during which a total of 2,594 P. aeruginosa isolates were collected. Twenty-six in vitro bacterial phenotypes were assessed among the isolates, including measures of motility, exoproduct production, colony morphology, growth, and metabolism. MEASUREMENTS AND MAIN RESULTS: P. aeruginosa phenotypes present at the time of culture were associated with both stage of infection (new onset, intermittent, or chronic) and the primary clinical outcome, occurrence of a pulmonary exacerbation (PE) in the subsequent 2 years. Two in vitro P. aeruginosa phenotypes best distinguished infection stages: pyoverdine production (31% of new-onset cultures, 48% of intermittent, 69% of chronic) and reduced protease production (31%, 39%, and 65%, respectively). The best P. aeruginosa phenotypic predictors of subsequent occurrence of a PE were mucoidy (odds ratio, 1.75; 95% confidence interval, 1.19-2.57) and reduced twitching motility (odds ratio, 1.43; 95% confidence interval, 1.11-1.84). CONCLUSIONS: In this large epidemiologic study of CF P. aeruginosa adaptation, P. aeruginosa isolates exhibited two in vitro phenotypes that best distinguished early and later infection stages. Among the many phenotypes tested, mucoidy and reduced twitching best predicted subsequent PE. These phenotypes indicate potentially useful prognostic markers of transition to chronic infection and advancing lung disease.

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.

Comparison of endoscopic versus 3D CT derived airway measurements.

OBJECTIVES/HYPOTHESIS: To understand: 1) how endoscopic airway measurements compare to three-dimensional (3D) CT derived measurements; 2) where each technique is potentially useful; and 3) where each has limitations. STUDY DESIGN: Compare airway diameters and cross-sectional areas from endoscopic images and CT derived 3D reconstructions. METHODS: Videobronchoscopy was performed and recorded on an adult-sized commercially available airway mannequin. At various levels, cross-sectional areas were measured from still video frames using a referent placed via the biopsy port. A 3D reconstruction was generated from a high resolution CT of the mannequin; planar sections were cut at similar cross-sectional levels; and cross-sectional areas were obtained. RESULTS: At three levels of mechanically generated tracheal stricture, the differences between the endoscopic measurement and CT-derived cross-sectional area were 1%, 0%, and 7% (1.8, 0.8, and 14 mm²). At the vocal folds, the difference was 9% (7.8 mm²). The tip of the epiglottis and width of the epiglottis differed by 27% and 10% (18.73 mm², 0.40 mm). The airway measurements at the base of tongue, minimal cross-sectional area of the pharynx, and choana differed by 26%, 36%, and 30% (101.40 mm², 36.67 mm², 122.71 mm²). CONCLUSIONS: Endoscopy is an effective tool for obtaining airway measurements compared with 3D reconstructions derived from CT. Concordance is best in geometrically simple areas where the entire cross-section measured is visible within one field of view (trachea, round; vocal folds, triangular) versus geometrically complex areas that encompass more than one field of view (i.e. pharynx, choana).

Pseudomonas aeruginosa antibiotic susceptibility during long-term use of aztreonam for inhalation solution (AZLI).

OBJECTIVES: Aztreonam for inhalation solution (AZLI) is an inhaled antibiotic for patients with cystic fibrosis (CF) and Pseudomonas aeruginosa airway infection. The risk of selecting for P. aeruginosa isolates with reduced susceptibility to antibiotics is inherent to their use, but is of particular concern following repeated exposure and when complete eradication of lung pathogens is difficult to obtain. We investigated whether repeated treatment courses of AZLI led to decreases in P. aeruginosa susceptibility to aztreonam or other antibiotics. METHODS: Serial sputum specimens were collected and processed for isolation and quantification of all P. aeruginosa isolates in a Phase 3 open-label, 18 month study (NCT00128492) including 274 CF patients receiving up to nine courses of AZLI twice daily (AZLI2) or thrice daily (AZLI3) (28 days on/28 days off). P. aeruginosa antibiotic susceptibility testing was conducted. RESULTS: No changes were observed in the aztreonam MIC(50) for all P. aeruginosa isolates collected from AZLI3 patients, while intermittent increases were observed in the aztreonam MIC(90). Approximately 70% of the P. aeruginosa isolates with the highest aztreonam MIC from each patient receiving AZLI3 remained unchanged or decreased relative to that patient's equivalent isolate at baseline; 30% experienced an increase in MIC. Few decreases in P. aeruginosa susceptibility to other antibiotics were observed in AZLI3 patients, while increases in P. aeruginosa susceptibility to tobramycin were observed. CONCLUSIONS: Few decreases in aztreonam susceptibility were reported in patients receiving AZLI3. Increases in tobramycin susceptibility were observed, suggesting that novel treatment paradigms may be able to prolong antibiotic susceptibility in CF patients.

An 18-month study of the safety and efficacy of repeated courses of inhaled aztreonam lysine in cystic fibrosis.

Chronic airway infection with Pseudomonas aeruginosa (PA) causes morbidity and mortality in patients with cystic fibrosis (CF). Additional anti-PA therapies are needed to improve health status and health-related quality of life. AIR-CF3 was an international 18-month, open-label study to evaluate the safety and efficacy of repeated courses of aztreonam for inhalation solution (AZLI, now marketed as Cayston®) in patients aged ≥ 6 years with CF and PA infection who previously participated in one of two Phase 3 studies: AIR-CF1 or AIR-CF2. Patients received up to nine courses (28 days on/28 days off) of 75 mg AZLI two (BID) or three times daily (TID) based on randomization in the previous trials. 274 patients, mean age 28.5 years (range: 8-74 years), participated. Mean treatment adherence was high (92.0% BID group, 88.0% TID group). Hospitalization rates were low and adverse events were consistent with CF. With each course of AZLI, FEV(1) and scores on the Cystic Fibrosis Questionnaire-Revised Respiratory Symptom scale improved and bacterial density in sputum was reduced. Benefits waned in the 28 days off therapy, but weight gain was sustained over the 18 months. There were no sustained decreases in PA susceptibility. A dose response was observed; AZLI TID-treated patients demonstrated greater improvements in lung function and respiratory symptoms over 18 months. Repeated intermittent 28-day courses of AZLI treatment were well tolerated. Clinical benefits in pulmonary function, health-related quality of life, and weight were observed with each course of therapy. AZLI is a safe and effective new therapy in patients with CF and PA airway infection.

Update on new pulmonary therapies.

PURPOSE OF REVIEW: Understanding the molecular and cellular processes responsible for the development of lung disease in cystic fibrosis (CF) has led to evaluation of a broad range of new therapies within multiple therapeutic classes. For these reasons, clinical research in CF is accelerating, as new agents progress through the early stages of drug development, move into clinical trials and are offered to study patients. This review focuses on the most notable clinical trials of pulmonary therapies reported in the last year. RECENT FINDINGS: Progress in gene therapy remains slow, but is offset by significant gains in development of cystic fibrosis transmembrane conductance regulator modulators and drugs that restore airway surface liquid. Although addressing downstream consequences of CF lung pathophysiology, the substantial burden of chronic infection makes both antibiotic and anti-inflammatory therapies a critical component of treatment, such that additional agents to manage sustained inflammation and resistant microorganisms along with improved delivery systems are needed. SUMMARY: The pace of drug development in CF will require an expanding pool of patients willing to participate in clinical research to test new agents. Although these potential therapies will likely improve quality of life for people with CF and contribute to improved survival, it will be important to avoid adding excessively to the already high burden of treatment. If the demands on patients' time continue to grow, a decrease in adherence to effective therapies may paradoxically lead to worse outcomes and negate the benefits new treatments bring.

Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis.

BACKGROUND: We assessed the short-term efficacy and safety of aztreonam lysine for inhalation (AZLI [an aerosolized monobactam antibiotic]) in patients with cystic fibrosis (CF) and Pseudomonas aeruginosa (PA) airway infection. METHODS: In this randomized, double-blind, placebo-controlled, international study (AIR-CF1 trial; June 2005 to April 2007), patients (n = 164; >or= 6 years of age) with FEV(1) >or= 25% and

Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis.

RATIONALE: The effectiveness and safety of aztreonam lysine for inhalation (AZLI) in patients with cystic fibrosis (CF) on maintenance treatment for Pseudomonas aeruginosa (PA) airway infection was evaluated in this randomized, double-blind, placebo-controlled study. OBJECTIVES: To evaluate the safety and efficacy of inhaled aztreonam lysine in controlling PA infection in patients with CF. METHODS: After randomization and a 28-day course of tobramycin inhalation solution (TIS), patients (n = 211; > or =6 yr; > or =3 TIS courses within previous year; FEV(1) > or = 25% and < or =75% predicted values) were treated with 75 mg AZLI or placebo, twice or three times daily for 28 days, then monitored for 56 days. The primary efficacy endpoint was time to need for additional inhaled or intravenous antipseudomonal antibiotics. Secondary endpoints included changes in respiratory symptoms (CF Questionnaire-Revised [CFQ-R] Respiratory Scale), pulmonary function (FEV(1)), and sputum PA density. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored. MEASUREMENTS AND MAIN RESULTS: AZLI treatment increased median time to need for additional antipseudomonal antibiotics for symptoms of pulmonary exacerbation by 21 days, compared with placebo (AZLI, 92 d; placebo, 71 d; P = 0.007). AZLI improved mean CFQ-R respiratory scores (5.01 points, P = 0.02), FEV(1) (6.3%, P = 0.001), and sputum PA density (-0.66 log(10) cfu/g, P = 0.006) compared with placebo; no AZLI dose-response was observed. Adverse events reported for AZLI and placebo were comparable and consistent with CF lung disease. Susceptibility of PA to aztreonam at baseline and end of therapy were similar. CONCLUSIONS: AZLI was effective in patients with CF using frequent TIS therapy. AZLI delayed time to need for inhaled or intravenous antipseudomonal antibiotics, improved respiratory symptoms and pulmonary function, and was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00104520).

A phase 2 study of aztreonam lysine for inhalation to treat patients with cystic fibrosis and Pseudomonas aeruginosa infection.

BACKGROUND: Aztreonam lysine for inhalation (AZLI) is being developed for treatment of CF patients with Pseudomonas aeruginosa airway infection. METHODS: This double-blind, randomized, placebo-controlled Phase 2 study evaluated the safety, tolerability and efficacy of 75 and 225 mg AZLI administered BID for 14 days using the eFlow Electronic Nebulizer (Pari Innovative Manufacturers, Inc., Midlothian, VA). Patients were 13 years and older with FEV1>or=40% predicted, chronic P. aeruginosa infection, and had used no anti-pseudomonal antibiotics for 56 days. RESULTS: Of 131 patients screened, 105 received AZLI or placebo. Mean age was 26 years and mean FEV1 percent predicted was 77% at baseline. There was a statistically significant reduction, compared to placebo, in P. aeruginosa CFU density in each AZLI group at Days 7 and 14 (P<0.001). The planned primary analysis, percent change in FEV1 at Day 14, demonstrated no statistically significant difference. Post hoc analysis demonstrated significant increase in FEV1 at Day 7 for the subset of patients with baseline FEV1<75% predicted in the 225 mg AZLI group. Bronchodilator use was associated with greater improvement in FEV1, as well as greater reduction in P. aeruginosa bacterial density and higher plasma aztreonam concentrations in the 225 mg AZLI group. Adverse events were similar between placebo and AZLI although there was a trend toward increased respiratory symptoms in the 225 mg AZLI group. CONCLUSION: These data support the further development of AZLI and provide information for the design of subsequent studies.

Computed tomography reflects lower airway inflammation and tracks changes in early cystic fibrosis.

RATIONALE: Detecting and tracking early cystic fibrosis (CF) lung disease are difficult due to lack of sensitive markers of airway dysfunction. OBJECTIVES: The goals were to detect regional distribution of airway disease through high-resolution computed tomography, correlate abnormalities to lower airway inflammation/infection, and compare computed tomography findings before and after intravenous antibiotic therapy in children with CF younger than 4 years experiencing a pulmonary exacerbation. METHODS: High-resolution computed tomography was performed in 17 children scheduled for bronchoscopy. The radiologist identified the lobes with the "greatest" and "least" disease based on computed tomography, and bronchoalveolar lavage was performed in these areas. In 13 subjects, imaging was repeated after antibiotic completion. Modified Brody scores were assigned by two radiologists. MEASUREMENTS AND MAIN RESULTS: The lobe with greatest disease was predominantly localized to the right and had higher modified Brody scores, indicating more severe abnormalities (p < 0.01), compared with the lobe with least disease. The total modified Brody score (p < 0.01), hyperinflation subscore (p < 0.01), and bronchial dilatation/bronchiectasis subscore (p < 0.01) improved after antibiotics and intensified airway clearance. Interleukin-8 levels (p < 0.01) and % neutrophils (p = 0.04) were increased in the lobe with greatest disease compared with the lobe with least disease. CONCLUSIONS: These results indicate that, in young children with CF experiencing a pulmonary exacerbation, computed tomography detects regional differences in airway inflammation, may be a sensitive outcome to evaluate therapeutic interventions, and identifies early lung disease as being more prominent on the right.

Microbiology, safety, and pharmacokinetics of aztreonam lysinate for inhalation in patients with cystic fibrosis.

BACKGROUND: Aztreonam lysinate for inhalation (AI) is a novel monobactam formulation being investigated for pulmonary Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF). METHODS: Pre-clinical studies investigated the pre- and post-nebulization activity of AI and its activity in the presence of CF sputum. A double-blind, placebo-controlled, dose-escalation trial determined pharmacokinetics and tolerability of AI in subjects with CF. Single daily escalating doses of AI 75, 150, or 225 mg, or placebo were self-administered using an eFlow Electronic Nebulizer. Sputum samples were collected up to 4 hr and blood samples up to 8 hr post-dose. RESULTS: AI activity against multiple CF isolates was retained after nebulization via eFlow, and activity was not inhibited by CF sputum. All 12 adult subjects and 11/12 adolescents tolerated all AI doses. One patient had an asymptomatic FEV1 decrease > 20% with the 150 mg dose. Median aztreonam sputum concentrations in adults 10 min after AI 75, 150, and 225 mg were 383, 879, and 985 microg/g, respectively. Median sputum concentrations in adolescents 10 min after AI 75, 150, and 225 mg were 324, 387, and 260 microg/g, respectively. Systemic exposure to AI was low. Plasma pharmacokinetics in adults receiving AI 75 mg were Cmax = 419 ng/g, Tmax = 0.99 hr, t1/2 = 2.1 hr. Aztreonam concentrations in sputum were at or above the MIC50 for at least 4 hr post-dose. CONCLUSION: These data support the continued development of AI for treatment of pulmonary infections in patients with CF.

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.