Aztreonam For Inhalation Solution Research Articles

ALPINE2: Efficacy and safety of 14-day vs 28-day inhaled aztreonam for Pa eradication in children with cystic fibrosis

BackgroundAntibiotic eradication therapies recommended for newly isolated Pseudomonas aeruginosa (Pa) in people with cystic fibrosis (pwCF) can be burdensome. ALPINE2 compared the efficacy and safety of a shortened 14-day course of aztreonam for inhalation solution (AZLI) with 28-day AZLI in paediatric pwCF. MethodsALPINE2 (a double-blind, phase 3b study) included children aged 3 months to <18 years with CF and new-onset Pa infection. Participants were randomized to receive 75 mg AZLI three times daily for either 28 or 14 days followed by 14 days' matched placebo. The primary endpoint was rate of primary Pa eradication (no Pa detected during the 4 weeks post AZLI treatment). Non-inferiority was achieved if the lower 95% CI bound of the treatment difference between the two arms was above −20%. Secondary endpoints included assessments of Pa recurrence during 108 weeks of follow-up after primary eradication. Safety endpoints included treatment-emergent adverse events (TEAEs). ResultsIn total, 149 participants were randomized (14-day AZLI, n = 74; 28-day AZLI, n = 75) and 142 (95.3%) completed treatment. Median age: 6.0 years (range: 0.3–17.0). Baseline characteristics were similar between treatment arms. Primary Pa eradication rates: 14-day AZLI, 55.9%; 28-day AZLI, 63.4%; treatment difference (CI), −8.0% (−24.6, 8.6%). Pa recurrence rates at follow-up end: 14-day AZLI, 54.1% (n = 20/37); 28-day AZLI, 41.9% (n = 18/43). TEAEs were similar between treatment arms. No new safety signals were observed. ConclusionsNon-inferiority of 14-day AZLI versus 28-day AZLI was not demonstrated. Both courses were well tolerated, further supporting AZLI short-term safety in paediatric and adolescent pwCF. ClinicalTrials.govNCT03219164

121 The short term effects of aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis

121 The short term effects of aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis

110 Aztreonam for inhalation solution (AZLI) for eradication of new onset Pseudomonas aeruginosa (PA) infection in children with cystic fibrosis (CF): Evaluation of treatment failures

Objectives In the ALPINE study (ClinicalTrials.gov NCT01375049), AZLI treatment for 28 days in children with CF age 3 months to PA infection resulted in culture-negativity in 89% of patients (pts) at end of treatment and in 75% of pts at 28 days post-treatment. Post-hoc analyses were performed to determine possible factors associated with failure to eradicate or regrowth of PA post-treatment. Methods Children age 3 mos to PA infection (first lifetime PA -positive culture [throat swab, sputum, BAL] or PA -positive after ≥2-yr history of PA -negative cultures) were treated with AZLI 75 mg 3x/day for 28 days via PARI Investigational eFlow® Nebulizer. Evaluable pts received a full 28 day AZLI course and no additional anti- PA antibiotics. Baseline (BL) factors were compared for pts with post-treatment cultures PA -positive vs. those who were PA -negative. Results 99 treated pts had culture data available at 28d post-treatment: PA was present in 23; absent in 76. No differences were seen in age, CF genotype, history of prior PA infection, FEV1 % predicted, PA antibody status, or presence of co-infecting pathogens at BL in PA present vs. absent groups. 22/23 pts who failed eradication were >90% treatment compliant. MIC50&90 were unchanged in PA strains isolated post-treatment vs. BL (4, 8 mg/mL respectively). Conclusion No BL factors examined predicted PA culture positivity after a 28-day course of AZLI. Inhaled antibiotic treatment is warranted for all pts with new onset PA infection. Further studies are needed to determine optimal treatment strategies for initial eradication failures. Supported by Gilead Sciences.

WS02.2 Aztreonam for inhalation solution (AZLI) for eradication of new onset Pseudomonas aeruginosa (PA) infection in children with cystic fibrosis (CF): Results of facemask vs. nebulizer mouthpiece use

Objectives Treating early PA infection in CF often requires giving inhaled antibiotics to very young patients (pts). In the ALPINE study (ClinicalTrials.gov NCT01375049), pts Methods Children age 3 mos to PA infection (first lifetime PA -positive culture [throat swab, sputum, BAL] or PA -positive after ≥2-yr history of PA -negative cultures) were treated with AZLI 75 mg 3x/day for 28 days via a PARI Investigational eFlow® Nebulizer. Recommended delivery was by SmartMask® Baby for pts 3 mos to PA eradication failure rates are presented. Results See the table. No specific safety issues were attributable to either mask or mouthpiece use. PA culture positive at day 28, end of treatment, n/N3 mo to Conclusion In young children with CF, AZLI treatment administered via eFlow nebulizer with SmartMask for initial PA infection had high eradication success rates and should be considered a valid treatment option. No safety issues were associated with specific mask/mouthpiece type. Supported by Gilead Sciences.

Quality of Life Questionnaire-Bronchiectasis: final psychometric analyses and determination of minimal important difference scores

BackgroundThe Quality of Life-Bronchiectasis (QOL-B), a self-administered, patient-reported outcome measure assessing symptoms, functioning and health-related quality of life for patients with non-cystic fibrosis (CF) bronchiectasis, contains 37 items on 8...

Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials

The clinical benefit of inhaled antibiotics in non-cystic fibrosis bronchiectasis has not been established in randomised controlled trials. We aimed to assess safety and efficacy of aztreonam for inhalation solution (AZLI) in patients with non-cystic fibrosis bronchiectasis and Gram-negative bacterial colonisation. AIR-BX1 and AIR-BX2 were two double-blind, multicentre, randomised, placebo-controlled phase 3 trials, which included patients aged 18 years or older who had bronchiectasis and history of positive sputum or bronchoscopic culture for target Gram-negative organisms. Patients were randomly assigned to receive either AZLI or placebo (1:1). Randomisation was done without stratification and the code was generated by a Gilead designee. In both studies, two 4-week courses of AZLI 75 mg or placebo (three-times daily; eFlow nebulizer) were each followed by a 4-week off-treatment period. Primary endpoint was change from baseline Quality of Life-Bronchiectasis Respiratory Symptoms scores (QOL-B-RSS) at 4 weeks. These trials are registered with ClinicalTrials.gov, numbers are NCT01313624 for AIR-BX1 and NCT01314716 for AIR-BX2. We recruited participants from 47 ambulatory clinics for AIR-BX1 and 65 ambulatory clinics for AIR-BX2; studies were done between April 25, 2011, and July 1, 2013. In AIR-BX1, of the 348 patients screened, 134 were randomly assigned to receive AZLI and 132 to receive placebo. In AIR-BX2, of the 404 patients screened, 136 were randomly assigned to receive AZLI and 138 to receive placebo. The difference between AZLI and placebo for adjusted mean change from baseline QOL-B-RSS was not significant at 4 weeks (0.8 [95% CI -3.1 to 4.7], p=0.68) in AIR-BX1, but was significant (4.6 [1.1 to 8.2], p=0.011) in AIR-BX2. The 4.6 point difference in QOL-B-RSS after 4 weeks in AIR-BX2 was not deemed clinically significant. In both studies, treatment-related adverse events were more common in the AZLI group than in the placebo group, as were discontinuations from adverse events. The most commonly reported treatment-emergent adverse events were dyspnea, cough, and increased sputum. Each was more common for AZLI-treated than for placebo-treated patients, but the incidences were more balanced in AIR-BX2. AZLI treatment did not provide significant clinical benefit in non-cystic fibrosis bronchiectasis, as measured by QOL-B-RSS, suggesting a continued need for placebo-controlled studies to establish the clinical benefit of inhaled antibiotics in patients with this disorder. Gilead Sciences.

Open label study of inhaled aztreonam for Pseudomonas eradication in children with cystic fibrosis: The ALPINE study

BackgroundConsensus guidelines recommend early treatment to eradicate newly acquired Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients although there is no single preferred regimen. Aztreonam for inhalation solution (AZLI) significantly reduces sputum Pa density in CF patients with chronic Pa infection and has been well tolerated in the pediatric population. This single-arm, open-label Aztreonam Lysine for Pseudomonas Infection Eradication (ALPINE) study was conducted to evaluate the safety and efficacy of a 28-day treatment course of AZLI to eradicate newly acquired Pa infection in pediatric CF patients. MethodsCF patients (3months to <18years) with new onset Pa infection were treated with AZLI 75mg 3 times daily for 28days. New onset Pa infection was defined as first lifetime Pa-positive respiratory tract culture (throat swab, sputum) or Pa-positive culture after a ≥2-year history of Pa-negative cultures (≥2cultures/year). Sputum or throat swab cultures were collected at study entry (baseline) and at weeks 4 (end of treatment), 8, 16, and 28. Primary endpoint was the percentage of patients with cultures negative for Pa at all post-treatment time points. ResultsA total of 105 pediatric CF patients enrolled (3months to <2years, n=24; 2 to <6years, n=25; 6 to <18years, n=56). Of the 101 patients who completed treatment, 89.1% (n=90) were free of Pa at the end of treatment and 75.2% (n=76) were free of Pa 4weeks after the end of treatment. Of the 79 patients evaluable for the primary endpoint, 58.2% were free of Pa at all post-treatment time points. ConclusionsAZLI was effective and well tolerated in eradicating Pa from newly infected pediatric patients with CF. These eradication rates are consistent with success rates reported in the literature for various antibiotic regimens, including other inhaled antibiotics studied for eradication.ClinicalTrials.gov: NCT01375049.

A Preliminary Quality of Life Questionnaire-Bronchiectasis: A Patient-Reported Outcome Measure for Bronchiectasis

The Quality of Life Questionnaire-Bronchiectasis (QOL-B) is the first disease-specific, patient-reported outcome measure for patients with bronchiectasis. Content validity, cognitive testing, responsivity to open-label treatment, and psychometric analyses are presented. Reviews of literature, existing measures, and physician input were used to generate the initial QOL-B. Modifications following preliminary cognitive testing (N = 35 patients with bronchiectasis) generated version (V) 1.0. An open-ended patient interview study (N = 28) provided additional information and was content analyzed to derive saturation matrices, which summarized all disease-related topics mentioned by each participant. This resulted in QOL-B V2.0. Psychometric analyses were carried out using results from an open-label phase 2 trial, in which 89 patients were enrolled and treated with aztreonam for inhalation solution. Responsivity to open-label treatment was observed. Additional analyses generated QOL-B V3.0, with 37 items on eight scales: respiratory symptoms; physical, role, emotional, and social functioning; vitality; health perceptions; and treatment burden. For each scale, scores are standardized on a 0-to-100-point scale; higher scores indicate better health-related quality of life. No total score is calculated. A final cognitive testing study (N = 40) resulted in a minor change to one social functioning scale item (QOL-B V3.1). Content validity, cognitive testing, responsivity to open-label treatment, and initial psychometric analyses supported QOL-B items and structure. This interim QOL-B is a promising tool for evaluating the efficacy of new therapies for patients with bronchiectasis and for measuring symptoms, functioning, and quality of life in these patients on a routine basis. A final psychometric validation study is needed and is forthcoming. ClinicalTrials.gov; No.: NCT00805025; URL: www.clinicaltrials.gov.

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

Individuals with Burkholderia spp. infection have historically been excluded from efficacy trials of inhaled antibiotics, including aztreonam for inhalation solution (AZLI). 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. 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. 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.

Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: A comparative efficacy trial

BackgroundOpen-label, parallel-group, international trial comparing aztreonam for inhalation solution (AZLI) and tobramycin nebulizer solution (TNS) for cystic fibrosis patients with airway Pseudomonas aeruginosa. Methods273 patients (≥6years); randomized to three 28-day courses (AZLI 75mg [three‐times/day] or TNS 300mg [twice/day]); 28 off-days separated each course. Results268 patients were treated (AZLI/TNS: 136/132). Mean baseline FEV1 was 52% predicted. Mean relative changes after 1 course (AZLI: 8.35%; TNS: 0.55%; p<0.001) and mean actual changes across 3 courses (AZLI: 2.05%; TNS: −0.66%; p=0.002) indicated AZLI statistical superiority vs. TNS. AZLI-treated patients had fewer respiratory hospitalizations (p=0.044) and respiratory events requiring additional antipseudomonal antibiotics (p=0.004); both treatments were well tolerated. 133 patients received 1 to 3 courses of AZLI treatment in the open-label extension-period (28-day courses separated by 28days off-treatment); lung function improvements were comparable regardless of whether patients had received TNS or AZLI in the preceding comparative period. ConclusionsAZLI demonstrated statistical superiority in lung function and a reduction in acute pulmonary exacerbations compared to TNS over 3 treatment courses (ClinicalTrials.gov: NCT00757237).

In vitro evaluation of tobramycin and aztreonam versus Pseudomonas aeruginosa biofilms on cystic fibrosis-derived human airway epithelial cells

Aztreonam for inhalation solution (AZLI) was recently approved by the FDA for treating cystic fibrosis (CF) patients infected with Pseudomonas aeruginosa. Here we investigated the effect of aztreonam alone or in combination with tobramycin on P. aeruginosa biofilms grown on CF airway epithelial cells. P. aeruginosa biofilms, produced by laboratory strains or clinical isolates, were formed on confluent CF airway cells before treatment overnight with aztreonam or tobramycin alone or in combination. Alternatively, antibiotics were added 1 h after bacterial inoculation to assess their ability to impair biofilm formation at 5 h. Bacterial cfu remaining after treatment were then determined by plate counting. In the absence of antibiotics, all strains developed biofilms that disrupted CF airway epithelial monolayers overnight. Tobramycin reduced the cfu of all strains grown as biofilms. Aztreonam reduced the cfu of some strains by ∼1 log unit without preserving the integrity of cystic fibrosis airway cell monolayers, while decreasing the biofilms of other clinical isolates by ∼4 log units and protecting the monolayers from being compromised. The combination of aztreonam and tobramycin reduced the cfu of two strains by an additional 0.5 and 2 log units, respectively. Of all the mechanisms explored, Psl exopolysaccharide production might explain the variations in biofilm tolerance to aztreonam in some of the strains. Effects of aztreonam on P. aeruginosa biofilms in the in vitro co-culture model are strain-dependent. The simultaneous application of aztreonam and tobramycin may be beneficial for a subset of CF patients by eliminating susceptible P. aeruginosa strains.

WS5.4 Aztreonam for inhalation solution (AZLI) in cystic fibrosis (CF) patients with chronic Burkholderia species (BURK) infection: final results from a randomized, placebo-controlled trial

WS5.4 Aztreonam for inhalation solution (AZLI) in cystic fibrosis (CF) patients with chronic Burkholderia species (BURK) infection: final results from a randomized, placebo-controlled trial

58 No antibiotic cross-resistance after 1 year of continuous aztreonam for inhalation solution (AZLI) in cystic fibrosis (CF) patients (pts) with chronic Burkholderia (BURK) infection

58 No antibiotic cross-resistance after 1 year of continuous aztreonam for inhalation solution (AZLI) in cystic fibrosis (CF) patients (pts) with chronic Burkholderia (BURK) infection

Fosfomycin/Tobramycin for Inhalation in Patients with Cystic Fibrosis with Pseudomonas Airway Infection

Fosfomycin/tobramycin for inhalation (FTI), a unique, broad-spectrum antibiotic combination, may have therapeutic potential for patients with cystic fibrosis (CF). To evaluate safety and efficacy of FTI (160/40 mg or 80/20 mg), administered twice daily for 28 days versus placebo, in patients greater than or equal to 18 years of age, with CF, chronic Pseudomonas aeruginosa (PA) airway infection, and FEV(1) greater than or equal to 25% and less than or equal to 75% predicted. This double-blind, placebo-controlled, multicenter study assessed whether FTI/placebo maintained FEV(1) % predicted improvements achieved following a 28-day, open-label, run-in course of aztreonam for inhalation solution (AZLI). A total of 119 patients were randomized to FTI (160/40 mg: n = 41; 80/20 mg: n = 38) or placebo (n = 40). Mean age was 32 years and mean FEV(1) was 49% predicted at screening. Relative improvements in FEV(1) % predicted achieved by the AZLI run-in were maintained in FTI groups compared with placebo (160/40 mg vs. placebo: 6.2% treatment difference favoring FTI, P = 0.002 [primary endpoint]; 80/20 mg vs. placebo: 7.5% treatment difference favoring FTI, P < 0.001). The treatment effect on mean PA sputum density was statistically significant for the FTI 80/20 mg group versus placebo (-1.04 log(10) PA colony-forming units/g sputum difference, favoring FTI; P = 0.01). Adverse events, primarily cough, were consistent with CF disease. Respiratory events, including dyspnea and wheezing, were less common with FTI 80/20 mg than FTI 160/40 mg. No clinically significant differences between groups were reported for laboratory values. FTI maintained the substantial improvements in FEV(1) % predicted achieved during the AZLI run-in and was well tolerated. FTI is a promising antipseudomonal therapy for patients with CF.

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

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. 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. 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. 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.

Aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis, mild lung impairment, and P. aeruginosa

Background Previous aztreonam for inhalation solution (AZLI) studies included patients with cystic fibrosis, Pseudomonas aeruginosa ( PA) airway infection, and forced expiratory volume in 1 s (FEV 1) 25% to 75% predicted. This double-blind, multicenter, randomized, placebo-controlled trial enrolled patients (≥ 6 years) with FEV 1 > 75% predicted. Methods AZLI 75 mg (n = 76) or placebo (n = 81) was administered 3-times daily for 28 days with a 14-day follow-up. Results Day 28 treatment effects were 1.8 points for CFQ-R-Respiratory Symptoms Scale (95% CI: −2.8, 6.4; p = 0.443; primary endpoint); −1.2 for log 10 sputum PA colony-forming units (p = 0.016; favoring AZLI), and 2.7% for relative FEV 1% predicted (p = 0.021; favoring AZLI). Treatment effects favoring AZLI were larger for patients with baseline FEV 1 < 90% predicted compared to ≥ 90% predicted. AZLI was well-tolerated. Conclusions Effects on respiratory symptoms were modest; however, FEV 1 improvements and bacterial density reductions support a possible role for AZLI in these relatively healthy patients. ClinicalTrials.gov identifier: NCT00712166.

A double-blind, multinational, randomized, placebo-controlled trial evaluating aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis (CF), mild lung disease and P. aeruginosa ( PA)

A double-blind, multinational, randomized, placebo-controlled trial evaluating aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis (CF), mild lung disease and P. aeruginosa ( PA)

Inhaled aztreonam

In February 2010, aztreonam for inhalation solution (Cayston; Gilead) - an inhalable formulation of the monobactam antibiotic aztreonam and lysine - was approved by the US FDA to improve respiratory symptoms in patients with cystic fibrosis infected with Pseudomonas aeruginosa.